NITRO GROUP PARTICIPATION IN TETRAZOLE ......tetrazole gives 2-phenylbenzotriazole and carbazole....
177
NITRO GROUP PARTICIPATION IN TETRAZOLE REARRANGEMENTS A Thesis submitted by DAVID FREDERICK PIPE in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON Hofmann Laboratory, Department of Chemistry, Imperial College, London, SW7 2AY. September, 1980.
Transcript of NITRO GROUP PARTICIPATION IN TETRAZOLE ......tetrazole gives 2-phenylbenzotriazole and carbazole....
NITRO GROUP PARTICIPATION IN
TETRAZOLE REARRANGEMENTS
A Thesis submitted by
DAVID FREDERICK PIPE
in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
OF THE
UNIVERSITY OF LONDON
Hofmann Laboratory,
Department of Chemistry,
Imperial College,
London, SW7 2AY. September, 1980.
For Charisse
The work, described in this thesis was carried out by
the author at Imperial College of Science and Technology, under
the supervision of Professor C.W. Rees. No part of it is
concurrently being submitted for any other degree.
I should like to express my sincere gratitude to
Professor Rees for providing a stimulating environment and for
his invaluable advice and encouragement throughout, and to
Imperial College for the provision of funds and facilities.
My thanks also go to my colleagues in the Hofmann Laboratory
for their help and friendship, particularly to Dr. P.G. Houghton
for the many fruitful discussions, and to the technical staff of
Imperial College for the general high standard of their services.
D.F. Pipe.
"The trick, Fletcher, is that we are trying
to overcome our limitations in order, patiently.
We don't tackle flying through rock until later
in the programme."
Johnathon Livingstone Seagull.
ABSTRACT
The decomposition of 1,5-diaryltetrazoles and the synthesis
of carbodiimides are described.
The reactions of o-nitrophenyl derivatives producing five
and six membered heterocycles are briefly reviewed.
The presence of a nitro group in the N-1 ring of 1,5-diaryl-
tetrazoles is shown to increase the rate of thermal decomposition,
and when the nitro group is ortho to the tetrazole ring it
intercepts the intermediate carbodiimide producing 2-arylbenzo-
triazoles.
The intermediacy of the carbodiimide is investigated and
confirmed by using alternative heterocyclic species and thioureas
as precursors to ortho- nitrophenylcarbodiimides. The reaction is shown
to be general for 2-arylbenzotriazoles but 2-alkylbenzotriazoles
could not be formed this way. A mechanism for the formation of
2-arylbenzotriazoles involving a series of electrocyclic ring
closing and opening reactions is proposed. Mild thermolysis of
the precursors results in the isolation of a second intermediate
in the postulated mechanism, 2-aryl-1,2,4-benzotriazin-3-one 1-oxide.
The reaction is investigated further by thermolysis of
i) 1-(8-nitronaphth-l-yl)-3-phenylcarbodiimide which gives
naphth[1,8-c,d]indazole N-oxide and
ii) 1-(2-nitrobiphen-2-yl)-3-phenylcarbodiimide.
Vapour phase pyrolysis of l-(2-nitrophenyl)-5-phenyl-
tetrazole gives 2-phenylbenzotriazole and carbazole. 2-Phenyl-
benzotriazole is shown to be an intermediate in this reaction
for which a mechanism is proposed and investigated.
Photolysis of 1-(2-substituted)-5-phenyltetrazoles shows
a tendency for the intermediate imidoyl nitrene to close to
the ortho-blocked position instead of a vacant position when
the ortho-substituent is an ester.
CONTENTS
INTRODUCTION
Decomposition of 1,5-Diaryl Tetrazoles 1
Synthesis of Carbodiimides 9
Synthesis of Heterocycles by ortho-Nitro Side-Chain Interactions 15
DISCUSSION
SECTION 1
A. Preparation of Tetrazoles 36
B. Thermolysis of Tetrazoles 41
C. Alternative Precursors to Carbodiimides 55
D. The Mechanism of Transformation 65
E. Alternative Routes to 2-Arylbenzotriazoles 75
F. Extensions to Nitro Group Interactions. 76
SECTION 2
A. The Carbazole Reaction 91
B. The Mechanism of Transformation 93
APPENDIX
Photochemistry of Tetrazoles 100
EXPERIMENTAL
Instrumentation and Experimental Techniques 105
SECTION 1
A. The Preparation of Synthetic Intermediates 109
B. The Preparation of Tetrazoles 111
C. Thermolysis of Tetrazoles 115
D. Identification of Volatile Components 122
E. The Preparation of Alternative Heterocyclic Precursors 124
F. Thermolysis of Alternative Heterocyclic Precursors 125
G. The Preparation of Thioureas 127
H. The Preparation of Carbodiimides and 2-Arylbenzotriazoles 131
I. The Preparation and Reactions of 2-Aryl-1,2,4-benzotriazin- 137
3-one 1-oxides
J, Extensions to Nitro Group Interactions 139
K, Independent Syntheses 142
SECTION 2
A. The Preparation of Precursors to Carbazoles 145
B, Vapour Phase Pyrolysis 1-(2-Nitrophenyl)-5-phenyltetrazole 145
and 2-Phenylbenzotriazole
C. The Preparation and Pyrolysis of 1,2,5-Dibenzotriazepine 147
D. Pyrolysis and Photolysis of Precursors to 3-Methylcarbazole 147
E. Independent Syntheses 150
APPENDIX
The Preparation and Photolysis of Tetrazoles 152
REFERENCES 154
INTRODUCTION
Decomposition of 1,5-Diaryl Tetrazoles.
Thermal decomposition of 1,5-diaryltetrazoles occurs
in the temperature range 200-230°C, yielding diaryl carbodiimides,
2-arylbenzimidazoles or both.1'2
The substituent at the 5-position migrates to form
diarylcarbodiimide which is the main product of the reaction.
Groups in the 5-position such as p-tolyl which accelerates
migration in the Beckmann rearrangement also favour carbodiimide
formation in 1,5-diaryltetrazole pyrolysis; 5-substituents that
retard migration in the Beckmann rearrangement, such as p-chloro-
phenyl, retard carbodiimide formation relative to cyclisation
to 2-arylbenzimidazoles.2
Pyrolysis of 1,5-diphenyltetrazole (1) in the melt at 210°C
gave diphenylcarbodiimide (2) as the major product and 2-phenyl-
benzimidazole (3).l Photolysis gave 2-phenylbenzimidazole as
the sole product.3'4
Ph~..N
PhN ,N N'
PhN=C=NPh + (3)
(2) 65% 14 °l°
1
N \ Ph
N H
(3) 64°l°
(1 )
In the pyrolysis of 5-(4-chlorophenyl)-1-phenyltetrazole
the yield of 2-arylbenzimidazole was increased to 19%, a
5-(4-nitrophenyl) group brought about a deep seated decomposition
from which no definite products could be found. Thermolysis of
5-methyl-l-phenyltetrazole produced a small amount of 2-methyl-
benzimidazole (7%) but carbodiimides or their derivatives could
not be detected.
It is significant that no diphenylcarbodiimide, the Curtius
rearrangement product, is formed in the photochemical decomposition
of (1), although it is the major product of pyrolysis.
It has been suggested that the mechanism of carbodiimide
formation involves eauilibrat_ion,ofthe tetrazole with the open
chain imidoyl azide, followed by a concerted migration of the
phenyl group and loss of nitrogen.5 A similar mechanism appears
to operate in the related Curtius rearrangement of acyl azides.6
Ph,
II k_)-- PhN
Thermal decomposition of ortho-blocked 1-aryltetrazoles gave,
as expected, mainly carbodiimides with minor amounts of product
derived from the rearrangement of N-arylimidoylnitrene through a
3aH-benzimidazole intermediate as shown.7
2
(1) (2 )
7//
Me (4) (5) 46%
Me
N=C=NPh
N NAN
600° Me 0.04mm
3
N )Ph Me /N
Me
Ph + \ Ph
Me H (6) 30/0 (7) (8)
i 10°/°
Photolysis of tetrazole (4) gave the cyclopentapyrimidine (6)
in increased yield (17%), the yield of carbodiimide being much
reduced (1.5%).7
Thermal decomposition of 1,5-diaryltetrazoles with a carboxyl
group in the ortho-position of either aryl group occurs at a
lower temperature than with the corresponding tetrazoles without
such a substituent.8'9
/NPh + HN3
I 0
(14) 98°I
165-70°
CHCl3
CO7H
N PhNN N
N
(13 )
165-700 CHCl3
4
(9 )
(10) 80%
H
N\-0 \-0
HC-0 PhC -0 (11) 8%
(12) .4%
On heating (9) at a higher temperature (170-230°C) in the absence
of solvent; less benzoxazinone (10) and more products derived
from secondary reactions are formed.8 Similar treatment of
tetrazole (13) produces (14) in a reduced yield (50%) and
3-phenyltetrahydroquinazoline-2,4-dione (15).
O
(13) 170-230 • (14) 50010 -~-
5
This product (15) is not found in thermolysis in chloroform.
That the ortho-carboxyl group participated in the thermal
decomposition reactions of the tetrazole ring is indicated
by the structure of the products, the absence of decarboxylation
and by the comparative stability of 1-(3-carboxyphenyl)-5 -phenyl-
tetrazole, which does not decompose until 230°C, then liberating
carbon dioxide.9
Alternative Precursors of N-Arylimidoylnitrene Derived Products.
1) From 5-Membered Heterocyclic Compounds,
The extruded fragment X = Y in structure (16) can be CO2, 10-15
COS,15 S02f16'17 Ph3P=0,18 or (Et0)3P=018 (Scheme 1).
Decomposition of (16) XY = CO2 in the presence of triplet
sensitisers such as benzophenone gave no.carbodiimide, but if
the photolysis was carried out in the presence of piperylene,
10,13
60-90°/°
6
18
PhN=C=NPh R=Ph 66°1 R=OEt 76 °I°
XY=CO2
XY=R3PO
080°
13 Phr- N
PhN Ph N
A or hv
XY=5O2
XY=COS
16,17
PhN=C=NPh 100 0/0
Scheme 1
15
PhSO2Cl
[PhN=C=NPh3 NaOH
R'=OH
R' =H MnO2
R=Ph Pb(0Ac) 4
NMR NR'
RL H R= Ph
NaOCI base
21,22,23
Ph
23, PhN=C=NPh
24
R 010
Ph 80 PhCh2 52 Me 36
H2O
PhNHCONHPh 25
R' =CI
Ag 20
20
20
>Ph
Scheme 2
8
a triplet quencher, the yield of carbodiimide was increased with
respect to photolysis in dioxan alone. This perhaps suggests
that carbodiimides arise from a singlet imidoyl nitrene, although
the authors14 favour a mechanism involving a phenyl group migration
concerted with loss of carbon dioxide. Benzimidazole formation
is thought to proceed through a triplet imidoylnitrene intermediate.14
Decomposition of (16) XY = SO 2 is presumed to proceed by a
concerted mechanism. 16,17
2) From Amidine-type Precursors
N-Arylimidoylnitrenes may be generated from amidines and
their derivatives as summarised in Scheme 2.
3) From Sulphimides.
Thermal decomposition of imidoylsulphimides gave only small
amounts of 'nitrene' - derived products. Photochemical decomposition
of imidoylsulphimides (17) gave 2-substituted benzimidazoles in
good yield, along with the corresponding sulphide.7
NI R 2
N--SR2 hv /CH3CN
R 2 + R12 S
(17)
NHCONHPh
hv CH3CN
Me
1Ph
Me (6) 13% (18) (5) 12%
H30•
(19)
N=C=NPh +
Photolysis of the ortho-blocked N-arylsulphimide (18) gave
some carbodiimide (5) isolated as the crystalline urea derivative
(19), the cyclopentapyrimidine (6) and a large amount of tarry
material.
9
Synthesis of Carbodiimides.
The earliest preparations of carbodiimides involved the
reaction of mercuric or lead oxide with thioureas.27-31
The most practical methods for the preparation of carbodiimides
are summarised in Scheme 3.
RNHCSNHR' 36 ,37
NaOCl/ NaOH
RNHCSNHR'
10
or
( ) 41,42
R"O
Ph~N
PhN 0 NS'
0 R,R'=Ph 16,17
R2
C R' O
2RNCO
32 P205
RNHCSNHR'
Scheme 3
•
33,35 RSO2Cl/py
RNHCSNHR'
RN=C= NR' 33,38
\ g0 Pb0 39,40
~NjCI_ 62 Me
1) Elimination Reactions.
Prolonged heating of free isocyanates in the absence of
catalysts gave poor yields of carbodiimides, unless nitrogen
was passed through the boiling isocyanate.41
Me
P N_C=0 Et 40 . 0 2 O,N
(22)
N=C=N NO2
(21) 1000t0
11
In thepresence of phosphorus catalysts41,42,44-48
aromatic
carbodiimides are obtained in high yield under mild conditions
from isocyanates, but not isothiocyanates.41 Aliphatic isocyanates
react more slowly but improved yields are obtained in high boiling
solvents. In the case of aromatic isocyanates, electron with-
drawing groups increase the rate of carbodiimide formation in
proportion to their electron withdrawing power. Electron releasing
groups tend to inhibit the reaction. Thus diphenylcarbodiimide (2)
is formed from phenyl isocyanate (20) after 2.5 h reflux in
anhydrous benzene,41 whereas 4,4'-dinitrodiphenylcarbodiimide
(21) is formed at 60°C in 2 min from isocyanate (22)
2 PhN=C=O
Me
Et P40 PhN=C=NPh
(20)
(2) 94°/°
These reactions are thought to proceed through four
membered cyclic intermediates [e.g., (23) and (24)].
R 3P-0 -j- RN=C=0 R 3P-0
RN -C=0 R3P=NR +CO2
12
R 3P=NR RN=C=0
(25)
(23)
RN=C-0 I
RN -PR3 RN=C=NR
(24 ) R3P=0
A compound similar to (25) has been prepared and shown to
react with isocyanate groups to give carbodiimides.50
) Dehydration of N,N'-Disubstituted Ureas.
The reagents used to effect dehydration of ureas in good
yield are p-toluenesulphonyl chloride and pyridine, as solvent
and base.34'35 Other reagents are phosgene,51 phosphorus
oxychloride,S2 and phosphorus pentachloride.47,53
1,1-Dichloro
compounds have been shown to be intermediates when phosgene and
phosphorus pentachloride react with ureas.
3) Oxidation Reactions.
Since substituted thioureas are readily available, the
desulphurisation of N,N'-disubstituted derivatives by
mercuric oxide is one of the best methods available.38 The
preferred solvents are ether, benzene or acetone. The presence
of drying agents such as calcium chloride,54 sodium sulphate,55
or magnesium sulphate,56 remove the water formed, thus preventing
formation of the corresponding urea derivative. Water may also
be removed by distilling it as an azeotrope.57 Other less
effective catalysts are lead oxide,29,31,58 zinc oxide,59 lead
carbonate, lead nitrate and lead chloride.60
The oxidation of N,N'-dialkylthioureas to the corresponding
carbodiimides can also be accomplished in excellent yields by
alkaline hypochlorites below 00 .36,37
Sensitive derivatives such as N-acylcarbodiimides were
efficiently generated by the use of diethyl azodicarboxylate and
triphenyl phosphine.61
RNHCSNHR- D E. D.E.A.D.
RN=C=NRI+EtO2CNNCO2Et+Ph3PS 3
Another excellent method produced aliphatic and aromatic
carbodiimides in high yield, under mild conditons, by the use
of 2-chloro-l-methylpyridinium iodide (26) and triethylamine
in acetonitrile at room temperature (Scheme 4).62
13
Et3N )■1Rl S— C~
\NR 2 H
R1NHCSNHR 2 +
(26)
Et 3N
14
+ Et3N.HI
R1
+ R1N=C=NR 2
R 2 time(h) 0/0 Ph Ph 5 85
p-TOL p-TOL 5 97 Ph . C6H11 5 98
Scheme 4
There are many other miscellaneous methods of preparing
carbodiimides,63 and one recent method of particular interest
involves the pyrolysis of imidoyl-N-imides (27) to give
N,N'-diarylcarbodiimides in good yield,64
Ph
* 1 h Ph N/ P
N-I
NR'
/ • RN=C=NR' +
Ph. Ph
(27)
Synthesis of Heterocycles by ortho-Nitro Side-Chain Interactions.
This review is not an exhaustive catalogue of the products
of ortho-nitro interactions, but aims to identify the range of
processes involved, and to indicate the scope and synthetic
value of ortho-nitro side-chain interaction. The types of
reactions considered involve redox processes, cyclisations
involving intramolecular condensations of the aldol type for
which the nitro group provides the electrophilic centre, intra-
molecular nucleophilic displacements of nitro groups and
photochemical and thermal transformations. Two broad mechanisms
may be differentiated depending on whether the oxygen or nitrogen
of the nitro group is the nucleophilic species. Such postulates
do not, however, specify the exact oxidation level of the
nitrogen atom when the ring forming step occurs; thus adjustments
within the conjugated system must be considered. Full mechanisms
are provided for selected transformations.
1) Formation of Five-Membered Rings.
Probably the best route to 1-hydroxyindoles (28) is through
the base catalysed cyclisation of o-nitrobenzyl derivatives.65-69
15
(28)
R 2
H
(29) a) R j = H, R2 = R3 = CO2CH3
b) R1 =H, R 2 = COCH3 , R =CO2C2H5
16
HCN CO2C2H5
Cyclisation occurs readily where the benzyl side chain has
at least one moderately acidic centre. Where two such acidic
centres are present, sometimes with widely varying acidity, the
compounds are remarkably consistent in their ability to yield
derivatives of 1-hydroxyindole. Nevertheless, in certain cases and
in a strongly alkaline environment this type of product is
accompanied by another derived from 1-hydroxyquinoline.67
Suitable substrates are available either by the base
catalysed condensation of o-nitrobenzoyl chloride with active
methylene compounds (29a, b) or by addition of hydrogen cyanide
to suitable o-nitrobenzylidene derivatives (30). Alternatively,
the 1-hydroxyindole can be prepared directly from the requisite
17
H CO2Et
09 COMe
CN CO2Et
NO2 CO2Et
H
NaOH CO2Et
COMe
~0H
CO2Et
hot KOH E t OH
Na CO3
CN
CO2Et
o-nitrobenzylidene derivative by warming with aqueous ethanolic
potassium cyanide; this reaction presumably involves the
intermediate formation and cyclisation of the corresponding
hydrogen cyanide adducts. This procedure suffers from the
simultaneous formation of quinoline N-oxides except when the
benzylidene side chain contains an alkyl group.69
COMe
1
0
(31)
OH
NO2 COMe Acetone Alkali
CHO
NO2
Indigo (31) is the end product of a number of base-catalysed
reactions of o-nitrobenzene derivatives.70-73
Indigo formation in alkaline acetone solutions (the Baeyer-
Drewson reaction) has been widely used as a test for o-nitrobenz-
aldehydes.74
18
The base catalysed condensation of o-nitrobenzaldehyde
with indan-1-one is reported to afford the indoxyl (32).75
0
19
CHO
NO2
In general, formation of indoxyl derivatives is of
limited synthetic value.
Isatin (33) and it's derivatives are formed in variable
yield by the base or acid catalysed transformations of a
variety of o-nitrobenzene derivatives.70'76-81
base
Reaction of o-nitrobenzylidene anils (34) with aqueous potassium
cyanide followed by acetic acid provides a general route to 2-aryl-
3-cyanoindazole 1-N-oxides (35).81,82
These reactions probably involve
the intermediate formation and base catalysed cyclisation of the
corresponding hydrogen cyanide adducts (36), as evidenced by the
conversion of the cyano compound (36) in warm aqueous sodium hydroxide
or sodium carbonate or in cold concentrated sulphuric acid into
3-cyano-2-phenyl-indazole-1-oxide (35).83
20
(34 ) (36)
NC H NPh
NO2 H
CN
+1N Ph N 1
(3 5) 0-
OMe McOH
CN
NAN
1 (37) 0-
NO2
NH
Use of methanol as solvent instead of acetic acid modifies the
reaction such that 4-arylamino-3-methoxy-cinnoline 1-oxides (37) are
also formed (15%).84,85 The reaction of N-o-nitrobenzylidene-o-nitro-
aniline (38) gave neither indazole or benzimidazole but mainly the
cinnoline 1-oxide (37).
