Post on 14-May-2020
55
After characterizing the structures of nitroketones 19(a-f), we
used them to convert to their corresponding 2-acetyl and 2-benzoyl
indoles. Here the substrates 19(a-f) were treated with two equivalent
of triphenyl phosphine and heated at 180° in diphenyl ether. In each
of these reactions, the time required for the conversion was 8 hours.
The workup of reactions were carried out by initially distilling off
diphenyl ether and then the residue obtained was chromatographed
using appropriatate solvent system. Recrystallisation of the solid
obtained gave pure compounds whose structures were characterised
by comparison with the products obtained by one pot method i.e, IR
superimposability, co-TLC, also the similarity of the melting point.
The results with respect to yields obtained are given below.
Compound Yield (%)
20 (b-f)
b 52
c 42
d 48
e 52
f 44
Once we obtained 2-acetyl indole in sizeable amount, we
turned on to our plan described earlier (Scheme XXX),. We mixed 2-
acetyl indole with phosphorane 11 under variety of condition by
changing solvent from toluene, xylene to diphenyl ether, adding
benzoic acid as catalyst, it failed to deliver any results. We also tried
neat heating of the reactants but here too reaction failed to take
place. Even microwave condition failed to give the expected result.
56
1.5 Present work directed towards synthesis of
carbazole ring system
Since we failed to synthesize carbazole precursor to ellipticine,
we tried to attempt synthesis of carbazoquinocin (7a) from 2-acetyl
indole. Our plan for synthesizing carbazoquinocin was as follows
(Scheme. XXXXI).
CH 2-- CCX1t
r-CCCEt l
H
H
H CH 3
CH Carl
_)11 OCC:Et
H CII
C1-I
O ,0
aI
LAH
al 3
N H
ai 3
achora____000a
Here the first step was to react 2-acetyl indole with diethyl
succinate under Stobbe condensation. When we tried this reaction it
failed to give Stobbe product.
We tried to use Wittig-Horner reaction as it is known to give
better yield (Scheme MOM).
coo-{-0 I I
57
1,1(0EQ,P COOEt
II
Th∎1 C" K 2CO3 , DMF
H I I 0
COOEt CH,
SchemeXXXXlI
However, again we failed to get the product. So, it was thought
that may be exchangeable hydrogen on indole nitrogen may be
causing failure. So, it was decided to protect as it's benzylsulphonyl
amide. This attempt also did not yield any result. Further, work is
needed to be done particularly using Emmons reaction.
58
1.6 CONCLUSION
1) We were able to demonstrate that stable Wittig reagent could
be used for the synthesis of carbazole precursor to olivacine.
Thereby, it constitutes a formal synthesis of olivacine. However,
we could not extend it for the synthesis of ellipticine.
2) A convenient method for the synthesis of 2-acyl and
2-benzoyl indoles has been developed.
1.7 EXPERIMENTAL
Expt.1.1 Preparation of triphenyl-a-ethoxycarbonyl-
methylene phosphorane
C-D PPh3 + BrCH2COOEt
Ph3P—CH2COOEt
Br NaOH
A?____CHC 0 OEt
Expt.1.2 Preparation of carboethoxv-(a-ally1)-
methylidene triphenvl phosphorane (11)
Br
Ph3P_CHCOOEt Ph 3 P—CH
° Br COOEt
Ph 3P^C
N-COOEt
11
59
•
Expt.1.3 Preparation of 3-Formyl indole (10a)
DMF, POC13 4 j -/j4D I U
HN H
9a 10a
Expt.1.4 Preparation of ethyl-(2-allv1-3-(3'-1H-indoly1)
propeonate (12)
10a
12
Expt.1.5 Preparation of 2-ethoxycarbony1-
4-methirlcarbazole (13)
COOFt
10% Pd/C
Ph20
12
13
H
0 1
H
Ph 3P -\\ COOEt
/COOEt
N 11
60
Pd/C, Ph20, reflux
COOEt
COOEt )
H
13 10a
PhS02C1 0 I '
H
CH3
O2Ph
Ac20 anhy AlC13
0 SO2Ph
Expt.1.6 One pot preparation of 2-ethoxycarbony1-
4-methylearbazole (13)
H
Ph 31
0 1 1
Expt.1.7 Preparation of N-tosylindole (10b)
9a 10b
Expt.1.8 Preparation of N-tosyl-3-acetylindole (10d)
9b 10d
H
61
62
PPh3
dry benzene C I CH2C0 CH, Ph3P—CH2COCH3
(
C
CH3 0 + Ph3P_CHCOCH3 Me0H
\\ NO2
19a 17a 18a
Expt.1.9 Preparation of triphen.yl-a-acetyl
methylene phosphorane (18a)
NaOH
Ph 3 P CH CO CH 3
18a
Expt.1.10 Preparation of 4-(2'-nitropheny1)-
3-buten-2-one (19a)
Expt.1.11 Preparation of 2-acetyl indole (20a)
VT -3
0 2eq PPh3 ,
1'1120, reflux 0 NO2
H CH3
19a 20a
63
HO
NO2
, 0
H3
Ph3P=CHCOCFI3
2 eqPPh 3, Ph20
17a 20a
CHO
HNO3
CHO
0 NO NO2
Expt.1.12 One pot preparation of 2-acetyl indole (20a)
Expt.1.13 Preparation of 4,5-methylenedioxy-
2-nitrobenzaldehyde (17b)
17b
Expt.1.14 Preparation of 4,5-dimethoxy-
2-nitrobenzaldehyde (17c)
1 13C0 C HO CHO
HOY 2
17c
HNO3
64
Expt.1.15 One pot preparation of 2-acetyl-5,
6-methylenedioxy indole (20b)
0 / Ph3P=CHCOCH3 / -- , N 0
2eePhi Ph20 <, j I L„...... ., NO------- NO2 N. ...,,,------,, \----- ----/ P '.„.„,,..,,,,7"----,,,...
'0 N . H
CH3
17b
20b
Expt.1.16 One pot preparation of 2-acetyl-5,
6-dimethoxy indole (20c)
H3C0 CHO H3C0_,,,..,....,____,----,..
Ph3P=CHCOCH3 U 11 0 ---
2eqPPh3, Ph 20 H 3C0 NO2 H 3C0 ---.. - F.1 .--'' -
H CH 3
17c 20c
CI-I0
65
CH2Br
0 I I PPh 3
+ 0 2eqPP113, P1120
NO2
Expt.1.17 Preparation of bromoacetyl benzene/
bromoacetophenone
Expt.1.18 Preparation of triphenyl-a-benzoyl methylene
phosphorane (18b)
-cH2Br
) PPh3
NaOH
18b
Br2 glacial acetic acid
H
Expt.1.19 One pot preparation of 2-benzoyl indole (20d)
17a 18b 20d
66
O HO
I 2eqPPh 3. Ph
17b 18b
17c 18b 20f
20e
Expt.1.20 One pot preparation of 2-benzoyl-5,
6-methylenedioxy indole (20e)
Expt.1.21 One pot preparation of 2-benzoyl-5,
6-dimethoxy indole (20f)
0 ,,,C HO I I _,,, PPh 3 H3CO3., -------,, ,--------'---------- '-------.<---
_, (----) 2eciPPh3, Ph20 I
H3C0.--- '''''-"-------'-\ \ No 2 ''''\./..-- I-13C
Ph
Expt.1.22 Preparation of 4,5-methylenedioxy-
2-nitro-3-buten-2-one (19b)
0
'NO2
19b
CHO
0 Ph3P=CHCOCH MC011
N 'NO2
17b 18a
0
67
Me0H
CHO
Ph3P=CHCOCH3 `NO2
CH3
0 H3C0 \ NO2
17c 18a 19c
-Ph
'NNO2
+ Ph3PHCOPh
18b 19d
Expt. 1.25 Preparation of 3-(2'nitro-4',5'-methylene-
dioxy)-1-phenyl-2-propenone (19e)
17a
17b 18b 19e
Expt 1.23 Preparation of 4,5-dimethoxy-
2-nitro-3-buten-2-one (19c)
Expt. 1.24 Preparation of 3-(2'-nitrophenv1)-
1-phenyl-2-propenone (19d)
0 + Ph3PLICOPh
\O- NO 2
N
Me0H reflux
0 Hco
I (—)
HO \\ NO2
I 0 Ph3P_CHCOPh
1-10-- \No2
19f 17c 18b
19b 20b
NO2 N Ho)
0
2cciPPh3, Ph20 180 ° C
19c 20c
Expt. 1.26 Preparation of 3-12'-nitro-4',5'-dimethoxy)-
1-pheny1-2-one (19f)
Expt. 1.27 Preparation of 2-acetyl-5,6-methylenedioxy
indole (20b)
Expt. 1.28 Preparation of 2-acetyl-5,6-dimethoxy
indole (20c)
68
Expt. 1.29 Preparation of 2-benzoyl indole (20d)
0 I I
0 2eqPPh 3 , Ph20 180°C
19d
20d
Expt. 1.30 Preparation of 2-benzo54-5,6-methylenedioxy
indole (20e)
0
••— Ph 2eq1313113, Ph20
I 180°C 0
0
Ph
19e 20e
Ph
Expt.1.31 Preparation of 2-benzov1-5,6-dimethoxy
indole (20f)
H3C Ph
2eciPP113, Ph20 iI 1 -o 180°C
H3C0 - 11 NO2
19f 20f
Ph
69
70
Expt.1.1 Preparation of triphenyl-a-ethoxycarbonyl
methylene phosphorane
Addition of a solution of triphenyl phosphine (15.7g, 60mmol)
in dry benzene (30m1) to a solution of ethylbromoacetate (11.7g,
60mmol) in dry benzene (10m1) at room temperature, resulted in an
elevation in temperature to about 70°C and the precipitation of a salt.
