total synthesis of (±)total synthesis of...

Chapter 2 2 2 2

Total synthesis of (±)Total synthesis of (±)Total synthesis of (±)Total synthesis of (±)----Physostigmine Physostigmine Physostigmine Physostigmine

Chapter 2

70

INTRODUCTION

Physostigmine, norphysostigmine, Physovenine, geneserine and

eseramine are alkaloids that have been isolated from the African Calabar

beans (Physostigma venenosum), of which Physostigmine 2 is one of the main

constituents. Physostigmine was first isolated in 1864 from the seeds of the

African Calabar bean Physostigma venenosum and was structurally

characterized in 1925.1 They have interesting physiological effects such as

cholinergic and miotic activities.2,3

N

N

HMe

Me

MeMeHNCO2

2

Physostigmine is used clinically in the treatment of glaucoma,

myasthenia gravis and protection against organophosphate poisoning. These

pharmacological effects of Physostigmine are mainly based on its inhibition of

acetylcholinesterase.4 It has been reported that oral and intravenous

administration of Physostigmine significantly improved memory in patients with

Alzheimer’s disease.5 Like many other indole alkaloids with a wide variety of

structural formats,6,7,8,9 hexahydropyrrolo[2,3-b]indoline ring system is at the

core of the structure of Physostigmine 2. Further, like many biologically

important indole alkaloids, Physostigmine 2 has a quaternary carbon center at

the C-3a position. The effective construction of such a quaternary center has

been one of the pivotal issues in the total synthesis of these indole alkaloids.

Chapter 2

71

As a result of these biological activities, unique structure and the difficulty in

generating a quaternary center, several syntheses of Physostigmine 2 have

been reported. An impressive total seventy-one syntheses of Physostigmine,

thirty-three racemic and thirty-eight chiral, have been reported in the literature.

Similarly, various racemic and/or chiral methods have been developed for the

construction of other indole alkaloids having the hexahydropyrrolo[2,3-

b]indoline in their core structure. The following discussion first narrates the

reported methods for the synthesis of such indole alkaloids having

hexahydropyrrolo[2,3-b]indole in their core structure, while the latter part

includes the discussion of various reported syntheses of Physostigmine.

Syntheses of Indole alkaloids (other than Physostigmine)

with hexahydropyrrolo[2,3-b]indole as the core structure.

Samuel J. Danishefsky and co-workers10 in 1994, reported the

synthesis of hexahydropyrroloindole alkaloid starting with bis (Boc) tryptophan

methyl ester 125. The reaction of 125 with N-phenylselenophthalimide and

catalytic p-toluenesulfonic acid gave 3-selenenylated pyrroloindole 126.

Treatment of 126 with methyl triflate and prenyl tributylstannane in presence of

2,6-di-tert-butylpyridine afforded 127 as a mixture of diastereomers. In a similar

fashion the synthesis of 3a-allyl hexahydropyrrolo[2,3-b]indoline 128 was

achieved by the same workers11 (Scheme 1).

Chapter 2

72

.

Scheme 1

Balkrishen Bhat and co-workers12 have constructed the

hexahydropyrrolo[2,3-b]indoline ring system in a novel way while achieving the

total synthesis of (-)-Dihydroaszonalenin. L-tryptophan methyl ester

hydrochloride was treated with methanesulphenyl chloride under Wieland’s

conditions13 to furnish the 2-(methylthio) derivative 129. Condensation of 129

with isatoic anhydride 130 in pyridine gave the desired benzodiazepine 131.

Alkylation of 131 with excess of 3,3-dimethylallyl bromide furnished the

diastereoisomeric 3-(1,1-dimethylallyl)indolenines. Finally, desulphurisation of

the indolenine 132 with deactivated Raney nickel which gave an inseparable

mixture of the product 133a and its dihydro-derivative 133b. This mixture was

hydrogenated over Adams’ catalyst to furnish (-)-Dihydroaszonalenin 133b

(Scheme 2).

NH N

H

H CO2Me

NH2.HCl

SMe

HN

HN

O

O

HN

O

O

O

NH

SMe

H CO2Me

NH2

+

129 130 131

Chapter 2

73

Scheme 2

Pedro Joseph-Nathan and co-workers14,15 have carried out

Grignard reaction for the synthesis of flustramine. The 2-hydroxyindolenines

134 was prepared from 3-acetonitrilindole.16 Prenylmagnesium bromide was

added to 2-hydroxyindolenines 134 which directly furnished prenylated 2-

oxofuro[2,3-b]indoline 135 (12:1 mixture of endo/exo-isomers). Hydrolytic

decyanation of the α-cyano-γ lactones 135 was conducted in the presence of

wet alumina, to afford the corresponding γ-lactones 136. N-decarboxylation and

N-prenylation of compound 136 was achieved by treating the compound with

sodium methoxide in methanol to get the compound 137. Lactone 137 was

then converted into lactam by treatment with methylamine. Further reduction of

lactam with LAH gave debromoflustramines A and B 138. The lactam was

reduced with alane-N,N-dimethylethylamine to afford flustramines A and B 138

(Scheme 3).

Chapter 2

74

Scheme 3

Miguel O. Mitchell and co-workers17 have achieved the synthesis

of (±)-Deoxypseudophrynaminol in one step starting from Nb-methyltryptamine.

Initially, Nb-methyltryptamine 139 was N-alkylated with 4-bromo-2-methyl-2-

butene. The compound 139 underwent insitu azaclaisen rearrangement with

concomitant capture of the intermediate indolenine to give desire product 140

(Scheme 4).

Scheme 4

Madeleine M. Joullie and co-workers18 have reported the

synthesis of Isoroquefortine C starting from L-tryptophan methyl ester

hydrochloride 141. Protection of both α- and side chain amino groups of ester

141 with Boc anhydride, followed by selenylation with N-

phenylselenophthalimide (NPSP) 142 directly provided hexadihydropyrrolo[2,3-

b]indole moiety 143. Displacement of the phenylselenide by treatment with

tributyl(3-methyl-2- butenyl)stannane, followed by saponification of the ester

group provided the desired carboxylic acid 144. It was converted to the

isoroquefortine C 145 (Scheme 5).

Chapter 2

75

Scheme 5

Ganesan A. and co-workers19 have reported the synthesis of

debromoflustramine B by the zinc triflate-mediated indole alkylation. Synthesis

began with tryptamine 146, which was converted to ethyl carbamate 147.

Carbamate 147 was reacted with Prenyl bromide, in presence of Zn(OTf)2,

Bu4NI, i-Pr2NEt to afford the dialkylated product 148. Finally, the compound

148 on treatment with Red-Al gave the debromoflustramine B 149 (Scheme 6).

Scheme 6

Chapter 2

76

Tomomi Kawasaki and co-workers20 have reported the synthesis

of (-)-Pseudophrynaminol through tandem olefination, isomerization and

asymmetric Claisen rearrangement. Bromination of indolin-3-one 150, followed

by substitution with (S)-1-nonen-3-ol gave a diasteromeric mixture of 2-

allyloxyindol-3-one 151. Horner–Wadsworth–Emmons reaction of 151 with

diethyl cyanomethylphosphonate proceeded smoothly with the tandem

olefination, isomerization, Claisen rearrangement, and deacetylation to afford

(E)-3-cyanomethyl-3-(2-nonenyl) indolin-2-one 152. Alkaline hydrolysis of the

nitrile 152 produced carboxylic acid. The acid was then condensed with

methylamine to give the corresponding amide. Oxidative cleavage of the olefin,

followed by Wittig reaction with the phosphorane derived from α

bromopropionate, gave the compound 153. Reductive cyclization of 153 with

LAH furnished (-)-Pseudophrynaminol 154. In a similar fashion the synthesis of

3a-allyl hexahydropyrrolo[2,3-b]indole 155 and 156 was achieved by the same

workers21 (Scheme 7).

155 156

Scheme 7

Chapter 2

77

Yoshinao Tamaru and co-workers22 have reported the

stereoselective synthesis of pyrroloindole frameworks by using Pd-Catalyzed

C-3 allylation. Allylation of L-tryptophan methyl ester 157 with allyl alcohol using

Pd(PPh3)4-Et3B afforded the compound 158. The authors speculate that this

stereoselective alkylative amination methodology could be utilized for the

synthesis of, among other natural products, ardeemine 159 and flustramine 160

family alkaloids (Scheme 8).

NH

NH N N

HH

NBr

O

O

Me

Ardeemine 159 Flustramine B 160

Scheme 8

Martha S. Morales-Rios and co-workers23 have reported the

synthesis of debromoflustramine B. Treatment of methyl 2-(2-oxo-3-

indolyl)acetate 161 with prenyl bromide under mild phase-transfer conditions

afforded the corresponding diprenylated 2-oxoindoline 162. Subsequent

hydrolysis of the ester group leads to 2-(1,3-diprenyl-2-oxo-3-indolyl)acetic acid

163. The amidation of 163 with ethyl chloroformate followed by treatment with

MeNH2 gave the corresponding acetamide 164. Reduction of 164 with LAH

afforded debromoflustramine B 167. Alternatively, reductive cyclization of 163

Chapter 2

78

with LiBHEt3 produced the corresponding 2-oxofuroindoline 165. Treatment of

165 with methylamine furnished the lactam 166. Further reduction of 166 with

LAH gave debromoflustramine B 167 (Scheme 9).

Scheme 9

Yong Qin and co-workers24 have reported the synthesis of chiral

3-substituted hexahydropyrroloindoline via intermolecular cyclopropanation.

Protection of the amide group in 168 with Boc gave the compound 169. N-

alkylation of 169 provided compound 170. Treatment of 170 with TFA afforded

oxazolidinone 171. When oxazolidinone 171 was treated with a diazoester

under diazo decomposition conditions of Cu(OTf)2 afforded the 3-substituted

hexahydropyrroloindoline 172. This methodology could be utilized for the

synthesis of, among other natural products, Physostigmine 2, bromoflustramide

173, mollenine 174, roquefortine 175, ardeemin 159, amauromine 176, and

aszonalenin 177 (Scheme 10).

Chapter 2

79

Scheme 10

Synthesis of Physostigmine:-

Julian and Pikl25 reported the first synthesis of racemic

Physostigmine starting from the 4-ethoxy-N-methylaniline 178. The compound

178 was treated with α-bromopropionyl bromide to yield the anilide 179. On

Chapter 2

80

treatment with aluminum chloride, the ethoxy group in 179 was cleaved

smoothly. In situ alkylation of 179 gave 1,3-dimethyl-5-hydroxyoxindole 180.

Latter on ethylation furnished 1,3-dimethyl-5-ethoxyoxindole 181. C-3

alkylation of oxindole 181 with chloroacetonitrile afforded the compound 182.

Catalytic reduction of the nitrile yielded the desired amine 183. Reductive

cyclization of 183 with sodium and alcohol yielded of d,l-desoxynoreseroline

185. The amine 183 was converted to the benzylidene derivative and it was

methylated by the Decker method to furnish 184. Reductive cyclization of 184

with sodium and alcohol afforded d,l-eserethole 70 (Scheme 11).

Scheme 11

Schonenberger and Brossi26 developed an efficient method for

separation of racemic N1-noresermethole obtained by Julian and Pickl27 and its

modification by Yu and Brossi.28 The method involved catalytic reduction of

methoxycyanooxindole 186 to afford the amine 187. The compound 187 was

Chapter 2

81

converted to the corresponding carbamate 188. Reductive cyclization of the

latter compound afforded racemic esermethole 189 (Scheme 12).

Scheme 12

Similarly, direct conversion of the cyanide 186 to N1-noresermethole 190 was

also achieved in 80% yield. The reaction of compound 190 with (-) (S)-(1-

methylphenyl) isocyanate afforded the less polar (+)-urea 191 and more polar

(-)-urea 191. The ureas (+)-191 and (-)-191 were decomposed easily by

refluxing in 1 M sodium pentoxide to afford (+) and (-)-N1-noresermethole. The

(+)-N1-noresermethole 190 underwent reductive methylation on treatment with

formaline followed by sodium borohydride to afford (+)-esermethole. The (-)-N1-

noresermethole when treated with benzyl bromide gave (-)-N1-benzyl-1-

noresermethole 192, which was converted to N1-benzylnorphysostigmine 193.

Hydrolytic debenzylation of 193 by palladium on carbon gave (-)-N1-

norphysostigmine 194. Finally reductive methylation with formaline and

sodiumborohydride afforded (-)-Physostigmine 2 (Scheme 13).

Chapter 2

82

(-)-Norphysostigmine 194 2

Scheme 13

John Harley-Mason and A. H. Jackson29 have reported the

synthesis of Physostigmine by employing ferricyanide oxidation. 2,5-

dimethoxyacetophenone was treated with ethyl cyanoacetate to give ethyl 1-

cyano-2-(2,5-dimethoxyphenyl)crotonate 195. Treatment of 195 with potassium

cyanide gave the compound 196. Hydrogenation of 196 over platinum oxide

afforded the compound 197. The compound 197 was treated with

benzaldehyde followed by methyl iodide to furnish NN'-dimethyl derivative 198.

Reaction of 198 with hydrobromic acid afforded de-O-methylated 199.

Dihydroxy-amine 199 was treated with potassium ferricyanide to afford the

eseroline 200, which was converted into the Physostigmine 2 (Scheme 14).

