[3 + 2] Cycloaddition of nonstabilized azomethine ylides. 7. Stereoselective synthesis of epibatidine and analogues

Article abstract of DOI:10.1021/jo971728+

Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5- bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3- (6-chloro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3- pyridyl moiety is endo-oriented. Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct 33, in which 6- chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by epimerization reaction using KO(t)Bu. An alternative route involving conjugate addition of 6-chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested for the stereoselective synthesis of 1. A number of substituted epibatidines (38, 39, 40, 41, and 42) are synthesized through this strategy using appropriate dipolarophiles. Formal synthesis of the N-methyl homoepibatidine 48 and its epimer 46 is suggested from the cycloaddition of homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.

Full text of DOI:10.1021/jo971728+

760
J . Org. Chem. 1998, 63, 760-768
[3 + 2] Cycloa d d ition of Non sta bilized Azom eth in e Ylid es. 7.
Ster eoselective Syn th esis of Ep iba tid in e a n d An a logu es†,‡
Ganesh Pandey,* Trusar D. Bagul, and Akhil K. Sahoo
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received September 16, 1997
Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via
nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of
N-benzyl-2,5-bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3-(6-chloro-
3-pyridyl)-2-propenoate (22a ) gives 26 in which the 6-chloro-3-pyridyl moiety is endo-oriented.
Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct
33, in which 6-chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing
cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by
epimerization reaction using KOtBu. An alternative route involving conjugate addition of 6-chloro-
3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested
for the stereoselective synthesis of 1. A number of substituted epibatidines (38, 39, 40, 41, and
42) are synthesized through this strategy using appropriate dipolarophiles. Formal synthesis of
the N-methyl homoepibatidine 48 and its epimer 46 is suggested from the cycloaddition of
homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.
In tr od u ction
studies.12-19,21-29 Basically, the strategies adopted for the
synthesis of this novel alkaloid, which are primarily
Epibatidine (1), a novel alkaloid possessing the 7-aza-
bicyclo[2.2.1]heptane ring system with a 6-chloro-3-
pyridyl substituent in exo orientation, isolated1 by Daly
et al. in 1992 from the skin extracts of Equadorian poison
frogs, Epipedobates tricolor, has been shown to exhibit
nonopiod analgesic activity 200-500 times more than
that of morphine. Recent studies have also shown that
1 is an extremely potent agonist of the acetyl choline
receptors2-5 that has been found to be involved in the
mediation of several human disorders such as Alzheimer
and Parkinson diseases.6 Epibatidine has also been
shown to have little or no activity at a variety of other
CNS receptors including muscarinic, adrenergic, dopam-
ine, sertonine, and GABA receptors.3 Therefore, renewed
interest is emerging to screen 1 for other nicotine receptor
mediated human disorders.4
(7) Damaj, M. I.; Creasy, K. R.; Grove, A. D.; Rosecrans, J . A.;
Martin, B. R. Brain. Res. 1994, 664, 34.
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Pharmocol. 1994, 113, 1487.
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Kaplan, M.; Buckley, M. J .; Gopalkrishnan, M.; Williams, M.; Americ,
S. P. J . Pharmacol. Exp. Ther. 1994, 271, 624.
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Alkaloids; Academic Press: New York, 1995; Vol. 46, p 95.
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35, 5417.
Due to its intriguing pharmacological activity, inter-
esting structural features, and scarcity in nature (less
than 5 mg was isolated1 from 750 frogs), epibatidine has
been the subject of many biological2-11 and synthetic
* Corresponding author. FAX: (91)-212-335153; e-mail: pandey@
ems.ncl.res.in.
†
Dedicated to Prof. G. S. R. Subba Rao on the occasion of his 60th
birthday.
‡ For parts 1-6, refer to (i) Pandey, G.; Lakshmaiah, G.; Kumar-
swamy, G. J . Chem. Soc., Chem. Commun. 1992, 1313. (ii) Pandey,
G.; Lakshmaiah, G. Tetrahedron Lett. 1993, 34, 4861. (iii) Pandey, G.;
Lakshmaiah, G. Synlett. 1994, 277. (iv) References 30 and 31. (v)
Pandey, G.; Lakshmaiah, G.; Gadre, S. R. Ind. J . Chem. 1996, 35B,
91.
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Pannell. L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475.
(2) Li, T.; Qian, C.; Eckman, J .; Huang, D. F.; Shen. T. Y. Bioorg.
Med. Chem. Lett. 1993, 3, 2759.
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J .; Biftu, T.; Ip, S. Eur. J . Pharmacol. 1993, 250, R13.
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S0022-3263(97)01728-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/16/1998

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides
J . Org. Chem., Vol. 63, No. 3, 1998 761
Sch em e 1
Sch em e 3
Sch em e 4a
a
Rea gen ts a n d con d ition s: (i) Ether, TMED, -78 °C, s-BuLi,
2 h, TMSCl; (ii) Ether, TMED, -45 °C, s-BuLi, -35 °C (15 min),
-45 °C, TMSCl; (iii) DCM, TFA, rt, 4 h; (iv) BnCl, K2CO3, CH3CN,
∆ 4 h.
yield. Moreover, these strategies lack easy adaptability
for the synthesis of epibatidine analogues. Harman et
al.29 have attempted the synthesis of 1 through the
cycloaddition of pentaamine-osmium(II) [(Os(NH3)5(η2-
pyrrole)]+2 (OTf)2 complex; however, their effort remained
unsuccessful owing to the lack of reactivity of the osmium
complex toward pyridyl acrylates. To provide an efficient
synthesis of 1 and its derivatives, we have developed a
[3 + 2] cycloaddition based strategy utilizing nonstabi-
lized azomethine ylide 10 as dipole and 6-chloro-3-vinyl
pyridine derivatives 11 as dipolarophile (Scheme 2). Full
details of our effort and success is delineated in this
article.30
Sch em e 2
Resu lts a n d Discu ssion
Ba ck gr ou n d a n d Con cep t. While designing the
synthesis of 1 through the retrosynthetic route as de-
picted in Scheme 2, we were guided by an earlier
investigation from our group31 on the construction of
7-azabicyclo[2.2.1]heptane skeleton (15) by the [3 + 2]
cycloaddition of azomethine ylide 10 with electron defi-
cient alkenes (Scheme 3). The generation of 10 involved
sequential double desilylation from 12 by electron-
transfer initiation using Ag(I)F as a one-electron oxidant.
It was, thus, envisaged that the cycloaddition of 10 with
11 would produce 9 and that on decarboxylation followed
by debenzylation would easily produce 1.
Syn th esis of Azom eth in e Ylid e P r ecu r sor 12. The
preparation of precursor 12 employed sequential silyla-
tion of 16a . The synthesis of N-Boc-2-(trimethylsilyl)-
pyrrolidine (17a ) essentially utilized the protocol reported
by Beak et al.32 (Scheme 4). Introduction of a second
trimethylsilyl group at the 5-position of 17a required
careful silylation reaction. Silylation by repeating the
sequence as described for 17a gave predominantly 18 in
based on the construction of 7-azabicyclic heptane skel-
eton,12 can be summarized in the retrosynthetic routes
as depicted in Scheme 1.
