Application of vicarious nucleophilic substitution to the total synthesis of dl-physostigmine

Article abstract of DOI:10.1021/jo026438u

A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively simple method that should be adaptable to the synthesis of homologous members of this type of alkaloid. The key step in the synthesis is a new vicariou

Full text of DOI:10.1021/jo026438u

Ap p lica tion of Vica r iou s Nu cleop h ilic Su bstitu tion to th e Tota l
Syn th esis of d l-P h ysostigm in e
Pankaj D. Rege† and Francis J ohnson*,†,‡
Departments of Chemistry and Pharmacological Sciences, State University of New York,
Stony Brook, New York 11790
francis@pharm.sunysb.edu
Received September 11, 2002
A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively
simple method that should be adaptable to the synthesis of homologous members of this type of
alkaloid. The key step in the synthesis is a new vicarious nucleophilic substitution reaction between
p-nitroanisole and a C-silylated derivative of N-methylpyrrolidinone. Subsequent conversion of the
initial adduct to the tricyclic framework of physostigmine follows a well-established protocol and
provides the key intermediate 8 in high yield. The vicarious nucleophilic substitution reaction has
also been extended to six-membered lactams, with encouraging results.
In tr od u ction
Alkaloids isolated from the African calabar beans have
shown encouraging pharmacological properties.1 The
simplest members of this family of compounds are (-)-
physostigmine (1) and (-)-physovenine (2) (Figure 1). (-)-
Physostigmine (1) was first isolated2 from calabar beans
as the principal base in 1864. It was later isolated from
Streptomyces as an insecticidal compound. This type of
alkaloid ring system has also been found in marine
alkaloids such as the flustramines from broyoza Flustra
foliacea.
The well-known pharmacological effects of (-)-physo-
stigmine (1) are based on inhibiton of acetylcholinest-
erase.3 (-)-Physostigmine (1) is used clinically in the
treatment of glaucoma4 and myasthenia gravis5 and for
protection against organophosphate poisioning.6 It has
also been reported that oral or intravaneous administra-
tion of (-)-physostigmine (1) significantly improved
memory in patients with Alzheimer’s disease;7 however,
opposite results have also been reported.8
Brossi and co-workers9 have examined the anticho-
linesterase activity of natural (-) and unnatural (+)
enantiomers of physostigmine (1) along with other re-
lated compounds. It was found that the unnatural (+)-
antipode inhibits acetylcholinesterase from electric eel
considerably less than the naturally occurring (-)-1, but
F IGURE 1. Basic ring system for alkaloids isolated from
calabar beans, Streptomyces, and Flustra foliacea.
the unnatural isomer exhibits lower toxicity and blocks
the open channel of the nicotinic acetylcholine receptor.10
Moreover, the unnatural antipode was found to prevent
organophosphate-induced subjunctional damage at the
neuromuscular synapse by a mechanism not related to
cholinesterase carbamoylation.11
The first total synthesis12 of (-)-physostigmine (1) was
achieved by J ulian and Pikl in 1935. Since then a
(7) (a) Mohs, R. C.;Davis, B. M.; J ohns, C. A.; Mathe´, A. A.;
Greenmald, B. S.; Horvath, T. B.; Davis, K. L. Am. J . Psychiatry 1985,
142, 28-33 and references therein. (b) Mohs, R. C.; Davis, B. M.;
Greenmald, B. S.; Mathe´, A. A.; J ohns, C. A.; Horvath, T. B.; Davis,
K. L. J . Am. Geriatr. Soc. 1985, 33, 749-757 and references therein.
(c) Beller, S. A.; Overall, J . E.; Swann, A. C. Psychopharmacology 1985,
87, 147-151 and references therein.
(8) (a) Caltagirone, C.; Gainotti, G.; Masullo, C. Int. J . Neurosci.
1982, 16, 247-249 and references therein. (b) J atkowitz, S. Ann.
Neurol. 1983, 14, 690 and references therein. (c) Agnoli, A.; Martucci,
N.; Manna, V.; Conli, L.; Fioravanti, M. Clin. Neuropharmacol. 1983,
6, 311.
* To whom correspondence should be addressed. Tel: 631-632-8866.
Fax: 631-632-7394.
† Department of Chemistry.
‡ Department of Pharmacological Sciences.
(1) For a review, see: Hino, T.; Nakagawa, M. Alkaloids 1989, 34,
1-75.
(2) Salway, A. H. J . Chem. Soc. 1911, 99, 2143-2148.
(3) Koelle, G. B. The Pharmacological Basis of Therapeutics, 5th ed.;
Goodman, R. S., Gilman, A., Eds.; Macmillan: New York, 1975; pp
445-466.
