tituted l'I-Sub Functionalization of · Reaction of B-lactams bearing activating substituents at...
Transcript of tituted l'I-Sub Functionalization of · Reaction of B-lactams bearing activating substituents at...
\b' 3'43
Regioselective
Functionalization of l'I-Sub s tituted
p- and y-Lactams
A thesis submitted for the
degree of
Doctor of Philosophy
rn the
Department of Organic Chemistry,The University of Adelaide
Michael Joseph Pitt B.Sc. (Hons.)
by
November 1992
RegioselectiveFunctionali zation of N-Sub stituted
B- and y-Lactams
CoNTENTS
Ansrnacr
SransMhlT
PusucanoN
ACTqNOWLSDGEMENTS
Irrm<opuctoN . .
TTESULTS AND DISCUSSION - I . . . .
Exocyclic Functionalization of N-Substituted B-LactamsPreparation of the 2-azetidinonesT2 -76 .
Reactions of the 2-azetidinones 72 - 76 .
RESULTS AND DISCUSSIoN - II . . .
Elaboration of Functionalized N-Substituted p-Lactams
RUSUITS AND DISCUSSION - III . .
Functionalization of N-Substituted ylactamsPreparation of the 2-pyrrolidinones L41 and 142 . .
Functionalization of the 2-pyrrolidinones 141 and L42 . .
Rnsurrs AND DISCUSSIoN - TV .
Endocyclic Functionalization and Elaboration of y-Lactams
Preparation of the 2-pyrrolidinones L71 and 772 . .
Functionalization of the 2-pyrrolidinones 769 -L72 . .
CoNcrusroN
ÐcgRn¡rnrneL
RPpgRH\rCES
24
31
tlt
ía
7)
.1
24
48
66
66
70
83
83
115
717
766
86
I
AeSTRACT
With the aim of developing methodology for direct regioselective
functionalization of N-substituted p-lactams at exocyclic carbon adjacent to
lactam nitrogen, free radical bromination of N-substituted p-lactams bearing
activating substituents at that carbon has been investigated.
Reaction of B-lactams bearing activating substituents at exocyclic carbon
adjacent to nitrogen with N-bromosuccinimide resulted in regioselective
bromination at the exocyclic carbon adjacent to nitrogen. The resultant
product bromides are suitable for elaboration and the simplicity of this
procedure points to its potential for use in synthesis. In particular, the direct
exocyclic bromination of N-substituted p-lactams aíø this methodology
provides a novel attractive alternative route to the synthesis of N-(a-halo-
alkyl)-substituted lactams, which are of interest in the synthesis of p-lactam
antibiotics.
To demonstrate the synthetic utility of the direct exocyclic
functionalization of N-substituted B-lactams, the elaboration of N-(cr-bromo-
alkyl)-substituted p-lactams thus obtained was investigated.
Reaction of ethyl cr-bromo-2-oxo-L-azetidineacetate with allyltributyltin
afforded the corresponding allylated derivative oia radical carbon-carbon bond
formation at the exocyclic carbon adjacent to nitrogen. Ionic carbon-carbon
bond formation at the exocyclic carbon was achieved in a Wittig reaction and
Lewis acid catalysed allylation and arylation reactions of this bromide.
tl
To examine the possibility of directing functionalization to the exocyclic
carbon adjacent to lactam nitrogen in y-lactams, the regioselectivity of free
radical bromination of N-substituted y-lactams bearing activating substituents
at the exoryclic carbon adjacent to nitrogen was investigated.
Whereas analogous p-lactams gave products of reaction at the exocyclic
carbon only, N-substituted y-lactams bearing activating substituents at the
exocyclic carbon reacted with N-bromosuccinimide to give both products of
reaction at the exocyclic carbon adjacent to nitrogen and of competing reaction
at the endocyclic carbon adjacent to nitrogen. The endocyclic methylenes
adjacent to nitrogen in the y-lactams are presumably more reactive towards
hydrogen atom abstraction than those in the corresponding p-tactams due to
the relative degrees of ring strain in the product radicals.
The contribution of activating substituents at the exocyclic carbon
adjacent to nitrogen to the regioselectivity of free radical bromination of
y-lactams was examined. N-Substituted y-lactams not bearing activating
substituents at the exocyclic carbon adjacent to nitrogen reacted with
N-bromosuccinimide to give predominantly products resulting from initial
bromination at the endocyclic carbon adjacent to lactam nitrogen.
Endocyclic free radical bromination of n¡lactams leads to the production
of 4,S-dibromopyrrolidinones and as such provides novel methodology for the
regioselective difunctionalization of y-lactams at C4 and C5. The difunction-
alized y-lactams thus obtained are amenable to further regioselective
elaboration and their utility in synthesis is demonstrated by conversion to the
bicyclic tetrahydrofuropyrrolidinone system.
111
SrarnMENT
This thesis contains no material which has been accepted for the award
of any other degree or diploma in any university or other tertiary institution
and, to the best of my knowledge and belief, this thesis contains no material
previously published or written by another person, except where due reference
has been made in the text.
I consent to this copy of my thesis being made available for
photocopying and loan, if applicable, if accepted for the award of the degree for
which it is presented.
November '1.992
ta
PueucATroN
Part of the work described in this thesis has been published in the
following paper:
"Exocyclic Bromination of N-Substituted p- and llactams"
Easton, C. J.; Pitt, M.l. Tetrøhedron Lett.1990,31-, 347'1..
a
AcTNoWLEDGEMENTS
I would like to foremost thank my supervisor Dr. Chris Easton for his
guidance, encouragement and enthusiasm throughout the course of this work.
I would also like to thank all my friends and colleagues within the
Department of Organic Chemistry for providing an intellectually stimulating
environment from which I gained both support and criticism.
I thank my fiancée Lina for her understanding, encouragement,
unending support and patience, the least of which exemplified by her typing of
the majority of this manuscript.
The continuing support and encouragement of my family is, as will
always be, greatly appreciated.
INrnoDUCTroN
In 1928 Flemingl observed the antibiotic activity of penicillíum notatum
and gave the name penicillin to the active component produced by this fungal
strain. Penicillin (1) was first isolated some ten years later by Chain, Florey and
co-workers,2 who demonstrated its marked biologicat activity and therapeutic
value. It was 1945 before the structure of penicillin (1) was fully established,3,4
being the first example of a p-lactam found in nature. The first total synthesis
of a penicillin, penicillin V (1 : R = PhOCHz) was reported by Sheehan and
Henry-Logan5 in 1957.
CHs
CHao
The B-lactam ring plays a crucial role in the antibacterial activity of
penicillin (1) and a large number of antibiotics with this structural feature are
now known.6 These include the penicillins 1, cephalosporins 2, cephamycins
3, l-oxacephems 4, clavulanic acids 5, penems 6, carbapenems 7, norcardicins 8
and monobactams 9.
HSRlCONH
2R2
CO2H
SH
N
H=RCONH
CO2HH
L
SHH
N
2
co2H
p2
R
3
INTRODUCTION
2
R1
Rl
o
H:
N
5
H
N
R2
R3
H
N
4
H
N
H
R2
CHR
co2H
c02H
cH2R2
OH
o
R1
H CO2H
co2H
so3
SR3
o o
H
7
¡¡32RR
H
co2HH
I
6
RCONH
N No
9
Although the majority of these antibiotics in clinical use are naturally
occurring, being produced commercially from fermentation cultures,T the
requirement for antibiotics with greater antibacterial activities as a
consequence of drug resistänce by certain bacteriaS has lead to the development
of many semi- or totally-synthetic p-lactam antibiotics.6
A common approach to the synthesis of p-lactam antibiotics involves
completion of the molecular backbone by annelation of non-fused p-lactams
bearing appropriate substitus¡¡s.9,lO In such a manner, the first total synthesis
of the carbapenem antibiotic thienamycin (12) was accomplis¡"¿.11,12 The key
step in this synthesis was the intramolecular alkylation of a malonate anion.
INTRODUCT/ON
3
Thus, treatment of the malonic acid derivative 10 with bromine followed by
triethylamine in dimethylformamide gave the carbapenam 11, which was
subsequently converted to (+)-thienamycin (12) and (t)-8-epithienamycin (13)
(Scheme 1).
gS-rr'^-
BrLIHH
H¡CHeC NHCO2R
7. Br2
2. Et3N / DMFRqC
10
OHH H
HsCS1,'NHz ,1-NH2
co2H
13
B = p-nitrobenzyl
Scheme L
Following the same approach as that above, the intramolecular reaction
of a stabilized phosphorane with an aldehyde, ketone or thioester has been
widely used in the synthesis of a variety of bicyclic p-lactam antibiotics.l3:18
Woodward and co-workersl9 have thus described the total synthesis of several
penem antibiotics 18 in this manner, as depicted in Scheme 2. The
acylthioazetidinones L4 were converted to the required phosphoranes 17 in
three steps aia a previously established proc"¿,r.".13,20 Condensation of the
azetidinones 1-4 with the hydrate of a gyloxylic ester gave the carbinolamines 15
which were converted to the corresponding chlorides 16 through treatment
with thionyl chloride in the presence of a base. The crude chlorides 16 were
Sl,.NHCO2R
lL
OH
=
+
H
N
H
N
co2H
12
INTRODUCT/ON
4
treated in dioxane solution with triphenylphosphine in the presence of a base
and afforded the desired phosphoranes 17. The phosphorane thioesters 17
cyclized uPon heating in toluene at 90C to give the penems 18 in good yield.
(HO)2CHCO2R2 soc12N base N
corR2
15 16
/ base
HS
toluene
olt
oHll
oI
1H=
H
NH
L4
1
Yo"co2R2
A¡1r
H
N
1
oil
SCR
18 17
Scheme 2
With the high susceptibility of B-lactam antibiotics to nucleophilic
reagents2l as a consideration, Bachi and co-worker s22,23 have used free radical
carbon-carbon bond forming reactions rather than ionic reactions to complete
the molecular backbone of some fused bicyclic B-lactams. For example, the
oxabicyclo-p-lactams 20 and 21 were obtained by the action of tri-z-butyltin
hydride on the appropriately substituted non-fused azetidinone L9 (Scheme 3).
The mixture of products obtained in the reaction of 19 arises from competitive
exo and endo cyclization of the initially formed radical 22 to give 20 and 21,
respectively. The relative stability of the radicals 23 and 24, produced during
the ring closure of 22, is an important factor in determining the relative extent
of the exo and endo modes of cyclizatíon (Scheme 4). When R1 = H, the
/NTRODUCTION
5
secondary radical 24 is more stable than the primary radical 23 and the reaction
occurs in the endo rnode, but when R1 = Ph or CO2CH3, the radical 23 is more
stable than the radical 24 and. exo additton is favoured. rt
'
t3
pr
tt-Bu3SnH
Scheme 3
+
endo
N
Yt'cqR2
N ¡1r
19 20 21
R1
exo
¡¡t N
co2R2
23
R
Scheme 4
Methods for the synthesis of fused bicyclic 1-lactams are of interest in the
synthesis of certain alkaloids.24 The pyrrolizidine alkaloids are a large class of
naturally occurring compounds isolated from a variety of plant sources.2S
These alkaloids exhibit diverse biological activities and various members of
this family, possessing the common azabicyclol3.3.0]octane ring system, have
been reported to act as antitumour, hypotensive, local anaesthetic,
N
24
INTRODUCTION
6
antispasmotic, antiinflammatory, mutogenic or hepatotoxic agents.26-28
Pyrrolizidine alkaloids are commonly isolated as esters, diesters or macrocyclic
bislactones of the basic ring system, although the free pyrrolizidine or "necine"
bases themselves have been isolated from natural sources.29 The most
common examples are the saturated diols, hastenecine (25a), turneforcidine
(25b), dihydroxyheliotridane (zøa) and platynecine (26b) and the 1,2-
unsaturated diols, heliotridine (27a) and retronecine (27b). The antitumour
agent indicine N-oxide (ZA)SO is then derived in nature from retronecine (27b).
R=
2 CH.'OH ¡12 H=
N
H=
N5
1
3
26
R1¡1.2
o
o
28
a: Rl =H,R2=OHb:R1 =OFI,R2=H
A synthetic approach analogous to that outlined above for the synthesis
of B-lactam antibiotics, but based on completion of the molecular backbone by
annelation of y-lactams bearing appropriate substituents, has found widespread
use in the synthesis of pyrrolizidine alkaloi¿5.31,32 A notable illustration of
this approach is provided by the work of Speckamp and co-workers,33 6ur"O
25
H
H:
N
H=
N
27
INTRODUCTION
7
upon the acid-catalysed cyclization of N-acyliminium ions. For example, the
alkaloids 33 and 34 were obtained aía cyclization of the S-ethoxypyrrolidinone
3034 as depicted in Scheme 5. Thus, reduction of the imide 29 with sodium
borohydride in ethanol3S afforded the S-ethoxylactam 30 which was cyclizedby
treatment with formic acid. After subsequent acid hydrolysis the thioesters 31
SPh
oEtNaBHa / EIOH
N
29 30
SPh
1. HCO2H2. HCI
SPhH
N
g
N
o
+
LiAlH4
31 32
H2OHC
T
N+
LI:
N
33
Scheme 5
34
INTRODUCT/ON
8
and 32 were obtained in an approximately 4 : 1 mixture. Lithium aluminium
hydride reduction at 70"C in tetrahydrofuran then furnished the pyrrolizidine
alkaloids (+)-trachelanthamidine (33) ur,¿ (+)-isoretronecanol (34), from 31 and
32 respectively.
It is noteworthy in this example that the products 31 and 32 obtained are
attributable to exo cyclization of the N-acyliminium ion 35 derived from 30,
with no products attributable to endo cyclization of 35 being detected. The
regioselectivity of. cyclization thus displayed in this example is due to the
presence of the phenylthio substituent on the alkenyl sidechain which may
mesomerically stabilize the exocyclic vinyl cation 36 formed upon exo
cyclization of the N-acyliminium ion 35 (Scheme 6). In this way, the normally
unfavourable ringstrain effects associated with the intermediacy of.36, thereby
favouring endo cyclization to give 37, are adequately compensated and exo
cyclization to 36 therefore predominates.
exo endoSPh
+ SPh
+
N
o
N+
35
N
3736
Scheme 6
INTROD UCTION
9
In a variation of this approach to the synthesis of pyrrolizidine
alkaloids, Flart and co-worke¡536-38 have utilized o-acylamino radical
cyclizations in construction of the molecular backbone. Thus treatment of the
S-phenylthiopyrrolidinone 38 with tri-n-butyltin hydride in the presence of
azobisisobutyronitrile (AIBN) gave an LL:5 mixture of the pyrrolizidinone 39
and the indolizidinone 40 (Scheme 7), presumably aiø competing exo and
endo cyclization respectively, of the cr-acylamino radical 4L (R =H) (Scheme 8)
formed upon initial phenylthiyl radical abstraction from 38. As for the case of
the N-acyliminium ion cyclization described above, the ratio of
z-Bu3SnH +AIBN
39
Scheme 7
39
N
o
NN
38
o40
R
N
oexo 4L endo
R R
a
N N
4342
Scheme B
/NTRODUCTION
10
Pyrrolizidinone 39 to indolizidinone 40 formation in this reaction may be
increased by introduction of appropriate substituents R on the alkenyl side-
chain. Thus, when R = Cozf-Bu or CN the radical 42 formed upon exo
cyclization of the cr-acylamino radical 4l is more stable than the radical 43
resulting from endo cyclization and pyrrolizidinone formation consequently
predominates to the extent that indolizidinone formation is not observed.3S
Radical cyclizations of silylated alkenyl and allenyl derivatives have also been
reported to proceed with high regioselectivity.39,ar
Common to all of the syntheses described above is that each involves
construction of lactams bearing functional groups, appropriate to cyclizanon, at
the endocyclic and exocyclic carbons adjacent to lactam nitrogen. In each case
the lactam is constructed or substituents are introduced onto nitrogen of the
lactam with this required functionality already in place. As such, these
syntheses require the somewhat elaborate synthesis of specific, and often
unstable, precursors to cyclization, and so are limited in their applicability as
general methods. For this reason, an alternative strategy based upon the later
introduction of functionality directly at carbon adjacent to lactam nitrogen of
non-functionalized N-substituted p- and y-lactam systems presents an
attractive proposition. In view of the aforesaid susceptibility of fused bicyclic
p-lactams to nucleophilic reagents2l it is preferable to investigate the utility of
free radical rather than ionic reactions as methodology for direct
functionalization of such B- and y-lactam systems.
The electrochemical oxidation of amides is a free radical process
involving an initial one electron removal from nitrogen,4l and results in
substitution at carbon adjacent to amide nitrogen.42 Electrochemical oxidation
of 2-azetidinones has been reported to similarly result in functionalization at
carbon adjacent to amide nitrogen.43-45 For example, Ban and co-workers44
have reported that electrolysis of the N-substituted azetidinone 44 in methanol
INTRODUCTION
77
affords a mixture of the endocyclic and exocyclic substitution products 45 and
46 (Scheme 9). As the products 45 and 46, thus obtained, were inseparable by
ocH3-e
cH3oH Nv"\ +CO2Me CO2Me
44ocH3
4546
Scheme 9
chromatography, their ratio of formation was estimated by 1H n.m.r. analysis
as ca.2:5. Thus, this example serves to illustrate that although electrochemical
oxidation of N-substituted azetidinones provides methodology for direct
functionalization at carbon adjacent to nitrogen, the non-regioselectivity of
reaction is manifest in competing reaction at both endocyclic and exocyclic
carbon adjacent to amide nitrogen.4S
A radical on carbon adjacent to amide nitrogen is stabilized through
interaction of the radical's semi-occupied p-orbital with the rc-orbitals of the
amide, and as such may forrn selectively by l'rydrogen atom transfer. Easton
and co-workers46,47 have reported use of hydrogen atom transfer reactions as
methodology for the direct functionalization of N-substituted 2-azetidinones.
Treatment of the N-methylazetidinone 47 with f-butyl perbenzoate, in the
presence of a copper I catalyst in benzene, resulted in reaction at the exocyclic
carbon adjacent to nitrogen, with competing reaction at the corresponding
endocyclic position.46 Thus, the exocyclic and endocyclic substitution products
48 and 49 were obtained as the primary products of reaction in the ratio of cø.
2:7 (Scheme L0). The mechanism of oxidation of organic substrates with ú-butyl
perbenzoate has been investigated48 and a free radical chain process is
F-o'
INTRODUCTION
72
HsCOCOPh
H¡C HeCÍ-BuO2COPh +
CuI
47
Scheme L0
proposed involving generation of ú-butoxy radical by one.electron reduction of
the perester (Scheme 1.1.). Hydrogen atom transfer from the substrate 50 to
ú-butoxy radical affords the substrate radical 51 which, upon incorporation of
benzoate at the site of abstraction, yields the benzoyloxylated product 52 and
regenerated copper I catalyst. The ratio of formation of the benzoyloxylated
ú-BuOOCOPh + Cu* f-BuO'+-OCOPh+Cu2*
f-BuO' + RH R' + ú-BuOH
+ -ocoPh + cu2* ROCOPh + CU*
Scheme 1.1.
products 48 and 49 in the present example may then be attributed to the
relative ease of formation of their free radical precursors. It is presumable that
the preference for exocyclic benzoyloxylation of the azetidinone 47 reflects that
the degree of ring strain engendered upon formation of the endocyclic radical
precursor to 49 outweighs the normal thermodynamic preference for the
production of secondary radicals over that of primary radicals.49
'a",NN
o
4948
'a*t,
5150
52
R
51
INTRODUCTION
13
With the exocyclic position blocked to reaction, Easton and Love46 have
demonstrated use of the free radical benzoyloxylation procedure for endocyclic
functionalization of azetidinones at carbon adjacent to lactam nitrogen.
Treatment of the 2-azetidinones 53 with ú-butyl perbenzoate afforded the
corresponding 4-benzoyloxy substituted Z-azetidinones 54 (Scheme L2). That
f-BuO2COPh
CLJR
R = f-Bu, Ph
Scheme 12
the benzoyloxy substituent is incorporated at C4 of the azetidinones 53, in this
example, is indicative of the greater reactivity of the C4 methylene protons to
hydrogen atom abstraction by f-butoxy radical over that of the methylene+6
protons of C3. This reflects the activating effect of the adjacent amide nitrogen,
whereby a radical generatecl at C4 of the azetidinones 53 would be resonance
stabilized through interaction of the radical's semi-occupied p-orbital with the
æ-orbitals of the lactam amide.
Through functionalization of azètidinones bearing a removable
protecting group on nitrogen, Easton and co-workers4T have further extended
this benzoyloxylation procedure to synthesis of N-unsubstituted -benzoyloxy-
azetidinones. Similarly, electrochemical oxidation has been applied to the
synthesis of N-unsubstituted 4-alkoxyazetidinones aia direct endocyclic
functionalization of N-unsubstituted azetidinones.4S
,n NR
5453
TNTRODUCT/ON
74
The above examples illustrate that free radical oxidation reactions
provide effective methodology for the direct functionalization at carbon
adjacent to lactam nitrogen in Z-azetidinones, and whilst functionalization
solely at the endocyclic carbon adjacent to nitrogen may be acheived simply
through blocking the corresponding exocyclic position to reaction,
functionalization at the exocyclic carbon adjacent to nitrogen in N-substituted
azetidinones is complicated by competing reaction at the corresponding
endocyclic position. There therefore exists a need in such methodology for a
procedure enabling the direct regioselective functionalization at exocyclic
carbon adjacent to lactam nitrogen in N-substituted 2-azetidinones. Prior to
the outset of the work presented in this thesis, such a procedure had not been
reported. The development of methodology for the direct regioselective
functionalization at exocyclic carbon adjacent to nitrogen in N-substituted 2-
azetidinones then forms the main aim of the work described in Chapter I of
this thesis.
The course of a free radical reaction is often affected by the stability of the
free radical intermediates involved and, as has been illustrated in the
examples discussed above in Schemes 3 and 7, radical stabilizing substituents
may be employed to control the regioselectivity of these reactions. As
discussed above, a radical on carbon adjacent to lactam nitrogen is stabilized
through resonance by interaction of the radical's semi-occupied p-orbital with
the æ-orbitals of the electron-donating amido substituent. Enhanced
stabilization of such a radical may be gained through the combined
participation of an electron-withdrawing substituent at the radical centre. For
example, the cr-centred radicals 55 and 56, generated from N-acetylglycine and
glycylglycine respectively, both having an electron-donating amido and an
electron-withdrawing carboxy substituent at the radical centre, possess an
inherent stability arising from extensive delocalization of unpaired spin
INTRODUCT/ON
density through resonance. The electron spin resonance spectra of the radicals
55 and 56 show that there is extensive conjugation in these radicals with only
70 - 75Vo of the unpaired spin density at the respective cr-carbons.50,51 In
o oH3NI
NH
56
addition, molecular orbital calculationsS2 also indicate that unpaired spin
density in the radical 55 is distributed over the molecule, the major
contribution being from from the c¿-carbon with contributions from both the
amido and carboxyl moieties (Figure 1.).
o-{.03H
0.10
+ aa
15
HgC
55
HsC-o.004
Fígure 1. Distribution of unpaired electron spin density in the c,-centred radical derivedby hydrogen atom transfer from N-acetylglycine.52'
Radicals of the type 55 have been classified by Veihe and co-workerss3 as
captodative radicals. The captodative effect was postulated as the combined
resonance effect of an electron-withdrawing (cøpto) and an electron-donating
(datiae) substituent on a radical centre, leading to an enhanced stabilization of
the radical. The theoretical basis of the combined stabilizing effect of an
electron-donor and an electron-acceptor substituent on a radical centre was
INTRODUCTION
76
originally formulated by Dewar54 in 7952. This concept was later observed
experimentally and termed "push-pull stabilization" by Balaban55 and in
independent observations by Katritzky and co-workersS6 the term
"merostabilization" was introduced. Although it remains debatable as to
whether or not a synergistic radical stabilizing effect is realized,ST-62 when a
radical is substituted by both electron-donor and electron-acceptor moieties, it
is clear that stabilization of the radical results from the combined but not
necessarily synergistic action of both substituents.
Thus, the present proposal was to attempt to direct the free radical
functionalization of N-substituted 2-azetidinones to the exocyclic carbon
adjacent to nitrogen through the use of electron-withdrawing substituents, as
radical stabilizing groups, at that position. N-Bromosuccinimide was chosen
as the reagent for functionalization in this investigation, as hydrogen atom
abstractions in reactions with N-bromosuccinimide are selective for formation
of the most stable product radical.63
The generally accepted mechanism for bromination by N-bromo-
succinimide, postulated by Goldfinger and co-workers& in 1953, is as depicted
in Scheme 1.3. Hydrogen atom abstraction from the substrate 57 by bromine
atom forms hydrogen bromide and the substrate radical 58. Reaction of
N-bromosuccinimide with hydrogen bromide produces a steady but very low
concentration of molecular bromine'in the reaction mixture. Bromine atom
transfer from molecular bromine to the substrate radical 58 then affords the
brominated product 59 and bromine atom, which propagates the chain. The
proposed mechanism is supported by the fact that allylic bromination can be
achieved either with N-bromosuccinimide or by slow introduction of
molecular bromine into an irradiated solution of olefin.65 Furthermore,
investigations by Walling and co-workers66 and Russell and co-workers6T have
INTRODUCTION
77
+ Br'
NBr + HBr
R.
58
+ Brz
R'+58
RIT
57
HBr
NH + Btz
RBr + Br'59
o
o
confirmed that reactivities of benzylic hydrogens with N-bromosuccinimide
are indentical to those with molecular bromine. Thus, the initial reaction of
reactive substrates with N-bromosuccinimide involves hydrogen atom
abstraction by bromine atom, a reaction in which there is relatively extensive
C-H bond homolysis and, consequently, much development of radical
character in the transition s¡¿1s.49,63 As such, this reaction is relatively
sensitive to the stability of the product radial.
The sensitivity of free radical bromination with N-bromosuccinimide to
radical stability effects is exemplified by the selectivity displayed in reactions
with amino acid derivatives.6S-72 For example, Lidert and GronowitzT3 have
reported treatment of the N-acylglycine derivative 60a with N-bromo-
succinimide in carbon tetrachloride, in the presence of benzoyl peroxide as
radical initiator, to give the cr-bromoglycine derivative 67a (Scheme 14).
Subsequently, Easton and Hay68 have demonstrated that the reaction with
N-bromosuccinimide is selective for monobromination of the glycine
derivative 60b. As the rate determining step of this reaction was shown to be
ø-hydrogen atom transfer, the selectivity for monobromination exhibited may
be attributed to the relative ease of formation of the o-centred radical 62,
TA/TRODUCTION
18
Broo
nrAruH^corRz ,\ **rÅNBS
¡¡1 co2R2
60 6L
a: R1 =Me,R2=Etb: R1 =Ph,R2:Me
generated upon hydrogen atom abstraction from 60b, with respect to that of the
radical 63, similarly derived from the bromide 61b. Thus it was proposed that
62 forms in preference to 63 as a result of greater stability. The greater stability
of 62 results as the radical may adopt a planar conformation, relatively free of
non-bonding interactions, in which there is maximum delocalization of the
unpaired electron aia overlap of the semi-occupied p-orbital with the
n-orbitals of the amido and methoxycarbonyl substituents (Figure 2). Severe
non-bonding interactions within the analogous conformation of 63 would,
however, distort this radical out of planarity, resulting in reduced orbital
overlap and, consequently, a much reduced stabilization of the radical. This
rationale is supported by the relative rates of reaction of several N-acylamino
acid derivatives with N-bromosuccini¡nids.68,71
Ph,/c
62
Fígure 2. Non-bonding interactions in planar conformations of the radicals 62 and 63
3
o
/.OCF{s\*
I
H
63
INTRODUCTION
79
Although a radical on carbon adjacent to an electron-withdrawing
group such as an alkoxycarbonyl substituent may be stabilized through
resonance, the formation of such a radical by hydrogen atom transfer to
bromine atom is often disfavoured.49,63,74 This is due to a polar effect
resulting from the inductive interaction between the electron deficient centre
of the substituent and that developing in the transition state at the site of
hydrogen abstraction by bromine atom. FIowever, Easton and co-workersT2
have demonstrated the proactive effect of an alkoxycarbonyl substituent
toward hydrogen atom abstraction at the adjacent carbon, when in cooperation
with an amido substituent at the same carbon. In this situation the charge
developing in the transition state of hydrogen atom abstraction by bromine
atom may be delocalized by the adjacent amido group (Figure 3), leading to a
lessening of the deactivating polar effect of the alkoxycarbonyl substituent to
the extent that radical stabilization factors dominate and an enhanced rate of
õ* õ*
RCONRI -CH-
CO2R2 RCONR1 ----CH-CO2R2
Figure 3 Delocalization of developing positive charge by an amido substituentin the transition state of hydrogen atom abstraction by bromine atom.
hydrogen atom abstraction results. On this basis, it was envisaged that
electron-withdrawing substituents at the exocyclic carbon adjacent to lactam
nitrogen in 2-azetidinones would activate that position to free radical
bromination.
ÒÒBr
IIIa
I
H
BrIIIa
I
HIII¡I
INTRODUCTION
20
The choice of N-bromosuccinimide as the reagent for regioselective
functionalization of azetidinones is attractive from a synthetic standpoint, as it
was expected that the product bromides thus obtained would be amenable to
further elaboration. The choice of electron-withdrawing substituents to
activate the exocyclic carbon adjacent to nitrogen of azetidinones towards
bromination provides for the use of alkoxycarbonyl or cyano substituents as
masked carboxylate functionality. This aspect is envisaged as advantageous
in syntheses toward mono- and bicyclic p-lactam antibiotics, which bear
carboxylate functionality at this position. In particular, the direct free radical
bromination at exocyclic carbon adjacent to amide nitrogen of an azetidinone
bearing an alkoxycarbonyl substituent at that position would provide
an alternative route to the synthesis of N-(ø-haloalkyl)-substituted
azetidinonesl3,lg such as 15, illustrated in Scheme 2 above.
The investigation of regioselective free radical bromination of
2-azetidinones bearing activating substituents at the exocyclic carbon adjacent
to lactam nitrogen is described in Chapter I of this thesis. The work presented
in Chapter II is then based upon an investigation into the synthetic utility of
methodology developed in Chapter I.
Free radical reactions have been employed as methodology for the
direct functionalization of Z-pyrrolidinones at carbon adjacent to lactam
nitrogen.42,43,75-79 Ban and co-workersT5 have reported that anodic oxidation
of N-alkylpyrrolidinones occurs regioselectively at the endocyclic carbon
adjacent to nitrogen. Controlled potential electrolysis of the pyrrolidinones 64,
in an electrolyte solution containing water, gave the corresponding S-hydroxy-
pyrrolidinones 65 as the major products, with minor amounts of the
respective imides 66 (Scheme L5).
INTRODUCTION
27
Electrochemical oxidation of N-unsubstituted 2-pyrrolidinones has
similarly been reported to result in functionalization at the endocyclic carbon
adjacent to nitrogen,43,76 and photochemical oxidations of Z-pyrrolidinones to
their corresponding imides have also been repofted.77,78
H
-e +Hzo
o64 65 66
R=Me,Et
Scheme L5
Easton and co-workersT9 have reported that free radical benzoyloxyl-
ation of the N-methylpyrrolidinone 67 results in reaction at both the
endocyclic and exocyclic carbons adjacent to lactam nitrogen (Scheme L6).
OCOPh
H¡C N
ú-BuO2COPh HsC
Hsc-c", CuICHa
69
*-o*-o*'*
o
N-..
H¡C
Hgc+HeC
oo
67 68
H¡CHsC
H¡C
o
HaC N-a",
7L
Scheme L6
70
/NTROD UCTION
22
Treatment of 67 with f-butyl perbenzoate in the presence of a copper I catalyst
gave both the exocyclic and endocyclic substitution products 68 and 69, isolated
upon hydrolysis during chromatography as the corresponding alcohols 70 and
7L. The ratio of formation of the benzoyloxylated products 68 and 69 was
determined by tg n.m.r. spectroscopic analysis of crude reaction mixtures as ca.
1:3 and may be attributed to the relative ease of formation of their free radical
precursors.
In each of the examples presented above, reaction at the endocyclic
carbon adjacent to nitrogen of the pyrrolidinones 64 and 67 exhibits preference
over reaction at the corresponding exocyclic carbon. In the case of free radical
benzoyloxylation of 67 this preference presumably reflects a greater reactivity of
the endocyclic carbon toward hydrogen atom abstraction, than that of the
corresponding exocyclic carbon. This may be attributed to the relief of ring
strain, as a result of the release of steric interactions between the C4 and C5
protons, upon hydrogen atom abstraction from the endocyclic carb6¡.80,81 1¡ ig
further possible that hydrogen atom abstraction from the endocyclic position is
favoured entropically by the inflexibility of the lactam ring of 67 maintaining
the amido group in the planar orientation required for stabilization of the
product radical.Tl
With the aim of directing functionalization to the exocyclic carbon
adjacent to nitrogen in 2-pyrrolidinones, the work presented in Chapter III of
this thesis is based upon application of methodology developed in Chapter I,
for exocyclic functionalization of azetidinones, to analogous pyrrolidinone
systems. Thus, an investigation of the regioselectivity of free radical
bromination of 2-pyrrolidinones bearing activating substituents at the exocyclic
carbon adjacent to nitrogen is described
INTRODUCT/ON
23
In the investigation of free radical bromination of pyrrolidinones
bearing activating substituents at the exocyclic carbon adjacent to nitrogen, as
presented in Chapter III, two factors were employed to direct the regio-
selectivity of reaction, in common with the work described in Chapter I.
Namely, the choice of a reagent for functionalization that is selective for
formation of the most stable product radical, and the choice of substituents at
the exocyclic carbon that in cooperation with the lactam amide substituent
activate this position to hydrogen atom abstraction. In work described in
Chapter IV of this thesis an assessment of the individual contributions of each
of these factors was made, through an investigation of the regioselectivity of
free radical bromination of pyrrolidinones not bearing activating substituents
at the exocyclic carbon adjacent to nitrogen. From a consideration of the
regioselectivity displayed in free radical benzoyloxylation of the N-methyl
pyrrolidinone 67, as discussed in Scheme 16 above, it was expected that free
radical bromination would occur with a high degree of regioselectivity at the
endocyclic carbon adjacent to nitrogen in pyrrolidinones not bearing activating
substituents at the corresponding exocyclic position. A subsequent aim of the
work presented in Chapter IV was the elaboration of the functionalized
pyrrolidinones obtained in this investigation, toward the synthesis of bicyclic
pyrrolidinones.