The [4 + 2]-cycloaddition strategy, utilizing N-protect-
ed pyrroles 4 and activated dienophiles 3, adopted for
assembling the skeletons 2 or 5 and their further
elaboration to 1 has involved many steps with overall
poor yield.13-18 Similarly, another well exploited meth-
odology for the synthesis of 1 has employed intramolecu-
lar nucleophilic ring closure of 1,4-aminocyclohexane
derivatives 7, originally developed for the construction
of 7-azanorbornane system,19 and employs multiple steps
even to reach the crucial trans-1,4-aminocyclohexanol
derivatives.20-27 More recently,28 the elaboration of tro-
pinone skeleton (6) into 1 via Favorskii rearrangement
by Bai et al., although elegant, suffers from the poor
(30) Pandey, G.; Bagul, T. D.; Lakshmaiah, G. Tetrahedron Lett.
1994, 35, 7439. U.S. Pat. No. 510,490, 1996.
(31) Pandey, G.; Lakshmaiah, G.; Ghatak, A. Tetrahedron Lett. 1993,
34, 7301.

762 J . Org. Chem., Vol. 63, No. 3, 1998
Pandey et al.
Sch em e 5a
Sch em e 7
on the walls of the flask. It may be mentioned that the
reaction time could be shortened to 10-15 min using dry
CH3CN as solvent; however, cycloaddition yields are
reduced due to the formation of polymeric materials.
Filtration of the reaction mixture through a Celite pad
and usual purification by silica gel column chromatog-
raphy using hexane:ethyl acetate (9:2) as eluent gave
cycloadducts 26 (60%) and 27 (20%). The exact ratio of
these isomeric adducts was found to be 3:1 by HPLC
[column: reverse phase C18 (bondapack 0.5 µm); MeOH:
H2O ) 80:20] analysis. These cycloadducts were char-
acterized by 1H NMR, 13C NMR, and mass spectral data.
The stereochemistry of the major cycloadduct 26,
indicating the endo-orientation of 6-chloro-3-pyridyl group
(H2exo) and exo-orientation of carbethoxy group (H3endo),
a
Rea gen ts a n d con d ition s: (i) THF, LiAlH4; (ii) DCM, PCC,
Celite, 3 h; (iii) Ph3PCHCO2Et, CH3CN, ∆ 3 h; (iv) THF, 18-crown-
6: CH3CN, (CF3CH2O)2P(O)CHCO2Et, KHMDS, -70 °C; (v)
CH3CN, Ph3PCHCN, ∆ 5 h; (vi) KF, CH3NO2, iPrOH; (vii) p-TsCl,
Et3N, DCM, 8 h.
Sch em e 6
1
1
was determined by detailed H NMR decoupling and H
COSY experiments. For illustration, H3 at δ 2.55 (d, J
) 6.16 Hz) was found to couple only with H2 at δ 3.95 (t,
J ) 4.55 Hz) and not with H4 at δ 3.89 (dd, J ) 0.87,
4.78 Hz). It is reported1,34,35 that in the 7-azabicyclo-
[2.2.1]heptane system no coupling is observed between
bridgehead and adjacent endo hydrogens. Therefore, H3
is assigned with endo-orientation. Similarly, exo-orienta-
tion for H2 is suggested based on its coupling with H1 (δ
3.60, dd, J ) 0.87, 4.48 Hz). Based on the above results,
thus, the relative stereochemistry between H2 and H3 in
product 26 can be assigned trans.
65% yield. However, 19a could be obtained in 70% yield
by carrying out the lithiation of 17a in ether using sec-
BuLi and tetramethylethylenediamine (TMEDA) initially
at -45 °C and afterward warming the reaction mixture
to -30 °C. After stirring the reaction mixture for 30 min,
the temperature was lowered once again to -45 °C at
which quenching with TMSCl gave 19a . It was noticed
that the use of THF as solvent gave mixtures of both 19a
and 18. Conversion of 19a to 12 was achieved by the
deprotection of Boc moiety by stirring with trifluoroacetic
acid at 0 °C followed by N-benzylation by refluxing the
deprotected amine with benzyl chloride in acetonitrile in
the presence of K2CO3.
Syn th eses of Dip ola r op h iles 22, 23, a n d 25. Di-
polarophiles 22a and 22b were prepared by the Wittig
olefination of 6-chloro-3-pyridinecarboxaldehyde (21),
obtained by simple chemical manipulations from com-
mercially available 6-chloronicotinic acid (13) as shown
in Scheme 5. Olefination of 21 using ethyl (triph-
enylphosphoranylidiene)acetate gave 22a in 80% yield.
However, 22b was obtained by treating 21 with bis(2,2,2-
trifluoroethyl) [(ethoxycarbonyl)methyl]phosphonate in
the presence of 18-crown-6 (5 equiv) and KHMDS (1.1
equiv).33 23a and 23b were obtained as 1:1 mixture by
the reaction of corresponding (cyanomethylene)triph-
enylphosphorane with 21 by following an identical reac-
tion sequence as described for 22a . 25 was prepared
through the steps as shown in Scheme 5.
1
In the H NMR spectrum of the minor cycloadduct 27,
no coupling was observed between H2 at δ 3.06 (d, J )
5.39 Hz) and bridgehead proton H1 at δ 3.24 (d, J ) 3.76
Hz) whereas H3 coupled with H2 and H4 at δ 3.65 (t, J )
4.07, 4.43 Hz) indicating the endo orientation for H2 and
exo orientation for H3. Confirmation of the stereochem-
ical assignment of 27 was further ascertained by trans-
forming 27 to the known carbamate 28 and comparing
its spectral characteristics with those reported by Bai et
al.28 Conversion of 27 to 28 was easily achieved by
following the simple reaction sequence as shown in
Scheme 7.
Since the cycloaddition of 12 with trans-dipolarophile
(22a ) gave 26 as major adduct in which the 6-chloro-3-
pyridyl moiety is endo-oriented, it was obvious that the
decarboxylation and debenzylation from 26 would provide
unnatural epimer (endo) of 1. Thus, we decided to utilize
26 for the synthesis of the unnatural isomer of 1 as well.
For this purpose, ester 26 was hydrolyzed by stirring in
methanol:water (3:1) at 45 °C in the presence of LiOH,
and the resulting crude acid was converted into corre-
sponding acid chloride using oxalyl chloride in benzene
at room temperature. Acid chloride was subjected to
Barton’s radical decarboxylation protocol36 to afford de-
carboxylated product 29 in 55% yield.
[3 + 2]-Cycloa d d ition a n d th e Syn th esis of 1. The
cycloaddition reaction involved slow addition of 12 (1
equiv) to a stirring suspension of vacuum-dried Ag(I)F
(2.0 equiv) and 22a (1.2 equiv) in dry DCM (Scheme 6)
at room temperature. The color of the reaction mixture
gradually turned to dark brown, and the reaction was
completed in 8-10 h with the formation of silver mirror
(34) Annet, F. A. L. Can. J . Chem. 1961, 39, 789.
(35) Ramey, K. C.; Gopal, H.; Welsh, H. G. J . Am. Chem. Soc. 1967,
89, 2401.