(9) Brossi, A.;Scho¨nenberger, B.; Clark, O. E.; Ray, R. FEBS Lett.
1986, 201, 190-192.
(4) Axelsson, U. Acta Ophthalmol. 1969, 47, 1057-1067.
(5) Walker, M. B. Proc. R. Soc. Med. 1934, 1, 1200.
(6) Deshpande, S. S.;Viana, G. B.; Kauffman, F. C.; Rickett, D. L.;
Albuquerque, E. X. Fundam. Appl. Toxicol. 1986, 6, 566-577.
(10) Yu, R.-S.; Brossi, A. Heterocycles 1988, 27, 1709-1712.
(11) Kawabuchi, M.;Boyne, A. F.; Despande, S. S.; Cintra, W. M.;
Brossi, A.; Albuquerque, E. X. Synapse (NY) 1988, 2, 139-147.
(12) J ulian, P. L.; Pikl, J . J . Am. Chem. Soc. 1935, 57, 563-566.
10.1021/jo026438u CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/04/2003
J . Org. Chem. 2003, 68, 6133-6139
6133

Rege and J ohnson
SCHEME 1. Retr osyn th etic An a lysis of P h ysostigm in e
significant number of total syntheses13 of this alkaloid
have been reported. Unfortunately, a practical and ef-
ficient synthesis for this seemingly simple molecule has
not been reported to date.
Alonso and co-workers15b have used 1-alkyl-2-pyrrolidi-
none enolate ions as nucleophiles to react with aryl
halides under UV irradiation. The reaction apparently
follows an SRN1 mechanism and leads to a single product
(yields 37-60%) for each of the three aryl halides that
were examined.
Resu lts a n d Discu ssion
Although no examples of the use of Pd-chemistry in
the intermolecular construction of the physostigmine
framework are known, intramolecular Pd-catalyzed chem-
istry has been utilized successfully by Overman13b (Heck
reaction) and Zhang13j (C-arylation of acyclic amide) for
the synthesis of (-)-physostigmine and dl-physovenine,
respectively. Extension to cyclic amides of the inter-
molecular Pd-catalyzed C-arylation of ketones and esters,
first developed by the groups of Buchwald16 and Hartwig,17
appeared an attractive possibility. The nitroarenes 13
and 14 were selected to examine this approach, and
compounds 15, 16, 17, and 5 were used as substrates.
Despite significant variations (a) in the base that was
used or (b) in the Pd/L system that was employed, we
failed to achieve the desired reaction.
In reviewing the known methods for the synthesis of
physostigmine we selected the N-methylpyrrolidinone (7)
first reported by Takano and co-workers14 in 1982, as the
most desirable target. Although their synthesis (which
is enantioselective) produces 7 in only low yield, comple-
tion of the total synthesis from 7 onward is simple and
efficient. We thought that at least the racemic form of 7
might be synthesized by a more efficient three-step
procedure starting from the commercially available and
inexpensive p-nitroanisole (4) and N-methylpyrrolidinone
(5), as indicated in the retrosynthetic analysis (Scheme
1).
The key to this proposed synthesis lies in coupling the
two rings to obtain compound 6. However, few examples
of C-arylation15 of a cyclic amide moiety have been
reported in the literature. Stewart and co-workers15a have
utilized an excess of strong base (lithium isopropylcyclo-
hexylamide, 3.2-8.0 equiv) in the presence of aryl halides
for the C3-arylation of 5. The reaction was thought to
follow the benzyne mechanism, because it led to two
isomeric products (yields 16-50%) in case of nonsym-
metric substituted aryl halides. On the other hand,
(13) For a full discussion of synthetic aproaches to physostigmine
before 1989, see: (a) Takano, S.; Ogasawara, K. The Alkaloids; Brossi,
A., Ed.; Academic Press: San Diego, 1989; Vol. 36, pp 225-251. For
recent syntheses, see: (b) Matsuura, T.; Overman, L. E.; Poon, D. J .
J . Am. Chem. Soc. 1998, 120, 6500-6503. (c) Kawahara, M.; Nishida,
A.; Nakagawa, M.; Org. Lett. 2000, 2, 675-678. (d) Ishibashi, H.;
Kobayashi, T.; Machida, N.; Tamura, O. Tetrahedron 2000, 56, 1469-
1473. (e) Nakagawa, M.; Kawahara, M. Org. Lett. 2000, 2, 953-955.