After allowing the mixture to cool to room temperature, it was
vigorously shaken and left overnight. The separated solid was filtered,
washed with dry benzene and dried.
The stirred solution of the above salt in water (150m1) and
benzene (100m1) was neutralised by aqueous sodium hydroxide to a
phenolphthalein end point. The benzene layer was separated, dried
(anhy. Na2SO4) and concentrated to about 1/3rd volume. Addition of
n-hexane (40-60°) resulted in the separation of the crystalline
product which was filtered and dried to afford triphenyl-a-
ethoxycarbonylmethylene phosphorane (14.6g, 70%) m.p.125-126°C
(lit. 83m.p. 125-127°C).
Expt.1.2 Preparation of carboethoxy-(a-ally1)-
methylidene triphenyl phosphorane (11)
A mixture of allyl bromide (25m1) and carboethoxymethylene
triphenyl phosphorane (10g, 2.87mmol) was refluxed for 5 hours and
kept overnight. It was filtered and the solid obtained was washed with
dry ether. On recrystallisation from chloroform+pet.ether it furnished
salt (8.1g, 60%) m.p.150-151°C. The above salt was dissolved in
water (125m1) and benzene (100m1) was added to it. Phenolphthalein
(1 or 2 drops) was added to it. Sodium hydroxide solution (10N) was
added to it with stirring till the pink colour persisted. The benzene
layer was separated and the aqueous layer was extracted with
benzene (50m1). The combined benzene layer was dried
73
dichloromethane:n-hexane (1:9) furnished pure white crystals as
product 10b (1.4g,81.85%) m.p.75°C (lit. 57m.p.75-79°C).
Expt.1.8 Preparation of N-tosyl-3 -acetylindole (10d)
A stirred suspension of Aluminium chloride (0.83g, 6.2mmol) in
dry CH2C12(17m1) under pressure was slowly treated with acetic
anhydride (0.679m1, 6.6mmol). The solution was stirred at room
temperature for 0.25hr. and then treated with a solution of 1-phenyl
sulphonylindole (10b) (0.75g, 3.1mmol) in dry dichloromethane
(10m1). The mixture was stirred for 0.5hr. poured over crushed ice
(50g) and and extracted with dichloromethane (3x125m1). The
combined organic extracts were then washed with brine (250m1),
saturated aqueous sodium bicarbonate (250m1) & brine (250m1) dried
over potassium carbonate & concentrated in vacuum. The crude
product was recrystallised using methanol (0.434g,45°/0) m.p.153°C
(lit. 59m.p. 155°C)
Expt.1.9 Preparation of triphenyl-a-acetyl methylene
phosphorane (18a)
Addition of a solution of triphenylphosphine (14. lg, 50mmol) in
dry benzene (5m1) to a solution .of chloroacetone (5g, 50mmole) in dry
benzene (5m1) at room temperature. The reaction mixture was
vigorously shaken and left overnight. The separated solid was filtered,
washed with dry benzene and dried.
The stirred solution of the above salt in water (10m1) and
benzene (15m1) was neutralised by aq.sodium hydroxide to a
phenolphthalein end point. The benzene layer was separated, dried
over anhy.Na2SO4 & concentrated (to about 1/3 rd volume). Crystalline
product was obtained by addition of n-hexane, which was filtered &
74
dried to afford triphenyl-a-acetyl methylene phosphorane (3.32, 80%).
m.p.205 °C (lit. 80m.p.205-206 °C).
Expt.1-10 Preparation of 4-(2'-nitropheny1)-3-buten-2-
one (19a)
A mixture of 2-nitrobenzaldehyde (2.0g, 13.2mmol) and
phosphorane 18a (4.11g, 13mmol) in methanol (15m1) was refluxed
for two hours. Methanol was removed on water bath and the residue
was chromatographed over silicagel using ethylacetate:pet.ether (1:9)
as an eluent. Solid obtained was recrystallised using methanol, 19a
(2.02, 80%) m.p.54°C (lit.75m.p.56-57°C).
Expt.1 - 11 Preparation of 2 -acetyl indole (20a)
Compound 19a (1g, 5.2mmol) with triphenyl phosphine (3.01g,
11.5mmol) was heated in diphenylether (5m1) at 180°C for 2 hrs.
Chromatography over silica gel using ethyl acetate: pet.ether (3:7) as
eluent furnished solid, which was recrystallised using
dichloromethane:pet.ether (5:5) (0.474g, 57%) m.p.152°C (lit. 76m.p.
152°C).
Expt.1 - 12 One pot preparation of 2 -acetyl indole (20a)
Compound 17a (0.5g, 3.3mmol), phosphorane 18a (1.05g,
3.3mmol) and triphenyl phosphine (1.73g, 6.6mmol) was refluxed in
diphenylether (5m1) for 2 hrs. Diphenyl ether was distilled under
vacuum.' Chromatography over silica gel using ethyl acetate:pet.ether
(3:7) as eluent furnished solid, which was recrystallised using
dichloromethane:pet.ether (5:5) (0.247g, 48%) m.p.152°C (lit. 76m.p.
152°C)
75
Expt.1.13 Preparation of 4,5-methylenedioxy-2-nitro
benzaldehyde (17b)
4,5-methylenedioxybenzaldehyde (2.0g, 13mmol) was heated
with conc.nitric acid (15m1) at 60°C for about 15-20mins. time
duration. Then the reaction mixture was poured into crushed ice
pieces with constant stirring. Yellow coloured precipitate separated
out, which was filtered and recrystallised using ethyl alcohol (1.71g,
66%) m.p.90°C (lit. 77 m.p.880C).
Expt.1.14 Preparation of 4,5-dimethoxy - 2-
nitrobenzaldehyde (17c)
Followed the same procedure as expt.1.13, yield (1.75g, 69%),
rn.p.129°C (lit. 78m.p.128-133°C).
Expt.1.15 One pot preparation of 2-acety1-5,6-
methylenedioxy indole (20b)
Followed the same procedure as expt.1.12, yield (0.09g,
43.22%), m.p.170°C.
Expt.1.16 One pot preparation of 2-acety1-5,6-
dimethoxy indole (20c)
Followed the same procedure for preparation as expt.1.12, yield
(0.07g, 36%), m.p.148°C.
76
Expt.1.17 Preparation of bromoacetyl benzene/
bromoacetophenone
Bromine (1.95m1) was added dropwise to a stirred solution
containing acetophenone (7.5g, 60mmol) and a drop of 48%
hydrobromic acid in 50m1 of glacial acetic acid in an ice bath. The
rate of addition was adjusted so that the temperature never exceeds
20°C. After the addition , stirring was continued for 30 mins. at room
temperature.
Calculated lml of the solution was withdrawn and crystallised
by scratching with a glass rod, while the remaining solution was
cooled to 3-4°C. The seed crystals were added, whereupon phenacyl
bromide precipitated out of solution. The colourless crystals were
collected by filtration, washed several times with a total of 30m1 of
ethanol/water (1:1) and dried in vacuum. The yield was (5.9g,
47.44%) m.p.47°C (lit. 79m.p.47-48 °C).
Expt.1.18 Preparation of triphenyl-a-benzoyl
methylenephosphorane (18b)
Addition of a solution of triphenylphosphine (6.55g, 25mmol) in
dry benzene (5m1) to a solution of bromoacetophenone (5.0g, 25mmol)
in dry benzene (5m1) at room temperature. The reaction mixture was
vigorously shaken and left overnight. The separated solid was filtered,
washed with dry benzene and dried.
The stirred solution of the above salt in water (10m1) and
benzene (15m1) was neutralised by aq.sodium hydroxide to a
phenolphthalein end point. The benzene layer was separated, dried
over anhy.Na2SO4 & concentrated (to about 1/3rd volume). Crystalline
product was obtained by addition of n-hexane, which was filtered &
dried to afford triphenyl-a-benzoyl methylene phosphorane (4.5,
47.8%) m.p.181°C (lit. 80 m.p.181-182°C)
77
Expt.1.19 One pot preparation of 2-benzoyl indole
(20d)
Compound 17a (0.5g, 3.3mmol), phosphorane 18b (1.25g,
3.3mmol) and triphenyl phosphine (1.73g, 6.6mmol) was refluxed in
diphenylether (5m1) for 2 hrs. Diphenyl ether was distilled under
vacuum. Chromatography over silica gel using ethyl acetate:pet.ether
(3:7) as eluent furnished solid, which was recrystallised using
dichloromethane:pet.ether (5:5) (0.21g, 48.5%) m.p.147°C
151-152°C)
Expt.1.20 One pot preparation of 2-benzoy1-5,6-
methylenedioxy indole (20e)
Followed the same procedure as expt.1.19, yield (0.06g, 30%),
m.p.200°C.
