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
Physostigmine 2 (Scheme 44).
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
Physostigmine 2 (Scheme 45).
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
1H NMR (300 MHz) Spectrum of the compound 365
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
1H NMR (300 MHz) Spectrum of the compound 366
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
1H NMR (300 MHz) Spectrum of the compound 369
1H NMR (300 MHz) Spectrum of the compound 368
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
1H NMR (300 MHz) Spectrum of the compound 370
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
1H NMR (300 MHz) Spectrum of the compound 363
13C NMR (75 MHz) Spectrum of the compound 363
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
1H NMR (300 MHz) Spectrum of the compound 371
13C NMR (75 MHz) Spectrum of the compound 371
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
1H NMR (300 MHz) Spectrum of the compound 372
13C NMR (75 MHz) Spectrum of the compound 372
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
1H NMR (300 MHz) Spectrum of the compound 373
13C NMR (75 MHz) Spectrum of the compound 373
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
1H NMR (300 MHz) Spectrum of the compound 288
13C NMR (75 MHz) Spectrum of the compound 288
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.
The corresponding aromatic carbons appeared at δ 107.38, 109.72, 112.10,
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
1H NMR (300 MHz) Spectrum of the compound 189
13C NMR (75 MHz) Spectrum of the compound 189
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.
The corresponding aromatic carbons appeared at δ 106.42, 116.08, 120.34,
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
1H NMR (300 MHz) Spectrum of the compound 2
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.
Anal. Calcd for C13H15NO6 : C, 55.51; H, 5.38; N, 4.98 found: C, 55.40; H, 5.45;
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.
1H NMR (300 MHz, CDCl3) δ: 1.52 (s, 3H, -CH3), 2.64 (d, J = 18.0 Hz, 1H, -
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
GCMS (rel. intensity) m/z: 295.
Anal. Calcd for C14H17NO6 : C, 56.94; H, 5.80; N, 4.74 found: C, 56.82; H, 5.82;
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.
GCMS (rel. intensity) m/z: 294.
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.
GCMS (rel. intensity) m/z: 233.
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
1H NMR (300 MHz, CDCl3) δ: 1.31 (s, 3H, -CH3), 2.40 (d, J = 6.2 Hz, 1H, -
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.
GCMS (rel. intensity) m/z: 233.
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
solvent was evaporated. The crude product was purified by silica gel column
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
GCMS (rel. intensity) m/z: 292.
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
GCMS (rel. intensity) m/z: 236.
Anal. Calcd for C13H20N2O2: C, 66.07; H, 8.53; N, 11.85 found: C, 65.98; H,
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.
GCMS (rel. intensity) m/z: 396.
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
GCMS (rel. intensity) m/z: 266.
Anal. Calcd for C13H18N2O4: C, 58.63; H, 6.81; N, 10.52 found: C, 58.48; H,
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
solvent was evaporated. The crude product was purified by silica gel column
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
GCMS (rel. intensity) m/z: 174.
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
crude product was purified by silica gel column chromatography with hexane
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
GCMS (rel. intensity) m/z: 202.
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
GCMS (rel. intensity) m/z: 232.
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
crude product was purified by silica gel column chromatography with hexane
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
GCMS (rel. intensity) m/z: 275.
Anal. Calcd for C15H21N3O2: C, 65.43; H, 7.69; N, 15.26 found: C, 65.31; H,
7.76; N, 15.21.
Chapter 2
170
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