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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82

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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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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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