Expt.1.21 One pot preparation of 2-benzoy1-5,6-
dimethoxy indole (20f).
Followed the same procedure as expt.1.19, yield (0.08g, 30%),
m.p. 180°C (lit. 81 m.p.176-178°C).
Expt.1.22 Preparation of 4,5-methylenedioxy-2-
nitro-3-buten-2-one (19b)
4,5-methylenedioxy-2-nitrobenzaldehyde (1.0g, 5.1mmol) was
refluxed with phosphorane 18a (1.63, 5.1mmol) in methanol (5m1) for
two hours. Solid separated on keeping overnight was filtered, washed
with little methanol & dried. Recrystallisation using methanol
furnished pure product 19b (1.04g, 86%) m.p.160°C.
78
Expt 1.23 Preparation of 4,5-dimethoxy-2-nitro-3-
buten-2-one (19c)
Followed the same procedure as expt.1.22, yield (1.0g, 84%),
m.p.168°C (lit. 82 m.p.172°C).
Expt. 1.24 Preparation of 3-(2'-nitropheny1)-1-pheny1-2-
propenone (19d)
Followed the same procedure as expt.1.22, using phosphorane
18b yield (2.25g, 67%), m.p.126 °C (lit." m.p.127-128 °C).
Expt. 1.25 Preparation of 3-(2'nitro-4',5'-
methylenedioxy)-1-pheny1-2-propenone
(19e)
Compound 17b (0.5g, 2.5mmol) was refluxed with phosphorane
18b (0.97g, 2.5mmol) in methanol (10m1) for 2 hours and kept
overnight. The solid separated was filtered and dried.
Recrystallisation using methanol gave pure product 19e (0.575g,
75.5%) m.p.154°C.
Expt. 1.26 Preparation of 3-(2'-nitro-4',5'-dimethoxy)-1-
pheny1-2-one (19f)
Followed the same procedure as Expt.1.25, yield (0.461g,
62%), m.p.180°C (lit. 81 m.p.182-183°C).
•
79
Expt. 1.27 Preparation of 2-acety1-5,6-
methylenedioxy indole (20b)
Compound 19b (0.5g, 2.1mmol) was heated with triphenyl
phosphine (1.22g, 4.6 mmol) in diphenyl ether (5m1) at 180°C for 8
hours. The reaction mixture on cooling was chromatographed using
ethylacetate:pet.ether (3:7) as eluent furnished product 20b (0.224g,
52%) m.p.170°C.
Expt. 1.28 Preparation of 2-acetyl-5,6-dimethoxy
indole (20c)
Followed the same procedure as Expt. 1.27, yield (0.183g, 42%),
m.p.148 °C.
Expt. 1.29 Preparation of 2-benzoyl indole (20d)
Followed the same procedure as Expt. 1.27, yield (0.170g,
48.5%), m.p.1470C (lit." m.p.151-152 °C).
Expt. 1.30 Preparation of 2-benzoy1-5,6-
methylenedioxy indole (20e)
Followed the same procedure as expt.1.27, yield (0.095g,
52.40%), m.p.200°C.
Expt. 1.31 Preparation of 2-benzoy1-5,6-dimethoxy
indole (20f)
Followed the same procedure as expt.1.27, yield (0.08g, 44.5%),
m.p.181°C.
80
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CHAPTER - II
87
SYNTHETIC STUDIES IN ISOXAZOLES
2.1 Introduction
Isoxazoles 1 (11, represent an important class of oxygen
heterocycles. It has potent biological activity. Isoxazoles have been
used for the synthesis of intermediates of various natural products.
They act as building blocks for construction of new molecular
systems2 .
RZ
O
N
12)
1
Various isoxazole derivatives are known to exhibit diverse
biological activity. Among these, ABT-418 3 (2), (S)-3- methyl-5- (1-
methyl-2- pyrrolidinyl) isoxazole represents a new class of isoxazole
acting as cholinergic channel activators. Such an activator has been
evaluated as a safe and effective treatment for Alzheimer's disease,
related personality changes and memory loss. Similarly, isoxazole
derivative (3), is an antihypertensive sulphonamide 4 . Isoxazole
carboxamides 5 and 4-benzoyl isoxazoles 6a,6b both act as herbicides for
controlling the growth of weeds.
Me \ /me
88
SO2NH
OWN
N H
Me, N
2 3
Monoamine oxidase inhibitor, a-S, 5S-a-Amino-3-chloro-4,5-
dihydro-5-isoxazole acetic acid is found to induce differentiation in
tumour cells'. Isoxazole compounds have also been used as
agrochemicals and fungicides 8 . Carbiniloyl isoxazole is an effective
antiinflammatory agent 9a. 3-aryl-5-alkyl isoxazole-4-carboxylic acid
derivatives are known to act as endoparasiticides 9b. Isoxazole
derivatives like 2-(3-arylisoxazol-5-yl) benzoic acid (4) have attracted
pharmaceutical & agricultural industriesm. They also find use as
herbicidal and plant growth regulator. Muscimol (5) has powerful
psychotropic effects due to it's activity in brain nerve cells "a. They
also find use in pharmaceuticals, agrochemicals, semiconductors and
polymersllb. Compound ma (6), an isoxazole fused derivative is a
potential analgesics while 5-substituted -4-isoxazole acetic acids are
also known to exhibit analgesic activity 12b. 3-Methyl-5-pyridinyl
isoxazole is an agent for lowering blood sugar levels 13 . 0
[ 0 H3NH2C
5
Or
H2N •
89
Other uses of isoxazole derivatives lies as improved
fluorescent probes for studying natural and synthetic lipid
membranes and related areas'''.
4
.
CH2OH
CHO
TFA-CH2C12 0
N H I H 37% (CH20) aq,
88% HCOOH Reflux
Scheme I
90
2.2 Synthesis of ABT-418
As mentioned above various isoxazole derivatives possess
diverse biological activities. We were attracted by ABT-418 (2), a novel
cholinergic agent. So far three syntheses of this compound have been
reported in literature. The first synthesis involves the original route
shown in Scheme I, Wherein eight steps are used for the
transformation from L-proline. The important step in this route
involves construction of isoxazole moiety via a [3+2] nitrile oxide
dipolar cycloaddition3a.
91
R.L. Elliot & coworkers 3b have successfully reported a second
approach (Scheme II) involving four steps starting from L-proline.
Here the main step is the addition of dianion of acetoneoxime to N-
methyl-methyl ester of L-proline.
The third approach by S.J. Wittenberger synthesizes 3c ABT-418
from L-proline in six steps as depicted in Scheme III. In this route the
conversion to the final molecule is afforded by treatment of methyl
enamino ketone' (b) with hydroxylamine hydrochloride to
regioselectively produce the ketoxime. The final step involves
cyclodehydration of this ketoxime by adding aqueous sulphuric acid
and on gentle heating.
92
All three approaches requires strongly basic conditions, for
example for the formation of acetylene, n-BuLi is used in the first
approach, while in the second and third approach lithium dianion of
acetoneoxime and sodioacetonitrile respectively is required. Use of
such highly basic conditions may lead to racemisation during large
scale synthesis. Also in the second and third approach reaction of
condensation of the proline ester has to be done carefully as the
product formed is a ketofunction which is more reactive than the
starting ester function for a nucleophile attack. In view of this, we
thought of devising a milder approach.
93
Our retrosynthetic analyses of ABT-418 is depicted in
Scheme IV
The first step in the approach was to prepare a,f3-unsaturated
ketone or the corresponding oxime from protected or N-methyl
prolinal. This would have been possible by a reaction between
phosphorane and the carbonyl group of the prolinal. The last step
required oxidative addition of the oxime to lead to isoxazole directly.
So, it was necessary to know the literature methods utilised for
the synthesis of isoxazoles to check whether such an approach is
reported for the synthesis of isoxazole.
94
2.3 Synthesis of Isoxazoles
Kochetkov and SokulovIs in their review in 1963 have reported
various routes towards synthesis of isoxazoles. The isoxazole ring has
3 carbon atoms, one oxygen and one nitrogen in its five membered
structure. Accordingly the synthetic routes towards isoxazoles may be
classified (given below) i.e according to the number of isoxazole ring
atoms in each component system. Presently various developments
have been made in the synthesis.
A] (3+2) routes [C-C-C + N-0] & [C-N-0 + C-C]
B] (4+1) routes [C-C-C-N + 0], [C-C-N-O + C] &
[C-C-C-O + N]
C] (3+1+1) route
D] (2+2+ 1) route
E] (5+0) routes [C-C-C-N-O]
Route A
This route involves three carbon atoms added to NO unit.
Usually 1,3-dicarbonyl system i.e 1,3-diketone or ketoaldehyde form
the CCC unit. Sometimes 13-substituted vinylketones, a, 13-acetylenic
ketones are also used. The NO unit is always hydroxylamine. Another
combination is carbon, nitrogen, & oxygen unit joined to C-C unit.
Here CCC unit forms a part of the ring with attack by
hydroxylamine leading to a labile acyclic intermediate which
recyclises to form an isoxazole. The most useful method for the
preparation of isoxazoles is the cyclocondensation of easily available
materials 1,3-diketones with hydrox-ylamine 16 (Scheme V).