Chapter 2

83

Scheme 14

Masazumi Ikeda and co-workers30 have reported the synthesis of

Physostigmine from cycloprop[b]indole. Ethyl 1-cyano-1,1a,2,6b-

tetrahydrocycloprop[b]indole-2-carboxylates 202 was prepared from ethyl 2-

cyano-1,2-dihydroquinoline-1-carboxylates 201 by photochemical reaction. The

compound 202 was heated with 10% KOH to afford the furo[2,3-b]indole 203.

Treatment of the compound 203 with methyl iodide gave the N-methyl

derivative 204. The N-methylfuroindole 204 was converted into esermethole

189 by Rosenmund’s method31 (Scheme 15).

Scheme 15

Chapter 2

84

In the synthesis of Physostigmine by Takano and co-workers,32

treatment of (-)-(S)-O-benzyl-2,3-epoxypropyl ether 205 with lithium

diisopropylamide, 3-methoxybenzyl cyanide afforded the compound 206.

Alkaline hydrolysis of 206 gave γ-lactone 207 as 1:1 epimeric mixture. Lactone

207 was alkylated with methyl iodide in the presence of LDA to furnish the

compound 208. Compound 208 was converted to the lactone 210 via multistep-

reaction sequence involving hydrogenolysis, hydrolysis, oxidative cleavage and

reduction followed by acidic workup. The lactone 210 was treated with

methylamine to give the lactam 211. The lactam 211 was treated with cupric

nitrite in acetic anhydride to yield the nitro compound 212. Catalytic

hydrogenation of 212 with platinum gave amine 213. The compound 213 was

treated with LAH to furnish tricyclic aminal. It underwent reductive N-

methylation to afford (-)-esermethole 189. (-)-Esermethole was easily converted

to Physostigmine via demethylation with borontribromide followed by

carbamylation with methylisocyanate (Scheme 16).

Scheme 16

Chapter 2

85

Tom Livinghouse and Richard Smith33,34 have reported the

synthesis of (±)-Physostigmine through intramolecular 1,3-dipolar addition of a

formamidine ylide to an unactivated olefin. Irradiation of p-methoxyacetanilide

214 in acetonitrile furnished the aminoacetophenone 215. Exposure of 215 to

methyllithium followed by thermal dehydration gave the aminostyrene 216.

Formylation of 216 with n-butyl formate, followed by N-methylation afforded

formamide 217. Treatment of 217 with methyl trifluoromethanesulfonate and

subsequent amination with trimethylsilylmethylamine provided the formamidine

218. Finally, cyclization of 218 to d,l-eserethole 189 via the transient ylide 219

was accomplished by sequential methylation with methyl

trifluoromethanesulfonate and desilylation with tetra-n-butyl ammonium fluoride

(Scheme 17).

Scheme 17

Keiichiro Fukumoto and co-workers35 have reported the

syntheses of (±)-Physostigmine by using Tandem Electrocyclic-

[3,3]Sigmatropic reaction of benzocyclobutene. Benzocyclobutene 8 was

prepared from readily available 1-cyano-1,2-dihydro-5-

methoxybenzocyclobutene 7. A solution of 8 was refluxed in o-dichlorobenzene

Chapter 2

86

to give 4-allyl-6-methoxy-4-methylisochroman-3-one 9, via tandem

electrocyclic-[3,3]sigmatropic reaction. Reduction of 9 with LAH gave the diol

10, which was then treated with N-bromosuccinimide to give the bromo ether

11. Oxidation of the primary alcohol of 11 with Jones reagent afforded the

aldehyde 12. Further, oxidation of aldehyde 12 afforded carboxylic acid 13. By

Curtius process, acid 13 was converted into the carbamate 14. Deprotection of

the bromo ether with zinc-copper complex afforded alcohol 15. Oxidation of

alcohol 15 with pyridinium dichromate provided the oxindole 16. Oxidative

cleavage of the double bond of 16 followed by reductive amination with

methylamine hydrochloride provided the lactam carbamate 221, via the initially

formed secondary amine 220. Finally, treatment of 221 with dimethyl sulfide

and aluminum trichloride36 gave the amino lactam 213, which was converted to

esermethole and Physostigmine 1 (Scheme 18).

Scheme 18

Chapter 2

87

A chiral route to both enantiomers of esermethole, the key

synthetic precursor of Physostigmine, has been established by Takano and co-

worker37 starting from (S)-O-benzylglycidole. Reaction of (S)-O-benzylglycidole

222 with crotylmagnesium chloride afforded the terminal olefin 223. The

compound 223 on subjecting to Mitsunobu38 reaction, followed by sequential

deacylation and carbamoylation furnished the carbamate 224. Oxidative

cleavage of the terminal olefin gave the aldehyde intermediate 225, which was

isolated in the hemiacetal form 226. Fischer indolization with 4-

methoxyphenylhydrazine hydrochloride in aqueous pyridine, at reflux 226

furnished an inseparable 2: 1 mixture of the diastereomers of 227. This mixture

of the diastereomers of 227 was treated with formalin and sodium

cyanoborohydride to give the compound 228. Reduction of 228 with LAH

afforded the mixture 229 and 230, which were separated by silica gel

chromatography to afford unnatural and natural amines 229 and 230 in 53%

and 29% respectively. The major isomer 229 was debenzylated under Birch39

condition to give the primary alcohol 231. The aldehyde was obtained from 231

by Swern40 oxidation and the crude product was successively treated with

hydroxylamine-O-sulfonic acid and sodium borohydride to give the unnatural

(+)-esermethole 189. The alcohol 232 was obtained from 230 and afforded the

natural (-)-esermethole 189 in a similar manner (Scheme 19).

Chapter 2

88

Scheme 19

The unnatural Physostigmine was obtained by Takano and co-

workers41 via lipase mediated asymmetric hydrolysis. Dihydronaphthalene 234,

obtained from dicyclopentadiene 23342 was treated with osmium tetraoxide

afforded the glycol 235. The glycol 235 was successively treated with sodium

periodate and sodium borohydride to give γ-lactone 236. When the γ-lactone

was subjected to Mitsunobu38 reaction condition, it afforded the corresponding

phathalimide 237. Refluxing the compound 237 with hydrazine hydrate

furnished lactam 238. The lactam 238 on sequential oxidation; N-alkylation and

oxidation gave the carboxylic acid 239. Through the Curtius reaction,43,44 the

acid 239 was converted into the lactam carbamate 221. The lactam carbamate

221 was treated with LAH to afford (+)-esermethole 189 (Scheme 20).

Chapter 2

89

Scheme 20

Node and co-workers45,46 in 1991, synthesized Physostigmine

using Diels-Alder reaction of (-)-nitroolefin47,48 61 with Danishefsky diene 62 as

a key step. The Diels-Alder reaction of nitroolefin 61 with Danishefsky diene 62

followed by protonation afforded the adduct 63. Reaction of compound 63 with

Nozaki reagent49 (Zn-TiCl4-CH2Br2) in a 2:1 mixture of THF and

dichloromethane effected methylation concomitant with reductive cyclization to

give the lactam 64. Methylation of 64 followed by ozonoloysis gave the cyclic

ketone 65. Cyclic ketone 65 was treated with p-PTS and was subsequently

oxidized with iodine. Ethylation of the intermediate phenol with ethyl iodide

gave aromatized compound 66. Selective demethylation with a combination of

reagent system of aluminum chloride-sodium iodide gave the alcohol 67.

Oxidation of alcohol 67 with pyridinium dichromate yielded the corresponding

carboxylic acid 68. The acid was transformed to the carbamate 69 via Curtius50

Chapter 2

90

degradation with diphenylphosphorylazide. Reductive cyclization of 69 with

LAH gave the desired (-)-eserethole 70 (Scheme 21).

Scheme 21

Node et al.51 synthesized the natural (-)-Physostigmine starting

with chiral nitroolefenic lactones 240. Bromination of 240 under basic

conditions afforded 241. The compound 241 was converted to aniline derivative

242 by treatment with potassium tertiary butoxide followed by hydrogenolysis of

the nitro group. Reaction of 242 with ethylchlorocarbonate afforded the

corresponding carbamate 243. Reductive cyclization of 243 with LAH followed

by the bromination gave tricyclic amine 244. The latter compound 244 was

converted to (-)-esermethole 189 by reaction with sodium methoxide and

cuprous iodide (Scheme 22).

Chapter 2

91

Scheme 22

Russell Rodrigo and co-workers52 have reported the synthesis of

(±)-Physostigmine starting from N-methyl-p-anisidine 29. Treatment of 29 with

tert-butyllithium and 1,2-diiodoethane afforded o-iodoanisidine 30. Acylation 30

with monoethyl fumarate and oxalyl chloride furnished the amide 31. The amide

31 was treated with n-butyllithium to give oxindole 32 via intramolecular

Michael addition. Methylation of 32 at C-3 furnished 33. Hydrolysis of ester 33

with NaOH afforded the acid 245 which when treated with LiBHEt3 gave the

tricyclic lactone 204. Finally the treatment of the lactone 204 with methylamine

and LAH afforded esermethole 189 (Scheme 23).

Scheme 23

Chapter 2

92

Wong and co-workers53 synthesized (-)-Physostigmine through

asymmetric alkylayion of oxindole. Alkylation of oxindole 49 with

chloroacetonitrile in presence chiral phase transfer catalysis 246 provided the

compound 186. Catalytic reduction of 186 yielded the corresponding primary

amine 187 as optically enriched mixture. Treatment of amine with dibenzoyl-D-

tartaric acid in acetonitrile afforded optically pure tartrate salt. Finally,

conversion of amine 187 to carbamate 247, followed by reductive cyclization

gave (-)-esermethole 189 (Scheme 24).

Scheme 24

Enantiocontrolled total synthesis of (-)-Physostigmine has been

achieved by Takano and co-workers54 starting from optically active tricyclic

enone 36 by employing Fischer indolization under non acidic conditions. The

optically active (-)-tricyclic enone 36, was prepared from racemic

dicyclopentadiene in a four step sequence of reactions including lipase-

mediated resolution.55 Alkylation of 36 with methyl iodide afforded the

Chapter 2

93

monomethyl ketone 37. The ketone 37 was refluxed with 4-

methoxyphenylhydrazine hydrochloride in aq. pyridine to afford the

carbinolamine 38 via [3,3]-sigmatropic rearrangement.56 Latter compound

underwent acetylation followed by methylation to afford a tertiary amide 40.

Refluxing 40 in 2-dichlorobenzene initiated retro-Diels-Alder reaction giving the

cyclopentanone 41. The enone 41, on sequential one flask ozonolysis,

borohydride reduction and periodate cleavage, furnished the lactol 42.

Oxidation of lactol 42 by silver carbonate gave the lactone 248, which was then

transformed to the lactam 249 by heating in aq. methylamine in sealed tube.

The lactam 249 was treated with diisobutylaluminium hydride and then with

LAH to afford (-)-esermethole 189 (Scheme 25).

Chapter 2

94

Scheme 25

Marino et. al.57,58,59 synthesized (-)-Physostigmine via Chiral

Sulfoxide. The reaction of 5-benzyloxyindole 250 with methylmagnesium

bromide, methyl iodide and (Boc)2O to afford compound 251. Treatment of 251

with chiral [(N-methylsulfinyl) oxazolidinone] produced 2-(methylsulfenyl)-indole

derivative, which was oxidized with m-CPBA to afford chiral sulfoxide 252. The

indolyl sulfoxide 252 underwent lactonization when treated with

trichloroacetylchloride in the presence of Zinc-Cupper complex to afford 253.

Desulfenylation and dechloronation were achieved by treatment of 253 with

aluminum amalgam and tributytin hydride respectively to afford the lactone 254.

The Boc group in 254 was replaced by a formyl group by treatment with formic

acid and acetic formic anhydride to give compound 255. This lactone 255 was

converted to the lactam 256 by treatment with methylamine. Reduction of both

lactam and formamide 256 with borane furnished O-benzyleseroline 257. The

benzyl group of 257 was cleaved with Raney nickel to afford a phenol. The

phenol was immediately treated with methylisocyanate to furnish (-)-

Physostigmine 2 (Scheme 26).

Chapter 2

95

Scheme 26

Paul A. Grieco and co-workers60 reported the synthesis of

Physostigmine from 2-azonianorbornene-2-spiro-1’-aziridinium triflate. An

aqueous imino Diels-Alder reaction61 between cyclopentadiene and the

immonium ion derived from formaldehyde and 2-bromoethylamine

hydrobromide provide 2-azanorbornene 258. 2-azanorbornene 258 was treated

with silver triflate in THF to give 2-azonianorbornene-2-spiro-1’-aziridinium

triflate 259. Oxindole 49 was treated with LDA, followed by addition of

spiroaziridinium triflate 259 to give 260. Compound 260 was treated with

trifluoroacetic acid in the presence of triethylsilane, azanorbornene 260

underwent a tandem acid catalyzed heterocycloreversion and reduction of the

incipient immonium ion with formation of 261. The compound 261 was treated

with LAH to give esermethole 189. Finally, demethylation, followed by

carbamoylation provided Physostigmine 2 (Scheme 27).

Chapter 2

96

Scheme 27

Arnold Brossi and co-workers62 reported the synthesis of

Physostigmine via chemical resolution. C-alkylation of oxindole 49 with methyl

bromoacetate gave ester 50.63 Alkaline hydrolysis of 50 yielded racemic acid

51. Chemical resolution of acid 51 with brucine in water yielded (-)-51. The

acid (-)-51 was converted to either the nitrile 186, or the lactone 204 or the

amides 262 and 263. From these intermediates, esermethole 189 and its

derivatives 192 and 190 were obtained through routine functional group

transformations (Scheme 28).