INTRODUCTION
RpsuLTS AND DrscussroN - I
Exocyclic Functionalization of N-Substitutedp-Lactams
Preparation of t}lre Z-azetidinones 72 - 76
T}:.e Z-azetidinones 72 - 76 were required for the investigation of their
possible functionalization each at the exocyclic carbon adjacent to amide
nitrogen. They were synthesized uiø cyclization of the corresponding
24
COzEtCNPhCH=CHzCOzCHzPh
72 R = COzEt73 R = Cl.J74 R=Ph75 R = CH=CHz76 R = COzCH2Ph
3-bromopropionamides 77 - 81, prepared by Schotten-Baumann coupling of
3-bromopropionyl chloride (8a) with the corresponding amines 83,86,88,89,
and 91. Details of the syntheses of the azetidinones 72 -76 are given below.
,n-ì
R
Br
NH
77 f{=78 f{=79 f{=80 f{=81. R-
R
RESULTS AND D/SCUSSION - I
25
Ethyl 2-oxo-7-azetidineacetate (72) was synthesized from glycine (82) as
shown in Scheme 17. Glycine ethyl ester hydrochloride (83), obtained by
esterification of glycine (82) with ethanol that had been pretreated with thionyl
chloride, was treated with 3-bromopropionyl chloride (8a) in the presence of
excess aqueous sodium bicarbonate to give the bromopropionamide 77 . Using
this procedure, 77 was obtained in 56To yield from the acid chloride 84 and
had physical and spectral characteristics in accord with those previously
reported.32
HCI.NH2CFI2CO2Et
83
/ EIOr{ +NH3CH2CO2
Br
/ aq. NaHCO3
CI
KOH / Bu4NBr +N NH
CO2Et co2Et77 72
Scheme L7
The cyclization of 3-halopropionamides to azetidinones is complicated
by the readiness with which these compounds undergo elimination to give
acrylamides.S3 However, Wasserman and co-workersS3 have reported that
high dilution and a slow rate of addition of propionamide to base favour the
desired cyclization over the competing elimination reaction. These
observations have also been made by Takahata and co-workers,82 who
82
84
Br
co2Et85
RESULTS AND DISCUSSION - 1
26
reported a convenient cyclization of 3-halopropionamides with potassium
hydroxide utilizing a phase transfer catalyst in a solid-liquid two phase system.
Using this methodolgy, the cyclization of 77 to give 72 has been previously
reported.S2 Accordingly, the propionamide 77 was cyclized by its slow
addition in dilute solution to a stirred suspension of powdered potassium
hydroxide and tetra-n-butylammonium bromide in a 1,9:7 mixture of
dichloromethane and acetonitrile. Chromatography of the reaction mixture
followed by distillation to separate the small amount of the acrylamide 85
formed, gave ethyl 2-oxo-L-azetidineacetate (72) in 61,Vo yield from the
propionamide 77. The lactam and ester carbonyl groups in 72 gave rise to
characteristic absorptions in the infrared spectrum at 7744 and 1758 cm-l
respectively. Other spectral characteristics were in accord with those
previously reported82 for the azetidinone 72.
2-Oxo-L-azetidineacetonitrile (73) was prepared as outlined in Scheme
18. Aminoacetonitrile bisulphate (86) was treated with 3-bromopropionyl
chloride (84) in the presence of excess aqueous sodium bicarbonate to give the
bromopropionamide 78 in 79Vo yîeld. The product exhibited physical and
spectral characteristics consistent with the structure of 78 and was fully
characterized. In particular, formation of the amide in 78 was confirmed by
the observation of a characteristic absorption at 1655 cm-1 in the infrared
spectrum. Treatment of the propionamide 78 with a suspension of powdered
potassium hydroxide and tetra-n-butylammonium bromide in
dichloromethane and acetonitrile, as for the cyclization of 77 above, afforded
the desired azetidinone 73 in 62Vo yield, with negligible formation of the
acrylamide 87. The lactam 73 was fully characterized, exhibiting satisfactory
spectroscopic properties and elemental analyses. It was distinguished by the
observation of a strong infrared absorption at 7754 cm-1, characteristic of the
lactam carbonyl group.
RESULTS AND D/SCUSSION - I
27
Br
H2SO4.NH2CH2C\I +
86
84
aq. NaHCO3
KOH / Bu4NBr
NH N + NH
78 73 87
Scheme 1-8
1-Benzyl-2-oxoazetidine (74) was synthesized as shown in Scheme 1-9.
Thus, treatment of 3-bromopropionyl chloride (84) with excess benzylamine
(88) in dichloromethane gave the bromopropionamide 79 in 67Vo yield, with
physicat and spectral properties in accord. with those previously reported.S2
Takahata and co-workersS2 have reported the cyclization of the propionamide
79 to give the lactam 74, using the methodology described above in the
synthesis of 72. Accordingly, Tg was treated with a suspension of powdered
potassium hydroxide and tetra-n -butylammonium bromide indichloromethane, affording the lactam 74in70% yield. Spectral characteristics
of the product 74 were consistent with those reported,S2 with the lactam
carbonyl giving rise to a characteristic absorption in the infrared spectrum
at 1734 cm-1.
Br
ìCNCNCN
RESULTS AND DISCUSSION - I
28
Br
NH2CH2Ph +CI
KOH / Bu4NBr
NH
79 74
Scheme L9
1-Allyt-2-oxoazetidineacetate (75) was synthesized from allylamine
(8e), similarly to the above synthesis of. 74, as shown in Scheme 20. N-411y1-3-
bromopropionamide (80) was obtained in 697o yield by treatment of 3-bromo-
propionyl chloride (8a) with excess allylamine (89) in dichloromethane.
The propionamide 80 was fully characterized exhibiting satisfactory
spectroscopic properties and elemental analyses. In particular, the amide
carbonyl of 80 gave rise to a characteristic infrared absorption at 1640 cm-1.
Treatment of the propionamide 80 with a suspension of powdered potassium
hydroxide and tetra-n-butylammonium bromide gave a mixture of 1.-allyl-Z-
oxoazetidine (75) and the by-product acrylamide 90, as judged by 1H n.m.r.
spectroscopic analysis. The methylene protons of the allylic carbon in 80
resonate as a doublet of doublets at ô 3.90 with / = 6.0 and 5.0 FIz. In the crude
product mixture obtained from 80 as above, a doublet resonance at õ 3.83
with I : 6.7 FIz was observed, consistent with the methylene protons of
88
84
Br
Ph Ph
RESULTS AND DISCUSSION - I
29
Br
+HzNCI
Br
KOH / Bu4NBr+
\,,^
80 75 90
Scheme 20
the allylic carbon of the azetidinone 75. The presence of the acrylamide 90
in the same product mixture was evident from the observation of a signal at
ô 6.33, indicative of the methine proton adjacent to the amide carbon. The
lactam 75 was readily isolated from the crude product mixture in 30Vo yield by
chromatography and subsequent distillation. The azetidinone 75 exhibited
consistent spectroscopic properties, with the observation of an infrared
absorption at 7744 cm-1 characteristic of the lactam carbonyl grouP.
Benzyl 2-oxo-1-azetidineacetate (76) was synthesized from glycine (82)
as shown in Scheme 21-. Glycine benzyl ester hydrochloride (91), obtained by
esterification of glycine (02¡ with benzyl alcohol which had been
pretreated with thionyl chloride, was treated with 3-bromopropionyl chloride
(84) under basic conditions and gave the bromopropionamide 81 in 77o yield.
The propionamide 81 was fully characterized, with the observation of an
infrared absorption at 1652 cm-1 confirming the presence of the amide
8984
Ão o
RESULTS AND DÌSCUSSION - /
30
group. The propionamide 81- was cyclized by treatment with powdered
potassium hydroxide and tetra-í -butylammonium bromide indichloromethane and acetonitrile affording benzyl 2-oxo-L-azetidineacetate
(76) in a yield of. 22Vo. The lactarn 76 was fully characterized, the lactam
carbonyl group giving rise to a characteristic infrared absorption at 7742 cm-1.
HCt.NH2CH2CO2CH2Phsocl2 / PhcH2oH +
NH3CH2CO2
9Í
Br
/ aq. NaHCO3
84
KOF{ / Bu4NBr + PhcH2oHNH N
CO2CH2Ph co2cH2Ph8L 76
Scheme 21
The low yield of the azetidinone 76 obtained was reasoned as due to hydrolysis
of the benzyl ester moiety of 81 under the basic conditions of cyclization.
Accordingly, a substantial amount of benzyl alcohol was observed in crude
product mixtures obtained upon cyclization of the propionamide 81.
82
Br
RESULTS AND DISCUSSION - I
37
Reactions of the 2-azetidínones 72-76
Reactions of the }-azetidinones 72 - 76 with N-bromosuccinimide were
studied in order to investigate free radical bromination at the exocyclic carbon
adjacent to nitrogen in B-lactams bearing activating substituents at that
position. The azetidinone 72 bearing an ethoxycarbonyl substituent at the
exocyclic carbon adjacent to the lactam nitrogen was chosen for intial study.
On the basis that an alkoxycarbonyl substituent exhibits a proactive effect
toward hydrogen atom abstraction at the adjacent carbon, when in cooperation
with an amido substituent at the same carbon,7z it was envisaged that the
ethoxycarbonyl substituent would facilitate free radical bromination at the
cr-carbon of 72. In addition, the choice of the ethoxycarbonyl substituent in
72 was attractive from a view to the synthesis of naturally occurring mono-
and bicyclic p-lactam antibiotics which bear a carboxylate functionality at the
same position relative to the lactam nitrogen.
Ethyl 2-oxo-7-azetidineacetate (72) was initially treated with one mole
equivalent of N-bromosuccinimide in carbon tetrachloride, at reflux under
nitrogen for 15 minutes, with reaction initiated by irradiation with a 300 W
mercury lamp. The cooled, filtered reaction mixture yielded, upon
evaporation of the solvent, a brown tarry residue containing the bromide 92
as the only identifiable product of reaction, as determined by 1H n.m.r.
spectroscopic analysis. Thus, although the bromide 92 was obtained in this
reaction, its production was accompanied by considerable decomposition of the
reaction mixture. This decomposition was reasoned as due to inadequate
solubility of the lactam 72 in the reaction solvent.
Tan and co-workersTO have reported the use of dichloromethane as a
suitable solvent for bromination of reactive amino acid derivatives with
N-bromosuccinimide, where the high rate of bromination of the substrate
RESULTS AND DISCUSSION - 1
32
presumably overcomes competing solvent reactions. However, when the
azetidinone 72 was treated with one mole equivalent of N-bromosuccinimide
as above, but in dichloromethane, lFI n.m.r. analysis of the crude reaction
mixture revealed the presence of the starting material 72 only. The lack of
reactivity of the azetidinone 72 with N-bromosuccinimide, in this instance,
was concluded as being due to the reduction in temperature uPon using
dichloromethane as the solvent. In order to elevate the temperature of the
reaction mixture whilst maintaining solubility of the substrate 72,
bromination in mixtures of carbon tetrachloride and dichloromethane was
investigated.
When the azetidinone 72 was treated with N-bromosuccinimide in a
mixture of carbon tetrachloride and dichloromethane containing just
sufficient dichloromethane to dissolve the substrate, bromination of 7 2
proceeded readily, without decomposition. Thus, ethyl 2-oxo-'l'-
azetidineacetate (72) was treated with one mole equivalent of
N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride and
dichloromethane, at reflux under nitrogen for L5 minutes, with reaction
initiated by irradiation with a 300 W mercury lamp. The reaction mixture was
cooled, filtered and concentrated to give cr-bromo-2-oxo-L-azetidineacetate
(SZ¡ as the only product of reaction (Scheme 22). Production of the
NBS
hv
co2Et CO2Et92
^
o'Br
72
Scheme 22
RESULTS ,AND D/SCUSS/ON - I
33
bromide 92 in this reaction was determined on the basis of 1H n.m.r.
spectroscopic analysis of the crude reaction mixture after evaporation of the
solvent. The methylene protons of the cr-carbon in 72 give rise to a singlet
resonance at ô 3.99. With the crude product mixture obtained from the
bromination of 72, a singlet resonance at ò 6.3k was observed, consistent with
the methine proton of the cr-carbon in 92.
The substitution of bromine at the cr-carbon of 92 also induces
magnetic non-equivalence of the four methylene protons of the azetidinone
ring such that each gives rise to a distinct 1FI n.m.r. signal. The coupling
constants associated with the C3 and C4 methylene protons are in accord with
those reported. for related systems. Barrow and Spotswood& have reported 1H
n.m.r. data for some C3 and C4 substituted Z-azetidinones, wherein the
substituent at C3 or C4 induces magnetic non-equivalence in the protons of the
neighbouring methylene group. For methylene protons at C3 the geminal
coupling constants (lgg,), in the systems studied, ranged from -l'4.3 to L5.0 ÉIz in
magnitude and for methylene protons at C4 the geminal coupling constants
(l++,) ranged from 5.5 to 5.6 Hz in magnitude. Ttre trans vicinal coupling
constants (lg+tron) ranged from 2.2 to 2.8 ÍIz, whilst the cis vicinal coupling
constants (lgk¡), of greater magnitude, were in the range of 4.9 to 5.9 Hz.
,. It is on the basis of the data reported by Barrow and SpotswoodS4 that
assignments for the coupling constants associated with the lactam methylene
protons of the bromide 92 were made (Figure 4).
RËSULTS AND DISCUSSION - I
34
FI'FI'H
Vicinal:
t
H
CO2Et
3 4
N
co2Er
92
Geminal: 133'=15.6Í12 144'=6$Í12
o
Fígure 4. 1H r,.^.r. coupling constants observed for C3 and C4 methylene protons
of cr-bromo -2-oxo -L -azetidineacetate (92).
The bromide 92 was not sufficiently stable for complete characterization,
and so was converted to the corresponding ethyl ether 92 through the addition
of two mole equivalents each of ethanol and 2,6-lutidine directly to the
crude reaction mixture after cooling to room temperature. After purification
by chromatography on silica, the ether 93 was isolated in 57Vo yield,
based on 72, and was fully characterized, exhibiting consistent spectral
]satit = 6.2EIzI3'4'rit = 5'9 Í12
N
I3'4t ors = 3.9 Hz]34't ont = 3.5}j2
93
properties and elemental analyses. In the 1H n.m.r. spectrum of the ether 93,
a characteristic singlet resonance at õ 5.35 was observed for the methine proton
of the cr-carbon. The presence of the ethoxy substituent in 93 was confirmed by
a characteristic triplet resonance al õ 7.27 (l = 7.0 FIz) arising from the methyl
protons, and two doublet of quartet resonances, at õ 3.59 (l = 9.5,7.0 Hz) and
RESULTS AND DISCUSSION - I
35
3.68 (l =9.5, 7.0Il2), corresponding to the two non-equivalent methylene
protons. Due to the presence of the ethoxy substituent at the cr-carbon in 93,
magnetic non-equivalence of the lactam methylene protons was observed, as
with the bromide 92. For the C3 methylene protons the geminal coupling
constant was 1.3.4 Hz, with a 5.4}12 geminal coupling constant observed for the
methylene protons of C4. The trans vicinal coupling constants observed were
of 3.3 and 3.9 Hz, while the cis vicinal coupling constants were both 4.9 fIz.
The mechanism proposed for the production of the ether 93 is as shown
in Scheme 23. The bromide 92 may be considered to be in equilibrium
with the N-acyliminium species 94. Ethanol readily adds to the electrophilic
cr-carbon of 94 giving 95 initially, with subsequent deprotonation to afford
the ether 93.
tr-oBr tr-o
tr-o
CO2Et
Br
ì
CO2Et92 93
-H*
,nH
IEtOH
Y?'t
-BaCO2Et co2Et
94 95
Scheme 23
Formation of the bromide 9 2 in the above reaction of
N-bromosuccinimide with 72, indicates reaction aiø initial hydrogen atom
RESUTTS ,AND DISCUSS/ON - I
36
abstraction from the exocyclic methylene adjacent to the amide nitrogen to
form the cr-centred intermediate radical 96, stabilized by the combined
resonance effects of the electron-donating amido and electron-withdrawing
ethoxycarbonyl substituents. This result in turn indicates that with the
ethoxycarbonyl substituent at the exocyclic methylene adjacent to nitrogen,
radical formation at the cr-carbon of 72 is facilitated.
o
oEt
The reaction of 2-oxo-L-azetidineacetonitrile (73) with N-bromo-
succinimide was studied in order to investigate the possible activating effect of
the cyano substituent in concert with the amido substituent toward free radical
bromination at the exocyclic carbon adjacent to the amide nitrogen. A cyano
substituent stabilizes, through resonance, a radical formed at the adjacent
carbon, but formation of such a radical by hydrogen atom transfer to bromine
may be disfavoured by the operation of a polar effect in the transition
s¡v¡s.49,63,74 Flowever, following the rationale for the proactive effect of an
alkoxycarbonyl substituent in cooperation with an amido substituent toward
hydrogen atom abstraction,T2 as discussed in the Introduction of this thesis, it
was envisaged that the cyano substituent would exhibit a similar activating
effect toward free radical bromination at the cr-carbon of 73 to that of the
ethoxycarbonyl substituent of 72. In addition, the choice of 73 was appealing
from a synthetic standpoint as the cyano substituent was considered a masked
carboxylate functionality, since nitriles may be readily hydrolysed by a variety
of reagents to give carboxylic acids.8S
,n96
RESULTS AND D/SCUSSION - I
J/
As with the azetidinone 72, bromination of the nitrile analogue 73
required use of a mixture of carbon tetrachloride and dichloromethane as
solvent in order to maintain substrate solubility and reactivity. Thus, 2-oxo-'1.-
azetidineacetonitrile (73) was treated with one mole equivalent of N-bromo-
succinimide in a 2;'l., mixture of carbon tetrachloride and dichloromethane at
reflux under nitrogen, whilst irradiating with a 300 W mercury lamp for 30
minutes. cr-Bromo-2-oxo-1-azetidineacetonitrile (97) was obtained as the only
product of reaction (Scheme 24), as determined by lH n.m.r spectroscopic
analysis of the crude reaction mixture after solvent evaporation. The
methylene protons of the q-carbon in 73 give rise to a singlet resonance at
õ 4.23. With the crude product mixture obtained from the bromination of 73,t?
a singlet resonance at ô 6.Sþ was observed, indicative of the methine proton of
the a-carbon in 97.
NBS
hv
97
Scheme 24
As with 92, the substitution of bromine at the o-carbon of 97 induces
magnetic non-equivalence of the lactam methylene protons and the associated
coupling constants are in accord with those observed for the bromide 92. For
the C3 methylene protons of 97 the geminal coupling constant is 15.7 Hz, with
a 6.'l,Hz geminal coupling constant observed for the methylene protons at C4.
The trøns vicinal coupling constants observed are 4.0 and 4.1. FIz, while the cis
vicinal coupling constants are 5.9 and 6.0 FIz.
-l Br
CNCN
rnY73
RESULTS AND D/SCUSSION - I
38
The bromide 97 was not sufficiently stable for complete characterization,
and so was converted to the corresponding ethyl ether 98 in the same manner
as for the bromide 92 above. Addition of two mole equivalents each of
ethanol and 2,6-Iutidine directly to the crude reaction mixture of 73 with
N-bromosuccinimide after cooling to room temperature, afforded 9I
Tn 41,Vo yield, based on 73. The ether 98 was fully characterized, exhibiting
tnyo,t
CN
98
consistent spectroscopic properties and elemental analyses. In the 1H n.m.r.
spectrum of the ether 98, the methine proton of the o-carbon gave rise to
a characteristic singlet resonance at ô 5.68. The presence of the ethoxy
substituent in 98 was confirmed by the observation of a characteristic triplet
resonance at õ 7.27 (] = 7.0 FIz) corresponding to the methyl protons, and two
doublet of quartet resonances, at ô 3.63 (l = 9.3, 7 .0 flz) and 3.67 (l = 9.3, 7 .0 F{z)
arising from the two non-equivalent methylene protons. As for the ether 93,
the four lactam methylene protons of 98 show non-equivalence due to the
presence of the ethoxy substituent at the cr-carbon. The mech4nism for the
formation of 98 from 97 is proposed as analogous to that depicted in
Scheme 23, above.
The formation of the bromide 97 in the above reaction of
N-bromosuccinimide with 73 is consistent with reaction aia initial hydrogen
atom abstraction to give the cr-centred intermediate radical 99. Consequently,
this indicates that the cyano substituent facilitates free radical formation at the
exocyclic carbon adjacent to the amide nitrogen of 73.
RËSULTS AND DISCUSSION - I
39
The N-benzylazetidinone 74 was chosen for investigation to compare
the activating effect of the phenyl substituent toward free radical bromination
at the cr-carbon to that of the ethoxycarbonyl substituent of 72. A phenyl
substituent may stabilize a radical at the adjacent carbon through resonance
and formation of such a radical by hydrogen atom transfer to bromine is not
influenced by the operation of a polar effect as, unlike the ethoxycarbonyl or
cyano substituents of 72 and 73 respectively, a phenyl substituent does not
possess an electron deficient centre adjacent to the site of hydrogen abstraction.
On this basis, it was envisaged that the phenyl substituent would facilitate free
radical bromination at the cr-carbon of 74 to a greater extent than the
ethoxycarbonyl substituent of 72.
When L-benzyl-2-oxoazetidine (74) was treated with one mole
equivalent of N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride
and dichloromethane at reflux under nitrogen, whilst irradiating with a 300 W
mercury lamp for 15 minutes, a complex mixture of products, containing a
minor amount of unreacted starting material 74, was obtained. 1H n.m.r.
spectroscopic analysis of the crude reaction mixture gave no evidence for the
presence of the bromide L00, but the observation of a singlet resonance at
õ 10.03 in particular, was indicative of the production of benzaldehyde (101).
The presence of benzaldehyde (101) in the reaction mixture was confirmed by
comparative thin layer chromatography against an authentic sample of the
aldehyde 10L.
,n N2C
99
RESULTS AND DISCUSSION - I
40
The production of benzaldehyde (fOf) in the reaction of 74 with
N-bromosuccinimide can be rationalized as resulting from a subsequent
reaction of any initially formed bromide 100 with adventitious water (Scheme
25). The N-acyliminium species 102, in equlilibrium with the bromide 100, is
readily attacked at the electrophilic a-carbon by nucleophiles, leading to the
subsequent formation of benzaldehyde (101) aia tli.e alcohol 103 in the case
where water is the nucleophile. Thus, the bromide 100 is unstable to the
extent that only products of its decomposition are obtained from the reaction
of the lactam 74wlth N-bromosuccinimide.
NBSBr
PhPh
hv ÃoPhCHO +
101
otherproducts
ì
74 L00
,n H- HBr
Ph1.02
Scheme 25
That the bromide 100 derived from 74 is markedly unstable in
comparison to the bromides 92 and 97 derived from the respective
azetidinones 72 and 73 may be rationalized in terms of the relative stabilities
of the corresponding N-acyliminium species 102,94 and 104 in equilibrium
with these bromides. The phenyl substituent of 102 may act to delocalize
ìPh
103
RESULTS AND D/SCUSSION - /
the positive charge over the phenyl ring through resonance, whereas such
delocalization by the ethoxycarbonyl substituent of 94 or the cyano
substituent of 104 involves less favourable interaction between adjacent
electron deficient centres and is therefore less efficient (Fígure 5). Thus the
iminium species 102, being more stable than either 94 or L04, forms more
readily through dissociation of its bromide precursor 100. In turn, this
results in a greater degree of instability of the bromide 100 with respect to the
bromides 92 and97.
47
++
!02
NN
94
<->Ã,
o'<+N
+
o o
+++ Et
+ v'cd !c 7N
104
Figure 5. Resonance contributors forLO2,94 and 104.
In order to ascertain the relative reactivity of the N-benzylazetidinone
74 and the azetidinone 72 a competitive bromination between the two
substrates was conducted. Thus a 1:1:1 mixture of 72,74 and N-bromo-
succinimide in a 5:1 mixture of carbon tetrachloride and dichloromethane was
heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp
"Æ
+
RESULTS .AND D/SCUSSION - I
42
for 15 minutes. 1H n.m.r. spectroscopic analysis of the crude reaction mixture
revealed a complex mixture of products containing benzaldehyde (101), a
minor amount of unreacted 74 and a major amount of unreacted 72. In
particular, the absence of the bromide 92 ín this product mixture was noted.
This result indicated that 74)i.ad reacted preferentially to 72 and consequently,
that the reactivity of 74 toward free radical bromination is greater than
that of 72.
The relative reactivity of 72 and 74 toward free radical bromination
reflects the relative rate of formation of the corresponding q,-centred radicals
96 and 105. It then follows that the phenyl substituent of 74 is more
activating towards hydrogen atom abstraction at the c-carbon than is the
ethoxycarbonyl substituent of 72. This is consistent with expectations based on
the absence of a polar effect in the fransition state of hydrogen atom abstraction
from the benzylic cr-carbon of 74.
,n1.05
The N-allylazetidinone 75 was chosen for investigation as the N-allyl
substituent was considered as a further example of an activating substituent for
hydrogen atom abstraction at the o-carbon. A radical formed at an allylic
carbon is resonance stabilized by the adjacent olefinic moiety and its formation
by hydrogen atom abstraction is not influenced by the operation of polar
effects, as the olefinic moiety does not possess an electron deficient centre
adjacent to the site of abstraction. Accordingly, it was envisaged that free
radical bromination could be affected readily at the cr-carbon of 104.
RESUTTS ,AND D/SCUSSION - I
43
In order to ensure solubility of the substrate, the bromination of 1-allyl-
Z-oxoazetidine (75) was initially investigated by treatment of the lactam 75
with one mole equivalent of N-bromosuccinimide in a L:1. mixture of carbon
tetrachloride and dichloromethane as solvent. The mixture was heated at
reflux under nitrogen whilst irradiating with a 300 W mercury lamp, for 15
minutes and 1H n.m.r. spectroscopic analysis of the crude reaction mixture
revealed a major amount of unreacted starting material 75. The azetidinone
75 was subsequently found to be soluble in neat carbon tetrachloride, and so in
order to increase the rate of reaction the reaction temperature was increased by
investigating the bromination of 75 in this solvent. When the azetidinone 75
was treated with one mole equivalent of N-bromosuccinimide as above, but
using carbon tetrachloride as the solvent, 1H n.m.r. spectroscopic analysis of
the crude reaction mixture indicated that a complex mixture of products
containing some of the unreacted starting material 75 was obtained.
In an attempt to derivatize and isolate any possible bromination
products of 75, a crude bromination mixture in carbon tetrachloride was
treated with ethanol and 2,6-lutidne as described above for the preparation of
the ethers 93 and 98. Upon chromatography of the crude reaction mixture thus
obtained however, no discrete identifiable products could be isolated. It is
presumable that the complex mixtures of products obtained in the reaction of
75 with N-bromosuccinimide result from the ready decomposition of any
intially formed bromide 106. As was postulated for the bromide 100, 106 may
readily dissociate to give the conjugated acyliminium species L07 which being
susceptible to attack by nucleophiles at the electrophilic cr-carbon reacts to give
various decomposition products (Scft¿me 26).
RESULTS ,AND DISCUSS/ON - 1
N
M
decompositionproducts
+ \^
106
Br-
107
Scheme 26
In order to ascertain the relative reactivity of the N-allylazetidinone 75
and the azetidinone 72 a competitive bromination between the two was
investigated. Thus, a 1.:1.:1. mixture of 72,75 and N-bromosuccinimide in a 5:1
mixture of carbon tetrachloride and dichloromethane was heated at reflux
under nitrogen whilst irradiating with a 300 W mercury lamp for 15 minutes.
lH n.m.r. spectroscopic analysis of the crude reaction mixture revealed a
complex mixture of products containing a minor amount of unreacted 75 and
a major amount of unreacted 72. In addition, the absence of the bromide 92 in
this product mixture was evident. This result indicated that 75 had reacted
preferentially to 101 and consequently that the reactivity of 75 toward free
radical bromination is greater than that of 72.
To the extent that it may be assumed that 75 reacts in free radical
bromination reactions oia hydrogen abstraction from the cr-carbon, the relative
reactivity of 72 and 75 then reflects the relative rate of formation of the
corresponding cr-centred radicals 96 and L08. This result in turn indicates that
the olefinic moiety at the c-carbon of 75 is more activating towards hydrogen
atom abstraction at the cr-carbon than is the ethoxycarbonyl substituent of 72,
consistent with the absence of polar effects in the transition state of hydrogen
atom abstraction from the allylic s-carbon of 75.
RESULTS AND DISCUSSION - I
,n a
45
CO,CHPh-l
,n\/^
hv
a
108
The reaction of benzyl 2-oxo-'1.-azetidineacetate (76) with N-bromo-
succinimide was studied in order to investigate the applicability of the
bromination procedure to functionalization of the cr -carbon in
oxoazetidineacetate systems bearing removable protecting groups for the
carboxyl group. Benzyl esters are readily cleaved by a variety of methods86
including hydrogenolysis8T,SS and mild alkaline hydrolysis,S9 and as
such have found wide application as protecting groups in p-lactam
chemistrY .88,89,90
The azetidinone 76 was treated with one mole equivalent of N-bromo-
succinimide in a 2:'l., mixture of carbon tetrachloride and dichloromethane
at reflux under nitrogen for 15 minutes, with reaction initiated by irradiation
with a 300 W mercury lamp. 1H n.m.r. spectroscopic analysis of the crude
reaction mixture after filtration and evaporation of the solvent gave evidence
for the production of two bromides, L09 and 110, in an approximately
3:1 ratio (Scheme 27). The methylene protons of the cr-carbon in 7 6
resonate as a singlet at ô 4.07, with the benzylic methylene protons
Ão
NBS tr-o+ ,nBr
ì IBrL09
co2cH2Ph 2Ph
11076
Scheme 27
RËSULTS AND D/SCUSS/ON - I
46
giving rise to a singlet resonance at õ 5.L2. In the crude product mixture
obtained from the bromination oÍ 76, a singlet resonance at ô 6.36 was
observed, indicative of the methine proton of the cr-carbon in 109. In
addition, a resonance observed at ô 5.18 with twice the peak area was consistent
with the downfield shift expected for the benzylic methylene protons of 109.
Evidence for the formation of the bromobenzyl ester 110 was given by a singlet
resonance at õ 7.49, corresponding to the methine proton of the benzylic carbon
and a singlet resonance of twice the peak area at ô 4.11, corresponding to the
methylene protons of the cx,-carbon.
Production of the bromide 109 in the above reaction is consistent with
reaction oia initial hydrogen atom abstraction from the exocylic methylene
adjacent to nitrogen to form the cr-centred intermediate radical 11-1-, stabiltzed
by the combined resonance effects of the electron-donating amido and
electron-withdrawing benzyloxycarbonyl substituents. Formation of the
bromobenzyl ester 110 would result from reaction aia initial hydrogen atom
abstraction from the benzylic carbon of 76, affording the intermediate benzylic
o
Ph Pho
oa
Na
11L L72
radical L12. The observed ratio of formation of the bromides 109 and 110
from the lactam 7 6 then reflects the relative rate of formation of the
corresponding intermediate radicals 111, and 112. Thus, since formation of the
benzylic radical L12 competes with that of the ct-centred radical L1-1 in the free
radical bromination of the azetidinone 76, ít is concluded that this procedure
RESULTS AND DTSCUSSION - I
47
may be unsuitable for regioselective functionalization of benzyl 2-oxo-
azetidineacetates.
Whilst the azetidinones 74-76 each gave mixtures of products, the free
radical bromination of the azetidinones 72 and 73 described in this chapter
demonstrates methodology for direct regioselective exocyclic functionalization
of these systems. In particular, the procedure provides an attractive alternative
method for the synthesis of N-(a-haloalkyl)-substituted azetidinones, to that
described in the Introduction of this ¡þssis.13,19 The simplicity of the
procedure and the relatively high conversion to product in the case of the
azetidinones 72 and 73 indicate the potential for use of this method in
synthesis. As such, an investigation of the synthetic utility of this
methodology is presented in the next chapter of this thesis
RESULTS ,4ND D/SCUSSION - I
48
REsuLrs AND DrscussloN - II
Elaboration of Functionalized N-Substituted
B-Lactams
In Chapter I of this thesis a procedure for selective bromination at the
exocyclic carbon adjacent to nitrogen in oxoazetidineacetate systems was
established. The study described in this chapter was aimed at an investigation
of the applicability of this procedure as a key step in the synthesis of bicyclic
and monocyclic p-lactam antibiotics. To this end, methods for the elaboration
of the bromide 92, obtained from the azetidinone 72, were investigated.
Bachi and co-workers23 have reported the conversion of N-(cr-chloro-
alkyl)-substituted azetidinones, analogous to the bromide 92, to the
corresponding phenylthioethers by treatment with thiophenol and sodium
hydroxide in benzene in the presence of a phase transfer catalyst. They
demonstrated use of these thioethers as free radical precursors in radical
cyclization reactions having the advantage of greater stability than the
corresponding chlorides. Conversion of the bromide 92 to the corresponding
thioether 113 was investigated aiø an analogous procedure to that of the
preparation of the ether 93 described in Chapter I.
The bromide 92, prepared from 72 by treatment with N-bromo-
succinimide in a 5:1 mixture of carbon tetrachloride and dichloromethane as
described in Chapter I, was treated in situ with two mole equivalents each of
thiophenol and 2,6-lutidine, Chromatography of the crude product mixture
thus obtained afforded the phenylthioether L13 in 64Vo yield, based on 72. The
RESULTS AND DISCUSSION - II
49
phenylthioether LL3 was fully characterized, exhibiting consistent spectral
properties and elemental analyses. In the 1H n.m.r. spectrum of the thioether
113 a singlet resonance observed at ô 5.82 was characteristic of the methine
proton of the o-carbon. The presence of the phenylthio substituent in 113 was
confirmed by the observation of multiplet resonances centred at ô 7.33 and 7.49
of three and two protons integration respectively. As noted for the ethers 93
and 98 and their corresponding bromides 92 and97, the four lactam methylene
protons of 113 each gave rise to distinct 1H n.m.r. resonances due to non-
equivalence, in this case arising from the presence of the phenylthio
substituent at the cr-carbon.
N SPh
CO2Et
113
The mechanism for the formation of L13 from the bromide 92 is
proposed as analogous to that of the ether 93 depicted in Scheme 23 above,
whereby the electrophilic cr-carbon of the iminium species 96 would in this
case be attacked by thiophenoxide anion. That the phenylthioether 113 was
obtained in greater yield from the azetidinone 72 than was the ether 93, may
reflect a greater reactivity of the iminium species 96 with thiophenoxide
anion than with ethanol. It should be noted that the yield of the
phenylthioether 113 obtained from the azetidinone 72, oia the bromide 92,
compares favourably with the yietds reported by Bachi and co-workers23
for the production of the analogous phenylthioethers from their
corresponding N-(cr-chloroalkyl)-substituted azetidinones. As such, synthesis
of the phenylthioether 113 provides good illustration of the free radical
RESULTS ,AND DISCUSSION - I1
50
bromination procedure as an attractive alternative to the use of N-(a-chloro-
alkyl)-substituted azetidinones.