95
0 0 z /R I
H2 NOII R'
/ 0 R 2
0 I I_
— Thz
Scheme V
It's limitation lies in the fact that it lacks real control over the
regioselectivity. Kamhiko Mizuno & coworkerslla have reported a
method wherein NO is inserted into cyclopropane ring using two
moles of nitrosonium salt NOBH4. This methodology is also shown for
use of 1,2-diaryl cyclopropane for the synthesis of 3,5-
diarylisoxazoles. Recently, Saginova et allib have reported such
reaction using sodium nitrite in trifluoroacetic acid (Scheme VI).
/Arl
2 NOBH4 ,CH3CN
N
OR NaNO2 / CF3C001-1 Ar e
Scheme VI
Isoxazole has also been synthesized by replacing
hydroxylamine with dinitrogentrioxide & reacting it with a, 13-
unsaturated ketones's (Scheme VII).
96
HCOAr2
Art—CH=CH—C—Ar 2
N203
All— CH-- NO)2
Pseudonitrosit es /\„ , cyclisation
NO2 Ar2
/L .o„N
Scheme VII
J.B. Carr & coworkers 19 have reported a method wherein
oximation of 1,3-diketone followed by cyclisation on heating in
presence of acetyl chloride furnishes isoxazole in 67% yield (Scheme
VIII).
F3C-,,,,,
ArCO CH2—CO—CF3 H2NOH N
N H
;>,----Ar \
OH '
ICH3COC1,
/ __CFI -
Ir N
Ar 67%
Scheme VIII
(3-ketoaldehyde on treatment with hydroxylamine in presence of
sodium acetate buffer has been reported to give 3 & 5
monosubstituted isoxazoles 2° (Scheme IX).
O
97
R C CH, CHO H2NOHHCI
NaOAc buffer
O
0 R
Scheme IX
Elnagdi & coworkers 21 have carried out cyclisation of
arylhydrazone in presence of varied basic conditions (Scheme X).
N=N-Ar NH, CN
ArNHN=C—COR
NH2NAor-NH=N\N,
H2 NOH
R/oN
-•Na0Ac NaOMe
H2 N
Scheme X
An intramolecular cycloaddition has been reported wherein
propagryl ether is constrained to give 4-substituted isoxazole 22
(Scheme XI).
n ,C NO
Scheme XI
i t Ar-C-NOH
Et3N. ether
0
COOH 0
0
98
Nitrile oxides are known to react with appropriate alkynes
giving 5-substituted, 4-acyl-5-substituted 23, and 4 & 5 substituted
isoxazoles24. Various substituted alkene aromatic systems have been
reported to be used for the synthesis of isoxazoles by reacting with
nitrile oxides25 (Scheme XII).
R-CNO + R'—CH=CHX —HX
IN
(R')11
Scheme XII
A route consisting of 1,3-dipolar cycloaddition of aromatic
nitrile oxides to 3-methylnaphthalide have also been reportedloa
(Scheme XIII).
Scheme XIII
Recently E. Dominguez et al have reported a novel synthesis of
4,5-diarylisoxazoles 2a (Scheme XIV).
99
Are Me 2N
NH LOH --- 0
Ar' Ar, // 0
HOB
NC
Arj
Arl
Scheme XIV
Route B
This involves CCNO unit joining another C unit. Nitrosyl
chloride addition compounds have been subjected to nucleophilic
attack. M. Dines & coworker have reported use of cyano anion as
nucleophile for the synthesis of isoxazoles 26 (Scheme XV).
Me /Me
Me CH___ cume NOC I Me CH— CH Me CN
NO CI / 0 NH2
>80%
Scheme XV
P. Bravo and C. Ticozzi 27 have employed dimethyl sulphide of
acetophenone as attacking agent for the same purpose (Scheme XVI)
also use of dimethyl sulphoxide of toluene has been reported as a
nucleophile28 (Scheme XVII).
12 1 CH CI
NO R2
ArCOCHSMc2
ArCO
N, I 1'
47-74%
Scheme XVI
Ar\
e e Ar CH C Ph ArCHSOMe2 I 11
/0" Ar"
31%
Scheme XVII
Demina et a129 have reported a method wherein 3,5-
diarylisoxazoles have been synthesized using nitroacetophenone
oxime and benzaldehyde in the presence of base (Scheme XVIII).
Ph—C—CH2NO2
NOFI
ArC1-10 base
Xylene, reflux
HON=C—C=CFIAr
NO2
-N 0"-
A/
Scheme XVIII
Acetophenone oxime on treatment with 2 equivalents n-BuLi,
followed by treatment with cyanobenzene (benzonitrile) has been
reported to give 3,5-diarylisoxazoles 30 , while a-substituted lithium
dianion of acetophenone oxime with esters or amides gives 3,4,5-
trisubstituted isoxazoles 31 (Scheme XIX).
100
/ Ph
NO
N
101
R 2
1) R 3 COX
2) H3&
R' R2
(30-87%)
Scheme XIX
Synthesis involving [CCCO + NI addition has also been employed 32
(Scheme XX).
.1i
COAT
HN3 (-N2)
Ar-/
45-76%
Scheme XX
Route C
The route involving (3+ 1+ 1) pathway has been less
established 33. The former involves condensation of nitro compounds
in presence of base.
Several routes involving ring transformations of other
heterocyclic compounds to isoxazoles have been reported. Although
theoretically several transformations involving oxazoles,
acylaziridines etc. have been reported, practically their use -is not
established.
Well known among them is the ring contraction of condensed
4-pyrones in the synthesis of steroidal isoxazoles 34,35 . As isoxazolines
are known to give isoxazoles, routes involving ring transformations to
isoxazolines are known such as ring expansion of oxiranes 36 and
oxetanones 37 , ring contraction of pyridinium salts, pyrimidinium-N-
/- R Ph Pd Complex Na0Ph"
Ph—CH==C Pb(OAc)4s6
- 57
12, KI/NaHCO3 58
TPCD
102
oxides, pyrilium salts38 , ketonylidinepyrans 39 , chromones,
thiochromones, chromylium salts40-46 and oxazinones47 .
Photoisomerisation of pyridazine dioxides". Other ring
transformations include of pyrrolenines 49 , furans80 , dithioles51 ,
oxaphosphazoles 52 , benzotriazepines 53 .
Route D
There seems to be no reports involving this route.
Route E
The last route that is described is of (5+0) synthesis. Such
reactions involve cyclisation of synthons containing all five ring
atoms, usually in the sequence C-C-C-N-O. Such a route provides
regiospecificity to great extent. All reactions must involve at some
stage cyclisation of a isoxazole ring. Most common is conversion
involving a,(3-unsaturated oximes. Hansen & Strong 54 have reported
a method using N-Bromosuccinimide, While Maeda et a1 88 have used
palladium complexes for the synthesis of 3,5-diaryl isoxazoles in 80-
90% yield. Similarly, lead tetracetate 56 and iodine/sodium
bicarbonate57 have also been used. The former synthesizes 3,5- diary'
isoxazoles in low yields, while the latter is mostly used for the
synthesis of aliphatic isoxazoles. Recently, X: Wei. et a1 88 have
reported the synthesis using TPCD [tetrakis(pyridine)lcobalt(II)
dichromate, where alongwith required product some starting
chalcones are also recovered. The schemes for the above have been
depicted below (Scheme XXI).
NB S"
Scheme XXI
103
Electrochemical reduction of nitroalkene systems has been reported
to give 3,4,5- trisubstituted isoxazoles 59 ( Scheme XXII).
ph Ph
Electrochemi cal Redn 02N--C=C—CN HON--C---CI I CN
R R
Ph R
1 1
H2 NZ '---0
Scheme XXII
Many nitro group containing substrates like a,(3-unsaturated
diesters60 (Scheme XXIII), ketones 6 ' (Scheme XXIV) are known to
give 3,5-disubstituted isoxazoles under acidic conditions.
R
Me02 C—C1,1-1—C—CI I CO2Me
NO2
CONHBun
Scheme XXIII
R—00 CH2-. — NO2
Ar
Scheme XXIV
Michael addition of alkene oxime to propargyl nitrile followed
by hydrolysis has been reported to give 3-amino isoxazole 62 (Scheme
XXV).
/X
FIX
104
H
H2 C—N CN
/NH2
H20
Scheme XXV
Dioximino compounds also yields isoxazoles63 ( Scheme XXVI).
CI
HO- NH—C—C.----CH—CONHOH 0
OH
II N
HONHCO/
Scheme XXVI
Cyclisations reactions play an important role in the synthesis
of the 3,5- disubstituted isoxazoles. 13- Keto oximes under sulphuric
acid conditions and in 'ethanolic HC1 yield isoxazoles 64 (Scheme
XXVII).
I N
H2SO4
EtOH HCI
Scheme XXVII
The above reactions involve CCCNO synthons with one NOCCC
synthon. Examples of OCCCN cyclisations are also rare.
105
2.4 Present work
Careful examination of literature methods revealed that there
are only five methods using the approach (5+0) via a,I3- unsaturated
oxime. Most of these methods are used for the synthesis of 3,5-
diarylisoxazoles. LTA method has reported low yields (24-28%),
alongwith recovery of starting chalcones. Similarly, the method using
TPCD complex could not rule the possibility of formation of the
starting ketone back in the reaction mixture.