Scheme 28

Chapter 2

97

Arnold Brossi and Xue-Feng Pei64 have reported the synthesis of

Physostigmine. The oxindole 49 was treated with 2-chloro-N,N-

dimethylethanamine hydrochloride to give 52. Stereoselective reduction of 52

was accomplished with sodium dihydridobis(2-methoxyethoxy)aluminate to give

aminoalcohol 53. The compound 53 was treated with methyl iodide to give the

methiodide 54. Treatment of 54 with methylamine furnished the corresponding

esermethole 189. Demethylation, followed by carbamoylation furnished

Physostigmine 2. Chemical resolution of aminoalcohol 53 with (+)-2,3-di-O-(p-

toluoyl)-D-tartaric acid provided (-)-53 and (+)-53. In a similarly manner to the

above route, synthesis of optically active (+)-Physostigmine 2 and (-)-

Physostigmine 2 were achieved from the resolved aminoalcohols (-)-53 and

(+)-53 (Scheme 29).

Chapter 2

98

Scheme 29

Synthesis of Physostigmine has been reported by Qian-sheng Yu

and Bao-yuan Lu65 using phase transfer catalyzed C-3 alkylation. Alkylation of

4-methylaminophenol 55 with 2-bromopropionyl bromide gave the compound

56. It was treated with AlCl3 to afford the oxindole 57. Hydroxyl group in 57 was

protected by 3,4-dihydro2H-pyran to furnish compound 58. The compound 58

was then alkylated in presence of TBAI to afford the nitrile 264. Reductive

cyclization of nitrile 264 with LAH gave 265. Reductive N-methylation, followed

by treatment with HCl furnished eseroline 200. The phenol 200 was treated

with methylisocyanate to provide Physostigmine 2 (Scheme 30).

Scheme 30

In 1994, Pallavicine and co-workers66 reported synthesis of

esermethole 189 through asymmetric alkylation. The synthesis was based on

asymmetric alkylation at C-3 of oxindolone 49 with 266 as chiral alkylating

agent to afford 267 and its isomer. This chiral alkylating agent 266 was

obtained from 1-phenylethylamine after condensation with methyl

Chapter 2

99

chloroformate, followed by reduction and again condensation with chloroacetyl

chloride. Hydrogenolysis of 267 with Pd-C, followed by reductive cyclization

gave esermethole 189 (Scheme 31).

Scheme 31

The synthesis of (-) and (+)-esermethole have been reported by

Valoti and coworkers67 through chemical resolution. The oxindole 268 was

treated with methyl iodide in the presence of phase transfer catalyst to furnish

dimethylated product 186. Hydrogenation of the cyano group gave amine 187.

Chemical resolution of amine 187 by using D and L tartaric acid afforded (-)

and (+)-187. Subsequent (-) and (+)-187 was treated with methyl

chloroformate, followed by LAH afforded (+) and (-)-esermethole 189 (Scheme

32).

Chapter 2

100

Scheme 32

Martha S. Morak-Ros and co-worker68 have reported synthesis of

Physostigmine from ethyl 2-cyano-2-(1-carboethoxy-5-methoxy-3-indoly)

acetate 269. Oxidation of 269 with chromium oxide in acetic acid gave the 2-

hydroxyindolenine 270. The 1,4 addition of 270 with methylmagnesium iodide

afforded the 3-methylindoline 271. Oxidation of 271 with Na2Cr2O7 furnished

the compound 272. Decarboxylation of ester group by treatment with NaCN

provided the compound 273. The compound 273 was treated with dimethyl

sulphate in presence of base to give the compound 186. Finally reductive

cyclization of 186 with LAH afforded the esermethole 189 (Scheme 33).

Scheme 33

Chapter 2

101

Sundaresan Prabhakar and co-workers69,70 reported the synthesis

of the Physostigmine via [3,3]-sigmatropic rearrangement. The reaction of

hydrazine 274 with formic acid under reflux gave formamide 275. Reduction of

formamide 275 with LAH yielded 276, which on reaction with methyl propiolate

provided 277. Thermolysis of 277 in diphenyl ether furnished the tricycle

compound 278 via [3,3]-sigmatropic rearrangement. It was converted into the

methylcarbamate derivative 279. Hydrogenation of 279 with Pd/H2 provided a

diastereomeric mixture of 280. Selective hydrolysis of ester group in 280 with

aq. NaOH gave the corresponding salt 281. The derived acid chloride 282,

formed in situ with oxalyl chloride, on reaction with N-hydroxypyridine-2-thione

yielded the Barton ester 284. The ester 284 on decarboxylation (AIBN, TBSH)

afforded 286 in poor yield. Compound 284, obtained from mixed anhydride 283,

on photolysis in the presence of tert-butylthiol as the hydrogen donor71

underwent decarboxylation to afford 286 in 51% yield. A considerable

improvement in this yield (92%) was achieved on irradiating72 the

benzophenone oxime ester 285 with the mixed anhydride 283, in a THF-

isopropanol mixture containing a large excess of tert-butylthiol. The reduction of

286 with LAH gave N8-nordesoxyeseroline 287. N-methylation of 287 with

aqueous formalin, NaBH3CN furnished desoxyeseroline 288, which was

converted to the Physostigmine 2 (Scheme 34).

Chapter 2

102

Scheme 34

Arnold Brossi and co-workers73 have reported yet another

synthesis of (-)-Physostigmine using asymmetric alkylation of oxindole 49.

Asymmetric alkylation of oxindole 49 gave the (+) and (-) nitrile 186 in a ratio of

3:7. These nitriles were separated on a column of microcrystalline cellulose

triacetate. Catalytic reduction of (-) 186 gave the amine, which on further

reductive cyclization afforded compound 190. Reductive methylation of 190 on

treatment with formaline followed by sodium borohydride furnished esermethole

189 (Scheme 35).

Chapter 2

103

Scheme 35

Fuji et al74 in 1998, reported the synthesis of (-)-Physostigmine

through enantioselective nitroolefination of 1,3-methyl-5-methoxy-2-oxindoles

49. Reaction of 49 with nitroenamine 289 in presence of butyllithium gave the

compound 290. Reduction of double bond in 290 with sodium borohydride

afforded the unsaturated nitro compound. The nitro group was reduced with

Pd-C to give the corresponding amine, which was converted into the carbamate

291. Reductive cyclization of 291 by LAH afforded esermethole 189.

Demethylation, followed by carbamoylation provided Physostigmine 2 (Scheme

36).

Scheme 36

The synthesis of (-)-Physostigmine from Z-butenanilide through

asymmetric Heck75, 76 cyclization reaction was achieved by Overman and co-

workers.77,78,79 2-butyn-1-ol 71 was reduced with sodium bis(2-methoxyethoxy)

Chapter 2

104

aluminum hydride (Red-Al). The resulting vinylalanate was iodinated to give

(Z)-3-iodo-2-butenol which was then protected and under palladium mediated,

was carboxylated to afford the (Z)-acid 72. Condensation of 72 and 2-iodo-N-

methyl-p-anisidine80 provided compound 73 in 76% yield.76,81 Asymmetric Heck

cyclization of 73 with 20% Pd-S-BINAP, in the presence of PMP followed by

hydrolysis gave (S)-oxindole aldehyde 74. Treatment of the aldehyde 74 with

methylamine and LAH afforded (-)-esermethole 189, which was converted to

(-)-Physostigmine 2. Heck cyclization of (Z)-butenanilide 73 with Pd-(R)-BINAP

in the presence of PMP followed by acid hydrolysis and recrystalization

provided (R)-74, and then converted to (+)-Physostigmine 2 (Scheme 37).

Scheme 37

A new efficient synthetic route for (-)-Physostigmine was

described by Nakagawa and co-workers82 via reaction of Corey-Kim reagent

with tryptamine. Reaction of tryptamine carbamate 292 with sulfonium salt - the

Corey-Kim83 reagent 293 in the presence of i-Pr2NEt afforded the

corresponding pyroloindole 294. Reductive N-methylation and desulfurization of

294 was carried out simultaneously with Raney nickel in the presence of

Chapter 2

105

formalin to furnish 295. Treatment of 295 with Red-Al gave racemic

esermethole 189 (Scheme 38).

Scheme 38

Nakagawa84 reported yet another concise synthesis of

Physostigmine from skatole and activated aziridine via alkylative cyclization.

1,3-dimethylindole 296 was treated with N-benzyloxycarbonyl-aziridine 297

catalyzed by SC(OTf)3 and TMSCl to give 298. Reduction of 298 with Red-Al

furnished desoxyeseroline 288, which can readily be converted to

Physostigmine 2.53 (Scheme 39).

Scheme 39

Kunio Ogasawara and co-workers85 have used chiral building

block approach for the synthesis of (-)-Physostigmine. Enantiopure (-)-75 was

obtained from furfural.86 The enone 75 was converted into the ketone 76 by

using catalytic hydrogenation. Monomethylation of 76 with iodomethane gave

Chapter 2

106

77 as an epimeric (5:2) mixture. This epimeric mixture 77 was refluxed with 4-

methoxyphenylhydrazine hydrochloride in aqueous pyridine,87 to afford

carbinolamine 78 via fischer indolization sequence involving a [3,3]-sigmatropic

rearrangement. Reduction of 78 with LAH, followed by alkaline workup in the

presence of carbobenzoxy chloride, furnished N-carbamate 79. The desilylation

of 79 by using TBAF gave alcohol 80, which was transformed into mesylate 81,

and then into iodide 82. Reductive cleavage of the internal acetal linkage gave

rise to vinylhemiacetal 83 as an epimeric mixture. The compound 83 was

heated with methylamine hydrochloride in the presence of sodium

cyanborhydride to afford the N-methylaminoalcohol 299, which was converted

into the bis-carbamate 300. Removal of the extra three-carbon moiety was

carried out by treating 300 with lead(IV) acetate to afford the crude acetate 301.

Then compound 301 was refluxed with 10% hydrochloric acid to give the

tricyclic carbamate 302. On reductive N-methylation under catalytic

hydrogenolysis conditions in the presence of formalin afforded esermethole 189

(Scheme 40).

Chapter 2

107

Scheme 40

Hiroyuki Ishibashi and co-workers88 have reported the synthesis

of (±)-Physostigmine using Bu3SnH-mediated aryl radical cyclization of o-

bromo-N-acryloylanilides. The starting 2-bromo-4-methoxyaniline89 43 was

prepared by treating p-anisidine with Br2 in AcOH. Condensation of 43 with

formaldehyde and succinimide in ethanol gave 86. Reduction of 86 with NaBH4

afforded the N-methyl derivatives 87. Treatment of 87 with pyruvyl chloride

followed by diethylphosphonoacetonitrile furnished the requisite radical

precursor 303. The compound 303 was treated with Bu3SnH and AIBN to give

the oxindole 186 via 5-exo selective aryl radical cyclization. The oxindole 186

used the key intermediate for synthesis of Physostigmine 2 (Scheme 41).

Scheme 41

Kunio Ogasawara and co-workers90 have reported the synthesis

of (-)-Physostigmine from enantiopure 7,7-dimethyl-6,8-dioxabicyclo[3.3.0]oct-

Chapter 2

108

3-en-2-one 90. The compound (-)-90 was first transformed into the α-iodo-

enone (+)-91,91 which was converted to the α-methyl-enone (-)-92, palladium-

mediated cross-coupling reaction.92 Catalytic hydrogenation of (-)-92 yielded

the α-methyl ketone 93 as a mixture of two epimers. On reflux with 4-

methoxyphenylhydrazine hydrochloride in aqueous pyridine, under the Fischer

indolization conditions, 93 furnished the carbinolamine (+)-94. The compound

94 was treated with hydrochloric acid to give the triol 95. Subsequently it was

treated with formalin, followed by sodium periodate to furnish N-

methyloxyindole 74. N-methyloxyindole 74 was treated with methylamine

followed by reduction with LAH to afford 189 esermethole, the key intermediate

of Physostigmine 2 (Scheme 42).

Scheme 42

Atsushi Nishida and co-workers93 have reported the synthesis of

(±)-Physostigmine by the reaction of aromatic hydrazine with 4-chloro-2-

methylbutanal. Reaction of N-methyl-p-anisidine 304 with NaNO2 afforded the

nitrosoaniline derivative 305, which was treated with Na2S2O4 to furnish the

hydrazine derivative 306. The reaction of hydrazine 306 with 4-chloro-2-

methylbutanal under reflux condition; subsequent acylation with methyl

Chapter 2

109

chloroformate gave carbamate 295. Finally it was easily converted into

esermethole 189 by reduction with Red-Al (Scheme 43).

Scheme 43

Pedro Joseph-Nathan and co-workers94 have reported the

synthesis of Physostigmine 2 starting from 5-methoxyindole-3-acetonitrile.

Reaction of 5-methoxyindole-3-acetonitrile 9695 with dimethyl carbonate in the

presence of sodium hydride afforded the dialkoxycarbonylindole derivative 97.

Oxidation of 97 with chromium oxide in acetic acid gave the N-protected 2-

hydroxyindolenine 98. The 1,4-addition of methylmagnesium iodide to 2-

hydroxyindolenine 98 gave 3-methylindoline 99. Lactonization of 99 with

potassium hydroxide afforded furoindolinone 100. Furoindolinone 100 was

decyanated with neutral alumina to produce the compound 101. The compound

101 was treated with sodium methoxide to give the compound 307. The

compound 307 was treated with dimethyl sulfate to give N-methylated 204.