(38 )
The base catalysed cyclisation of dinitrobenzylidene arylhydrazones
(39) affords moderate to high yields of the corresponding 1-arylindazoles
(40) involving intramolecular nucleophilic displacement of an
aromatic nitro group.86-93
O N \(v
N Ph
(40)
base
(39)
Cyclisation fails when the substituent attached to the hydrazone
nitrogen is electron withdrawing,
The standard route94 to benzimidazoles involves the condensation
of o-arylenediamines with a carbonyl containing compound, The method
is simple and the yields are often high. In the bourse of an
(41) (42)
H 1\4.1 CHPh
--a 220
0
base
(43)
+ /RI
0
(44)
21
investigation into the reductive cyclisation of N-substituted
o-nitroanilines95 it was found that N-benzyl-o-nitroaniline
underwent thermal uncatalysed cyclisation to yield 2-phenyl-
benzimidazole. Cyclisation reactions of this type are
presumed95'96
to involve the aci-nitro form (42) of the nitro
compound (41).
A similar aci-nitro species has been proposed to explain the
thermal cyclisations of 2-methyl-2'-nitro biphenyl to phenan-
thridines in diphenyl ether.97
Base catalysed aldol-type cyclisations of N-substituted
o-nitroanilines (43) containing an active methylene side chain have
been successfully applied to the synthesis of a number of benzimidazole
N-oxide derivatives (44).98'99
(45)
N 0 OH
SO2C6H4CH3 N. H
Ar
Use of the N-tosyl derivative (45) in sodium methoxide
results in the formation of alkoxybenzimidazoles (46),100
Variation of base and substituents. has extended the process
to yield 2-alkoxy-benzimidazole 1-oxides (47),101
22
Ts NCH2Ar
NO2
Me0 -S0 2C6H4CH3 N)
~Ar +NJ
0
N Ar
N ~>Ar
OCH3
N"
0 Me-0-502C 6H4CH3
(46 )
Ts NCH2OCOPh
NO2
Et0
NNW
(47) 40- 800/o
NO2 N
j 0 N
NO2
,Ph
N= 0
(48 )
02N
Intramolecular acid-catalysed cyclisations of N,N-disubstituted
o-nitroanilines provide an excellent route to benzimidazole N-oxides.102
Photochemical cyclisation of aziridines (48) also produce benzimi-
dazole N-oxides in excellent yield via a seven membered
intermediate.103
23
Ph
02N H CPh Ph 07N -)N(
(0
Ph 02N
Ph
95 0/0
24
Reactions leading to benzisoxazoles (anthranils) include
some of the earliest recorded nitro-group side-chain interactions.
A variety of o-nitrobenzylcarbonyl derivatives (49) cyclise
under both acidic and basic conditions and thermally to afford
simple anthranil derivatives (50). 104-112
R 2 CHCOR1
NO2
(49)
(50)
R1 R2 Me H Me COMe OH H
Following earlier work on the reactions of benzhydrol,113 an
ion pair, generated by intramolecular nucleophilic attack of the
nitro oxygen has been postulated as the precursor of the two
alternate reaction products.of the benzyl bromide derivative (51). 114
A new heterocyclic system, 3,3a-dihydrobenzofuro[3,2-c]
isoxazole (52), formed by initial (4 + 2) cycloaddition of a
conjugated nitro group with an ynamine has recently been
reported,115 This process has subsequently been extended to
other isoxazoles such as (53),116
25
(51)
1
0 +N
>_0
C— Br H -Ph
Br-
\+,, N-- ■ NEt 2
12,/ 16h/5-10.
Me
0
-F HBr
(52)
NO2+ Ph=-N
il
0
Ph (53) 0
(54)
(56)
o-Nitrobenzene derivatives are key starting materials for
the synthesis of benzotriazoles and benzotriazole N-oxides.117
The base catalysed cyclisation of o-nitrophenylhydrazines to
1-hydroxybenzotriazoles,118,119
and the subsequent related
procedures involving reaction of o-nitroarylhydrazines, provides
routes to 2- and 3-substituted benzotriazole N-oxides.120
In
related procedures o-nitrohydrazobenzene derivatives (54) are
converted into benzotriazole N-oxides (55) in hydrochloric acid,121
acetic acid,120 or acetic anhydride122 or to benzotriazoles (56)
by heating in ethanol 120,123,124
or treatment with y g potassium
iodide in acetic acid.125
26
Ph
H ,~ N Br
(57)
Ph NI N Br
NaOEt i NO2 CNCH2CO2Et Br
The hydrazidic halide (57) is converted by treatment with
triethylamine into the benzotriazole (58). A mechanism invoking
the intermediacy of a nitrile imine has been suggested.126,127
However, use of sodium ethoxide with ethyl cyanoacetate on (59)
gave only the benzotriazine (60) and benzoxazole (61).128
27
N N/ 0C0Ph
(58 )
(59)
(60)
(61)
N=NMe Toluene/ a 7h
0 2N NO2
(62)
N + NMe + / N
0
(63) 970/0
A seven membered ring intermediate is postulated in the
thermolysis of the diazirine (62) to 2-methyl-benzotriazole-l-
oxide (63).129
28
With few exceptions the available methods130
for the
' synthesis of benzofuroxans involve nitro-group side-chain
interactions. Thermolysis or photolysis of o-nitroarylazides
provides a high yield route to benzofuroxans.131 A closely
related process is presumably involved in the thermal isomerisation
of nitrobenzofuroxans (64 ) 65),132
(65)
R3 2 \ R2
~ R1
(69 ) 0 (68)
The thermal rearrangement of 6-chloro-7-nitroanthranil (66)
into 7-chloro-4-formylbenzofuroxan (67) provides the first
example of a benzofuroxan being formed by an isomerisation of
the general type not involving another benzofuroxan,133
29
CHO
AcOH / Reflux
N\ /O
0
770/0
Cl Cl
(66)
(67)
Six-Membered Heterocycles.
Strongly basic catalysts and electron withdrawing groups in
o-nitrobenzylidene derivatives (68) favour the formation of the
otherwise inaccessible quinoline N-oxides (69) as opposed to
formation of 1-hydroxyindoles in such reactions.67-69
0 R 3 OFF
000CH2R2
(70)
(71)
OH
CORS
Hitherto unreported 2-acyl-3-hydroxyquinolines (71) are
prepared by base catalysed cyclisation of 2_(2'-nitrobenzyl)-
derivatives of certain 1,3-diketones (70) in a reaction
explained in terms of a new version of the Smiles rearrangement.134
30
R3 = Me 55- 83 °A
R 3 = Ph 15%
The base catalysed cyclisation of 2-nitrobiphenyl derivatives
(72) having an activated methylene group in the 2'-position
provides a valuable synthetic route to phenanthridine N-oxides
(73).135,136
(72)
R
a ' H
b COPh c CO2Me d SO2Ph
(73) 50-80°/°
R
a H
d SO2Ph
CH 2R
NO2
31
(74) 800/°
Cyclisation of the ketone(72b) proceeds with loss of the
benzoyl group giving phenanthridone (73a) in good yield.136
At high base concentration the ester (72c) likewise gives (73a).
Cyclisation of (72d) fails to give the expected sulphone affording
the cyclic hydroxamic acid (74) instead. Phenanthridine
derivatives are also formed in moderate yields by the photocyclisation
of o-nitrobiphenyl derivatives such as (75) and (76). 137 138
N aq NaOH H
+N~ NO2 McOH /Reflux/ 2h /~ U
NH2
Cl hv
32
(75)
25 0/0
H NPh
hv CN
(76)
Aldol-type condensations between amino and nitro groups in
biphenyl derivatives provides a fairly general synthetic route
to benz[c]cinnoline N-oxides,136
92- 98 °I°
0
~N~O R2
1
(79)
N-O
N%R2
0 (80)
1-Hydroxyquinazoline-2,4-diones (78) are formed in high
yield by heating the benzoylaminoacetonitriles (77) in ethanolic
sodium ethoxide.139
(77)
(78)
Similarly, base catalysed condensation of o-nitro acetanilides
(79) provide a valuable route to the formerly unreported
quinoxaline-3(4H)-one 1-oxides (80). 140
33
02N
NH2 Ph
. b (81) -
09N Ph
The reaction of electron-deficient arenes or halides with
a-phenyl-N,N-disubstituted and unsubstituted amidines has
been used as an efficient route to quinoxalines (81) and (82),141
and similarly to indoles, quinolines, benzoquinolines, iso-
quinolines,142
and pteridines,143
-}- PhCH2i=NH NH2
-~ PhCH2
34
Phenazine (83) is obtained from the thermolysis of o-nitro-
diphenylamine,144 and in a reaction almost certainly involving
intramolecular nucleophilic displacement of a nitro group,
dibenzodioxans (84) are obtained from catechol and o -chloro-
nitrobenzene in warm acetone.145
35
The base catalysed cyclisation of o-nitrophenylguanidines
and ureas provides an excellent method for the synthesis of
1,2,4-benzotriazine 1-oxides.146
The scope of this reaction
has been modified and extended to include a variety of o-nitro-
phenylguanidine derivatives (85) which are prepared in situ
by the acid catalysed condensation of an o-nitroaniline derivative
with cyanamide and subsequently cyclised to benzo-1,2,4-triazine
1-oxides (86) under alkaline conditions. 147-149
(8 5 )
"INH2 +~N NI
(86) 50
1 80010
Closely related to the above reactions are the base catalysed
transformations of o-nitrophenylureas150 and thioureas146,150
into benzotriazinone N-oxides and benzotriazinthione N-oxides.
DISCUSSION
SECTION 1
As an extension to a series of tetrazoles used as
N—arylimidoylnitrene precursors, 1-(2-nitrophenyl)-5-phenyl
tetrazole was prepared. The aim of this thesis is to report
and explain the deep seated thermal rearrangement resulting
in the formation of a single major product, to examine the
scope of the reaction, and to investigate the role of the
nitro group in tetrazole decompositions, and compare the results
with those published in the literature.
A. Preparation of Tetrazoles.
The 1,5-diaryltetrazoles were prepared according to the
procedure outlined in Scheme 5.
36
NH2
R 1
ArCOCI / Py NHCOAr R1
PCl5
Anr
N, ~N jv NaN3 / DMF N
R 1
C Cl 0A r
Scheme 5
The amines were commercially available or were prepared by
literature methods. The imidoyl chlorides were prepared by
refluxing the anilide in benzene or toluene, with a slight
excess of phosphorus pentachloride. The imidoyl, chlorides
were then converted to tetrazoles by stirring with an excess
of finely ground sodium azide, in dry dimethylformamide.
Excellent yields (80-90%) of high purity tetrazoles (87) were
then obtained by adding sufficient water to dissolve residual
salts.151
(87)
87 R1 R2 R3 R4
a H
N
x x x x 0 x x x x x x
H
b H H
c NO2 H
d H NO2.
e H H
f
M H C?
g H C?
h H NO2
i NO2 C$
j NO2 NO2
k NO2 H
37
N3 + PhCN -E- NaC l
02N NO2
Attempts to prepare (87k) by this route failed. Reaction
of the imidoyl chloride in situ with sodium azide in dimethyl-
formamide produced a moderate yield (51%) of 6-nitrobenzo-
furoxan (88).
38
02N
Tetrazole (87k) had previously been prepared152
by reaction
of the imidoyl chloride and sodium azide in aqueous acetone of
unspecified concentration. The corresponding imidoyl chloride
was prepared153
and isolated. Reaction with sodium azide in a
10:1 acetone-water mixture gave 2,4-dinitrophenyl azide in moderate
yield O60%), which was subsequently quantitatively converted into
6-nitrobenzofuroxan in boiling benzene. The following nucleophilic
displacement mechanism is proposed for this reaction.
/ 1
N NN
NO2
(89)
A 1:1 mixture of acetone-water gave the required tetrazole
in low yield (30%). 2,6-Dinitroaniline failed to react with
benzoyl chloride in refluxing pyridine. Use of catalytic and
equimolar amounts of N,N'-dimethylaminopyridine in the reaction,
also failed to produce the required benzanilide. Some
monoaryltetrazoles such as (89a-c) were also required.
39
a) R =H
b) R = Cl
c) R = CH3
Compounds (89a and b) were prepared in good yield by
literature methods,154 Compound (89c) was prepared in moderate
yield (47%). There appeared to be some reaction of the o-nitro
group in the imidoyl chloride producing a mixture with an
intense acid chloride carbonyl band (1780 cm-1). This suggests
an intramolecular elimination of acetyl chloride initiated
by the oxygen of the o-nitro group.
Attempted preparation of ethyl'1-(2-nitrophenyl)-5-carboxylate
failed to produce the required product, Attempted preparation
of ethyl 1-phenyltetrazole-5-carboxylate also failed to produce
the required product, Treatment of ethyl oxanilate (90) with
phosphorus pentachloride in toluene, followed by sodium azide
in dimethylformamide gave a pale yellow oil (25%) which was
tentatively assigned as structure (91) on spectroscopic evidence.
NHC00O2Et 1) PCL 5 /TOt. 0. 2) NaN3 / DMF
OH
NHCCO2Et
N3
(90)
(91)
Reaction with phosphorus pentachloride in benzene followed
by treatement with sodium azide in acetone at 0°C155•g
ave an
oil with spectral data corresponding to (91). There was also
evidence for the presence of phenyl isonitrile: vacuum distillation
of the imidoyl chloride formed in refluxing toluene and in the
melt, produced a small amount of brown oil with an intense peak
at 2280 cm-1 in its i.r. spectrum. There was also spectral evidence
for an acid chloride. The following mechanism is proposed to
explain the latter results.
The formation of (91) could arise from hydration of the
first formed imidoyl azide, since it is known156
that electron
withdrawing groups favour the azide in the tetrazole-imidoyl-
azide equilibrium.
40
-E—r c -s° Ç OEt CI
C=0
OEt
N=C -E- C[CO2Et
B. Thermolysis of Tetrazoles.
1. Thermolysis Reactions. _
The mononitrophenyltetrazole (87b) produced a trace of
a high Rf fluorescent product when treated under reflux in
chlorobenzene, under nitrogen. However, heating in bromobenzene
at 165°C for 20 h, and in dichlorobenzene at 185°C and
1,2,4-trichlorobenzene at 215°C for 0.5 h respectively, caused
complete decomposition. The single isolated product was
2-phenylbenzotriazole in each case, (Table 1).
41
TABLE 1 42
Starting material Product Sol v. Temp. Time Yield (°/0)
0
SS 165 20h 80
P~~ (tN, 0
O:N..N~N DeB 185 0·5h 91
NPh ~ ~N" 0
O'5h ~ N02 TeB 215 92
P~N - \ ():N\ 0
Q·75h 60 O:N'N~N 0 ~ ,.... )lPh SS 165 02N:.:..... NO 2 tJ N
Cl~ 0
56 8B 165 24h
~ -N ():N'NOCI 0
82 . DeB 185 4h \
O:N'N~ ~ ~N' - 0
84° TeB 215 2 ·5h ~ N02
a) 0
0)0 Ba 165 24h (XN,O b) 0
02~ fJ N02
0 ~ --N - DeB 185 5·5h a) 13
~ -N b) H b) 66 \
(J(N~N02 O:N'N~N 0
5min 0)72 TeB 215 ~ N -
b) 0 ~ N02 N02
0
24h 0 0;2 BB 165
~ -N o:~ 0
0 DeB 185 24h \ NPh 81 S.M. aN'N-::::N ~ ~N/ 0
9h 75 TeB 215
Solvents:· BS= Bromobenzene
DeB = 1, 2 - 0 i c h lor 0 b en zen e
TeB = 1,2,4-Trichlorobenzene
Ph~—N
i N~ /11N
NO2
(87b)
Ph/7-77-
NNN'N
02N NO2
(87k ) (92)
43
N\
N"
The formation of 2-phenylbenzotriazole is not simply
explained. Tetrazole decompositions normally occur at a
higher temperature, although the presence of an o-carboxyl
group has been shown to reduce the decomposition temperature.8'9
Thermolysis of the dinitrophenyltetrazole (87k) was even
more facile in bromobenzene, producing a good yield (60%) of
the corresponding 2-phenylbenzotriazole in 0.75 h.
Under the same conditions 1,5-diphenyltetrazole (87a) failed
to react, as did the 1-(4-nitrophenyl)-5-phenyltetrazole (87c).
Ph/
PhN. rN
. N
44
(87a) (87c)
Refluxing the o-cyano compound (92) in 1,2,4-trichlorobenzene
at 215°C for 0.5 h produced exclusively carbodiimide. Under
identical conditions, 1,5-diphenyltetrazole remained largely
unchanged. Thus, the presence of an ortho-electron withdrawing
group in the 1-phenyl ring facilitates decomposition of the
tetrazole, this effect being enhanced by the presence of a
second electron withdrawing group in the same ring.
2. Identification of Volatile Components.
Transformation of these 1-(2-nitrophenyl)-5-phenyltetrazoles
(87) to 2-phenylbenzotriazoles requires the loss of nitrogen,
as expected for a tetrazole, and either carbon dioxide or carbon
monoxide and oxygen. Decomposition of 1-(2 —nitrophenyl)-5-
phenyltetrazole (87b) diluted with acid-washed sand produced
gases at a slow rate which were bubbled through lime water solution
producing a copious white precipitate indicating the presence of
carbon dioxide. To preclude the presence of carbon monoxide,
45
(87b) was decomposed under argon, in a vacuum line. The gases
produced after thermolysis were transferred in the vacuum line -
to an evacuated gas cell. The gases were then analysed by high
resolution mass spectrometry. There were significant increases
in the carbon dioxide and nitrogen peaks but no evidence for
carbon monoxide.
Thermolysis under argon in the presence of a pre-coated
palladous chloride indicator strip157
also failed to detect any
carbon monoxide. When exposed to carbon monoxide generated from
oxalic acid, the strip immediately turned black.
A pungent odour, characteristic of phenyl isocyanate was
evident when working up the sand diluted melt thermolyses.
Repetition of this thermolysis under water aspirator vacuum,
produced a colourless oil, which partially distilled from the
reaction mixture. This oil had a characteristic isocyanate band
(2260 cm-1) in the i.r. spectrum. The product of a solution
thermolysis was treated with aniline and pyridine at 80°C for 1 h.
Treatment-with benzene produced 1,3-diphenylurea (4%). Acid
catalysed decompositionsof (87b) in refluxing bromobenzene with
acetic acid and trifluoroacetic acid produced 2-phenylbenzotriazole
in yields of 15% and 11% respectively with a large amount of
tarry products. Vapour phase pyrolysis at 400°C produced two compounds
with similar Rf values on t.l.c., from which was isolated
2-phenylbenzotriazole (See Section 2).
RZ ~R1 R3~N N
NO2
3. Evidence for an Intermediate.
Several pathways may be considered for the transformation
of the 1-(2-nitrophenyl)-5-aryltetrazoles (87 R1 = NO2)
into benzotriazoles. The photochemical decomposition of 1-(o-nitro-
'phenyl)pyrazoles resulting in the formation of 2-substituted
benzotriazole N-oxides has recently been reported.159, 160 The
authors were unable to distinguish between two possible
mechanisms: 1,3-dipolar cycloaddition of the nitro group to the
pyrazole moiety or a 1,5-dipolar cyclisation mechanism. This
route involves the intermediacy of an o-nitrosoazo intermediate,
46
compounds which have not been isolated but are frequently proposed
as precursors of 2-arylbenzotriazole-l-oxides.161-163
An alternative mechanism may involve nucleophilic attack
of the nitro group oxygen on the tetrazole carbon. However,
the simplest pathway which can be considered for this transformation
appears to involve the carbodiimide (93), which leaves the final
problem of the somewhat curious loss of carbon dioxide.
47
(93)
(87e)
Support for this postulate can be found in the thermolysis
of (87e) which in 1,2,4-trichlorobenzene at 215°C for:9 h
produced 2-phenylbenzotriazole in high yield (75%). 1,5-Diaryl-
tetrazoles are known to decompose thermally to carbodiimides.1'2
Thev•steric interaction between the nitro-group and the tetrazole
ring can be expected to twist the 5-aryl group out of the plane
of the tetrazole ring, thus the electron withdrawing effect of
the nitro group will be somewhat diminished in the transition
state (94) ,
NO2
(94)
The increase in potential energy due to the partial loss
of resonance stabilisation, the desire to release strain in the
azacyclopropene ring, and the possible steric or charge transfer
effect of the nitro group oxygens impinging on the nitrogen
leaving group will faciliate the migration of the 5-nitrophenyl
group, This 'ortho-effect' is well known in the Beckmann
rearrangement.164
Thus the carbodiimide (93) could well be a
common intermediate formed from tetrazoles (87b) and (87e).