Dichlorodicyanoquinone (DDQ) is a well known oxidising
reagent mainly used for aromatisation 65 . Two reports are available for
the oxidative cyclisation of o-hydroxy chalcone to chromone 66 and 3-
o-hydroxy phenyl coumarins to coumestan 67 . We thought of using
this reagent for oxidative cyclisation of chalcone oximes. Initially, we
thought of synthesizing 3,5-diarylisoxazoles, as mentioned earlier
that, we were attracted towards ABT-418, which is a 3,5-
disubstituted isoxazole. Also 2-(3-aryl-isoxazol-5-y1) benzoic acid
derivatives have interesting biological activities Ma .
Thus, we decided to test the use of DDQ on chalcone oxime
(Scheme XXVIII), which was easily available by Claisen-Schmidt
condensation68 between benzaldehyde and acetophenone followed by
treatment with hydroxylamine hydrochloride in presence of a weak
base. The chalcone oxime was prepared by the known literature
method69.
106
Compound(7-9) R R 1
a b c d e
H OCH20 H OCH3 OCH2O
H H OCH3 OCH3 OCH3
The chalcone oxime obtained was stirred in methanol with two
eq. of DDQ at room temperature. After 2 hours tic indicated absence
of the starting chalcone oxime, while two new spots were observed.
One of them could be corresponding to isoxazole 9a and the other
could be. dichlorodicyanohydroquinone. The solvent methanol, was
removed at the pump and the residue was chromatographed on silica
gel. Initial fractions gave a solid , which on recrystallisation melted at
140°C. In it's IR spectrum it showed absence of a peak between
3000-3500 cm-1 indicating that oxime function is absent in the
product obtained. Also absence of a peak in the carbonyl region
107
indicated that there is no recovery of the chalcone in the reaction. In
it's PMR (CDC13) [Fig.2A] it showed a singlet at 6.84 8 for one proton
which could be attributed to C-4 hydrogen of isoxazole nucleus. In
the aromatic region a multiplet was seen between 7.2-7.98 integrating
for ten protons which could be assigned to the ten hydrogens of the
two phenyl groups at 3 & 5 positions. Thus, on the mode of formation
and spectral data structure 9a was assigned to the compound. This
was further supported by the similarity of it's melting point 140°C
with the lit. 56,70 m.p.141-142°C. The yield of the product was found to
be 75%.
0
SGT-96-33 OBSERVE HI FREQUENCY 399.951 MHz SPECTRAL VIDTH S088.0 Hz ACQUISITION TIME 3.744 sec RELAXATION DELAY 1.000 sec PULSE VIM 3.8 usec AMBIENT TEMPERATURE NO. REPETITIONS 32 DOUBLE PRECISION ACQUISITION DATA PROCESSING FT SIZE 65536 TOTAL ACQUISITION TIME 2 smut s
Nov 2 96 Virginia Tech SIC NOR Facility
•
I ' I T ,
a 6 S 4 2 PP.
33.26 -0.02 -0.68 4.59 108.50 7.41 12.73 0.42
Fig. 2 A
109
After the successful synthesis of parent 3,5-diphenyl isoxazole,
we thought of checking the generality of this reaction. Initially, we
thought of testing it for few substituted diaryl isoxazoles.
Acetophenone was then condensed with pipernal. The product
obtained showed carbonyl peak at 1665cm -1 in it's IR spectrum. It's
m.p.120°C was closely matching with lit. 71 m.p.122°C. The structure
7b was suggested. The chalcone 7b was then treated with
hydroxylamine using the usual conditions to obtain the oxime, which
melted at 140°C and also showed presence of a band in the hydroxyl
region at 3300 cm -, in it's IR spectrum. Based on it's mode of
formation and spectral [Fig.2B) data structure 8b was assigned to the
oxime.
OR
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.... _ .... , i •
_ • -
4
i• 1 . 111I.11‘ 1. 11 1
9 8
6 5 4
Fig. 2 B
. ! ... .. ...... ..... ....
....... .. ................................... ... ... .. .. .. . . 17 ..... 7
.... . ;.: . . ..... ... . . • . . .....
0
1.
.. .. . .
. ... .. .... ... ... .
. . . ;: ......
........
...... ... . i" _ . .
•• • „__
... . y ..
._-• .... . . . ...... .. .. ..... ......... . • ••--... ......... ' . .. .....
.1 ... ; . ..•
......... .... ............. ' ...... ........ ............. . • .. . • . ..... - . .. .......... . .. .. . . .
'1" . ............
3 2 ppm
•
111
This oxime was then stirred with two eq. DDQ in methanol and
kept overnight (monitored by tic). Chromatographic separation on
silica gel gave a compound which has following spectral data.
IR (KBr) : v. 1250 cm -1
PMR (CDC13) :
(6 )
6.048 C/) V
)
2H -OCH20-
6.69 1H C4-H
7.2-7.48 8H Ar-H
The mode of formation, spectral data & similarity of it's m.p.
120°C with the lit. 72 m.p.122-123°C attributed structure 913 for this
compound. The yield was found to be 72%.
p-Methoxy acetophenone was then similarly, condensed with
benzaldehyde and subjected to oxime formation . Structures for both
these compounds obtained were attributed based on it's mode of
formation, IR and comparison with the lit. 73,74 m.p.
Structure IR(KBr) v. m.p.
7c 1650 cm- ' 100°C (102°C)
8c 3280 cm-1 138°C (140°C)
The oxime 8c was then treated with 2 eq. DDQ in methanol.
The reaction was stirred overnight as the reaction reached to
completion (monitored by tic). The residue obtained after evaporation
of methanol was column chromatographed on silica gel. The initial
fractions gave a solid. The IR and PMR spectral data (given below)
[Fig.2C] suggested structure 9c for this compound.
•
SCT-97-39 OBSERVE HI FREQUENCY 399.951 MHz SPECTRAL. UIDTH 5000.0 Hz ACQUISITION TIME 3.744 sec RELAXATION DELAY 1.000 00C PULSE UIDTH 3.4 usec AMBIENT TEMPERATURE ND. REPETITIONS 24 DOUBLE PRECISION ACOVISITIDt DATA PROCESSING FT SIZE 65536 TOTAL AGOUISITION TIME 1 tes Soy 9 97 VLrginle Tech ETC NOR Fest' t6
I ' 1 — , 7 •. - r—,
B.0
7.5 7.0 6.5
6.0 5.5 5.0
4.5
1.0
PP.
36.34 128.77
26.63 12.12
2.33 3.08 Fig. 2 C
36.25
113
IR (KBr) : v. 1250 cm -1
PMR (CDC13) :
(8)
3.87
6.78
s
s
3H
1H
OCH3
C4-H
6.86 d(6.3 Hz) 1H Ar-H
7.00 d(6.3 Hz) 1H Ar-H
7.2-7.8 m 7H Ar-H
The structure was further confirmed by it's m.p.120°C, which
closely matched with the lit. 75 m.p.120°C. The yield of the product
was found to be 74%.
p-Methoxy acetophenone was then condensed with
anisaldehyde to get the corresponding chalcone 7d. The structure of
this chalcone showed in it's IR spectrum a peak at 1660 cm -1 for a,(3-
unsaturated ketone and similarity of it's melting point 100°C to it's
lit. 76 m.p.101-102°C, further confirmed it's structure to be 7d . This
chalcone was then subjected to usual oxime formation, the structure
of it was again suggested by a peak at 3150 cm -1 in it's IR spectrum
for =N-OH function and it's m.p.130°C matching with that of he
literature 74 m.p.132°C. This chalcone oxime 8d was then treated with
two eq of DDQ in methanol. The product obtained from this reaction
was recrystallised. The mode of formation, it's melting point matching
with lit. 17a m.p. and the spectral data given below suggested structure
9d for this compound.
Melting point: 140°C ( lit.17am.p141-142°C).
3.85
5.97
3H
2H
OCH3
OCH2O
6.67 d(J=16.6 Hz) 1H C2-H
6.7-6.9 m 4H Ar-H
7.4 m 3H Ar-H
7.51 d(J=16.6 Hz) 1H Ar-H
2.31 bs 1H OH
(exchangeable with D20)
114
IR (KBr): vinax 1510, 1250 cm -1
PMR(CDC13) :
( 6 )
3.86 s 6H 2 xOCH3
6.65 s 1H C4-H
6.99 d(J=6.6 Hz) 4H Ar-H
7.75-7.8 m 4H Ar-H
Yield was found to be 64%.
Similarly, p-methoxy acetophenone was condensed with
pipernal to get the corresponding chalcone. It melted at 130°C (lit. 76
m.p.131°C). In it's IR spectrum it showed a band at 1660 cm-, in the
carbonyl region for a,13- unsaturated carbonyl and 1250 cm -1 in 0-C
region. The chalcone 7e was then subjected to treatment with
hydroxylamine hydrochloride under the usual conditions. The
product obtained had melting point of 180°C. It's spectral properties
(shown below) indicated structure 8e for this compound.
IR (KBr) : vin. 3250 cm - ' , 1250 cm-1
PMR (CDC13), [Fig.21)]
(6 )
.....
... ... 7. 7. 7117. 7. ............................ ... . ... ...... . . .. .
.. . .....
.............. ........ .
. . ... . ..
. .... . .... ...... .. .
.... ......... .. . ... . . ... . HI . .. . ............ ... .
• ..