Finally, the compound 204 on treatment with methylamine and reduction of the

resulting lactam with LAH afforded esermethole 189. It was converted into the


Chapter 2

110

Scheme 44

Pankaj D. Rege, and Francis Johnson96 have reported the

synthesis of dl-Physostigmine through nucleophilic substitution reaction. When

p-nitroanisole 308 was treated with excess of the silyl compound 309 in the

presence of TASF, and then oxidized, the intermediate nitronate with DDQ

furnished the compound 310. The compound 310 was treated with methyl

iodide using tetrabutylammonium bromide as the catalyst to give the compound

311. The compound 311 on catalytic reduction with 10% Pd/C provided the

aminoarene 312. The reductive cyclization of amino compound 312 using LAH

afforded the tricyclic compound 313, an intermediate in the synthesis of


Chapter 2

111

Scheme 45

Larry E. Overman and co-workers97 reported the synthesis of (-)-

Physostigmine starting from the commercially available 4-(methylamino) phenol

which was converted to oxindole 49 following the procedure of Julian25 and

Brossi.98 Dialkylation 5-methoxy-1,3-dimethyloxindole 49 with enantiopure

ditirfliate 31499 using KHMDS as the base furnished dialkylated product 315.

Deprotection of the acetonide of 315, followed by oxidative cleavage of the

resultant vicinal diol, provided aldehyde 74. Condensation of aldehyde with

methylamine followed by in situ reduction of the crude imine with LAH afforded

(-)-esermethole 189, which was converted to (-)-Physostigmine 2 (Scheme 46).

Scheme 46

Chapter 2

112

Yasuyuki Kita and co-workers100 have reported the synthesis of

Physostigmine via the lipase-catalyzed desymmetrization Protocol. The bis-

hydroxymethylation at C-3 position of 316 was performed with an formalin and

Na2CO3 to give the diol 317. The diol 317 was treated with furan-2-caboxylic

acid in presence of DCC, DMAP to afford the difuroates 318.

Desymmetrization of the prochiral difuroates 318 by using Lipase OF catalyst in

iPr2O-THF-H2O yielded the corresponding enantioselectively hydrolysed

product (S)-(-) oxindole 319. The hydroxymethyl group in 319 was converted to

the methyl group 320 via the radical reduction of the corresponding iodide

using 2,2’-azobis(2,4-dimethyl-4-methoxyvaleronitrile) and (Me3Si)3SiH.

Furoyloxy group in 320 was cleaved by using DIBAL-H to give 321. Treatment

of 321 with I2 and sodium cyanide furnished the nitrile 322. The nitrile 322 was

in turn transformed to the known aldehyde 323, by treating with 10% NaOH,

BH3.Me2S, and Dess-Martin periodinane. This was further converted to

esermethole 189 and Physostigmine 2 (Scheme 47).

Scheme 47

Chapter 2

113

Albert Padwa and co-workers101 have reported the synthesis of

(±)-desoxyeseroline through [3,3]-sigmatropic rearrangement. Reaction of

sulfilimine 324 with dichloroketene furnished the pyrrolo[2,3-b]indole 325.

Pyrrolo[2,3-b]indole 325 was treated with zinc in acetic acid and TMDEA,

followed by formic acid to furnish lactam 326. Removal of the N-tosyl group by

reduction with sodium naphthalinide afforded 327. Further reaction of 327 with

sodium hydride and methyl iodide gave 328. Finally, reduction of 328 with

BH3THF furnished desoxyeseroline 288 (Scheme 48).

Scheme 48

The synthesis of (-)-Physostigmine have been achieved by Barry

M. Trost and co-workers102 through Molybdenum-catalyzed asymmetric

allylation. Allylation of oxindole 49 with allyl carbonate in presence of

Molybdenum- catalyzed, LiOtBu as base afforded allylated 3-alkyl oxindole (S)

329. Oxidation of allylated oxindole with OsO4, NaIO4 provided the aldehyde

(S) 74. Treatment of the aldehyde with methylamine followed by reduction with

LAH afforded (-)-esermethole 189, which was converted to (-)-Physostigmine 2

(Scheme 49).

Chapter 2

114

Scheme 49

Chisato Mukai and co-workers103,104 have demonstrated the use

of Co2(CO)8-catalyzed intramolecular aza-Pauson-Khand reaction of

alkynecarbodiimide for the synthesis of (±)-Physostigmine. Treatment of 330

with triphosgene and triethylamine was followed by exposure to methylamine to

furnish the urea derivative 331. The compound 331 was treated with carbon

tetrabromide and triphenylphosphine effected dehydration to provide

carbodiimide 332. Carbodiimide 332 was treated with Co2(CO)8,

tetramethylthiourea in toulene under CO atomsphere to give pyrrolo[2,3-b]-

indol-2-one 333 via intramolecular aza-Pauson-Khand-type reaction. Reductive

methylation of 333 with NaCNBH3 in the presence of aq. HCHO and AcOH

effected the consecutive reduction, hydroxymethylation, and N-methylation to

produce 334. Removal of the TMS group from 334 with TBAF gave 335. The

compound 335 was treated with iodine, PPh3 and imidazole to afford the iodo

derivative 336. Finally, treatment of 336 with LAH afforded 189 esermethole,

which was transformed to Physostigmine 2 (Scheme 50).

Chapter 2

115

Scheme 50

Yoshiji Takemoto and co-workers105,106 have reported the

synthesis of (±)-Physostigmine using Pd(0)-catalyzed intramolecular

cyanoamidation of alkenyl cyanoformamides. The reaction of 337 with 10 mol%

of Pd(PPh3)4 afforded the oxoindoline derivative 322 via intramolecular

cyanoamidation, bearing both a quaternary carbon center and a β-cyano group.

Hydrolysis of nitrile 322 into amide 338 with hydrogen peroxide, followed by the

reductive cyclization with LAH gave the tricyclic product 339. The compound

339 was treated with methyl chloroformate and NBS to give 340. Treatment of

340 with sodium methoxide in the presence of cuprous iodide107 and LAH

afforded the desired esermethole 189, which was converted to Physostigmine 2

(Scheme 51).

Scheme 51

Chapter 2

116

Jieping Zhu and co-workers108 have reported the synthesis of (±)-

Physostigmine using a palladium-catalyzed intramolecular domino Heck–

Cyanation reaction. Acylation of 2-iodo-4-methoxyaniline 341 with methacryloyl

chloride 342 afforded anilide 343. Latter the compound 343 was N-methylated

to give 344. Treatment of 344 with potassium ferro(II)cyanide, in the presence

of palladium acetate and sodium carbonate afforded oxindole 186 via

intramolecular domino Heck-Cyanation reaction. Oxindole 186 was treated with

LAH to provide hexahydropyrroloindole 190.109 N-methylation under reductive

amination conditions afforded esermethole 189. Cleavage of the methyl ether

group under acidic conditions (aqueous HBr) afforded the corresponding

phenol. Reaction of sodium phenoxide with N-succinimidyl-N-methylcarbamate

afforded Physostigmine 2 (Scheme 52).

Scheme 52

James H. Rigby co-workers110 have reported the synthesis of (±)-

Physostigmine employing [4+1] cyclization between bis(alkylthio)carbene and

indole isocyanate. Indole 345, obtained by using Cook’s procedure,111 on

reaction with methyl iodide followed by saponification furnished the compound

346. Treatment of 346 with diphenylphosphorazidate in the presence of Et3N

generated the acyl azide 347. The acyl azide 347 was refluxed in benzene to

Chapter 2

117

effect Curtius rearrangement to the indole isocyanate. Excess

dithiooxadiazoline 348 was then added, and the solution was refluxed to afford

adduct 349. The crude adduct was exposed to LAH to give tricycle 350. The

compound 350 was N-methylated to furnish compound 351. The reductive

cleavage of the carbon-sulfur bonds, by treatment with Raney Ni gave

compound 352. Further reduction of the lactam carbonyl group 352 with LAH

produced esermethole 189, which was converted to the Physostigmine 2

(Scheme 53).

Scheme 53

Masahisa Nakada and co-workers112 have reported the synthesis

of (-)-Physostigmine via the highly enantioselective PLE-mediated hydrolysis of

dimethyl 2-(2-chloro-5-methoxyphenyl)-2-methylmalonate. Reaction of 4,5-

dichloro-2-nitrophenol 353 with iodomethane gave the corresponding methyl

ether. The reaction of this ether with dimenthyl malonate proceeded in a

Chapter 2

118

regioselective manner to afford the compound 354 which on reaction with

iodomethane produced the quaternary center to provide the dimethyl ester 355.

Catalytic hydrogenation of 355 with Pd-C provided arylamine 356. Arylamine

356 was treated with sodium nitrate in aqueous hypophosphorous acid to

furnish the dimethyl ester 357. PLE-mediated hydrolysis of 357 at pH=8

afforded the corresponding monoester 358. The compound 358 was converted

into the corresponding acid chloride, which was reduced with NaBH4 to provide

alcohol which was subsequently protected as MOM ether 359. Ester 359 on

reaction with ammonia provided amide 360. Amide 360 was treated with

K2CO3, CuI, N-N’-dimethylthylenediamine in refluxing DMF afforded

corresponding lactam. This lactam was treated with iodomethane to effect N-

methylation to give lactam 361. Deprotection of MOM group and iodination of

resulting alcohol afforded the corresponding iodide, which was subjected to a

reaction with sodium cyanide to provide the compound 186. This was

converted to the esermethole 189 (Scheme 54).

Scheme 54

Chapter 2

119

Most of the syntheses discussed above are a result of

demonstration of efficiency of methodologies developed by various workers.

We have successfully achieved a total synthesis of Physostigmine by applying

Wittig Olefination Claisen rearrangement protocol, developed in our laboratory

previously. The efforts in this dimension are discussed in the following section.

Chapter 2

120

EXPERIMENTAL DISCUSSION

In the proposed synthetic plan, the synthesis of (±)-Physostigmine

2 could be achieved from a key intermediate, namely, a 4-pentenal derivative.

Such a 4-pentenal derivative could be prepared via Wittig Olefination - Claisen

rearrangement protocol,113 which is now a well established theme in our

laboratory.

According to the retrosynthetic analysis given above, the

Physostigmine synthesis and the previously described synthesis of

Physovenine have the aldehyde 120 as a common interemediate. As described

in the previous chapter this aldehdye was obtained by applying the Wittig

Olefination - Claisen rearrangement protocol to o-nitroacetophenone.

Accordingly the Wittig reaction of o-nitroacetophenone with

allyloxymethylenetriphenylphosphorane under standard conditions113 furnished

the corresponding allyl vinyl ether, which on heating in refluxing xylene

underwent the Claisen rearrangement to furnish the 4-pentenal 118. After

protecting the aldehyde group in 118 as its acetal, the double bond was

ozonolyzed to get the common intermediate namely, the aldehyde 120. The

further synthetic steps towards Physostigmine differed from this point.

Chapter 2

121

In order to construct the hexahydropyroindole skeleton of

Physostigmine, it was essential to convert the –CHO group in compound 120 to

-CH2NH2 group. This operation could be achieved in a variety of ways. Initially

a simple reductive amination method was attempted on the aldehyde 120. For

this purpose a mixture of aldehyde 120, excess methylamine hydrochloride,

triethylamine and little less than equimolar quantity of sodium cyano

borohydride in dry methanol at pH 6 was stirred at room temperature. The

reaction did not materialize as unchanged aldehyde was recovered back.

Attempts to effect this transformation under a variety of reaction condition,

unfortunately did not give the expected product with the starting aldehyde being

recovered every time.

Due to the above failures, the reductive amination of the aldehyde

120 through corresponding oxime was attempted. For this purpose, the

aldehyde 120 was heated with hydroxyl amine hydrochloride and sodium

acetate in refluxing aq. methanol for 10 min., when the oxime 362, was

obtained in near quantitative yield as a pale yellow liquid. The IR spectrum the

compound showed absorption bands at 3334 cm-1 and 1650 cm-1 indicating the

presence of the oxime group in the compound. Reduction of the oxime 362 with

Raney nickel under hydrogen atmosphere at room temperature for 2 hr gave a

crude product after non-aqueous work up. This crude product was purified by

column chromatography using ethyl acetate - hexane solvent system to furnish

the pure product.

The IR spectrum of the compound showed a single strong

absorption band at 3398 cm-1, which indicated the presence of a secondary

amino group rather than a primary amino group in the compound. The methyl

Chapter 2

122

protons appeared as a singlet at δ 1.31. The methylene protons alpha to the

amine group appeared separately – one gave a multiplet at δ 3.19 and while

the other proton appeared as a multiplet at δ 3.39. The methylene protons beta

to the amine gave two multiplets at δ 1.72 and δ 2.07 each integrating for one

proton. The four methylene protons of the acetal group appeared as multiplet at

δ 3.83 and the proton on the acetal carbon appeared as a singlet at δ 4.97. A

doublet at δ 6.45 integrating for one proton with coupling constant 8.0 Hz,

corresponded to the aromatic proton ortho to the amino group. A triplet at δ

6.62 for one proton with coupling constant 7.4 Hz, was attributed to the

aromatic proton para to the amine group. A triplet at δ 6.95 for one proton with

coupling constant 7.7 Hz and a doublet at δ 7.29 integrating for one proton

with coupling constant 7.7 Hz were assigned to the aromatic protons meta to

the amine group. The mass spectrum of the compound showed a molecular ion

peak at m/z 219 which did not correspond to the molecular weight of the

expected compound 363. On the other hand the molecular ion peak at m/z 219

matched well, among other possible molecular formulae, with a molecular

formula C13H17NO2. Elemental analysis also supported this molecular formula.