(f) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2,
2757-2759. (g) Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2001, 42, 1049-1052. (h) Morales-Rios, M. S.; Santos-Sanchez,
N. F.; J oseph-Nathan, P. J . Nat. Prod. 2002, 65, 136-141. (i) Robinson,
B. Heterocycles 2002, 57, 1327-1352. (j) Zhang, T. Y.; Zhang, H.
Tetrahedron Lett. 2002, 43, 1363-1365.
(14) The only two examples noted in the literature are those reported
by (a) Stewart, J . D.; Fields, S. C.; Kochhar, K. S.; Pinnick, H. W. J .
Org. Chem. 1987, 52, 2110-2113. (b) Alonso, R. A.; Rodriguez, C. H.;
Rossi, R. A. J . Org. Chem. 1989, 54, 5983-5985.
(15) Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm.
Bull. 1982, 30, 2641-2643.
At this point, the “vicarious” nucleophilic substitution
(VNS) of hydrogen developed by Makosza and co-work-
ers18 appeared to be the next best available methodology
to achieve the needed carbon assembly. 1-Methyl-3-
phenylsulfanylpyrrolidin-2-one19 (9) was chosen initially
as the nucleofuge. However, 9 was found to be unstable
under the strong basic conditions needed for the VNS
reaction, and this led only to the formation of thiophenol
(16) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
11108-11109.
(17) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119,
12382-12383.
(18) Maksoza, M.; Wojceiechowski, K. Liebigs Ann./ Reueil 1997,
1805-1816 and references therein.
(19) Zoretic, P. A.; Soja, P. J . Org. Chem. 1976, 41, 3587-3589.
6134 J . Org. Chem., Vol. 68, No. 16, 2003

Total Synthesis of dl-Physostigmine
SCHEME 2 a
a
Different cases investigated were R ) OCH3, NO2, Cl, CH3.
SCHEME 3
treated with excess of the silyl compound 18 in the
presence of TASF at - 78 °C and the reaction mixture
was then allowed to warm to room temperature and then
stirred for 15 h before oxidizing the intermediate nitr-
onate with DDQ, the expected product 6 was now
obtained in 85% yield (Scheme 4). Attempts to use
tetrabutylammonium fluoride (TBAF) instead of TASF
failed. It is likely that the water normally present in
TBAF hydrolyzes the silyl compound 18 prior to the
Micheal reaction that leads to the nitronate ion. An
annoying feature of TASF is that it is hydroscopic and
in an attempt to avoid this the use of tetrabutylammo-
nium triphenyldifluorosilicate (TBAT)24 as a source of F-
was examined. Unfortunately, with this reagent a com-
plex reaction mixture was obtained with only a partial
consumption (25%) of the starting material.
We also examined the use of bromine in the place of
DDQ as the oxidant in the second step of the process.
This also proved to be satisfactory, although the desired
product 6 (∼60% yield) was contaminated with 15% of
3-(6′-bromo-5′-methoxy-2′-nitro-2′,4′-cyclohexadienyl)-1-
N-methylpyrrolidin-2-one (31). Nevertheless this did not
constitute a problem because subsequent treatment with
Et3N led to 6 in approximately 73% overall yield
In continuing with the synthesis of 1, an ion-pair-
mediated reaction using the phase-transfer catalysis
(PTC) method was employed to achieve methylation of
6. When the latter was treated with methyl iodide using
tetrabutylammonium bromide as the catalyst, compound
3 was obtained in 95% yield (Scheme 4). Its structure
was confirmed by X-ray crystallographic analysis.27
Encouraged by this result we attempted an asymmetric
methylation using the dihydrocinchodinium salt devel-
oped by Corey and co-workers,28 as the chiral catalyst
for the alkylation reaction under PTC conditions. In our
case the catalyst failed to give any selectivity whatsoever
(as determined by chiral HPLC of compound 7 and the
lack of optical rotation in the subsequent tricyclic com-
pound 8). A second attempt at enantioselective alkylation
was made using a chiral tetradentate lithium amide
developed by Matsuo and co-workers29 as the base.
However, in this case no alkylation occurred at all as
judged by TLC analysis.
and the pyrrolenones 11 and 12 (detected in the reaction
mixture by 1H NMR) (Scheme 2). Again all of our
attempts to use 3-chloro-1-methyl-2-pyrrolidinone20 (10)
in place of 9 met with the same fate. Also, during the
course of attempting these VNS reactions it was observed
that under a variety of conditions the color of the
mixtures turned dark blue on the addition of the base.