(32) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(33) Still, W. C.; Gennari, C. Tetrahdron Lett. 1983, 24, 4405.
(36) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901.

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides
J . Org. Chem., Vol. 63, No. 3, 1998 763
Sch em e 8
Sch em e 10
mentioned in Scheme 8. The spectral values of 1 were
found in complete agreement with the values reported
in the literature.16,17,23,28
Alter n a tive Ap p r oa ch F or th e Syn th esis of 1.
While pursuing the synthesis of 1 through the routes as
described above, we also envisioned that 1 could be
obtained by the introduction of 6-chloro-3-pyridyl moiety
at appropriate position of 36. It was expected on the
basis of the addition stereochemistry known on the
related norbornene substrate38 that this reaction would
be stereoselective toward the exo isomer. The crucial
precursor 36 was visualized to be obtained through the
cycloaddition of azomethine ylide 10 with ethyl propi-
olate. Toward this end, when the cycloaddition of 10 was
performed by following the experimental protocol as
described for 26; utilizing 12 (1 equiv) and ethyl propi-
olate (1.2 equiv) in the presence of Ag(I)F (2 equiv) gave
36 in 75% yield (Scheme 10). Initially, we tried to
introduce the 6-chloro-3-pyridyl group into 36 through
the reductive palladium-catalyzed coupling (Heck reac-
tion39) of 6-chloro-3-iodo pyridine (37); however, this was
not successful. Therefore, we decided to solve this
problem by carrying out conjugate addition of 37 via its
lithio derivative onto 36. Addition of 36 (0.97 mmol) to
a stirring mixture of 37 (0.97 mmol) containing n-BuLi
(0.97 mmol) in THF at -78 °C followed by workup and
purification gave 27 in 65% yield. The characterization
and assignment of stereochemistry of the product thus
obtained was ascertained by comparing the spectral
characteristics with the same product realized earlier
through the reaction sequence delineated in Scheme 6.
It may be mentioned that while our effort in this direction
was in progress, a similar strategy for the synthesis of 1
was reported by Simpkins et al.18
Syn th esis of Su bstitu ted Ep iba tid in es. Due to the
structural resemblance to nicotine, epibatidine and many
of its derivatives and isomers have been found to exhibit
a very high affinity, in the picomolar range, for [3H]
nicotine and [3H] cystine binding sites in brain.2 There-
fore, there is growing interest in devising methodologies
to synthesize various derivatives and structural ana-
logues of 1. To extend the scope of our methodology for
this purpose, cycloadditions with different dipolarophiles
having the 6-chloro-3-pyridyl group were studied. Cy-
cloaddition of 10 with trans-3-(6-chloro-3-pyridyl)-2-pro-
pionitrile (23a ) as well as cis-3-(6-chloro-3-pyridyl)-2-
propionitrile (23b) gave corresponding cycloadducts 38
(45%) and 39 (18%), and 40 (55%) and 41 (13%), respec-
tively. The stereochemistry of these cycloadducts, as
shown in Scheme 11, was assigned on similar logic to
that described for the corresponding ester derivatives (26
and 27, and 33 and 34, respectively).
Sch em e 9
N-Debenzylation of 29, achieved by refluxing at first
with R-chloroethyl chloroformate in 1,2-dichloroethane
for 1.5 h followed by heating the crude salt in methanol37
for 0.5 h, gave 30 in 52% yield. Due to the polar nature
of 30, its purification by chromatography was found
difficult and therefore, it was purified and characterized
as its tert-butyl carbamate derivative 31. To synthesize
1 employing this reaction sequence, we also evaluated
to utilize epimerized exo-isomer 32 (Scheme 8). However,
poor yield (45%) of epimerization, performed by reacting
31 with potassium tert-butoxide in refluxing tert-butyl
alcohol, to 32 (1H NMR and 13C NMR were in complete
agreement with the literature reports16,17,23,29) (Scheme
8) led us to seek an improved strategy.
Although, we could achieve the synthesis of 1 through
the above route (Scheme 8), the poor yield of epimeriza-
tion and multiple steps involved led us to envision the
use of cis-dipolarophile 22b for the cycloaddition reaction
where exo-orientation of 6-chloro-3-pyridyl moiety was
expected in the resultant cycloadduct. Keeping this logic
in mind, cycloaddition of 12 with 22b, utilizing exact
experimental protocol as described above in Scheme 6,
furnished cycloadducts 33 (62%) and 34 (7%) (Scheme
9). The exo-orientation of both 6-chloro-3-pyridyl and
carbethoxy group in the adduct 33 was assigned by
observing two sets of doublets at δ 2.9 (d, J ) 10.12 Hz)
and δ 3.1 (d, J ) 10.13 Hz) corresponding to H3endo and
H2endo, respectively, in the 1H NMR spectrum. Both these
protons (H2 and H3) did not couple with their respective
bridgehead protons (H1 and H4) and thereby confirmed
their endo orientations. Cycloadduct 33 was converted
to 1 by following the identical reaction sequence as
(38) Arcadi, A.; Marinelli, F.; Bernocchi, E.; Cacchi, S.; Ortar, G. J .
Organomet. Chem. 1989, 368, 249.
(37) Yang, B. V.; O’Rourke, D.; Li, J . Synlett 1993, 195.
(39) Heck, R. F. J . Am. Chem. Soc. 1968, 90, 5518.

764 J . Org. Chem., Vol. 63, No. 3, 1998
Pandey et al.
Sch em e 11
Sch em e 12
Cycloaddion of 10 with trans-2-(6-chloro-3-pyridyl)-1-
nitro ethylene (25) gave adduct 42 (Scheme 11). The exo-
orientation of the 6-chloro-3-pyridyl moiety in this com-
pound was confirmed by observing a doublet for H2endo
at δ 3.45 (d, J ) 5.36 Hz) and a multiplet for H3exo at δ
4.75. The 1H NMR decoupling experiments suggested
that H2 couples only with H3 as observed in the case of
27. The exo-selectivity for the 6-chloro-3-pyridyl moiety
observed in the cycloaddition reaction using 25 as dipo-
larophile appears to be in contrast to the cycloaddition
stereochemistries observed with dipolarophiles 22a as
well as 23a . Although at present we do not have
explanations for the reversal of stereochemistry in 42,
the difference in the orbital coefficients of nitro olefin
from that of the ester may be considered for this observa-
tion.
Con clu sion
In conclusion, synthesis of 1 is accomplished in a
stereoselective manner employing [3 + 2] cycloaddition
of azomethine ylide, as a key step. Our approach has
provided the scope for its application toward the synthe-
sis of the various analogues of 1 and homoepibatidine.
Exp er im en ta l Section
All the yields reported refer to isolated material but are not
optimized. Temperatures above and below ambient temper-
ature refer to bath temperature unless otherwise stated.
Solvents and anhydrous liquid reagents were dried according
to the established procedures by distillation under argon
atmosphere from an appropriate drying agent. Chemicals and
reagents were procured from Aldrich, Milwaukee, WI, and SD
Fine Chemicals, India.