This indicated that the compound in hand contains one nitrogen atom only,

rather than expected two. Further it became clear from the IR spectrum that the

nitrogen in the compound is a secondary rather than primary. On the basis of

this information structure 364 was assigned to the compound.

NH

Me O

O

363 364

Chapter 2

123

The structure of the compound 364 was further confirmed by the

detailed analysis mass spectral peaks observed besides the molecule ion peak

at (M+) 219. The fragment at m/z 146 and m/z 73 were formed through the loss

of acetal group. The fragment at m/z 131 arises through the loss of the methyl

group from the fragment m/z 146. The fragment at m/z 91 was derived from the

compound involving the formation of tropylium ion. This fragmentation pattern

in mass spectrum further supported the structural assignment. Elemental

analysis also supported the molecular formula C13H17NO2.

Reduction of the oxime 362 with Raney nickel was hoped to give

the diamine product 363. However, unfortunately under these as well we got

the 2,3-tetrahydroquinoline derivative 364. As a result, reduction of oxime as

well as the nitro group in 362 was attempted using other reducing agents like

LAH in refluxing THF. Under these conditions also we ended up getting the

compound 364.

As the desired product was not obtained, there was a need to

change the route. For this purpose, aldehyde 120 was oxidized with chromium

Chapter 2

124

trioxide in aq. acetone at room temperature. On completion (TLC check) of the

reaction the normal aqueous extractive workup gave the crude product. After

purification of the crude product on a silica gel column the pure product was

obtained in good yield.

The IR spectrum the compound showed a broad absorption

bands at 3325 cm-1, 1705 cm-1, which indicated the presence of the acid group

in the compound. In the 13C NMR spectrum showed the peak at δ 178.65

corresponded to the carbonyl carbon of the acid. The methyl protons appeared

as a singlet at δ 1.54 in the 1H NMR spectrum and corresponding carbon at δ

20.60. Two doublets at δ 2.84 and δ 3.20 each integrating for one proton were

attributed to the methylene protons alpha to the carboxylic acid group and

corresponding carbon resonated at δ 47.85. The four methylene protons of the

acetal appeared as multiplet at δ 3.88 and corresponding carbons gave a

signal at δ 65.33 and δ 65.68. The proton on the acetal carbon appeared as a

singlet at δ 5.25 and at a signal in 13C NMR at δ 107.45 corresponded to this

acetal carbon. A multiplet at δ 7.34, integrating for two protons, corresponded

to the aromatic protons meta to the nitro group. A multiplet at δ 7.44 integrating

for one proton was assigned to the aromatic proton para to the nitro group. A

multiplet at δ 7.58 integrating for one proton was attributed to the aromatic

proton ortho to the nitro group. The aromatic carbons appeared at δ 123.45,

127.33, 130.13, 130.98, 132.45 and 149.50. The mass spectrum of the

compound showed a molecular ion peak at m/z 281 (M+) which corresponded

to the molecular weight of the compound and the elemental analysis confirmed

the molecular formula C13H15NO6 for the compound. Thus the above data

confirms the structure of the acid 365.

Chapter 2

125

1H NMR (300 MHz) Spectrum of the compound 364


Chapter 2

126

365

In the next step, esterification of acid 365 under usual conditions

using methanol and concentrated sulphuric acid gave the corresponding methyl

ester. The crude product was purified by column chromatography using

acetone - hexane solvent system to furnish the pure product in quantitative

yield.

The IR spectrum of the compound showed, absence of the acid

hydroxyl stretching and a strong absorption band at 1736 cm-1, which clearly

indicated the formation of the ester. In the 13C NMR spectrum showed the peak

at δ 175.85 corresponded to the carbonyl carbon of the ester. The methyl

protons of the ester functionality appeared as a singlet at δ 3.58 and

corresponding carbon resonated at δ 50.24. Molecular ions peak at m/z 295

and the elemental analysis correlated to the molecular formula C14H17NO6 for

the compound. The above spectral information confirmed the structure of the

compound of the ester 366.

366

Next step was to convert the ester 366 into corresponding amide.

This was attempted by heating ester 366 with methyl amine in sealed tube at

100O C. However, to our dismay the ester was recovered quantitatively without

Chapter 2

127

any trace of the expected amide. Reaction of the acid 365 with methylamine in

presence of DCC gave a crude product which was purified by column

chromatography using acetone - hexane solvent system to furnish the pure

product in quantitative yield.

The IR spectrum the compound showed absorption bands at

3331 cm-1 and 1714 cm-1 indicating the presence of the amide group in the

compound. In the 1H NMR spectrum a broad exchangeable singlet at δ 5.65

integrating for one proton, corresponded to the amide proton. In the 13C NMR

spectrum the carbonyl carbon atom of the amide appeared at δ 170.48. The

methyl protons of amide appeared as a doublet at δ 2.54 with coupling constant

4.6 Hz. The corresponding carbon resonated at δ 35.08. Molecular ions peak at

m/z 294 and the elemental analysis correlated to the molecular formula

C14H18N2O5 for the compound. From this spectral analysis, the compound was

confirmed to be amide 367.

367

In the next step, reduction of amide 367 with LAH under reflux

condition in THF gave a crude product. The crude product was purified by silica

gel column chromatography with acetone - hexane as a solvent system to

provide the pure product.

Chapter 2

128

1H NMR (300MHZ) Spectrum of the compound 367


Chapter 2

129

The 1H NMR spectrum, the methyl protons appeared as a singlet

at δ 1.32 in the in the 1H NMR spectrum and corresponding carbon appeared at

δ 21.23. Another, N-methyl protons appeared as a singlet at δ 2.17 and

corresponding carbon resonated at δ 36.02. The methylene protons alpha to

the amino group gave two multplets at δ 3.21 and δ 3.40 each integrating for

one proton and corresponding carbon appeared at δ 51.06. The methylene

protons beta to the amino group gave two multplets at δ 1.71 and δ 2.05 each

integrating for one proton and corresponding carbon appeared at δ 38.54. The

mass spectrum of the compound showed a molecular ion peak at m/z 233

which did not corresponded to the molecular weight of the expected compound

363. On the other hand the molecular ion peak at m/z 233 matched well with a

molecular formula - C14H19NO2. This indicated that the compound in hand

contains one nitrogen atom only, rather than expected two. Elemental analysis

also supported this molecular formula C14H19NO2. Further it became clear from

the IR spectrum that it did not showed any absorption peak in amino region. On

the basis of the above information structure 368 was assigned to the

compound.

N

MeO

O

Me

368

As a result no expected product was obtained. Hence there was a

need to change the reaction conditions. Reduction of amide 367 with Raney

nickel under hydrogen atmosphere at room temperature for 2 hr (TLC check)

Chapter 2

130

gave a crude product. After purification of the crude product on a silica gel

column the pure product was obtained in good yield.

The IR spectrum of the compound, absorption bands at 3315 cm-1

and 1660 cm-1 indicated presence of amide group rather than a primary amino

group in the compound. In the 13C NMR spectrum showed the peak at δ 170.48

corresponded to the carbonyl carbon atom of the amide. The methyl protons

appeared as a singlet at δ 1.31 in the in the 1H NMR spectrum and the

corresponding carbon appeared at δ 21.68. The 1H NMR spectrum the

compound showed two doublets at δ 2.40 and δ 2.68 each integrating for one

proton and with a coupling constant of 6.2 Hz which corresponded to the

methylene protons alpha to the amide. The corresponding carbon appeared at

δ 38.04. The four methylene protons of the acetal group appeared as a

multiplet at δ 3.71 and corresponding carbons gave a signal at δ 65.45 and δ

65.65. The proton on the acetal carbon appeared as a singlet at δ 4.78 and the

corresponding carbon appeared at δ 108.16. A broad exchangeable singlet at δ

8.6 integrating for one proton corresponded to the N-H amide proton. A doublet

at δ 6.72 integrating for one proton with coupling constant 6.8 Hz corresponded

to the aromatic proton para to amino group. A triplet at δ 6.94 integrating for

one proton with coupling constant 6.6 Hz, and a triplet at δ 7.10 integrating for

one proton with coupling constant 6.9 Hz, was attributed to the aromatic

protons meta to the amino group. A doublet at δ 7.24 integrating for one proton

with coupling constant 6.8 Hz was assigned to the aromatic proton ortho to the

amino group. The aromatic carbons appeared at δ 115.63, 122.99, 126.29,

126.74, 128.18 and 137.89 in the 13C NMR spectrum. The mass spectrum of

the compound showed a molecular ion peak at m/z 233 which corresponded to

Chapter 2

131



N

MeO

O

Me

Chapter 2

132

the molecular weight of the compound 369. Elemental analysis also supported

the molecular formula C13H15NO3 for the compound 369.

369

With the failures piling on, it became necessary to look for

alternative strategy to obtain the elusive diamine 363. The diamine 363 was

conceived to be accessed through the alcohol 121, obtainable by reducing the

aldehyde 120 by sodium borohydride. So, as described in the previous chapter,

the reduction of aldehyde group in 120 by using sodium borohydride in

aqueous THF at room temperature for 30 min was effected to get the alcohol

121. The crude alcohol was purified by silica gel column chromatography to

furnish the pure alcohol in 92 % yield.

121

In the next step, alcohol 121 was treated with methanesulphonyl

chloride in the presence of TEA at room temperature to form corresponding

mesylate. This crude mesylate was as such heated with NaN3 in DMF at 90O C

to give crude product. The crude product was purified by column

chromatography using hexane – ethyl acetate solvent system to get pure

product.

Chapter 2

133

The IR spectrum the compound showed absorption band at 2125

cm-1 typical for the azide group in the compound. The methyl protons appeared

as a singlet at δ 1.55 in the 1H NMR spectrum. The corresponding carbon

resonated at δ 26.60. The methylene protons alpha to the azide gave two

multiplets at δ 3.54 and δ 3.72 each integrating for one proton. The

corresponding carbon appeared at δ 52.32 in the 13C NMR spectrum. The

methylene protons beta to the azide also gave two multiplets at δ 2.29 and δ

2.47 each integrating for one proton. The corresponding carbon appeared at δ

37.24 in the 13C NMR spectrum. The quaternary carbon at benzylic position

appeared at δ 42.47 in the 13C NMR spectrum. The four methylene protons of

the acetal group appeared as a multiplet at δ 4.09 and the corresponding

carbons gave a signal at δ 65.45 and δ 66.51. The proton on the acetal carbon

appeared as a singlet at δ 4.99 and the acetal carbon gave a signal at δ 106.09

in 13C NMR. The four aromatic protons, two appeared as a multiplet at δ 7.39,

while the other two protons appeared as a multiplet at δ 7.55. The aromatic

carbons appeared at δ 123.89, 126.76, 130.99, 131.92, 139.37 and 149.54 in

the 13C NMR spectrum. The structure of the compound was further confirmed

by the mass spectrum, wherein the molecular ion peak was observed at (M+)

292. Elemental analysis also supported the molecular formula C13H16N4O4.

From the above spectral analysis it was clear that the compound in hand was

the expected azide 370.

NO2

Me

O

O

N3

370

Chapter 2

134


13C NMR (75 MHz) Spectrum of the compound 370

Chapter 2

135

In the next step reduction of an azide 370 with triphenyl

phosphine was conducted in refluxing aqueous THF. From this reaction mixture

starting material was recovered back quantitatively. As a result, reduction of

azide group in 370 was attempted using other reducing agents like sodium

borohydride in refluxing aqueous dioxane. But in this case also starting azide

was recovered back. These failures forced us ones again to change the

reducing agent in our synthetic plan.

Reaction of azide 370 with Zinc and ammonium chloride in

aqueous alcohol stirred at room temperature. After the reaction is over

(monitored by TLC), the mixture was filtered, and the filtrate was evaporated

under reduce pressure. The crude product was extracted with ethyl acetate and

washed with brine, dried over anhydrous sodium sulfate. After removal of

solvent under reduced pressure, the crude product was purified by column

chromatography using hexane - acetone solvent system to furnish the pure

product in a low yield.

Mass spectrum of this compound showed a molecular ion peak

at m/z 236. The elemental analysis was well in accordance with the molecular

formula C13H20N2O2 for the compound. In the IR spectrum the compound

showed strong absorption bands at 3421 cm-1 and 3356 cm-1 indicating the

presence of primary amino group in the compound. In the 1H NMR spectrum

the methylene protons on the carbon carrying the amino group appeared

separately- one gave a multiplet at δ 2.04, while other gave a triplet at δ 2.64

with coupling constant 8.2 Hz. The methylene protons beta to the amine gave a

doublet at δ 2.87-2.90 with coupling constant 8.2 Hz, integrating for two

protons. The corresponding methylene carbon appeared at δ 44.86 and δ

Chapter 2

136

45.97 in the 13C NMR spectrum. The quaternary carbon at benzylic position

appeared at δ 23.25 in the 13C NMR spectrum. The methyl protons appeared at

δ 1.44 in the 1H NMR spectrum and the corresponding carbon resonated at δ

9.03 in the 13C NMR spectrum. The four methylene protons of the acetal

group appeared as a multiplet at δ 3.75-3.85 in the 1H NMR. The

corresponding carbon appeared at δ 64.61 and δ 65.08 in the 13C NMR. The

singlet in the 1H NMR spectrum at δ 4.84 corresponded to the proton on the

acetal carbon while the corresponding carbon appeared at δ 109.33. A multiplet

at δ 6.67-6.76 integrating for two protons corresponded to the aromatic protons

ortho and para to the amino group. A triplet at δ 7.00 with coupling constant

7.7 Hz and a doublet at δ 7.15 with coupling constant 8.0 Hz each integrating

for one proton, was attributed to aromatic protons meta to the amino group.