4. The Role of Substituents in 1,5-Diaryltetrazoles.
The decomposition of tetrazole (87d) and (87f) in the melt
at 210°C, has been described in the literature.1,2 Migration of
the 5-(4chlorophenyl)-group was claimed to be retarded significantly,
relative to migration of a phenyl group, and no products were
obtained with the 5-(4-nitrophenyl)-substituent present.
(87d) (87f )
48
N Ph N~
N N
(87d) TCB
No Reaction
C l
15°/0
On thermolysis of (87d) in 1,2,4-trichlorobenzene at 215°C
for 4 h, we found a very similar product distribution compared
to the products of 1,5-diphenyltetrazole thermolysis,1'2
Thermolysis of (87f) under identical conditions gave a
lower material return with approximately equal amounts of
carbodiimide and imidoyl nitrene derived products. The tetrazoles
(87d) and (87f) are stable at lower temperatures.
Ph —N 210° PhN=C=NPh +
PhN~N ,N
49
>Ph
(87a)
80°10 20010
Cl BB DCB
215 °
330/0 + mixture of disproportionated l 'ureas 25 °/°
PhN=C=N Cl +
NO PhN=C=N
(87f) TCB 215°
9 Of
-~- mixture of disproportionated1 ureas 20°I°
Cl
N
NO2 (95)
(87g )
BB No Reaction DCB
50
Thus while the chlorine substituent in (87d) has very
little effect on the migratory aptitude of the 5-aryl group
compared to phenyl migration, the nitro group in (87f)
significantly retards migration. When compared to the above
results, decomposition of tetrazoles (87g) and (87h) show clearly
part of the -function of the o-nitro group in the 1-phenyl ring.
BB 24h 56°I°
CI DCB 4h 82°/0
TCB 2h 84°/°
NO2
(87h)
(96)
BB 24h - No Reaction
DCB 5.5h 13°/°
TCB 5 min 72 °I°
H
(97)
66%
0
N N N
NO2
(89)
The o-nitro group reduces the decomposition temperature of
the tetrazoles, and promotes decomposition of the tetrazole ring
by exerting some influence other than the purely electronic
effect, since in bromobenzene the 1-(2-nitrophenyl)-derivatives
decompose, whereas the 1-(4-nitrophenyl)-derivatives are stable,
(Tables 1 and 2). Thermolysis of (87g) gives good to excellent
yields of the benzotriazole (95). Thermolysis of (87h), however,
shows the o-nitro group exerting a compelling influence over the
course of the reaction. In 1,2-dichlorobenzene at 185°C, the
major product results from the loss of nitrogen from the tetrazole
(or imidoyl azide) followed by cyclisation of. the imidoyl
nitrene to the benzimidazole (97), with the minor component of the
reaction, benzotriazole (96), attributed to initial migration to
a carbodiimide intermediate, and rearrangement. At 215°C in
1,2,4-trichlorobenzene, the only product of the reaction is derived
from migration of the 5-(4-nitrophenyl)-group to give benzotriazole
(96), a formerly disfavoured process which is now the sustained
mode of action. Nitro groups in the 5-phenyl ring do not reduce
the tetrazole decomposition temperature,
Decomposition of compound (89) was less productive.
51
a) R = H
b) R= Cl
c) R = CH3
(9 8)
TABLE 1 52
Starting material Product Sol v. Temp. Time Y i e l d (%)
l~b 0 0
SB --1:6:5-- 20h 80 Pty=~ .(j:N 185
0
O·5h 91 . (XN /N :;;..- , DeB NPh I 'N" 0-... ~r{
215 0
~ N02 TCB G'5h 92
P~N ) S-b 0 - \ ():N\ 0
Q-75h 60 O:N'N~N 0 ::::.... 0-- ,NPh BB +G-5-
02N ~ NO 2 zN N •
fS{-, ~
CI~ 0
56 BS 1~ 24h
~ -N ():N'NOCI 0
4h 82 DCB 185 \
O:N'N~ ~ ~N' -0
2 -5 h 84 TCB 215 ~ N02
I
d) 0
24h 0)0 B8 --113-5-(tN, 0 1$(:,0
N N02 b) G 02NO;- ~ '- I 0 N - DCB 185 5 ·5h a) 13 ~ -N b) H . b) 66
\
(IcN~N02 O:N'N~N 0
0)72 TCB 215 5min ~ N -
b) 0 ~ N02 N02
[.!)"'bl;)
0
24h 0 0;:2 BB -+&5-
~ -N ():~ 0
24h 0 DCB 185 \ NPh 81 S.M. ON, -::;N 0-.. ~N/ 0
9h 75 _ I N TCB 215 0-..
Solvents: BS= Bromobenzene
DeB = 1, 2 - 0 i c h lor 0 ben zen e
TCB = 1,2,4-Trichlorobenzene
TABLE 2
Start i ng material Sol v. Ti me (h) Product
carbodiimidel urea Phr=N, TCB 0·6
PhN'N~
Cl~ BB 24 a) carbodiimidel urea
~ -N DCB 24 b) ben zi mid az ole ,
PhN'N~N TCB 48
\
02NOr- 88 24
a) c arbodii mide I urea
~ -~ DCB 24 b) benzimidazole
PhN ,.N TCB 48 'N/
carbodii mide lure Cl
PhpN\ 24
NN'N;:::.N DCB
o ~ \
. CIO;- BS 24 carbodiimide I urea
" _N DCB 22 \
~N' -;::N TCB 7 02 ,I N
Sol vents: 8 B = Bromobenzene
DCB = 1,2 -Dichlorobenzene TCB = 1,2 , 4 -Trichlorobenzene
53
Y i e 1 d (°/0)
0
98 (SM)
77 (SM)
59(0) 15(b)
NO REACTION
73 (SM)
29(a) 34(b)
35
33 UREA 5 9(SM)
76 UREA
92 UREA
Refluxing (89a) in bromobenzene at 165°C overnight
produced a complex mixture (t.l.c.), from which was isolated
a small amount of o-nitrophenylcyanamide (98)(5%). Extended
thermolysis of (98) did not cause any further rearrangement.
The product (98) is probably formed by migration of hydrogen
to give a carbodiimide which then isomerises to the more stable
cyanamide. A rapid evolution of gas was noted when (89b) was
heated in bromobenzene. The solution became dark red and the
reaction mixture exhibited an intense i.r. band at 2260 cm-1.
Further heating consistently caused considerable decomposition
and no products could be isolated. Thermolysis of (89c) generated
tarry products only. The reduced ability of alkyl groups to
migrate, thereby chang ing the nature of reactions has been noted
previously.19
Since we had'no direct evidence for the postulated
carbodiimide intermediate in the conversion of tetrazoles into '
benzotriazoles, alternative precursors offering milder routes to
the rearrangement products were sought.
C, Alternative Precursors to Carbodiimides.
Other reactions in which carbodiimides are formed are the
fragmentation of-other heterocycles and the oxidation or
elimination reactions of thioureas, (see Introduction).
54
Ph NO
~~ NN ,0
I I 0
1. Heterocyclic Precursors.
The formation of diarylcarbodiimides from 1,5-diaryltetrazoles
requires the extrusion of the thermodynamically stable fragment
N2 from the molecule.
The oxadiazolone (99),10 the oxadiazolthione (100), and the
oxathiadiazole-2-oxide (101) can rearrange to the same carbodiimide
(93) on extrusion of CO2, COS and SO2 respectively.
NOPh~N N0
Ph[=N\ N` ~0 2
Ó N0
II it 0. S
(99)
(100)
55
(101)
(93)
Ph__N NO. Ī
NNC
O
II S
(10 0) 77%
NyPh
NO2 NHOH c sc l 2 Et3N
NH2OH
Na/EtOH
(102)
Compound (99) was prepared by the literature route;° and
compounds (100) and (101) were prepared by a modification of
the literature route, by treatment of amidoxime (102) with
thiophosgene or thionyl chloride respectively (Scheme 6).
56
Ph, -N 2
I 0 (101) 67 °/°
Scheme 6
The very stable oxadiazoles (99) and (100) required
strong heating (255°C) in boiling diphenyl ether or in the
melt and gave 2-phenylbenzotriazole in low yield only (ca.
10%), the major product being that of nitrene cyclisation,
4-nitro-2-phenylbenzimidazole (103) (Table 3). However, the
oxathiadiazole (101) decomposed under much milder conditions,
in boiling bromobenzene at 165°C or in the melt at 135°C to
give 2-phenylbenzotriazole in good yield (Table 3); formation
and decomposition of carbodiimide (93) can be clearly seen
inithe infrared spectra (2160 cm-1). 3,4-Diaryloxathiadiazole-
2-oxides such as (101) are known to give carbodiimides almost
quantitatively on heating (see Introduction).17
The formation of 2-phenylbenzimidazole (104) is thought to
arise from closure of the N-arylimidoyl nitrene on to the ortho-
blocked position giving a 3aH-benzimidazole intermediate which then
rearranges by a 1,5-sigmatropic shif,t of the nitro group to nitrogen.
The N-nitro group is then lost on work up to give 2-phenylbenzimidazole.
Thermolysis of 4-nitro-2-phenylbenzimidazole in the melt at 260°C
overnight gave unchanged starting material, precluding this as the
source of 2-phenylbenzimidazole.
N-nitro heterocycles have been prepared by low temperature
(ice-salt) nitration using nitric acid and acetic anhydride,165
but attempts to apply this method to the synthesis of 1-nitro-
2-phenylbenzimidazole failed.
57
Solv. Temp 0 C Time(h)
P'Y=N\ Ph 20 255 24
O:'8~0 ~ N02 Melt 255 7
(99 )
Ph, N\ Ph 20 255 6
(XN' ,,0 ::::-... 'N02~ Mel t 260 4
(100)
Pt;=N\ PhBr 165 1
Q:N'S"O :--.... I N02 0
Mel t 135 1
(101 ) - '--- - ------ ~ - ~ ----
TABLE 3
(XN\ N02
. NPh O:~Ph :::--..... ......... N' ~ N (1 03) H % (1070) %
11 34
9 37
4 25
9 7
88 -
64 -
------- - --------_._-
(tN ~ '_JPh H
(104 ) °/0
3
4
13
4
-
-
Recovered
Starting Material
1 8
19
13
-
-
-
I
I
I
Ln ex>
(103) (104)
ti
N \>Ph N H
(99) or
(100) NO2
2.. Thioureas.
The N,N'-disubstituted thioureas shown in Table 4 were
prepared in good yield by the procedure outlined below.166
59
NH2 csct 2 NCS
NO2 NO2
R1NH2
NHCSNH
NO2
NHCSNHRI
NO2
(105 0-g ) (105)
Where R1 was an aryl group, substituents are labelled R2,
R3, and R4.
TABLE 4
105 R R1 R2 R3 R4 Yield
a H Ar H H H 80
b H Ar H Me H 40
c H Ar Me H Me 84
d H Ar Me Me Me 72
e H Ar H OMe H 92
f H Ar H NO2 H 68*
g Me0 Ar H H H 62
h H t-butyl - - - 93
j H benzyl - - - 72
k H 2-pyridyl - - - 75
1 Me0 2-pyridyl - - - 29
__ _ -
* This yield is based on starting material consumed;
much being recovered from the reaction.
Attempted synthesis of 1-(2,6-dinitrophenyl)-3-phenyl-
thiourea and 2,2!-dinitrophenylthiourea failed.
60
N=C=N-R1 ; R1= Ar =
NO2 R4
2a. Preparation of Carbodiimides.
Carbodiimides (106) were prepared in good yield from the
alkyl, benzyl and most arylthioureas using mercuric oxide, as
described in the Introduction. This method was efficient on
a small scale (up to 300 mg) but on a larger scale it was
difficult to remove mercury salts from the product. Mercuric
oxide failed to produce carbodiimides from the 2-pyridyl-
substituted thioureas (105 k and 1), and also from the
3-(4-nitrophenyl)-derivative (105f). The use of silver(II) oxide
also failed with these compounds and left metal residues in the
carbodiimides, where formed. The use ōf 2-chloro-l-methyl-
pyridinium iodide62 enabled clean, large scale reactions to be
performed in short reaction times. However, this reagent did not
generate carbodiimide from the 3-(4-nitrophenyl)-derivative (105f)
and gave only a very low yield (4%) of carbodiimide from the
3-(2-pyridyl)-derivative (105k) as shown in Table 5. Attempts
to prepare the pyridine N-oxide and thus remove the electron
withdrawing effect of the pyridine nitrogen failed.
61
(106) (106a-f )
TABLE 5
106 R 'R1 R2 R3 R4 Reagent Time (h)
Yield (7) **
a H Ar H H H 40 18 76
b H Ar H Me H CMI 5 83
c H Ar Me H Me Hg0 2 92
d H Ar Me Me Me Hg0 18 -
H Ar Me Me Me CMI 2 98
e H Ar H Me0 H 40 18 -
H Ar H Me0 H CMI 0.5 85
f H Ar H NO2 H Hg0 •* 0
H Ar H NO2 H CMI - p
h H t-butyl - - - Hg0 18 -
j H benzyl - - - Hg0 18 0
k H 2-pyridyl - - - Hg0 - 0
H 2-pyridyl - - - Ag0 - 0
H 2-pyridyl - - - CMI - 4
CMI = 2-chloro-l-methylpyridinium iodide.
* A wide range of reaction times and conditions failed to
produce any carbodiimides.
** Where yields are not quoted the carbodiimide was used directly
after isolation.
62
The symmetrical carbodiimide (106m) was prepared from the
isocyanate as shown-.^
63
NH2 coCl2 NCO
NO2
NO2
/Me
0'rP -Ph
(106m)
50 0/o
The use of alternative catalysts such as triphenylphosphine
oxide and triphenylarsine oxide gave (106m) in very impure form,
in low yield. This is the only arylcarbodiimide with an o-nitro
group previously recorded,41 but there is no report of this
undergoing rearrangement.
2b. Thermolysis of Carbodiimides.
The carbodiimides as prepared above were isolated pure (t.l.c.),
with a characteristic intense band in the i.r. spectrum (2120-2170 cm-1)
R
R4
(106)
64
and were used without further purification. The oils or solids
were dissolved in a suitable solvent, usually bromobenzene, and
heated to reflux temperature under nitrogen. The diarylcarbodiimides
(106a-e) gave 2-arylbenzotriazoles (107a-e) in good overall -
yield from the thioureas as shown below and in Table 6. The
reaction times varied from a few minutes to several hours
depending on the aryl-substituents and the reaction temperature.
The overall yield obviously reflects the efficiency of the carbodiimide
formation.
3 N, R4
(107) + N2 + CO2
TABLE 6
106 Rggt R RZ R3 R4 Solvent T° . Time Yield (%)
a Hg0 H H H H BB 165 10 min 50
b Hg0 H H Me H BB 165 2 h 37
b CMI H H Me H TCB 215 5 min 43
c Hg0 H Me H Me BB 165 1.5 h 59
d Hg0 H Me Me Me BB 165 1.5 h 54
d CMI H Me Me Me BB 165 15 min 73
e Hg0 H H OMe H BB 165 15 min 25
e CMI H H OMe H BB 165 10 min 55
m - H NO2 H H melt 165 5 min 84*
* This yield was calculated from the carbodiimide.
Thermolysis of the t-butyl (106h) and benzyl (106j)
carbodiimides failed to give any product. Extensive heating
in a range of solvents culminating in 1,2,4-trichlorobenzene at
215°C for long periods failed to cause any rearrangement of the
carbodiimide.Infra-red monitoring of the reactions indicated
the carbodiimides were extremely stable thermally. The carbodiimide
-N=C=N- stretching vibration at (2120-2170 cm-1) decreases with
an associated build up of tarry baseline products over a period
of 24 h.
D. Mechanism of Transformation.
1. Isolation of Reaction Intermediates.
Evidence for the intermediacy of a carbodiimide in the
transformation of 1-(2-nitrophenyl)-5-aryltetrazoles, and other
heterocyclic precursors (99), (100) and (101) is implicit, since
owing to the unstable nature of the carbodiimides (106) none have
been fully characterised.
65
Ph N N09
N ~C~O
I I 0
(99)
N07 Ph1N
NO2 Ph1N
N NC 0
Ó NO
N5/
II 0
(100)
(101)
IS
NHC NH
NO2 (105a)
V
N=C=N
NO2
The explicit evidence was obtained by generating the carbodiimide
(106a) from the thiourea (105a). The carbodiimide was made up
to a fixed volume and half was hydrolysed to the known urea
(108), which was characterised against an authentic sample,
while half was thermolysed to 2-phenylbenzotriazole (107a) as
shown.
66
Hg0
N NPh
N (107a )
ii NHCNHPh
NO2
(108)
N=C=0
NPh
0
(110a)
Attempted bulb to bulb distillation of carbodiimide (106a)
under high vacuum, using a mercury diffusion distillation
apparatus, resulted in a red oil distilling from the carbodiimide.
Thin layer analysis of the red oil shows two components, which
when heated were converted exclusively to 2-phenylbenzotriazole.
Attempted crystallisation of the carbodiimide (106a) resulted in
the formation of two sets of crystals which were mechanically
separated. Bright orange needles with a low melting point
(19-21°C) were identified as the carbodiimide (106a). The second
product, deep red needles, m.p., 126-128°C corresponded on t.l.c.
to the red component from the carbodiimide distillation. Infra-red
analysis of the red compound in the solid phase shows a band at
1695 cm-1 and in solution this carbonyl absorption diminishes and
a new absorption at 2260 cm-1 (CC$4) appears. On the basis of
this spectroscopic evidence, the red solid carbonyl compound was
tentatively assigned the structure (1O9a) which is isomerised to
structure (11Oa) in solution. Removal of the solvent leaves the red
solid with the original infra-red spectrum, demonstrating the
reversibility of (109a) -- (110a).
67
(101)
N=C= NO2
(106 e )
OMe Ar = 4 -methoxyphenyl (109e)
That the 2-aryl-1,2,4-benzotriazin-3-one 1-oxide is an
intermediate in the reaction sequence was shown as follows;
low temperature thermolysis in toluene of the oxathiadiazole-
2-oxide (101) and of the carbodiimide (106e), for a longer period
produced a red solution in each case from which was isolated a
red solid by careful removal of the solvent and crystallisation from
acetone.
Further heating of the red solution in toluene produced the
corresponding 2-arylbenzotriazole quantitatively. Thermolysis
of the isolated red compounds in bromobenzene again produced a
quantitative yield of the 2-arylbenzotriazole. Elemental analysis
68
Me0 NH2
benzene NAN P h
0
(109a)
NHCNH OMe
IV—NPh
0 (111 )
supported the assignment of (109a) and (109e) although this
evidence is of less significance since the 2-aryl-1,2,4-benzo-
triazin-3-one 1-oxides are isomeric with other structures up
to the point that carbon dioxide is lost. Further support for
(109a) came from the reaction in benzene with p-anisidine which
produced the corresponding azoxyurea (111). Hydroylsis of (109a)
in aqueous acid gave 2-phenylbenzotriazole. The structure (109a)
was subsequently confirmed by X-ray crystallography
69
To rationalise the transformation of carbodiimide (106a)
into benzotriazole (107a) in which the benzotriazine (109a) is
an intermediate, a sequenceof electrocyclic ring closing and
opening reactions is proposed, as in Scheme 7.