...... ..... '
..... „ . ..... . • • .
C
N C
EN
TR
E
UM
EN
TA
T
I
,, .. .... . . ... .... ... . : . .....
..... ...
. ...... .. ....... . .. ..
.. ... ..............
. I
. .. ...
....... . . . ................ ........... . .............. . ..... ...... .. . . .. . ....
. ....
....... . ... . : .... ... . ....... ............. .. ................ .........
....... .......... . ......... ............ ..
....... ... ..... . "
......... ......
.... ......
— . . .......
. ... .. .......................... . . .. _ ...... . .......
▪ . ..
........ .. •
...
▪ .............
;' ......... . . •
..... . . . , ...
. ..... • • • • •• ■ • .. : . . : .. ....
..... ............ • •
. . ...
....... .. ..
, .......... . . „ . „.: ...... . . .. . .... . .. . . ....... : .. ................
;""' . . : . ..... ...... . . .. ......
. : .. ..... .... . ......... ... ..... .. .......
- _ "' .... ...... ...... ..
..... - ..... ... — - ..
cn .
-
..
. . . . . ....................
. ... .. E.:7E
..... ......... .........
... .... ..
I..... •
...
....... : .
.. . ..
.... .. .!., . . ......
.. .. ....... ......
..... . .. 0
C
... . ... . .. ...
.... ".: ....... .. ...............
..........
... ... .... „ .. ...... ; . ..
. .... ............... .. .
. . .
• ..... ... 2: ;: . .... -
. . .
. . : ..
a 6 5 4
JI
7.
...
Fig. 2 D
-HCa---C—OCH3
0 N
1 .-,--, 1 I
,,-- -„:: __...- - / (---- /\
m/z= 239
iN \̂ 6-
-0-CH3
m/z= 149 e
116
The oxime was then stirred with 2 eq. of DDQ in methanol for
two hours (monitored by tic). Usual workup provided a solid melting
at 152°C. It's analysis suggests C17H13N04 as it's molecular formula.
The mode of formation, analysis and spectral data (given below)
suggested structure 9e for this compound.
IR (KBr) : vi-na. 1619 cm -1 , 1514 cm -1 , 1450 cm-1 , 1269 cm-1 ,
1058 cm -1 , 813 cm-1
Mass m/z :149(100), 239, 280(4), 295 (M+, 52)
0 N 1 1
n I 1 0
\o„------- ."------- ''' '- -'0+. I \----/
miz= 280 4 -di,
0 NII
r
M+= 295
117
PMR (CDC13) [Fig.2E]
(8)
3.86 s 3H OCH3
6.04 s 2H OCH2O
6.63 s 1H C4-H
6.88 d(9 Hz) 2H Ar-H
6.99 d(9 Hz) 2H Ar-H
7.26-7.78 m 3H Ar-H
13CMR : 55.43, 77.10, 96.39, 101.68, 106.23, 108.88, 114.37,
120.52, 121.74, 121.80, 128.25, 148.3, 149.30, 161.06, 162.64,
169.64.
The yield was found to be 76%.
8. 8
7.5 7.0
26.69 134.61
•
SGT-97-38 OBSERVE Hi FREOUENCY 399.951 MHz SPECTRAL UIDIN 5888.0 No ACQUISITION TIME 3.744 eec RELAXATION DELAY 1.880 sec PULSE UIDTH 3.4 vaec AMBIENT TEMPERATURE NO. REPETITIONS 48 DOUBLE PRECISION ACQUISITION DATA PROCESSING FT SIZE 65536
TOTAL ACQUISITION TIME 3 minutes Sep 9 97 Ulrylnle Tech SIC OMR FecIlay
6.5 5.5 5.0 4.5 4.0 3.5 PPP
$
0.24 30.20
0.49
45.06 0.03 0.37 -0.16 A.40
Fi_ . 2 E 0,e
119
After synthesizing five 3,5-diarylisoxazoles, we thought of
checking the generality of this reaction by changing the substituent
at 3 &5 positions, as we needed to synthesize ABT-418 which is also
a 3,5- disubstituted isoxazole. Initially, we opted for preparation of 3-
pheny1-5-styrylisoxazole. For this, we required cinnamaldehyde as
starting compound. Thus, cinnamaldehyde was condensed with
acetophenone to give the corresponding chalcone 7f , the structure
was assigned based on ifs IR spectrum, which showed a band at
1660 cm-1 for carbonyl group of unsaturated ketone and also it's
similarity of melting point 102°C with the lit. 77m.p.103-105°C. This
was then treated with hydroxylamine to obtain a solid, which melted
at 133°C (lit. 78m.p.135°C). In its IR spectrum it showed a band at
3400 cm- lfor the hydroxyl group of the oxime formed. This oxime 8f
obtained was then stirred in methanol with 2 eq. of DDQ for two
hours. Usual workup of the reaction mixture gave a solid. The
spectral data (given below) of this solid indicated that it may be
3-phenyl-5-styryl isoxazole 9f.
IR(KBr) : vmax 1400 cm-,
PMR (CDC13), [Fig.2F]
( 6)
6.58 s 1H C4-H
6.76 d(16 Hz) 1H CH
7.01 d(16 Hz) 1H CH
7.1-8.0 m 10H Ar-H
It's melting point 130°C, matched with the lit. 79m.p.132°C. The
yield of the product was found to be 70%.The mode of formation,
spectral data & similarity of m.p. with literature m.p. suggested
structure 9f for the compound.
rotes
tg
SGT-97-4I OBSERVE HI FREOUENCV 399.951 MHz SPECTRAL UIDTH 5000.0 Hz
• ACOUISITION TIME 3.744 sec RELAXATION DELAY 1.000 sec PULSE UIDTH 3.4 usec AMBIENT TEMPERATURE NO. REPETITIONS 24 DDUBLE PRECISION ACOUISITIO DATA PROCESSING FT SIZE 65536 TOTAL ACQUISITION TIME mi Sep 9 97 Virginia Tech STC NMR F cll
8 6 • I
S
4 3 2 • I PP",
15.55
3.12 3.15
2.99 0.59 -e. 12
2.41 126.58
5.20
3.07 0.83 2.04
7.23
Fig. 2 F
121
We then prepared cinnamaldehyde oxime as per literature
procedure80 . This when subjected to 2 eq. Of DDQ in methanol and
stirring for 4 hours indicated absence of starting compound
(monitored by tic). Column chromatography over silica gel did not
result in isolation of any pure compound.
Similarly, we thought of synthesizing 3-methyl-5-phenyl
isoxazole from the corresponding oxime which was prepared by
literature procedure 81 . In this case also under variety of conditions,
we failed to get the product. We also prepared the oxime of 13-ionone
as per literature procedure 32 . In this case the reaction did not take
place at any time and we always recovered the starting oxime.
Thus, we realised that, there is a limitation to the present
method of oxidative cyclisation of a,I3- unsaturated oxime using DDQ
and the requirement is that two aryl groups must be present at 3 & 5
positions.
122
2.5 Present work towards synthesis of ABT-418
We had simultaneously started our work on the synthesis of
isoxazole ABT-4 18. As per our retrosynthetic analysis depicted in
(Scheme IV), we thought of preparing N-methyl prolinal and then
condensing it with a stable phosphorane to get an a,f3- unsaturated
oxime and cyclise the oxime as per any of the literature 54-58 method
(Scheme XXIX).
123
Thus, L-proline was treated with ethylchloroformate under
basic conditions to get N-carboethoxy prolinol. The structure of it was
suggested by the mode of formation, spectral data (given below) and
similarity of it's melting point with lit. 83 m.p. The yield obtained was
95%.
IR : vmax 3420, 1740, 1675 cm -1
PMR: (CDC13), [Fig.2G]
(5 )
1.19-1.34
1.9 -2.24
3.38-4.22
4.31-4.4
m
m
m
m
3H
4H
2H
3H
COOCH2CH3
CH2-CH2
N-CH2
CH &
COOCH2CH3
COOH 4.92 bs
(exchangea
1H
ble with D20)
125
N-carboethoxy proline was then treated with excess of lithium
aluminium hydride in ether at room temperature for
3 hours (monitored by tic). Usual work up gave a liquid. It's IR and
PMR spectral data is given below.
IR : Vmax 3400 cm -1
PMR : (CDCI3)
(8 )
1.66-1.95
2.11-2.4
m
m
4H
5H
CH2CH2
N-CHs, CH2
3.0-3.1 m 1H CH
3.43 dd(2.56 Hz) 1H CH-OH
3.65 dd(3.6 Hz) 1H CH-OH
The yield of the product obtained was 61%.
The above spectral data and the mode of formation suggested
structure of the compound to be N- methyl prolinol.
N- methyl prolinol was then subjected to PCC oxidation by
stirring at room temperature in dichloromethane. TLC indicated
consumption of the starting compound after 24 hours. After usual
workup, we were not able to obtain the corresponding aldehyde. So,
we thought of using PDC as oxidizing agent as PCC is slightly acidic
in nature and also in literature PDC has been used for synthesis of a-
amino aldehydes from its corresponding alcohol 84 . Thus N-methyl
prolinol was stirred in dichloromethane with PDC for 24 hours. TLC
indicated completion of the reaction as it showed absence of the
starting material but, again we were not able to isolate any product.