N-(a-Chloroalkyl)-substituted azetidinones have enjoyed widespread
use in the synthesis of B-lactam antibiotics.2O Their use has chiefly centred
upon their role as the precursors to phosphoranes used in a Wittig reaction to
complete the molecular backbonel3-19, as described in the Introduction of this
thesis. The application of the analogous bromides, obtained aía tÞ.e
methodology established in Chapter I, to this synthetic procedure was studied.
Thus, conversion of the bromide 92 to the corresponding phosphorane L14 was
investigated using methodology previously reported9l for preparation of
phosphoranes from the analogous chlorides.
Accordingly, a sample of the crude bromide 92 was dissolved in dry
L,4-dioxane and treated with two mole equivalents each of triphenylphosphine
and 2,6-lutidine, at room temperature under nitrogen. Flowever, upon
chromatography of the crude product mixture, none of the desired
phosphorane L1.4 was obtained. The maleate derivative 115 was isolated as the
only identifiable product of reaction in 30% yield, based on the amount of the
azetidinone 72 used in preparation of the bromide 92.
N CO2Et
CO2Et
174 11s
The 1H n.m.r. spectrum of the maleate derivative 115 exhibited a singlet
resonance at ô 6.31 attributable to the single vinylic proton, whereas triplet
resonances at ô 3.10 (/ = 4.9 FIz) and 3.92 (l = 4.9 Hz) were indicative of the C3
RESULTS AND DISCUSSION - II
51
and C4 methylene protons, respectively. The presence of two ethoxy
substituents in the molecule was indicated by a triplet resonance at ô 1.31 (/ =
7.1,IJ2) and a quartet resonance at E 4.23 (l = 7.1, Hz) being attributable to one
ethoxy substituent, with the other giving rise to a triplet and a quartet
resonance at ô 1.34 and 4.30 respectively, each with ,Ivic = 7.7FJ2. The
assignments for the two ethoxy substituents of 115 were enabled by
homonuclear decoupling of resonances in the lH n.m.r. spectrum. The
presence of the alkenyl moiety in 115 was indicated by an infrared absorption at
1.628 cm-1 with resonances at õ 133.19 and 115.50 in the 13C n¡pT n.m.r.
spectrum being characteristic of the quaternary and tertiary alkenyl carbons
respectively. The Electron Impact (EI) mass spectrum of 115 exhibited a
molecular ion at mlz 247 and in addition elemental analyses were consistent
with the structure.
Formation of the maleate derivative 115 in the above reaction of the
bromide 92 may be rationalized as due to reaction of the phosphorane 1-L4,
upon its formation, with the bromide 92 as outlined in Scheme 28. Thus,
reaction of the bromide 92 with triphenylphosphine initially gives the
phosphonium salt 116 which, upon deprotonation from the cr-carbon, affords
the phosphorane L14, stabilized by resonance delocalization of the charge on
carbon over the ester carbonyl moiety. Attack by the phosphorane 114 at the
electrophilic ø-carbon of the N-acyliminium species 94, in equilibrium with
the bromide 92, yields the intermediate LL7, which then eliminates L18 to give
the maleate derivative 115. The by-product 1,18 was not observed in the crude
product mixture as it is presumably unstable, hydrolysing upon workup to
give triphenylphosphine oxide.
RESUTTS AND D/SCUSSION - I1
52
BrPPh3
CO2Et
CO2Et
+N PPh3
co2Et
CO2Et
92 1L6
+
^Ro
94 174
co2Et
+Br CO2EtN
)+
EtO2C co2Et
177r*-PPh3
118
Scheme 28
In support of the above rationale for the production of the maleate
derivative 115, Sharma and Stoodley92 have reported reaction of the
phosphorane 120 with the N-(a-chloroalkyl)-substituted azetidinone 119 to
tr-o
115
Br
RESULTS ,4ND DISCUSSION - II
53
give the substituted phosphorane 12'1, (Scheme 29). The reaction of
phosphoranes with imines at elevated temperatures has also been reported.93
+ Ph3P:CHCO2EI
120
Scheme 29
Whereas reaction of the phosphorane 1,T4 with the bromide 9 2
competes with its formation from the bromide 92, the similar reaction is not
observed in the preparation of phosphoranes from N-(cr-chloroalkyl)-
substituted azetidinones.13-19 This is consistent with expectations of a greater
electrophilicity of the cr-carbon of the bromide 92 over that of corresponding
chlorides. Although the phosphorane 114 was not isolated, the reaction of the
bromide 92 with triphenylphosphine to give the maleate derivative 115
nevertheless illustrates that the phosphorane LL4 can be formed from the
bromide 92. Furthermore, formation of the maleate derivative 115 in this
reaction illustrates use of the bromide 92 in a Wittig reaction, achieving
carbon-carbon bond formation at the ü-carbon. Other methods for elaboration
of the bromide 92 aia carbon-carbon bond formation at the g-carbon were
subsequently investigated.
Keck and co-workers94 have reported the use of allyltributyltin for the
synthesis of carbon-carbon bonds aia addition reactions with alkyl radicals
derived from alkyl halides. Subsequently allylstannanes have been shown to
be amenable to the elaboration of s-bromoglycine derivatives,70,95,96 which
bear functional similarity to the bromide 92. The proposed mechanism of
lttco2R
t
co2R
727lT9
RESULTS AND D/SCUSSION - II
54
reaction of allytributyltingT is as depicted in Scheme 30. Bromine atom
abstraction from the substrate 122 by tributyltin radical forms the substrate
RBr
122
+ BurSn' R' + BurSnBr
123
R1,r\ + Bu3sn'
123
Scheme 30
radical L23. Homolytic allyl group transfer from allytributyltin to the
substrate radical 123 affords the allylated product L24 and tributyltin radical,
which propagates the chain. Allylation of the bromide 92 with allyltributyltin
was investigated as a method for functionalization uia free radical carbon-
carbon bond formation, at the cr-carbon of oxoazetidineacetates. The
incorporation of an allyl substituent at the cr-carbon of 72 was considered an
attractive proposition from a synthetic standpoint as an allyl substituent has
the potential for further elaboration. As an example, Kametani and Honda9S
have previously reported intramolecular cyclization of an allyl substituent at
the cr-carbon of an oxoazetidineacetate system onto C4 of the lactam as
methodology for the synthesis of bicyclic B-lactams.
?xThe bromide % was initially treated with two mole equivalents of
allyltributyltin in the presence of a catalytic amount of AIBN as radical
initiator, in dry benzene heated at reflux under nitrogen, for five hours.
However, upon chromatography of the crude product mixture, no product
identifiable as the desired allylated compound 125 was isolated. Indeed, no
discrete identifiable products could be isolated from the crude product mixturel^
and this was attributed to decomposition of the bromide :t3å under the
"'^\73ftnBu3L24
RESULTS AND DISCUSS/ON - 1I
55
reaction conditions employed. Thus, milder reaction conditions were applied
to the allylation of the bromide 72.
Ethyl c-bromo-2-oxo-L-azetidineacetate (72) was treated with two and
a half mole equivalents of allyltributyltin in the presence of a catalytic amount
of AIBN in dry benzene at room temperature, under nitrogen overnight.
Chromatography of the crude product mixture thus obtained afforded ethyl cr-
allyl-2-oxo-1-azetidineacetate (125) (Scheme 31) in 25Vo yíeld, based on the
amount of 7|used in the preparation of the brom ¡a" b. On a subsequent
occasion a minor amount of the alcohol 126 was also obtained.
,n 4/SnBu3AIBN
t co2Et co2Er
92 125 126
Scheme 31
The 1H n.m.r. spectrum of 725 exhibited a doublet of doublets resonance
at õ 4.49 (] = 5.2,9.7 }jlz) attributable to the methine proton of the cr-carbon and
distinct resonances were observed, attributable to each of the four non-
equivalent methylene protons of the lactam ring. The presence of the allyl
substituent in 125 was indicated by resonances characteristic of the olefinic
protons observed at õ 5.17 (2H) and 5.76 (7H). The allylic methylene protons
of L25 were non-equivalent, giving rise to multiplet resonances centred at
õ 2.50 and 2.66. Further evidence of the allyl substituent ol 725 was given by
an infrared absorption at 1640 cm-1. A molecular ion was observed at mlz 197
in the EI mass spectrum and other spectroscopic properties were in accord with
the structure of L25.
tr-oBrI
co2E
+ ,n
RESULTS ,AND DISCUSSION - 11
56
The alcohol 126 was identified on the basis of 1H n.m.r. spectroscopic
evidence whereby a singlet resonance observed at ô 5.49 was attributable to the
methine proton of the o-carbon with a broad resonance at õ 4.86 being
consistent with the hydroxyl proton. A broad infrared absorption at 3350 cm-1
was further evidence of the hydroxyl group ín'126. Production of the alcohol
126 presumably results from reaction of the bromide 92 aia the iminium
species 94, with adventitious water.
Whilst production of the altyl derivative 126 in the above reaction of
the bromide 92 with allyltributyltin illustrates methodology for free radical
carbon-carbon bond formation at the cr-carbon of 92, the relatively low yield of
product L25 obtained in this reaction prompted an investigation of alternative
methodology for allylation of the bromide 92. Castelhano and co-workers99
have reported ionic allylation of an cr-methoxyglycine derivative in high yield
by treatment with allyltrimethylsilane under Lewis acid conditions. The use of
this methodology to effect allylation of the bromide 92 was investigated as an
alternative to free radical allylation.
The crude bromide 92 was treated in situ at 0 - 5'C with four mole
equivalents each of allytrimethylsilane and boron trifluoride etherate and the
reaction mixture was allowed to warm to room temperature overnight. Upon
workup, chromatography of the crude product mixture afforded the allyl
derivative '1.25 in 347o yield based on 72. The product 125 obtained in this
reaction bore identical spectroscopic properties to that previously obtained pia
the free radical allylation of the bromide 92. It was considered that the greater
yield of the allyt derivative 125 aia this procedure over that obtained oiø free
radical allylation was in part due to the greater ease of chromatographic
separation of the product from the crude reaction mixture.
RESULTS AND DISCUSS/ON - II
57
The reactions of the bromide 92 described above exemplify methods for
its elaboration and serve to illustrate the synthetic utility of the selective
bromination procedure described in Chapter I of this thesis. Whilst this
methodology may then be considered applicable to the synthesis of bicyclic
p-lactams, the selective bromination at the cr-carbon of 72 to give the bromide
92 was further considered as a basis for an approach to the synthesis of
analogues of the norcardicins (8), monocyclic p-lactam antibiotics. Thus a
method for the substitution of bromine in 92 with a suitable aryl group would
provide a route to the synthesis of norcardicin analogues. Williams and
Hendrixl00 have reported arylation of an cr-bromoglycine derivative with
electron rich aromatic compounds such as furan under Friedel-Crafts
conditions, and it was considered that this methodology might be amenable to
arylation of the bromide 92. Accordingly, arylation of the bromide 92 with
furan in the presence of a Lewis acid was investigated.
The bromide 92 was treated with a twenty-fold excess of furan, in the
presence of two mole equivalents of zinc chloride in dry tetrahydrofuran, and
afforded ethyl cr-(2-furyt)-2-oxo-1-azetidineacetate (L27) (Scheme 32) in 62Vo
yield, based on the amount of 72 used in preparation of the bromide 92.
o(}N
ZnCl2
co2Et CO2Et
92 127
Scheme 32
The furyl derivative L27 was characterized by 1H n.m.r. spectroscopic
evidence. A singlet resonance observed at ô 5.62 was attributable to the
methine proton of the cx,-carbon and the presence of the 2-substituted furyl
Br ,n
RESULTS AND DISCUSSION - 1I
58
group was confirmed by resonances observed at ô 6.31 (d,l = 3.2LIz), 6.34 (dd,
I = 3.2, 7.9 }lz) and 7.37 (d, I = 7.9IIz), that were characteristic of the aromatic
protons of C3', C4' and C5', respectively. In addition, the four lactam
metþlene protons of 127 showed non-equivalence due to the presence of the
furyl substituent at the G-carbon, each giving rise to distinct resonances. A
molecular ion was observed at mlz 223 in the EI mass spectrum and other
spectroscopic properties were in accord with the structure of !27.
Production of the furyl derivative 127 from the bromide 92 illustrates
the viability of the procedure for direct exocyclic bromination of
oxoazetidineacetates as a route to the synthesis of norcardicin analogues. In
extending this approach, ultimately to the synthesis of analogues of
3-aminonorcardicinic acid (728), the structural element common to all
members of the norcardicin family (8),ror an investigation of the free radical
bromination of a protected 3-aminosubstituted oxoazetidineacetate was
warranted. A phthalimide group provides a convenient protecting
group for an amino substituent, being readily removable by
aminolysislO2 6¡ borohydride reduction,103 under mild conditions. Thus the
3-phthaloylazetidinone 1.29 was subsequently chosen for investigation, the
H NH o
H CO2Me
L29128
co2H
RESUTTS AND DTSCUSSION - II
59
synthesis of which has previously been reported by Miller and Mattingly.loa
Accordingly, synthesis of 129 aia cyclization of N-phthaloylserylglycine methyl
ester (136) was investigated as described below.
N-Phthaloylserylglycine methyl ester (136) was synthesized from
N-phthaloylserine (133), prepared according to the method of Nefkens and co-
workers,105 ¿s outlined in Scheme J3. Thus, phthalimide (L30) was treated
with excess ethyl chloroformate in the presence of triethylamine in
dimethylformamide and afforded N-carboethoxyphthalimide (131) in 92%
yield after recrystallization. Treatment of an aqueous solution of serine (132)
with a slight excess of N-carboethoxyphthalimide (131) under basic conditions
then afforded N-phthaloylserine (133) in 86% yield after recrystallization from
ethyl acetate / Iight petroleum, bearing consistent physical and spectroscopic
properties.
The dipeptide 136 was synthesized oia the Schotten-Baumann
procedure, in preference to the dicyclohexylcarbodiimide (DCC) coupling
procedure employed by Milter and Mattingly,704 as it was found in practice to
provide comparable yields of the product from reaction mixtures affording a
greater ease of chromatographic separation. Thus, N-phthaloylserine (133)
was treated with thionyl chloride to give N-phthaloylseryl chloride (134).
Glycine methyl ester hydrochloride (135), prepared by esterification of glycine
(S2) by treatment with methanol that had been pretreated with thionyl
chloride, was then treated with the crude acid chloride 134 in dichloromethane
in the presence of excess aqueous sodium bicarbonate, and gave the dipeptide
136 in 57Vo yield. The product L36 thus obtained exhibited spectroscopic
properties in accord with those previously reported.lO4
RESULTS ,AND DISCUSS/ON - 1I
60
NHCICO2Et
Er3N
socl2
HCI.NH2CHTCOTMe
135
MeOH / ÐCl2 I 'NH3CH2CO2
82
N
o
+HsNt
130 132131
Na2C03
OH
134 L33
aq. NaHCO3
Phth = N-NH
o136
Scheme 33
Cyclization of the dipeptide 136 was investigated under Mitsunobu
conditionsl06-108 as reported by Miller and Mattingly.l04 Thus, a solution of
L36 in tetrahydrofuran was treated with one mole equivalent of
diethylazidodicarboxylate (DEAD) and a slight excess of triphenylphosphine
o
RESUTTS ,4ND DISCUSS/ON - 1I
67
(Scheme 34). Chromatography of the crude product mixture afforded the
dehydrop"plilÊry_ ll 13,t", li.'t$ rhe 3-phthaloylazetidinone 12e w as isolated
in only 3Vo yield after further chromatography of the crude product
NH
L36
DEAD / PPh3
Phth
-CO.'Me\./
L
-lo
CO2Me
129137
Scheme 34
mixture and subsequent selective recrystallization to remove dicarboethoxy-
hydrazine, the by-product of reaction of DEAp.108 The 3-phthaloylazetidinone
129 thus obtained bore physical and spectroscopic properties in accord with
those previously reporte 6.213 In the 1H n.m.r. spectrum of 729 a doublet of
doublets resonance at õ 5.56 (/ = 5.5, 2.9 }lz) was attributable to the C3 methine
proton, with doublet of doublets resonances at õ 3.U (l = 5.3, 2.9ffò and 3.91
(/ = 5.5, 5.3 Hz) being consistent with the non-equivalent methylene protons of
C4. The methylene protons of the cr-carbon of 129 were non-equivalent, giving
rise to doublet resonances at ô 4.02 and 4.58 each with /t"* = 18.0 FIz.
Ph
o
+
RESULTS AND DISCUSSÌON - II
62
Owing to the low irreproducible yield of the 3-phthaloylazetidinone
L29 from the above treatment of the dipeptide 136, concomitant with the
inherent difficulty of isolation of this product from the reaction mixture/ an
alternative method for the synthesis of 129 was sought. To this end,
conversion of the seryl dipeptide 136 to the p-chloroalanyl dipeptide 138 was
investigated. Treatment of the dipeptide L36 with 1.2 mole equivalents of
phosphorous pentachloride in the presence of one mole equivalent of calcium
.ut6on¿¡s218 in dry tetrahydrofuran solution afforded N-phthaloyt-p-
chloroalanylglycine methyl ester (138), in 69Vo yield after chromatography and
subsequent recrystallization (Scheme 35). The p-chloroalanyl dipeptide 138
Phth* .. CO2Me
CaCO3NH
o136 L38
Scheme 35
thus obtained was fully characterized, exhibiting satisfactory spectroscopic
properties and elemental analyses. It was distinguished by the observation of
two molecular ions in the EI mass spectrum at mlz 324 and 326 in the ratio of
3:1,, thus confirming the presence of chlorine in the molecuie.
Cyclization of the chloride 138 using the methodology of Takahata and
co-workersS2 as described in Chapter I was subsequently investigated, where in
this case, tetra-n-butylammonium chloride was the catalyst of choice.
Accordingly, the chloride L38 was added slowly in dilute solution to a stirred
suspension of powdered potassium hydroxide and tetra-n-butylammonium
chloride in a 19:1 mixture of dichloromethane and acetonitrile. Flowever,
PCls
o
RESULTS AND DTSCUSS,TON - II
63
PhPh
oo
upon chromatography of the crude product mixture, none of the desired
3-phthaloylazetidinone 129 was obtained. The dehydropeptide 137 was the
only product of reaction, isolated in 57% yield, with 797o of the starting
material 138 being recovered unreacted (scheme 36). Owing to the lack of
azetidinone 129 obtained in this reaction, synthesis oÍ L29 aia cyclization of the
chloride 138 was not investigated further.
KOH / BuaNCl NH Me
138 137
Scheme 36
Although it would appear from the investigations described above that
the 3-phthaloylazetidinone 129 does not provide a viable target for synthesis,
an initial investigation of the free radical bromination of 729 was
nevertheless conducted on the limited amount of this azetidinone 'l'29
obtained aiø qclization of the seryl dipeptide L36.
Bromination of the 3-phthaloylazetidinone L29 was investigated by
treatment with N-bromosuccinimide under the conditions employed
previously in the bromination of the azetidinone 72. Thus, methyl
3-phthaloyl-2-oxo-1-azetidineacetate (129) was treated with one mole
equivalent of N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride
and dichloromethane at reflux under nitrogen, whilst irradiating with a 300 W
mercury lamp for 15 minutes. Methyl cr-bromo-3-phthaloyl-2-oxo-1-
azetidineacetate (139) was obtained as the only product of reaction as a 3:2
mixture of diastereomers (Scheme 37), as determined by 1g n.m.r.
spectroscopic analysis of the crude reaction mixture, after solvent evaporation.
RESULTS AND DISCUSSION - II
64
Phrh
NBS
CO2Me CO2Me
139
Scheme 37
The 1H n.m.r. spectrum of the crude bromide 139 exhibited two singlet
resonances at õ 3.83 and 3.84 in a 3:2 ratio, attributable to the methyl ester
protons of the major and minor diastereomers respectively. Two doublet
resonances in a 3:2 ratio at õ 6.44 and 6.46, each with / : 0.8H2, were
attributable to the methine proton at the cr-carbon of each diastereomer of 139,
wherein the observed multiplicity of these resonances was due to long range
coupling to the corresponding methine proton at C3. Accordingly, doublet of
doubtet of doublets resonances were observed at ô 5.56 (l = 6.0,3.8, 0.8 FIz) and
5.M (] = 6.5,3.5, 0.8 }Jz) for the methine proton at C3 of the major and minor
diastereomers, respectively. In addition, the non-equivalent methylene
protons of C4 each gave rise to distinct resonances attributable to the major and
minor diastereomers of 139.
The above reaction of the azetidinone 729 with N-bromosuccinimide to
give the bromide 139 is consistent with reaction oía inittal hydrogen atom
abstraction from the a-carbon of '1.29 to give the cr-centred intermediate radical
L40. Formation of the bromide 139 in this reaction illustrates the viability
Phrh
CO2Me
Ph
BrNhv-l
729
140
RESULTS AND DISCUSSION - II
65
of the free radical bromination procedure for direct regioselective exocyclic
functionalization of a protected 3-amino substituted oxoazetidineacetate
system. As such, use of this methodology holds promise as a possible route to
analogues of the norcardicins (8) through synthesis of analogues of 3-amino-
norcardicinic acid (128).
RESULTS AND DISCUSSION - II
66
REsuLrs AND DrscussloN - III
Functionalization of N-Substituted y-Lactams
Preparation of the 2-pyrrolidinones L41 and L42
The 2-pyrrolidinones L4L and L42 were required for the investigation
described in this chapter, of the regioselectivity of functionalization of
y-lactams bearing activating substituents at the exocyclic carbon adjacent to
amide nitrogen. They were synthesized in an analogous manner to the
f{=R-NI
R
L4L142
COzMeCN
2-azetidinones 72-76 prepared in Chapter I of this thesis,uia cyclization of
the corresponding 4-chlorobutyramides 143 and 144. This route to the
preparation of the pyrrolidinones 14L and L42 was chosen for its simplicity and
convenience over that of methods involving N-alkylation of 2-pyrrolidinone
reported previously.ll'0' 111 Ths butyramides 143 and L44 were readily obtained
743 R: COzMeL44 R=CN
Ro NH
RËSULTS AND DISCUSSION - //I
67
by Schotten-Baumann coupling of 4-chlorobutyryl chloride (145) with the
corresponding amines 135 and 146. Details of the syntheses of the
pyrrolidinones L41 and L42 are given below.
Methyl 2-oxo-1-pyrrolidineacetate (141) was synthesized from glycine
(82) as shown in Scheme 38. Glycine methyl ester hydrochloride (135),
obtained by esterification of glycine (SZ¡ with methanol that had been
pretreated with thionyl chloride, was treated with 4-chlorobutyryl chloride
(145) in the presence of excess aqueous sodium bicarbonate, affording the
chlorobutyramide L43 in 477o yield. The product 143 thus obtained was fully
characterized, exhibiting spectral properties and elemental analyses consistent
with its structure. In particular, the amide carbonyl of L43 gave rise to a
characteristic infrared absorption at 1656 cm-1 and further evidence for the
production of the amide in L43 was given by the observation of a resonance at
õ 172.71, in the 13C n.m.r spectrum.
HCI.NH2CH2COTMe
L35
MeOH / SOCII
æÇz
C1
/ aq. NaHCO3
745
KOH / BuaNClN
NHCO2Me
L4t
o
o143
Scheme 38
RESULTS AND D/SCUSS/ON - 1II
68
Cyclization of the butyramide 743 was achieved using the methodology
of Takahata and co-workers,82 ¿"r.ribed in Chapter I, with the choice of phase
transfer catalyst in this case being tetra-n-butylammonium chloride.
Accordingly, 143 was added slowly in dilute solution to a stirred suspension of
powdered potassium hydroxide and tetra-r-butylammonium chloride in a 19:1
mixture of dichloromethane and acetonitrile, affording the desired
pyrrolidinone 141 in 55Vo yield after purification by chromatography and
subsequent distillation. Spectral characteristics of the product 141 were
consistent with those previously reported,Tlz with the lactam carbonyl giving
rise to a characteristic infrared absorption at 1685 cm-1, and in addition the
amide carbon giving rise to a resonance at ô 175.32 in the 13C n.m.r. spectrum.
2-Oxo-L-pyrrolidineacetonitrile (L42) was synthesized as outlined in
Scheme 39. 4-Chlorobutyryl chloride (145) was treated with aminoacetonitrile
hydrochloride (146) in the presence of excess aqueous sodium bicarbonate to
give the chlorobutyramide 1,44 ín 54Vo yield. The butyramide 144 was fully
characterized, exhibiting consistent spectroscopic properties and elemental
analyses. In particular, the observation of an infrared absorption at 1645 cm-1
and the further observation of a resonance at õ 172.24 in the 13C n.m.r.
spectrum, both confirmed the presence of the amide in 144. Treatment of the
butyramide L44 with a suspension of powdered potassium hydroxide and tetra-
n-butylammonium chloride in dichloromethane and acetonitrile, as for the
cyclization of 143 above, afforded the pyrrolidinone L42 in 67Vo yield af.ter
purification by chromatography and distillation. The white crystalline
pyrrolidinone 142 thus obtained was unstable, discolouring at room
temperature over a period of days. However, minimal decomposition of the
pyrrolidinone L42 occurred in storage under refrigeration in a sealed vial. The
RESULTS .AND DISCUSSION - III
69
HCI.NH2CH2CN +L46
145
aq. NaHCO3
C1
KOH / BuaNCl
NH
144CT\,I
1l2
Scheme 39
pyrrolidinone L42 was fully characterized, exhibiting satisfactory spectroscopic
properties and elemental analyses. The lactam carbonyl in L42 gave rise to a
characteristic infrared absorption at 1685 cm-1 with a resonance observed in
the 13C n.m.r spectrum at õ 174.41, corresponding to the amide carbon.
ì
RESULTS AND D/SCUSSION - IIl
70
Functionalization of the 2-pyrrolidinones '1.41 and L42
The investigation described in Chapter I of this thesis established that
free radical bromination may be affected regioselectively at the exocyclic carbon
adjacent to nitrogen in p-lactams bearing activating substituents at that
position. The study described in this chapter was based upon an investigation
of the regioselectivity of free radical bromination of analogous y-lactams, with
the aim of directing functionalization to the exocyclic carbon adjacent to
nitrogen. The pyrrolidinones 141 and L42, bearing methoxycarbonyl and cyano
substituents respectively at the exocyclic carbon adjacent to nitrogen, were tltus
chosen for study.
To ensure the solubility of the substrate in the reaction mixture, the
bromination of the pyrrolidinone 141 was initially investigated in a mixture of
carbon tetrachloride and dichloromethane as solvent. Methyl 2-oxo-1-
pyrrolidineacetate (14L) was treated with one mole equivalent of N-bromo-
succinimide in a 1:1 mixture of carbon tetrachloride and dichloromethane at
reflux under nitrogen for 10 minutes, with reaction initiated by irradiation
with a 300 W mercury lamp. 1H n.m.r. spectroscopic analysis of the cooled
crude reaction mixture revealed a mixture of products containing unreacted
starting material 141.
The extent of reaction was increased when the pyrrolidinone 141 was
treated with a slight excess of N-bromosuccinimid.e in neat carbon
tetrachloride, heating at reflux under nitrogen whilst irradiating as above, for
10 minutes. In this instance, 1H n.m.r. spectroscopic analysis of the crude
reaction mixture revealed the absence of starting material 141 and in addition
gave evidence for the production of the bromide L47 and t}:re trans-dibromide
148+ in an approximately 3:1 ratio (Scheme 40). The methylene protons of the
t Otrly one enantiomer of each racemic mixhrre is shown.
RESULTS,4ND DISCUSSION - lII
77
o-carbon of L4'/.. give rise to a singlet resonance at õ 4.08, with a triplet
resonance at ô3.50 (l =7.1H2) arising from the methylene protons of C5. In
the 1H n.m.r. spectrum of the crude product mixture obtained from the
bromination of 14l a singlet resonance at õ 6.76 was observed, consistent with
the methine proton of the cr-carbon of the bromide 1-47. The presence of the
trøns-dibromide 148 in the same reaction mixture was indicated
Br
--+
N Br+
Nì
hv N
CO2Me CO2Me117 747 148
Scheme 40
by an observed singlet resonance at ô 6.34 attributable to the methine proton of
C5, with an observed doublet resonance of equal peak area at ô 4.90 (l = 6.1flz)
being attributable to the methine proton of C4. That the resonance observed
for the C5 methine proton of 148 appeared as a singlet is consistent with a
minimal vicinal coupling constant for the C4 and C5 protons. On the basis of
the Karplus equation,113,114 this is in accord with a dihedrat angle for the C4
and C5 methine protons of approximately 90 degrees, thus indicating that these
protons are in a trans geometry. This in turn is consistent with expectations of
a trans geometry based on the proposed mechanism of formation of the
dibromide 148 from L3L, as described in Scheme 43 below. The observed
doublet resonance attributed to the C4 methine proton of L48 may be
rationalized in terms of a very small vicinal coupling to the trans methylene
proton of C3, such that the observed vicinal coupling constant of 6.\ Hz is due
to coupling to the cis methylene proton of C3 only.
Br
SNB
o
RESUTTS AND D/SCUSSION - III
72
The bromides L47 and 1.48 were insufficiently stable for isolation and so
conversion of these products to stable derivatives for isolation and
characterization was necessary to further ascertain the course of reaction of the
pyrrotidinone 141 with N-bromosuccinimide. Accordingly, methyl 2-oxo-L-
pyrrolidineacetate (141) was treated with N-bromosuccinimide in carbon
tetrachloride as described above and this was followed by treatment of the
cooled crude reaction mixture with two mole equivalents each of ethanol and
2,6-lutidine. Chromatography of the crude product mixture thus obtained
afforded the ether 149 and the 4-bromo-5-ethoxypyrrolidinone 150 in yields
of 37 artd 9% respectively, based on 141 (Scheme 41). On a subsequent occasion
the 4-bromo-5-hydroxypyrrolidinone 151 was also obtained as a minor
product.
N
CO2MeL47
1. NBS / hv2. EIOH / 2,6-lutidine
Et
+N -l
CO2Meo
CO2Me
1,50 15L
Br=
Bra.
N*ì+
749
CO2Me
Scheme 41
RESUITS,4ND DISCUSSION - lII
73
Identification of the ether 149 was made initially on the basis of
1H n.m.r. spectroscopic evidence. A singlet resonance observed at õ 5.75 was
attributable to the methine proton of the cr-carbon. The presence of the ethoxy
substituent in 149 was confirmed by the observation of a characteristic triplet
resonance at õ 1.26 (] = 7.0 Hz), corresponding to the methyl protons, and a
quartet resonance at õ 3.57 (l =7.0 FIz) arising from the methylene protons. In
addition, two doublet of doublet of doublets resonances at õ 3.37 and 3.47 were
indicative of the two non-equivalent methylene protons of C5, with the
associated geminal coupling constant being,l55' = 9.8F{2. The non-equivalence
of the C5 methylene protons is consistent with the presence of the cr-ethoxy
substituent at the cr-carbon of 149. Although the ether 149 was insufficiently
stable for elemental analyses, a molecular ion at mlz 207 was observed by Fast
Atom Bombardment (FAB) mass spectrometry, and in addition, an ion
observed at mlz '1.42 corresponded to the fragmentation M+ - CO2Me. Other
spectral properties were consistent with the structure of L49.
The 4-bromo-5-ethoxypyrrolidinone 150 was fully characterized,
exhibiting consistent spectral characteristics and elemental analyses. The
presence of bromine in 150 was confirmed by the observation of two ions of
equal abundance at mfz 280 and 282in the FAB mass spectrum, corresponding
to M+ + H. The high field 1H n.m.r. spectrum of this compound was
particularly characteristic. The ethoxy substituent of 150 gave rise to a
characteristic triplet resonance at õ1..24 with /rriç = 7.0F{2 for the methyl
protons, and two doublet of quartets resonances at õ 3.61 and 3.70 each with
,Igem = 9.4TIz and /yi¡ = 7.0 FIz being due to the two non-equivalent methylene
protons. A doublet resonance at õ 5.21 (/ = 1.5 Hz) was attributable to the
methine proton of C5 and a doublet of doublet of doublets resonance at õ 4.24
Çz+ = 7.4,Il,q - 2.9, Iqs = 1.5tlz) was consistent with the methine proton of C4.
Further, two distinct resonances at õ 2J6 (dd, ¡33' = 78.2,12't = 2.9 ÍIz) and 3.23
RESULTS .AND DISCUSS.ION - II1
74
(ddd, Igz' = 1.8.2, lga = 7.4,lgo = 0.9 HÐ were attributable to the non-equivalent
methylene protons of C3. The methylene protons of the cr-carbon of 150 also
exhibited non-equivalence, giving rise to distinct resonances at ô 3.81 (dd,
I c¡a' = 77.6, lgs = 0.9 flz) and 4.43 (d, /cra' = 77.6 ÍIz).
The vicinal coupling constant of 1.5 Hz observed for the C4 and C5
methine protons of 150 is of the magnitude expected for these protons when in
a trøns orientation, where the dihedral angle would approximate 90 degrees.
From an application of the Karplus equation,773,7\4 it can be seen that for such
protons in a cis orientation, where the dihedral angle would be less than that
for the trans orientation, a larger vicinal coupling constant would be expected.
It is on this basis, that a trans geometry was assigned to the substituents at C4
and C5 of the 4-bromo-5-ethoxypyrrolidinone L50 (Fígure 6).
H BrEt
F{',.r,, ,,,rIfr
N
ì
L50
Figure 6. Numbering of methyl trans-A-bromo-5-ethoxy-2-oxo-1-pyrrolidineacetate (150).
The alcohol 151 was identified by 1H n.m.r. spectral characteristics that
were similar to those of the 4-bromo-5-ethoxypyrrolidinone 150, with a doublet
resonance at õ 5.40 with / = 1.5 Hz, attributable to the methine proton of C5 and
a broad resonance at õ 5.11, consistent with the hydroxyl proton. Further
indication of the hydroxyl group in 15L was given by a broad infrared
absorption at 3400 cm-1. As for the ether 1,50, a trøns geometry was assigned to
H
CO2Me
RESULTS AND DISCUSSION - III
75
the substituents at C4 and C5 of the alcohol 151, on the basis of the observed
vicinal coupling constant for the methine protons of C4 and C5.
Production of the ether 149 above is consistent with formation of the
bromide 147 in the reaction of the pyrrolidinone 141 with N-bromo-
succinimide. The mechanism for formation of L49 is proposed as analogous
to that of the formation of the ethers 93 and 98 discussed in Chapter I
above. The N-acyliminium species 152, in equilibrium with the bromide 747,
is attacked at the electrophilic cr-carbon by ethanol thus giving the ether 149
(Scheme 42).