Such color changes are known to be associated with acid-
base reactions of the nitronate ion, which lead to the
destruction of the nitroarene.21
An alternative approach that proved to be more suc-
cessful was the fluoride-assisted nucleophilic addition of
enol silyl ethers to aromatic nitro compounds (Scheme
3) developed by RajanBabu and co-workers.22 Oxidation
of the resulting intermediate nitronate gives R-nitroaryl
carbonyl compounds. Formally, this is a variation of the
VNS of hydrogen, but because the C-arylation proceeds
under nonbasic reaction conditions, it seemed likely that
the destructive acid-base reactions noted above could be
avoided.
The R-silylated derivative 18 of 1-methyl-2-pyrrolidi-
none (5) needed to follow this strategy was prepared in
high yield by the method of Kramarova and co-workers.23
It is well-established23 in the literature that the cleavage
of such R-silyl carbonyl compounds using fluoride anion
leads to the generation of stabilized enolate anions.
Indeed Kramarova and co-workers,23 in studying the
reactivity of 1-methyl-3-trimethylsilyl-2-pyrrolidinone
(18), found that it reacts easily with a series of electro-
philic reagents to give R-substituted pyrrolidin-2-ones.
Following the exact experimental procedure by Rajan-
Babu and co-workers,22 the reaction of the silyl compound
18 with p-nitrotoluene (19) took place smoothly to give
the coupled product 20 but in only 11% isolated yield.
The remainder was the unreacted starting material.
Better results were obtained in the case of p-nitroanisole
(4) where a 50% isolated yield of compound 6 was
obtained, again the remanider being unreacted starting
material. Modification of the reaction conditions then led
to more satisfactory results. When p-nitroanisole (4) was
Compound 3 on catalytic reduction with 10% Pd/C in
(24) Pilcher, A. S.;Ammon, H. L.; DeShong, P. J . Am. Chem. Soc.
1995, 117, 5166-5167.
(25) Woodbury, R. P.; Rathke, M. W. J . Org. Chem. 1978, 43, 881-
884.
(20) Vedejs E.; Galante R. J .; Goekjian P. G. J . Am. Chem. Soc. 1998,
120, 3613-3622.
(26) Maksoza, M.; Winiarski, J . J . Org. Chem. 1984, 49, 1494-1499.
(27) Crystal data is available in Supporting Information.
(28) (a) Corey, E. J .;Xu, F.; Noe, M. C. J . Am. Chem. Soc. 1997, 119,
12414-12415. (b) Corey, E. J .; Bo, Y.; Busch-Peterson, J . J . Am. Chem.
Soc. 1998, 120, 13000-13001.
(29) Matsuo, J .;Kobayashi, S.; Koga, K. Tetrahedron Lett. 1998, 39,
9723-9726.
(21) Paradasi, C.; Scorrano, G. Acc. Chem. Res. 1999, 32, 958-968.
(22) RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. J . Am. Chem.
Soc. 1985, 107, 5473-5483.
(23) Kramarova, E. P.; Anisomova, N. A.; Baukov, Y.; I. Zh. Obshch.
Khim. 1991, 61, 1406-1413.
J . Org. Chem, Vol. 68, No. 16, 2003 6135

Rege and J ohnson
SCHEME 4. F or m a l Tota l Syn th esis of d l-P h ysostigm in e
EtOAc then provided in quantitative yield the ami-
noarene 7, whose spectroscopic data were identical to
those previously reported in the literature.30 Although
the synthesis of compound 7 formally completes a new
short total synthesis of dl-physostigmine 1, we repeated
the reductive cyclization of the amino compound 7 using
lithium aluminum hydride. As reported by Takano and
co-workers14 the required tricyclic intermediate 8 was
obtained in 60% yield. The final three steps to obtain 1
are efficient and well-established.14
The lack of a general method in the literature for the
C-arylation of cyclic amides prompted us to explore the
application of the VNS reaction to other systems. In this
regard, the silyl derivative of the six-membered lactam
21 smoothly underwent coupling with p-nitrotoluene (19)
and p-bromonitrobenzene (22) (entries 3 and 4, Table 1).
As has been observed by RajanBabu and co-workers,22
the halo groups of nitroarenes are stable under these
reaction conditions (entry 3, Table 1). By contrast reac-
tion of the silyl derivative of the seven-membered lactam,
namely, N-methyl caprolactam, failed with several dif-
ferent nitroarenes to give any product on attempted
reaction whatsoever. However, as expected, the coupling
reaction itself is sensitive to steric effects. When the silyl
compound 23 was allowed to react with p-nitroanisole
(entry 6, Table 1), in comparison with the same reaction
of 3 a dramatic decrease in the yield was observed (to
1
around 15% as judged by H NMR and GC/MS analysis
of the crude product). Despite this low yield it is worth
noting that the reaction does lead to the formation of a
carbon quaternary center in one step. Interestingly and
in constrast to the intramolecular case,13j when the
reaction was applied to the acyclic amide 24,24 only
compound 2525 was isolated as the sole product (entry 7,
Table 1).