F or m a l Syn th esis of Hom oep iba tid in e. Homoepi-
batidine and its N-methyl derivatives (48) have been
reported to possess analgesic properties comparable to
epibatidine.11,28 The synthetic efforts devoted toward
homoepibatidine have involved Heck-coupling of iodopy-
ridyl derivative with 8-azabicyclo[3.2.1]oct-6-ene;28,40 how-
ever, the yields of 48 were poor. In the general context
of our strategy, as outlined in Scheme 12, cycloadditon
of homologous azomethine ylide (44), derived from 43,
with 22b was visualized to provide an easy synthetic
route toward the synthesis of N-methylhomoepibatidine
(48). The required precursor 43 for the generation of 44
was obtained from 19b in 80% yield through the reaction
sequence as described in Scheme 12. Usual cycloaddition
of 43 (1 equiv) with 22b (1.2 equiv) in the presence of
Ag(I)F (2 equiv) afforded 47 in 61% yield (Scheme 12).
Analytical TLC was performed using precoated silica gel
plates (0.25 mm). Column chromatography was performed
using silica gel by standard chromatographic techniques.
Product ratios were determined using HPLC analysis, per-
formed on a liquid chromatograph using reverse phase (C18
bondapack 0.5 µm) column, eluting with MeOH:H2O (80:20).
All nuclear magnetic resonance spectra were recorded on
either 200 MHz NMR or 300 MHz NMR spectrometers. All
chemical shifts are reported in parts per million downfield from
TMS; coupling constants are given in hertz. Mass (m/z,
relative intensity) spectra were recorded at a voltage of 70 eV.
N-Boc-2-(tr im eth ylsilyl)p yr r olid in e (17a ). A 40 mL so-
lution of N-Boc pyrrolidine (16a ) (6.84 g, 39.99 mmol) in dry
ether, charged into a 250 mL flask equipped with a magnetic
stirring bar and argon gas balloon, was cooled to -78 °C.
TMEDA (5.57 g, 47.99 mmol) followed by s-BuLi (1.5 M
solution in cyclohexane, 31.99 mL, 47.99 mmol) was intro-
duced. The mixture was allowed to stir for 2 h at -78 °C.
Chlorotrimethylsilane (5.21 g, 47.99 mmol) was added drop-
wise. The reaction mixture was allowed to warm to rt and
diluted with 15 mL of saturated aqueous NH4Cl solution. The
organic layer was separated, and the aqueous layer was
extracted with ether (2 × 30 mL). The combined extracts were
washed with water (80 mL), brine (80 mL) and dried over Na2-
SO4. The crude oily residue, obtained after the concentration,
was purified by fractional distillation (bp 55 °C/0.5 mm) to give
1
Adduct 47 was characterized by H NMR, 13C NMR,
and mass spectral data. Adduct 47 is expected to produce
N-methylhomoepibatidine (48) upon simple chemical
manipulations. Similarly, compound 45 required for the
synthesis of corresponding endo-epimer 46 was obtained
(64%) by the cycloaddition of 44 with 22a .
(40) Malpass, J . R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett.
1996, 37, 3911.

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides
17a as colorless oil (8.74 g, 90%). IR (neat) 1692, 1478, 1365,
J . Org. Chem., Vol. 63, No. 3, 1998 765
a THF (50 mL) solution of 6-chloronicotinic acid (13) (5.12 g,
32.5 mmol) was cooled to 0 °C. A 1.0 M solution of lithium
aluminum hydride (32.5 mL, 32.5 mmol) in THF was intro-
duced to the flask while stirring. The stirring was allowed to
continue for 3 h at 0 °C. The reaction mixture was quenched
at 0 °C itself by the addition of NaF (5.46 g, 130 mmol) followed
by H2O (3.50 mL). The resulting slurry was washed with ethyl
acetate (5 × 100 mL). The crude product obtained after
concentration was purified by silica gel column chromatogra-
phy (1:3/EtOAc:hexane) to afford 2.09 g (45%) of alcohol 20 as
a white solid. Mp 40 °C. IR (CHCl3) 3356, 1681, 1593, 1456,
1137 cm-1; 1H NMR (CDCl3, 200 MHz) δ 3.7 (bs, 1H), 4.75 (s,
2H), 7.3 (d, J ) 8.2 Hz, 1H), 7.7 (dd, J ) 2.1, 8.1 Hz, 1H), 8.35
(d, J ) 1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 61.0, 124.0,
135.7, 137.8, 147.6, 149.7; mass (m/z, relative intensity) 142
(98), 114 (100), 78 (60).
6-Ch lor o-3-p yr id in eca r boxa ld eh yd e (21). Compound 20
(2.09 g, 14.61 mmol) dissolved into CH2Cl2 (20 mL) was
introduced to a stirring mixture of Celite (4.8 g) and pyri-
dinium chlorochromate (4.72 g, 21.89 mmol) containing 40 mL
of dry CH2Cl2 in one portion at 0 °C. The resulting black slurry
was stirred for an additional 2 h at rt and finally diluted with
dry ether (80 mL). The supernatant solution was decanted
from the black residue and thoroughly washed with dry ether
(2 × 50 mL). The combined washings were evaporated under
vacuum, and the brown residue was purified by silica gel
column chromatography (2:8/EtOAc:hexane) to afford 1.65 g
(80%) of 21 as white solid. Mp 80 °C. IR (CHCl3) 2870, 1746,
1587, 1137 cm-1; 1H NMR (CDCl3, 200 MHz) δ 7.5 (d, J ) 8.2
Hz, 1H), 8.15 (dd, J ) 2.4, 8.2 Hz, 1H), 8.9 (d, J ) 2.4 Hz,
1H), 10.1 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 123.9, 130.3,
137.9, 152.3, 156.8, 189.1; mass (m/z, relative intensity) 140
(100), 112 (27).
1
1246, 1170 cm-1; H NMR (CDCl3, 200 MHz) δ 0.05 (s, 9H),
1.45 (s, 9H), 1.75-1.95 (m, 3H), 1.95-2.05 (m, 1H), 3.15-3.3
(m, 2H), 3.35-3.6 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ -2.3,
27.8, 28.4, 46.7, 47.5, 78.0, 154.5; mass (m/z, relative intensity)
243 (M+, 1), 186 (43), 172 (100), 142 (94).
An identical reaction procedure was adopted for the syn-
thesis of N-Boc-2-(trimethylsilyl)piperidine (17b). Colorless
oil. Yield (90%). IR (neat) 1688, 1415, 1159, 1098, 838 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 0.06 (s, 9H), 1.43 (s, 9H), 1.55-
1.75 (m, 6H), 2.15-2.30 (m, 2H), 3.60-3.75 (bs, 1H); 13C NMR
(CDCl3, 50 MHz) δ -1.0, 23.0, 25.7, 28.1, 45.0, 78.4, 154.5;
mass (m/z, relative intesity) 257 (M+, <1), 156 (84), 128 (54),
84 (75), 73 (100).
N-Boc-2,5-Bis(tr im eth ylsilyl)p yr r olid in e (19a ). A 250
mL two-neck flask, equipped with a magnetic stirring bar and
argon gas balloon, was charged with a solution of 17a (4.86 g,
20 mmol) in 30 mL of ether and was cooled to - 45 °C.