EtOH
-
Br- tI - HBr
CO2Me CO2Me CO2Me
.wtv7
752 749
Scheme 42
Formation of the endocyclic substitution product 150 may be attributed
to bromination of t47 at the endocyclic carbon adjacent to nitrogen to give the
corresponding intermediate S-bromopyrrolidinone 153, which undergoes
subsequent reaction during treatment with N-bromosuccinimide as shown
in Scheme 43. Elimination of hydrogen bromide from the S-bromo-
pyrrolidinone L53 aiø the N-acyliminium species 154 gives 155, with
which molecular bromine present in the reaction mixture, reacts aia anti
addition, to give the trans-dibromide 148. Reaction of the N-acyliminium
species 156, in equilibrium with the dibromide 148, with ethanol then affords
the ether l-50. TÌr.e trans geometry of the C4 and C5 substituents of 150 is
consistent with intermediacy of the iminium species 156 in the conversion of
NBrNo
RESULTS .AND DISCUSSION - 1I1
76
Br Br-- HBr
N-ì
CO2Me CO2Me CO2Me
L53 \54
Br-
EtOHN
+- HBr NI
CO2Me CO2Me148
Hzo- HBr
N-ì
CO2Me151
Scheme 43
the dibromide 148 to the ether 150. Attack at the planar S-position of the
iminium species 156 by ethanol occurs from the opposite face of the lactam
ring to that occupied by the bromo substituent of C4. The minor product L51
then presumably results from the similar reaction of any unreacted dibromide
148, aiø the iminium species 156, with adventitious water.
N tì
Btz
I+
Br=.
BrBr-z
*l+
t
150 156
Br
RESULTS AND D/SCUSSION - III
77
As for the pyrrolidinone 14L, the bromination of the nitrile analogue
142 was initially investigated in a L:1 mixture of carbon tetrachloride and
dichloromethane in order to ensure the solubility of the substrate. ÉIowever,
1H n.m.r. spectroscopic analysis of the crude reaction mixture obtained upon
treatment of 2-oxo-L-pyrrolidineacetonitrile (tlz) with a slight excess of
N-bromosuccinimide in this solvent mixture revealed the presence of a
substantial amount of unreacted starting material 142. The extent of reaction
was increased when 2-oxo-1-pyrrolidineacetonitrile (142) was treated with a
slight excess of N-bromosuccinimide in a.2:'1, mixture of carbon tetrachloride
and dichloromethane, heated at reflux under nitrogen whilst irradiating with
a 300 W mercury lamp, for 10 minutes. 1H n.m.r. spectroscopic analysis
revealed the absence of unreacted starting material L42 in the crude reaction
mixture and gave evidence for the production of the two bromides 1-57 and
L58 in an approximately 3:L ratio (Scheme 44). The methylene protons of the
Br
NBSN hv
Bri
NBr+
CN CN1.42 157 158
Scheme 44
cr-carbon in 142 give rise to a singlet resonance at õ 4.26 with the methylene
protons of C5 giving rise to a triplet resonance at ô 3.53. In the 1H n.m.r.
spectrum of the crude product mixture obtained from the bromination of 142,
a singlet resonance at õ 6.76 was attributable to the methine proton of the
cr-carbon in the bromide 157. A singlet resonance observed at ô 6.13 was
RESULTS AND DISCUSS/ON - III
78
indicative of the methine proton at C5 of the trans-dibromide 1,58. As for the
case of the dibromide 148 above, the observed singlet resonance attributed to
the methine proton at C5 of 158 is consistent with a minimal vicinal couping
constant for the C4 and C5 protons, thus indicating a trans geometry for the
bromo substituents at C4 and C5.
The bromides 157 and 158 were not stable for isolation and
characterization and so were converted to the corresponding ethers 159 and
160, in the same manner as for the case of the bromides L47 and 148 above.
Addition of two mole equivalents each of ethanol and 2,6-lutidine directly to
the crude reaction mixture of 742 with N-bromosuccinimide after cooling to
room temperature afforded, after chromatography, the ether 159 and the
4-bromo-5-ethoxypyrrolidinone 160 in yields of 26 and 8Vo respectively, based
onL42. In addition, the 3,4-didehydro-5-ethoxypyrrolidinone 161 was obtained
as a minor product on one occasion.
Br
CNCNCN
t
N t N
o
1s9 160 t6t
The ether 159 was fully characterized, being identified initially by u
singlet resonance at ô 6.02 in its 1H n.m.r. spectrum, attributable to the methine
proton of the cr-carbon. The ethoxy substituent of 159 gave rise to a triplet
resonance at õ 1.25 (l =7.0 Hz), however the resonance arising from the
methylene protons of this substituent was coincident with that arising from
the methylene protons of C5 and as such was not distinct. Additionally, a
*ì
RESULTS AND DISCUSSION - III
79
molecular ion was observed at mlz 168 in the EI mass spectrum, with a further
fragment ion at mlz 142 corresponding to M+ - CN. All other spectroscopic
properties were in accord with the structure of 159.
The 4-bromo-5-ethoxypyrrolidinone 160 was fully characterized,
exhibiting spectral characteristics and elemental analyses consistent with its
structure. The observation of two ions of equal abundance in the FAB mass
spectrum at mlz 247 and249, that were consistent with M+ + H, confirmed the
presence of bromine in 160. The high field 1H n.m.r. spectrum of 160 was
particularly characteristic. The ethoxy substituent gave rise to a characteristic
triplet resonance at õ 1.29 with/.,0¡. =7.0Ílzfor the methyl protons and two
doublet of quartet resonances at õ 3.77 and 3.76, each with /g"- = 9.4 FIz and
/vic : 7.0H2, due to the two non-equivalent methylene protons. A doublet
resonance at õ 5.15 (l = 7.1H2) was attributable to the methine proton of C5 and
a doublet of doublet of doublets resonance at õ4'25 (l =7'2,2'1',1"7 Hz) was
consistent with the methine proton of C4. Two resonances at õ 2.76 (dd,
I = 18.4,2.1, }lz) and 3.24 (ddd, I = 78.4, 7.2, 0.8 Hz) were consistent with the two
non-equivalent methylene protons of C3. The methylene protons of the
cr-carbon, being non-equivalent, gave rise to resonances at E 4.07 (dd, ¡ = 17.5,
0.8 Hz) and 4.51 (d, I = 77.5H2). With the vicinal coupling constant observed
for the C4 and C5 methine protons being 1,.7H2, a trans geometry was assigned
to the substituents at C4 and C5 of L60, as for the analogous case of L50 above.
The 3,4-didehydropyrrotidinone L61 was identified by characteristic
resonances in its 1H n.m.r. spectrum. A doublet resonance at õ 5.53 with
I = 7.5 ÍIz was attributed to the methine proton of C5 and further resonances at
õ 7.07 (dd, ¡ = 6.1,7.5}12) and 6.30 (d, I = 6.7F{2) were consistent with the
olefinic methine protons of CLand C3 respectively. In addition, the methylene
protons of the cr-carbon were non-equivalent, giving rise to doublet resonances
atõ 4.77 and 4.46 with a geminal coupling constant of 77.5fI2. The presence of
RËSULTS AND DISCUSS/ON - IlI
80
the olefinic moiety in 161 was confirmed by the observation of an infrared
absorption at 1598 cm-1 and a molecular ion at mlz 766 was also observed in
the EI mass spectrum. All other spectroscopic properties were consistent with
the structure of L61.
Formation of the ethers 159 and 160 in the above reaction of the
pyrrolidinone 142 with N-bromosuccinimide and ethanol confirms the
production of the corresponding bromides 157 and 158 in the reaction of 142
with N-bromosuccinimide. The mechanisms for the production of the ethers
1"59 and 160 from the respective bromides L57 and 158 are proposed as being
analogous to those depicted in Schemes 42 and 43, respectively. Formation of
the minor product 16L may be attributed to subsequent elimination of
hydrogen bromide from the 4-bromo-5-ethoxypyrrolidinone 161.
In the reactions of the pyrrolidinones 141 and'1,42 with N-bromo-
succinimide, production of the respective bromides L47 and 157 is consistent
with reaction aia initial hydrogen atom abstraction from the exoryclic carbon
adjacent to nitrogen, to form the corresponding cr-centred intermediate
radicals 162 and 163. Formation of the dibromides 148 and 158 from the
corresponding pyrrolidinones 141 and 142 indicates initial formation of
the S-bromopyrrolidinones 153 and 164, which in turn is consistent with
reaction uia initial hydrogen atom abstraction from the endocyclic carbon
adjacent to nitrogen, to form the corresponding endocyclic intermediate
radicals 165 and L66.
RESULTS AND DISCUSSION - III
81
Br
ìRCN
N*ì*ì'
R
162 R = COzMe163 R=CN
164 165 R = COzMe166 R = Cl.J
To the extent that the observed ratios of formation of the bromides 147
and L57 to the respective dibromides 148 and 158 from the corresponding
pyrrolidinones 1-4L and L42 are indicative of the relative rates of formation of
the ¡adicals 762 and L63 to 165 and 166 respectively, it follows that formation of
the endocyclic radicals L65 and L66 competes with formation of the
corresponding exocyclic radicals L62 and763. The exocyclic radicals 162 and
163 are stabilized by the combined resonance effects of the electron-donating
amido and electron-withdrawing methoxycarbonyl or cyano substituents,
whereas the endocyclic radicals L65 and L66 are resonance stabilized by the
electron-donating amido group only. However hydrogen atom abstraction
from the endocyclic methylene adjacent to nitrogen in the pyrrolidinones 141
and 142 is favoured by the relief of ring strain due to the release of steric
interactions between the C4 and C5 protons upon formation of the
corresponding radicals 165 ¿n¿ 15,5.80,81 Further, it is possible that formation of
the radicals 165 and.166 is favoured entropically by the inflexibility of the
lactam ring in each of 141 and L42, maintaining the amido group in the planar
orientation required for stabilization of the radicals.Tl
Whereas free radical bromination of the pyrrolidinones 141. and 142
gave both products of reaction at the exocyclic methylene adjacent to nitrogen
and of competing reaction at the endocyclic methylene adjacent to nitrogen,
the azetidinones 72 and 73 investigated in Chapter I, gave products resulting
from reaction at the exocyclic methylene adjacent to nitrogen exclusively.
RESUTTS ,4ND DTSCUSSION - III
82
Thus the relative reactivity of the endocyclic methylenes adjacent to nitrogen
compared to the exocyclic methylenes adjacent to nitrogen is greater for the
pyrrolidinones 141 and 142 than for the corresponding azetidinones 72 and
73. Presumably the endocyclic methylenes adjacent to nitrogen in the
pyrrolidinones 741 and 142 are more reactive towards hydrogen atom
abstraction than those in the corresponding azetidinones 72 and 73 due to the
relative degrees of ring strain in the product radicals 165 - 168 resulting from
hydrogen atom abstraction from the pyrrolidinones 141 and 142 and the
azetidinones 72 and 73 respectively. The change in hybridization from sp3 to
sp2 accompanying radical formation will engender greater strain in the
endocyclic azetidinone radicals 167 and L68 than in the corresponding
pyrrolidinone radicals 165 and 166.
L67 R = COzEt168 R=CN
a
R
RESULTS ,AND DISCUSSION - III
83
RESULTS AND DrscussroN - IV
E ndo cyclic Functio nalization and EIab orationof y-Lactams
Preparation of the 2-pyrrolidinon es 17L and 172
The 2-pyrrolidinones 769 - 172 were required for the investigation
described in this chapter, of the endocyclic functionalization of y-lactams.
1,3,3-Trimethyl-2-oxopyrrolidine (169), prepared according to the method of
Gassman and Fox,115 was the generous donation of Ms. C. Ward116 and
1-methyl-2-oxopyrrolidine (770), a common HPLC solvent, was commercially
¿rr¿i1¿61s.117 The syntheses of the pyrrolidinones 17L and 772 are detailed
below.
Ntat,
R
RN
o771
169 R = CHs170 R=H
172
Following a method reported by Mazzocchi and co-workers118 for the
synthesis of 1-(2-methylbutyl)-2-oxopyrrolidine, 1-(3-butenyl)-2-oxopyrrolidine
(l7L) was prepared aiø N-alkylation of 2-pyrrolidinone (773) as shown in
Scheme 45. Thus, treatment of Z-pyrcolidinone (773) with a slight excess of
sodium hydride in xylene at 110'C for one hour followed by treatment of the
resulting salt with excess 4-bromo-1-butene, whilst heating at reflux overnight,
RESULTS ,AND DISCUSSION - IY
u
1. NaHNH N
2.Bré173 L7L
Scheme 45
afforded the N-butenylpyrrolidinone l7l in'1.47o yíeld after distillation. The
product 171 thus obtained exhibited spectral characteristics consistent with its
structure. In the lH n.m.r. spectrum of L7L, the methylene protons of the
exocyclic and endocylic carbons adjacent to nitrogen gave rise to triplet
resonances at õ 3.36 (l =7.2H2) and 3.39 (l = 7.']-. FIz) respectively, with the
olefinic protons of the butenyl moiety giving rise to characteristic resonances at
õ 5.07 (2H) and 5.77 (7H). The amide carbon of 171gave rise to a characteristic
resonance at õ 774.64 in the 13C n.m.r. spectrum, with resonances at õ 1,34.84
and L16.53 being due to the two alkenyl carbons. In addition, a molecular ion
was observed at mlz 739 in the EI mass spectrum.
1-(p-Methoxyphenyl)-2-oxopyrrolidine'/..72 was synthesized in an
analogous manner to the pyrrolidinones 14L and 1.42 prepared in Chapter III,
aia cyclízation of the corresponding 4-chlorobutyramide L75 as depicted in
Scheme 46. Thus, 4-chlorobutyryl chloride (146) was treated with an excess of
freshly recrystallized p-anisidine (1,74) in dichloromethane, affording the
chlorobutyramide 1,75 in 547o yield. The butyramide 175 thus obtained was
fully characterized, exhibiting spectral properties and elemental analyses
consistent with its structure. In particular, the amide carbonyl of 775 gave rise
to a characteristic infrared absorption at 7662 cm-1 and further evidence for the
production of the amide in 175 was given by the observation of a resonance at
ô 169.84 in the 13C n.m.r. spectrum. The butyramide 175 was added slowly in
dilute solution to a stirred suspension of powdered potassium hydroxide and
RESULTS AND DISCUSSION - IY
85
tetra-n-butylammonium chloride in dichloromethane, to give the
pyrrolidinone 172 in 637o yield after chromatography and subsequent
recrystallization. The pyrrolidinone L72 was fully characterized, exhibiting
satisfactory spectroscopic properties and elemental analyses. The lactam
carbonyl in L72 gave rise to a characteristic infrared absorption at1,682 cm-l,
and the amide carbon gave rise to a resonance at õ 173.90 in the 13C n.m.r.
spectrum.
+ HzN ocH3
L46 L74
KOH / BuaNCl
NH
L75 \72
Scheme 46
ocH3
RESULTS AND DTSCUSSION - IV
86
Functionalization of the 2-pyrcolidinones L69 - L72
The investigation described in Chapter trI of this thesis established that
substitution at the endocyclic carbon adjacent to nitrogen competes with
substitution at the corresponding exocyclic carbon in the free radical
bromination of pyrrolidinones bearing activating substituents at the exocyclic
carbon adjacent to nitrogen. The study described in this chapter was aimed at
assessment of the separate contributions of the brominating reagent and
exocyclic activating substituent to the regioselectivity of reaction, based on an
investigation of the regioselectivity of free radical bromination of
pyrrolidinones not bearing activating substituents at the exocyclic carbon
adjacent to nitrogen.
The trimethylpyrrolidinone 169 was chosen for initial investigation as it
was reasoned that the methyl substituents at C3 would block this position to
possible side reactions leading to formation of unidentifiable decomposition
products. Free radical bromination of 769 was investigated by treaûnent with
two mole equivalents of N-bromosuccinimide in carbon tetrachloride at reflux
under nitrogen for 10 minutes, with reaction initiated by irradiation with a
300 W mercury lamp. The crude reaction mixture thus obtained was not
analysed directly but the products of reaction were converted to stable
derivatives for isolation and characterization. Accordingly, the crude reaction
mixture of the pyrrolidinone L69 with N-bromosuccinimide was treated with
two mole equivalents of ethanol and one mole equivalent of 2,6-Iutidine and
afforded, after chromatography, the 4-bromo-5-ethoxypyrrolidinone 176 and
the 4,4-dibromo-5-ethoxypyrrolidinone 777 (Scheme 47) in yields of 9 and'1.47o
respectively, based on L69.
RESULTS AND DISCUSSION - IY
87
H¡C
t69
1. NBS / hv2. EIOH / 2,6lutidine
Br Br
OEt
HsC HeCtc",
176 \77
Scheme 47
The 4-bromo-5-ethoxypyrrolidinone 176 was identified on the basis of
characteristic resonances in its 1H n.m.r. spectrum. Two doublet resonances at
õ 3.98 and 4.89 each with -lvic = 3.8Í12 were attributable to the methine protons
of C4 and C5 respectively. The presence of the ethoxy substituent in L76 was
confirmed by the observation of a characteristic triplet resonance at õ'1,.29
(l = 7 .0 ÍIz) for the methyl protons, with doublet of quartets resonance s at õ 3 .7 4
and 3.80, each with /t"^ = 9.4FIz and /vic = 7.0H2, being due to the two
methylene protons. The EI mass spectrum of L76 exhibited two molecular ions
of equal abundance at mfz249 and 251, confirming the presence of bromine in
the molecule. In addition, other spectral characteristics were in accord with the
structure of L76. Whilst the vicinal coupling constant observed for the C4 and
C5 methine protons of 176 was not diagnostic, it was nevertheless consistent
with the assignment of a trans geometry for the substituents at C4 and C5,
made on the basis of mechanistic considerations presented below.
N'ct,
Br-i
+Ntct,
RESULTS .AND D/SCUSS/ON - /Y
88
The 4,4-dibromo-5-ethoxypyrrolidinone 177 was identified on the basis
of mass spectrometric and 1H n.m.r. spectroscopic evidence. Three molecular
ions observed at mlz 327, 329 and 331 in the ratio of 1.:2:7 in its EI mass
spectrum confirmed the presence of two bromine atoms in 177. The 1H n.m.r.
spectrum exhibited characteristic triplet and two doublet of quartets resonances
due to the ethoxy substituent, with the three methyl substituents of 777 each
giving rise to distinct singlet resonances. A singlet resonance at ô 5.02,
attributable to the methine proton of C5 was the only other signal observed in
the 1H n.m.r. spectrum. Other spectroscopic properties were consistent with
the structure of 177.
Production of the 4-bromo-5-ethoxypyrrolidinone '1,7 6 and the
4,4-dibromo-5-ethoxypyrrolidinone 777 in the above reaction of the
pyrrolidinone 169 indicates formation of the corresponding dibromide 179 and
tribromide 182 respectively, in the reaction of 169 with N-bromosuccinimide.
The mechanism of formation of the ether 176 frorn the pyrrolidinone L69, ttia
the dibromide 179,is proposed as analogous to that of the formation of the
4-bromo-5-ethoxypyrrolidinone 150, from 14L, depicted in Scheme 43 of
Chapter trI. Thus, initial bromination of 169 at the endocyclic carbon adjacent
to nitrogen affords the intermediate S-bromopyrrolidinone L78 which
undergoes subsequent reaction during treatment with N-bromosuccinimide,
as described'for the analogous prod.uction of 148 above, to give tlne trans-
dibromide L79. The N-acyliminium species 180, in equilibrium with the
dibromide 179 is then attacked by ethanol from the least hindered face to give
the trans-4-bromo-5-ethoxypyrrolidinone 176 (Scheme 48). Formation of the
4,4-dibromo-5-ethoxypyrrolidinone 177 may be attributed to subsequent
reaction of the dibromide L79 during treatment with N-bromosuccinimide as
shown in Scheme 48. Thus elimination of hydrogen bromide from L79 pia
RESULTS AND DISCUSSION - IY
89
BriBr BrH¡C
o
H¡C ......+€ HsC
N Ntct, tct,
L78 L79
Br BrBr
- HBr 'T:ç EtOHtr lagu
Br- Et
HsC
tct, tat,o
tct,
L80 176
Btz
Br Br Br Br B Br
Br HsC Br- HeC
+ H¡CNN tat, tct,tct,
L82 1.83
Scheme 48
the iminium species 180 gives L81,, which upon reaction with molecular
bromine present in the reaction mixture, affords the tribromide 182. Reaction
of the N-acyliminium species L83, in equilibrium with L82, with ethanol then
affords the ether 177.
N
L8L
o
tHsC
H¡C
177
RESULTS .AND DISCUSSION - IY
90
No products attributable to bromination at the exocyclic carbon adjacent
to nitrogen were observed in the above reaction of the pyrrolidinone L69, the
products 176 and L77 obtained being due to initial bromination at the
endocyclic carbon adjacent to nitrogen. Given that this result indicates that
exocyclic bromination is not a major reaction pathway of the pyrrolidinone
169, it was considered to test the generality of the bromination procedure for
endocyclic functionalization of pyrrolidinones not bearing blocking
substituents at C3. The pyrrolidinone L70, not bearing substituents at C3, was
readily availablellT and was therefore next chosen for investigation.
l-Methyl-2-oxopyrrolidine (170)'t17 was treated with two mole
equivalents of N-bromosuccinimide in carbon tetrachloride at reflux under
nitrogen for 10 minutes, with reaction initiated by irradiation with a 300 W
mercury lamp. 1H n.m.r. spectroscopic analysis of the crude reaction mixture,
after filtration and evaporation of the solvent, revealed a mixture of products
and gave evidence for the production of a major amount of the trøns-
dibromide 184 and the tribromide 185 in an approximately 5:2 ratio (Scheme
49). The methylene protons of C5 in 170 resonate as a triplet at õ 3.47
Br Br Br
3
Br
SNB____+ +hv
'at,L70
Scheme 49
U = 7.7 FIz), with the methylene protons of C4 giving rise to a triplet of triplets
resonance at õ 2.04 (l - 7.7, 8.7FJ2), whereas the protons of the methyl
N'at,
N
L85L84
RESULTS AND DISCUSSION - IY
97
substituent give rise to a singlet resonance at ô 2.84. In the 1H n.m.r. spectrum
of the crude product mixture obtained from the bromination of 170, an
observed singlet resonance at ð 6.12 was attributable to the methine proton of
C5 in t}rre trans-dibromide 184 with the observation of a doublet resonance of
equal peak area at õ 4.87 being consistent with the methine proton of C4. A
singlet resonance of three times the peak area at õ 2.90 was then due to the
methyl substituent of 184. Evidence for the production of the tribromide 185
in the same reaction mixture was given by the observation of a singlet
resonance at õ 6.34 indicative of the methine proton of C5 with two doublet
resonances at ô 3.39 (l = 77.5 FIz) and 3.47 (l = 77.5 fU) being consistent with the
non-equivalent methylene protons of C3. In addition, a singlet resonance
observed at ô 2.95 was consistent with the methyl substituent of 185.
The bromides 184 and 185 were insufficiently stable for isolation and
characterization and so were converted to the corresponding ethers 186 and
187, through the addition of two mole equivalents of ethanol and one mole
equivalent of 2,6-lutidine directly to the cooled crude reaction mixture of L70
with two mole equivalents of N-bromosuccinimide. Chromatography of
the crude product mixture thus obtained afforded the 4-bromo-S-
ethoxypyrrolidinone 186 and the 4,4-dibromo-5-ethoxypyrrolidinone 187 in
yields of 9 and 177o respectively, based on 170.
Br BrBr
t Et
N Ntat.
187186
tcH3
RESULTS ,AND D/SCUSSION - IV
92
Identification of the ether 186 was made initially on the basis of lH
n.m.r. spectral characteristics that were similar to those of the 4-bromo-5-
ethoxypyrrolidinones 1-50 and 160 of Chapter III, above. A doublet resonance at
õ 4.97 (l : 0.9 FIz) was attributable to the methine proton of C5 and a doublet of
doublet of doublets resonance at ô 4.24 (l = 6.8,'1.4, 0.9 FIz) was then consistent
with the methine proton of C4. In addition, two doublet of doublets
resonances at õ 2.65 (] = 17.9,1,.48fò and 3.21 (l = 17.9, 6.8Hò were attributable
to -the non-equivalent methylene protons of C3. The ethoxy substituent oftc661# Eave rise to a characteristic triplet resonance at õ L.26 (l =7.0 Hz) and two
doublet of quartets resonances at õ 3.63 and 3.68, each with .Igem = 9.2IJ2 and
,Ivic = 7.0H2. The presence of bromine in 186 was confirmed by the observation
of two molecular ions of equal abundance at mfz 221 and223 in the EI mass
spectrum. Other spectral properties were in accord with the structure of 186.
On the basis of the vicinal coupling constant observed for the C4 and C5
methine protons being 0.9 ÍIz a trans geometry was assigned to the substituents
at C4 and C5 of L86.
The 4,4-dibromo-5-ethoxypyrrolidinone 787 exhibited characteristic lH
n.m.r. spectroscopic properties enabling its identification. A singlet resonance
at ô 5.02 was attributable to the methine proton of C5 with a singlet resonance
of three times the peak area at ô 2.93 corresponding to the methyl substituent.
Two doublet resonances observed at ô 3.36 urrA a.St each with /g"- = 77.6]H2
were indicative of the methylene protons of C3 and the ethoxy substituent of
187 gave rise to a characteristic triplet resonance at õ 1.32 and two doublet of
quartets resonances at ô 3.80 and 4.07. Although the ether 187 w a s
insufficiently stable for elemental analyses, three molecular ions at mf z 299,
30L and 303 were observed in the ratio of. 7:2:7 in the EI mass spectrum,
confirming the presence of two bromine atoms in the molecule. In addition,
other spectral properties were consistent with the structure of 1.87.
RESU¿TS .AND DISCUSSION - IV
93
Production of the 4-bromo-5-ethoxypyrrolidinone 186 and the
4,4-dlbromo-5-ethoxypyrrolidinone L87 above, confirms formation of the
dibromide 184 and the tribromide L85 respectively, in the reaction of the
pyrrolidinone 170 withN-bromosuccinimide, consistent with subsequent
reaction of the initially formed S-bromopyrrolidinone 188. The mechanisms
for the formation of 186 and 187 from 184 and 185 respectively, are proposed as
analogous to those of the formation of the ethers L76 and 177 from the
pyrrolidinone 169, depicted in Scheme 48 above.
Ntat,
188
The yields of the ethers 186 and L87 from the pyrrolidinone 170 quoted
above were not optimized, but given the ready availability of the starting
material L70, they nevertheless serve to illustrate the accessibility of
functionalized pyrrolidinones uía t)i.e free radical bromination procedure.
From a consideration of the synthetic potential of this procedure for endocyclic
difunctionalization of pyrrolidinones it was sought to optimize production of
the 4-bromo-5-ethoxypyrrolidinone 186 with respect to that of the 4,4-dibromo-
S-ethoxypyrrolidinone 187. In an initial attempt to limit subsequent reaction
of the dibromide 184 leading to the production of the tribromide 185, the
pyrrolidinone L7 0 was treated with only one mole equivalent of
N-bromosuccinimide and subsequently with ethanol and 2,6-lutidine, as
above. Flowever, upon chromatography of the product mixture thus obtained,
the 4-bromo-5-ethoxypyrrolidinone L86 and the 4,4-dibromo-5-ethoxy-
Br
RESULTS ,4ND DISCUSSION - IY
pyrrolidinone 187 were obtained in yields of 2 and 6Vo respectively, based on
170. In addition, the 3,4-didehydropyrrolidinone 189 was obtained in 27o yield
and a minor amount of the alcohol 190 was also obtained.
94
Br Br
t
189 190
The didehydropyrrolidinone 189 was identified by characteristic
resonances in its 1H n.m.r. spectrum. In addition to characteristic resonances
arising from the ethoxy substituent, a singlet resonance observed at õ 5.21 was
attributable to the methine proton of C5, with a singlet resonance at õ 6.42 then
being consistent with the olefinic methine proton of C3. The presence of the
olefinic moiety in 189 was confirmed by an infrared absorption at 1638 cm-1
and the observation of two molecular ions of equal abundance at mfz 219 and
22'1, in the EI mass spectrum confirmed the presence of bromine in the
molecule.
NN tat,'at,
The alcohol 190 was identified by 1H n.m.r. spectral characteristics that
were similar to those of the 4,4-dibromo-5-ethoxypyrrolidinone 1-87. A singlet
resonance observed at ô 5.29 was attributable to the methine proton of C5 and a
broad resonance at ô 4.69 with equal peak area was consistent with the hydroxyl
proton of 190. Further evidence of the hydroxyl group of 190 was given by a
broad infrared absorption at 3380 cm-1.
RESULTS AND D/SCUSSION - IV
95
Formation of the didehydropyrrolidinone L89 above may be attributed
to a subsequent elimination of hydrogen bromide from the 4,4-dibromo-5-
ethoxypyrrolidinone 787 during chromatography and the alcohol 190
presumably results from the reaction of the tribromide 185 with adventitious
water.
As for the pyrrolidinone 169, no products attributable to brornination at
the exocyclic carbon adjacent to nitrogen were observed in the above reactions
of the pyrrolidinone 170, the products obtained each resulting from initial
bromination at the endocyclic methylene adjacent to nitrogen. In the case of
the reactions of each of the pyrrolidinones 169 and 170, the 4,4-dibromo-5-
ethoxypyrrolidinones L77 and 187 were obtained in greater yields than those of
the respective 4-bromo-5-ethoxypyrrolidinones L76 and L86. This presumably
indicates the facility with which the initially formed S-bromopyrrolidinones
L78 and 188 undergo subsequent ionic reaction during bromination to give the
corresponding tribromides 182 and 185.
It was reasoned that in order to ensure a high rate of formation of the
dibromopyrrolidinone 184 with respect to the tribromopyrrolidinone 185 from
the pyrrolidinone 170, an increase in the efficiency of hydrogen atom
abstraction leading to the initial production of the S-bromopyrrolidinone 188
was necessitated. Free radical bromination reactions with N-bromo-
succinimide are known to be accelerated by chemical intiatorsll9 and to this
extent bromination of the pyrrolidinone 170 was investigated as before, but in
the presence of a catalytic amount of AIBN. Coincidently, conversion of the
products of bron.ination of 170 in this manner, to their corresponding
phenylthioethers through reaction with thiophenol was investigated. The
preparation of such phenythioethers was considered attractive from a synthetic
standpoint as S-phenylthiopyrrolidinones have previously been shown to
RËSULTS AND D,ISCUSSION - IV
96
provide stable precursors for site specific generation of o-acylamino radicals in
the synthesis of pyrrolizidine alkaloi¿s.36-38
The pyrrotidinone 770 was treated with two mole equivalents of
N-bromosuccinimide in the presence of a catalytic amount of AIBN in carbon
tetrachloride at reflux under nitrogen for 6 minutes, whilst irradiating with a
300 W mercury lamp. The cooled crude reaction mixture was subsequently
treated with two mole equivalents each of thiophenol and 2,6-lutidine.
Chromatography of the product mixture thus obtained afforded the 4-bromo-5-
phenylthiopyrrolidinone L9L in 25% yield, based on 170. In addition the
exocyclic substitution product 192 was obtained in 3% yield.
SPh
N SPh-.rí79L
The 4-bromo-5-phenylthiopyrrolidinone 191 was identifiable on the
basis of 1H n.m.r spectral characteristics that were similar to those of its ethoxy
analogue 186' A doublet resonance observed at õ 4'98 (l = 7'1Hz) was
attributable to the methine proton of C5, with a doublet of doublet of doublets
resonance at ô 4.53 (] = 6.5, 1,.2, 1,.7 Hz) being consistent with the methine
proton of C4. The presence of the phenylthio substituent in 191 was confirmed
by the observation of a multiplet resonance centred atõ7.37. Two molecular
ions of equal abundance in the EI mass spectrum at mf z 285 and 287 confirmed
the presence of bromine in 1,9L, and in addition other spectroscopic properties
Br
'at,L92
RESULTS AND DISCUSSION - IY
97
were in accord with the structure. As for the ether 186 above, a trans-geometry
was assigned to the substituents at C4 and C5 of L91,, on the basis of the
magnitude of the observed vicinal coupling constant for C4 and C5 methine
protons.
The exoryclic substitution product 192 was identifiable on the basis of its
1H n.m.r. spectral characteristics. The protons of the methyl substituent of 170
give rise to a singlet resonance at õ 2.85. A singlet resonance observed at õ 4J7
in the lH n.m.r. spectrum of 792 was then attributable to the methylene
protons of the phenylthiomethyl substituent. The presence of the phenylthio
moiety in 192 was confirmed by the observation of multiplet resonances
centred at õ 7.27 and ô 7.44 of three and two protons integration respectively.
The EI mass spectrum of 792 gave rise to a molecular ion at mf z 207 and in
addition the compound exhibited consistent elemental analyses confirming its
structure.
Formation of the 4-bromo-5-phenylthiopyrrolidinone 19L in the above
reaction of the pyrrolidinone 170 with N-bromosuccinimide and thiophenol is
consistent with reaction uia the dibromide L84 as for the analogous reaction to
give the ether 186 above, whereas formation of the exocyclic substitution
product 192 provides evidence for the production of the exocyclic bromide
193 in the reaction of 170 with N-bromosuccinimide. The N-acyliminium
species 194, in equilibrium with the exocyclic bromide 193, is presumably
attacked at the electrophilic imine carbon, thus affording the thioether L92
(Scheme 50).
RESULTS AND DISCUSS/ON - IY
98
Br:
uå
NBS / hv
N .........'................-
PhSH.*
- HBr
Br
NBS / hvBr
+
N
170
tcH,N'cH,
N
184
'cH,
791
NBrPhSH
- HBr N SPhCHzo
\CHz CHz
193 \94
Scheme 50
Formation of the exocyclic bromide 193 from the pyrrolidinone 170 is
consistent with reaction oíø initial hydrogen atom abstraction from the
exocyclic carbon adjacent to nitrogen to form the corresponding primary
exocyclic radical 195, whereas formation of the dibromide 184 indicates
initial formation of the S-bromopyrrolidinone L80, consistent with reaction aiø
initial hydrogen atom abstraction from the endocyclic carbon adjacent to
nitrogen to form the corresponding endocyclic radical 196. To the extent that
the observed ratio of formation of the thioethers 791 and L92 from the
pyrrolidinone 170 reflects the relative rate of formation of the radicals 195 and
196, it follows that the endocyclic methylene adjacent to nitrogen in 170 is
more reactive towards free radical bromination than is the exocyclic methyl
substituent on nitrogen. In comparison with the results of Chapter III, it may
be concluded that in the absence of an activating substituent at the exocyclic
carbon adjacent to nitrogen, free radical bromination at the endocyclic carbon
L92
RESULTS AND DTSCUSS/ON - ,rY
99
adjacent to nitrogen in 2-pyrrolidinones predominates over that at the
corresponding exocyclic carbon.
a
NNtéH2
ta",
195 L96
Production of the 4-bromo-5-phenylthiopyrrolidinone 191 from the
pyrrolidinone 170 illustrates methodology for the synthesis of 4,S-disubstituted
pyrrolidinones which may be utilized as cr-acylamino radical precursors in
subsequent reactions. On this basis it was considered an attractive proposition
to investigate application of the endocyclic functionalization procedure to the
synthesis of bicyclic pyrrolidinones aia functionalization of a pyrrolidinone
bearing a substituent on nitrogen suitable for further elaboration. To this end,
reaction of the N-butenylpyrrolidinone 171 with N-bromosuccinimide was
investigated.