The corresponding aromatic carbons appeared at δ 118.80, 119.05, 125.72,

127.78, 129.63 and 145.79 in the 13C NMR spectrum. The above spectral

information confirmed the structure of the compound as the diamine 363.

Although the preparation of the diamine 363 was successful, the

disappointingly poor yield of 8% thwarted the progress of the synthetic plan.

363

.

Chapter 2

137



Chapter 2

138

In order to proceed towards the goal, an alternative strategy was

conceived for the conversion of alcohol 121 into amine. This was to be

achieved in two steps sequence involving the subjecting of the alcohol to

Mitsunobu conditions. To a solution of alcohol 121, phathalimide in THF was

added, and the resulting suspension was cooled to 0O C, and then DIAD was

added and the reaction mixture was stirred at 0O C to room temperature. On

completion of the reaction the crude product was purified by column

chromatography using acetone - hexane as a solvent system to get the pure

product in 68% yield.

The IR spectrum the compound showed absorption band at 1712

cm-1 corresponding to the amide group. The 13C NMR spectrum showed the

peak at δ 167.80 and δ 168.56 corresponding to the amide carbonyl. The

methyl protons appeared at δ 1.51 in the 1H NMR spectrum and corresponding

carbon resonated at δ 21.89 in the 13C NMR spectrum. The methylene protons

alpha to the amide gave two multiplets at δ 3.52 and δ 3.64 each integrating for

one proton. The corresponding carbon appeared at δ 45.59. The methylene

protons beta to the amide gave two multiplets at δ 2.02 and δ 2.50 each

integrating for one proton and corresponding carbon resonated at δ 33.69 in

the 13C NMR spectrum. The four methylene proton of the acetal group

appeared as a multiplet at δ 3.81-3.93 in the 1H NMR. The corresponding

carbon gave at δ 65.27 and δ 65.37 in the 13C NMR. The proton on the acetal

carbon appeared as singlet at δ 5.18 and the corresponding carbon appeared

at δ 107.13. The quaternary carbon of the benzylic position appeared at δ

33.87 in the 13C NMR spectrum.

Chapter 2

139



Chapter 2

140

The mass spectrum of this compound showed a molecular ion

peak at m/z 396(M+) corresponding to the molecular weight of the compound.

Elemental analysis also supported the molecular formula C21H20N2O6 for the

compound. Thus the above spectral data confirmed the structure of the

compound 371.

371

The phathalimide derivative 371 was refluxed in methylamine at

100O C for 2 hr to afford the corresponding crude product. The crude product

was purified by using column chromatography by using appropriate solvent

system to give pure product in 68% yield.

The IR spectrum the compound showed absorption bands at

3439 cm-1 and 3381 cm-1 corresponding to the primary amine group in the

compound. In the 1H NMR spectrum a broad exchangeable singlet at δ 4.35

integrating for a one proton, corresponded to the amine N-H proton. In the 1H

NMR spectrum the methylene proton alpha to the amine gave two multiplets at

δ 2.63 and δ 2.78 each integrating for one proton. The corresponding carbon

appeared at δ 36.04 in the 13C NMR spectrum. The methylene proton beta to

the amine gave two multiplets at δ 2.04 and δ 2.32 each integrating for one

proton and the corresponding carbon appeared at δ 45.65 in the 13C NMR

spectrum. The quaternary carbon at benzylic position appeared at δ 30.30 in

the 13C NMR spectrum. The methyl protons appeared as a singlet at δ 1.37 and

Chapter 2

141

corresponding carbon resonated at δ 21.50. The four methylene protons of the

acetal appeared at δ 3.84-3.91. The corresponding carbon gave at δ 64.89 and

δ 68.87 in the 13C NMR. The proton on the acetal carbon appeared as singlet at

δ 5.11 in the 1H NMR spectrum and the corresponding carbon resonated at δ

107.02. A multiplet at δ 7.29 integrating for two protons, corresponded to the

aromatic protons meta to the nitro group. A multiplet at δ 7.44 for one proton

was assigned to the aromatic proton para to the nitro group. A doublet at δ 7.62

integrating for one proton with a coupling constant of 8.3 Hz was attributed to

the aromatic proton ortho to the nitro group. The aromatic carbons appeared at

δ 123.35, 127.08, 129.72, 130.80, 133.10 and 156.13 in the 13C NMR

spectrum. The mass spectrum of this compound showed a molecular ion peak

at m/z 266(M+) corresponding to the molecular weight of the compound.

Elemental analysis also supported the molecular formula C13H18N2O4 for the

compound. Thus the above spectral data confirmed the structure of the

compound 372.

NO2

NH2

Me O

O

372

Chapter 2

142



Chapter 2

143

In the next step, reduction of the nitro group in 372 with Raney-Ni

in presence of hydrogen atmosphere under ambient temperature and pressure

conditions was attempted. On completion, the reaction mixture was filtered

through celite bed, concentrated under reduced pressure and the crude product

was purified by silica gel column chromatography with acetone - hexane

solvent system to afford the pure product in (82%) yield. The spectral

information confirmed the structure 363 for the compound.

363

With the successful preparation of the diamine 363 in an efficient

manner, we proceeded further to complete the synthesis of Physostigmine.

According to the synthetic plan, hydrolysis of the acetal in 363 was effected by

hydrolyzing the acetal in aqueous THF using catalytic amount of p-TSA. The

reaction mixture was refluxed for 2h (TLC check) to give the crude product.

After removal of THF under reduced pressure, reaction mixture was diluted with

water and extracted in ether. Ether layer dried over sodium sulphate and

solvent was evaporated. The crude product was purified by silica gel column

chromatography with acetone - hexane solvent system to afford the pure

product in (65%) yield.

In the IR spectrum the compound showed strong absorption peak

at 3406 cm-1 indicated the presence of secondary amine group in the

Chapter 2

144

compound. In the 1H NMR spectrum peak at δ 5.01 showed singlet integrating

for one proton at C-8a#. This is a typical distinguishing value for such proton in

Physostigmine 2. Therefore, it is confirmed that the tricyclic skeleton of

Physostigmine 2 was directly obtained under the hydrolytic conditions. The

corresponding C-8a carbon appeared at δ 83.28 in the 13C NMR spectrum. The

methylene protons at C-2 position gave two multiplets at δ 3.04 and δ 3.60

each integrating for one proton. The corresponding C-2 methylene carbon

appeared at δ 42.01 in the 13C NMR spectrum. The methylene protons at C-3

appeared as two multiplets at δ 2.05 and δ 2.33 each integrating for one

proton. The corresponding C-3 carbon appeared at δ 46.82 in the 13C NMR

spectrum. The methyl protons at C-3a appeared as singlet at δ 1.38 in the 1H

NMR spectrum and the corresponding carbon resonated at δ 26.80 in the 13C

NMR spectrum. The 1H NMR spectrum of the compound showed broad

exchangeable singlet at δ 4.79, corresponding to the amine proton. The

quaternary carbon at the benzylic position resonated at δ 53.11 in the 13C NMR

spectrum. A doublet at δ 6.57 integrating for one proton with a coupling

constant 7.7 Hz, corresponded to the aromatic proton at C-7. A triplet at δ 6.76

for one proton with coupling constant 7.4 Hz was assigned to aromatic proton

at C-5. A multiplet at δ 7.02 integrating for two protons was attributed to the

aromatic protons at C-4 and C-6, in the 1H NMR spectrum. The corresponding

aromatic carbons appeared at δ 106.82, 116.10, 122.11, 127.75, 135.05 and

150.51 in the 13C NMR spectrum.

__________________________________

# The numbering of the atoms follows the standard Physostigmine numbering.

Chapter 2

145



Chapter 2

146

The mass spectrum of this compound showed a molecular ion peak at m/z

174(M+) corresponding to the molecular weight of the compound. Elemental

analysis also supported the molecular formula C11H14N2 for the compound.

Thus the above spectral data confirmed the tricyclic pyrolo[2,3-b]indole

structure 373 for the compound.

N

N

H

Me

H

373

In the next step, the pyrolo[2,3-b]indole 373 was subjected to

reductive N-methylation with formalin in the presence 10% pd/C under

hydrogen at room temperature in ethyl acetate. The crude product was filtered

through celite bed and concentrated under reduced pressure. The crude

product was purified by silica gel column chromatography with hexane - ethyl

acetate to afford pure product (90%) yield as a faint yellow liquid.

In the 1H NMR spectrum the N-methyl protons showed a singlet

at δ 2.55 and δ 2.94 each integrating for three protons. The corresponding N-

methyl carbons appeared at δ 36.41 and δ 38.42 respectively in the 13C NMR

spectrum. The methylene protons at C-2 position appeared as a multiplet at δ

2.61-2.78 integrating for two protons in the 1H NMR spectrum. The

corresponding C-2 methylene carbon appeared at δ 53.18 in the 13C NMR

spectrum. The methylene protons at C-3 position appeared as a multiplet at δ

1.90-2.09 integrating for two protons. The corresponding C-3 methylene carbon

Chapter 2

147

appeared at δ 40.89 in the 13C NMR spectrum. The methyl protons at C-3a

appeared as singlet at δ 1.43 and the corresponding methyl carbon resonated

at δ 27.30 in the 13C NMR spectrum. The C-8a proton appeared as a singlet at

δ 4.15 integrating for one proton. The corresponding C-8a carbon appeared at

δ 97.47 in the 13C NMR spectrum. The quaternary carbon at the benzylic

position resonated at δ 52.51 in the 13C NMR spectrum. A doublet at δ 6.42

integrating for one proton with a coupling constant 7.8 Hz corresponded to the

aromatic proton at C-7. A triplet at δ 6.68 for one proton with coupling constant

7.4 Hz, was attributed to the aromatic proton at C-5. A doublet at δ 6.98 for one

proton with a coupling constant 7.8 Hz, was assigned to the aromatic proton at

C-4. A triplet at δ 7.00 integrating for one proton with coupling constant 7.6 Hz,

was assigned to aromatic proton at C-6 in the 1H NMR spectrum. The

corresponding aromatic carbons appeared at δ 106.43, 117.46, 122.10, 127.68,

136.67 and 151.99 in the 13C NMR spectrum. The structure of the compound

was further confirmed by the mass spectrum, wherein the molecular ion peak

observed at (M+) 202. Elemental analysis also supported the molecular formula

C13H18N2. From the above spectral analysis it was clear that the compound in

hand was desoxyeseroline 288.

288

Chapter 2

148



Chapter 2

149

This completes the formal synthesis of Physostigmine, However

to complete the synthesis of Physostigmine, the functionalization of the

aromatic ring 288 was necessary which was accomplished by following the

known steps.106 The compound 288 was treated with N-Bromosuccinimide in

DMF at 0O C for 2h. After addition of water, the aqueous solution was extracted

with ether. Ether part of the extract was dried over sodium sulphate and

concentrated. In the next steps the crude product was treated with CuI and

sodium methoxide solution in DMF at 120O C for 2 h, the crude reaction mixture

was cooled and the insoluble materials were filtered off. The filtrate was

concentrated in vacuo and water was added to the residue. The aqueous layer

was extracted with ether and concentrated under reduced pressure. The

residue so obtained was purified by column chromatography on silica gel with

hexane and ethyl acetate to give pure product (70%) yield.

In the IR spectrum the compound showed absorption band at

1280 cm-1, indicating the presence of the ether in the compound. In the 1H

NMR spectrum the compound showed a singlet at δ 3.75 integrating for three

protons corresponding to the methoxy protons. The corresponding methoxy

carbon appeared at δ 55.95 in the 13C NMR spectrum. In the 1H NMR spectrum

the N-methyl protons showed a singlet at δ 2.52 and δ 2.88 and the

corresponding N-methyl carbons resonated at δ 37.90 and δ 38.15 respectively

in the 13C NMR spectrum. The C-8a proton appeared as singlet at δ 4.05

integrating for one proton. The corresponding C-8a carbon appeared at δ 98.31

in the 13C NMR spectrum. The methylene proton at C-2 position appeared two

multiplets at δ 2.61 and δ 2.73 each integrating for one proton in the 1H NMR

spectrum. The corresponding C-2 methylene carbon appeared at δ 52.68 in the

Chapter 2

150

13C NMR spectrum. The methylene proton at C-3 position appeared as a

multiplet at δ 1.92 integrating for two protons. The corresponding C-3

methylene carbon appeared at δ 40.73 in the 13C NMR spectrum. The methyl

proton at C-3a appeared as singlet at δ 1.43 and the corresponding methyl

carbon resonated at δ 27.35 in the 13C NMR spectrum. The quaternary carbon

at the benzylic position resonated at δ 53.02 in the 13C NMR spectrum. A

doublet at δ 6.35 integrating for one proton with a coupling constant 8.1 Hz

corresponded to the aromatic proton at C-7. Multiplet at δ 6.64 for two protons

was attributed to the aromatic protons at C-4 and C-6 in the 1H NMR spectrum.


138.22, 146.54 and 152.90 in the 13C NMR spectrum. The structure of the

compound was further confirmed by the mass spectrum, wherein the molecular

ion peak observed at (M+) 232. Elemental analysis also supported the

molecular formula C14H20N2O. The above spectral analysis it was clear that the

compound in hand was the esermethole 189.