2-Aryl-1,2,4-benzotriazin--3-one 1-oxides have not previously
been recorded although the 2H-derivatives have been prepared
by base catalysed condensation of o-nitrophenyl ureas, (see
Introduction), 146,150,167
o
N NPh + 0O2
N
N=C=O
N=NPh 0 (110a) (107a)
N=C=NPh
NPh
NO2
0
(106a)
Jf
(109a)
Scheme 7
72
0
NHC NH2
NO2 base
NH
(112) 0
We were unable to synthesise a 2-phenyl-derivative by
treating 1-(2-nitrophenyl)-3-phenylurea with base. Hydrolysis
of (112) with aqueous sodium hydroxide produced benzotriazole,185
The valence tautomerism of 6-methyl-2-(4-methylpbenyl)-
1,2,4-benzotriazin-3-one (113) and the isocyanate form (114)
has previously been investigated by Busch.168
(113)
(114)
The benzotriazine (113) was shown to be stable to high temperature,
aqueous acid and ethanol, whereas ethanolic alkali produced the
corresponding carbamate, and reaction with aniline gave the
Q=C=NPh
N0 0
corresponding urea. In a system which requires physical methods
for absolute determination of structure, the author concluded that
the cyclic form (113) existed exclusively, on the basis of
chemical results that predated the use of infrared spectroscopy
as an analytical tool by approximately 40 years.
Mechanism; Stage 1.
The mechanism for transformation of carbodiimide (106a) into
benzotriazole (107a) can be seen as an initial electrocyclic ring
closure followed by a Dimroth type rearrangement to give the
benzotriazin-3-one (109a). However, the fact that the alkyl
and benzyl substituted carbodiimides do not undergo rearrangement
might suggest the first step is nucleophilic attack by the oxygen of
the nitro group ōn the carbodiimide carbon.
73
nucleophilic attack electrocyclic ring closure
Thus in the case of aromatic substituents the delocalisation
into the ring increases the electrophilicity of the carbodiimide
carbon atom and thus favours the rearrangement. This is supported
by the fact that the 5-(4-nitrophenyl)-tetrazole precursor (87 h) is
transformed into the benzotriazole in high yield (72%),
the 2,2'-dinitrophenylcarbodiimide (106m) produced a benzotriazole
—N N 'N~
NO2
(87h)
N=C=N
NO2 02N
in high yield (84%), whereas the 4-methoxyphenylcarbodiimide
(106e) having less capacity to delocalise the negative charge from
the nitro group oxygen produces the corresponding benzotriazole
in somewhat reduced yield (65%).
74
(106m) (106 e )
OMe
The inductive effect of the t-butyl group and benzyl group
might, therefore, be reducing the electrophilic nature of the
carbodiimide carbon so much that the nitro group oxygen would not
be attracted to that position.
The ability of the system to delocalise negative charge,
and the relative degree of electrophilicity of the carbodiimide
carbon, would not be expected to have such a marked effect on
reactivity in a purely thermal sterically favoured, electrocyclic
ring closure.
Mechanism: Stage 2
Valence tautomerism of (109a) to (110a) gives the azoxy
isocyanate which by nucleophilic attack of the azoxy N-oxide
oxygen produces the intermediate (115) which is now set up to
lose carbon dioxide and form the final product, 2-phenylbenzo-
triazole (107a).
E. Alternative Routes to 2-Arylbenzotriazoles.
The use of o-nitrohydrazino derivatives and o-nitroazo
compounds reacting through an o-nitrosoazo intermediate was
illustrated in the Introduction. Formation of o-nitrosoazobenzene
and then 2-phenylbenzotriazole 1-oxide has been achieved by treatment
of o-chloromercuryazobenzene (116) with nitrosyl chloride.169
75
NOCI N\
NPh
0
(116 )
o-Aminoazobenzenes have been treated with cuprammonium salts,170
copper acetate in pyridine,171 and copper sulphate in pyridine,172,173
to give 2-arylbenzotriazoles in good yield. Thermolysis of o-azido-
azobenzene also gives 2-phenylbenzotriazole.174
Condensation reactions between benzotriazole and chlorobenzene
derivatives activated by at least two o-nitro groups give a mixture
of 1- and 2-arylbenzotriazoles, the 1-substituted derivative being
p -}- CO2 -{- ROH
71°/0
the major product.175 Condensation between benzotriazo]e and
2,4-dinitrofluorobenzene gives exclusively the 1-isomer in benzene
at 80°C but still gives a 3:2 mixture of the 1- and 2-isomers in
dimethylformamide,176 Thus our new route to 2-arylbenzotriazoles
has the advantage of giving exclusively 2-substitution, usually
in very high yield.
Conclusion.
The nitro group can clearly be seen to play an important
role in the thermal decomposition of 1,5-diaryltetrazoles. The
o-nitro group facilitates the formation of the carbodiimide and then
intercepts it very efficiently, providing a route to 'the
previously unrecorded 2-aryl-1,2,4-benzotriazin-3-one 1-oxides,
and subsequently a novel route to 2-arylbenzotriazoles substituted
exclusively in the 2-position.
F. Extensions to Nitro Group Interactions.
We found o-nitrophenylisocyanate and the analogous isothiocyanate
were stable to thermolysis conditions. The isocyanate had
previously been excluded as an intermediate in the thermal
rearrangement of o-nitrophenylcarbamates.177
76
0 I
NHCOR 250-270°
NO2
NL ~0 C cOCH3
+~0 N II 0
0
C H 30b, H
r.1 I\L.O
-4 +C0 N 11 0
The experimental results favour initial attack by the
oxygen of the nitro group at the carbonyl carbon atom.177
77
In view of the novel interaction of a carbodiimide function
with an ortho-nitro group described above, we considered the reac-
tions of peri-naphthalene derivative (117) and 2,2'-disubstituted
biphenyl derivative (118) were of interest.
N=C=NPh
NO2
N=C=NPh
NO2
78
(117) (118)
1. peri-Naphthalene Interaction.
With compound (117) there is no conjugation between the
nitro group and the carbodiimide, whereas in (118) the two function-
alities are conjugated through the biphenyl system. Each compound
exhibits a considerably changed steric arrangement compared to the
o-nitrophenylcarbodiimide. Very few geometries of peri-substituted
naphthalenes have been reported.178
Evidence for donor-acceptor interactions in 1,8-disubstituted
naphthalenes is available from crystallographic data and from
35N p.m.r. measurements,179. The naphthalene derivative (117) was
prepared as shown in Scheme 8.
Solution thermolysis of (117) produced only tarry material.
Vapour phase pyrolysis performed by distilling the carbodiimide
through a pre-heated quartz tube at 750°C and 0.015 mm gave, after
work up, a single crystalline product which was identified by m.p.
and mass spectrometry180
as naphtho[1,8][c,d]indazole N-oxide (119).
Scheme 8
CSC 12
I I NHCNHPh
NO2
(117) (119)
PhNH2
l I- /C[
N=C=NPh +Me 45
NO2
NH2 NO2 NCS NO2
HNO3/H2504
Scheme 9 (119)
+ Ph NC
,Q N =C=NPh
This product could arise from initial nucleophilic attack of the
nitro-group oxygen in (117) on the carbodiimide nitrogen or carbon,
with the subsequent rearrangements generating either phenyl
isonitrile or phenyl isocyanate as the volatile component of the
reaction, as indicated in Schemes 9 and 10.
80
81
O
NF, C=NPh
N~O
_ NPh
(119)
Scheme 10
-i- PhNCO
Owing to the low volatility of the carbodiimide (117), only
a small amount of material distilled through the quartz tube, and
was pyrolysed (10 mg) and the volatile component was not found.
2, 2,2'-Biphenyl Interaction.
The biphenyl derivative (118) was prepared as shown.
Solution thermolysis of (118) in 1;2,4-trichlorobenzene at
215°C for 3 days produced tarry products only. Vapour phase
pyrolysis at 750°C and 0.015 mm gave a single product isolated
from a polar mixture by column chromatography. The it spectrum of
NO2 NaSH NH2 cscl2
NO2
NCS
82
NO2
NO2
PhNH2
N=C=NPh
NO2
S
NHCNHPh
NO2
(118)
a second component suggested this to be phenyl isonitrile and the
reaction product isolated from the cold finger had a characteristic
pungent isonitrile odour. This suggested the major product might
be benzocinnoline di-N-oxide (120), formed by initial attack of
the nitro group oxygen on the carbodiimide nitrogen as shown,
or the benzocinnoline mono-N-oxide (121) or benzocinnoline
(122) formed by thermal deoxygenation.
83
N= 0
N= 0
(120)
Comparison of the product with independently synthesised
(120),181 (121),182
and (122),181
failed to identify the reaction
product as any of these benzocinnoline derivatives.
Mass spectral evidence subsequently indicated the molecular
ion of the thermolysis product to be starting material - 47 mass
units. This could indicate a product isomeric with the starting
material losing a nitro group and one hydrogen in the mass spectrum
or less likely, a product formed by rearrangement and denitration
of the carbodiimide (118).
Desulphurisation of the thiourea (123) with mercuric chloride
to give 6-anilinophenanthridine (124) has been reported.183
84
S
NHCNHPh HgCl2
NHPh
(123)
(124)
That the carbodiimide is an intermediate in this reaction was
shown by intercepting the carbodiimide as the urea, by hydrolysis.183
We considered that thermolysis of the biphenyl carbodiimide (118)
might produce the anilinophenanthridine (125) by an electrocyclic
ring closure, followed by a 1,5-hydrogen shift; possible thermal
denitration can also be accounted for in Scheme 11.
O -N
(116) .
1,5[H]
1,7{NO2 ]
N ti
NHPh 02N
(124) (125)
Scheme 11
85
NPh
R
NCO AtCl3 0
NH2 coct2
N II • C
NHPh
PhNH2
R = H (124)
R = NO2 (125)
NH C~
Authentic specimens of (124) and (125) were prepared as
shown
Comparison of spectral data indicates significant similarities
between the product of pyrolysis of carbodiimide (118) and
compounds (124) and (125), however, the compounds do not correspond
86
Acid
(126) (127)
C /NHPh H NPh
N C N=C=NPh
on t.l.c. and the nitro group in (125) is stable under identical
mass fragmentation conditions, exhibiting a parent ion at M+ 315.
The structure of this thermolysis product is not known at
the- present time.
3. Intramolecular Electrophilic Substitution by the Carbodiimide.
The proposed mechanism for formation of 6-anilinophenanthridine
(124) from the biphenylthiourea (123) and mercuric chloride requires
the ring closure reaction to be an intramolecular electrophilic
substitution reaction, aided by protonation of a carbodiimide
nitrogen by hydrogen chloride generated in situ, (See Scheme 12).
If this were the case then the 1-(a-naphthyl)-3-phenyl-
carbodiimide (126) might be expected to undergo acid catalysed ring
closure to (127),
Vapour phase pyrolysis of the carbodiimide (126) resulted in
recovery of unchanged starting material, A stirred solution of
(126) in methylene chloride in the presence of aluminium chloride
gave a yellow solid i,r. and n,m.r. spectra of which were complex.
87
N ! + HCl
H~NHPh
(124 )
88
NHCNHPh HgC12 N=C=NPh + HgS + 2 HCl
(123)
Scheme 12
The parent ion in the mass spectrum was at 488 m.u., suggesting
a dimer. As a means of simplifying the problem 1,3-diphenyl-
carbodiimide was prepared by an analogous route and treated with
aluminium chloride in methylene chloride as before. A yellow
solid was again produced, exhibiting similar spectral characteristics
to the product of the naphthylcarbodiimide, the mass spectrum again
indicating a dimer. This product was identical with that obtained
by quaternisation of 1,3-diphenylcarbodiimide using fluoroboric
acid, and is thus 2-phenylamino-3-phenyl-4-phenyliminoquinazoline
(128).184
2 Ph N= C=NPh
NPh (128)
By analogy, the product of the 1-naphthyl-3-phenyl-carbodiimide
reaction is considered to be one of the several corresponding
naphthoquinazolines, e.g ,, (129).
89
ALCl3
N=C=NPh
Intramolecular cyclisation across the peri-position has
thus not occurred, presumably because of the strain in the
five-membered ring which would be formed; intermolecular
reaction has supervened.
90
(87b)
Ph - N
NN 400°C
NO2 0.05mm
(107a
800°C 0.05mm
SECTION 2
A) The Carbazole Reaction
Thermolysis of 1-(2-nitropheny1)-5-phenyltetrazole (87b)
has been shown in the preceeding section to give 2-phenylbenzotri-
azole (107a) in good yield. Vapour phase pyrolysis of tetrazole
(87b) at 400°C and 0.05 mm/Hg gave a second component which had
a similar Rf to 2-phenylbenzotriazole and was difficult to
isolate. Pyrolysis of 2-phenylbenzotriazole under the same
conditions gave the same product (tic) and on increasing the
pyrolysis temperature to 800°C we were able to transform
2-phenylbenzotriazole in good yield to the second component (80%).
This was subsequently identified as carbazole (130), by mixed
. m.p., and comparison of the i,r. spectrum of an authentic sample.
91
N la
(130)
Owing to the difficulty we experienced in separating
carbazole from unreacted 2-phenylbenzotriazole, a range of temperatures
was used, see Table 7, to find the optimum conditions for this
transformation. The pyrolysis product was recovered with very
little material loss and after removal of traces of baseline
material by column chromatography the two component mixtures
were analysed by h.p.l.c. There seems to be a rapid
increase in product formation after 700°C with the optimum
temperature at about 1000°C.
Temp.
°C. Carbazole
Yield (%)
300 0
500-20 0
600 < 1
700-20 17
750 76
800 56
900 91
The projected optimum temperature was above the working
range of the apparatus and was not attempted. 2-Phenylbenzotriazole
was found to be stable photochemically. The synthesis of carbazole
and substituted carbazoles is well known, several reviews covering
this extensive literature.I86-188
Although carbazoles have been
prepared by thermal and photochemical rearrangement of 1-aryl-
benzotriazoles, there is no record of 2-arylbenzotriazoles
undergoing this rearrangement.
92
(
B) The Mechanism of Transformation.
The stoichiometry of the transformation of 2-phenylbenzo-
triazole (107a) to carbazole (130) demands loss of nitrogen (N2).
93
(107a)
H
(130)
The similarity between this transformation and the Graebe-
Ullmann synthesis of carbazole from 1-phenylbenzotriazole186
cannot be ignored. Thus, a logical postulate would be migration
of the phenyl group from the 2- to the 1-position followed by
loss of nitrogen as shown below.
N~--1 ~~ ,~1N---Ph —.. ~N N
Ph (107a)
A second mechanism worthy of consideration involves ring
opening of 2-phenylbenzotriazole, without migration of the phenyl
group, to give an azobenzene nitrene. The nitrene could then
insert into the C-H bond of the phenyl group followed by two
[1,5]H or a [1,7]H shift to give 1,2,5-dibenzotriazepine (131)
as an intermediate.
FVP
800Oc
(131) (132 )
H NO2
2
Zn / NaOH
94
(107 a )
2x1,5[H]
or 1,7[H]
(131)
Pyrolysis of the dibenzotriazepine (131), which was
synthesised from o-dinitrodiphenylamine (132) as shown, added
some support to the postulated mechanism in giving carbazole
as the only isolated product.
(130) 30 0/0
1) Tests for the Postulated Mechanisms.
The introduction of a label into the 2-arylbenzotriazoles
seemed an obvious way to investigate the rearrangement pathway.
Introduction of a label in the 5-position of the benzotriazole
ring was convenient since 5-nitro-2-phenylbenzotriazole was
readily available from 1-(2,4-dinitrophenyl)-5-phenyltetrazole
(87k) .
However, substituents in this position can give rise to
two isomeric products in mechanisms 1 and 2, and thermolysis
of 1-arylbenzotriazoles with nitro groups in either ring have
been shown to give very poor yields of carbazoles, (3%).189
A label in the 2-aryl ring offers a means of detecting the mode
of rearrangement unambiguously.
95
Mech 1
(132)
Mech 2
(107b)
(133)
(Et0)3P 4Ilis 02N
(134)
Pyrolysis of 2-(4-methylphenyl)benzotriazole (107b) would
thus be expected to give 3-methylcarbazole (132) by migration
to the 1-position followed by loss of nitrogen and ring closure,
and 2-methylcarbazole (133) through the azobenzene nitrene
mechanism. Vapour phase pyrolysis of (107b) at 850°C and 0.05 mm
was incomplete. The pyrolysis product after removal of baseline
material was not resolvable by t.l.c. H.p.l.c. analysis of the
mixture enabled us to identify starting material (14%), with two
other components. To identify the rearrangement product authentic
specimens of 3-methylcarbazole and 2-methylcarbazole were
prepared. The synthesis of 2-methylcarbazole required 4-methyl-
2f-nitrobiphenyl (134) as a precursor. Many attempts using
o-nitroaniline and toluene or p-toluidine and nitrobenzene in
the Gomberg-Bachmann reaction190 failed completely to produce
the required biphenyl (134). The intermediate (134) was prepared
by a modified Ullman reaction as an oil, which was converted
directly to 2-methylcarbazole (133) as shown.
96
3-Methylcarbazole (132) was prepared by the standard literature
97
route as shown.
NHNH2 -}-
HAc
Me o-chloranil .-
(132)
H.p.1,c. analysis of the authentic samples (compared to the
pyrolysis mixture) shows a mixture of 2- and 3-methylcarbazole to
be inseparable. This mixture does however, correspond with a
second component of the pyrolysis mixture. Analysis of the n.m.r.
spectra of the two authentic samples and the pyrolysis mixture
shows clearly that there is no 2-inethylcarbazole in the mixture.
A 1-proton doublet at 67.06 in the n.m.r. spectrum of 2-methyl-
carbazole is not present in the n.m.r. spectrum of the mixture.
There is no resonance in that area of the spectrum of the
pyrolysis mixture. Thus, we are able to conclude that the
most likely mechanism for rearrangement of 2-phenylbenzotriazole
to carbazole is by migration of the 2-phenyl group to the
1-position followed by loss of nitrogen in the Graebe-Ullmann
mode of carbazole synthesis.
Given this result we considered the intermediate 1-(p-tolyl)-
benzotriazole (136) might be the third component of the pyrolysis.
H.p.l.c. analysis of an authentic sample prepared from the
diphenylamine, compared with the pyrolysis mixture shows this is
riot the case.
98
i) H2
ii) HNO2/H'
The third component of the pyrolysis is as yet unidentified.
Conclusion to Section 2.
The investigation of the carbazole synthesis shows the most
likely mechanism for the rearrangement, to be migration of the
2-arylsubstituent to the 1-position of the benzotriazole,
followed by the loss of nitrogen and ring closure. The optimum
temperature requirements for rearrangement are significantly
above the safe operating conditions of the flash vacuum
pyrolysis apparatus. Thus, in our hands, the scope of this
novel rearrangement is limited.
99
Ph~N e NAN N h'v
CO2Me
(137) (138)
APPENDIX
Photochemistry of Tetrazoles.
1) Introduction
The products of photochemical decomposition of N-arylimidoyl-
nitrenes in which both ortho-positions are blocked by alkyl
substituents have been described.192 3aH-Benzimidazoles were
suggested as intermediates in these reactions, the products
being derived from these intermediates by way of sigmatropic
skeletal rearrangements, or at higher temperatures sigmatropic
alkyl shifts. In order to test this hypothesis further tetrazoles
with one ortho-substitutent that would migrate more easily than
alkyl were investigated. The preliminary investigation was
carried out on tetrazole (137) which when photolysed gave (138)
and (139) with other products.
100
>Ph -F ~ N>Ph
CO2Me (139)
The structure of benzimidazole (138) was confirmed by authentic
synthesis; 4-methyl-2-phenylbenzimidazole (139) was shown to derive
from (138) on chromatographic work up.
Ph~N
NNiN N
NO2
Phl---N NNN/N
CO2Me '
Formation of (138) and hence (139) requires the nitrene
to cyclise at the carbon bearing the methoxycarbonyl group;
alkoxycarbonyl groups are known to undergo sigmatropic shifts
very readily.193,194 It has been noted, previously that alkoxy-
carbonyl groups and other groups which migrate easily tend to
move to an adjacent nitrogen rather than an adjacent carbon
atom. Surprisingly, no products were detected which could have
come from closure of the nitrene on to the methyl bearing carbon
atom.
2) Investigation of Mono ortho-Substituted Tetrazoles.
The above results encouraged us to investigate the
analogous photolysis of tetrazoles (140), (141) and naturally
(87b).
101
(87b) (140)
It was hoped that the tendency of the nitrene to close
on to the carbon bearing a single electron withdrawing substituent
would still be maintained in competition with closure at the
unblocked position. This apparent directing effect had
previously been noted in the thermolysis of the oxadiazolone
(99) and the oxadiazolthione (100), (as discussed in Section 1),
N07 Phr N
NO2Ph~-N NNC,O NNC
'O
II 0 SI
(99) (100)
from which 2-phenylbenzimidazole was obtained in yields of 4% and
13% respectively.
a) Photolysis of Tetrazoles.