1-(3-Butenyl)-2-oxopyrrolidine (771) was treated with two mole
equivalents of N-bromosuccinimide in the presence of a catalytic amount of
AIBN in a 4:1 mixture of carbon tetrachloride and dichloromethane at reflux
under nitrogen, whilst irradiating with a 300 W mercury lamp for 1,0 minutes.
Chromatography of the crude product mixture, following removal of by-
product succinimide aia a brine wash, afforded three products L97,L98 and
199, in yields of 1.0, 21 and 57o respectively, based on 17L. The structural
elucidation of each of the bromides 197 - 199 is presented below.
RESULTS AND D^TSCUSSION - /Y
100
Br
N
Br
197
NBr Br
Br Br
199
Br
Br
N
OH
Both the FAB and EI mass spectra of L97 exhibited five molecular ions
at mlz 453, 455, 457, 459 and 461 in the ratio of 1,:4:6;4;7, indicating the presence
of four bromine atoms in the molecule. From this mass spectral evidence the
molecular formula of L97 was deduced as CaHrrNOBr¿. Whilst the
tetrabromide 197 was insufficiently stable to afford elemental analyses within
the usual limits of acceptability, the analyses obtained were nonetheless
supportive of the molecular formula determined on the basis of the mass
spectral evidence. The infrared spectrum of the tetrabromide L97 exhibited a
strong absorption at 77'l,4cm-1 indicating retention of the lactam carbonyl
moiety, whereas the absence of absorptions in the region of 1620 - 1680 cm-1
indicated the absence of an alkenyl moiåty in the molecule. The 13C Dnpt
n.m.r. spectrum of L97 indicated that the compound possessed five methylene
carbons, one methine carbon and one quaternary carbon in addition to that of
the amide, which gave rise to a characteristic resonance at õ 1,67.86. In the 1H
n.m.r. spectrum of 197 a doublet of doublets resonance observed at õ 3.06
(l = 6.0,5.8 Hz) was attributable to the two methylene protons of C3, with two
doublet of doublet of doublets resonances at õ 3.39 (l = 9.9,6.0, 5.8 IJz) and 3.44
(l = 9.9,6.0, 5.8 Hz) being consistent with the two non-equivalent methylene
Br
198
RESULTS AND DISCUSSION - IV
.r{-:,...i '.'
!':ii' "ì'::,''
1''\ ror*' l'--
"'' -':r -:: . , -
protons of C4. The methylene protons of C4' gave rise to two doublet of
doublets resonances at õ 3.62 (l = 10.5, 9.6H2) and 3.87 (l = 70.5,4.2Í12), and the
methine proton of C3' gave rise to a resonance at ô 4.10 (dddd, I = 9.6,9.6, 4.2,
3.1,}J2). Homonuclear decoupling of each of the resonances of the 1H n.m.r.
spectrum of 'I',97 confirmed the presence of two spin systems within the
molecule, thus confirming the arrangement of the one methine and
five methylene carbons within the partial structures -CH2CH2- and
-CHzCHzCHCHz- (Fígure 7). The non-equivalence of the methylene
protons of both CL' and C2' manifested by the observation of distinct
I{',ßBr
BrH I{* H I{',É
N1 2 4 Br
H I{* H Br
197
Figure 7. Numbering of 1-(3,4dibromobutyl)-5,5-dibromo-2-oxopyrrolidine (197).
resonances attributable to each of these protons, and in addition that similarly
exhibited by the methylene protons of C4', points to a particular
conformational'preference of the dibromobutyl moiety of 797. 1FI - 13ç
Heteronuclear shift correlation n.m.r. spectroscopic analysis of 197 was
performed and enabled the unambiguous assignment of the resonances of the
13C n.m.r. spectrum.
Compound 198 was identifiable on the basis of a comparison of its
spectral characteristics with those exhibited by the tetrabromide 197. Both the
EI and FAB mass spectra of 198 exhibited four moleculer ions at mlz 397,393,
45
RESULTS AND DISCUSSION - IV
1.02
395, and 397 in the ratio of 1:3:3:1, indicating the presence of three bromine
atoms in the molecule and being consistent with a molecular formula of
CgHl2NOzBrg. The presence of a hydroxyl substituent in 198 was indicated by
the observation of four ions at mlz 373,375,377 and 379, corresponding to the
fragmentation M+ -HzO. As for L97, elemental analyses obtained for 198
were supportive of the molecular formula deduced from the mass spectral
evidence. The retention of the lactam amide in 198 was indicated by the
observation of a characteristic infrared absorption at 1706 cm-l and a broad
absorption observed at 3440 cm-l was further evidence of the presence of a
hydroxyl substituent in the molecule. The 13C DEPT n.m.r. spectrum of 198
revealed the same pattern of carbon substitution as that of L97, namely
containing five methylene, one methine and two quaternary carbons. The
chemical shifts of each of the carbons of 198 varied little to those exhibited by
197, with the exception of the single methine carbon of 198 giving rise to a
resonance at õ 67.77, consistent with the presence of the hydroxyl substituent at
this carbon. The structure of L98 was therefore deduced as that depicted
above. Homonuclear decoupling of resonances in the 1H n.m.r. spectrum of
198 confirmed the presence of two spin systems within the molecule,
attributable to the -CHzCH2- and -CHzCHzCHCHz- substructures. The 1H
n.m.r. spectrum of the alcohol 198 bore close similarity to that of the
tetrabromide L97, with the methine proton of C3' giving rise to a resonance at
õ3.77 (dddd, I = 9.8,5.8, 4.g,3.2ff¡,) and a broad resonance of equal peak area at
õ 3.42 being attributable to the hydroxyl proton. As for L97, the methylene
protons of CL', C2' and C4' of the alcohol L98 were each non-equivalent, giving
rise to distinct 1H n.m.r. resonances, presumably indicating the adoption of a
particular conformation by the 4-bromo-3-hydroxybutyl substituent on
nitrogen.
RESULTS AND DISCUSSION - IY
103
The dibromide 199 was identified on the basis of characteristic
resonances in its 1H n.m.r. spectrum. The presence of the unsubstituted
pyrrolidinone ring in 199 was indicated by the observation of resonances at
õ2.05 (tt,¡ =8.3,7.0ÍIz),2.40(t,l =83Hz,) and 3.43 (t,l =7.0F{z.), attributable to
the methylene protons of C4, C3 and C5 respectively. In addition, resonances
were observed that were attributable to the dibromobutyl moiety of L99,by
comparison with the corresponding resonances of the 1H n.m.r. spectrum of
the tetrabromide 197. Similarly, the 13C n.m.r. spectrum of L99 exhibited
resonances consistent with its structure. Further confirmation of the structure
of 199 was given by the observation of three ions at mlz 298,300 and 302 in the
EI mass spectrum in the ratio of 1.:2:L, each corresponding to M+ + H.
Formation of the tetrabromide '1,97 in the above reaction of the
pyrrolidinone L7L is consistent with ionic bromination of the butenyl
sidechain by molecular bromine concomitant with free radical bromination at
the endocyclic carbon adjacent to nitrogen, as outlined in Scheme 5L.
Whereas the reactions of the pyrrolidinones T4L,L42,169 and L70 with
N-bromosuccinimide, described above, in each case gave products resulting
from molecular bromine addition to the corresponding 4,5-didehydro-
pyrrolidinones, it is peculiar in this instance that products of the analogous
reaction of 17L are not observed. It is presumable that the didehydro-
pyrrolidinone 203 formed, for example, by hydrogen bromide elimination
from the bromide 200 reacts by hydrogen bromide addition to give 203,
rather than by molecular bromine addition to give the dibromide 204
(Scheme 52).
Formation of the alcohol L98 may be explained by the same rationale as
for that of '1.97 with the exception that adventitious water presumably
intervenes in the ionic bromination of the butenyl moiety of L7L.
RESULTS AND D/SCUSSION - IV
704
Brz
Brz
Brz
Scheme 57
203
fr Br
Br\71
Br
NBS
Br
NBS
L99
NBS
Br
N
Br201
NBS
BrBr
N
L97
204
Br
200
Br
NBr
Br202
BrBr Br
- HBr200
o
Scheme 52
RESULTS i4ND DTSCUSSION - IV
105
Production of the dibromide 199 then simply results from ionic bromination
of the butenyl moiety of 77T as described in Scheme 51 above, and points to
the facility with which this process occurs.
The N-(p-methoxyphenyl)pyrrolidinone L72 was next chosen for study
as it was envisaged that endoryclic functionalization of a pyrrolidinone bearing
a removable protecting group on nitrogen would alternatively afford the
possibility of synthesis of bicyclic pyrrolidinones, through the subsequent
incorporation of a substituent on nitrogen suitable for further elaboration.
Removal of a para-methoxyphenyl substituent from nitrogen is achieved by
oxidative dearylation with ceric ammonium nitratel2O and this has been
reported as a general method for the preparation of N-unsubstituted
azetidinones.l2l Alternatively, a p-methoxyphenyl substituent may be cleaved
from nitrogen of azetidinones electrochemically, oia anodic oxidatio¡.l22 11i5
expected that these methods may similarly apply to the N-deprotection of
N-(p-methoxyphenyl)-substituted pyrrolidinones.
1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with two mole
equivalents of N-bromosuccinimide in the presence of a catalytic amount of
AIBN in an 8:L mixture of carbon tetrachloride and dichloromethane, heated
at reflux under nitrogen for 10 minutes, whilst irradiating with a 300 W
mercury lamp. The cooled crude reaction mixture thus obtained was treated
with two mole equivalents each of ethanol and 2,6-lutidine and afforded a
complex mixture of products containing a substantial amount of the unreacted
starting material 1^42, as judged by thin layer chromatographic analysis. No
attempt was made to isolate individual components of this product mixture.
The complex mixture obtained above was rationalized as due to
decomposition of the products of bromination of 172 during treatment with
N-bromosuccinimide. Accordingly, optimal yields of the products of reaction
RESULTS AND DISCUSSION - IY
706
of 172 were obtained when the pyrrolidinone L72 was treated with a limited
amount of N-bromosuccinimide over a shorter reaction time than above.
1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with a slight molar
excess of N-bromosuccinimide in the presence of a catalytic amount of AIBN
in an 8:L mixture of carbon tetrachloride and dichloromethane at reflux under
nitrogen whilst irradiating as above, but for only 5 minutes. Subsequent
treatment of the cooled crude reaction mixture with two mole equivalents
each of ethanol and 2,6-lutidine afforded, after chromatography, the desired 4-
bromo-S-ethoxypyrrolidinone 205 in 38Vo yield, based on 772. In addition, the
alcohol 206 and the S-succinimidopyrrolidinone 207 were obtained in yields of
L4 and 7Vo respectively, and 33Vo of the starting material 172 was recovered
unreacted.
o
Et N
N N N
o3
206
The 4-bromo-5-ethoxypyrrolidinone 205 was identifiable on the basis of
lH n.m.r. spectral characteristics that bore close similarity to those of the ether
186. A doublet resonance at õ 5.27 (l = 0.9 FIz) was consistent with the methine
proton of C5, with a doublet of doublet of doublets resonance at õ 4.35 (l = 6.4,
7.0,09H2) being attributable to the methine proton oÍ C4. The ethoxy
substituent of 205 gave rise to characteristic triplet and two doublet of quartets
resonances, at ô 1.19, 3.54 and 3.59, respectively. The EI mass spectrum
exhibited two molecular ions of equal abundance at mlz 313 and 315,
Br'-
Br
o
ocH3
207205
RESULTS AND DTSCUSSION - IY
707
confirming the presence of bromine in 205, and other spectroscopic properties
were in accord with this structure. The substituents at C4 and C5 of 205 were
assigned a trans geometry on the basis of the vicinal coupling constant being
0.9 Hz for the methine protons of C4 and C5.
The alcohol 206 was identified by 1H n.m.r. spectral characteristics that
were similar to those of the 4-bromo-5-ethoxypyrrolidinone 205. A doublet
resonance at ô 5.5L with / = 7.2FIz was attributable to the methine proton of C5
and a broad resonance at õ 1,.77 with equal peak area was then consistent with
the hydroxyl proton of 206. Further evidence of the hydroxyl group of 206 was
given by the observation of a broad infrared absorption at 3400 cm-1. Two
molecular ions of equal abundance at mfz 285 and 287 were observed in the EI
mass spectrum of 206 and other spectral characteristics were consistent with
the structure. As for 205, the C4 and C5 substituents of 206 were assigned a
trans geometry on the basis of the magnitude of the vicinal coupling constant
of the C4 and C5 methine protons.
The S-succinimidopyrrolidinone 207 was identified on the basis of
characteristic resonances in its 1H n.m.r. spectrum. A doublet of doublets
resonance at ô 6.20 (l = 8.9,2.2}lz-) and a singlet resonance at õ 2.55 in the ratio
of 1.:4, were consistent with the methine proton of C5 and the methylene
protons of the succinimide ring, respectively. Further evidence of the
succinimido substituent of 207 was given by the obiervation of an infrared
absorption at 1780 cm-1, characteristic of the imide carbonyl system, in addition
to that at 1712 cm-1 due to the lactam carbonyl. A molecular ion was observed
at mlz 288 in the EI mass spectrum and other spectroscopic properties were in
accord with the structure of.207.
Formation of the ether 205 in the above reaction of t72 is attributed to
initial bromination to give the S-bromopyrrolidinone 208 (Scheme 53>,
RESULTS AND DISCUSSION - IV
108
which undergoes subsequent reaction to give the dibromide 2L0 as postulated
for the analogous production of L49 from L41 in Chapter III, above. Reaction of
ethanol with the dibromide 270 then affords the ether 205. Similar reaction
R_ ocH3
NBS / hv
oBr Br o N
N- HBr
208 209 207
N..R
172
NH
RN
R+N..
R
Brz
- HBr
BrBrBr
NN
Et r
3
HHzo
RR
205 206
of adventitious water with the dibromide 2L0 accounts for production of the
alcohol 206. Formation of the minor product then presumably results from
reaction of the iminium species 219, in equilibrium with the S-bromo-
RESULTS AND DISCUSSION - IV
709
pyrrolidinone 208, with succinimide, present in the reaction mixture as the by-
product of bromination with N-bromosuccinimide.
The yield of the 4-bromo-5-ethoxypyrrolidinone 205 obtained in the
above reaction of the pyrrolidinone "172 with N-bromosuccinimide and
ethanol represents a 687o yield of product based on the mole quantity of
N-bromosuccinimide employed in the bromination step. As such, production
of the 4bromo-S-ethoxypyrrolidinone 205 from the pyrrolidinone 172 provides
good illustration of the free radical bromination procedure, described in this
chapter, as efficient methodology for the regioselective endocyclic
difunctionalization of pyrrolidinones. It was subsequently considered to
exploit this procedure in the synthesis of bicyclic pyrrolidinones aiø the
annelation of appropriate substituents thus introduced at C4 and C5 of a
pyrrolidinone. To this end, it was envisaged that substitution of an alkenyl
moiety for bromine at C5 of the dibromide 210 derived from L72 would
provide for subsequent cyclization onto C4 of the pyrrolidinone ring.
Accordingly, reaction of the pyrrolidinone L72 with N-bromosuccinimide
followed by altyl alcohol was investigated.
1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with a slight
molar excess of N-bromosuccinimide as described previously and the cooled
crude reaction mixture was treated with excess allyl alcohol and two mole
equivalents of 2,6-lutidine. Chromatogrupiy of the crude product mixture
then afforded the desired 4-bromo-5-altyloxypyrrolidinone 21L in 29Vo yield
based on L72, representing a 52% yíeld based on the amount of N-bromo-
succinimide employed in the reaction. In addition, the alcohol 206 was
obtained in ïVo yield and 487o of the pyrrolidinone 172 was recovered
unreacted. The yield of the allyl ether 21.L from the pyrrolidinone 172, aiø
this procedure, was improved to 47To when bromination of T72 was conducted
as above, but with five mole equivalents of N-bromosuccinimide. In this
RESULTS AND D/SCUSSION - IY
110
instance the alcohol 206 was obtained in addition, in 9Vo yietd and 31'Vo of the
starting material 172 was recovered. In each case above, production of a minor
amount of the S-succinimidopyrrolidinone 207 was also detected.
N
The ether 211 was characterized on the basis of its lH n.m.r. spectral
characteristics, being similar to those of its ethyl ether analogue 205. A doublet
resonance observed at õ 5.33 (/ = 0.8 FIz) and a doublet of doublet of doublets
resonance at õ 4.37 (l = 6.3,0.9, 0.8 FIz) were attributable to the methine protons
of C5 and C4, respectively. The presence of the allyl moiety in 211 was
confirmed by the observation of resonances at õ 5.20, 5.22 and 5.81 in the lH
n.m.r. spectrum, characteristic of the three olefinic protons, with resonances at
ô 132.90 and 118.27 in the 13C n.m.r. spectrum being attributable to the two
alkenyl carbons. Although the ether 211 was not sufficiently stable for
elemental analyses, two molecular ions of equal abundance were observed at
mlz 325 and 327 in the EI mass spectrum and other spectroscopic properties
were consistent with the structure. The substituents at C4 and C5 of 2LL were
assigned a trans geometry on the basis of the observed vicinal coupling
constant for the methine protons of C4 and C5.
Intramolecular free radical cyclization of the 4-bromo-5-allyl-
oxypyrrolidinone 21,1 was investigated by treatment with tri-n-butyltin
hydride according to the methodology reported by Hart and co-we¡¡"¡537,38 ¡o.
the intramolecular cyclization of related systems. Thus a dilute solution of tri-
Br
2T1
RESULTS AND DISCUSSION - IY
111
rx-butyltin hydride and a catalytic amount of AIBN in benzene was added
dropwise to a solution of the bromide 21L in benzene, whilst heating at reflux
under nitrogen. Chromatography of the crude product mixture thus obtained
afforded the tetrahydrofuropyrrolidinone 212 only, in 38Vo yield from the
bromide 211.
272
The product 21.2 was identified on the basis of a diagnostic doublet
resonance observed in the 1H n.m.r. spectrum at õ1.06 (l = 6.9 Hz), consistent
with the methyl substituent of the tetrahydrofuran ring. A doublet resonance
at õ 5.78 (l = 6.2H2) was attributable to the bridgehead methine proton at C5 of
the pyrrolidinone ring of 2L2, with a doublet of doublet of doublet of doublets
resonance at õ 3.02 (/ = 10.0, 8.0, 6.4, 6.2flz) being consistent with the second
bridgehead proton, at C4 of the pyrrolidinone ring. A molecular ion at mlz
247, was observed in the EI mass spectrum and other spectroscopic properties
were in accord with the structure of 212.
Formation of the tetrahydrofuropyrrolidinone 212 in the above
reaction of the bromide 211 with tri-z-butyttin hydride is attributable to exo
cyclization of the 3-oxa-5-hexenyl radical 213, formed upon initial bromine
atom abstraction by tri-n-butyltin radical (Scheme 54). Reduction of the
resulting exocyclic rad.ical 2L5 then affords the product2l2. The reduction of
S-hexenyl radicals by bimolecular hydrogen atom transfer from tributyltin
RESULTS AND DTSCUSSION - IV
Bra \
N
772
R
n-Bu3Sn'
exo
z-Bu3SnH
endo
N
2tL
RRN
273 214
aa
Hzc
216
n-Bu3SnH n-Bu3SnH
R
2L7
f{= ocH3
Scheme 54
hydride competes with their unimolecular ring closurelz3 and low stannane
concentrations are therefore required to minimize the amount of reduction
product obtained. To an extent, the lack of reduction product 21.4 from the
RNNtR
275
NR
212
RESULTS AND DISCUSSION - IV
113
above reaction of 21L then reflects the facility with which the 3-oxo-5-hexenyl
radical 2L3 cyclizes to 215. This is consistent with the high rate of cyclization
exhibited by analogous 3-oxo-5-hexenyl radicals.124,125 That tlrre exo cyclization
product 212 was obtained in the above reaction of 2Ll, with none of the endo
cyclization product 277 being obtained, is consistent with the usual course of
S-hexenyl radical cyclizations wherein products resulting from exo cyclization
form preferentially to those of endo cyclization.723,726
Free radical 1.,5-cyclizations of '1.,2-disubstituted S-hexenyl systems
analogous to 211 occur with a high degree of stereoselectivity,3S,l2T-129
whereby the major diastereomer obtained is invariably the thermodynamically
less favourable product, of which the three substituents of the newly formed
S-membered ring are in an all-cis geometry. For example, free radical
cyclization of the bromide 219127 afforded 2L9 as the major diastereomer in
54Vo yield and 220 as the minor diastereomer in 6.5Vo yield (Scheme 55). The
BrH
n-Bu3SnH +AIBN
218H
21.9
Scheme 55
stereochemical preference of such cyclizations may be rationalized as due to.Ji.o'- elt-.1 e-¡clv-rç,.l {i..rr-o*¡i1
^ the requirement of reaction aia a transition state geometry that affords the
rnaximal overlap between the semi-occupied p-orbital of the radical centre and
the æ*-orbital of the alkenyl moiety.123,128,129
Both 1H and 13C n.m.r. analysis of the tetrahydrofuropyrrolidinone 212
obtained from the free radicai cyclization of the bromide 211 indicated it to be a
single diastereomer. On the basis of the stereoselectivity exhibited in the free
ÇHa.ìH
H
220
RESULTS AND D/SCUSSION - IV
774
radical cyclization of related systems, the single diastereomer of 2L2 obtained
was assigned as that with the all-cis geometry, namely the (3S,3aR,6aS)-, (3R,
3aS, 6aR)-diastereomer (Figzre B).
F{sC¡,,
FI¿,
4'rlIJr
5 N
3
35,3aR, 6aS- 3R,3aS,6aR-
212
Figure I Numbering of (3S, 3aR, 6aS)-, (3R, 3aS, 6aR)-6-(p-methoxyphenyl)-3-methyl-S-oxotetrahydro f:ur oí2,3-blpyrrolidine (212).
Synthesis of the tetrahydrofuropyrrolidinone 212 Írom 172 exemplifies
the viability of the free radical bromination procedure described in this chapter
for the synthesis of bicyclic pyrrolidinones. Moreover, this example highlights
the provision of this methodology for selective elaboration of functionality
thus introduced at both C4 and C5 of a pyrrolidinone system.
HH
RESULTS ,AND DISCUSSION - IV
115
CoNcLUSToN
Free radical bromination of N-substituted p-lactams bearing activating
substituents at exocyclic carbon adjacent to lactam nitrogen results in
regioselective reaction at the exocyclic carbon adjacent to nitrogen. Although
the major mode of free radical bromination of the analogous y-lactams is
reaction at the exocyclic carbon adjacent to nitrogen, reaction at the endocyclic
carbon adjacent to nitrogen competes in this case. That the endocyclic
methylenes adjacent to nitrogen in y-lactams are more reactive towards free
radical bromination than those in the corresponding p-lactams is presumably
as a result of the relative degrees of ring strain in the endocyclic product
radicals resulting from hydrogen atom abstraction.
In the absence of activating substituents at the exocydic carbon adjacent
to nitrogen, the predominant mode of reaction of y-lactams in free radical
bromination is at the endocyclic carbon adjacent to lactam nitrogen. With
comparison to the regioselectivity displayed in radical bromination of
y-Iactams bearing activating substituents at the exocyclic carbon adjacent to
lactam nitrogen, the regioselectivity of reaction displayed in this case serves to
illustrate the influence of activating substituents at the exocyclic carbon
adjacent to lactam nitrogen of y-lactams upon the regioselectivity of radical
bromination.
Free radical bromination of N-substituted p-lactams bearing activating
substituents at exocyclic carbon adjacent to lactam nitrogen provides viable
methodology for direct regioselective exocyclic functionalization of
N-substituted p-lactams in synthesis. The product bromides thus obtained are
116
amenable to further elaboration at the exocyclic carbon adjacent to nitrogen oîa
both ionic and free radical carbon-carbon bond forming reactions.
Free radical bromination of y-lactams with N-bromosuccinimide at the
endocyclic carbon adjacent to nitrogen affords production of 4þ-dibromo-
pyrrolidinones, thus providing novel synthetic methodology for the
regioselective difunctionalization of 1-lactams at C4 and C5. The synthetic
utility of the difunctionalized y-lactams lies in their ability to be regio-
selectively modified at C5 aia ionic methodology and at C4 aia fuee radical
methodology.
Free radical bromination followed by elaboration of introduced bromide
functionality provides significant methodology for the regioselective
functionalization of N-substituted p- and 1-lactams.
777
ExpEnTMENTAL
General
Melting points were recorded on a Kofler hot-stage aPparatus and are
uncorrected.
Electron Impact (EI) mass spectra were recorded at 70 eV on an AEI MS-
30 spectrometer. Chemical Ionization (CI) and Fast Atom Bombardment (FAB)
mass spectra were recorded on a ZAB 2HF spectrometer. Major fragments are
given with their relative abundances in parentheses.
Elemental analyses were performed by Canadian Microanalytical
Service Ltd., New Westminster, British Columbia, Canada.
Infrared spectra were recorded on a Hitachi2T0-30 spectrometer as nujol
mulls between sodium chloride plates, or as liquid films or solutions where
indicated.
1¡1 n.m.r. spectra were recorded at 60 l:|ldHlz on a Varian T-60
spectrometer, or where indicated, at 300 ll'lÍIz on either a Bruker AC-P 300 or
CXP 300 spectrometer. 13C n.m.r. spectra were recorded either at 75.5 MHz on
either a Bruker AC-P 300 or CXP 300 spectrometer, or at 20Ji|rdÍIz on a Bruker
WP-80 spectrometer. N.m.r. spectra were recorded as dilute solutions in
deuterochloroform, using tetramethylsilane as an internal standard.
Flash column chromatography was carried out using MatrexrM silica gel
(pore size 60 Å, particle size 50 pm, No. 84072). Squat colrl*rfund preparative
thin layer chromatographies were carried out using Merck silica gel 60pp-25a
# ¡làric-L,n- ic¿a A.lo , níí, ,9 ,rf EXPERIMENTAL
118
(Art. 7749). Unless otherwise indicated, preparative thin layer
chromatographies were carried out on a Chromatotron 7924T (Harrison
Research; Palo Alto, California, USA).
A WOTAN Ultra-Vitalux@ 300 W sunlamp was used as the light source
in reactions of N-bromosuccinimide. N-bromosuccinimide was recrystallized
from water and dried under reduced pressure before use. Solvents were
purified and dried using standard methods. All organic extracts were dried
over anhydrous magnesium sulphate. Light petroleum refers to the fraction
with b.p. 66 - 69"C.
EXPERIMENTAL
719
Exocyclic Functionalizatíon of N-Substitutedp-Lactams
Preparation of the 2-azetidinones 72 - 76
N-(3-Bromopropionyl)glycine ethyl ester (77)
Thionyl chloride (30.5 g, 256 mmol) was added dropwise to ethanol
(200m1). Glycine (82) (19.2g,255 mmol) was added and the solution was
stirred in dry apparatus at room temperature, overnight. The solution'was
then concentrated under reduced pressure to give glycine ethyl ester
hydrochloride (83).
3-Bromopropionyl chloride (84) (39.0 g, 228 mmol) was dissolved in
dichloromethane (300 ml) and a solution of the crude glycine ethyl ester (83)
in dichloromethane (150 ml) and water (150 ml) was added. Sodium
bicarbonate was added as required to keep the solution basic and the mixtu¡e
was stirred at room temperature for 4 hr. The reaction mixture was filtered
and the dichloromethane layer was separated, washed with water (3 x 50 ml),
dried, and concentrated under reduced pressure to give a crude white solid
which was recrystallized from ethyl'acetate / Iight petroleum to give N-(3-
bromopropionyl)glycine ethyl ester (77) as fine white crystals. (30.5 g, 56%)-
m.p. 82'C (lit.az æ"C); v*o, 3245, 7746,7646 crn-l (lit.82 3240,7740,1640 cm-l);
1H n.m.r. (CDCle) õ 1.31 (3H, t, I 7.0H2, CHa), 2.87 (2}J, t,l 6.5H2, CH2CHzBT),
3.68 (zJJ, t,l 6.5Í12, CH2Br), 4.07 (2H, d, | 5.0H2, NCHz), 4.28 (2rI, q, | 7.0H2,
OCH2), 6.10 (1H, broad, NH).
EXPERIMENTAL
720
Ethyl 2-oxo-7-azetidineacetate (ZÐez
A solution of N-(3-bromopropionyl)glycine ethyl ester (77) (2.40 g,
10 mmol) in dichloromethane and acetonitrile (19:1., 200 ml) was added
dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide
(672 mg, 12 mmol) and tetra-n -butylammonium bromide (645 mg, 2 mmol) in
dichloromethane and acetonitrile (791-., 200 ml). After the addition was
complete, stirring was continued for 30 min. The precipitate was filtered off
and washed with dichloromethane (2 x 50 ml). The combined filtrates were
dried, and concentrated under reduced pressure to give an oil that was
chromatographed on a squat column of silica gel, gradient eluting with light
petroleum and ethyl acetate. The resulting oil was distilled to give ethyl 2-
oxo-'1.-azetidineacetate (72). (958 mg, 6'1.7o)- b.p. 110'C/0.05mm (block); Ymax
(liquid film) 2980, 7736 cm-7 (tit.82 1733 cm-1), (CHzCLù 7758, 1744 cm-7;
lHn.m.r. (300MH2, CDCI¡) õ 1,.29 (3Ft t, I7.7TIz, CHa), 3.03 (2F],,t,l 4.'L}lz,
C3-Hz), 3.M (211, t, I 4.7 llz, C4-Hz) , 3 .99 (2H., s, Co.-}{2) , 4.27 (2Il', q, | 7 .7 fIz,
OCHz); 13C n.m.r. ô 168.15,'1,67.82, 6'!..31., 42.98, 39.85, 37.50, 14.00.
N-(3-Bromopropionyl)aminoacetonitrile (78)
3-Bromopropionyl chloride (84) (42.9 g, 250 mmol) was dissolved in
dichloromethane (200 ml) and a solution of aminoacetonitrile
bisulphate (86) (40 g, 260 mmol) in water (100 ml) and dichloromethane
(100 ml) was added. Sodium bicarbonate was addecl as reqttired to keep the
solution basic and the mixture was stirred at room temperature for 4 hr. The
reaction mixture was filtered and the dichloromethane layer was separated,
washed with water (3 x 50 ml), dried, and concentrated under reduced pressure
to give a crude white solid which was recrystallized from ethyl acetate / light
EXPERIMENTAL
727
petroleum to give N-(3-bromopropionyl)aminoacetonitrile (78) as fine white
crystals. (9.2g,79Vo)- m.p. 64C; (Calcd for C5H7N2OBr lM+lmlz 1,89-9742.
Found: mlz 1.89.9730); (Anal. calcd for C5H7N2OBr: C, 31'.44; H, 3.69; N, 14.66.
Found: C, 37.67; H, 3.66; N, 14.76) ) \max 3300, 2250, 1655 cm-1; 1H n.m.r.
(CDC13) ô 2.90 (2I1, t, I 6.5}12, CH2CH2BT), 3.67 (2F{, t, I 65H2, CHzBr), 4.23
(2ÍI, d, ] 6.0 Hz, CH2CN), 6.80 (1H, broad, NH).
2-Oxo-1-azetidineacetonitrile (73)
A solution of N-(3-bromopropionyl)aminoacetonitrile (78) (1.91' g,
L0 mmol) in dichloromethane and acetonitrile (1.9:7, 200 ml) was added
dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide
(672mg, 12 mmol) and tetra-z-butylammonium bromide (645 mg, 2 mmol) in
dichloromethane and acetonitrile (19:1, 200 ml). After the addition was
complete, stirring was continued for 30 min. The precipitate was filtered off
and washed with dichloromethane (2 x 50 ml). The combined filtrates were
dried, and concentrated under reduced pressure to give an oil that was
chromatographed on a squat column of silica gel, gradient eluting with light
petroleum and ethyl acetate. The resulting oil was distilled to give 2-oxo-L-
azetidineacetonitrile (73). (611 mg, 62%)- b.p. 110'C/0.02mm (block); (Calcd
for CiH5,NzO Íl/r+l mlz 110.0480. Found mf z 110.0486); (AnaI. calcd for
CsHaNzO: C,54.54; H,5.49; N, 25.43. Found: C, 54.78; H, 5.77; N, 25.32); \max
(liquid film) 2972,2256,7754 cm-l; 1H n.m.r. (CDCls) õ 3.10 (2H, t,l 4.5ÍIz,
C3-Hz), 3.47 (2H', t,l 4.5Í12,C4-H2), 4.23 (2}{, s, CHzCN).
EXPERIMENTAL
122
N-Benzyl-3-bromopropionamide (79)
3-Bromopropionyl chloride (84) (t0 g, 58 mmol) was dissolved in
dichloromethane (80 ml) and a solution of benzylamine (88) (12.5 g,
117 mmol) in dichloromethane (20 ml) was added dropwise with stirring.
After the addition was complete the solution was stirred at room temperature
for a further 3 hr., then dichloromethane (50 ml) and water (100 ml) were
added. The organic layer was separated, washed successively with water (100
ml), dilute hydrochloric acid (2 x 50 ml), brine, saturated aqueous sodium
bicarbonate and brine again, then dried and evaporated under reduced
pressure. The residual solid was recrystallized from ethyl acetate / Light
petroleum to give N-benzyl-3-bromopropionamide (79) as fine white crystals.
(9.+ g, 677o)- m.p. 103"C (lit.sz 702 -1.,04'C); vrnaa 3288, 3092, '1.638, 1558, 726,
696 cm-l (1it.82 3280,1635 cm-l); rH n.m.r. (CDCls) õ 2.80 (zIJ., t, | 6.5H2,
CHzCHzBT), 3.68 (zIJ,t, ] 6.5Í1z,, CHzBr), 4.50 (zFl, d, ] 6.0 FIz, NCHz), 6.00 (1H,
broad, NH), 7.37 (5H, s, ArH).