TMEDA (2.79 g, 24 mmol) followed by s-BuLi (1.5 M in
cyclohexane, 15.92 mL, 24 mmol) were added to the flask
dropwise while stirring. After 15 min of stirring at -45 °C,
the temperature was raised to -30 °C. After 30 min, it was
recooled to -45 °C and afterward chlorotrimethylsilane (2.6
g, 24 mmol) was added dropwise. The reaction mixture was
allowed to warm to rt, diluted with 10 mL of saturated aqueous
NH4Cl solution, and worked up as mentioned in the previous
experiment, to get an oily residue which was purified by silica
gel column chromatography (1:99/EtOAc:hexane) to give 19a
(4.41 g, 70%) as a pale yellow oil. Only a trace amount of 18
was isolated. IR (neat) 1684, 1406, 1365, 1171 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 0.05 (s, 18H), 1.45 (s, 9H), 1.75-2.00 (m,
4H), 3.00-3.10 (bs, 1H), 3.20-3.30 (bs, 1H); 13C NMR (CDCl3,
50 MHz) δ -1.03, -0.50, 28.93, 29.0, 49.44, 50.0, 78.96, 154.82;
mass (m/z, relative intensity) 315 (M+, 1), 258 (83), 244 (41),
228 (45), 214 (71), 186 (33), 73 (100).
tr a n s-Eth yl(6-Ch lor o-3-p yr id yl)-2-p r op en oa te (22a ). A
solution of ethyl triphenylphosphoranylidine acetate (4.18 g,
12 mmol) dissolved in 30 mL of acetonitrile was added, while
stirring, to a 20 mL acetonitrile solution containing 21 (1.69
g, 12 mmol). The reaction mixture was refluxed for 10 h. After
the completion of the reaction, solvent was removed under
vacuum to afford a solid compound which was purified by silica
gel column chromatography using hexane:EtOAc (9:1) as
eluent to give 2.03 g (80%) of 22a as a white crystalline solid.
Mp 81 °C. IR (CHCl3) 1711, 1464, 1215 cm-1; 1H NMR (CDCl3,
200 MHz) δ 1.25 (t, J ) 7.30 Hz, 3H), 4.25 (q, J ) 7.30 Hz,
2H), 6.5 (d, J ) 14.45 Hz, 1H), 7.35 (d, J ) 8.4 Hz, 1H), 7.65
(d, J ) 14.45 Hz, 1H), 7.8 (dd, J ) 2.10, 8.42 Hz, 1H), 8.5 (d,
J ) 2.23 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 14.3, 60.9,
121.3, 124.6, 129.3, 136.7, 139.3, 149.5, 152.7, 166.0; mass (m/
z, relative intensity) 211 (M+, 30), 183 (42), 166 (100), 138 (53).
cis-Eth yl(6-Ch lor o-3-p yr id yl)-2-p r op en oa te (22b). 18-
Crown-6 acetonitrile complex (10.83 g, 35.46 mmol) and
bis(2,2,2-trifluoroethyl) [(ethoxycarbonyl)methyl]phosphonate
(5.8 g, 15.60 mmol) dissolved in THF (400 mL) were charged
into a two-neck flask equipped with a magnetic stirring bar
and argon gas balloon. The contents were cooled to -78 °C.
Potassium bis(trimethylsilyl)amide (1.0 M solution in THF,
15.60 mL, 15.60 mmol) was introduced into the flask while
stirring. 21 (2.0 g, 14.13 mmol) dissolved in 10 mL of THF
was later added to the reaction mixture, and the whole
contents were allowed to stir for 30 min. Contents were poured
into 120 mL of a saturated aqueous solution of NH4Cl, and
the aqueous layer was extracted with ether (3 × 50 mL).
Combined extracts were washed with brine, dried over Na2SO4,
and concentrated to give crude oil which was purified by silica
gel column chromatography (2:8/EtOAc:hexane) to afford 2.24
g (75%) of 22b as pale yellow oil. IR (neat) 1721, 1636, 1555,
1462 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.25 (t, J ) 7.12 Hz,
3H), 4.15 (q, J ) 7.22 Hz, 2H), 6.1 (d, J ) 12.49 Hz, 1H), 6.85
(d, J ) 12.33 Hz, 1H), 7.30 (d, J ) 8.30 Hz, 1H), 8.10 (dd, J )
2.44, 8.29 Hz, 1H), 8.45 (d, J ) 2.45 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 14.0, 60.6, 122.7, 123.4, 129.6, 138.2, 139.5, 150.7,
151.3, 165.3; mass (m/z, relative intensity) 211 (M+, 28), 182
(42), 166 (100), 138 (53).
N-Boc-2,2-Bis(tr im eth ylsilyl)p yr r olid in e (18). IR (neat)
1690, 1392, 1248, 1169 cm-1 1H NMR (CDCl3, 200 MHz) δ
;
0.1 (s, 18H), 1.45 (s, 9H), 1.75 (m, 2H), 1.95 (t, J ) 6.8 Hz,
2H), 3.35 (t, J ) 6.8 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ
0.18, 25.5, 28.8, 32.2, 46.5, 48.5, 78.1, 154.6; mass (m/z, relative
intensity) 258 (72), 244 (70), 214 (37), 186 (36), 73 (100%).
N-Boc-2,6-Bis(tr im eth ylsilyl)p ip er id in e (19b). Pale yel-
low oil. 75% yield. IR (neat) 1684, 1421, 1175 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 0.08 (s, 18H), 1.45 (s, 9H), 1.55-1.75 (m,
6H), 2.15 (m, 1H), 3.60-3.75 (bs, 1H); 13C NMR (CDCl3, 50
MHz) δ -0.7, 0.1, 24.7, 26.2, 26.9, 28.7, 47.7, 48.5, 78.8, 155.8;
mass (m/z, relative intensity) 272 (100), 258 (46), 242 (66), 228
(51), 200 (80), 156 (44), 73 (98).
N-Ben zyl-2,5-bis(tr im eth ylsilyl)pyr r olidin e (12). A stir-
ring solution of 19a (3.15 g, 10 mmol) in 40 mL of dry CH2Cl2
was cooled to 0 °C and was treated with trifluroacetic acid (5.70
g, 50 mmol) dropwise. The mixture was allowed to warm to
rt, and stirring was continued for an additional 4 h. The
reaction mixture was recooled to 0 °C and basified with 20%
aqueous NaOH solution (pH ) 10). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The combined extracts were washed with brine,
dried over Na2SO4, and concentrated to give 1.93 g of crude
amine which was utilized for the next step.
To a 40 mL solution of the crude amine (1.93 g, 8.97 mmol)
in acetonitrile, were added K2CO3 (1.49 g, 10.8 mmol) and
benzyl chloride (1.08 g, 8.55 mmol). The resultant suspension
was refluxed for 5-6 h. Progress of the reaction was moni-
tored by TLC. On completion of the reaction, the mixture was
cooled and filtered, and the solvent was evaporated under
vacuum. The crude yellow oil was purified by silica gel column
chromatography, eluting with EtOAc:hexane (2:98), to obtain
2.44 g (80%) of 12 as a pale yellow oil. 1H NMR (CDCl3, 200
MHz) δ 0.1 (s, 18H), 1.65-1.80 (m, 2H), 1.90-1.95 (m, 2H),
2.25-2.30 (m, 2H), 3.35 (d, J ) 12.85 Hz, 1H), 3.8 (d, J ) 12.87
Hz, 1H), 7.20-7.35 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ -1.6,
26.8, 56.0, 60.1, 126.8, 128.1, 129.4, 141.7; mass (m/z, relative
intensity) 305 (M+, 3), 290 (17), 233 (100), 91 (90), 73 (54).