The tetrazoles had previously been prepared as described in
the literature.195 Photolysis of tetrazole (87b) gave only one
product, derived from closure of the imidoyl nitrene to the
vacant ortho-position followed by rearrangement of the 3aH-benzimidazole.
102
Phr=_—N
N\N/N h N
NO2
(87b)
Ph
N \ Ph
N H
1.10/0
Ph + hv
N N Ph -f- \ Ph
N 29% CO2Me 10%
CO Me N \) Ph
N H
(140) h"
41%
Photolysis of the amide substituted tetrazole (141) gave a
good yield of product derived from closure to the vacant ortho-
position with only a very small amount of 2-phenylbenzimidazole.
103
However, photolysis of the tetrazole ester (140) gave products
derived from closure to both the vacant and blocked ortho-positions
without any apparent selectivity.
Photolysis of an ortho-cyano substituted tetrazole had
previously been shown to give exclusively the product derived
from closure to the vacant ortho-position.195
This selection of ortho-substituents enables us to see
whether there is any through space interaction, which would
enhance the directing effect in the nitro, amide and ester
tetrazoles, or whether a conjugated electron withdrawing species
alone is directing towards the blocked position.
The results show that the directing effect in the photochemical
decomposition of tetrazoles is peculiar to the ortho-ester
derivative (139). Neither the electron withdrawing capacity of
the substituent nor its potential for 'through space'
interaction satisfactorily accounts for these results.
3) Conclusion
The results are consistent with the basic hypothesis that
N-arylbenzimidoyl nitrenes cyclise to 3aH-benzimidazole intermediates
which subsequently rearrange by way of sigmatropic shifts. The
unexpected directing effect of the methoxycarbonyl group lacks
a convincing explanation at present. Cyclisations onto a
substituted position when vacant positions are available is certainly
very rare; one example involving thermal cyclisations of a stable
side-chain onto a benzene ring, is provided by the Claisen
rearrangement of an allyl phenyl ether where closure occurs at
an acetylated as well as an unsubstituted position.
104
EXPERIMENTAL
INSTRUMENTATION AND EXPERIMENTAL TECHNIQUES
1) Spectra
Infrared spectra (ir) were recorded in the range 600-4000 cm-1
using Perkin Elmer 257 and 298 spectrophotometers and
calibrated against polystyrene. Spectra of solids were taken
as Nujol mulls and liquids as thin films between sodium chloride
plates unless otherwise stated. Abbreviations used are strong (s),
weak (w) and broad (br).
Ultra-violet and visible spectra (uv) were recorded in
the range 200-700 nm using a Pye Unicam SP 800 recording
spectrophotometer and calibrated against holmium glass. Solvents
used are indicated in the experimental data. Where no
extinction coefficients are quoted the specta were of a
qualitative nature only.
Proton nuclear magnetic resonance spectra (nmr) were recorded
using Varian T60 (operating at 60 MHz), Perkin Elmer R32 (operating
at 90 MHz) or Bruker WM 250 (operating at 250 MHz) instruments,
with an internal tetramethylsilane reference. Signals are
quoted as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), or broad (br). Solvents are indicated in the
experimental data.
105
Low resolution mass spectra (ms) were recorded on
A.E.T. M S12 and VG Micromass 7070 B instruments. High resolution
spectra were recorded on the VG Micromass 7070 B instrument.
All spectra were recorded at 70 eV using a direct insertion
probe.
2) Melting Points.
Melting points (mp) and mixed melting points (mixed mp)
were carried out on a Kofler Hot Stage apparatus and are
uncorrected.
3) Solvents.
Petrol refers to petroleum ether, b.p., 40-60° unless
otherwise stated, and was distilled before use. Dichloromethane
was distilled prior to use. Acetonitrile and dimethylformamide
were dried by refluxing over calcium hydride, followed by
distillation directly into the reaction vessel. Hydrocarbon
solvents were dried by standing over sodium wire. Acetone,
chloroform, ethyl acetate, ethanol and methanol were used as
supplied commercially unless otherwise stated.
4•j Chromatography.
Column chromatography was carried out on Silica Gel H Art 7736
(Merck), under pump pressure. Thin layer chromatography (tic) was
used extensively as a qualitative analytical technique for following
106
the progress of reactions and assessing the purity of compounds;
silica gel GF254 (Merck) was used.
Preparative layer chromatography was carried out on
20 x 20 cm or 20 x 40 cm glass plates coated with a layer of
silica gel PF254 (Merck). Loading of material varied according
to the efficiency of the separation. All plates were observed
under ultra violet light (254 nm). This technique was eventually
discontinued in favour of the low pressure column chromatography
method.
High pressure liquid chromatography (hplc) was performed
using an Altex 110A pump, an ODS reverse phase column and a
Cecil CE2012 ultra violet detector. Samples were injected as
methanol solutions and were eluted with methanol-water mixtures
as indicated.
5) Photolysis.
Photochemical reactions were carried out using a Rayonet
photochemical reactor with lamps of 253.7, 300 or 350 nm wavelength.
The solvent used was dry acetonitrile unless otherwise stated.
6) Vapour Phase Pyrolysis.
This technique has been fully described elsewhere.197
The
apparatus consists of a quartz tube with a carbon dioxide condenser
and a connection to a vacuum pump fitted at one end. A 50 ml
107
round bottom flask containing the sample is attached to the
bottom end of the quartz tube and is heated in an oil bath
or Kugelrohr oven. The sample in the flask is then heated
under vacuum until it vapourises, the vapour passing through
the pre-heated quartz tube, the temperature of which can
be varied up to 900°C, and the products condense on
the cold. head . The pyrolysate is then worked up in a
conventional manner.
108
SECTION 1
A) THE PREPARATION OF. SYNTHETIC INTERMEDIATES.
1. Amines.
1-Amino-8-nitronaphthalene198 and 2-amino-21 -nitro-
biphenyl199 were prepared by the literature procedures.
Other anilines were used as suppled commercially.
2. Amides.
Amides were prepared by standard methods,200 and were known
compounds. The following amides were prepared.
Benzanilide, m.p., 164-5°C (lit.,201 163°C)
2-Nitrobenzanilide, m.p., 152-4°C (lit.,201 155°C)
2'-Nitrobenzanilide, m.p., 94-5°C (lit.,202
96-7°C)
,204 4-Nitrobenzanilide, m.p., 214°C (lit. 216°C)
4'-Nitrobenzanilide, m.p., 214°C (lit.,201 199°C)
21 ,4'-Dinitrobenzanilide, m.p., 199°C (lit.,203 201-2°C)
21 ,4-Dinitrobenzanilide, m.p., 223°C (lit.,204 223°C)
4,4'-Dinitrobenzanilide, m.p., 272-3°C (lit.,205 268-9°C)
4-Chloro-2'-nitrobenzanilide, m.p., 160.5-162°C (lit.,214 155-6°C)
4-Chloro-4'-nitrobenzanilide, m.p., 220-1°C (lit.,206 222-3°C)
4-Chlorobenzanilide, m.p., 206-7°C (lit.,207
195-6°C)
2'-Nitroacetanilide, m.p., 93-4°C (lit.,208 93°C)
Ethyl oxanilate, m.p., 65-7°C (lit.,209 66-7°C)
Ethyl 2'-Nitrooxanilate, m.p., 113°C (lit.,201 113°C)
109
2,6-Dinitroaniline failed to give the corresponding
benzanilide under standard conditions. The use of catalytic
amounts or equimolar amounts of 4-N,N-dimethylaminopyridine
at room temperature for several days or under reflux in pyridine,
failed to generate the required amide; the starting amine
was recovered in > 90% yield from these reactions.
3. N-Arylimidoyl Chlorides.
These were prepared from the corresponding amide by stirring
a solution of the amide in toluene with a slight excess (10%)
of phosphorus pentachloride, at room temperature. When the
reaction did not go to completion, as indicated by residual
carbonyl absorption in the it spectrum, the solutions were refluxed
for 1 h, The imidoyl chlorides were used without further
purification with the exception of N-(2,4-dinitrophenyl)benzimidoyl
chloride, m.p., 118-20°C (lit.,153
117.5-120.5°C).
This procedure failed to give the corresponding imidoyl
chloride from ethyl 2V-nitrooxanilate. Refluxing a solution of
ethyl oxanilate in dry benzene for 2 h failed to form any imidoyl
chloride, Reaction of ethyl oxanilate and phosphorus pentachloride
in the melt, at 130°C, for 24 h produced a yellow oil with an intense
absorption at 2260 cm-1 suggesting the formation of phenyl isonitrile.
The characteristic isonitrle odour was apparent. Melt thermolysis
at 160°C under partial aspirator pressure for 30 min produced an
110
oil with a band at 1780 cm-1 in the it spectrum. Ethyl
oxanilate, in dry benzene with a slight excess (10%) of
phosphorus pentachloride was refluxed for 3 days. The reaction
was cooled, quenched with water and the organic phase separated.
The benzene solution was dried over sodium sulphate and the
solvent removed at the pump. At this stage the isonitrile
odour was apparent. Tlc analysis (CHC€3) of the residue
shows the recovered material to be starting material. Thus,
any decomposition occurring is a very minor reaction, since
work up of the reaction gave ethyl oxanilate (90%), m.p.,
65-7°C (lit.,209 66-7°C) .
B) THE PREPARATION OF TETRAZOLES.
The tetrazoles were made according to the method of
Kadaba,151
as outlined below.
The appropriate N-arylimidoyl chloride (0.012 mol) in
dry dimethylformamide (15 ml) was added dropwise over a period
of 45 min to an excess of finely ground sodium azide'(0.024 mol)
in dry dimethylformamide (15 ml) with vigorous stirring. The
reaction temperature was kept below 25°C during the addition
by means of a cold water bath. When the addition was complete,
the suspension was stirred for a further 45 min. Water, sufficient
to dissolve any residual inorganic salts and then to cause
turbidity (1-10 ml) was then added and the solution placed in the
cold room (5°C) for 1-4 days. The crystals thus produced were
filtered, washed with water and crystallised from ethanol.
111
112
The following tetrazoles were thus prepared.
1,5-Diphenyltetrazole (87a), m.p., 145 -6°C (lit.,151 145-6°C)
1-(2-Nitrophenyl)-5-phenyltetrazole (87b), m.p., 167-9°C (lit.,151 168-9°C)
1-(4-Nitrophenyl)-5-phenyltetrazole (87c), m.p., 153.5-155°C (lit.,151 155-7°C)
5-(4-Nitrophenyl)-1-phenyltetrazole (87d) m.p., 181-3°C (lit.,151 182-3°C)
5-(2-Nitrophenyl)-1-phenyltetrazole (87e), m.p., 175-7°C (lit.,151 179-81°C)
5-(4-Chlorophenyl)-1-phenyltetrazole (87f),m.p., 155-7°C (lit.,2 155.5°C)
5-(4-Chlorophenyl-1-(4-nitropheny])tetrazole (87i), m.p., 187-8°C,
(lit.,210 188-9°C)
1,5-Di(4-nitrophenyl)tetrazole (87j) m.p., 264°C (dec) (lit.,211
262°C)
5-Methyl-1-(2-nitrophenyl)tetrazole, (89c) m.p., 113-116°C (lit.,212 116.5-7°C)
5-(4-Chlorophenyl)-1-(2-nitrophenyl)tetrazole, (87 g), (58%),
m.p., 163-4°C (ethanol)(Found: C, 51.79; H, 2.64; N, 23.23.
C13H8N5Ci02 requires C, 51.75; H, 2.67; N, 23.21%); vmax 1600,
1520, 1340 (s), 1090, 850, 820, 780 and 730 (s); Amax (CHC13)
249 nm (20 326); S(CDC(3) 7.26-7.64 (5 H, m), 7.75-7.95 (2 H, m),
8,19-8.35 (1 H, m); m/e 301 M+ 273 153 (base), 139, 125.
1-(2-Nitropheny1) -5-(4--nitrophenyl) tetrazole, (87h) , (46%) ,
m.p., 210-212°C (ethanol) (Found: C, 50.12; H, 2.60; N, 26.89.
C13H8N604 requires C, 50.00; H, 2.58; N, 26.92%); vmax 1610, 1540 (s),
1520 (s), 1345 (s), and 860 cm 1; Amax (CHCl3) 267 nm (24960);
S(DMSO-d5) 8.12 (4 H, br, m) 8.17 (4 H, q); m/e 313 (M+ + 1), 284,
240, 164, 150, 134, 120, 90 (base).
The 5-chloro and 5-H-1-(2-nitrophenyl)tetrazoles were
prepared by the method of Kauer et al.154
1-(2-Nitropheny])tetrazole (89a), m.p., 84-5°C (lit.,154 85-6°C)
5-Chloro-1-(2-nitrophenyl)tetrazole, (89b), m.p., 85-7°C (lit.,154 88.8-9.6°C).
The method of Bianchetti, et al.,152 was used for the preparation
of 1-(2,4-dinitrophenyl)-5-phenyltetrazole. In this procedure
the solvent is acetone-water (1:1). 1-(2,4-Dinitrophenyl)-5-phenyl-
tetrazole (87k), m.p., 183°C (dec) (lit.
Attempted preparation of (87k) using the method of Kadaba as
outlined above gave after work up a low melting solid, m.p., 30-5°C,
with an intense band at 2120 cm-1-in the it spectrum. The mass
spectrum gave M+ 181. The solid was very unstable and difficult to
purify. The structure was postulated as 2,4-dinitrophenylazide.
2,4-Dinitrophenylazide, as formed above, (0.53 g) was dissolved in
dry benzene (15 m1) and refluxed for 2 h. The solvent was removed
and the solid produced crystallised from acetic acid giving 6-nitro-
benzofuroxan (88) (0.4 g, 51%), m.p., 67-9°C (lit.,213
68-9°C).
The Kadaba procedure also failed to produce ethyl 1-phenyl-
tetrazole-5-carboxylate. This tetrazole had previously been
prepared by Lozinskii, et al.,155 but we were unable to repeat
this reaction.
113
,152 183°C).
114
Attempted Preparation of Ethyl 1-Phenyltetrazole-5-Carboxylate .
Ethyl oxanilate (3.0 g, 0.016 mol) was dissolved in dry
toluene, to which was added phosphorus pentachloride (4.2 g, 0.02 mol).
The solution was refluxed overnight (17 h). Removal of the solvent
gave an oil, which was dissolved in dry dimethylformamide (5 ml) and
added to a suspension of finely ground sodium azide (3.94 g, 0.06 mol)
in dry dimethylformamide (15 ml) during 30 min. The mixture was
stirred for a further 45 min. Sufficient water was added to
produce a clear solution, from which an oil separated. The solution
was placed in the cold room (5°C) for 5 days, but failed to crystallise.
The oil was purified by column chromatography, from which a major
component was isolated. On the basis of the following spectral
evidence the structure was postulated as ethyl 2-azido-2-hydroxyanilino-
3-carboxylate (91),(25%). vmax 3400, 3340 (NH and OH), 2130 (N3), 1700
(s'), 1600, 1530, 1440, 1235, 1050, 755 and 690 cm-1; d(CDCe3) 1.26
(3 H, t), 3.84 (2 H, q), 4.20 (1 H, s), 7.05-7.75 (5 H, m), 8.30-8.60
(1 H, br s); m/e 182 (M-44), 167, 133, 105, 104, 91 (base).
Ethyl oxanilate (2 g, 0.01 mol) and phosphorus pentachloride
(2,37 g, 0.11 mol) were refluxed in dry benzene (30 ml) overnight.,
The solvent was removed and the residual oil dissolved in acetone
(5 ml). The acetone solution was added dropwise to a suspension of
finely ground sodium azide (2,23 g, 0.034 mol) at 0-5°C and the
mixture stirred at 0-50C for a further 6 h. The reaction was
quenched with sufficient water to form a clear solution and was
worked up as above. The isolated'.oil was not distinguishable
from the product previously isolated, by tic or comparison of
it spectra.
C) THERMOLYSIS OF TETRAZOLES
1. Solution Thermolysis: General Procedure.
To a 25 ml round bottom flask was added the solid tetrazole.
To the flask was then added freshly distilled solvent (1 ml/ 50 mg
tetrazole). The solvents used were bromobenzene (BB), b.p., 165°C,
1,2-dichlorobenzene (DCB), b,p., 185°C, and 1,2,4-trichlorobenzene
(TCB), b,p., 215°C. The flask was fitted with an air condenser
and the apparatus flushed out with dry nitrogen. A nitrogen supply,
as a nitrogen balloon or bubbler, was fitted to the top of the
air condenser. The flask was placed in a Wood's metal bath,
preheated to between 20-30°C above the boiling point of the solvent.
The solutions rapidly attained reflux temperature, and were then
monitored by tic until all starting material had been consumed
or until a period of at least 24 h had elapsed without any
indication of reaction occurring. The flask was allowed to cool
and the solvent removed by short path distillation. The products
were purified by column chromatography and crystallisation.
Unstable carbodiimides were hydrolysed by refluxing in dioxan-30%
aqueous hydrochloric acid for 1 h.
115
The following tetrazoles were thermolysed.
1. 1-(2-Nitrophenyl)-5--phenyltetrazole (87b).
The tetrazole (87b) (140 mg, BB, 20 h) gave 2-phenylbenzotriazole,
(81 mg, 80%), m.p., 108-9°C, mixed m.p., 108.5-110.5°C (lit.,215
104-6°C); (87b), (152 mg, DCB, 0.5 h) gave 2-phenylbenzotriazole
(101 mg, 91%); (87b) (200 mg, TCB, 0.5 h) gave 2-phenylbenzotriazole
(134 mg, 92%) .
2. 1-(2,4-Dinitrophenyl)tetrazole (87k).
The tetrazole (87k) (112 mg, BB, 0.75 h) gave 5-nitro-2-phenyl-
benzotriazole(51 mg, 60%) m.p., 175-7°C (lit.,216
176.6-7°C).
3. 5-(2-Nitrophenyl)-1-phenyltetrazole, (87e).
Thermolysis of (87e) (500 mg, BB, 24 h) followed by tic analysis
of the reaction mixture showed only a faint trace of a fluorescent blue
spot, corresponding to 2-phenylbenzotriazole. The major component
corresponded to starting material. The tetrazole (87e) (200 mg,
DCB, 24 h) gave 2-phenylbenzotriazole (7.5 mg, 5%) and the
tetrazole (87e) (161 mg, 817); (87e) (500 mg, TCB, 9 h) gave
2-phenylbenzotriazole (272 mg, 75%).
4, 5-(4-Chlorophenyl)-1-(2-nitrophenyl)tetrazole (87g).
The tetrazole (87g) (500 mg, BB, 24 h) gave 2-(4-chlorophenyl)-
benzotriazole (95), (213 mg, 56%) m.p., 169-70°C (lit.,215 170-71°C).
The tetrazole (87g) (35 mg, 7%) was recovered. Tetrazole (87g)
(200 mg, DCB, 4 h) gave 2-(4-chlorophenyl)benzotriazole, (124 mg, 82%);
(87g) (500 mg, TCB, 2.5 h) gave 2-(4-chlorophenyl)benzotriazole,
(320 mg, 84%).
116
5. 1-(2-Nitrophenyl)-2-(4-nitrophenyl)tetrazole (87h).
The tetrazole (87h), (100 mg, BB, 24 h), gave a pale yellow
solution. Tic of this solution showed one component which corresponded
to starting tetrazole (87h). The tetrazole (87h)(200 mg, DCB, 5.5 h)
gave 4-nitro-2-(4-nitrophenyl)benzomidazole (97) (121 mg, 66%)
m.p., 284-5°C, and 2-(4-nitrophenyl)benzotriazole (96),
(20 mg, 13%), m.p., 284°C (lit.,218
282°C); (87h) (200 mg, TCB, 5 min)
gave a yellow solution from which crystallised a pale yellow solid.
The product was filtered and crystallised (ethanol-dimethylformamide)
producing 2-(4-nitrophenyl)benzotriazole, (110 mg, 72%).
6. 2-(5-Phenyltetrazol-1-yl)benzonitrile, (92).