1, -Benzyl -2-oxoazetidine Q Ðsz
A solution of N-benzyl-3-bromopropionamide (79) (4.84 g, 20 mmol) in
dichloromethane (200 ml) was added dropwise over 6 hr., to a stirred
suspension of powdered potassium hydroxide (1.34 g, 24 mmol) and tetra-ru-
butylammonium bromide (7.29 g, 4 mmol) in dichloromethane (200 ml).
After the addition was complete, stirring was continued for 30 min. The
precipitate was filtered off and washed with dichloromethane (2 x 50 ml). The
combined filtrates were dried, and concentrated under reduced pressure to give
an oil that was chromatographed on a squat column of silica gel, gradient
eluting with light petroleum and ethyl acetate. The resulting oil was distilled
EXPERIMENTAL
123
to give 1-benzyl-2-oxoazetidine (74). (2.26 g, Z0%)- b.p. 115C/0.08mm (block);
ymax (liquid film) 3024, 2956, 2904, 1734, "1.600, 7584, 7498, 71,4 cm-l (lit.sz
7740 cm-7); 1H n.m.r. (300MH2, CDCIs) õ 2.94 (2}l, t,l 4.1. ÍIz, C3-Hù, 3.73 (2ÍI,
t, I 4."1. Hz, C -Hz), 4.37 (2F{, s,Cg-Hz), 7.22 - 7.38 (5H, m, ArH).
N-Altyl-3-bromopropionamide (80)
3-Bromopropionyl chloride (84) (9.3 g, 54.2 mmol) was dissolved in
dichloromethane (60 ml) and allylamine (89) (6 g, '1.05 mmol) was added
dropwise with stirring. After the addition was complete the solution was
stirred at room temperature for a further 3 hr., then dichloromethane (50 ml)
was added. The solution was washed successively with water (3 x 50 ml),
dilute hydrochloric acid (2 x 50 ml), brine, saturated aqueous sodium
bicarbonate and brine again, then dried and evaporated under reduced
pressure to give an oil which solidified on standing. The residual solid was
recrystallized from ethyl acetate / light petroleum and subsequently distilled to
give N-allyl-3-bromopropionamide (80) as white crystals. (7.2 g, 69To)- b.p.
150'C/0.06mm (block); (Calcd for C6HlsNOBr Í]|l{+l mh 790.9943. Found; mlz
190.9950); (Anal. calcd for C5HlsNOBr: C,37.52;H,5.25;N,7.29. Found: C,37.73;
H,5.11; N,6.88); vTor (liquid film) 3288,3080, \640,930 cm-1; 1H n.m.r. (CDC13)
E 2.82 (2H, t, | 6.5 Hz, CHzCHzBT), 3.65 (2IF^, t, I 6.5 Hz, CHzBr), 3.90 (2H, dd, I6.0, 5.0 Hz, CH2CH=CHz), 5.00 - 5.35 (2H, m, CH=CH2), 5.57 - 6.18 (1H, m,
CH=CHz) , 6.60 (1H, broad, NH).
EXPERIMENTAL
1.24
7 - Allyl-2-oxo az etidine ( 7 5 )
A solution of N-allyl-3-bromopropionamide (80) (1.92 g, 70 mmol) in
dichloromethane and acetonitrile (79:-1,,200 ml) was added dropwise over 6 hr.,
to a stirred suspension of powdered potassium hydroxide (672m9, 12 mmol)
and tetra-n -butylammonium bromide (645 rr.g, 2 mmol) in dichloromethane
and acetonitrile (19:'1,,200 ml). After the addition was complete, stirring was
continued for 30 min. The precipitate was filtered off and washed with
dichloromethane (2 x 50 ml). The combined filtrates were dried, and
concentrated under reduced pressure to give an oil that was chromatographed
on a squat column of silica gel, gradient eluting with light petroleum and ethyl
acetate. The resulting oil was distilled to give L-allyl-2-oxoazetidine (75).
(335 mg, 30%)- b.p. 50C/0.2mm (block); (Calcd for C6HeNO [M+] mlz 1.11..0687.
Found: mlz 1.1,1..0686); \max (liquid film) 3080, 2960, 'J.744, '1,676,930 cm-l;
1H n.m.r. (300MFIZ, CDCIg) E 295 (2]F', t, I 4.1, flz, C3-Hz), 3.24 (2Í1, t,l 4.'j., Hz,
C4-Hù, 3.83 (2H, d,l6.7TIz,CHzCH=CHz), 5.19 -5.25 (2}l., m, CH=CHù,5.76
(1H, ddt, ] 77.3, 9.9, 6.'1, Hz, CH=CÍþ).
N-(3-Bromopropionyl)glycine benzyl ester (81)
Thionyl chloride (34.9 g, 293 mmol) was added dropwise to benzyl
alcohol (200 mt). Glycine (82) (20 g, 266 mmol) was added and the solution
was stirred in dry apparatus at room temperature, overnight. The white solid
that had precipitated during this time was extracted with watcr (3 x 100 ml) and
the combined aqueous layers were washed with dichloromethane (100 ml).
The aqueous solution was then concentrated under reduced pressure to give
glycine benzyl ester hydrochloride (91) as a white crystalline solid.
EXPERIMENTAL
725
3-Bromopropionyl chloride (84) (35 g, 204 mmol) was dissolved in
dichloromethane (200 ml) and a solution of the crude glycine benzyl ester
(91) in dichloromethane (100 mt) and water (100 ml) was added. Sodium
bicarbonate was added as required to keep the solution basic and the mixture
was stirred at room temperature for 4 hr" The reaction mixture was filtered
and the dichloromethane layer was separated, washed with water (3 x 50 ml),
dried, and concentrated under reduced pressure to give a crude white solid
which was recrystallized from ethyl acetate / light petroleum to give N-(3-
bromopropionyl)glycine benzyl ester (81) as fine white crystals. (4 g, 7Vo)-
m.p. 73C; (Calcd for C12H1¿NOgBr llú+l mlz 299.01.57. Found: mlz 299.0t73);
(Anal. calcd for C12H1aNO3Br: C,48.02;H,4.70; N,4.66. Found: C,47.99;H,4.53;
N, 4.66); v*o* 3308,3092, 1740,1,652, 7554,754,702 cm-1; 1H n.m.r. (CDCtg) õ
2.80 (zJJ, t, I 6.5tlz, CH2CHzBT), 3.60 (zFj, t, ] 6.5H2, CHzBr), 4.12 (2F{, d,l5.0Í12, NCHÐ, 5.18 (2H, s, CH2Ph), 6.57 (1H, broad, NH), 7.33 (5H, s, ArH).
Benzyl 2-oxo-'1,-azetidineacetate (76)
A solution of N=(3-bromopropionyl)glycine benzyl ester (81) (2.2 g,
10 mmol) in dichloromethane and acetonitrile (79:7, 200 ml) was added
dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide
(672mg, 12mmol) and tetra-n-butylammonium bromide (645mg,2mmol) in
dichloromethane and acetonitrile (79:7, 200 ml). After the addition was
complete, stirring was continued for 30 min. The precipitate was filtered off
and washed with dichloromethane (2 x 50 ml). The combined filtrates were
dried, and concentrated under reduced pressure to give an oil that was
chromatographed on a squat column of silica gel, gradient eluting with tight
petroleum and ethyl acetate. The resulting oil was distilled to give benzyl2-
oxo-l-azetidineacetate(76). (490 mg, 227o)- b.p. 160"C/0.001mm (block); (Calcd
EXPERIMENTAL
126
for Cl2HreNOs [M+] mlz 21,9.A895. Found: mlz 279.0885); (Anal. calcd for
C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.59; H, 6.01,; N, 6.40); Ymax
(liquidfilm)3030,2964,1760,1742,1502,744,700 cm-1; 1Ff n.m.r. (CDClt õ 2.99
(2Êl,t,l AJl,lfz, C3-H/, 3.38 (2H, t,] A|l.Hz,C4-Í12), 4.01, (2Ê1,s, Ccr-Hz), 5.12(2Í1,
s, CH2Ph), 7.33 (5H, s, ArH).
EXPERIMENTAL
127
Reactions of the 2-azetidinones 72 - 76
Ethyl cr-bromo -Z-oxo-7-aze tidinea ce tate (9 2)
A mixture of ethyl 2-oxo-1.-azetidineacetate (72) (156 mg, 0.99 mmol) and
N-bromosuccinimide (1,77 mg, 0.99 mmol) in carbon tetrachloride and
dichloromethane (5:1, 9 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for 15 min. The cooled reaction
mixture was filtered through glass wool and concentrated under reduced
pressure to give ethyl cr-bromo-2-oxo-1-azetidineacetate (92) as a pale yellow
o7l:- vrna, (liquid film) 2960, 1783, 1752 crn-7; 1H n.m.r. (300MH2, CDCI3) ô
1.33 (3H, t, I 7.t IJz, CHs), 3.01 (1H, ddd, /33' 15.6, þ4ç¡s 6.2, ]34' tro* 3.5 ÍIz, C3-H),
3.11 (1H, ddd, /33, 15.6, 13'4'çis 5.9, ]3'Atronr 3.9 Hz, C3-H'), 3.56 (1H, ddd, I++' 6.5,
IUr¡" 6.2, Ig,Atrort 3.9 Í12, C+H), 3.70 (1H, ddd, I++, 6.5, Ig,A'rir 5.9, ]34,trøns 3.5H2,
C4-H'), 4.27 (2F{, q,, I 7.1 ÍIz, OCH2), 6.33 (1H, s, Ccr-H).
Ethyl a-ethoxy-2-oxo-1-azetidineacetate (93)
Ethyl cr-bromo-2-oxo-1-azetidineacetate (92) was prepared, as described
above, from ethyl 2-oxo-1-azetidineacetate (72) (168 mg, 1.07 mmol) and
N-bromosuccinimide (190 mg, 1.07 mmol) in carbon tetrachloride and
dichloromethane (5:1, 9 ml). To the cooled crude reaction mixture was added
dry ethanol (130 ¡tl, 2.22 mmol) and 2,6-lutidine (250 pl, 2.15 mmol) and the
resulting mixture was stirred at room temperature under nitrogen for L hr.
The reaction mixture was filtered and evaporated under reduced pressure.
The residue was taken up in ethyl acetate and washed successively with very
dilute hydrochloric acid, brine, saturated aqueous sodium bicarbonate, and
EXPERIMENTAL
728
brine again. The organic layer was separated, dried and evaporated under
reduced pressure and the residue was purified by flash column
chromatography on silica, eluting with a mixture of chloroform and methanol
(100:1) to give ethyl cr-ethoxy-2-oxo-L-azetidineacetate (93) as an oil. (1.23 mg,
57%):- b.p.60"C/0.001.mm (block); (Calcd for CeHl5NO¿ [M* +H]m12202.7079.
Found: mlz 202.7089); (Anal. calcd for C9H15NO4: C,53.72; H,7.57; N, 6.96.
Found: C, 53.69; H,7.33; N, 6.85); v*o¡ (liquid film) 2984, 1750, 121'8, t094 cm-l;
lH n.m.r. (300MI{2, CDCts) õ 1.27 (3H, t, I 7.0ÍIz, CHOCHzCHù, 1.32 (3H, t, I7.2H2, COzCHzCHg), 3.01 (1H, ddd, /33' 13.4, lg4ç¡r 4.9,148tuon, 3.3ÍIz, C3-H),
3.07 (1H, ddd, /33' 13.4, lg'4'çis 4.9,143'trorr 3.9 Hz, C3-H'), 3.41' (1H, ddd, 144' 5.4,
Igari" 4.9,l4g,tror,3.9H2, C4-H), 3.46 (LH, ddd, I+t 5.4,19,4'rit 4.9,l4ltrone 3.3flz,
C4-H'), 3.59 (1H, dq,, 19.5,7.0II2, CHOCHHCH3), 3.68 (1H, dq, if9.5,7.0H2,
CHOCHHCHI), 4.26 (?,F{, q, I 7.2ÍIz, COzCHzCH¡), 5.35 (1H, s, Ccr-H).
cr-Bromo -2- oxo -I-azetidineacetonitrile (9 7)
A mixture of 2-oxo-L-azetidineacetonitrile (73) (1'62rng, L.47mmol) and
N-bromosuccinimide (288 mg, 1.62 mmol) in carbon tetrachloride and
dichloromethane (2:7, 9 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for 30 min. The cooled reaction
mixture was filtered through glass wool and concentrated under reduced
pressure to give cr-bromo-2-oxo-1-azetidineacetonitrile (97) as a yellow oil :-
vmax (CCIQ 2986,2308,7794,7725 crn-l; 1H n.m.r. (300MFIz, CDCI3) ô 3.11 (1H,
ddd, /ag' 75.7,134¿¡5 6.0, J43tuors 4.1.flz, C3-H), 3.21 (1H, ddd, /33' 1.5.7, l3'4'çis 5.9,
]4Z,tron, 4.0 Hz, C3-H'), 3.52 (7H, ddd, 144' 6.7, Iz+ci, 6.0, I+3'tron, 4.0 ÍIz, C4-H),
3.56 (1H, ddd,l++' 6.7,I3'+,rir5.9,|+Btrons 4.7Ífz, C4-H'), 6.M (1H, s, Ccr-H).
EXPERIMENTAL
729
cr-Ethoxy -2-oxo-L-azetidineacetonitrile (98)
cr-Bromo-2-oxo-L-azetidineacetonitril e (97) was prePared, as described
above, from 2-oxo-1-azetidineacetonitrile (73) (184 mg, l'.67 mmol) and
N-bromosuccinimide (327 mg, 1.84 mmol) in carbon tetrachloride and
dichloromethane (2:1, 9 ml). The cooled crude reaction mixture was treated
with dry ethanol (200 ¡rl, 3.40 mmol) and 2,6-lutidine (390 ¡tl, 3.34 mmol) as
described above for the preparation of the cr-ethoxy-azetidineacetate 93. The
residue obtained upon workup was purified by flash column chromatography
on silica, eluting with a mixture of chloroform and methanol (100:1), to give
c-ethoxy-2-oxo-1.-azetidineacetonitrile (98) as an oil. (1.06m9,47Vo)¡ 115 -120C /0.08mm (block); (Calcd for CzHroNzOz [M+l mlz 1,54.0742. Found: mlz
1.54.0740); (Anal. calcd for C7H16N2O2: C, 54.54; H, 6.53; N, L8.16. Found: C,
54.97;H, 6.39; N, 18.60); v*a¡ (liquid film) 2975,2250,1755,7245,1075 cm-1; 1H
n.m.r. (300MH2, CDCIg). ô 1.27 (3H, t, I 7.0ÍIz, CI{ù, 3.07 (LH, ddd, lss'1.5.2,
]gqri"5.5,I4S¡.ans3.8H2, C3-H), 3.13 (1H, ddd,/33'75.2,13'4'¿¡55.4,I+g't ons3.9Hz,
C3-H'), 3.50 (1H, ddd,ld+,7.9,[g+rir5.5,il43'trans3.9TIz,CA-H), 3.52 (1H, ddd,l+q'
7.9,1g'+,rir5.4,l4ltrar, 3.8 TIz, C4-H'),3.63 (fFI, dq, I 9.3,7.0H2, CHHCHg), 3.62
(1H, dç 19.3,7.0H2, CHHCH3), 5.68 (1I{, s, Ccr-H).
Treatment of 1-benzyl-2-oxoazetidine (74) with
N-bromosuccinimide
A mixture of 1-benzyl-2-oxoazetidine (74) (100 rng, 0.62 mmol) and
N-bromosuccinimide (111 mg, 0.62 mmol) in carbon tetrachloride and
dichloromethane (5:1, 18 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for 15 min. The cooled reaction
mixture was filtered through glass wool and concentrated under reduced
EXPERIMENTAL
130
pressure to give a yellow residual oil. Thin layer chromatography and 1H
n.m.r. spectroscopic analysis of the residue revealed a complex mixture of
products containing benzaldehyde (10L) and a minor amount of unreacted 1-
benzyl-2-oxoazetidine (74):- 1H n.m.r. (CDCts) õ 10.03 (sharp singlet, PhCHO).
No discrete products were isolated from this mixture.
Competitive reaction between ethyl 2-oxo-L-azetidineacetate (72)
and L -be nzyl-Z-oxoazetidine (74) with N-bromosuccinimide
A mixture of ethyl 2-oxo-1-azetidineacetate (72) (57 mg, 0.36 mmol), 1-
benzyl-2-oxoazetidine (7 4) (70 mg, 0.43 mmol) and N-bromosuccinimide
(65 mg, 0.37 mmol) in carbon tetrachloride and dichloromethane (5:1, 12 ml)
was heated at reflux under nitrogen, whilst irradiating with a 300 W mercury
lamp, for L5 min. The cooled reaction mixture was filtered through glass wool
and concentrated under reduced pressure. 1H n.m.r. spectroscopic analysis
of the residue revealed a complex mixture of products containing
benzaldehyde (10L) a minor amount of unreacted 1-benzyl-2-oxoazetidine (74)
and a major amount of unreacted ethyt 2-oxo-1.-azetidineacetate (72). 1H n.m.r.
spectroscopic analysis gave no evidence for the presence of ethyl cr-bromo-2-
oxo-l-azetidineacetate (92) in the crude product mixture.
Treatment of 1-allyl-2-oxoazetidine (75) wi th N-bromosuccinimide
A mixture of 1,-allyl-2-oxoazetidine (75) (64.2 rng, 0.58 mmol) and
N-bromosuccinimide (103 mg, 0.58 mmol) in carbon tetrachloride (8 ml) was
heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp,
for L5 min. The cooled reaction mixture was filtered through glass wool and
EXPERIMENTAL
131
concentrated under reduced pressure to give a brown residual oil. 1H n.m.r.
spectroscopic analysis of the residue revealed a complex mixture of products
containing unreacted l-allyl-2-oxoazetidine (75). No discrete products were
isolated from this mixture.
Competitive reaction between ethyl 2-oxo-'1.-azetidineacetate (72)
and L -allyl-2-oxoazetidine (75) with N-bromosuccinimide
A mixture of ethyl 2-oxo-1-azetidineacetate (72) (97 rng, 0.62 mmol), L-
allyl-2-oxoazetidine (75) (68 mg, 0.6L mmol) and N-bromosuccinimide (109 mg,
0.6L mmol) in carbon tetrachloride and dichloromethane (5:7, '1,2 ml) was
heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp,
for L5 min. The cooled reaction mixture was filtered through glass wool and
concentrated under reduced pressure. 1H n.m.r. spectroscopic analysis of the
residue revealed a complex mixture of products containing a minor amount of
unreacted 1-altyl-2-oxoazetidine (75) and a major amount of unreacted ethyl 2-
oxo-l-azetidineacetate (72). 1H n.m.r. spectroscopic analysis gave no evidence
for the presence of ethyl cx,-bromo-2-oxo-1.-azetidineacetate (gZ) in the crude
product mixture.
Treatment of benzyl 2-oxo-1.-azetidineacetate (76) with
N-bromosuccinimide
A mixture of benzyl 2-oxo-7-azetidineacetate (76) (57.7 rr.g, 0.26mmol)
and N-bromosuccinimide (47 mg, 0.26 mmol) in carbon tetrachloride and
dichloromethane (2:7, 6 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for 15 min. The cooled reaction
EXPERIMENTAL
1,32
mixture was filtered through glass wool and concentrated under reduced
pressure to give an oil comprising of an approximately 3:1 mixture of benzyl a-
bromo-2-oxo-1-azetidineacetate (109) and cr-bromobenzyl 2-oxo-7-
azetidineacetate (110) as judged by 1H n.m.r. spectroscopic analysis. No discrete
products were isolated from this crude reaction mixture.
Benzyl cr-bromo-2-oxo-7-azetidineacetate (109):- 1H n.m.r. (300MH2,
CDCIs) ô 2.93 (l!l, m, C3-H), 3.05 (1H, m, C3-H'), 3.52 (7H, ddd, ] 6.6, 6.6,
4.0 ÍIz, C4-H), 3.62 (1H', ddd, / 6.7, 6.6, 3.4H2, C4-H'), 5.18 (2H, s, CHzPh) , 6.36
(1.H, s, Ccr-H), 7.33 (5H, m, ArH).
a-Bromob enzyl 2-oxo-L-azetidineacetate (110):- lH n.m.r. (300MH2,
CDCIg) õ 2.99 (2}l,m, C3-Hz), 3.38 (2H, m,C4-H2), 4.77 (2H,,s, Ccr-Hz), 7.32-
7.56 (sIJ, m, ArH), 7.49 (1H, s, CHBr).
EXPERIMENTAL
133
Elaboration of Functional ized N-Substituted
B-Lactams
Ethyl a-phenylthio -2 -o xo -1. -azetidinea cetate (1L3 )
Ethyl o-bromo-2-oxo-1-azetidineacetate (92) was prepared, as described
above, from ethyl 2-oxo-1.-azetidineacetate (72) (779 mg, 1.14 mmol) and
N-bromosuccinimide (224 rng, 1.26 mmol) in carbon tetrachloride and
dichloromethane (5:1, 12 ml). The reaction mixture was cooled in an ice-bath
to 0 - 5"C, thiophenol (240 ¡tL,2.34 mmol) and 2,6-lutidine (270 ¡tI, 2.32 mmol)
were added and the resulting mixture was stirred under nitrogen for 2.5 hr.
The reaction mixture was filtered and evaporated under reduced pressure.
The residue was taken up in ethyl acetate and washed successively with very
dilute hydrochloric acid, brine, saturated aqueous sodium bicarbonate, and
brine again. The organic layer was separated, dried and evaporated under
reduced pressure and the residue was purified by preparative thin layer
chromatography on silica, gradient eluting with a mixture of light petroleum
and ethyl acetate to give ethyl cr-phenylthio-2-oxo-1-azetidineacetate (113) as an
oil. (192mg,647o)- b.p. 120"C/0.03mm (block); (Anal. calcd for C13H15NO3S:
C, 58.85; H, 5.70; N, 5.28. Found: C, 58.32; H,5.57; N, 5.24); vlnaa (Iiquid film)
2980, 7736,7582,1482 cm-1; 1H n.m.r. (300MH2, CDCIs) õ 7.27 (3H, t, I 7.']..Ífz,
CHa), 2.73 (7F{, ddd, /33' 74.9,124,c¡s5.9, ht'trrns3.7F{z, C3-H), 290 (1H, ddd, /33'
74.9, J3'4'cis 5.7, J3' tront 3.7 Hz, C3-H'), 3.46 (7F{, ddd, lgaçis 5.9, Iq+' 5.8, J3, trort
3.7 Hz, C4-H), 3.53 (1H, ddd, laa, 5.8, IZ'q'rir 5.7, I3+'tra* 3.7 Hz, C4-H'), 4.20 (2F{,
q, I 7.7 Hz, OCHù, 5.82 (1H, s, Ccr-H) 7.30 - 7.35 (3H, m, ArH), 7.46 - 7.57 (2}I,
m, ArH); 13C n.m.r. õ 767.24,766.46,733.23,1,30.99,729.28,728.79,62.27,58.48,
37.72,36.60,13,95.
EXPERIMENTAL
734
Di ethyl 2- (2- oxo -'I., - azetidin e ) mal e a te ( 1 1 5)
Ethyl cr-bromo-2-oxo-L-azetidineacetate (92) was prepared as described
above from ethyl 2-oxo-7-azetidineacetate(72) (202mg, 1.29 mmol) and
N-bromosuccinimide (252mg, 1.42mmol) in carbon tetrachloride and
dichloromethane (5:1, 12 ml). The crude bromide 92 was dissolved in dry
L,4-dioxane (20 ml), triphenylphosphine (675 mg, 2.57 mmol) and 2,6-lutidine
(300 pl, 2.58 mmol) were added and the resulting mixture was stirred at room
temperature under nitrogen, overnight. The reaction mixture was filtered,
evaporated under reduced pressure and the residue was worked up as
described above for the preparation of the thioether L1-3. The resulting crude
oil was purified by preparative thin layer chromatography on silica, eluting
with a mixture of light petroleum and ethyl acetate (50:50) and afforded diethyl
2-(2-oxo-'1.-azetidine)maleate (115) as an oil. (47 mg, 1.5Vo)- b.p.70"C/ 0.02mm
(block); (Calcd for C11H1sNOs lM+) mþ 247.0950. Found: mk 247.0958); (Anal.
calcd for C11H1SNOs : C,54.77;H,6.27; N, 5.80. Found: C,55.22;H,6.28; N, 5.86);
v¿a¡ (liquid film) 3080, 2988, 7774, 1722, 7628,1028 cm-1; 1H n.m.r. (300MH2,
CDCIg) ô 1.31 (3H, t,l 7.1.H2, CHs), 7.34 (3H, t, I 7.'l.Hz, CHg), 3.70 (2H.,t,l
4.9 TIz, C3'-H2), 3.92 (2F{, t, I 4.9 tlz, C4'-H2), 4.23 (2}I, q, I 7.'1. ffz, OCHz), 4.30
(zJJ, q,l 7.'l.Hz, OCHz), 6.31 (1H, s, C=CH); 13C n.m.r. ô 165.33 (C=O), 1.64.26
(COzEt),762.77 (COzEt),733.79 (C2),115.50 (C3),62.33 (OCHÐ, 60.94 (OCHÐ,42.66
(C4' ¡, 37 .55 (C3'), 1,4.06 (CFt3¡, 73.92 (CU3¡.
tzíEthyl u-altyl-2-oxo - L -aze tidine a ce tate (Æ) a i ø fr ee radical allylation
of 92
Ethyl cr-bromo-2-oxo-1-azetidineacetate (92), prepared from ethyl 2-oxo-
1-azetidineacetate (72) (754 mg, 0.98 mmol) by treatment with N-bromo-
EXPERIMENTAL
135
succinimide (774 mg, 0.98 mmol) as described above, 'was dissolved in dry
benzene (10 ml). Allyltributyltin (840 mg, 2.54 mmol) and a catalytic amount
of AIBN were added and the mixture was stirred under nitrogen at room
temperature overnight. The reaction mixture was concentrated under reduced
pressure and preparative thin layer chromatography of the residue on silica,
gradient eluting with light petroleum and ethyl acetate afforded ethyl u-ally[-2-
oxe"l.-azetidineacetate (125) as an oil. (48 mg,25Vo):- (Calcd for C1¡HlsNOg [M*]
mlz 197.1,052. Found: mlz 197.7067); vvloa (liquid film) 3075,2970, 1750, 1730,
1640 cm-1; 1H n.m.r. (300MH2, CDCIg) ô 1.29 (3H,t,17.2H2, CHs), 2.M-2.56
(1.H, m, CHHCH=CHz), 2.67 -2.70 (1H, m, CHHCH=CHz), 2.92(1H, ddd, /33'
74.7, Igq,cis 5.4,134'trønr 3.0 flz, C3-H), 2.99 (1H, ddd, /ga' 1.4.7, l3'4,¿is 5.3, Ig' trort
3.1,ÍIz, C3-H'), 3.34(1H,ddd,ldt,5.4,lgnrir5.4,l3'4trarr3.1t7z,C4-F{), 3.50 (1H,
ddd,144, 5.4,[g'4,cis5.3,l34,trans3.0Hz, C4-H'), 4.20 (2I{, q.,l 7.7 FIz, OCH2), 4.49
(1H, dd, ] 5.2,9.7H2, Ca-H), 5.72-5.27 (2H, m, CH=CHù, 5.76 (1H, dddd,l17.0,'1.0.2, 7.0, 6.4H2, CH=CHz); 13C n.m.r. ô 170.06, 767.83, 1.32.97, 71.8.49, 67.40,
53.30, 37.94, 36.48, 34.21., 74.1.6.
In a subsequent preparation of 125, as described above, chromatography
of the reaction mixture gave, in addition, ethyl ø-hydroxy-2-oxo-L-
azetidineacetate (726) as an oil:- \max (CnCtg) 3350 (broad), 1755, 1735,
7720 qn-L; 1H n.m.r. (300MFIz, CDCI¡) ô 1.34 (3H, t, 17.7Í12, CHr), 3.01, (2}l,t,l
4.6flz, C3-Hz), 3.29 (7H, dt,l 4.6,4.6H2, C4-H), 3.48 (1H, dt,l 4.6, 4.6H2, C4-H'),
4.32(2ÞI, q,,l7.1Hz,OCHz), 4.86 (1H, broad (exchanges), OH), 5.49 (1H, s, Ccr-H).
This compound was not stable for complete characterization.
EXPERIMENTAT
736
Ethyl u- altyl-Z-oxo - 1 -azetidine acetate ( 1 2 5) a i a ionic allylation
of 92
Ethyl cr-bromo-2-oxo-1-azetidineacetate (92) was prepared from ethyl 2-
oxo-1.-azetidineacetate (72) (174mg, 1..11. mmol) by treatment with N-bromo-
succinimíde (217 mg, 'I-..22 mmol) in a mixture of carbon tetrachloride and
dichloromethane (5:'1,, 72ml) as described above, and the crude reaction
mixture was cooled in an ice bath to 0 - 5"C and stirred over powdered
molecular sieves @ Ã, 100 mg). Allyltrimethylsilane (700 ¡tl, 4.40 mmol) was
added with stirring followed by boron trifluoride etherate (550 pl, 4.47 mmol)
and the mixture was allowed to warm to room temperature whilst stirring
under nitrogen overnight. The reaction mixture was vacuum filtered into
brine (20 ml). The organic layer was separated, washed with brine (2 x 20 ml),
dried and evaporated under reduced pressure. Preparative thin layer
chromatography of the residue on silica, eluting with a mixture of light
petroleum and ethyl acetate (50:50) afforded ethyl o-allyl-2-oxo-L-
azetidineacetate (125) as an oll (74mg,347o).
E thyl u- (2-fur yI) -2 - ox o - 1 - azetidin e a c e ta t e (127 )
Ethyl c-bromo-2-oxo-1-azetidineacetate (92), prepared as described
above, from ethyl 2-oxo-L-azetidineacetate (72) (304 mg, 1.93 mmol) by
treatment with N-bromosuccinimide (378 rr.g, 2.12 mmol) in carbon
tetrachloride and dichloromethane (5:1, 18 ml), was dissolved in anhydrous
tetrahydrofuran (20 ml) and stirred over powdered molecular sieves (4 L,
250 mg). Furan (2.8 ml, 38.6 mmol) and zinc chloride (527 mg, 3.87 mmol)
were added and the resulting solution was stirred at room temperature for
3.5 hr. The reaction mixture was filtered into water (20 ml) and the resulting
EXPERIMENTAL
737
mixture was extracted with dichloromethane (3 x 50 ml). The combined
organic extracts were dried and evaporated under reduced pressure.
Preparative thin layer chromatography of the residue on silica, eluting with a
mixture of ethyl acetate and methanol (100:2) gave ethyl a-(2-furyl)-2-oxo-1-
azetidineacetate (127) as an oil. (268 mg,62Vo):- (Calcd for C11H1aNIO¿ lM+l mlz
223.0845. Found: mlz 223.0853); \møx (CHzClz) 2968, 1752, '1.608, 1504 cm-1;
lHn.m.r. (300MLIZ,CDCIg) õ 1.23(3H,t, I7.\tIz,CHs), 2.88(1H, ddd,lss,'1.4.7,
Igqrit 5.6, ]z+t ons 2.9 Hz, C3-H), 2.99 (1H, ddd, /33' 1,4.7, J3,4'ç¡s 5.5, I3'4trort 2.8 ÍIz,
C3-H'), 3.17 (lF{, ddd, laa' 5.5, |g+cis 5.6, l4g,t ons 2.8 ÍIz, C4-H), 3.61 (1H, ddd, l+t'
5.5, ]3,4'"is 5.5,lg4,trorr 2.9Hz, CA-H'), 4.18 (1H, dq,, I 1,"1,.2,7.0H4 OCIIHCHS),
4.22 (1H, dq J 1,7.2,7.0H2, OCHHCHù, 5.62 (1H, s, Ccr-H), 6.31 (1H, d, ] 3.2ÍIz,
C3'-H), 6.34(1H,dd,l'3.2,1-..9ÍIZ,C4'-H), 7.37 (1H,d,17.9H2,Cs'-}j); 13Cn.m.r.
õ 1.68.M,1,67.32,'].,46.96,1,43.76,110.60, 1,09.39,62.72,57.46,38.75,36.83,74.02.
N-Carboethoxyphthalimide (1gr) t os
Phthalimide (13 0 ) (72.5 g, 493 mmol) was dissolved in
dimethylformamide (325 ml) with the aid of triethylamine (90 ml) and the
solution was cooled to 3 - 5'C. Ethyl chloroformate (100 ml, 1046 mmol) was
added dropwise with vigorous stirring whilst the temperature of the mixture
wus Àaintained at 3 - 5C. After the addition was complete the mixture was
stirred for a further 1. hr., during which time the mixture was allowed to warm
to room temperature. The reaction mixture was then poured into water
(3000 ml) with vigorous stirring. The crystalline white precipitate was
collected by vacuum filtration, washed thoroughly with water, air dried and
recrystallized from ethanol to give N-carboethoxyphthalimide (L31) as fine
white crystals. (98.95 g,92To)- m.p. 78"C (lit.tos 80"C); v*o, 1808, 7768,7724,
EXPERIMENTAL
138
l604cm-1; 1Hn.m.r. (CDCI3) õ 1.48 (3H,t,l7.5flz, CHs), 4.53(2F{,q,17.5ÍIz,
OCHz), 7.77 - 8.1.3 (4H, m, ArH).
N-Phthaloylserine (1gg) t os
Serine (132) (2.1,0 g,20 mmol) and sodium carbonate (2.15 g, 20 mmol)
were dissolved in water (15 ml), then finely powdered N-carbo-
ethoxyphthalimide (131,) (4.5 g, 21 mmol) was added and the mixture was
stirred at room temperature for 30 min. The mixture was filtered and the
filtrate was extracted with ether (5 x 50 ml) to remove the by-product of
reaction, urethane. The aqueous layer was acidified with 6N hydrocNoric acid
to approximately pH 3, then extracted with ether (3 x 60 ml) and the resulting
organic extracts were dried and concentrated under reduced pressure. The
residue was recrystallized from ethyl acetate / Light petroleum to give
N-phthaloylserine (133) as a white crystalline solid. (4.05 g, 867o)- m.p. 152C
11i¡.10s 152C); v*o¡ 3528,3284,1752,7694,1606 cm-1; 1H n.m.r. (CDCls) E 4.24
(2IJ, d,l 6.5 Hz, CHzOH), 5.02 (1H, t, ] 6.5 Hz, Co-Il), 7.68 - 8.05 (4H, m, ArH).
N-Phthaloylserylglycine methyl ester (136)
A solution of N-phthaloylserine (133) (8.0 g, 34.0 mmol) in thionyl
chloride (70 ml) was heated at 80 - 90'C in dry apparatus for 4 hr. After
cooling, the solution was concentrated under reduced pressure, benzene
(30 ml) was added and the solution was again concentrated under reduced
pressure to give N-phthaloylseryl chloride (134) as a yellow oil.