6-Ch lor o-3-pyr idylcar bin ol (20). A 250 mL flask, equipped
with a magnetic stirring bar and argon gas balloon, containing
3-(6-Ch lor o-3-p yr id yl)p r op ion itr iles (23a /23b). 23 was
obtained in 1:1 ratio (23a /23b), in 70% yield, by the reaction

766 J . Org. Chem., Vol. 63, No. 3, 1998
Pandey et al.
of (cyanomethylene)triphenylphosphorane (3.61 g, 12 mmol)
and 21 (1.40 g, 10 mmol) by following the identical reaction
procedure as described for 22a .
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-3-en d o-ca r beth oxy-
7-a za bicyclo[2.2.1]h ep ta n e (27). IR (neat) 1728, 1457, 1101
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.20 (t, J ) 7.05 Hz, 3H),
1.55 (dt, J ) 2.32, 7.93 Hz, 2H), 2.0 (m, 2H), 2.85 (dt, J )
1.83, 5.07 Hz, 1H), 3.06 (d, J ) 5.39 Hz, 1H), 3.24 (d, J ) 3.76
Hz, 1H), 3.54 (s, 2H), 3.65 (t, J ) 4.07, 4.43 Hz, 1H), 4.10 (q,
J ) 7.09 Hz, 2H), 7.20 (d, J ) 8.35 Hz, 1H), 7.23-7.35 (m,
5H), 7.84 (dd, J ) 2.47, 8.26, 1H), 8.42 (d, J ) 2.41 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.1, 21.8, 26.8, 47.4, 51.7, 57.5,
60.6, 66.1, 66.4, 123.6, 127.0, 128.2, 128.5, 137.9, 139.2, 140.2,
148.9, 172.0; mass (m/z, relative intensity) 370 (M+, 20), 166
(72), 159 (100), 138 (30), 91 (90).
23a : mp 168 °C. IR (Nujol) 2120, 1580, 1460 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 6.00 (d, J ) 16.67 Hz, 1H), 7.40 (d, J )
16.67 Hz, 1H), 7.45 (d, J ) 8.36 Hz, 1H), 7.45 (d, J ) 8.36 Hz,
1H), 7.80 (dd, J ) 2.55, 8.34 Hz, 1H), 8.50 (d, J ) 2.49 Hz,
1H); 13C NMR (CDCl3, 50 MHz) δ 98.6, 116.3, 123.5, 127.6,
135.4, 144.5, 148.0, 151.9; mass (m/z, relative intensity) 164
(M+, 100), 137 (29), 129 (82), 102 (59).
23b: mp 97 °C. IR (Nujol) 2120, 1580, 1460 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 5.65 (d, J ) 12.00 Hz, 1H), 7.10 (d, J )
12.00 Hz, 1H), 7.45 (d, J ) 8.50 Hz, 1H), 8.40 (dd, J ) 2.40,
8.49 Hz, 1H), 8.60 (d, J ) 2.40 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 98.3, 116.2, 124.4, 128.2, 137.0, 143.5, 150.5,
153.1; mass (m/z, relative intensity) 164 (M+, 100), 129 (82),
102 (59).
Gen er a l Deca r boxyla tion P r oced u r e. Decarboxylation
was achieved by following the Bartons procedure.36 It is
exemplified by taking 26 as an example. A solution of 26 (1.0
g, 2.7 mmol) in MeOH:H2O (3:1, 20 mL) containing LiOH:H2O
(0.17 g, 4.04 mmol) was warmed to 45 °C with stirring. After
1.5 h, the mixture was cooled and washed with CH2Cl2 (3 ×
20 mL). The aqueous layer was cooled to 0 °C, acidified with
6 N HCl to pH ) 5, and extracted with ethyl acetate. The
combined organic layers were dried over sodium sulfate.
Evaporation of the organic layer gave crude acid as a white
solid. The resultant crude acid was dissolved in 30 mL of dry
benzene and was transferred to a 50 mL flask equipped with
argon gas balloon. Oxalyl chloride (1.18 mL, 13.52 mmol) and
DMF (one drop) were added to the flask at rt and stirred for
2 h. Evaporation of the solvent under vacuum gave acid
chloride as a brown solid. The crude acid chloride was
dissolved in dry benzene (30 mL) and to the resultant solution
were added DMAP (0.033 g, 0.26 mmol), N-hydroxy-2-mer-
captopyridine (0.41 g, 3.24 mmol), and 1.2 mL pyridine,
maintaining the argon atmosphere. The reaction mixture was
stirred for 1.5-2 h at rt. The solid suspension was allowed to
settle, and the supernatant solution was syringed out and
added to a refluxing solution of t-BuSH (1.5 mL) in 40 mL of
dry benzene. The mixture was refluxed for 2.5-3 h, cooled,
washed with aqueous 1 N NaOH solution, water, and brine,
and dried over Na2SO4. Concentration gave a brownish black
residue which upon silica gel column chromatographic puri-
fication using EtOAc:hexane (2:8) as eluent afforded 29 (0.442
2-(6-Ch lor o-3-p yr id yl)-1-n itr oeth ylen e (25). A 10 mL
i-PrOH solution of 21 (1.41 g, 10 mmol) was treated with KF
(0.03 g, 0.5 mmol) and nitromethane (1.2 mL, 20 mmol). After
stirring for 6 h at rt, solvent was evaporated to dryness, and
the residue was purified by silica gel column chromatography,
eluting with hexane:EtOAc (8:2), to obtain 2-hydroxy-2-(6-
chloro-3-pyridyl)nitroethane (24) (1.63 g, 90%) as a thick dark
yellow oil. 1H NMR (CDCl3, 200 MHz) δ 4.6 (d, J ) 4.36 Hz,
2H), 5.6 (dd, J ) 9.72, 4.32 Hz, 1H), 7.3 (d, J ) 8.40 Hz, 1H),
7.80 (dd, J ) 2.6, 8.41 Hz, 1H), 8.40 (d, J ) 8.35 Hz, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 67.9, 80.7, 124.7, 134.0, 137.3, 147.2,
151.2; mass (m/z, relative intensity) 202 (M+, 4), 155 (82), 140
(100), 128 (20).