In summary, we have developed a new procedure for
the C-arylation of cyclic amides, application of which to
the formal total synthesis of (()-physostigmine leads to
a substantially improved and much shorter route to this
biologically important natural product. This approach
should also provide easy access to other natural products
having a similar framework and is versatile enough to
allow significant variations in the basic structure of
physostigmine itself.
(30) Shishido, K.;Shitara, E.; Komatsu, H.; Hiroya, K.; Fukumoto,
K.; Kametani, T. J . Org. Chem. 1982, 51, 3007-3011.
6136 J . Org. Chem., Vol. 68, No. 16, 2003

Total Synthesis of dl-Physostigmine
TABLE 1. Exa m p les of th e Vica r iou s Nu cleop h ilic Su bstitu tion Rea ction
a
b
Yield based on recovered starting material is reported in brackets. Reaction carried out for 2 h at -40 °C c Yield on the basis of
GC/MS analysis of crude reaction product.
complex of benzophenone before use. Acetonitrile was freshly
distilled from CaH2. All compounds were judged pure by TLC
(single spot/ two solvent systems) using a UV lamp or an iodine
chamber for detection purposes. Elemental analysis was
performed by Schwarzkopf Microanalytical Laboratory, Wood-
Exp er im en ta l Section
All reactions were performed under nitrogen gas in glass-
ware that was flame-dried and equipped with a magnetic bar.
Tetrahydrofuran (THF) was freshly distilled from the sodium
J . Org. Chem, Vol. 68, No. 16, 2003 6137

Rege and J ohnson
side, NY. TLC analysis was performed on silica gel sheets
containing a fluorescent indicator. Flash column chromato-
graphic separation was carried out on 60 Å (230-400-mesh)
silica gel. All experiments dealing with moisture-sensitive
compounds were conducted under an atmosphere of dry
nitrogen. TASF was transferred under an atmosphere of dry
nitrogen in a glovebox.
1-N -Me t h yl-3-(5′-b r om o-2′-n it r op h e n yl)p ip e r id in -2-
on e (26). Treatment of 450 mg of 22 with 530 mg of 21 and
680 mg of TASF resulted in 415 mg of 26 (silica gel column
chromatography, eluent 70% ethyl acetate in hexanes). Yield:
60%. 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J ) 6 Hz, 1H),
7.52 (dd, J 1 ) 3 Hz, J 2 ) 6 Hz, 1H), 7.465 (d, J ) 3 Hz, 1H),
3.97 (q, J ) 6 Hz, 1H), 3.61-3.52 (m, 1H), 3.39-3.32 (m, 1H),
2.98 (s, 3H), 2.24-2.12 (m, 1H), 2.05-1.96 (m, 1H). 13C NMR
(62.5 MHz, CDCl3): δ 168.4, 147.7, 138.5, 135.0, 130.8, 127.8,
126.7, 49.9, 47.3, 34.9, 29.7, 22.5. ES (M + H)+ m/z: 313.1 (calcd
for C12H13BrN2O3 312.01). Anal. Calcd for C12H13BrN2O3: C,
46.03, H, 4.18, Br, 25.52, N, 8.95. Found: C, 46.23, H, 4.21,
Br, 25.72, N, 8.90.
1-N-Met h yl-3-(5′-m et h yl-2′-n it r op h en yl)p ip er id in -2-
on e (27). Compound 19 (249 mg) was treated with 506 mg of
21 and 500 mg of TASF to obtain 237 mg of 27 (silica gel
column chromatography, eluent 50% ethyl acetate in hexanes).
Yield: 53% (70% brsm). 1H NMR (300 MHz, CDCl3): δ 7.92
(d, J ) 9 Hz, 1H), 7.18-7.15 (m, 1H), 7.09-7.08 (d, J ) 3 Hz,
1H), 4.00-3.94 (m, 1H), 3.62-3.53 (m, 1H), 3.38-3.30 (m, 1H),
2.99 (s, 3H), 2.40 (s, 3H), 2.21-2.09 (m, 1H), 2.00-1.92 (m,
1H). 13C NMR (62.5 MHz, CDCl3): δ 169.2, 146.3, 144.3, 136.7,
132.8, 128.2, 125.4, 50.0, 47.6, 34.8, 29.8, 22.4, 21.2. ES (M +
H)+ m/z: 248.9 (calcd for C13H16N2O3 248.12). Anal. Calcd for
1-Meth yl-3-(tr im eth ylsilyl)-2-pyr r olidin on e (18). To 16.9
g (0.156 mol; 2 M solution in heptane/ethyl benzene/THF) of
LDA in 78 mL of dry THF at -78 °C under an atmosphere of
nitrogen was added 10.28 g (0.14 mol) of 1-methyl-2-pyrroli-
dinone (5) (freshly distilled from CaH2) dropwise with stirring.