The tetrazole (92) (50 mg, TCB, 0.5 h) gave a solution which
showed one component on tic. The ir spectrum showed an intense
band at 2140 cm-1 indicating the product to be 2-(1-phenylcarbodiimid-
3-yl)benzonitrile. The solvent was removed and the remaining oil
was placed in a Wood's metal bath at 268°C. The yellow oil rapidly
darkened. After 20 min at 268°C tic and ir show no change; the
carbodiimide was still present.
6a. Control Thermolysis.
1,5-Diphenyltetrazole(87a) was thermolysed (TCB, 40 min). Tic
showed one major component corresponding to tetrazole (87a).
There was a trace of high Rf material.
117
7. 5-(4-Chlorophenyl)-1-phenyltetrazole, (87f).
The tetrazole (87f) (500 mg, BB, 24 h) did not react. Starting
material (87f) (490 mg, 98%) was recovered; (87f) (200 mg, DCB, 24 h)
gave a mixture of three components. Tlc.showed the mixture was
mainly tetrazole (87f). After hydrolysis in hydrochloric acid=
dioxan, the solution was neutralised, extracted into ethyl acetate,
dried (MgSO4) and the solvent removed producing a solid. The
solid was identified as tetrazole (87f) (154 mg, 77%). No other
products were isolated. (87f) (300 mg, TCB, 48 h) gave an oil,
a single component on tic, it 2120 cm-1
, 1-(4-chlorophenyl)-3-
phenylcarbodiimide (87 mg, 33%), a colourless solid 2-(4-chloro-
phenyl)benzimidazole (39 mg, 15%), m.p., 292°C (lit.,219 296°C) and
a colourless solid, 77 mg. Tlc showed the solid to be one component
but a sharp melting point could not be obtained. Ir showed bands
at 3380 (NH) and 1650 cm-1 (s, > C=0) suggesting a urea. However,
the mass spectrum showed m/e 280 (M+) with a chlorine isotope
pattern for two chlorine atoms (10:6:1: at M, M + 2, M + 4).
M-16 gave m/e 262 with the same chlorine isotope pattern.
Superimposed on this spectrum was m/e 246, with an isotope pattern
for one chlorine atom (3:1 at M, M + 2) with M-16 giving m/e
228 with the same one chlorine isotope pattern. The molecular
weight of the symmetrical 1,3-di(4-chlorophenyl)urea is 280. The
unsymmetrical 1-(4-chlorophenyl)-3-phenylurea has a molecular weight
of 246, Thus, the third component is a disproportionated mixture of
the above ureas.1
118
8. 5-(4-Nitrophenyl)-l-phenyltetrazole (87d).
The tetrazole (87d) (300 mg, BB, 24 h) gave unreacted starting
material, identified by tic and ir (87d) (300 mg, DCB, 24 h)
gave unreacted starting material (218 mg, 73%) and no other products
were isolated ; (87d) (300 mg, TCB, 48 h) produced an orange solution
from which crystallised an orange solid. The solid was washed with
methylene chloride and dried giving (i) 2-(4-nitrophenyl)benzimidazole,
(90 mg, 34%), m.p., 325°C (lit.,220 329°C),(ii) an oil, one component
by tic, identified by ir (2130 cm 1) as l-(4-nitropheny1)-3-phenyl-
carbodiimide with a trace of solvent (253 mg, 9%) and (iii) a solid
which could not be crystallised to a constant, sharp melting
point. Mass spectral evidence suggests the product is a mixture
of 1-(4-nitrophenyl)-3-phenylurea mle 257, which loses water to
give m/e 239, and the disproportionated 1,3-di(4-nitrophenyl)-
carbodiimide.) The total yield was 58 mg representing ca. 20% product
derived from migration of the 5-(4-nitrophenyl)-group in the first
formed imidoyl.nitrene. Ir showed bands at 3280 (NH) and 1635 cm-1
(>C=0). There was a small band at 2120 cm-1.
9. 1-(4-Nitrophenyl)-5-phenyltetrazole (87c).
The tetrazole (87c) (353 mg, DCB, 24 h) gave a clear solution
from which on cooling was deposited a grey solid. The solvent was
removed and the residue triturated under diethyl ether. The solid
was removed by filtration and the residue chromatographed to produce
a further yield of the same solid (tic), 1-(4-nitrophenyl)-3-phenyl-
119
carbodiimide (110 mg, 35%) m.p., 240°C (sub) (lit.,221
238°C).
Two Unidentified minor components (7 mg) were eluted from the
column.
10. 5-(4-Chlorophenyl)-1-(4-nitrophenyl)tetrazole (87i).
The tetrazole (87i) (300 mg, BB, 24 h) gave, after hydrolysis
and column chromatography of the product (i) tetrazole (87i)
(178 mg, 59%) (ii) a solid, the it spectrum of which suggested a
urea or mixture of ureas with bands at 3380 (NH), 3340 (NH),
1725 (>C=0) and 1740 cm l (>C=0). The mass spectrum clearly
indicated a disproportionated mixture' of 1-(4-chloropheny1)-3-
(4-nitropheny1)urea, m/e 291 with a single chlorine isotope pattern
(3:1 at M, M + 2) and 1,3-di(4-chloropheny1)urea, m/e 281, with
a two chlorine isotope pattern (10:6:1 at M, M + 2, M + 4). The yield
was 93 mg (ca. 33%) of carbodiimide derived products. The tetrazole
(87i) (300 mg, DCB, 22 h) gave, after hydrolysis of the product
1-(4-chlorophenyl)-3-(4-nitrophenyl)urea (220 mg, 76%), m.p., 295-305°C
(ethanol) (lit.,222 250°C); vm 3380, 3340, 1735, 1630, 1600, 1540,
1335, 1300, 1180 and 1110 cm-1 ; m/e 291 (M+) 273, 164, 153, 138 (base)
127 and 108. The tetrazole (87i) (300 mg, TCB, 7 h) after hydrolysis
of the thermolysis product gave 1-(4-chlorophenyl)-3-(4-nitrophenyl)-
urea (266 mg, 92%), m.p., 305°C, m/e 291 (M+).
120
11. 1-(2-Nitrophenyl)tetrazole, (89a).
The tetrazole (89a) (50 mg, BB, 19 h) gave 2-nitrophenyl-
cyanamide (5.3 mg, 12.5%) m.p., 148-50°C (lit.,201
150-2°C). The
remainder of the thermolysis product was an extremely complex,
multicomponent mixture as analysed by tic.
11a. Control Thermolysis.
2-Nitrophenylcyanamide (30 mg) was refluxed in bromobenzene
for 24 h. Tlc showed one component corresponding to a sample
of 2-nitrophenylcyanamide. There were no other products.
12, 5-Chloro-1-(2-nitrophenyl)tetrazole (89b).
The tetrazole (89b) (50 mg, TCB) was placed in a pre-heated
Wood's metal bath. A rapid and steady evolution of gas was noted
during which time the solution became deep red. Ir of the reaction
solution after 10 min at 215°C showed a band at 2240 cm 1. After
heating at 215°C for 1 h the solution was still red;., the band at
2240 cm-1 in the it spectrum was no longer present. Tlc showed a
dark base line only.
13. 5-Methyl-1-(2-nitrophenyl)tetrazole (89c).
The tetrazole (89c) (160 mg, BB, 24 h) gave after plc, four
components, one of which was starting material (89c) (20 mg, 12.5%).
The remaining three components totalling 50 mg of material were all
impure. A second component (17 mg) was replated from which was recovered
3 mg of material. Replating a third component (12 mg) gave < 1 mg of
material. The remainder of the reaction product was on the baseline.
121
D) IDENTIFICATION OF THE VOLATILE COMPONENTS FROM THE THERMOLYSIS
OF 1-(2-NITROPHENYL)-5-PHENYLTETRAZOLE (87b).
1. Carbon Dioxide.
The tetrazole (87b, 509 mg) was finely ground and mixed with
acid-washed sand (5 g). The mixture was placed in a 25 ml round
bottom flask to which was added a wide bore gas outlet, the open
end of which was placed in a lime water solution. The diluted
tetrazole mixture was heated in a Wood's metal bath at 210°C. A
slow rate of bubbling was noted;' the tetrazole melted with an increase
in gas evolution. A copious precipitate was formed, by the evolved
gases, in the lime water solution. Under identical conditions a
flask containing acid washed sand (5 g) was heated. A few bubbles
of gas were expelled from the flask into the lime water solution;
no precipitate was formed. Tlc of the thermolysis residue showed
2-phenylbenzotriazole as the major component.
2a, Carbon Dioxide, Carbon Monoxide.
The tetrazole (87b, 200 mg) was placed in a thermolysis vessel
attached to a vacuum line. The system was evacuated and filled
with argon. The vessel was placed in a Wood's metal bath and heated
at 210°C. The solid melted and gas was slowly evolved. The evolved
gases were transferred to a gas cell which was then attached
directly to a mass spectrometer. The spectrometer background has
peaks at m/e 28.00615 (N2), 28.0313 (C2H4), 43.9898 (CO2), 44.0011 (N20)
122
123 -
and 44.0626 (C3H8). There was no background peak at 27.9949 (CO).
Analysis of the gas sample showed an increase in the peaks for
N2, CO2 and argon. There was no peak at 27.9949 (CO).
2b. Carbon Monoxide.157
The tetrazole (87b, 200 mg) was ground with acid-washed sand
(5 g) and placed in a vacuum bottle. From inside the neck of the bottle
was suspended an indicator strip impregnated with aqueous palladous
chloride solution. The system was evacuated and filled with argon.
The flask was heated at 210°C'_in a Wood's metal bath. The sample
melted, gases were evolved but caused no colour changetin the
indicator strip, confirming the absence of carbon monoxide.
PdC.C2 + CO + H2O Pd + 2HC( + CO2
The thermolysis product was chromatographed producing
2rphenylbenzotriazole (27Z).
The palladous chloride test strip was exposed to carbon monoxide,
generated:'_by heating oxalic acid, and immediately became black.
3. Phenyl Isocyanate.
The tetrazole (87b, 517 mg) was mixed with acid-washed sand
(30 g) and place in a round bottom flask to which was attached a
1171 tube. The system was maintained under partial aspirator pressure,
with the 111' tube immersed in liquid nitrogen. The diluted tetrazole
was thermolysed at 240°C for 10 min. The 'U' tube was removed from
P hr= N
NN VO I I 0
(99)
NO Ph --N
N07 11 NO2 N
N NC,O 5,0
s 0 (100)
(101)
the cold trap and the liquid collected was allowed to evaporate.
A colourless oil remained in the entrance of the 'U' tube, which
had a pungent odour. The it spectrum showed an intense peak
at 2260 cm-1.
In a separate experiment tetrazole (87b, 628 mg) was refluxed
in bromobenzene (10 ml) for 20 h. The solvent was removed and the
residue treated with pyridine (1 drop) and aniline (2 ml). The
mixture was heated on a water bath (80°C) for 1 h. Removal of the
solvent and addition of benzene produced a precipitate from which
was crystallised 1,3-diphenylurea (19.6 mg, 4%), m.p., 235-7°C
(ethanol) (lit.,221
2380C).
E)* THE PREPARATION OF ALTERNATIVE HETEROCYCLIC PRECURSORS.
1, The alternative heterocyclic precursors (99), (100), and (101),
were prepared from N-(2-nitrophenyl)benzamidoxime m.p., 185°C
(lit.,223 184-5°C). Reaction of the benzamidoxime with ethyl chloroformate
by the procedure of Bacchetti, et al.,10 gave 4-(2-nitrophenyl)-3-
phenyl-1,2,4-oxadiazol-5-one (99), m.p., 126°C (lit.
2. 3-(2-Nitropheny1)-4-phenyl-1,2,3,5-oxathiadiazol-2-one (101), (67%).
To a solution of N-(2-nitrophenyl)benzamidoxime (1 g, 0.004 mol),
in dry benzene (200 ml) was added thionyl chloride (0.46 g,
0,0.0.4 mol), The mixture was stirred at room temperature for 1 h,
filtered and the solvent removed without heating. The pale yellow
solid was crystallised from ethanol, m.p., 102-3°C (benzene-hexane).
124
10 125°C) .
Denotes experiment performed by Dr. P.G. Houghton.
(Found: C, 51.22; H, 2.85; N, 13.74. C13119N304S requires
C, 51.48; H, 2.99; N, 13.85). vmax
1530, 1350, 1205, 845, 770 and
695 cm 1; Amax (CHC?3) 242 (10468); S 7.33-8.06 (br, m, 9 H);
m/e 303 (M+), 239 (base) 195, 119.
3. 4-(2-Nitrophenyl)-3-phenyl-1,2,4-oxadiazol-5-thione, (100), (77%).
To a solution of N-(2-nitrophenyl)benzamidoxime (1.07 g,
0.004 mol) in dry benzene (300 ml) at room temperature was added
thiophosgene (0.46 g, 0.004 mol). A few drops of triethylamine
were added and the mixture stirred at room temperature for 1.5 h.
The solvent was evaporated and the orange solid purified. by column
chromatography. The pale yellow solid was crystallised from aqueous
ethanol, m.p., 126-8°C (Found: C, 56.11; H, 2.97; N, 13.93;
C14H9N305 requires C, 56.18; H, 3.03; N, 14.04);
1350, 1265, 1170, 850, 785 and 690 cm-1; Amax (CHCt3) 222 (11976),
248 (23053), 285.5 (23952) nm; S 7.1-8.35 (m, 9 H); m/e 299 (M+),
242, 225, 149,105 (base).
F)* THERMOLYSIS OF COMPOUNDS (99), (100), and (101).
Solution thermolyses were performed as previously described
in the general procedure for tetrazole thermolysis. Melt thermolyses
were performed by placing the solid sample in a 25 ml round bottom
flask to which was attached an it condenser and nitrogen supply.
The flask was placed in a preheated Wood's metal bath at 255-60°C.
After heating for 1 h the flask was removed and the products worked
up by column or layer chromatography.
125
\max 1610, 1530,
1.* 4-(2-Nitrophenyl)-3-phenyl-1,2,4-oxadiazol-5-one (99).
A solution of the oxadiazole (99) (245 mg, diphenylether, 24 h)
gave after plc (CHC(3-EtOAc 9:1/Si02) (i) 2-phenylbenzotriazole
(19 mg, 11%), (ii) 4 -nitro-2 -phenylbenzimidazole (103), (70 mg, 34%)
m.p., 192-4°C (lit.,10 194-6°C) (iii) starting material (99), (44 mg,
18%) and (iv) 2-phenylbenzimidazole (104) (5 mg, 3%) identified
by comparison with an authentic sample by tic.
Melt thermolysis of the oxadiazole (99) (200 mg, 1 h) gave
(i) 2-phenylbenzotriazole (13 mg, 9%) (ii) starting material
(38 mg, 19%), (iii) 4-nitro-2-phenylbenzimidazole (62 mg, 37%)
and (iv) 2-phenylbenzimidazole (6 mg, 4%).
2. 4-(2-Nitropheny1)-3-phenyl-1,2,4-oxadiazol-5-thione (100).
The oxadiazole (100) (190 mg, diphenylether, 6 h) gave after
plc (CHCt3-EtOAc 9:1) (i) 2-phenylbenzotriazole (5 mg, 4%),
(ii) starting material (25 mg, 13%), (iii) 4-nitro -2-phenylbenzimidazole
(38 mg, 25%) and (iv) 2-phenylbenzimidazole (16 mg, 13%). Melt
thermolysis of the oxadiazole-5-thione (100) (193 mg, 260°C, 4 h)
gave 2-phenylbenzotriazole (11 mg, 9%), 4-nitro-2-phenylbenzimidazole
(10 mg, 7%) and 2-phenylbenzimidazole (5 mg, 4%).
3! 3-(2-Nitropheny1)-4-pheny1-1,2,3,5-oxathiadiazol-2-one (101).
Solution thermolysis of the oxathiadiazol-2-one (101), (200 mg,
BB, 1'h) gave 2-phenylbenzotriazole (113 mg, 88%). Melt thermolysis
at 135-40°C for 1 h gave after plc (CHCl3-EtOAc, 9:1/Si02) 2-phenyl-
benzotriazole (103 mg, 64%).
126
Denotes experiment performed by Dr. P.G. Houghton.
4. Control Thermolysis
4-Nitro-2-phenylbenzimidazole(103) (50 mg) was thermolysed
in the melt overnight. Tlc of the melt reaction showed one
component, corresponding to starting material (103).
G) THE PREAPARATION OF THIOUREAS
General Procedure.
To a vigorously stirred solution of the appropriate 2-nitro-
phenylisothiocyanate166 (0.01 mol) in dry benzene (10 ml) was
added a solution of freshly distilled (or crystallised) amine
(0.01 mol) in dry benzene (5 ml). The solution was stirred at
room temperature for 5 min. If a solid was not produced during
that time the solution was warmed on a water bath (80°C) for 10 min.
On cooling a copious precipitate was formed. The mixture was
stirred for a further 30 min, filtered and the solid crystallised.
The thioureas prepared by the above procedure were all new
compounds except 1-(2-nitrophenyl)-3-phenylthiourea (105a), m.p.,
142-40C (lit. ,224
142°C), 1-(2-nitrophenyl)-3-(4-nitrophenyllthiourea
(105f) m.p., 145-8°C (lit.,166 153°C) and 1-(4-methylphenyl)-3-(2-nitro-
phenyl)thiourea (105b) m.p., 207°C (lit.
1-(2,6-Dimethylphenyl)-3-(2-nitrophenyl)thiourea, (105c) (84%).
m,p., 171-3°C (ethanol), (Found: C, 59.83; H, 5.02; N, 13.93;
C13H15N302S requires C, 59.78; H, 5.02; N, 13.94; vmax 3350, 3160,
1610, 1550, 1520, 1460, 1265, 1210, 855, 780, 725, and 710 cm-1;
Amax (EtOH) 208 (20463), 216 (2007) nm; 6 (acetone-d6) 2.37 (s, 6 H),
[7.16-7.61 (m, 7.67-8.08 (t), 8.08-8.35 (d), 8.37 -9.02 (m) 7 H],
9.15-9.59 (br, s, NH, D20 exchangeable); m/e 300 (M+ - 1), 255 (base),
163, 138 and 130.
127
,166 207°C).
1-(2,4,6-Trimethylphenyl)-3-(2-nitrophenyl)thiourea (105d), (72%).
m.p., 175-7°C, (Found; C, 60.84; H, 5.45; N, 13.32; C16H17N302S
requires C, 60.93; H, 5.43; N, 13.32%); vmax 3340, 3130, 1615,
1535, 1350, 1270, 1230, 860, 790, and 750 cm-1, Xmax (EtOH) 236
(18716), 308 (3785) nm; S (acetone-d6) 2.30 (s, 9 H), 6.80-8.16
(m, 5 H), 8.54-9.38 (m, 2 H); m/e 314 (M+ - 1), 269 (base), 177.
1-(4-Methoxyphenyl)-3-(2-nitrophenyl)thiourea, (105e),(92%).
m.p., 165-7°C (ethanol), (Found: C, 55.42; H, 4.27; N, 13.83;
C141113N303S requires C, 55.43; H, 4.32; N, 13.85%); vmax 3180, 1610,
1590, 1520, 1455, 1350, 1250, 1170, 1030, 830, 785, and 745 cm1;
Xmax (EtOH) 205 (22608), 245 (20000), 262 (17174) nm; 6 (acetone-d5)
3.86 (s, 3 H), 7.26 (q, 4 H, J = 8.1 Hz), 7.76 (t, 2 H) 8.13 (d, 1 H),
8.50 (d, 1 H), 9.50-9.80 (br, s, 1 H); m/e 303 (M+), 285, 269, 257,
180, 165 (base), 150, 138, 108.
1-(4-Methoxy-2-nitrophenyl)-3-phenylthiourea, (105g), (62%).
m.p„ 159-61°C (Found: C,56.19; H, 4.23 ; N, 14.26 ;.'C14H13N303S
requires C, 55.43; H, 4.32; N, 13.85%); max 3340, 3100, 1605, 1550,
1535, 1380, 1370, 1230, 1040 and 860 cm-1; Amax (EtOH) 214 (18181),
250 (16969), 265 (17424) nm; 6 (acetone-d6) 3.90 (s, 3 H), 7.00-8.10
(m, 9 H), 9.03-9.67 (br, m, 2 H); m/e 303 (M+) 257, 168, 138, 135, 93 (base).