Compound 24 (1 g, 4.94 mmol) dissolved in 50 mL of dry
DCM was cooled to 0 °C and was treated with pyridine (0.78
g, 9.89 mmol) followed by p-toluenesulfonyl chloride (1.035 g,
5.43 mmol). After the completion of the reaction, the reaction
mixture was stirred at rt overnight. The mixture was suc-
cessively washed with aqueous 1 M NaHCO3 solution (2 × 25
mL), water, and brine and finally dried over Na2SO4. Evapo-
ration of the solvent gave crude solid which was purified by
silica gel column chromatography eluting with hexane:EtOAc
(9:1) to get 25 (0.68 g, 75%) as a white solid, mp 139 °C. IR
(Nujol) 1637, 1583, 1506, 1340, 1099 cm-1; H NMR (CDCl3,
g, 55%) as a thick yellow oil. IR (neat) 1460, 1105 cm-1; H
1
1
200 MHz) δ 7.45 (d, J ) 8.30 Hz, 1H), 7.65 (d, J ) 12.25 Hz,
1H), 7.85 (dd, J ) 2.38, 8.30 Hz, 1H), 8.0 (d, J ) 12.25 Hz,
1H), 8.55 (d, J ) 2.38 Hz, 1H); mass (m/z, relative intensity)
184 (M+, 41), 137 (91), 126 (19), 102 (100%), 75 (79%).
Gen er a l Cycloa d d ition P r oced u r e. Exem p lified by
th e Rea ction of 12 w ith 22a . A two-neck flask, equipped
with a magnetic stirring bar and argon gas balloon, was
charged with Ag(I)F (1.58 g, 12.5 mmol) (dried previously
under vaccum at 40 °C), dipolarophile 22a (1.32 g, 6.26 mmol),
and 40 mL of dry dichloromethane. Compound 12 (1.73 g, 5.69
mmol), dissolved in 30 mL of dry DCM, was introduced into
the reaction flask dropwise over a period of 10 min. The color
of the reaction mixture gradually turned dark brown with
concomitant deposition of silver on the surface of the flask in
the form of mirror, and the progress of the reaction mixture
was periodically monitored by TLC. After stirring for 8-10
h, the reaction mixture was filtered through a small plug of
Celite, and the solvent was evaporated to give a crude brown
residue. Purification of the crude residue by silica gel column
chromatography, eluting with hexane:EtOAc (9:1), afforded
0.42 g (20%) of 27. Further elution with hexane:EtOAc (9:2)
afforded 1.26 g (60%) of 26 as thick yellow oil.
NMR (CDCl3, 200 MHz) δ 1.30-1.40 (m, 2H), 1.45-1.60 (dd,
J ) 5.36, 17.92 Hz, 1H), 1.60-1.85 (m, 1H), 1.90-2.0 (m, 1H),
2.35 (m, 1H), 3.45 (t, J ) 4.7 Hz, 2H), 3.55 (m, 1H), 3.70 (s,
2H), 7.25-7.50 (m, 7H), 8.25 (d, J ) 2.51 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 21.6, 28.3, 33.7, 42.7, 51.7, 60.2, 63.9, 123.5,
126.8, 128.2, 128.3, 136.1, 138.3, 139.6, 148.9, 149.5; mass (m/
z, relative intensity) 298 (M+, 9), 159 (70), 91 (100), 83 (36).
Gen er a l Deben zyla tion P r oced u r e. Exem p lified by
t h e con ver sion of 29 t o 30. R-Chloroethyl chloroformate
(0.18 g, 1.26 mmol) was added at rt to a 20 mL solution of 29
(0.3 g, 0.99 mmol) in dry 1,2-dichloroethane. The reaction
mixture was refluxed for 2 h, cooled, and concentrated under
vacuum. The residue was dissolved in 15 mL of methanol and
further refluxed for 3 h. The reaction mixture was evaporated
to dryness, and the solid residue was dissolved in chloroform
(20 mL) and basified with aqueous 1 N NaOH solution to pH
) 8. The chloroform layer was separated, and the aqueous
layer was further extracted with (2 × 10 mL) chloroform.
Combined extracts were dried over anhydrous CaCl2 and
concentrated to give brown oily residue. Column chromato-
graphic purification eluting with hexane:EtOAc (8:2) gave
0.025 g of unreacted 29. Further elution using (9:0.5:0.1/
CHCl3:MeOH:NH4OH) as eluent gave 30 (0.107 g, 52%).
en d o-2-(6-Ch lor o-3-p yr id yl)-7-a za b icyclo[2.2.1]h e p -
ta n e (30). 1H NMR (CDCl3, 200 MHz) δ 1.4-1.5 (m, 6H), 2.25
(m, 1H), 3.55 (m, 1H), 3.9 (bs, 2H), 7.3 (d, J ) 8.30 Hz, 1H),
7.5 (dd, J ) 8.28, 2.47 Hz, 1H), 8.24 (d, J ) 2.45 Hz, 1H).
en d o-N-Boc-Ep iba tid in e (31). To a stirring solution of
30 (0.10 g, 0.48 mmol) in 15 mL of THF was added (Boc)2O
(0.126 g, 0.576 mmol) followed by triethylamine (0.06 g, 0.576
mmol) under argon atmosphere. The resulting mixture was
stirred for 6-8 h and concentrated, and the residue was
purified by silica gel column chromatography, eluting with
hexane:EtOAc (9:1), to afford 0.132 g (89%) of 31. IR (neat)
7-Ben zyl-2-en d o-(6-ch lor o-3-p yr id yl)-3-exo-ca r beth oxy-
7-a za bicyclo[2.2.1]h ep ta n e (26). IR (neat) 1728, 1462, 1142,
1
1052 cm-1; H NMR (CDCl3, 200 MHz) δ 1.20 (t, J ) 7.1 Hz,
3H), 1.35-1.45 (m, 2H), 1.60-1.80 (m, 1H), 1.95-2.05 (m, 1H),
2.55 (d, J ) 6.16 Hz, 1H), 3.60 (dd, J ) 0.87, 4.48 Hz, 1H),
3.61 (d, J ) 13.71 Hz, 1H), 3.72 (d, J ) 13.70 Hz, 1H), 3.89
(dd, J ) 0.84, 4.78 Hz, 1H), 3.95 (t, J ) 4.55 Hz, 1H), 4.20 (q,
J ) 7.21 Hz, 2H), 7.25-7.52 (m, 7H), 8.25 (d, J ) 2.7 Hz, 1H);
13C NMR (CDCl3, 50 MHz) δ 14.0, 20.9, 27.2, 47.1, 51.3, 52.4,
60.7, 63.3, 63.9, 123.6, 126.7, 128.0, 134.7, 138.2, 139.4, 149.2,
173.1; mass (m/z, relative intensity) 370 (M+, 3), 159 (100),
131 (26), 91 (81%).

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides
1693, 1582, 1460, 1104 cm-1 1H NMR (CDCl3, 200 MHz) δ
1.37-1.45 (m, 2H), 1.5 (s, 9H), 1.55-1.65 (dd, J ) 5.6, 12.39
Hz, 2H), 1.85-1.95 (m, 1H), 2.30 (m, 1H), 3.45 (m, 1H), 4.30
(bs, 2H), 7.30 (d, J ) 8.67 Hz, 1H), 7.50 (dd, J ) 2.63, 8.69
Hz, 1H), 8.26 (d, J ) 2.46 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 23.1, 28.1, 30.0, 34.2, 43.4, 57.1, 60.1, 79.8, 123.7, 134.6,
138.3, 149.3, 155.3; mass (m/z, relative intensity) 308 (M+, 2),
208 (37), 140 (72), 126 (11), 69 (51), 57 (100).