189

Chapter 2

151



Chapter 2

152

To complete the synthesis of Physostigmine 2, compound

esermethole 189 was subject to the demethylation using with BBr3. The crude

phenol was as such treated with NaH in dry THF and the reaction mixture was

stirred at room temperature for 5 min. Then freshly prepared Methylisocyanate

from reaction of triphosgene and methyl amine hydrochloride, was added

dropwise at room temperature (TLC check). The reaction mixture on normal

aqueous extractive work up gave the crude product which was purified by silica

gel column chromatography with hexane - ethyl acetate to get pure

Physostigmine 2.

The IR spectrum of the compound showed peak at 3406 cm-1

corresponded to the amine carbamates. The 1H NMR spectrum of the

compound showed a broad exchangeable singlet at δ 5.20 for the carbamate

N-H proton. In the 13C NMR spectrum carbonyl carbon of the carbamate

appeared at δ 156.15. The N-methyl protons of carbamate appeared as a

doublet at δ 2.81 with coupling constant 4.0 Hz. The corresponding N-methyl

carbon of carbamate appeared at δ 27.64. Methyl protons at C-3a appeared as

a singlet at δ 1.41 and the corresponding carbon resonated at δ 27.24. The C-

8a proton appeared as a singlet at δ 4.12 and corresponding carbon appeared

at δ 98.13. In the 1H NMR spectrum the N-methyl groups showed two singlet

at δ 2.53 and δ 2.91 each integrating for three protons. The corresponded N-

methyl carbons appeared at δ 36.86 and δ 38.45. The methylene protons at C-

2 position appeared as a multiplet at δ 2.66-2.75 integrating for two protons in

the 1H NMR spectrum and corresponding carbon resonated at δ 53.20. The

methylene protons at C-3 position appeared as a multiplet at δ 1.95 integrating

for two protons in the 1H NMR spectrum and corresponding carbon appeared at

Chapter 2

153

δ 40.76. In the 13C NMR spectrum at C-3a carbon appeared at δ 52.58. A

doublet at δ 6.33 integrating for one proton with a coupling constant 8.1 Hz,

corresponded to the aromatic proton at C-7. Multiplet at δ 6.75-6.82 for two

protons was attributed to the aromatic at C-4 and C-6 in the 1H NMR spectrum.


137.44, 143.10 and 149.40 in the 13C NMR spectrum. The structure of the

compound was further confirmed by the mass spectrum, wherein the molecular

ion peak was observed at (M+) 275. Elemental analysis also supported the

molecular formula C15H21N3O2. The above spectral data of the Physostigmine 2

was well in accordance with the reported values.

2

This completed the synthesis of Physostigmine 2 which was achieved in eleven

steps with overall yield of 10%.

Chapter 2

154


Chapter 2

155

EXPERIMENTAL SECTION

All solvents were distilled before use. Dry THF was prepared by

distilling over sodium and benzophenone, under dry nitrogen atmosphere and

stored over sodium wire and was freshly distilled before use. All the liquid

reagents were distilled and stored under anhydrous and nitrogen atmosphere.

Dry benzene was prepared by washing it with conc. H2SO4 and distilling over

sodium and was stored over sodium wire by similar treatment toluene and

xylene was rendered dry. Dry acetone was obtained by refluxing over KMnO4

till permanent pink color persisted (6h to 8h) and then refluxed over anhydrous

K2CO3 for 4 h, distilled and stored over anhydrous K2CO3. Tert. butanol was

dried by refluxing and distilling over calcium hydride and was stored over

molecular sieves (4Aο). Dry diglyme was prepared by refluxing over calcium

hydride for 7-8 h and was distilled and stored over molecular sieves (4Aο). All

the anhydrous reactions were carried out under dry nitrogen atmosphere. IR

spectra were recorded on Shimadzu 8400 FT-IR instrument. 1H NMR and 13C

NMR spectra [ppm, TMS-internal standard] in CDCl3 were recorded on Varian

Mercury 300 instrument. Mass spectra were recorded at ionization energy of 70

eV on Shimadzu GCMS-QP5050A automated GC/MS instrument and mass

values are expressed as (m/z). Silica gel (100-200 mesh) was used for column

chromatography.

Chapter 2

156

3-(1,3-dioxolan-2-yl)-4-methyl-1,2,3,4-tetrahydroquinoline 364.

To a solution of aldehyde 120 (1.88 mmol) in aq. methanol and

added it hydroxyl amine hydrochloride (2.26 mmol), sodium acetate (2.82

mmol) and resulting reaction mixture was refluxed for 20 min TLC indicated

total consumption of the staring material. The methanol was concentrated

under reduced pressure, diluted with water and extracted in ethyl acetate (3 x

15 ml). Ethyl acetate layer dried over sodium sulphate and solvent was

evaporated. To a solution of crude compound 362 without further purification in

methanol was added Raney (catalytic) at room temperature. The reaction

mixture was stirred for 2 h under hydrogen atomsphere. Reaction mixture was

filtered through celite bed and concentrated under reduced pressure and the

crude product was purified by silica gel column chromatography with hexane

and ethyl acetate to afford 364 (68%) was obtained.

1H NMR (300 MHz, CDCl3) δ: 1.31 (s, 3H, CH3), 1.72 (m, 1H, -NCH2CH2-), 2.07

(m, 1H, -NCH2CH2-), 3.19 (m, 1H, -NCH2CH2-), 3.39 (m, 1H, -NCH2CH2-), 3.83

(m, 4H, -OCH2CH2O-), 4.97 (s, 1H, -OCHO-), 6.45 (d, J = 8.0 Hz,1H, Ar-H),

6.62 (t, J = 7.4 Hz,1H, Ar-H), 6.95 (t, J = 7.7 Hz,1H, Ar-H), 7.29 (d, J = 7.7

Hz,1H, Ar-H)

IR (Neat): 3398, 2962, 2877, 1604, 1500, 1315, 1103, 748 cm-1.

GCMS (rel. intensity) m/z: 219, 146, 131, 73, 65, 45.

Anal. Calcd for C13H17NO2 : C, 71.21; H, 7.81; N, 6.39 found: C, 71.12; H, 7.92;

N, 6.30.

Chapter 2

157

3-(1,3-dioxolan-2-yl)-3-(2-nitrophenyl)butanoic acid 365.

To a solution of aldehyde 120 (3.77 mmol) in aq. acetone was

added chromium trioxide (9.43 mmol) stirred the reaction mixture for 2hr. at

room temperature. The acetone was evaporated under reduced pressure to

give crude product. The reaction mixture was diluted with water and extracted

in ethyl acetate (3 X 15 ml), the combined organic layer dried on anhydrous

sodium sulphate and concentrated under reduced pressure. The crude product

was purified on a silica gel column chromatography with hexane- ethyl acetate

to furnish the acid 365 in 70% yield.

1H NMR (300 MHz, CDCl3) δ: 1.54 (s, 3H, -CH3), 2.84 (d, J = 19.0 Hz, 1H, -

CH2COOH), 3.20 (d, J = 17.4 Hz, 1H, -CH2COOH), 3.88 (m, 4H, -OCH2CH2O-),

5.25 (s, 1H, -OCHO-), 7.34 (m, 2H, Ar-H), 7.44 (m, 1H, Ar-H), 7.58 (m, 1H, Ar-

H).

13C NMR (75 MHz, CDCl3) δ: 178.65, 149.50, 132.45, 130.98, 130.13, 127.33,

123.45, 107.45, 65.68, 65.33, 47.85, 38.45, 20.60.

IR (Neat): 3325, 2889, 1705, 1529, 1367, 1101, 914 cm.-1

GCMS (rel. intensity) m/z: 281.


N, 4.87.

Chapter 2

158

Methyl3-(1,3-dioxolan-2-yl)-3-(2-nitrophenyl)butanote 366.

To a solution of acid 365 (0.35 mmol) in dry methanol was added

catalytic amount of concentrated sulphuric acid, the resulting mixture reflux for

2hr. The methanol was evaporated under reduced pressure. The residue was

extracted into ether (3 X 20 ml), dried on anhydrous sodium sulphate and

concentrated under reduced pressure. The crude product was purified on a

silica gel column chromatography using 2% acetone in hexane to furnish the

ester 366 in 78% yield.


CH2CO2CH3), 2.95 (d, J = 17.4 Hz, 1H, CH2CO2CH3), 3.58 (s, 3H, CO2CH3),

3.88 (m, 4H, -OCH2CH2O-), 5.25 (s, 1H, -OCHO-), 7.36 (m, 2H, Ar-H), 7.47 (m,

1H, Ar-H), 7.57 (m, 1H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 175.85, 150.65, 133.78, 130.65, 130.55, 127.85,

123.22, 108.75, 64.26, 65.33, 50.24, 45.25, 35.45, 21.33.

IR (Neat): 2889, 1736, 1529, 1367, 1101 cm.-1



N, 4.68.

3-(1,3-dioxolan-2-yl)-N-methyl-3-(2-nitrophenyl)butanamide 367.

Chapter 2

159

To a solution of acid 365 (0.7117 mmol) in dry DCM was added

methyl amine hydrochloride (3.5585 mmol) followed by triethylamine (3.5585

mmol) the solution cooled to 0O C, 1,3-dicyclohexylcarbodiimide (DCC) (0.3558

mmol) was added in one portion. The solution allowed stirring at 0O C for 2hr.

The DCM was evaporated under reduced pressure to give crude product. The

reaction mixture was diluted with water and extracted in ethyl acetate (3 X 15

ml), the combined organic layer was concentrated and purified on a silica gel

column using 2% acetone in hexane to furnish the amide 367 in 78% yield.

1H NMR (300 MHz, CDCl3) δ: 1.52 (s, 3H, -CH3), 2.54 (d, J = 4.6 Hz, 3H,

NHCH3), 2.60 (d, J = 14.6 Hz, 1H, -CH2CONH), 2.95 (d, J = 14.6 Hz, 1H, -

CH2CONH), 3.87 (m, 4H, -OCH2CH2O-), 5.37 (s, 1H, -OCHO-), 5.65 (bs, 1H,

NH), 7.34 (m, 2H, Ar-H), 7.45 (m, 1H, Ar-H), 7.61 (d, J = 8.0 Hz, 1H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 170.48, 151.87, 133.56, 130.95, 130.25, 127.85,

123.52, 107.65, 65.24, 65.74, 43.89, 37.54, 35.08, 19.20.

IR (Neat): 3331, 2931, 2877, 1635, 1714, 1529, 738 cm-1.


Anal. Calcd for C14H18N2O5: C, 57.13; H, 6.16; N, 9.52 found: C, 57.05; H, 6.20;

N, 9.43.

4-(1,3-dioxolan-2-yl)-1,4-dimethyl-3,4-dihydroquinolin-2(1H)-one 368.

To a solution of compound 367 in dry THF was added LAH, the

resulting mixture reflux for 2hr. On completion of reaction excess LAH was

quenched by adding ethyl acetate, the reaction mixture was filtered trough

Chapter 2

160

celite bed and concentrated under reduced pressure. The crude product was

purified by silica gel column chromatography with hexane – acetone to afford

368 (65%) as faint yellow thick oil.

1H NMR (300 MHz, CDCl3) δ: 1.32 (s, 3H, -CH3), 1.71 (m, 1H, -NCH2CH2), 2.05

(M, 1H, -NCH2CH2), 2.17 (s, 3H, NCH3), 3.21 (m, 1H, -NCH2CH2), 3.40 (m, 1H,

-NCH2CH2), 3.89 (m, 4H, -OCH2CH2O-), 4.99 (s, 1H, -OCHO-), 6.47 (d, J = 8.0

Hz, 1H, Ar-H), 6.63(t, J = 7.2 Hz, 1H, Ar-H), 6.96 (t, J = 7.1 Hz, 1H, Ar-H), 7.29

(d, J = 7.7 Hz, 1H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 143.25, 136.25, 127.48, 122.62, 117.14, 110.85,

107.88, 65.78, 65.35, 51.06, 42.65, 38.54, 36.02, 21.23.

IR (Neat): 2931, 2877, 1635, 1714, 1529, 738 cm-1.


Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00 found: C, 71.93; H, 8.33;

N, 6.07.

4-(1,3-dioxolan-2-yl)-4-methyl-3,4-dihydroquinolin-2(1H)-one 369.

To a solution of compound 367 (0.340 mmol) in methanol was

added Raney nickel (catalytic) at room temperature. The reaction mixture was

stirred for 2 h under hydrogen atomsphere. Reaction mixture was filtered

through celite bed and concentrated under reduced pressure. The crude

product was purified by silica gel column chromatography with hexane -

acetone to afford 369 (71%) yield.

Chapter 2

161


COCH2), 2.68 (d, J = 6.2 Hz, 1H, -COCH2), 3.71 (M, 4H, -OCH2CH2O-), 4.78 (s,

1H, -OCHO-), 6.72 (d, J = 6.8 Hz, 1H, Ar-H), 6.94 (t, J = 6.6 Hz, 1H, Ar-H), 7.10

(t, J = 6.9 Hz, 1H, Ar-H), 7.24 (d, J = 6.8 Hz, 1H, Ar-H), 8.6 (s, 1H, NH).

13C NMR (75 MHz, CDCl3) δ: 170.48, 137.89, 128.18, 126.74, 126.29, 122.99,

115.63, 108.16, 65.65, 65.45, 41.39, 38.04, 21.68.

IR (Neat): 3315, 2931, 2877, 1660, 1103, 738 cm-1.


Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00 found: C, 66.80; H, 6.56;

N, 5.94.