When the addition was complete, the resulting mixture was
stirred for an additional 10 min, at which point 24 mL (0.87
mol) of Me3SiCl was rapidly added to the mixture. Stirring
was then continued for 3 h, by which time the reaction mixture
had warmed to room temperature. Solvent was then removed
in vacuo by rotoevaporation, and then ca. 150 mL of cold (0
°C) pentane was added to the residue. Rapid filtration and
evaporation of the filtrate in vacuo yielded the crude product.
Fractional distillation at 55-60 °C (1 mm of Hg) gave pure
product 18 in 85% yield. 1H NMR (300 MHz, CDCl3): δ 3.37-
3.23 (m, 2H), 2.78 (s, 3H), 2.21-2.11 (m, 1H), 1.94-1.84 (m,
2H), 0.08 (s, 9H). Because the NMR data was identical to that
previously reported,23 the compound was used in the next step
without further characterization.
C
13H16N2O3: C, 62.89, H, 6.50, N, 11.28. Found: C, 63.07, H,
6.67, N, 11.28.
3-(5′-Meth oxy-2′-n itr op h en yl)bu tyr ola cton e (28). Reac-
tion of 290 mg of 4 with 450 mg of 29 and 525 mg of TASF
gave 150 mg of 28 (silica gel column chromatography, eluent
50% ethyl acetate in hexanes). Note: The reaction was stopped
after 2 h at -40 °C. Longer reaction times gave side products
with no substantial improvement in yield. Yield: 38% (68%
Gen er a l P r oced u r e for Cou p lin g Rea ction Exem p li-
fied by Syn th esis of 1-N-Meth yl-3-(5′-m eth oxy-2′-n itr o-
p h en yl)p yr r olid in -2-on e (6). (Note: An identical procedure
was employed to synthesize compounds 20 and 26-29). To a
mixture of 555 mg (3.63 mmol) of p-nitroanisole (4) and 1.06
g (1.7 equiv, 6.16 mmol) of 1-methyl-3-(trimethylsilyl)-2-
pyrrolidinone (18) in 5 mL of dry THF at -78 °C (dry ice and
acetone) was added 1.0 g (3.63 mmol) of TASF dissolved in 3
mL of CH3CN and 2 mL of THF. The mixture was stirred for
15 h, by which time it had reached room temperature. The
mixture was then cooled to -78 °C, and 1.4 g of DDQ (6.16
mmol) in 5 mL of dry THF was added dropwise. After the
addition was complete, the reaction mixture was brought to
room temperature and stirred at room temperature for another
hour. The volatiles were removed under reduced pressure, and
the crude solid was dissolved in CH2Cl2 (15 mL) and washed
with water (15 mL). The aqueous layer was extracted with
CH2Cl2 (2 × 5 mL), and the combined organic layers were
washed with 5% NaOH (15 mL) and then brine (15 mL). The
organic layer was dried (MgSO4), and the solvent was evapo-
rated. The crude product was chromatographed on a silica gel
column (eluent ethyl acetate/hexanes 4:1) to give the pure
product (6, 770 mg) in 85% yield. 1H NMR (300 MHz, CDCl3):
δ 8.06 (d, J ) 9 Hz, 1H), 6.85 (dd, J 1) 3 Hz, J 2) 9 Hz, 1H),
6.78 (d, J ) 3 Hz, 1H), 4.38 (t, J ) 9 Hz, 1H), 3.87 (s, 3H),
3.50-3.44 (m, 2H), 2.96 (s, 3H), 2.75-2.71 (m, 1H), 2.07-2.00
(m, 1H). 13C NMR (62.5 MHz, CDCl3): δ 175.9, 163.2, 142.4,
137.6, 127.5, 115.7, 112.2, 55.6, 47.2, 45.5, 29.8, 27.7. IR
(KBr): 1521.65, 1696.19, 1706.32 cm-1. GC/MS (EI) (M - NO2)
m/z: 204 (calcd for C12H14NO2 - NO2 204.11). Anal. Calcd for
1
brsm). H NMR (300 MHz, CDCl3): δ 8.16 (d, J ) 9 Hz, 1H),
6.92 (dd, J 1 ) 3 Hz, J 2 ) 9 Hz, 1H), 6.83 (d, J ) 3 Hz, 1H),
4.58-4.37 (m, 3H), 3.89 (s, 3H), 2.92-2.81 (m, 1H). 13C NMR
(62.5 MHz, CDCl3): δ 175.97, 163.71, 142.31, 134.97, 128.50,
117.17, 113.28, 66.75, 56.05, 44.56, 30.97. GC/MS (EI) (M):
237.0 (calcd for C11H11NO5: 237.06). Anal. Calcd for C11H11
-
NO5: C, 59.73, H, 5.01, N, 6.33. Found: C, 55.96, H, 4.69, N,
5.90.