The crude acid chloride 134 was dissolved in dichloromethane (200 ml)
and a solution of glycine methyl ester hydrochloride (135) (4.70 g, 37.4 mmol)
EXPERIMENTAL
739
(prepared as described below in the preparation of methyl 2-oxo-7-
pyrrolidineacetate (14L)) in water (100 ml) was added with stirring. Sodium
bicarbonate was added as required to keep the solution basic and the mixture
was stirred at room temperature for 4 hr. The reaction mixture was filtered
and the dichloromethane layer was separated, washed with water (2x100 ml),
dried and evapourated under reduced pressure. The residue was
chromatographed on a squat column of silica, gradient eluting with a mixture
of ethyl acetate and light petroleum to give N-phthaloylserylglycine methyl
ester (136) as a foamy toffee-like solid. (5.22 g, 57%)- v^o, (CHzClz) 3432, 3040,
2976,1776,1748,1722 c:n-7; 1H n.m.r. (300MH2, CDCIg) õ 2.93 (1H, broad, OH),
3.68 (3H, s, OCHa), 4.02 (1H, dd, I 1'1'.4, 5.4Í12, CH}{;OH), 4.03 (zfl', d, ] 5.4ÍIz,
NCHz), 4.38 (1H, dd, I 1,1,.4,7.6H2, CFT.HOH), 4.94 (7H, dd, I 7.6,5.4H2,
CHCHzOH), 7 .51. (l H, broad, NH), 7 .66 - 7 .72 (2H m, ArH), 7.76 - 7.84 (2}l, m,
ArH); (lit.to¿ 3.0 - 3.4 (1H, br), 3.73 (3H, s), 3.94 - 4.6 (3H, m), 4.9 - 5.06 (1H,
m), 7.6 - 8.0(5H, m)); 13C n.m.r. ô 170.33,168.78,1.68.07,1.34.29,]..3'1..6't',123.58,
60.72, 54.19, 52.40, 41,.29.
M e thyt 2- oxo -3 -phth aI o yI-L - azetidine ac e t v¡s (129)1' 0 a
N-Phthaloylserylglycine methyl ester (136) (7.57 g, 5.13 mmol) and
triphenylphosphine (1.36 g, 5.'J.9 mmol) were dissolved in tetrahydrofuran
(100 ml), then diethylazidodicarboxylate (DEAD) (O.Sf ml, 5.14 mmol) was
added dropwise under nitrogen. The reaction mixture was stirred at room
temperature overnight then quenched by the addition of water (100 ml) and
the resulting mixture was extracted into dichloromethane (2x100 ml). The
organic layer was washed with brine, dried and concentrated under reduced
pressure. The residue was purified by repeated preparative thin layer
chromatography on silica, eluting with a mixture of dichloromethane, light
EXPERIMENTAL
740
petroleum and íso-propanol (80:20:0.8) to give N -phthaloyl-cr, p-
didehydroalanylglycine methyl ester (137) as fine white needles (564 mg, 38Vo)
and a mixture of methyl 2-oxo-3-phthaloyl-1,-azetidineacetate (129) and
dicarboethoxyhydrazine. Repeated recrystallization of this mixture from
dichloromethane / light petroleum afforded methyl 2-oxo-3-phthaloyl-1-
azetidineacetate (729) as a white crystalline solid (48 mg,37o).
Methyl 2-oxo-3-phthaloyt-L-azetidineacetate (L29)- m.p. 178'C (lit.to¿
1,78 - f 80C); \max (CHCls) 7786, 7775, 7748, 1720 cm-7 (lit.to¿ (CHCI3) 1785,
'1,770, 1750, 1.720 cm-l); lH n.m.r. (300MFI2, CDCIg) ô 3.80 (3H, s, CHs), 3.84
(1H, dd, ]++, 5.3, 134,t orr 2.9 Í12, C4-H'), 3.91 (1H, dd, lZqrit 5.5, lq4, 5.3 Hz, C4-F{),
4.02 (1H, d,lglo, 18.0H2, Ccr-H), 4.58 (1H, d, Iao' 'l-.8.0H2, Cc-H'), 5.56 (1H, dd,
Igqri"5.5,lg4,tronr2.9ÍIz,C3-H), 7.73 -7.89 (4H,m, ArH); 13C n.m.r. ô "1.68.22,
766.86, 'l..64.99, ]34.M, 737.78, "123.69, 54.49, 52.42, 47.04, 43.76.
N-Phthaloyl-ø,8-didehydroalanylglycine methyl ester (137)- m.p. 121 -1,22"C; \max 3264, 7752,'].,722,']-,662,1628 cm-l; 1H n.m.r. (300MFIZ, CDCIg) ô
3.75 (3H, s, OCHe), 4.1,3 (2F{, d, / 5.1 FIz, NHCHz), 5.83 (1H, d, I 1..2H2, C=CHH),
6.24 (1H, d, I ],.2LIz, C=CFIH), 6.73 (1H, broad, NH), 7.73 - 7.77 (zFl,, m, ArH),
7.87 - 7.89 (2H, m, ArH); 13C n.m.r. õ 170.08, 1.66.40, 763.08, 1.34.55, 7432.29,
73]'66, 123.94, 120.9'1., 52.53, 41..57 .
N-Phthaloyl-B-chloroalanylglycine methyl ester (138)
N-Phthaloylserylglycine methyl ester (L36) (7,79 g, 5.84 mmol) was
dissolved in freshly distilled dry tetrahydrofuran (60 ml) under nitrogen.
Calcium carbonate (58 mg, 5.84 mmol) was added and the stirred mixture was
cooled in an ice bath to 0 - 5"C. Phosphorous pentachloride (7.46 g,
7.01 mmol) was added and the mixture was stirred at 0 - 5C for 10 min. The
EXPERIMENTAL
74't
ice bath was then removed from the reaction mixture and stirring was
continued at room temperature for a further t hr. The reaction mixture was
filtered, dried and evaporated under reduced pressure to give an oily residue
that was chromatographed on a squat column of silica, gradient eluting with
light petroleum and ethyl acetate. Recrystallization from ethyl acetate / light
petroleum afforded N-phthaloyl-B-chloroalanylglycine methyl ester (138) as a
white crystalline solid (1..31, g, 697o)- m.p. L3L'C; EI mass spectrum: mlz
326([M+], 1), 324 ([M+], 3),289 ([M+ - Ct],2), 288 ([M+ -HCl], 4), 257 (3), 238 (4),
236 (72), 21,0 (33), 208 (100); (Calcd for C1aH13N2O5CI [U+1 mlz 324.051,3.
Found: mlz 324.0502); (Anal. calcd for C14H1¡NzOsCl: C,57.78;H,4.04; N, 8.62.
Found: C, 52.07 ; H, 4.12; N, 8.42); v max 3272, 7782, 17 M, 7720, 7650, 722 cm-7 ; 7H
n.m.r. (300MIIZ, CDCIg) õ 3.77 (3H, s, CHr), 4.05 (2H., dd,15.7,2.7ÍIZ,NHCH2),
4.27 (7H, dd, ] 7'1,.3,5.7 flz, CIIHCI), 4.35 (lH, dd, I 1.'].,.3,70.5Ífz, CHHCI), 5.13
(lH dd, ] '1,0.5,5.7 Í1z., CHCHzCI), 6.77 (1H, broad, NFf), 7.76 -7.92 (4H, m, ArH);
13C n.m.r. õ 1,69.71.,'1.67.56,'1.66.45,734.65,"13'1,.35,1,23.95,55.13, 52.52, 47.36, 40.99.
Attempted cyclization of N-phthaloyl-B-chloroalanylglycine
methyl ester (138)
A solution of N-phthaloyl-B-chloroalanylglycine methyl ester (138)
(854 mg, 2.63 mmol) in dichloromethane and acetonitrile (19:1, 100 ml) was
added dropwise over 4 hr., to a stirred suspension of powdered potassium
hydroxide (177 mg, 3.15 mmol) and tetra-n -butylammonium bromide (1.46 mg,
0.53 mmol) in dichloromethane and acetonitrile (79:7, 100 ml). After the
addition was complete, stirring was continued for 30 min. The precipitate was
filtered off and washed with dichloromethane and the combined filtrates were
dried, and concentrated under reduced pressure. The residue was separated by
preparative thin layer chromatography on silica, eluting with a mixture of
EXPERIMENTAL
742
light petroleum and ethyl acetate to give N-phthaloyl-cr,p-didehydro-
alanylglycine methyl ester (137) (435 mg, 577o) and unreacted starting material
138 (165 mg,19Vo).
M ethyl cr-bromo -2- oxo-3-phthalo yl-7 - azetidine ace tate (13 9 )
A mixture of methyl 2-oxo-3-phthaloyL-'1.-azetidineacetate (129) (5.0 mg,
17.3 pmol) and N-bromosuccinimide (3.1 mg, 17.4 pmol) in carbon
tetrachloride and dichloromethane (5:1, 3 ml) was heated at reflux under
nitrogen, whilst irradiating with a 300 W mercury lamp, for 15 min. The
cooled reaction mixture was filtered through glass wool and concentrated
under reduced pressure to give a 3:2 mixture of diastereomers of methyl a-
bromo-2-oxo-3 -phth aüoyl-1. - azeti dine acetate ( L 3 9 ) : -
Major diastereomer: 1H n.m.r. (300MlIz, CDCte) ô 3.83 (3H, s, CHs), 3.96 (1H,
dd, I+q' 6.3, Ig¡'trors 3.8FJ2, C4-H'), 4.12 (7F{, dd, I+t' 6.3,lgatit 6.0H4 C4-H), 5.56
(1H, ddd, Ig¿rir 6.0, I34,t onr 3.8, /eo 0.8 Llz, C3-H), 6.M (1H, d, /go 0.8 Hz, Co-}{),
7.74 - 7.91 (4H, m, ArH).
Minor diastereomer: 1H n.m.r. (300MH2, CDCIs) ô 3.84 (3H, s, CHg), 4.02 (7H,
dd, ]+4, 6.8,lgqrit 6.5H2, C4-H), 4.08 (1H, dd, ]++' 6.8,I3t'trons3.5ÍIz, C4-H'), 5.M
(1H, ddd, Iz+tit 6.5, Isq't onr 3.5, /ao 0.8 ÍIz, C3-H), 6.46 (1H, d, /ac, 0.8 Hz, Co.-FI),
7.74 -7.97 (4I{, m, ArH).
EXPERIMENTAL
1.43
Functionalization of N-Substituted y-Lactams
Preparation of the 2-pyrrolidinones 14L and \42
N-(4-Chlorobutyryt) glycine methyl ester (143)
Thionyl chloride (30.5 g, 256 mmol) was added dropwise to methanol
(150 mt). Glycine (82) (19 g,253 mmol) was added and the solution was stirred
in dry apparatus at room temperature, for 3 hr. The solution was then
concentrated under reduced pressure to give glycine methyl ester
hydrochloride (135).
4-Chlorobutyryl chloride (L45) (32 g, 227 mmol) was dissolved in
dichloromethane (200 ml) and a solution of the crude glycine methyl ester
(135) in dichloromethane (100 ml) and water (100 ml) was added. Sodium
bicarbonate was added as required to keep the solution basic and the mixture
was stirred at room temperature for 4 hr. The reaction mixture was filtered
and the dichloromethane layer was separated, washed with water (3 x 50 ml),
dried, and concentrated under reduced pressure. The residue was distilled to
give N-(4-chlorobutyryl)glycine methyl ester (143) as an oil. (20.6 g,47Vo)i b.p.
136"C / O.0S mm; (Calcd for C7H12NO3C1 [M+] mlz 193.0506. Found: mf z
193.0699); (Anal. calcd for CTHzNO3CI: C, 43.41,; H, 6.25; N, 7.23. Found: C,
43.23; H,6.55; N,7.15); v*a¡ (liquid fitm) 3304,2952,7752,1656 cm-l; 1H n.m.r.
(300MH2, CDC13) õ 2.13 (2F{, tt,l 7.2,6.2H2, CHzCHzCI), 2.46 (2F{, t,l 7.2H2,
CHzCONH), 3.63 (2F{, t, | 6.2H2, CHzCI), 3.76 (3H, s, CH3), 4.04 (2I{, d, | 5.4H2,
NCHz), 6.67 (7H, broad, NH); 13C n.m.r. E 172j17, 770.30, 52.1.5, M.20, 41'.03,
32.62,27.98.
EXPERIMENTAL
.I.M
Methyl 2-oxo-1-pyrrolidineacetate (141)
A solution of N-(4-chlorobutyryl)glycine methyl ester (143) (1.94 g,
10 mmol) in dichloromethane and acetonitrile (\9:7, 200 ml) was added
dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide
(672mg, 12 mmol) and tetra-n-butylammonium chloride (556 mg, 2 mmol) in
dichloromethane and acetonitrile (79:'1,, 200 ml). After the addition was
complete, stirring was continued for 30 min. The precipitate was filtered off
and washed with dichloromethane (2 x 50 ml). The combined filtrates were
dried, and concentrated under reduced pressure to give an oil that was
chromatographed on a squat column of silica gel, gradient eluting with light
petroleum and ethyl acetate. The resulting oil was distilled to give methyl 2-
oxo-1-pyrrolidineacetate (14L). (877 rng, 55Vo)¡ b.p. 130'C /0.02 mm (block);
vrry¡ï (liquid film) 2940,1754,1.685,1430 cm-1 (lit.trz 2960,1752,1685, 1440 cm-l);
1H n,m.r. (300MH2, CDCIa) ô 2.01 (2I{,tt, ]'8.1,7."1.ÍIz,C4-H2), 2.43(zfl,,t,l
8.1.H2, C3-H2), 3.50 (2H, t, I 7.7H2, CS-Hz), 3.74 (3H, s, CH¡), 4.08 (2FI, s,
Ccr-Hz); 13C n.m.r. õ 775.32 (amide C=O), 168.85 (ester C=O),51.83 (CH3¡, 47.41,
(c5), 43.61(Ca), 29.96 (C3),17.66 (C4) (lit.ltz 175.36,'1.68.94,5'1..87, 47.43, 43.69,
30.02,17.68).
N- (4-Chlorobutyryl) aminoacetonitrile (1-44)
4-Chlorobutyryl chloride (145) (35.3 g, 250 mmol) was dissolved in
dichloromethane (200 ml) and a solution of aminoacetonitrile
hydrochloride (146) (24 g, 259 mmol) in water (100 ml) and dichloromethane
(100 ml) was added. Sodium bicarbonate was added as required to keep the
solution basic and the mixture was stirred at room temperature for 4 hr. The
EXPE,RIMENTAL
1.45
reaction mixture was filtered and the dichloromethane layer was separated,
washed with water (3 x 50 ml), dried, and concentrated under reduced pressure
to give a crude white solid which was recrystallized from ethyl acetate / light
petroleum to give N-(4-chlorobutyryl)aminoacetonitrile (744) as fine white
crystals. (21,.5 9,547o)- m.p. 73"C; (Calcd for C6HeNzOCl ïi|'l+l mlz 160.0403.
Found: mlz 160.0478); (Anal. calcd for C6HeN2OCI: C, M.86; H, 5.65; N, 17.43.
Found: C, 45.06; H, 5.47; N, 17.56); \,tmax 3325, 2250, 1645 cm-1; 1H n.m.r.
(300MFIZ, CDCts) õ 2.1,4 (2}l, tt, ] 7 .2, 6.2Í12, CHzCHzCI), 2.47 (2ÉI, t, ] 7.2H2,
CH2CONH), 3.62 (2F{, t, I 6.2Í12, CH2CI), 4.79 (2F{, d, / 5.8 Hz, NCHz), 6.62 (1H,
broad, NH); 13C n.m.r. õ 772.24,1.'1.6.1,5, M.20, 32.49,27.63,27 .51..
2-Oxo-L -pyrrolidineacetonitrile (1,42)
A solution of N-(4-chlorobutyryl)aminoacetonitrile (L44) (1.6t g,
10 mmol) in dichloromethane and acetonitrile ('1,9:1,, 200 ml) was added
dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide
(672m.9, 12 mmol) and tetra-n-butylammonium chloride (556 mg, 2 mmol) in
dichloromethane and acetonitrile (79:'1., 200 ml). After the addition was
complete, stirring was continued for 30 min. The precipitate was filtered off
and washed with dichloromethane (2 x 50 ml). The combined filtrates were
dried, and concentrated under reduced pr"rr,rr" to give an oil that was
chromatographed on a squat column of silica gel, gradient eluting with light
petroleum and ethyl acetate. The resulting oil was distilled to give 2-oxo-1-
pyrrolidineacetonitrile (L42), which solidified upon refrigeration as a
translucent white crystalline solid. (842mg, 677o):- m.p. 32 - 34"C; b.p.
115"C/0.02mm (block); (Calcd for C6HgNzO [M+] mlz 724.0637. Found: mlz
724.0699); (Anal. calcd for C5,H3N2O: C, 58.05; H,6.50; N, 22.56. Found: C,57.78;
H,6.29;N,22.79); ymax (liquid film) 2940,2725, 1685, 1420 cm-1; 1H n.m.r.
EXPERIMENTAL
746
(300MFIZ,CDCI¡) E 2.1.4(2I-{,tt,18.7,7.'l.flz,C4-Hz),2.42(2Í1,t,]'8.'l.TIz,C3-Hz),
3.53 (zIJ', t, I 7.1,H2, C5-H2), 4.26 (2}{, s, CHzCN); 13C n.m.r. õ 774.4'1., 'j..74.29,
46.03, 29.97, 29.'1.4, 1,6.75.
EXPERIMËNT.AL
147
Functionalization of tlrre 2-pyrrolidinones L4l and T42
Methyl a-ethoxy-2-oxo-'1.-pyrrolidineacetate (149) and methyl trans-
4-bromo -5 -e thox y -Z-oxo -L -pyrrolidine ace tate (1 5 0 )
A mixture of methyl 2-oxo-1-pyrrolidineacetate (141) (412mg'
2.62 mmol) and N-bromosuccinimide (514 mg, 2.89 mmol) in carbon
tetrachloride (15 ml) was heated at reflux under nitrogen, whilst irradiating
with a 300 W mercury lamp, for 10 min. The reaction mixture was then cooled
to room temperature, dry ethanol (310 pl, 5.28 mmol) and 2,6-lutidine (620 ¡tl,
5.32 mmol) were added and the mixture was stirred at room temperature
under nitrogen for 2.5 hr. The reaction mixture was filtered and evaporated
under reduced pressure. The residue was taken up in ethyl acetate and washed
successively with very dilute hydrochloric acid, brine, saturated aqueous
sodium bicarbonate and brine again. The organic layer was dried and
concentrated under reduced pressure and flash column chromatography of the
residue on silica, eluting with a mixture of ethyl acetate and light petroleum
(40:60), yielded two products,149 and 150.
Methyl a-ethoxy-2-oxo-L-pyrrolidineacetate (L49) as an oil. (195 mg,
37Vo)- b.p. 75'Cl0.015 mm (block); FAB mass spectrum: mfz 201 ([M+], 12),
156 ([M+ - OEt], 100), 142 ([M+ - CO2Me),36), 728 (77), t08 (79); (Calcd for
C7H12NO2 [M+ - CO2Me] mlz 142.0868. Found: mlz 142.0875); Ymax (liquid
film) 2980,7754,1702,741,8,1268,1100 cm-1; lH n.m.r. (300MH2, CDCIg) õ 1'.26
(3H, t, 17.0ÍIz, OCHzCHa), 2.70 (2I{, m, C4-H2), 2.47 (2F{,1,] 8.7H2, C3-Hz),
3.37 (1H, ddd, / 9.8,7.8, 6.5}l2, Cs-H), 3.47 (7H, ddd, / 9.8, 7.8, 6.2Ílz, Cs-H'),
3.57 (zIJ, q, I 7.0}ir2, OCHzCHg), 3.79 (3H, s, CO2CHù, 5.75 (lH, s,Ca-H); 13ç
EXPERIMENTAL
748
n.m.r. ô 'J,76.04,'I..67.45, 78.36, 64.32, 52.50, 42.39, 30,80, 77.94,'1,4.58. This
compound was not stable for elemental analyses.
Methyl trans-4-bromo-5-ethoxy-2-oxo-1-pyrrolidineacetate (150) as an oil.
(60 mg, 9Vo)¡ b.p. 85'C/0.015 mm (block); EI mass spectrum: mlz 282 ([M+ +
Hl,7), 280 ([M+ + H, M+ - H], 72), 278 ([M* - H], 5), 249 ([M+ - MeOH], 8), 247
([M+ - MeOH] , 8), 235 ([M+ - EtOH], 11), 234 ([M+ - H - EtOH],98), 233 ([M+ -EtOHl, 11), 232 ([M+ - H - EtOH], 100), 199 ([M+ - HBr], 28); (Anal. calcd for
CsHr¿NO4Br: C, 38.59; H,5.04; N, 5.00. Found: C, 38.58; H,4.95;N,4.90); vrnay
(liquid film) 2980, 1750, 1720, 1.M2, 121.2, ],072, 702 crn-7; 1H n.m.r. (300MIIz,
CDCIa) õ 1,.24 (3H, t, I 7.0 Í12, OCH2CHI), 2.76(7H, dd, Iz3' 1.8.2, ls'4¡¡ans 2.9 Í12,
C3-H'), 3.23 (7H, ddd, /33' 1.8.2, ls4ç¡e 7.4, Isg- 0.9 Hz, C3-H), 3.67 (1H, dq, J 9.4,
7.0ÍIz, OCHHCH3), 3.70 (1H, dq, 19.4,7.0Ílz,OCI{HCÍb), g.ZZ (3H, s, COzCHs),
3.81 (1H, dd, /o,o,' 77.6,lg¡^ 0.9H4 Ccr-H), 4.24 (1H, dd, Igqr¡t 7.4, Iz'+tror, 2.9,
Ils'trorr7.5Hz, C -H), 4.43 (1H, d, Ioo' 77.6H2, Cg-H'), 5.2'l' (1H, d, I4s'tront
'l'.5ÍIz, CS-H'); 13C n.m.r. õ 17"1.22,1'68.64,96.30,64.35,52.'l'8,41'.3'l',4'l'.'l'7,39.48,
75.17.
In a subsequent treatment of the pyrrolidinone 1-41 with N-bromo-
succinimide and ethanol as described above, chromatography of the crude
product mixture yielded, in addition, methyl trøns-4-bromo-5-hydroxy-2-oxo-L-
pyrrolidineacetate (151) as an oil- vrn6 (liquid film) 3400,2980,1750,1722,7256,
7057, 706 cm-l;1H n.m.r. (300MH2, CDCIg) ô 2.73 (1lH, dd, /ss' 78.7, ls'4¡ysng
2.4Ífz, C3-H'), 3.33 (1H, dd,lgg'78.7,lg4ç¡56.9flz, C3-H), 3.78 (3H, s, COzCHg),
4.09 (1H, d, /crs, 77.8}{2, Ccr-H), 4.27 (7H, ddd, J3aç¡t 6.9,lg,4tront2.4, I1s'tront
'1..5Í12, C4-H), 4.36 (7H, d, /oo' 77.8H2, Ccr-H'), 5.11 (1H, broad, OH), 5.40 (1H,
d, I4s'trons1..5Hz, CS-H'). This compound was not stable for complete
characterization.
EXPERIMENTAL
749
cr-Ethox y -2- oxo -1, -pyrrolidineace to ni trile (1 5 9 ) and tr ans -4 -bromo -
S-ethoxy -2- oxo -'1,-pyrrolidineace tonitrile (L 6 0 )
A mixture of 2-oxo-1-pyrrolidineacetonitrile (L42) (260 mg, 2.09 mmol)
and N-bromosuccinimide (410 mg, 2.30 mmol) in carbon tetrachloride and
dichloromethane (2:1,, 78 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for L0 min. The reaction mixture was
then cooled to room temperature, dry ethanol (250 pl, 4,26 mmol) and 2,6-
lutidine (490 pl,4.2L mmol) were added and the mixture was stirred at room
temperature under nitrogen for 2.5 hr. The reaction mixture was filtered and
evaporated under reduced pressure. The residue was taken up in ethyl acetate
and washed successively with very dilute hydrochloric acid, brine, saturated
aqueous sodium bicarbonate and brine again. The organic layer was dried and
concentrated under reduced pressure and flash column chromatography of the
residue on silica, eluting with a mixture of ethyl acetate and light petroleum
(40:60) yielded two products, 159 and L60.
cr-Ethoxy-2-oxo-L-pyrrolidineacetonitrile (L59) as an oil. (92.2mg,26Vo)-
b.p.70"C/ 0.01 mm (block); EI mass spectrum: mlz 768 ([M+], 7), 167 ([M+ - H],
M), 1.42 ([M+ -CN], 46), 1,23 ([M* - OEt], 100); (Calcd for CsHl2N2OzlM+)mlz
168.0899. Found: mlz 1.68.0897; Calcd for CTFJ¿NOz [M+ - CN] mlz 1,42.0868.
Found: mlz 1,42.0875); (Anal. calcd for C3H12N2O2: C,57.'1.3;H,7.79; N, 16.65.
Found: C, 56.07; H, 6.86; N, 16.26); v^o, (CHzClz) 2900, 2250, 1772, 1.404, 1260,
1084 cm-1; lH n.m.r. (300MH2, CDC\) õ 1.25 (3H, t, I7.0flz, OCHzCHg), 2J1,5
(2IJ, m, C4-H:), 2.48 (2H., t, I 8.2H2, C3-Hù, 3.53 - 3.66 (4H, m, OCHzCH3 and
CS-HÐ, 6.02 (1}{, s, Ca-H); 13C n.m.r. õ 775.74,1.1.4.77,70.08,64.49,42.63,30.24,
17.36,14.20.
trans-4-Bromo-5-ethoxy-2-oxo-1-pyrrolidineacetonitrile (160) as an oil.
(39.5 mg, 8Vo)- b.p.75"C/ 0.01 mm (block); FAB mass spectrum: mlz 249 (ÍMr+
EXPERIMENTAL
150
+ Hl, 51), Z+7 ([M+ + H),52), 203 ([M+ - EtOH], 9B), 201. ([M* - EtOH], 700), 178
(85),776 (87), 1,67 (Í]¡l'{+ - HBrl, 52), (Anal. calcd for CgH11N2O2Br: C, 38.89; H,
4.49;N, 11.33. Found:C,38.58;H,4.47;N,L1.11); vmax (CDCLI)2984,2248,1730,
'1,4'1,0,7262,7078,708 cm-1; 1H n.m.r. (300MH2, CDCIg) õ 1.29 (3H,t,17.0ÍIz,
OCH2CH3), 2.76 (1H, dd, þy 1,8.4, 13'4t orr 2.1. Hz, C3-H'), 3.24 (1F{, ddd, lgg, ]..8.4,
Igati"7.2,]so0.8Hz,C3-H), 3.77(1H,dq,19.4,7.0Í|4OCHHCH1).3.76(7H,dql
9.4,7.0ÍIz, OCHHCHg), 4.07 (7H, dd, /ocr, 17.5,lg.-0.8Ífz, Ccr-H), 4.25 (1H, ddd,
IUc¡s7.2, Ig'¡trons2.7,l45,t øns'I.,.7H2, C -H), 4.51, (7H, d, I9.g, 77.5ÍIz, Ca-H'), 5.1.5
(1H, d, I45,tror, 1..7 Í12, CS-H'); 13C n.m.r. ô 177.73, 774.17, 95.77, 64.85,40.80,
39.'1.0,29.54,15.05.
In a subsequent treatment of the pyrrolidinone 142 with N-bromo-
succinimide and ethanol as described above, chromatography of the crude
product mixture yielded, in addition, 3,4-didehydro-5-ethoxy-2-oxo-L-
pyrrolidineacetonitrile (161) as an oil:- EI mass spectrum: mlz 166 (llll'4+1,2),
121 ([Vf+ - OEt], 100), 55(35); (Calcd for CaHrolrizOz [M+] mlz 166.0742. Found:
mlz 1.66.0730); ymax (liquid film) 3090, 2978, 7776, 1598, 7406, 1098 cm-li 7H
n.m.r. (CDCI¡) õ '1,.25 (3H, t, I 7.7H2, OCHzCHI), 3.60 (1H, dq,,]f9.3, 7.1. Hz,
OCHHCH3), 3.61(1H, dq, I 9.3,7.7H4 OCHHCHg), 4.77 (1H, d, lg;s' 17.5fI2,
Ca-H), 4.46 (1H, d,loo,77.5Hz, Ccr-H'), 5.53 (1H, d,lqs7.5ffz, C5-H), 6.30 (1H,
d,lgq6.7ÍIz, C3-H), 7.07 (7H,dd,lsq6.7,lqS7.5flz, Ca-H); 13C n.m.r. õ '1.68.46,
'1.45.5'].., 728.99, 11,4.7 g, g7 .69, 60.24, 27 .32, 74.93.
EXPERIMENTAL
151
Endocyclic Functionalization and Elaborationof y-Lactams
Preparation of the 2-pyrrolidinon es L71. and 172
1 -(3-Butenyl) -2-oxopynolidine (17 1)
Sodium hydride (80% w/w, 1.83 g,61.0mmol) was washed with light
petroleum and then stirred in xylene (125 ml) under nitrogen. To this
suspension, Z-pyrcolidinone (L73) (4.75 g, 55.8 mmol) in xylene (50 ml) was
added slowly with stirring under nitrogen. After the foaming had subsided the
mixture was heated at 110"C for L hr. Upon cooling to room temperature,4-
bromo-l-butene (77.25 ml, 111 mmol) was added to the salt, and the mixture
was then heated at reflux overnight under nitrogen. The reaction mixture was
cooled to room temperature, washed with water (150 ml), dried, and
concentrated under reduced pressure. The residue was distilled to give 1-(3-
butenyl)-2-oxopyrrolidine (771) as a colourless liquid. (1,.43 g, 747o)7 b.p.
80'C/0.Lmm (block); EI mass spectrum: mfz 139 ([M+],9), 98 ([M+ - C¡HS],
100), 70 (28); (Calcd for CsHl3NO [M+] rnlz 1.39.0997. Found mlz 139.1003);
Vmax (liquid film) 3076 ,2920, 7674, 1,61,8,918 cm-1; 1H n.m.r. (300MIlz, CDCIg) ô
2.00 (zIJ, tt, I 8.7, 7.7 Hz, C4-r{), 2.29 (2}l, ddt, / 7.2, 6.9, '1..7 flz, CH2CH=CH2),
237 (2}J, t, I 8.7 Hz, C3-Hz), 3.36 (2H, t, | 7.2H2, NCHz), 3.39 (2}j,', t, I 7.7 Hz,
C5-H2), 5.01 - 5.1,2 (2}]., m, CH=CH2), 5.77 (tI-{, ddt, / 1.7.1., 70.2, 6.9H2,
CH:CHz); 13C n.m.r. õ 774.64 (C=O), 734.87 (C3'), 116.53 (C4'), 46.88 (C5),41,.43
(Cl'¡, 37.54 (Cz',¡,30.77 (C3), 77.64 (C4).
EXPERIMENTAL
L52
N- (p-Me thoxyphenyl) -4 -chlorobutyrami de (17 5)
4-Chlorobutyryl chloride (146) (30 g, 213 mmol) was dissolved in
dichloromethane (200 ml) and a solution of freshly recrystallized p-anisidine
(L74) (28.8 g,266 mmol) in dichloromethane (100 ml) was added dropwise with
stirring. After the addition was complete the solution was stirred at room
temperature for a further 4 hr. The solution was then washed with water (3 x
100 ml), dried, and evaporated under reduced pressure to give an oil that
solidified on standing. The residual solid was recrystallized from ethyl acetate
/ light petroleum to give N-(p-methoxyphenyl)-4-chlorobutyramide (L75) as a
white crystalline solid. (23.8 g,547o):- m.p. 85"C; (Calcd for C11H1¿NOzCI [M+]
mlz 227.071.3. Found: mlz 227.0757); (Anal. calcd for C11H1¿NOzCI: C, 58.01.; H,
6.20; N, 6.15. Found: C, 58.31 ; H, 5.87; N, 6.14); v*o, 3308, '1.662, 7620, 1518, 1240,
7024, 840 cm-1; 1H n.m.r. (300 MHz, CDCIa) õ 2.73 (2}l, tt, I 7.2, 6.2H2,
CHzCHzCI), 2.48 (2F{, t, I 7.2ÍIz, CHzCI), 3.59 (2}l., t, J 6.2H2, CH2CONH), 3.76
(3H, s, OCH3), 6.80 (2H, m, ArH), 7.38 (zIF', m, ArH), 8.06 (1H, broad, NH); 13ç
n.m.r. õ']..69.U,756.40,1.30.70,721,.80,774.07,55.44,M.50,33.89,27.94.
1 - (p-Methoxyphenyl) -2-oxopyrrolidine (L7 2)
A solution of N-(p-methoxyphenyl)-4-chlorobutyramide (175),(2.28 g,
10 mmol) in dichloromethane (200 ml) was added dropwise over 6 hr., to a
stirred suspension of powdered potassium hydroxide (672mg, 12 mmol) and
tetra-n-butylammonium chloride (556 mg, 2 mmol) in dichloromethane
(200 ml). After the addition was complete, stirring was continued for 30 min.
The precipitate was filtered off and washed with dichloromethane (2 x 50 ml).
The combined filtrates were dried, and concentrated under reduced pressure to
give an oil that was chromatographed on a squat column of silica gel, gradient
EXPERIMENT,AL
1s3
eluting with light petroleum and ethyl acetate. The resulting solid was
recrystallized from ethyl acetate / light petroleum to give 1-(p-methoxy-
phenyl)-2-oxopyrrolidine (172) as fine transparent leaves. (1.19 g,63Vo)- m.p.
108C; (Calcd for C11H1gNOz [M+) mlz 791..0946. Found: mlz 791..7005); (Anal.
calcd for C11H13NO2: C,69.09;H,6.85;N,7.32. Found: C,69.09;H,6.93; N, 7.35);
v*or 1,682,]612,151,4,1252,],032,830 cm-1; lH n.m.r. (300MH2, CDCIg) õ 2.12
(2Ê1, tt, I 8.1, 7 .0 ÊIz, C4-Hz), 2.56 (2Il, t, I 8.'1. TIz, C3-H2), 3.78 (3H, s, OCHg), 3.80
(zIJ, t,l 7.0H2, CS-Hz\, 6.89 (2f1, m, ArH), 7.48 (2t{, m, ArH); 13C n.m.r. õ
173.90,756.49,1,32.53,'1,21..79,'1.'1.3.96,55.4'1,,49.'1.5,32.42,17.98.