1-(t-Butyl)-3-(2-nitrophenyl)thiourea, (105h), (93%).
m.p., 155-65°C (ethanol) (Found: C, 52.33; H, 6.03; N, 16.57;
C11H15N302S requires C, 52.15; H, 5.97; N, 16.59%); vmax 3280,
3220, 1610, 1565, 1510, 1470, 1350, 1270, 1190, 865, 780, and 720 cm-1;
128
Xmax (EtOH) 205 (12791), 204 (20284) nm; S (acetone-d6) 1.58
(s, 9 H), 7.37 (t, 1 H), 7.73 (t, 1 H), 8.16 (t, 2 H), 9.30-9.47
(br, s, 1 H, D20 exchangeable); m/e 254 (M+ + 1), 219, 207, 189,
163, 151, 138, 133.
1-Benzyl-3-(2-nitrophenyl)thiourea, (105j), (72%).
H, 4.55; N, 14.65;'C14H1sN302S
%); vmax 3240, 3180, 1610, 1595,
m.p., 119.5-121°C, (Found: C, 58.73;
requires C, 58.52; H, 4.56; N, 14.62
1510, 1480, 1460, 1350, 975, 780, 740, and 700 cm l; A ax
(EtOH)
204.5 (15171), 239.5 (16 313)nm; S (acetone-d6) 4.96 (s, 2 H),
[7.42 (br, m), 7.73 (t), 8.13 (d), 8.48-8.70 (br, m), 9.52-9.80
(br, m), (11 H)]; m/e 287 (M+), 241, 220, 180, 164, 106, 91 (base).
1-(2-Nitrophenyl)-3-(2-pyridyl)thiourea, (105k), (75%).
m.p., 191-20 C, (Found: C, 52.67; H, 3.71; N, 20.08; C1211104025
requires C, 52.54; H, 3.68; N, 20.43%); vmax 3240, 1610, 1550, 1520, 1485,
1350, 1325, 1260, 1190, 1155 and 775 cm-1; Xmax (EtOH) 255.5 (22 222),
299 (16 186) nm; S (acetone-d6) 7.14-7.86 (m, 9 H); m/e 274 (M+)
242, 228, 196, 168, 136, 120, 78 (base).
1-(4-Methoxy-2-nitrophenyl)-3-(2-pyridyl)thiourea (105?), (29%)
zn.p., 199-201°C, (Found: C, 51.10; H, 3.92; N, 18.26;'C13H12N403S
requires C, 51.31; H, 3.98; N, 18.41%); vmax 3250, 1610, 1590, 1530,
1385, 1325, 1280, 1240, 1190, 1155, 1030 and 780 cm-1, Xmax (Et0H)
209 (12 633), 259 (18873), 295.5 (14612) nm; S (acetone-d6) 3.89 (s,
3 H), 7.04-8.70 (m, 9 H); m/e 304 (M+) 258, 226, 168, 136, 120, 78 (base).
129
130
Attempted synthesis of 1-(2,6-dinitrophenyl)-3-phenylthiourea
failed, since it was not possible to prepare the corresponding
2,6-dinitrophenylisothiocyanate. 2,6-Dinitroaniline (1 g, 0.0055 mol)
and thiophosgene (0.48 ml of solution in 15% CCt4, 0.0055 mol) were
added to a solution of toluene (5 ml) and aqueous hydrochloric acid
(1 ml, Mt: 5 ml, H20). The mixture was gently refluxed for 8.5 h,
after which time tic showed only starting material.
Mixing aniline and phenylisothiocyanate in equimolar amounts in
benzene gave 1,3-diphenylthiourea (53%) m.p. 154°C (lit.,201 154-5°C).
Warming equimolar amounts of 1-naphthylamine and phenylisothiocyanate
in ethanol gave 1-(1-naphthyl)-3-phenylthiourea (66%), m.p., 172-4°C
(lit.,201 162-3°C).
A mixture of 2-amino-2'-nitrobiphenyl199 (200 mg, 0.00095 mol),
thiophosgene (125 mg, 0.00095 mol), concentrated hydrochloric acid
(1 -ml) in water (5 ml) and toluene (5 ml) was refluxed for 2.5 h.
The cooled mixture was separated, the organic phase washed once with
water, dried over magnesium sulphate and the solvent removed. The
isothiocyanate thus formed was dissolved'in benzene to which was added
aniline (88.5 mg, 0.00095 mol). The solution was heated on a water
bath.for 2 min•and the solvent removed. Addition of petrol (5 ml)
followed trituration produced a yellow solid which was crystallised
from ethanol giving 1-(2'-nitrobiphen-2-)-3-phenylthiourea (150 mg,
45%, (from amine)), m.p., 155-6°C, (Found: C, 65.12, H, 4.33; N, 12.03;
C191115N302S requires C, 65.31; H, 4.43; N, 11.84%); vmax 3360, 3150,
1 1530, 1360, 1240, 855, 790, 770 and 755 cm ; Xmax (CHCt3) 245, 273 nm;
S (dmso-d 6) 7.03-7.58 (m, 11 H), 7.65 (t, 1 H), 7.76 (t,1 H),
8.08 (d, 1 H), 9.12 (s, 1 H), 9.50 (s, 1 H); m/e 350 (M+ + 1),
315, 303, 285, 269, 256, 167, 135, 93.
1-Amino-8-nitronaphthalene198 (1 g, 0.0053 mol), thiophosgene
(0.69 g, 0.0053 mol), concentrated hydrochloric acid (1 ml) in
water (10 ml) and toluene (10 ml) were refluxed for 1.75 h. The
cooled organic phase was separated and washed with water, dried
over sodium sulphate and the solvent removed. The red oil was
dissolved in benzene (5 ml) to which was added aniline (0.5 g, 0.0053 mol).
After 2-3 min a yellow solid was precipitated which after
crystallisation from ethanol-dimethylformamide gave 1-(8-nitronaphth-l-yl)-
3-phenylthiourea (1.7 g, 42% (from amine)), m.p., 186-8°C
(Found: C, 63.23; H, 4.08; N, 12.79;'C17H13N302S requires C, 63.14;
H, 4.05; N, 13.00%); umax 3320, 3160, 1515, 1375, 1240, 825, 765,
755, and 740 cm 1; Xmax
(EtOH) 216 (49 838) nm; d (dmso-d 6 )
7.20-8.43 (m, 1 H), 9.26 (br, s, 1 H, D20 exchangeable), 9.82 (br,
s, 1 H, D 20 exchangeable); m/e 277 (M+ - 46 (NO2)) 230, 184, 172,
140, 93 (base) .
H) THE PREPARATION OF CARBODIIMIDES AND THENCE 2-ARYLBENZOTRIAZOLES
1. Two general procedures were used for the preparation of
carbodiimides, depending on the reagent used to eliminate H 2S
from the corresponding thioureas.
131
Method a; for metal oxides HgO, AgO.
To a solution of the corresponding thiourea (0.001 mol) in
a suitable solvent (methylene chloride or acetone) was added
the metal oxide (generally 0.002 mol) and an excess of magnesium
sulphate as dessicant. The suspension was vigorously stirred
until tic showed complete consumption of starting material.
The metal salts were removed by filtration and the solvent
removed producing the carbodiimide. The carbodiimides thus
produced were thermolysed without purification.
Method b; for 2-chloro-l-methylpyridinium iodide.62
To a solution of the appropriate thiourea (0.001 mol) in
dry acetonitrile (10 ml) was added a slight excess of 2-chloro-l-
methylpyridinium iodide (0.0012 mol). To the rapidly stirred
suspension was added triethylamine (0.002 mol). The suspension
rapidly became a clear solution from which was precipitated a
solid. The reaction was stopped when tic showed complete consumption
of starting material. The solvent was removed at the pump and
the residue suspended in dry methylene chloride (ca. 3 ml). The
methylene chloride suspension was loaded onto a prepared
chromatography column (Silica H - petrol) and eluted with petrol
(100 ml) under hand pump pressure! The column was then eluted
with mixtures of methylene chloride-petrol (usually 1:1) which
rapidly removed the carbodiimide from the column as a fast running
band. The solvent was removed and the carbodiimide used without
further purification. The carbodiimides were in contact with the
silica for very short periods (ca. 2-5 min).
132
2. Thermolysis of Carbodiimides.
The carbodiimide as prepared above, were dissolved in freshly
distilled bromobenzene in a 25 ml round bottom flask, to which was
attached an air condenser and a nitrogen supply. The solutions were
placed in a pre-heated Wood's metal bath and rapidly came to reflux.
The solutions were refluxed until tic showed complete consumption to
starting material. The solvent was removed u.r.p. and the resulting
solid purified by low pressure column chromatography (Si021i,gradient
elution) and crystallisation. The following 2-arylbenzotriazoles were
thus prepared;
2-Phenylbenzotriazole, (107a), 50% (method a, HgO, 18 h) (BB, 10 min),
m.p., 109-110°C (lit.
2-(4-Methylphenylbenzotriazole, (107b) 37% (method a, HgO, 18 h),
(BB, 2 H); 43% (method b, 5 h), (TCB, 5 min) m.p., 119-121°C (lit.,215
120-121°C).
2-(4-Methoxyphenyl)benzotriazole (107e) 25% (method a, HgO, 18 h), (BB,
15 min); 55% (method b, 0.5 h) (BB, 10 min) m.p., 111-3°C, (lit. ,215108-110°C).
2-(2,6-Dimethylphenyl)benzotriazole, (107c).59% (method a, HgO, 2 h),
(BB, 1.5 h) m.p., 91-4°C 91 -4 C '(Found: C, 75.32; H, 5.88; N, 18.83; Ci4H13N3
requires C, 75.31; H, 5.87; N, 18.82%); vmax 1340, 1275, 1230, 970, 815,
790 and 755 cm 1, Xmax (EtOH) 277 (1227), 208 (2008) nm; 6 (CDCe3) 1.90
(s, 6 H), 7.06-7.60 (m, 5 H), 7.82-8.05 (m, 2 H); m/e 223 (M+), 207, 195,
118, 91.
2-(2,4,6-Trimethylphenyl)benzotriazole, (107d) 54% (method a, HgO, 18 h),
(BB, 1.5 h); 73% (method b, 2 h), (BB, 15 min). M.p. 117-117.5°C (Found:
C, 75.72; H, 6.37; N, 17.74;'C15H15N3 requires C, 75.92;
133
,215 104-6°C).
134
H, 6.37; N, 17.71%); vmax
1345, 1285, 1275, 1225, 970, 860 and 740 cm 1;
Amax (EtOH) 210 (29830), 277 (15254) nm; d (CDC?3) 1.86 (s, 6 H),
2.30 (s, 3 H), 6.96 (s, 2 H), 7.35-7.46 (m, 2 H), 7.80-8.00 (m,
2 H); m/e 237 (M+, base), 222, 209.
Attempts to prepare 2-t-butyl- and 2-benzylbenzotriazoles
from the readily available carbodiimides failed.
1-(t-Butyl)-3-(2-nitrophenyl)carbodiimide (106h) was prepared
from the appropriate thiourea (0.2 g, 0.008 mol), (method a, HgO,
18 h). The ir spectrum showed an intense band at 2140 cm-1. The
carbodiimide was dissolved in bromobenzene and refluxed under
nitrogen for 18 h. Tlc and ir showed that carbodiimide was still
present. The solvent was removed and replaced with I,2,4-trichloro-
benzene. The solution was refluxed under nitrogen for 24 h after
which time there was no longer evidence for carbodiimide (tic, ir).
The solvent was removed and the black residue chromatographed
(SiO2 H) producing a low melting solid (12.5 mg) as the only
isolated component, which was not identified.
1-Benzyl-3-(2-nitrophenyl)carbodiimide (106j) was prepared
(method a, HgO, 18 h). Thermolysis in bromobenzene for 3 h
resulted in consumption of the carbodiimide (ir, tic) with the
formation of a tarry residue.
Attempted preparation of carbodiimides from thioureas containing
1-pyridyl substitutents or 4-nitrophenyl substitutents failed in
the nitro case and gave carbodiimide in very low yield in the pyridyl
case.
135
1-(2-Nitrophenyl)-3-(4-nitrophenyl)thiourea (105f) (100 mg,
0.00035 mol) and mercuric oxide (151 mg, 0.0007 mol) were reacted
in methylene chloride according to method a. Tlc indicated no
reaction after 18 h at room temperature. The mixture was
refluxed in methylene chloride for 18 h then replaced with benzene
(24 h reflux) and toluene (24 h reflux). After this time tic
showed the thiourea was one component not distinguishable from
an authentic sample. The thiourea (105f) was treated with
2-chloro-l-methylpyridinium iodide by method b. Tic of the
reaction mixture after 6 h showed the thiourea to be one
component.
1-(4-Methoxy-2-nitrophenyl)-3-(2-pyridyl)thiourea•(105?) (130 mg,
0.0004 mol) was treated with 2-chloro-l-methylpyridinium iodide
according to general method b. Tic after 6 h at room temperature
showed one component corresponding to thiourea (105?).
1-(2-Nitrophenyl)-3-(2-pyridyl)thiourea (105k) (300 mg, 0.0011 mol)
was treated according to method a, (AgO,. 6 h, room temperature),
tic showed one spot corresponding to starting material. A further
18 h at room temperature and 8 h reflux in methylene chloride failed
to produce any reaction (tic). Treatment of the thiourea (105k)
(300 mg, 0.0011 mol) by method b gave a complex mixture (tic) with
a high Rf component in the usual region for carbodiimides.
Column chromatography gave a single colourless crystalline product
(10,4 mg, 4%) with an intense band at 2120 cm -1 in the ir spectrum.
The above reaction was repeated in refluxing acetonitrile
for 2 h producing (9.6 mg, 4%) of the same compound (ir, tic).
Attempted preparation of the pyridine N-oxide of the thiourea
(105k) failed. A solution of the thiourea in methylene chloride was
treated with a 25% excess of m-chloroperbenzoic acid at room
temperature for 3 h and then at reflux for 18 h. Tlc showed
one component corresponding to (105k). The same result was
achieved with m-chloroperbenzoic acid in dioxan at room temperature
and under reflux conditions. The use of sulphuric acid, hydrogen
peroxide and either acetic or trifluoroacetic acid at room
temperature or 80°C failed to affect any reaction (tic).
1-(2-Nitrophenyl)-3-phenylthiourea (105a) (0.5 g, 0.0018 mol)
was treated with mercuric oxide by method a. The carbodiimide
(106a) thus produced was dissolved in acetone and made up to
50 m1, A 25 ml aliquot was withdrawn and the solvent removed.
Thermolysis in bromobenzene according to the general procedure gave
2-phenylbenzotriazole (107a) (81 mg, 30%); the second 25 ml
aliquot was withdrawn and the solvent removed. The oil was
dissolve in dioxan-water (20 ml, 4-1) to which was added concentrated
hydrochloric acid (1 ml). The solution was refluxed for 1.5 h
poured into ice cold water and the oil separated. Trituration
gave a solid which was crystallised from ethanol, l-(2-nitrophenyl)-
3-phenylurea (108) (148 mg, 31% (from thiourea)), m.p., 168-70°C,
Clit,,120 1700C),
Attempted distillation of carbodiimide (106a) (0.003 mm -
90-130°C) as prepared above, produced a red oil which appeared
as three components on tic. Further heating of the red oil at
atmospheric pressure gave 2-phenylbenzotriazole exclusively.
136
Crystallisation of carbodiimide (106a), as prepared above,
from petroluem spirit (40-60) produced two crystal forms, orange
needles, which corresponded to 1-(2-nitrophenyl)-3-phenylcarbodiimide
(106a), m.p., 19-21°C; vmax (neat) 2150, 1605, 1590, 1520, 1490,
1355, 1215, 1070, 860, 760., 740, and 690 cm 1; m/e 239 (M+),
and red needles, m.p., 126-28°C.
Attempts to prepare the symmetrical 1,3-di(2,2'-nitrophenyl)
carbodiimide (106m) using triphenylphosphine oxide or triphenyl
arsine oxide as catalyst by the method of Monagle44 gave only
impure products (tic) in poor yield. The use of 3-methyl-l-phenyl-
3-phospholine-1-oxide in the method of Monagle, et al.,41 gave
1,3-di(2,2'-nitrophenyl)carbodiimide (106m), (50%), m.p., 94-6°C
(lit.,41 97-98.5°C). Thermolysis of (106m) in the melt (165°C,
5 min) gave, after column chromatography (SiO2 H) and crystallisation
(ethanol) 2-(2-nitrophenyl)benzotriazole (107m)(84%), m.p., 127-30°C ,
(lit.,l73 132.8-3.8°C),
THE PREPARATION AND REACTIONS OF 2 -ARYL-1,2,4-BENZOTRIAZIN--3-
ONE 1-OXIDES
A solution of 3-(2-nitropheny1)-4-pheny1-1,2,3,5-oxathiadiazol-
2-one (101) (200 mg, 0.00066 mol) in dry toluene (15 ml) was
thermolysed at reflux under nitrogen for 3 h. The solvent was
evaporated and the red product crystallised from acetone giving
2-phenyl-1,2,4-benzotriazin-3-one 1-oxide (109a) (81 mg, 51%),
m.p., 124°C (Found: C, 65.12; H, 3.86; N, 17.36; CIKH9N302 requires
C, 65.27; H, 3.79; N, 17.56%); Umax (CC€4) 2260, 1695, 1610 cm-1 (KBr)
1690, 1610, 1470, 1445, and 1350 cm 1; X (CHC$3) 242 (6425) 319 (4183)nm;
d (dmso-d6) 6.56-8.02 (m, 9 H); m/e 239 (M+), 195.
137
Denotes experiment performed by Dr. P.G. Houghton.
A few crystals of (109a) were heated in the melt at 145°C
for 5 mins, resulting in complete transformation to 2-phenyl-
benzotriazole (tic). Addition of dilute sulphuric acid to (109a)
(100 mg) after neutralisation, extraction and crystallisation gave
2-phenylbenzotriazole (107a) (75 mg, 93%).
* To a warm solution of (109a) (200 mg, 0.00084 mol) in
dry benzene (15 ml) was added 2 anisidine (103 mg, 0.00084 mol).
The solution was heated under reflux for 15 min. The solid
produced was filtered and crystallised from ethanol 1-(4-methoxyphenyl)-
3-(2-azoxyphenyl)phenylurea (277 mg, 91%) (111) m.p., 183-4°C
(Found: C, 66.05; H, 5.01; N, 15.37; C20H18N403 requires C, 66.29;
H, 5.01; N, 15.46%); vmax 3270, 1665, 1590, 1380, 1250, 760 and
725 cm 1; Xmax
(CHCt,) 244 (13496), 319 (6612) nm; S(CDCt 3) 3.8
(s, 3 H), 6.5-8.7 (m, 14 H), 9.9 (br, s, 1 H); m/e 362 (M+),213, 197, 195,
149, 134.
1-(4-Methoxyphenyl)-3-(2-nitrophenyl)thiourea (105e) (500 mg,
0.0016 mol) was treated with 2-chloro-l-methylpyridinium iodide
according to method b, (p.132). The carbodiimide thus produced
(266 mg, 85%) was dissolved in toluene and refluxed under nitrogen
for 20 min. The solvent was removed and the red solid crystallised
from acetone giving 2-(4-methoxyphenyl)-1,2,4-benzotriazin-3-one
1-oxide (109e) (80 mg, 22%), m.p., 109-112°C, (Found: C, 62.09;
H, 4.07; N, 15.54;'C14Ha1N302 requires C, 62.44; H, 4.12; N, 15.61%);
1 vmax (Nujol) 1690, 1615, 1510, 1440, 1350, 1170, 1030 and 840 cm ,
138
(CC-C4) 2260 cm -1 ; Xmax (CHC€3) 244 (10224) nm; d(CDC?3) 3.92
(s, 3 H), [7.07 (d), 8.82 (d).4 H, J = 9HZ], [7.20-7.65 (m),
7.90 (d) 4 H]; m/e 225(M+ -44), 210, 182, 154, 121, 106.
Attempted synthesis of 2-phenyl-1,2,4-benzotriazin-3-one
1-oxide by base catalysed condensation of 1-(2-nitrophenyl)-3-
phenylurea according to the method of Wolff et al.,150 failed
to give the required product.
J) EXTENSIONS TO NITRO-GROUP INTERACTIONS
1. Thermolysis of 2-Nitrophenylisocyanate.
Melt thermolysis of 2-nitrophenylisocyanate224 at 170°C
for 30. min showed starting material (tic).