(4-Nitr o-3-bip h en ylyl)a ceton itr ile (25). Treatment of 160
mg of 30 with 229 mg of 24 and 220 mg of TASF resulted in
70 mg of 25 (silica gel column chromatography, eluent 70%
ethyl acetate in hexanes). Yield: 39% (50%, brsm). The
spectroscopic data were identical to those previously reported.26
1H NMR (300 MHz, CDCl3): δ 8.29 (d, J ) 9 Hz, 1H), 7.92 (t,
J ) 1.05 Hz, 1H), 7.75 (dd, J 1 ) 3 Hz, J 2 ) 9 Hz, 1H), 7.66-
7.63 (m, 2H), 7.52-7.26 (m, 3H), 4.30 (s, 3H). 13C NMR (62.5
MHz, CDCl3): δ 147.52, 146.06, 137.67, 129.49, 129.32, 129.23,
127.76, 127.33, 126.51, 126.33, 22.99. IR (KBr pellet): 1344.31,
1513.07 (NO2), 2235.04 (CN). The structure was also confirmed
by X-ray analysis.
1,3-Dim eth yl-3-(5′-m eth oxy-2′-n itr op h en yl)p yr r olid in -
2-on e (3). To a mixture of 1-methyl-3-(5′-methoxy-2′-nitroben-
n
zene)pyrrolidin-2-one (6) (250 mg, 1.0 mmol), Bu4NBr (32.23
mg, 10 mol %), and CsOH‚H2O (1.67 g, 10.0 mmol) in toluene
(10 mL) was added methyl iodide (4 mL, 12.4 mmol) dropwise.
The reaction was stirred rigorously at room temperature for
10 h, by which time complete consumption of the starting
material was observed. The volatiles were removed under
reduced pressure, the solid residue was dissolved in Et2O (20
mL), and then the extract was washed with water (2×) and
brine, dried (MgSO4), and concentrated in vacuo. The crude
solid (253 mg) was purified by silica gel column chromatog-
raphy (eluent ethyl acetate/hexanes 4:1) to give the required
product 1,3-dimethyl-3-(5′-methoxy-2′-nitrophenyl)pyrrolidin-
C
12H14N2O4: C, 57.59, H, 5.64, N, 11.19. Found: C, 57.87, H,
5.62, N, 10.86
1-N-Met h yl-3-(5′-m et h yl-2′-n it r op h en yl)p yr r olid in -2-
on e (20). Compound 19 (497 mg) was allowed react with 750
mg of 18 and 1.0 g of TASF to obtain 20 (100 mg) (silica gel
column chromatography, eluent 70% ethyl acetate in hexanes).
Note: The reaction was stopped after 2 h at -40 °C. Yield:
11% (92% based on recovered starting material (brsm)). 1H
NMR (250 MHz, CDCl3): δ 7.82 (d, J ) 7.5 Hz, 1H), 7.13 (d,
J ) 7.5 Hz, 1H), 7.07 (s, 1H), 4.23 (t, J ) 10 Hz, 1H), 3.46-
3.40 (m, 2H), 2.92 (s, 3H), 2.73-2.63 (m, 1H), 2.61 (s, 3H),
2.36-2.96 (m, 1H). 13C NMR (62.5 MHz, CDCl3): δ 173.4, 147.1,
144.6, 135.0, 130.9, 128.4, 124.9, 47.3, 45.1, 30.0, 28.1, 21.3.
ES (M + H)+ m/z: 235.1 (calcd for C12H14N2O3 234.10). Anal.
Calcd for C12H14N2O3: C, 61.53, H, 6.02, N, 11.96. Found: C,
62.67, H, 5.92, N, 11.63.
1
2-one (3) in 95% yield (246 mg). H NMR (300 MHz, CDCl3):
δ 7.87 (d, J ) 9 Hz, 1H), 7.12 (d, J ) 3 Hz, 1H), 6.82 (dd, J 1
)
3 Hz, J 2 ) 9 Hz, 1H), 3.87 (s, 3H), 3.49-3.43 (m, 2H), 2.91 (s,
3H), 2.63-2.59 (m, 1H), 2.13-2.05 (m,1H), 1.62 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 171.67, 157.96, 138.07, 135.57,
123.73, 111.63, 106.64, 51.26, 43.71, 41.90, 29.68, 25.52, 20.15.