While doing this work, we came across in literature 85 another method
using IBX as oxidising agent in conjugation with a stable Wittig
reagent to obtain the product in one step. Thus, we prepared IBX as
per the literature method and treated with N-methyl prolinol along
126
with 1 eq. of stable phosphorane in DMSO. After stirring for 24 hours
tic indicated absence of starting compound. Usual workup did not
give any product except triphenylphosphine oxide.
Our failure to get N-methyl prolinal or further product
prompted us to think of using N-carboethoxy prolinal. We thought of
preparing it via N-carboethoxy prolinol (Scheme XXX), wherein
proline was to be subjected to treatment with ethylchloroformate to
form the N-protected mixed anhydride and subsequent reduction of
the mixed anhydride with NaBH4 in THE would have provided us N-
carboethoxy prolinol.
Although, this method86 is reported to give excellent yields to all
commonly used aminoacids, there is no mention of it on L-prolinol.
When proline was subjected with the same sequence of reaction, we
failed to get the N-carboethoxy prolinol. So, we then subjected N-
carboethoxy proline for the mixed anhydride reduction
(ethylchloroformate/ sodium borohydride) method but, again we
could not get the corresponding N-carboethoxy prolinol. Having failed
to get N-carboethoxy prolinol by mixed anhydride method we opted
for the more common method of diborane reduction. When we
subjected N-carboethoxy proline with NaBH4-I2 method 87 , first time
we got N-carboethoxy prolinol in 46% yield. When we carried out the
same experiment the second time under the same conditions, we got
N-methyl prolinol instead. Hence, we thought instead of
standardizing this reduction, we can prepare the expected
127
product using an alternate approach via prolinol (Scheme XXXI) as
we can also use other protecting groups like BOC anhydride.
Thus, proline was reduced with lithium aluminium hydride in
THF88 . The prolinol obtained was treated with ethylchloroformate in
aq. NaOH condition89 . The product obtained was characterized by it's
spectral properties (given below), which was also identical with the
product obtained in the first method of diborane reduction.
IR : vmax 3450, 1750, 1675 cm -1
PMR (CDC13), [Fig.2H]
(6)
1.28 t(6.9 Hz) 3H COOCH2CH3
1.79-1.2 m 4H CH2—CH2
3.3-3.4 m 1H CH
3.63 m 2H CH2OH
4.15 q(6.9 Hz) 2H COOCH2CH3
4.51 bs 2H CH2OH
Once N-carboethoxy prolinol was synthesized, we subjected it
to one pot IBX method. However, again we failed to get any product.
Fig. 2 H
129
2.6 CONCLUSION
We have developed a convenient method for the synthesis of
3,5-diarylisoxazoles. Studies in total synthesis of ABT-418 are
incomplete.
2.7 EXPERIMENTAL
130
0
Expt. 2.1 Preparation of 1,3-diphenv1-2-propenone (7a)
0 0
0 NaOH 0 0
7a
Expt. 2.2 Preparationof 1,3-dipheny1-2-propenone-oxime (8a)
OH
0 0I
7a 8a
Expt. 2.3 Preparation of 3,5-diphenyl isoxazole (9a)
OH 0 N
0 'x'-, 0 0 1
8a 9a
131
Expt. 2.4 Preparation of 3-(3',4'-methylenedioxyphenyl) -1-phenyl-2-propenone (7b)
0
NaOH
7b
Expt. 2.5 Preparation of 3-(3',4'-methylenedioxyphenyl) -1-phenyl-2-propenone oxime (8b)
0
0 I rm NH 20H
7b Sb
Expt. 2.6 Preparation of 5-(3',4'-methylendioxyphenyl) 3-phenyl isoxazole (9b)
--011 N"
\
\ ,..1 ,..
,----....: -- 0 -- '‘.
' ----"-
Sb
o
O i 9b
Sc 9c
/OH
( 1 1)1)Q. Me0H
OC H3
132
Expt. 2.7 Preparation of 1-(4'-methoxypheny1)-3- pheny1-2-propenone (7c)
0
Na011 [ 0 0
113C 0 H3
Expt. 2.8 Preparation of 1-(4'-methoxypheny1)-3-phenyl-2- propenone oxime (8c)
7c
0
NH2OH 0
OCH3
7c
0
Sc
Expt. 2.9 Preparation of 3-(4'-methoxvpheny1)-5- phenyl isoxazole (9c)
133
Expt. 2.10 Preparation of 1,3-bis(4',4'-methoxyphenyl) -2-propenone (7d)
0 - NaOH r - u
H3C( -OCH3 7d
Expt. 2.11 Preparation of 1,3-bis(4',4'-methoxypheny1)-2- propenone oxime (8d) me (8d)
7d 7d 8d 8d
Expt. 2.12 Preparation of 3-(4'-methoxvpheny1)-5- (4"-methoxyphenyl) isoxazole (9d)
Expt. 2.12 Preparation of 3-(4'-methoxvpheny1)-5- (4"-methoxyphenyl) isoxazole (9d)
.0H I\K
0
.0H I\K
0
? N
DDQ, Me01-1 I 0U-13
C14 30
? N
DDQ, Me01-1 I 0U-13
C14 30 CH3O
0 1 ' 'OCH3 OH
9d 9d 8d 8d
0 1
0 C1 \7
7e
N
0 0 C) OCH3
8e
134
Expt. 2.13 Preparation of 1-(4'-methoxyphen34)-3-(3",4"- methvlenedioxvpheny1)- 2-propenone (7e)
0 0
CH3
0 0 NaOH
H3C0
Expt. 2.14 Preparation of 1-(4'-methoxypheny1)-3-(3",4"- methvlenedioxyphenv1)- 2-propenone oxime (8e)
0
70\
0 N1-120H
7e
Expt. 2.15 Preparation of 3-(4'-methoxvpheny1)-513",4"- methylenedioxvphenyl) isoxazole (9e)
OH
DIN, Me01.1
OCf13
8e
0--N
\.\/•/1.[\-%'\ 0 0
9e
0 OH
.it 7-7-\ DDQ, Me011 r 0 0- v--)
135
Expt. 2.16 Preparation of 1-phenyl-3-styryl-2-propenone
(7f)
0 HO I .043
0 + 0 NaOH (7)
7f
Expt. 2.17 Preparation of 1-phenyl-3-styryl-2-propenone oxime (8f)
O „„OH
0
NH2 OH' I 0 0
7f 8f
Expt. 2.18 Preparation of 3-phenyl-5-stvryl isoxazole (9f)
8f 9f
4
NH2OH
OH N
NH2OH
N
0 1
O
0
Na OH
0 II .14 0
0 I
H3C
Expt. 2.19 Preparation of Cinnamaldehyde oxime 110)
10
Expt. 2.20 Preparation of Benzalacetone (11)
11
Expt. 2.21 Preparation of Benzalacetone oxime (12)
OH
CH3 CH3 NH2OH 0
12
Expt. 2.22 Preparation of 0-ionone oxime (13)
13 4
136
137
COOH
CH2OH
CH2OH
Expt. 2.23 Preparation of N-carboethoxy proline (141
COOH 1)C1COOEt 2) NaOH
COOEt 14
Expt. 2.24 Preparation of N-methyl prolinol (15)
LAH, dry ether COOH CH-0H
Expt. 2.25 Preparation of L-prolinol (16)
COOH
____Ae"-- LAH, dry THE ------, N----- H
H
Expt. 2.26 Preparation of N-carboethoxv L-prolinol (17)
H\ C 20H / 1)C1COOEt --.... '-'- 1\1"-- H 2) NaOH '-" N H
H I COOEt
17
4
138
Expt.2.1 Preparation of 1,3-dipheny1-2-propenone (7a)
Sodium hydroxide (10%)(1.91g in 17.36 ml water) in ethanol
(8.69g, 10.64m1) was kept in ice bath for 10 min. & poured into a
mixture of benzaldehyde (4.0g, 30mmol) and acetophenone (4.53g,
30mmol) with constant shaking. Then stirred the reaction mixture for 4
hours at room temperature. Poured the reaction mixture into ice cold
water containing dil. HC1. Yellow coloured solid separated, which was
recrystallised using ethanol to yield pure yellow crystals (6.12g, 80%)
m.p.57°C (lit. 68 m.p.57-58°C).
Expt.2.2 Preparation of 1,3-diphenyl-2-propenone oxime
(8a)
A mixture of chalcone 7a, (2.0g, 9mmol) hydroxylamine
hydrochloride (0.80g, lmmol), and pyridine (0.8701g, lmmol) in
ethanol (10m1) was refluxed on water bath for 45 mins. Ethanol was
distilled off and water (10m1) was added. It was then extracted with
ether (3 x 10m1). The combined ether layer was washed with dil HC1
and water and then dried over anhydrous sodium sulphate. The ether
layer was evaporated and the residue obtained was chromatographed
over silica gel using ethyl acetate: pet.ether (1:9) as solvent for elution.
The initial fractions gave a solid, which was recrystallised using
ethanol to yield 8a (1.69g, 79%) m.p.116°C (lit 69 m.p.115-116°C).
Expt.2.3 Preparation of 3,5-diphenyl isoxazole (9a)
Chalcone oxime 8a, (0.5g, 2.4mmol) & DDQ (1.0g, 4.4mmol) was
stirred overnight in methanol (5m1) at room temperature. After
evaporation of methanol on water bath, the reaction mixture was
taken in dichloromethane (20m1) and washed with 2N NaOH (2x15m1).