2, Thermolysis of 2-Nitrophenylisothiocyanate.
2-Nitrophenylisothiocyanate (560 mg, 0.003 mol) was dissolved
in benzene and refluxed for 20 h, after which time tic showed no
reaction. The isothiocyanate was refluxed successively in toluene,
chlorobenzene (135°C), bromobenzene (165°C), and 1,2,4-trichloro-
benzene (215°C). Before thermolysis in 1,2,4-trichlorobenzene the
isothiocyanate absorption was still present in the it spectrum.
Reflux for 24 h at 215°C produced a dark solution which was a
multicomponent mixture (tic).
3. Preparation and Thermolysis of 1-(8-Nitronaphth-l-yl)-3-Phenyl-
carbodiimide (117).
The synthesis of 1-(8-nitronaphth-l-yl)-3-phenylthiourea
was described previously (p. 131). The carbodiimide (117) was
prepared using 2-chloro-l-methylpyridinium iodide (method b, p. 132).
139
Thermolysis of the carbodiimide (117) in 1,2,4-trichlorobenzene
under nitrogen produced a solution in which black particles were
visible after 5 h at 215°C. Tlc showed one component corresponding
to starting material with insoluble black baseline material.
The carbodiimide (117) (145 mg) was distilled through a
pre-heated quartz tube at 750°C (0.015 mm). After 5 h, starting
material (117, 135 mg) was recovered from the bottom flask.
An orange compound was washed from the cold finger. Removal of
methylene chloride gave a solid which was crystallised from
petroluem ether (60-80°) producing benz[1,8-c,d]indazole N-oxide (119)
(4 mg), m.p., 145°C (lit. ,180 156-7°C); m/e 170 (M+).
4. The Preparation and Thermolysis of 1-(2'Nitrobiphen-2-yl)-3-
phenylcarbodiimide (118).
The preparation of 1-(21-nitrobiphen-2-yl)-3-phenylthiourea
was described previously (p. 130). The carbodiimide (118) was
prepared using 2-chloro-1 methylpyridinium iodide (method b, p. 132)
The carbodiimide (118, 200 mg) was dissolved in bromobenzene
and refluxed for 20 h. Tlc showed one component corresponding to
starting material (118), Thermolysis in 1,2,4-trichlorobenzene
under nitrogen for 3 days gave tarry products with some starting
material still remaining (tic). Vapour phase pyrolysis of
carbodiimide (118) at 650°C and 0.015 mm gave after chromatography
an oil in trace amounts. The it spectrum of the oil was not
distinguishable from their spectrum of an authentic sample of
phenylisonitrile; Vmax
2140, 1590, 1485, 1200, 750 and 690 cm-1.
A colourless solid, m.p., 136-140°C was isolated in low yield.
140
Vapour phase pyrolysis of (118, 248 mg) at 750°C and 0.015 mm
gave after column chromatography a polar, colourless solid (90 mg)
which was crystallised from petroleum ether-methylene chloride
and the crystalline solid sublimed. M.p., 145-6°C;
1530, 1440, 1370, 1260, 755 and 730 cm-1
; S(CDCfs) 7.27 (s),
7.45-7.60 (m), 7.65-7.85 (m), 8.05-8.15 (d) 8.32-8.48 (t), 8.55 (d),
8.65 (d), 8.94 (d); m/e 268 (SM - 46), 164, 134.
5. The Preparation and Reaction of 1-('1-Naphthyl)-3-phenyl
carbodiimide (126).
The preparation of 1-(1-naphthyl)-3-phenylthiourea was
described earlier (p. 130 ). Distillation of the carbodiimide (126)
at 750°C and 0.015 mm through the quartz tube resulted in recovery ,
of unreacted starting material (tic).
5a. Reaction with Aluminium Chloride.
The carbodiimide (126, 605 mg) was dissolved in methylene
chloride, to which was added aluminium chloride (330 mg). The mixture
was stirred at room temperature for 7 days, quenched with water,
the organic phase separated, washed with water and dried over
sodium sulphate. The solvent was removed and the solid crystallised _
from petroluem ether (60-80°C)-methylene chloride giving one of
the isomeric quinazolines (129) (200 mg, 33%), m.p., 226-8°C
(pound; C, 82,05,' H, 4.95; N,11.14; Cs4H24N4 requires C, 83.58;
H, 4,95; N, 11,47%); vmax 3410, 1640, 1580, 1530, 1390,
and 760 cm-1; Amax 234, 280, 320, 357 nm; S (CDC?g) 6.10
1330,
(br,
770
s, 1 H,
D20 exchangeable), 6.70-6.90 (d,
(br, m, 1 H); m/e 488 (M+), 411,
1 H),
396,
7.14
244,
-7.95
140,
(m, 23 H), 8.80-8.98
127, 77 (base).
141
vmax 3350 (br),
6. Preparation and Reaction of 1,3-Diphenylcarbodiimide.
1,3-Diphenylthiourea was prepared as described on p.130
The carbodiimide was prepared using 2-chloro-l-methylpyridinium
iodide (method b, p.'132). The carbodiimide (376 mg, 0.0019 mol)
was dissolved in methylene chloride to which was added aluminium
chloride (257 mg, 0.0019 mol). The suspension was stirred at
room temperature for 48 h. The reaction was quenched with water,
the organic phase separated, washed with water and dried over
magnesium sulphate. The solvent was evaporated and the yellow
solid crystallised from petroluem ether (40-60)-methylene chloride,
producing 2-phenylamino-3-phenyl-4-phenyliminoquinazoline (128),
(340 mg, 40%), m.p., 175°C (lit. transition 171°C, m.p., 181-5°C);
m/e 388 (M+) .
K) INDEPENDENT SYNTHESES
1, 5-Nitro-2-Phenylbenzotriazole (87k).
The reaction of 2,4-dinitrochlorobenzene with phenylhydrazine
by the method of Mallory et al.,216 gave 5-nitro-2-phenyl-benzotriazole
(25%) m.p., 178-79°C (lit,,216 176-7°C).
2, Benzocinnoline (122).
Reduction of 2,2'-dinitrobiphenyl225 with lithium aluminium
hydride according to the method of Badger, et a1.236 gave benzocinnoline
(14%) m.p., 155-6°C (lit.,181
I54-6°C).
3. Benzocinnoline N-oxide (121).
Reduction of 2,2'-dinitrobiphenyl225 with sodium hydrosulphide
according to the method of King, et al.,182 gave benzocinnoline N-oxide
(31%) m.p., 139-41°C (lit.,182 138°C ).
142
4. Benzocinnoline di-N-oxide (120).
Reduction of 2,2'-dinitrobiphenyl with zinc and potassium
hydroxide according to the method of Tauber181
gave benzocinnoline
di-N-oxide (46%) m.p., 243°C (lit.,181 243°C).
5. 6-Anilinophenanthridine (124).
Treatment of 6-chlorophenanthridine with aniline according to
the method of Seidler226 gave 6-anilinophenanthridine (60%) m.p.,
156-7°C (lit.,226
156-7°C).
6. 6-Anilino-10-nitrophenanthridine (125).
2-Nitro-2'-biphenylisocyanate prepared by using the analogous
route of Fraenkel-Conrat, et al.,227 was treated with aluminium
chloride according to the procedure of Butler228
gave 10-nitro-6(5H)-
phenanthridone (10%) m.p., 319-320°C (lit.,229 316-18°C).
10-Nitro-6(5 H)phenanthridōne (100 mg, 0.00042 mol) was refluxed
with an excess of phosphoryl chloride for 4 h. Excess phosphoryl
chloride was evaporated leaving an orange oil which crystallised
on cooling. To the solid was added a 6-fold excess of aniline in
benzene (5 ml), and the solution refluxed overnight. The solution
was cooled, washed with water and the organic phase dried over
sodium sulphate. The solvent was removed and the yellow oil
triturated under ethanol-water (20 ml, 1:1). The yellow solid
was filtered and crystallised from petroluem ether (60-80°)-methylene
chloride producing 6-anilino-l0-nitro-phenanthridine (125) (85 mg,
65%) m.p., 144-7°C (Found:C, 72.44; H, 4.31; N, 13.27;'C19H13N302
143
requires C, 72.37; H, 4.16; N, 13.33%); vmax 3440, 1590 (w),
1525, 1370, 750, 705 and 690 cml; Xmax (CHCt3) 353 (7098) nm;
6 (CDC-(3) [6.88-7.02 (m), 7.08 (t), 2.5 H], 7.20 (s, 2 H), 7.36
(t, 3 H), 7.50-7.78 (m,.3 H), 7.85 and 8.18 (2 x d, 2.5 H);
m/e 315 (M+) 268, 182, 157, 129 (base).
144
SECTION 2-
A) THE PREPARATION OF PRECURSORS TO CARBAZOLES.
1. Tetrazoles.
The preparation of tetrazoles has already been described
on p. 111.
2. 2-Arylbenzotriazoles.
The preparation of 2-arylbenzotriazoles has already been
described on p. 131.
B) VAPOUR PHASE PYROLYSIS OF 1-(2-NITROPHENYL)-5-PHENYLTETRAZOLE (87b)
AND 2-PHENYLBENZOTRIAZOLE (107a).
1. 1-(2-Nitrophenyl)-5-phenyltetrazole (87b).
The tetrazole (87b, 242 mg, 0.0009 moles) was vapourised at
120°C and 0.02 mm Hg, and the vapour passed through a quartz tube
at 400°C. Tetrazole (87b, 185 mg, 0.0007 mol) was recovered
unsublimed. Column chromatography (SIX/2H) gave a crystalline
product which was two spots on tic. We were not able to separate
the two components. The mixture showed -NH vibration at 3490 cm-1
in the it spectrum. Comparative tic suggested one component was
2-phenylbenzotriazole. Crystallisation from petroleum ether (60-80°)-
methylene chloride gave 2-phenylbenzotriazole (19 mg, 40%).
145
2. 2-Phenylbenzotriazole (107a).
a) 2-Phenylbenzotriazole (107a, 187 mg, 0.00096 mol) was vapourised
at 90°C and 0.08 mm Hg and the vapour passed through a quartz tube
at 600°C. The pyrolysate was crystallised from petroleum ether
(60-80°)-methylene chloride producing carbazole (23 mg, 14.4%)
m.p., 235-8°C (lit.,201 246).
b) Yield Optimisation Experiments.
General Procedure
2-Phenylbenzotriazole (107a) was vapourised at between 80-85°C
and the vapour passed through a quartz tube pre-heated to the
required temperature (see Table, p. 92 ). The pyrolysate was
chromatographed to remove any baseline material and the weight
of recovered material was established. In only one case was
the material return less than 95% (900°C, 76%). The pyrolysate
was analysed by hplc with authentic specimens as reference, using
a reverse phase column, eluting with methanol-water mixtures (4:2
or 7:3) with a UV detector at 293 nm. The yields were calculated
by first finding the response factor for a carbazole 2-phenylbenzo-
triazole mixture of known concentration, then applying the constant
to find the relative peak areas of the mixtures of unknown
concentration.
The following results are given as pyrolysis temperature,
percentage carbazole; 300°C, 0; 500-20°, 0; 600°C, < 1; 700-20°C,
17; 750°C, 76; 800°C, 56; 900°C, 91.
146
C) THE PREPARATION AND PYROLYSIS OF 1,2,5-DIBENZOTRIAZEPINE (131).
1. Preparation of 1,2,5-dibenzotriazepine (131).
Reduction of 2,2'-dinitrodiphenylamine230
(132) with zinc dust
and sodium hydroxide using the method of Grundon231 gave after
column chromatography and crystallisation 1,2,5-dibenzotriazepine
(131) 15% , m.p., 192°C (lit.,231 190-1°C).
2. Vapour Phase Pyrolysis of 1,2,5-Dibenzotriazepine (131).
1,2,5-Dibenzotriazepine (131, 110 mg, 0.00056 mol) was
vapourised at 110°C and 0.03 mm Hg and the vapour passed through a
quartz tube at 800°C. The pyrolysate was chromatographed (Si02 H)
producing starting material (131) (22.4 mg, 20%) and a colourless
solid which ,was crystallised from petroleum ether (40-60°)-methylene
chloride giving carbazole (130) (29 mg, 31%).
D) PYROLYSIS AND PHOTOLYSIS OF PRECURSORS TO 3-METHYLCARBAZOLE
1. Pyrolysis of 2-(4-methylphenyl)benzotriazole (107b).
2-(4-Methylphenyl)benzotriazole (107b, 62 mg) was vapourised
at 100°C and 0.015 mm Hg and the vapour passed through a quartz
tube at 850°C. The pyrolysate was chromatographed (Si0 2 H) to remove
baseline material and the product mixture analysed by hplc.
147
HPLC Analysis.
The pyrolysis product was shown to be a mixture of three
components. Co-injection of the pyrolysis mixture with an authentic
sample of 2-(4-methylphenyl)benzotriazole (107b) identified one
component as benzotriazole (107b). Conditions under which the
pyrolysis product mixture could be separated failed to resolve
authentic specimens of 2-methylcarbazole and 3-methylcarbazole.
Co-injection of the pyrolysis mixture with 2-methylcarbazole and
then with 3-methylcarbazole identified a second component as
2-methylcarbazole (133) or 3-methylcarbazole (132) or a mixture of
the two compounds. Co-injection of 1-(4-methylphenyl)benzotriazole
(136) and the pyrolysis mixture showed that this compound did not
correspond to any component in the pyrolysis mixture.
b) NMR Analysis.
Since the second component of the pyrolysis could not be
determined as 2-methylcarbazōle (133) or 3-methylcarbazole (132) or
a mixture of (132) and (133), the nmr spectra were compared.
2-Methylcarbazole (133) d (CDC-(3) 1.54 (s, 1 H, D20 exchangeable), 2.52
(s, 3 H), 7.06 (d, 1 H), 7.16-7.29 (m, 1 H), 7.35-7,42 (m, 2 H), 7.86-8.08
(m, 3 H) .
3-Methylcarbazole (132).d (CDC?3) 2.52 (s, 3 H), 7.17-7.40 (m, 6 H),
7.86 (s, 1 H), 8.03 (d, 1 H).
2-(4-Methylphenyl)benzotriazole (107b) d(CDC?3)2.45 (s, 3 H), 7.25-7.45
(m, 4 H), 7.85-8.00 (m, 2 H), 8.26 (d, 2 H).
148
Pyrolysis Mixture 6 (CDC€s) 1.26 (br, s), 1.56 (br, s), 2.44 (s,
107b - CH3), 2.52 (132-CH3), 7.13-7.32 (m), 7.36-7.40 (m),
7.36-7.50 (m), 7.85-7.98 (m), 8.02-8.10 (t), 8.25 (d).
Analysis of the spectra shows the presence of starting
material (107b) with a methyl group at 6 2.44 and a doublet at
6 8.25, which is part of an AB quartet.
The 2- and 3-methyl groups in the monomethyl carbazoles
have been shown to have identical resonance positions.232
Thus, either 2- or 3-methylcarbazole is present in the pyrolysis
mixture, 6 2.52 (3 H, CH3). The nmr spectrum of 2-methylcarbazole
has a one proton doublet at C°7.06. This resonance does not
occur in 3-methylcarbazole or in the pyrolysis mixture.
2. Photolysis of 2-(4-methylphenyl)benzotriazole (107b).
2-(4-Methylphenyl)benzotriazole (150 mg) was photolysed in
dry, degassed acetonitrile (150 ml) at 300 nm for 30 h. Tlc
showed a single component corresponding to starting material (107b).
3. Melt Thermolysis of 1-(4-methylphenyl)benzotriazole (136).
1-(4-Methylphenyl)benzotriazole (136, 200 mg) was thermolysed
in the melt at 350°C under nitrogen for 2 h. Column chromatography
of the pyrolysate produced colourless crystals which were crystallised
from petroleum ether-methylene chloride producing 3-methylcarbazole
(132) (80 mg, 40Z), m.p „ 199-202°C (lit,,233 199-202°C).
149
E) INDEPENDENT SYNTHESES
1. 2-Methylcarbazole (133).
Attempts to prepare the required 4-methyl-2'-nitrobiphenyl
(134) following the Voge1200 procedure for the Gomberg-Bachmann
reaction190 failed to produce the require product. p-Iodotoluene
(1 g, 0.0046 mol), 2-bromonitrobenzene (0.93 g, 0.0046 mol) and
copper powder (0.88 g, 0.0014 g'atom) were mixed with dry dimethyl-
formamide (5 ml) and the mixture refluxed for 18 h. The reaction
mixture was cooled, poured into cold water (400 ml) and stirred
for 2 h. The aqueous phase was decanted, the residue extracted
into hot chloroform, filtered, dried over magnesium sulphate and
the solvent removed. Column chromatography (SiO2 H) gave 4-methyl-2'-
nitrobiphenyl (134) as a yellow oil (153 mg, 16%) S (CDC-(3)
2.20 (s, 3 H), 7.26-8.15 (m, 8 H). The oil was used without further
purification.
Treatment of 4-methyl-2'-nitrobiphenyl (134) (150 mg, 0.00074 mol)
with triethyl phosphite under nitrogen for 24 h according to the
method of Cadogan, et a1.,215 gave after crystallisation from
ethanol 2-methylcarbazole (133) (84 mg, 66%) m.p., 257-9°C (lit.,233
259°C) .
2. 3-Methylcarbazole (132).
6-Methyl-1,2,3,4-tetrahydrocarbazole was prepared by the
234 procedure of Rogers, et a1.
150
6-Methyl-1,2,3,4-tetrahydrocarbazole (90 mg, 0.00049 mol)
was dissolved in dry toluene (5 ml) and the solution warmed.
To the hot, but not refluxing solution was added o-chloranil
(287 mg, 0.0012 mol) and the solution refluxed for 18 h. Column
chromatography (Si02 H,twice) failed to separate the two product
components. Plc (CHC€ 3 - Petrol, 4:1) gave 3-methylcarbazole
(132) (25 mg, 28%), m.p., 199-202°C (lit.,233 199-202°C).
3. 1-(4-Methylphenyl)benzotriazole (136).
Reduction and diazotisation of 4 -methyl-2'-nitrodiphenylamine191
using the method of Fitton, et al.,235 gave 1-(4-methylphenyl)benzo-
triazole (136, 46%), m.p., 85-8°C (lit.,237
84°C).
151
APPENDIX
1. The Preparation of Tetrazoles.
The preparation of tetrazoles has already been described
on p. 111 and in reference 195.
2. Photolysis of Tetrazoles.
a) Photolysis of 1-(2-nitrophenyl)-5-phenyltetrazole (87b).
The tetrazole (87b) (400 mg, 0.0015 mol) was photolysed in
dry, degassed acetonitrile (150 ml) under nitrogen at 254 nm for-
92 h. Plc (chloroform-ethyl acetate 50:1, twice) followed by
column chromatography and crystallisation from petroleum ether (60-80°)-
methylene chloride gave 4-nitro-2-phenylbenzimidazole (68 mg, 17%)
m.p., 192-4°C (lit.,195 194-6°C). Tetrazole (87b) (14 mg, 3.5%)
was recovered.
b) Photolysis of 1-[2-(5-phenyltetrazol-1-yl)benzoyl]pyrrolidine (140).
The tetrazole (140) (600 mg, 0.0019 mol) was photolysed in
dry, degassed acetonitrile (120 ml) under nitrogen for 14 h.
Removal of solvent and plc of the mixture gave 1-[2-(2-phenylbenzimidazol-
4-yl)benzoyl]pyrrolidine (343 mg, 63%), m.p., 139-141°C (lit.,195
138-40°C) and 2-phenylbenzimidazole (4 mg, 1.1%).
152
c) Photolysis of Methyl 2-(5-phenyltetrazol-1-yl)benzoate (139).
The tetrazole (139) (1.00 g, 0.0036 mol) was photolysed in
dry, degassed acetonitrile, under nitrogen for 12 h. Column
chromatography gave tetrazole (139) (325 mg); methyl-2-phenylbenz-
imidazole-1-carboxylate (175 mg, 29%) which was identical with
an authentic specimen; methyl-2-phenylbenzimidazole-4-carboxylate
(250 mg, 41%) m.p., 125°C (lit.,195 127°C); 2-phenylbenzimidazole
(50 mg, 10%) .
153
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