2-(4-azido-2-(2-nitrophenyl)butan-2-yl)-1,3-dioxolane 370.

NO2

O

O

N3

To a solution of alcohol 121 (1.87 mmol) in dry DCM (5ml) was

added dry triethylamine (1.87 mmol), and mesyl chloride (1.87 mmol). After 30

min. at room temperature TLC indicated total consumption of the staring

material. The reaction mixture was concentrated in vacuo, followed by addition

of water, extract with ethyl acetate. The organic layer was dried over anhydrous

sodium sulphate and concentrate. The crude mesylate without further

purification or characterization was mixed with sodium azide (1.87 mmol) in dry

DMF and resulting solution was heated at 90O C for 6hr. the reaction mixture

brought to room temperature it was quenched with water and crude azide was

extract with ethyl acetate. Ethyl acetate layer dried over sodium sulphate and

Chapter 2

162


chromatography with hexane and ethyl acetate to afford 370 (92%) yield.

1H NMR (300 MHz, CDCl3) δ: 1.55 (s, 3H, -CH3), 2.29 (m, 1H, -CH2CH2N3),

2.47 (m, 1H, -CH2CH2N3), 3.54 (m, 1H, -CH2CH2N3), 3.72 (m, 1H, -CH2CH2N3),

4.09 (m, 4H, -OCH2CH2O-), 4.99 (s, 1H, -OCHO-), 7.39 (m, 2H, Ar-H), 7.55 (m,

2H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 149.54, 139.37, 131.92, 130.99, 126.76, 123.89,

106.09, 66.51, 65.45, 52.32, 42.47, 37.24, 26.60.

IR (Neat): 2970, 2889, 2125, 1529, 1369, 1101, 1047, 771 cm.-1


Anal. Calcd for C13H16N4O4: C, 53.42; H, 5.52; N, 19.17 found: C, 53.34; H,

5.59; N, 19.06.

2-(3-Amino-1-[1,3]dioxolan-2-yl-1-methyl-propyl)-phenylamine 363.

To a solution of compound 370 (0.342 mmol) in aqueous ethanol

was added Zinc (0.684 mmol) and ammonium chloride (1.36 mmol) at room

temperature. The reaction mixture was stirred for 2h. After the reaction is over

(monitored by TLC), the mixture was filtered, and the filtrate was evaporated

under reduce pressure. The crude product was extracted with ethyl acetate and

washed with brine, dried over anhydrous sodium sulfate. After removal of

solvent under reduced pressure, the crude product was purified by column

chromatography using hexane – acetone solvent system to furnish the pure

product in low yield 8%.

Chapter 2

163

1H NMR (300 MHz, CDCl3) δ: 1.44 (s, 3H, -CH3), 2.04 (m, 1H, -CH2CH2NH2),

2.64 (t, J = 8.2 Hz, 1H, -CH2CH2NH2), 2.87- 2.90 (d, J = 8.2 Hz, 2H, -

CH2CH2NH2), 3.75-3.85 (m, 4H, -OCH2CH2O-), 4.84 (s, 1H, -OCHO-), 6.67-

6.76 (m, 2H, Ar-H), 7.00 (t, J = 7.7 Hz, 1H, Ar-H), 7.15 (d, J = 8.0 Hz, 1H, Ar-

H).

13C NMR (75 MHz, CDCl3) δ: 145.79, 129.63, 127.78, 125.72, 119.05, 118.80,

109.33, 65.08, 64.61, 45.97, 44.86, 23.25, 9.03.

IR (Neat): 3421, 3356, 2980, 2889, 1626, 1390, 1116, 732 cm.-1



8.60; N, 11.78.

2-(3-(1,3-dioxolan-2-yl)-3-(2-nitrophenyl)butyl)isoindoline-1,3-dione 371.

To a solution of alcohol 121 (0.374 mmol) in dry THF was added

PPh3 (0.411 mmol) followed by the addition of pthalimide (0.411 mmol) and

diisoprophyl azodizacarboxylate (DIAD) (0.411 mmol). The resulting mixture

was allowed to stir at room temperature, under a nitrogen atomsphere for 8hr.

the solvent was removed in vacuo, followed by addition of water, extract with

ethyl acetate. Ethyl acetate layer dried over sodium sulphate and solvent was

evaporated. The crude product was purified by silica gel column

chromatography with hexane and ethyl acetate to give the compound 371

(92%) yield.

Chapter 2

164

1H NMR (300 MHz, CDCl3) δ: 1.51 (s, 3H, -CH3), 2.02 (m, 1H, -CH2CH2N),

2.50 (m, 1H, -CH2CH2N), 3.52 (m, 1H, -CH2CH2N), 3.64 (m, 1H, -CH2CH2N),

3.81-3.93 (m, 4H, -OCH2CH2O-), 5.18 (s, 1H, -OCHO-), 7.33 (d, H, J = 3.6 Hz,

1H, Ar-H), 7.5 (m, 1H, Ar-H), 7.66-7.81 (m, 6H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 168.56, 167.80, 156.33, 133.94, 133.67, 132.58,

132.25, 131.85, 131.25, 130.37, 127.70, 124.03, 123.24, 122.92, 107.13,

65.37, 65.27, 45.59, 33.87, 33.69, 21.89.

IR (Neat): 2982, 1712, 1531, 1369, 721 cm-1.


Anal. Calcd for C21H20N2O6: C, 63.63; H, 5.09; N, 7.09 found: C, 63.49; H, 6.15;

N, 7.00.

3-[1,3]Dioxolan-2-yl-3(2-nitro-phenyl)-butylamine 372.

To a solution of pthalimide derivative 371 (0.252 mmol) in THF,

was added methylamine solution (0.505 mmol) and reaction mixture was

refluxed for 2hr. Removed THF under reduced pressure, reaction mixture was

diluted with water and extracted with ethyl acetate (3 x 15 ml). Ethyl acetate

part of the extract dried over sodium sulphate and concentrated. The crude

product was purified by silica gel column chromatography with hexane -

acetone to afford 372 (68%) as a colorless thick liquid.

1H NMR (300 MHz, CDCl3) δ: 1.37 (s, 3H, -CH3), 2.04 (m, 1H, -CH2CH2NH2),

2.32 (m, 1H, -CH2CH2NH2), 2.63 (m, 1H, -CH2CH2NH2), 2.78 (m, 1H, -

CH2CH2NH2), 3.84-3.91 (m, 4H, -OCH2CH2O-), 4.35 (bs, 2H, NH2), 5.11 (s, 1H,

Chapter 2

165

-OCHO-), 7.29 (m, 2H, Ar-H), 7.44 (m, 1H, Ar-H), 7.62 (d, J = 8.3 Hz, 1H, Ar-

H).

13C NMR (75 MHz, CDCl3) δ: 156.13, 133.10, 130.80, 129.72, 127.08, 123.35,

107.02, 68.87, 64.89, 45.65, 36.04, 30.30, 21.50.

IR (Neat): 3439, 3381, 3155, 2958, 2891, 1531, 734 cm.-1



6.88; N, 10.41.

3a-methyl-1,2,3,3a,8,8a-hexahydro-pyrrolo[2,3-b]indole 373.

N

N

H

Me

H

To a solution of compound 363 (0.423 mmol) dissolved in aq.

THF and added catalytic amount of p-TSA & refluxed for 2h (TLC check).

Removed THF under reduced pressure, reaction mixture was diluted with water

and extracted in ether (3 x 15 ml). Ether layer dried over sodium sulphate and


chromatography with hexane -acetone to afford 373 (65%).

1H NMR (300 MHz, CDCl3) δ: 1.38 (s, 3H, C-3a-H), 2.05 (m, 1H, C-3-H), 2.23

(m, 1H, C-3-H), 3.04 (m, 1H, C-2-H), 3.60 (m, 1H, C-2-H), 4.79 (bs, 1H, NH),

5.01 (s, 1H, C-8a-H), 6.57 (d, J = 7.7 Hz, 1H, Ar-H), 6.76 (t, J = 7.4 Hz, 1H, Ar-

H), 7.02 (m, 2H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 150.51, 135.05, 127.75, 122.11, 116.10, 106.82,

83.28, 53.11, 46.82, 42.01, 26.80.

IR (Neat): 3406, 3005, 2964, 1712, 1361, 912, 734 cm.-1

Chapter 2

166


Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08 found: C, 75.69; H, 8.19;

N, 15.97.

1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydro-pyrrolo[2,3-b]indole 288.

To a solution of compound 373 (0.287 mmol) in ethyl acetate and

added it aqueous formalin (2ml) and resulting mixture was stirred at room

temperature for 2h. Then, 10% Pd-C (catalytic) was added. The reaction

mixture was stirred 12h. under hydrogen atomsphere. The Reaction mixture

was filtered through celite bed and concentrated under reduced pressure; the


and ethyl acetate to afford 288 (90%) as a yellowish thick liquid.

1H NMR (300 MHz, CDCl3) δ: 1.43 (s, 3H, -CH3), 1.90-2.09 (m, 2H, C-3-H),

2.55 (s, 3H, NCH3), 2.61-2.78 (m, 2H, C-2-H), 2.94 (s, 3H, NCH3), 4.15 (s, 1H,

C-8a-H), 6.42 (d, J = 7.8 Hz, 1H, Ar-H), 6.68 (t, J = 7.4 Hz, 1H, Ar-H), 6.98 (d, J

= 7.8 Hz, 1H, Ar-H), 7.00 (t, J = 7.6 Hz, 1H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 151.99, 136.67, 127.68, 122.10, 117.46, 106.43,

97.47, 53.18, 52.51, 40.89, 38.42, 36.41, 27.30.

IR (Neat): 2957, 2864, 1605, 1492, 1451, 1346, 1299, 1255, 1191, 1124, 1034,

957, 737 cm.-1


Chapter 2

167

Anal. Calcd for C13H18N2: C, 77.18; H, 8.97; N, 13.85 found: C, 77.06; H, 9.05;

N, 13.78.

Esermethole 189.

N-Bromosuccinimide (0.594 mmol) was added to a solution of

288 (0.495 mmol) in DMF (2 ml) at 0O C. The mixture was stirred for 2 h at 0O

C. After addition of water, the aqueous solution was extracted with ether. Ether

part of the extract dried over sodium sulphate and concentrated. To a

suspension of the crude product and CuI (0.355 mmol) in DMF (2 ml) was

added a sodium methoxide solution (1.779 mmol). After the resulting mixture

was stirred at 120O C for 2 hr., the reaction mixture was cooled and the

insoluble materials were filtered off. The filtrate was concentrated in vacuo and

water was added to the residue. The aqueous layer was extracted with ether

and the extract was washed with brine and dried over sodium sulphate and

concentrated under reduced pressure. The obtained residue was purified by

column chromatography on silica gel with hexane - ethyl acetate to give 189

esermethole (70%).

1H NMR (300 MHz, CDCl3) δ: 1.43 (s, 3H, -CH3), 1.92 (m, 2H, C-3-H), 2.52 (s,

3H, NCH3), 2.61 (m, 1H, C-2-H), 2.73 (m, 1H, C-2-H), 2.88 (s, 3H, NCH3), 3.75

(s, 3H, OCH3), 4.05 (s, 1H, C-8a-H), 6.35 (d, J = 8.1 Hz, 1H, Ar-H), 6.64 (m,

2H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 152.90, 146.54, 138.22, 112.10, 109.72, 107.38,

98.31, 55.95, 53.02, 52.68, 40.73, 38.15, 37.90, 27.35.

Chapter 2

168

IR (Neat): 2955, 1595, 1495, 1423, 1346, 1280, 1220, 1121, 1066, 1032, 958,

707 cm.-1


Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N, 12.06 found: C, 72.27; H,

8.73; N, 11.98.

Physostigmine 2

To a solution of compound 189 (0.215 mmol) was demethylated

with BBr3. A mixture of the resulting phenol (0.091 mmol), NaH (0.110 mmol),

and THF (5.0 ml) was stirred at room temperature for 5 min, and

methylisocyanate (0.091 mmol) was added drop wise. After 10 min, the solution

was concentrated, and the residue was added to a mixture of ethyl acetate and

saturated aqueous NaHCO3. The phases were separated, the aqueous layer

was extracted with ethyl acetate, and the combined organic extracts were

washed with brine, dried over sodium sulphate and concentrated, and the


and ethyl acetate gave Physostigmine. It was dissolved in ether and equivalent

ethanolic solution of salicylic acid was added. Crystallization gave salicylate of

Physostigmine 2 as crystals mp 160-161O C (lit., mp 161-162O C).

1H NMR (300 MHz, CDCl3) δ: 1.41(s, 3H, -CH3), 1.95 (m, 2H, C-3-H), 2.53 (s,

3H, NCH3), 2.66-2.75 (m, 2H, C-2-H), 2.81 (d, J = 4.0 Hz, 3H, -NHCH3), 2.91

Chapter 2

169

(s, 3H, NCH3), 4.12 (s, 1H, C-8a-H), 5.20 (bs, 1H, NH), 6.33 (d, J = 8.1 Hz, 1H,

Ar-H), 6.75-6.82 (m, 2H, Ar-H).

13C NMR (75 MHz, CDCl3) δ: 156.15, 149.40, 143.10, 137.44, 120.34, 116.08,

106.42, 98.13, 53.20, 52.58, 40.76, 38.45, 36.86, 27.64, 27.24.

IR (Neat): 3406, 3005, 2964, 1712, 1361, 912, 734 cm.-1



7.76; N, 15.21.

Chapter 2

170

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