6138 J . Org. Chem., Vol. 68, No. 16, 2003

Total Synthesis of dl-Physostigmine
GC/MS (EI) (M - NO2): 218 (calcd for C13H16N2O4 - NO2
218.13). Anal. Calcd for C13H16N2O4: C, 59.08, H, 6.10, N, 10.06.
Found: C, 60.13, H, 6.72, N, 10.71. X-ray crystallographic data
is available in Supporting Information.
and the reaction mixture was stirred at room temperature for
40 min, by which time complete consumption of 7 had occurred
(TLC analysis). The reaction mixture was then cooled to 0 °C,
and 3 mL of EtOAc was added to destroy unreacted lithium
aluminum hydride. The solution was then filtered through
Celite, and the Celite plug was thoroughly washed with EtOAc.
The filtrate and the washings (∼15 mL) were combined and
washed with 1.0 N HCl (10 mL), water (10 mL), and brine (10
mL). The organic layer was dried (MgSO4), filtered, and
concentrated to give 430 mg of crude material. Silica gel
column chromatography (eluent 90% ethyl acetate in hexanes)
then afforded compound 8 (140 mg) in 60% as reported by
Takano and co-workers,14 mp 70 °C (reported14 68-69 °C). 1H
NMR (300 MHz, CDCl3): δ 6.65-6.51 (m, 3H), 4.39 (s, 1H),
4.22 (broad singlet, 1H, NH), 3.73 (s, 3H), 2.75-2.62 (m, 2H),
2.44 (s, 3H), 2.03-1.99 (m, 2H), 1.42 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 153.7, 143.0, 138.2, 112.4, 109.9, 109.4, 89.8,
55.8, 53.8, 52.2, 40.1, 36.5, 26.5.
1,3-Dim eth yl-3-(2′-am in o-5′-m eth oxyph en yl)pyr r olidin -
2-on e (7). An ethyl acetate solution (20 mL) of 1,3-dimethyl-
3-(5′-methoxy-2′-nitrophenyl)pyrrolidin-2-one (3) (578 mg) was
hydrogenated at 50 psi in the presence of 10% Pd/C (70 mg)
for 3 h at room temperature. The reaction mixture was then
filtered through a plug of Celite to remove the Pd/C. The Celite
plug was thoroughly washed with ethyl acetate, and the
washings and the filterate were combined and evaporated on
a rotary evaporator to obtain almost pure 7. This product was
then subjected to silica gel column chromatography (eluent
ethyl acetate) to give 1,3-dimethyl-3-(2′-amino-5′-methoxyben-
zene)-pyrrolidin-2-one (7) in quantitative yield (518 mg). 1H
NMR (300 MHz, CDCl3): δ 6.81 (d, J ) 3 Hz, 1H), 6.67-6.59
(m, 2H), 4.12-4.09 (m, 2H, NH2), 3.73 (s, 3H), 3.44-3.29 (m,
2H), 2.86 (s, 1H), 2.76-2.67 9m, 1H), 2.00-1.91 (m, 1H), 1.60
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.18, 148.09, 134.84,
123.63, 114.82, 190.40, 107.98, 51.26, 43.39, 41.98, 28.83,
25.81, 17.08. The spectral data were identical to those previ-
ously reported.30 FABMS (M + H)+ m/z: 235.08 (calcd for
Ack n ow led gm en t. We thank Professor J oseph W.
Lauher and Sean M. Curtis for the X-ray crystal-
lographic analysis. Robert A. Rieger and Avalyn Lewis
are also gratefully acknowledge for performing the mass
analysis.
C
13H18N2O2 234.14). Anal. Calcd for C13H18N2O2: C, 66.63, H,
7.74, N, 11.96. Found: C, 66.30, H, 7.82, N, 11.76.
5-Meth oxy-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h yd r o-p yr -
r olo[2,3-b]in d ole (8). To an ice-cooled 3 mL THF (dry)
solution of 1,3-dimethyl-3-(2′-amino-5′-methoxybenzene) pyr-
rolidin-2-one (7) (270 mg, 1.16 mmol) was added 67 mg (1.75
mmol) of lithium aluminum hydride under a nitrogen stream
in roughly three equal portions. The ice bath was removed,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and X-ray crystallographic data in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026438U
J . Org. Chem, Vol. 68, No. 16, 2003 6139