EXPERIMENTAL
tv
Functionalization of the 2-pyrrolidinones 769 - L72
tr ans-4-Bromo-5-ethoxy- L,3,3-trimethyl-2-oxopyrrolidine (1 76) and
4,4- dlbr omo -5 -e th oxy -1,3,3- trim e thyl-2 - ox op yrr oli d ine (17 7 )
A mixture of 1.,3,3-trimethyl-2-oxopyrrolidine (L69) (252 mg, 1.98 mmol)
and N-bromosuccinimide (705 mg, 3.96 mmol) in carbon tetrachloride (a0 ml)
was heated at reflux under nitrogen, whilst irradiating with a 300 W mercury
lamp, for 10 min. The reaction mixture was cooled to room temperature, dry
ethanol (240¡rl,4.09mmol) and 2,6-lutidine (230¡.t1, 1.97 mmol) were added
and the mixture was stirred under nitrogen for 3 hr. The reaction mixture was
filtered and evaporated under reduced pressure, the resultant residue was
taken up in ethyl acetate and washed successively with very dilute
hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine. The
organic layer was dried and concentrated under reduced pressure and flash
column chromatography of the residue on silica, eluting with a mixture of
light petroleum and ethyl acetate (2:5), then afforded two products, L76 andL77.
trans-4-Bromo-5-ethoxy-1.,3,3-trimethyl-2-oxopyrrolidine (176) as an oil.
(46mg,9Vo)- EI mass spectrum: mlz 251 ([M+],6), 249 (íM+),6), 206 ([M+ -OEtl, 66), 204 ([M+ -OEt], 67), 792 (11), 190 (77), 770 ([M+ - Br],21), 1,49 (13.5),
1.47 (1,4), 113 (100), 85 (81); (Calcd for CqHrcl.JOzBr lM+1m12249.0364. Found:
mlz 249.0¡55); ymax (liquid film) 2972, 7708, 1,276, 7064,760 cm-l; 1H n.m.r.
(300MH2, CDCIs) E 1,.22 (3H, s, C3-CHg), 1.28 (3H, s, C3-CHg), 1..29 (3}j,, t,l7 .0 Hz, OCH2CH s), 2.87 (3H, s, NCH3), 3.74 (7H, dq, | 9.4, 7 .0 Hz, OCHHCHa),
3.80 (1H, dql9.4,7.0Hz,CHHCH3), 3.98 (1H, d, Ils'trans3.8Hz,C4-H),4.89 (1H,
d,145'trrnr 3.8F{z, C5-H'); 13C n.m.r. õ 775.55,95.57, 65.67,57.92, 44.84,27.1.3,
24.19,23.95,75.47.
EXPERIMENTAL
155
4,4-D ibr omo-S- eth oxy -1.,3,3 -trimethyl- 2-oxopyrrol idine (L7 7) as an oil.
(91 mg, l47o)- EI mass spectrum: mlz 337 ([M+], 9), 329 ([M+], 18), 327 ([M+],
9), 286 ([M* - OEt], 21), 284 ([M+ - OEt], 42), z9z ([M+ - OEt], 21), 250 ([M+ - Br],
5), 248 ([M+ - Br], 5), 206 (31.), 204 (32), 165 (98), 163 (100); (Calcd for
CeHl5NOzBrz [M+] mlz 326.9470. Found: mlz 326.9a6D; v,,a¡ (liquid film) 2976,
17'1.4, 1294,'1.064,770 cm-7; 1H n.m.r. (300MFIz, CDCIg) õ 1.30 (3H, t,l 7.0ÍIz,
OCHzCHa), 1.38 (3H, s, C3-CHs), 1..42 (3H, s, C3-CH3),2.92 (3H, s, NCHs), 3.81
(1H, dq, 19.4,7.0ÍIz, OCHHCHg), 4.77 (1H, dq, 19.4,7.0H2, OCHHCHù, 5.02
(1H, s, C5-H); 13C n.m.r. ô 173.52,98.55, 75.70, 68.39,51.81., 26.97, 24.54, 24.08,
15.15.
Treatment of 1-methyl-2-oxopyrrolidine (L70) with
N-bromosuccinimide
A mixture of l-methyl-2-oxopyrrolidine (170)177 1239 ng, 2.32mmol)
and N-bromosuccinimide (826 mg, 4.64 mmol) in carbon tetrachloride (20 ml)
was heated at reflux under nitrogen, whilst irradiating with a 300 W mercury
lamp, for 1.0 min. The cooled reaction mixture was filtered through glass wool
and concentrated under reduced pressure to give an oil containing an
appfoximately 5:2 mixture of trans-4,5-dibromo-1-methyl-Z-oxopyrrolidine
(184) and 4,4,5-tribromo-1-methyl-2-oxopyrrolidine (L85) as judged by 1H n.m.r.
spectroscopic analysis. No discrete products were isolated from this reaction
mixture.
trans-4,5-Dibromo-L -methyl-2-oxopyrrolidine (184):- 1H n.m.r. (300MH2,
CDCIg) õ 2.90 (3H, s, NCH3), 3.08 (1H, d,133'78.5H2, C3-H'), 3.29 (1H, dd, /s¡'
1.8.5, Is+c¡s 5.9 Hz, C3-H), 4.87 (1H, d, ]sqr;r 5.9 Hz, C4-H), 6.72 (7H, s, C5-H').
EXPERIMENTAL
156
4,4,5-Tribromo-L-methyl-2-oxopyrrolidine (185):- 1H n.m.r. (300MH2,
CDCIs) õ 2.95 (3H, s, NCH3), 3.39 (1H, d,I33'77.5Í1,2, C3-H), 3.47 (7H, d, ]33'
17.5ÍIz, C3-H'), 6.34 (1H, s, CS-H).
tr ans - 4-Bro mo -5 - etho xy- L -me thyl- 2-oxopyrr olidine ( L 8 6 ) and
4,4-dibr omo-5-ethoxy- 1 -methyl-2-oxopyrrolidine (L87)
A mixture of l-methyl-2-oxopyrrolidine (170)117 (769mg, 1,.7L mmol)
and N-bromosuccinimide (607 rr.g,3.4L mmol) in carbon tetrachloride (20 ml)
was heated at reflux under nitrogen, whilst irradiating with a 300 W mercury
Iamp, for 10 min. The reaction mixture was cooled to room temperature, dry
ethanol (200 ¡.t1, 3.41 mmol) and 2,6-lutidine (200 ¡tI, 7.72 mmol) were added
and the mixture was stirred under nitrogen for 3 hr. Upon workup, as above
for the similar treatment of the pyrrolidinone 169, the residue obtained was
purified by preparative thin layer chromatography on silica, eluting with a
mixture of light petroleum and ethyl acetate (50:50), affording two products,
186 and 187.
trans-4-Bromo-5-ethoxy-L-methyl-2-oxopyrrolidine (186) as an oil.
(34rng, 97o)- EI mass spectrum: mlz 223 (îM+1,9), 221. ([M+1,9), 178 ([M+ -OEtl, 98), 776 ([M+ - OEt], 100), 150 (28), 748 (29), 1,42 ([M* - Br], 11); (Calcd for
CTHl2NOzBr [M+] mlz 221,.0051. Found: mlz 221.0058); v¡7aa (liquid film) 2976,
7772,'1.262, 1.068,708 cm-l; 1H n.m.r. (300MFIz, CDCIa) õ 7.26 (3H, t, I 7.0f12,
OCHzCHg), 2.65 (7H, dd, /gg' 77.9, ]z'q,tror, 7.4H2, C3-H'), 2.92 (3H, s, NCHg),
3.2'1. (7H, dd, /g¡' 77.9,lzq,cis 6.8}{2, C3-H), 3.63 (1H, dq, J 9.2,7.0ÍIz, OCHHCH3),
3.68 (1H, dq., I 9.2,7.0H4 OCHHCHT), 4.24 (7H, ddd, Izqc¡s 6.8, I3,Atrons 7.4,
EXPERIMENTAL
1,57
I4s,tronr 0.9 tIz, C4-H), 4.97 (1H, d, I1s't orr 0.9 Hz, CS-H'); 13C n.m.r. ô 771,.29,
97 .90, 63.93, 4'1..64, 39.54, 27 .50, 1.4.99.
4,4-Dibromo-5-ethoxy-1-methyl-2-oxopyrrolidine (187) as an oil. (54 mg,
'1.'1,7o)- EI mass spectrum: mlz 303 ([M+], 18.5), 301 ([tt4+¡ ,37.5), 299 ([M+] , 19),
258 ([M+ - OEr], 49.5), 256 ([M+ - OEt], 't00), 254 ([M+ - OEt],50.5), 230 (9), 228
(18), 226 (9), 222 ([M+ - Brf,7), 220 ([M+ - Br],7); (Catcd for CTHIlNOzBrz [M+]
mlz 298.9157. Found: mlz 298.9153); v¡nay (Iiquid film) 2976, 17'1,0, 1,282,1..072,
752 cm-l; 1H n.m.r. (300MH2, CDC13) ô 1.32 (3}]', t, ] 7.0 ÍIz, OCH2CH), 2.93
(3H, s, NCH3), 3.36 (1H, d,lss' 17.6Ílz, C3-H), 3.51 (1H, d,l3s, 17.6Í12, C3-H'),
3.80 (1H, dq, I 9.3, 7 .0 Hz, OCHHCH3), 4.07 (1H, dq,, I 9.3, 7 .0 I{2, OCHHCHT),
5.02 (1H, s, CS-H); 13C n.m.r. õ 168.8,99.19,67.76,57.33,52.29,27.64,74.89.
Upon a subsequent treatment of 170 (691, mg, 6.97 mmol) with N-bromo-
succinimide (1.37 g,7.67 mmol) followed by treatment with dry ethanol and
2,6-lutidine as described above, chromatography of the crude product mixture
thus obtained afforded 186 (30 mg, 2Vo) and Í87 (137 mg, 6%) and in addition
189 and L90.
4-Bromo-3,4-didehydro-5-ethoxy-1-methyl-2-oxopyrrolidine (189) as an
oil. (26l¡:.g,2%)- (Calcd for CTHlsNO2Br [M+] mlz 278.9895. Found: mlz
218.9887); v*r, (liquid film) 3078, 2980, 1706, 1,633, 7282,1118, 950, 688 cm-1;
1Hn.m.r. (300MH2, CDCIg) ô 1.25 (3H, t, J 7.OHz, OCHzCHg), 2.93 (3H, s,
NCHa), 3.32 (2fI, q, I 7.OHz, OCH2CHg), 5.21, (1H, s, C5-H), 6.42 (1H, s, C3-H);
13C n.m.r. õ 1,67.58,138.08, 130.00, 90.9'1., 58.37, 26.40, 74.96.
4,4-Dtbromo-5-hydroxy-1.-methyl-2-oxopyrrolidine (190) as an oll.;- v¡nay
(CHzClz) 3380, 7708, '1256,1034 cm-1; 1H n.m.r. (300MH2, CDCII) õ 2.96 (3H, s,
NCH3), 3.40 (1H, d,]zz'17.6ÍIz, C3-H), 3.57 (7H, d,133'17.6H2, C3-H'), 4.69 (1H,
broad, OH), 5.29 (7H, s, CS-H).
EXPERIMENTAL
158
trans-4-Bromo-L-methyl-2-oxo-5-phenylthiopyrrolidine (191) and
L -phenylthiomethyl-2-oxopyrrolidine (192)
A mixture of 1-methyl-2-oxopyrrolidine (170) (195 mg, 1.97 mmol),
N-bromosuccinimide (740mg,4.1.6 mmol) and a catalytic amount of AIBN in
carbon tetrachloride (35 ml) was heated at reflux under nitrogen, whilst
irradiating with a 300 W mercury lamp, for 6 min. The reaction mixture was
immediately cooled to room temperature, thiophenol (410 ¡tt,3.99 mmol) and
2,6-lutidine (460 pl, 3.95 mmol) were added and the mixture was stirred at
room temperature under nitrogen for 2 hr. The residue obtained upon
workup was purified by preparative thin layer chromatography on silica,
eluting with a mixture of light petroleum and ethyl acetate (50:50) and afforded
two products, 191 and 192.
trans-4-Bromo-L-methyl-2-oxo-5-phenylthiopyrrolidine (191) as an oil.
(139 mg, 25Vo)- EI mass spectrum: mlz 287 ([M*], 3), 285 ([M+], 3), 205 ([Vf+ -HBrl, 45), 177 ([M* - PhSH], 98), 775 ([M* - PhSH], 1.00), 749 (50), 1,47 (51), 108
(7t¡; (Calcd for CrrHr2NOSBr lM*l mlz 284.9823. Found: mlz 2M.9871); ymax
(liquid film) 3054,2934, 1722, 1,584, 7476 crn-1; 1H n.m.r. (300MI{2, CDCIg) ô
2.38 (7H, dd, .lgg' 78.4, Jg4ç¡e 6.5 TIz, C3-H), 2.57 (1H, dd, /ga' 18.4, l3'4¡yans L.2H2,
C3-H'), 3.06 (3H, s, NCH¡), 4.53 (1H, ddd, Izq,c¡s 6.5, I3,4trons 7.2,l4s'trans 1..LÍIz,
C4-H) , 4.98 (7H, d, I 45' tron, '!. .7 tIz, Cs-H'), 7 .23 - 7 .57 (slts,', m, ArH); 13C n.m.r.
'ô 171.08, 734.55,734.75,129.60,729.36,77.27,44.63,40.20,28.20. This compound
was not stable for elemental analyses
1-Phenylthiomethyl-2-oxopyrrolidine ('1.92) as an oil. (10.4 mg, 3Vo)- EI
mass spectrum: mfz 207 ([lr4+],14), 93 ([M+ - PhS], 100), Z0 (23); (Calcd for
CrrHl3NOS Í]l.l+l mlz 207.0778. Found: mlz 207.0727); (Anal. calcd for
C11H13NOS: C, 63.74; H, 6.32; N, 6.75. Found: C, 63.66; H, 6.52; N, 7.02); ,,/max
(tiquid film) 3054,2926, 1,696,7584,1488 cm-1; 1H n.m.r. (300MH2, CDCIe) ô
EXPERIMENTAL
759
7.96(zIJ',tt,18.'1.,7.7ÍIz,C4-}l),2.30(2Il,t,lg.7Hz,C3-Hz),3.44(2}{,t,17.7H2,
CS-Hz), 4.77 (2f1, s, NCH2S), 7.27 - 7.33 (3H, m, ArH), 7.42 - 7.46 (zFI, m, ArH);
13Cn.m.r. ô 174.85,'1,33.51,130.87,1,29.07,127.16,46.65,45.86,30.80,77.54.
Treatment of 1-(3-butenyl)-2-oxopyrrolidine (l7l) withN-bromosuccinimide
A mixture of 1-(3-butenyl)-2-oxopyrrolidine (L77) (238 rr.g, 1.71 mmol),
N-bromosuccinimide (668 mg,3J5 mmol) and a catalytic amount of AIBN in
carbon tetrachloride and dichloromethane (4:"1,,25 ml) was heated at reflux
under nitrogen, whilst irradiating with a 300 W mercury lamp, for L0 min.
The cooled reaction mixture was concentrated under reduced pressure and the
residue was taken up in ethyl acetate and washed with brine. The organic layer
was separated, dried and evaporated under reduced pressure and preparative
thin layer chromatography of the residue on silica, eluting with a mixture of
ethyl acetate and light petroleum (50:50) yielded three products, L97,198 artd
199.
5,S-Dibromo-l -(3,4-dibromobutyl)-2-oxopyrrolidine ('1.97) as an oil.
(77 m9,1,07o)- EI mass spectrum: mlz 461. ([M+], 3), 459 ([M*], 12), 457 ([M+],
18), 455 ([M+], 72), 453 ([M+], 3), 379 ([ttt* - HBr], 29), 377 ([M* - HBr], 87), 375
([M+ - HBr], B8), 373 ([M+ - HBr], 29.5), 297 (lM+ - 2IJ.Br),77), 295 ([M+ - 2FIBr]
22), 293 ([M+ -2H,Br],1,1), 257 (49.5), 255 (100), 253 (50.5), 2'1.6(1,0), 274(10);
(Calcd for CsHllNOBra Í]l.l+l mlz 456.7533. Found: mlz 456.7543); (Anal. calcd
for CgHllNOBr4: C, 27.03; H, 2.43; N, 3.07. Found: C, 22.38; H, 2.48; N, 3.18);
v1a¡ (liquid film) 171,4,698 cm-l; 1H n.m.r. (300MH2, CDCIa) ô 1.98 (1H, dddd,
IZ,Z'* 14.8, ]2,3, 9.6, Jy*2' 7.3,17,2' 5.2H4 C2'-H), 2.52 (1H, dddd, I2,Z'* 14.8,1t2*
7.4,ly*2'* 7.4,l2'*g, 3.7H2, C2'-H*), 3.06 (2H., dd,l3qtrons 6.0,134^ri,5.8H2, C3-F{),
3.39 (1H, ddd, 144* 9.9,lgttrors 6.0, Jg+r¡, 5.8I{2, C -H), 3.M (7H, ddd, I++* 9.9,
EXPERIMENTAL
160
]34t ont 6.0, ]gqcis 5.8H2, C4-}{*), 3.49 (1H, ddd, /1'1,* 14.0, ly2,* 7.4,/t2, 5.2H2,
CL'-H), 3.59 (1H, ddd, /1'1'* 74.0,11,*2,* 7.4,11,.2, 7.2H2, C7'-H*), 3.62 (7H, dd,
I4'4'* 10.5,1g'+'9.6H2, C4'-H), 3.87 (1H, dd, 14,4,* 10.5, fu'4'* 4.2ÍIz, C4'-H*), 4.1.0
(1H, dddd, I2'g' 9.6, Ig'4, 9.6, þ'4'* 4.2, 12,*g, 3.'1, ÍIz, C3'-H); 13C n.m.r. ô 1,67.85
(C=O), 55.26 (C5), 48.51 (C3'), M.93 (C4), M.1,0 (C3), 42.17 (Cl'¡, 35.97 (C4'),33.37
(cz'¡.
S,S-Dibromo-1-(4-bromo-3-hydroxybutyl)-2-oxopyrrolidine (198) as an
oil. (138 mg, 2'l.Vo)- EI mass spectrum; mlz 397 (lt¡+1, 5.5), 395 ([M+], 16),
393([M+],76),39'].. ([M+],5.5),379 ([M+-HzO],4),377 ([M+-HzO], 12),375(Í]ll.{+
-HzOl,72), 373 ([M+-HzO],4), 3t5 ([M*-HBr],29.5),313 ([M+-HBr], 60), 37'l-.
([M* - HBr], 30.5), 297 (lM+ - HBr - HzOl, 31.5), 295 ([M+ -HBr - HzO], 64), 293
([M+ - HBr - HzO], 32.5), 245 (50), 243 (700), zal $0); (Calcd for CaH12NO2Br3
lM+l mlz 392.8398. Found: mlz 392.8387); (Anal. calcd for CsH12NO2Br3: C,
24.39;H,3.07; N, 3.55. Found: C,25.70; H, 3.01; N, 3.67); v¡naa (Iiquid film) 3440,
1706,'j,066,698 cm-1; lH n.m.r. (300MH2, CDCIa) ô '1..69 (7H, dddd, Iz,z,* 14.1,
I2B, 9.8, Jy*2' 5.8,1.1,2, 4.9H2, C2'-}{), 1.91 (1H, dddd, ]2,2'* 14.1, It*2,* 9.3, f y2'*
6.2, f2,*g, 3.2flz, C2'-H*), 3.07 (2}l, dd,l3qtronr 6.l,lzqris 5.8TIz, C3-Hz), 3.31 (1H,
ddd, /1'1'* 1.4.7, Jy2'* 6.2, Itz' 4.9 Í12, C1'-H), 3.37 (1H, ddd, I¡ø* 10.1, I34t ons 6.1,
Ig+at 5.8F{z,, C4-H), 3.47 (1H, dd, J4,4,* 1.0.4,1g,4, 5.8}lz,, C4'-H), 3.42 (1}l, broad,
OH), 3.45 (1H, dd, l4'4'* 1.0.4, lg'4'* 4.9H4 C4'-H*), 3.46 (7H, ddd, 144* !Q.1,
]34tront 6.1,13+cis 5.8}l2, C4-H*), 3.70 (7H, ddd, /1'1'. 1.4.1,ly*2,* 9.3,11,*2, 5.8LIz,
C1'-H*), 3.77 (1H, dddd, Iz'2, 9.8, Ig'+' S.B, Iz,q'* 4.9, J2,*g, 2.2ÍIz, Cj'-}l); 13C
n.m.r. ô 1,68.72 (C=O), 67.77 (C3'), 55.04 (C5), 45.10 (C4), M.tS (C3), 40.93 (Cl'¡,
38.52 (C4'¡, 32.29 (CZ'¡.
1-(3,4-Dibromobutyl)-2-oxopyrrolidine (199) as an oil. (26 mg,57o)- EI
mass spectrum: mfz 302 ([M+ + H],5), 300 ([M+ + H], L0), 298 (M+ + Hl, 5), 220
([M+ - Br], 98), 218 ([M+ - Br], 100), 138 ([M* - HBr - Br), 44); (Calcd for
CsHlaNOBr2 [N4+ + H] mlz 2979M2. Found: mlz 297.9433); v¡nw (liquid film)
EXPERIMENTAL
767
2940,7774, 646 cm-7; 1H n.m.r. (300MH2, CDCIg) ô 7.99 (lIF., dddd, I2'2,* 73.7,
12, 3, 9.3, I y*2' 7 .2, ] n, 5.5 ffz, CZ -}{), 2.05 (2F{, tt, I 8.3, 7 .0 ÍIz, C*F{z), 2.40 (2F{, t,
/ 8.3 ÍIz, C3-H2), 2.46 (1H, dddd, IZ'2,* 13.'1,, 17,2,* 7.4, f1'*2,* 7.2, 12,*g, 3.3ÍIz,
C2'-H'+), 3.43 (zFJ, t, I 7.0H4 CS-Hz), 3.43 (7H, ddd, Iyt,* 74.0, It,z,* 7.4, It,z,
5.5H2, Cl.'-H), 3.54 (1H, ddd, /1'1'* 1.4.0,ly*2,*7.2,ly*2, 7.zÍfz, Cl.'-H'ß), 3.68 (1H,
dd, l4'4'*'1.0.5,13'4'9.3ÍIz, C4'-H), 3.90 (1H, dd, J4'4,* 10.5, /3,4,* 4.3H2, C4'-}l*),
4.74 (1H, dddd, I2B, 9.3, Ig,4'9.3, 1g,4,* 4.3, 12,3, 3.3flz, C3'-H); 13C n.m.r. ô
175.34 (C=O), 49.1,8 (C3'), 47.40 (C5),40.57 (C1'), 36.24 (C4'),33.80 (C2'),30.86 (C3),
17.e1. (C4).
tr ans-4-Bromo-5 -ethoxy- 1 - (p-methoxyphenyl) -2-oxopyrrolidine(2os)
A mixture of 1.-(p-methoxyphenyl)-2-oxopyrrolidine (172) (92.3 rng,
0.48 mmol), N-bromosuccinimide (100 mg, 0.56 mmol) and a catalytic amount
of AIBN in carbon tetrachloride and dichloromethane (8:1, 18 ml) was heated
at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp, for
5 min. The reaction mixture was cooled to room temperature, dry ethanol
(60 ¡tl, 1.02 mmol) and 2,6-lutidine (720 ¡tl, 1.03 mmol) were added and
the mixture was stirred at room temperature under nitrogen for 2 hr. The
residue obtained upon workup was purified by preparative thin layer
chromatography on silica, eluting with ethyl acetate, to give trans-4-bromo-5-
ethoxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (205), the alcohol 206, the
S-succinimidopyrrolidinone 207 and unreacted starting material 172
(30 mg, 33Vo).
trans-4-Bromo-5-ethoxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (205) as
an oil which solidified on standing. (58.1 mg, 387o):- m.p. 53"C; b.p.
EXPERIMENTAL
1.62
105C/0.02mm (block); EI mass spectrum: mlz 375 ([M+],84), 313 ([M+],86),
269 ([M+ - EtOH], 42), 267 ([M+ - EtOH], 43), 234 ([M* - Brf ,1.4),203 (36),799
(100); (Calcd for C13H16NO3Br ÍM+l mlz 313.0314. Found: mlz 3'1,ï0306); ymax
(liquid film) 2972, 1722,1,670, 7574, 7250, 7066,700 cm-1; 1H n.m.r. (300MH2,
CDCIg) ô 1.19 (3H, t, | 7.0H2, OCH2CH1), 2.82 (1H, dd, lss,L8.2,l3,4trorr'/.,.0H2,
C3-H'), 3.42 (1H, dd, /eg' L8.2, ls4ç¡s 6.4H2, C3-H), 3.54 (1H, dq, I 9.3,7.0ÍLz,
OCHHCH3), 3.59 (1H, dç I9.3,7.jtIz,OCÍLHCHa), 3.81 (3H, s, OCH3), 4.35 (1H,
ddd, Igqrit 6.4, Ig,4tran, 1.0, I4s,tron, 0.9 Hz, C4-H), 5.27 (1H, d, I4s'tron¡ 0.9 Hz,
Cs-H'), 6.93 (2}l, m, ArH), 7.34 (2}{, m, ArH); 13C n.m.r. ô 177.29, 158.30,
129 .35, 125.98,'I.,'l., 4.3 4, 98.37, 64.52, 55.40, 42.57, 40.78, 1 5. 20.
trans-4-Bromo-5-hydroxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (206) as
an oil. (19.7 mg,1,4%)- EI mass spectrum mlz 287 ([M+], 54), 285 ([M+, 55), 269
([tvl+ - HzO], 98), 267 ([M+ - HzO], 1.00), 254 (29.5), 252 (30), 205 ([M+ -HBr],23),
760 (61); (Calcd for CllHrzNOsBr [M*] mlz 285.0001. Found: mlz 284.9992);
Ymax (CDCI3) 3400, 1704, 7670, 7574,7254, 1034 cm-1; 1H n.m.r. (300MH2,
CDCIg) ô 1,.77 (1H, broad, OH), 2.74 (1H, dd, /¡g' 78:4,13,4¡¡ans 1.4H2, C3-H'),
3.36 (1H, dd, /gg' 1,8.4,l3aç¡s 6.5 Hz, C3-H), 3.89 (3H, s, OCHg), 4.23 (1H, ddd,lgaç¡g
6.5,l3, tronr 1.4,l45,trons 1..2ÍIz, C -H), 5.51 (1H, d, I4s,tron, 1..2H2, Cs-H'), 6.90
(2IJ, m, ArH), 7.32 (2}l, m, ArH); 13C n.m.r. õ 1,71,.95, 158.39, 729.02, 125.9'1.,
11,4.40, 92.47, 55.45, M.7 0, 40.95.
1-(p-Mettroxyphenyl)-2-oxo-5-(l-succinimido)pyrrolidine (207) as a white
crystalline solid. (9.7 mg,77o)- m.p.77"C; EI mass spectrum: mlz 288 ([M+],
100), 233 (33), 190 ([M+ - CaHaNOz],38), 734 (52), 123 (53); (Calcd for
C15H16NzO¿ [M+] mlz 288.'1,110. Found: mlz 288.1113); ymax (CHzClz) 2960,
1780, 7772, 1.61.0, 1514 cm-1; 1H n.m.r. (300MH2, CDCII) E 2.20 - 2.26 (1H, m,
lactam methylen e) , 2.52 - 2.77 (2F{, m, lactam methylen e) , 2.55 (4H, s, 2 x CHz) ,
2.98-3.12(7H,m, lactammethylene),3.78(3H,s,OCHg), 6.20(7H,dd,145ç¡58.9,
EXPERIMENTAL
1,63
]A'strors 2.2H2, Cs-H), 6.87 (2t{^, m, ArH), 7.22 (2F{, m, ArH); 13C n.m.r. ô
176.09,174.62, L58.03, 128.24,725.93,1.'1,4.47,65.95,55.34,30.59,27.74,22.57.
tr ans-S- Allyloxy-4-bromo- L - (p -methoxyphenyl) -2-oxopyrrolidine
(27L)
A mixture of 1.-(p-methoxyphenyl)-2-oxopyrrolidine (172) (37'1. mg,
L.94 mmol), N-bromosuccinimide (380 mg, 2.1-.3 mmol) and a catalytic amount
of AIBN in carbon tetrachloride and dichloromethane (6:1, 55 ml) was heated
at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp, for
L0 min. The reaction mixture was then cooled to room temperature, allyl
alcohol (3 ml, excess) and 2,6-lutidine (450 pl, 3.86 mmol) were added and the
mixture was stirred at room temperature under nitrogen overnight. The
reaction mixture was filtered and evaporated under reduced pressure. The
residue was taken up in ethyl acetate and washed successively with very dilute
hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine
again. The organic layer was then dried and concentrated under reduced
pressure. Preparative thin layer chromatography of the residue on silica,
eluting with a mixture of ethyl acetate and light petroleum (50:50), afforded
trans-5-allyloxy-4-bromo-1-(p-methoxyphenyl)-2-oxopyrrolidine (2Tl) (181 mg,
297o), the alcohol 206 (46 mg, 8%), unreacted starting material L72 (1,77 rng,
48%) and a minor amount of the S-succinimidopyrrolidinone 207.
A greater yield of 2'1,1, was obtained from 172 when the pyrrolidinone
172 was treated with excess N-bromosuccinimide. Thus, 1-(p-methoxyphenyl)-
2-oxopyrrolidine (172) (108 mg, 0.56 mmol), was treated with N-bromo-
succinimide (502 m9,2.82 mmol) in the presence of a catalytic amount of AIBN
in carbon tetrachloride and dichloromethane (6:1, 35 ml) as described above.
The reaction mixture was then cooled to room temperature, allyl alcohol
EXPERIMENTAL
764
(1 ml, excess) and 2,6-lutidine (130 ¡rl, 1.12 mmol) were added and the mixture
was stirred at room temperature under nitrogen for 4.5 hr. Upon workup,
preparative thin layer chromatography of the residue on silica, eluting with a
mixture of ethyl acetate and light petroleum (50:50), afforded trans-5-ally[oxy-4-
bromo-l-(p-methoxyphenyl)-2-oxo-pyrrolidine (211) (87.3mg,47Vo), the alcohol
206 (1,4m9,9Vo), unreacted starting material 172 (33.8mg,31.Vo) and a minor
amount of the S-succinimidopyrrolidinone 207.
trans-5-Allyloxy-4-bromo-L-(p-methoxyphenyl)-2-oxopyrrolidine (211) as
an oil:- EI mass spectrum: mf z 327 (l},l+1, 1.3.5), 325 ([M+], 14), 270 ([M+ -C3H5O], 17.5), 268 ([M+ - C3H5OJ ,18), 245 (M+ - HBr], 10), 189 (100); (Calcd for
C1aH15,NO3Br Ílú+l mlz 325.0374. Found: mlz 325.0299); Ymax (CDCI3) 3020,
77'1.4,'1.612,1.572,1224 cm-7; 1H n.m.r. (300MFIz, CDCIg) õ 2.82 (1H, dd, [ss,1.8.2,
Ig,Atronr 0.9Hz, C3-H'), 3.43 (1H, dd, /¡e' 1.8.2,l3aç¡s 6.3ÍIz, C3-H), 3.81 (3H, s,
OCH3), 4.00 (1H, dddd, 172.8,5.7,7.5,7.3Ílz, CHHCH=CHz), 4.04(1H, dddd,/
12.8,5.7,'l.,.5,7.3flz CÍXICH=CHz), 4.37 (7H, ddd, J3aç¡s 6.3, ]3'4t ort0.9, ]41trans
0.8ÍIz, C4-H), 5.20 (1H, ddt, / 70.5,7.4,'1..3H2, CH=CHH), 5.22 (1H, ddt, I 17.'1.,
7.5, '1..4 Hz, CH=CHH), 5.33 (1H, d,l41tronr0.8Hz, Cs-H), 5.81 (1H, ddt,l 17.1.,
1.0.5,5.7H2, CH=CHz), 6.94 (2}j', m, ArH), 7.33 (2}l, m, ArH); 13C n.m.r. ô
77'1..36,158.31,73290,129.53,726.72,779.29,1.74.28,97.67,69.64,55.32,42.45,40.02.
(3S, 3aR , 6aS)-, (3R, 3aS , 6aR)-6-(p-Methoxyphenyl)-3-methyl-S-
oxotetrahydrofu rol2,3 -blpyrrolidine (21-2)
A solution of tri-n-butyltin hydride (475 ¡tl, 1.77 mmol) and a catalytic
amount of AIBN in dry benzene (15 ml) was added dropwise with stirring,
over 2.5 hr. to a solution of. ftøns-5-allyloxy-4-bromo-1-(p-methoxyphenyl)-2-
oxopyrrolidine (2lL) (384mg, 1.18mmol) in dry benzene (20mt) heated at
EXPERIMENTAL
165
reflux. After the addition was complete the reaction mixture was further
heated at reflux under nitrogen, overnight. The reaction mixture was then
evaporated under reduced pressure and preparative thin layer
chromatography of the resultant residue on silica, gradient eluting with amixture of light petroleum and ethyl acetate gave an oil which solidified on
standing. Subsequent recrystallization from dichloromethane / light
petroleum afforded (3S, 3aR, 6aS)-, (3R, 3aS, 6aR)-6-(p-methoxyphenyl)-3-
methyl-S-oxotetrahydrofuro [ 2,3-b)pyrrolidine (212) as a white crystalline solid.
(111 mg, 38Vo)- m.p. 95C; (Calcd for C14H1zNOs [M+]mlz 247.1,208. Found
mlz 247.121,6); ymax (CHzCtz) 2960, 7700, 1.672, 1.51.4, 1036 cm-1; 1H n.m.r.
(300MH2, CDCIg) õ 1.06 (3H, d, Isz 6.9 }]rz, C7-Hù, 2.49 (1I! dddq , l2s7'L.3,lsguris
8.0,lgz 6.9, ]z'g 6.8Í1z,, C3-H), 2.53 (7}J, dd,l+q,18.2,1sv470.0Í12, C4-H), 2.62 (1H,
dd, ]qq' 1,8.2, lga4' 6.4H2, C4-H'), 3.02 (1H, dddd, lg¿4'!,0.0, I3gacis 8.0, 13v4, 6.4,
I3a6acis 6.2H2, C3a-H), 3.44 (7H, dd, Izg 11.3, 122, B.BfIz, CZ-H), 3.80 (3H, s,
OCH3), 3.98 (1H, dd, Izz' 8.8,12'z 6.8Í12, Cz-}jr'), 5.78 (1H, d, ]ga6acis 6.2H2,
C6a-H), 6.97 (2I{, m, ArH), 7.48 (2H', m, ArH); 13C n.m.r. ð "172.49,'L,SZ.SB,
130.62,124.71.,7"1.4.1.0,95.97,77.50,55.36,39.59,36.07,30.12,1,0.97.
EXPERIMENTAL
4.
5.
766
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