The dichloromethane layer was dried over anhydrous sodium
139
sulphate, concentrated and adsorbed over silica gel. Column
chromatography using ethylacetate:pet.ether (2:8) gave product, which
was recrystallised using chloroform:pet.ether (3:7) to give pure white
solid (0.37g, 75.33%) m.p.141°C (lit. 56 m.p.140-141°C).
Expt.2.4 Preparation of 3-(3',4'-methylenedioxypheny1)-1-
pheny1-2-propenone (7b)
Prepared following the same procedure given in expt. 2.1.
(2.55, 76%) m.p.120°C (lit. 71 m.p.122°C).
Expt.2.5 Preparation of 3-(3',4'-methylenedioxypheny1)-1-
pheny1-2-propenone oxime (8b)
Prepared following the same procedure given in expt. 2.2
(1.10g, 52%) m.p.140°C.
Expt.2.6 Preparation of 5- (3',4'-methylendioxypheny1)-
3-phenyl isoxazole (9b)
Prepared following the same procedure given in expt. 2.3
(0.14g, 72.27%), m.p.120°C (lit. 72 m.p.122-123°C).
Expt.2.7 Preparation of 1-(4'-methoxypheny1)-3-pheny1-2-
propenone (7c)
Prepared following the same procedure given in expt. 2.1.
(2.6g, 82%) m.p.110°C (lit.73m.p.109-110°C).
140
Expt.2.8 Preparation of 1-(4'-methoxypheny1)-3-pheny1-
2-propenone oxime (8c)
Prepared following the same procedure given in expt. 2.2
(0.89g, 42%) m.p.140°C (lit. 74 m.p.140°C).
Expt.2.9 Preparation of 3-(4'-methoxyphenyl)-5- phenyl
isoxazole (9c)
Prepared following the same procedure given in expt. 2.3
(0.140g, 74%) m.p.120°C (lit. 75m.p.120-121°C).
Expt.2.10 Preparation of 1,3-bis(4',4'-methoxypheny1)-2-
propenone (7d)
Prepared following the same procedure given in expt. 2.1
(3.15g, 80%) m.p.100°C (lit. 75m.p.101-102°C).
Expt.2.11 Preparation of 1,3-bis(4',4'-methoxypheny1)-2-
propenone oxime (8d)
Prepared following the same procedure given in expt 2.2
(0.63g, 30%) m.p.132°C (lit. 74m.p.132°C).
Expt.2.12 Preparation of 3-(4'-methoxypheny1)-5-(4"-
methoxyphenyl) isoxazole (9d)
Prepared following the same procedure given in expt, 2.3
(0.12g, 64.2%) m.p.140°C (lit.' 7aM.p.141-142°C)
141
Expt.2.13 Preparation of 1-(4'-methoxyphenyl)-3-(3",4"-
methylenedioxyphenyl)- 2-propenone (7e)
Prepared following the same procedure given in expt. 2.1
(2.82g, 75%) m.p 130°C (lit. 76m.p 1310C).
Expt.2.14 Preparation of 1-(4'-methoxyphenyl)-3-(3",4"-
methylenedioxyphenyl)- 2-propenone oxime
(8e)
Prepared following the same procedure given in expt. 2.2
(1.24g, 59%) m.p.180°C.
Expt.2.15 Preparation of 3- (4'- methoxyphenyl) -5- (3",4"-
methylenedioxyphenyl) isoxazole (9e)
Prepared following the same procedure given in expt. 2.3
(0.14g, 71%) m.p.152°C.
Expt.2.16 Preparation of 1-phenyl-3-styry1-2-propenone
(7f)
Prepared following the same procedure given in expt. 2.1
(2.73g, 77%) m.p.102°C (lit. 77m.p.103°C).
Expt.2.17 Preparation of 1-phenyl-3-styry1-2-propenone
oxime (8f)
Prepared following the same procedure given in expt. 2.2
(1.13g, 53.37%) m.p.135°C (lit.78m.p.1350C).
142
Expt.2.18 Preparation of 3 -phenyl -5 -styryl isoxazole (9f)
Prepared following the same procedure given in expt. 2.3
(0.13g, 69. 8%) m.p.130°C (lit." m.p.132-134°C).
Expt.2.19 Preparation of Cinnamaldehyde oxime (10)
Cinnamaldehyde (2.0g, lOmmol), hydroxylamine hydrochloride
(1.26g, lOmmol), pyridine (0.61g, lmmol) in ethanol (10m1) was
refluxed in water bath for one hour. The solvent was removed on water
bath and the residue chromatographed over silica gel using
ethylacetate: petether (2:8) afforded oxime 10 (1.31, 59%) m.p.135°C
(lit .80 m. p 134-1350C).
Expt.2.20 Preparation of Benzalacetone (11)
Mixture of sodium hydroxide (10%)(1.91g in 17.36 ml water),
benzaldehyde (4.0g, 30mmol) and acetone (4.53g, 30mmol) was stirred
at room temperature for two hours. Rendered the mixture acidic to
litmus paper. Then, transferred it into a separating funnel and
extracted the aqueous layer with ether (2x20m1). The organic extracts
were combined and dried over anhydrous sodium sulphate and
concentrated to give light yellow solid, which was recrystallised using
ethanol (6.12g, 80%) m.p.42°C (lit.68 m.-. p 42-43°C).
Expt.2.21 Preparation of Benzalacetone oxime (12)
Compound 11 (2.0g, lOmmol), hydroxylamine hydrochloride
(1.26g, lOmmol), pyridine (0.61g, 1 mmol) in ethanol (10m1) was
refluxed in water bath for one hour. The solvent was removed on water
bath and the residue chromatographed over silica gel using
143
ethylacetate:pet.ether (2:8) afforded oxime 12 (1.31, 59%) m.p.115°C
m.p.115-116°C).
Expt.2.22 Preparation of f3 -ionone oxime (13)
To a stirred solution of 13-ionone (1.0g, 5.2mmol), hydroxylamine
hydrochloride (0.48g, 6mmol), ethanol (10m1), & water (6m1) was
added solid sodium bicarbonate (0.71g). The reaction was refluxed for
90 mins, poured into water (60m1), & extracted with ether (3x20m1)
and also with chloroform (2x10m1). The organic extracts were
combined and dried over anhydrous sodium sulphate. Evaporation of
the solvent gave liquid as product. (1.07, 80%) b.p.76°C (literature 82
b.p 75-77°C).
Expt.2.23 Preparation of N -carboethoxy proline (14)
Ethylchloroformate (1.02m1, lmmol) was added slowly to stirred
solution of L-proline (1g, 8mmol) in 1M sodium hydroxide (8.58m1) at
0°C for a period of half an hour in 3 portions. Then, the reaction
mixture was allowed to attain room temperature and stirred further
for one and a half hour. On completion of the reaction, it was checked
for basicity. The mixture was washed with dichloromethane (2x10m1)
and was then acidified to pH 1 by adding 6M HC1. The mixture was
extracted using dichloromethane (3x15m1). The organic extracts dried
over anhydrous sodium sulphate. The solvent was evaporated off
under reduced pressure & the product was obtained as low melting
white solid (1.5g, 92.24%) m.p.64 (lit. 83 m.p.63-64°C).
Expt.2.24 Preparation of N -methyl prolinol (15)
To a stirred solution of lithium aluminium hydride (0.263g,
6.84mmol) in dry ether (10m1) was added N-carboethoxy proline (0.9g,
5.7mmol) in portions over a period of one hour. The stirring was
144
continued at room temperature for two hours. Water (1m1) was added
dropwise to the reaction mixture. The solid separated was filtered off
and washed with ether (15m1). The ether layer was further washed
with sat. sodium bicarbonate solution (2x10m1). The ether layer was
dried over anhydrous sodium sulphate and concentrated on water
bath. Evaporation of the solvent gave a liquid (61%).
Expt.2.25 Preparation of L-prolinol (16)
To a stirred suspension of lithium aluminium hydride (0.5g,
13.15mmol) was added L-proline (1.0g, 8.6mmol) in dry
tetrahydrofuran (22m1) over a period of 40 min. with refluxing and
stirring. The reaction mixture was refluxed for six hours. The reaction
mixture was cooled and 10% potassium hydroxide (2m1) was slowly
added to it, so that the reaction barely refluxes. Then slowly water
(1m1) was added to it and the reaction mixture refluxed for further
15 mins. On cooling, the solid mass was filtered, washed with
tetrahydrofuran (3x5m1). The organic layer was then dried over
anhydrous sodium sulphate & concentrated to give colourless oil
(90%).
Expt.2.26 Preparation of N -carboethoxy L -prolinol (17)
Ethylchloroformate (1.28g, lOmmol) was added to stirred
solution of (16) (1g, 9mmol) in 4N sodium hydroxide solution (6m1) at
0°C, and the mixture was stirred at the same temperature for
30 mins. Then, at room temperature for 30 mins. The reaction
mixture was neutralised with 10% hydrochloric acid and extracted
with dichloromethane (3x15m1). The extract was dried over anhydrous
sodium sulphate and concentrated. The residue was chromatographed
using ethyacetate:pet.ether (1:9).
145
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