J . Org. Chem., Vol. 63, No. 3, 1998 767
;
2.10-2.20 (m, 1H), 3.15 (d, J ) 4.03 Hz, 1H), 3.45 (m, 2H),
3.65 (d, J ) 16.8 Hz, 2H), 4.15 (m, 1H), 7.25-7.42 (m, 7H),
8.10 (dd, J ) 2.19, 8.0 Hz, 1H), 8.40 (d, J ) 2.30 Hz, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 17.3, 26.9, 29.1, 51.5, 54.4, 63.7, 66.6,
79.9, 123.3, 127.8, 128.2, 137.4, 148.2.
7-Ben zyl-2-ca r b et h oxy-7-a za b icyclo[2.2.1]h ep t -2-en e
(36). Compound 36 was prepared by the reaction of 12 (0.50
g, 1.64 mmol) with ethyl propiolate (0.178 g, 1.8 mmol) using
Ag(I)F (0.458 g, 3.6 mmol) in DCM (30 mL) in an identical
manner as described for compound 26. The crude residue was
purified by silica gel column chromatography eluting with
EtOAc:hexane (1.5:8.5), to obtain 0.29 g (75%) of 36 as a pale
yellow oil. IR (neat) 1714, 1606, 1456 cm-1; 1H NMR (CDCl3,
200 MHz) δ 1.10 (d, J ) 10.20 Hz, 2H), 1.30 (t, J ) 7.10 Hz,
3H), 1.98 (dd, J ) 3.0 Hz, 10.45 Hz, 2H), 3.42 (s, 2H), 3.89
(bs, 1H), 4.10 (d, J ) 2.49 Hz, 1H), 4.25 (q, J ) 7.15 Hz, 2H),
6.95 (d, J ) 2.1 Hz, 1H), 7.25-7.40 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 14.1, 23.5, 51.8, 60.1, 64.0, 65.1, 126.7, 127.1, 128.1,
128.5, 128.7, 139.1, 142.9, 164.5; mass (m/z, relative intensity)
257 (M+, 2), 228 (80), 183 (68), 91 (100).
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-3-en d o-ca r beth oxy-
7-a za bicyclo[2.2.1]h ep ta n e (27). To a stirring solution of
37 (0.233 g, 0.97 mmol) into a mixture of ether (8 mL) and
THF (4 mL) at -70 °C was introduced n-BuLi (1.6 M in
hexane, 0.61 mL, 0.97 mmol) dropwise. The mixture was
stirred at -70 °C for 20 min before a solution of 36 (0.25 g,
0.97 mmol) dissolved in ether (4 mL) was introduced. The
reaction mixture was allowed to stir additionally for 2 h at
-70 °C before warming to -50 °C. After stirring for 30 min
at -50 °C, saturated aqueous NH4Cl (2 mL) was added, and
the mixture was warmed to rt. The aqueous phase was
extracted with EtOAc (15 mL), and the combined organic
layers were dried over Na2SO4 and evaporated. The residue
was purified by silica gel column chromatography eluting with
hexane:EtOAc (8.5:1.5) to give 27 (0.215 g, 60%).
7-Ben zyl-2-en do-(6-ch lor o-3-pyr idyl)-3-exo-cyan o-7-aza-
bicyclo[2.2.1]h ep ta n e (38). Yellow oil. Yield 45%. IR
(CHCl3) 2221, 1462, 1107 cm-1; 1H NMR (CDCl3, 200 MHz) δ
1.40-1.52 (m, 2H), 1.70-1.90 (m, 1H), 1.95-2.12 (m, 1H), 2.65
(d, J ) 5.94 Hz, 1H), 3.65 (t, J ) 4.15 Hz, 1H), 3.75 (m, 4H),
7.5-7.25 (m, 7H), 8.25 (d, J ) 2.46 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 20.5, 27.2, 36.6, 49.9, 51.2, 63.5, 64.4, 121.4, 124.0,
127.1, 128.1, 128.3, 132.2, 137.9, 138.5, 148.7, 150.1; mass (m/
z, relative intensity) 323 (M+, <1), 159 (34), 140 (55), 126 (54),
105 (39), 91 (100), 83 (55).
7-Ben zyl-2-exo-(6-ch lor o-3-pyr idyl)-3-en do-cyan o-7-aza-
bicyclo[2.2.1]h ep ta n e (39). Viscous yellow oil. Yield 18%.
IR (CHCl3) 2400, 1461, 1217, 1046 cm-1; 1H NMR (CDCl3, 200
MHz) δ 1.55-1.70 (m, 1H), 2.00-2.15 (m, 3H), 2.85 (dd, J )
4.76, 9.73 Hz, 2H), 3.30 (s, 1H), 3.55 (s, 2H), 3.65 (s, 1H), 7.25-
7.45 (m, 6H), 7.58 (dd, J ) 2.45, 8.24 Hz, 1H), 8.45 (d, J )
2.45 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.0, 26.8, 41.4,
51.2, 51.7, 61.59, 65.7, 119.9, 124.0, 127.3, 128.4, 128.5, 137.5,
138.4, 148.5, 150.2.
Ep im er iza tion of 31 to 32. A mixture containing 31 (0.10
g, 0.32 mmol) and t-BuOK (0.182 g, 1.62 mmol) in tert-butyl
alcohol (5 mL) was refluxed for 40 h under argon atmosphere.
Removal of the solvent and the purification of the residue by
silica gel column chromatogrphy gave 0.045 g (45%) of 32 along
with unreacted 31 (0.03 g). IR (CHCl3) 1693, 1582, 1460, 1155
cm-1 1H NMR (CDCl3, 200 MHz) δ 1.45 (s, 9H), 1.55-1.65
;
(m, 2H), 1.75-1.85 (m, 3H), 1.95 (dd, J ) 8.93, 12.3 Hz, 1H),
2.87 (dd, J ) 5.04, 8.93 Hz, 1H), 4.16 (bs, 1H), 4.38 (bs, 1H),
7.25 (d, J ) 8.35 Hz, 1H), 7.65 (dd, J ) 2.42, 8.32 Hz, 1H),
8.25 (d, J ) 2.46 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 28.1,
28.6, 29.5, 40.2, 44.7, 55.9, 61.8, 79.8, 124.0, 137.1, 139.9, 148.5,
155.1; mass (m/z, relative intensity) 308 (M+, 3), 208 (37), 140
(72), 69 (51), 57 (100).
Ep iba tid in e (1). Trifluoroacetic acid (0.1 mL, 1.16 mmol)
was added to a stirring solution of 32 (0.045 g, 0.15 mmol) in
DCM (5 mL) at 0 °C under argon atmosphere. Contents were
further stirred for additional 4 h at room temperature. The
reaction mixture was basified with saturated aqueous Na2CO3
solution. The organic layer was separated, and the aqueous
layer was extracted with DCM (3 × 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography, eluting with CHCl3:MeOH:NH4OH
(98:2:1), to give 1 (0.028 g, 90%) as a thick pale yellow paste.
1H NMR (CDCl3, 200 MHz) δ 1.5-1.65 (m, 5H), 1.91 (dd, J )
12.1, 8.8 Hz, 1H), 2.77 (dd, J ) 8.6, 4.8 Hz, 1H), 3.57 (bs, 1H),
3.8 (bs, 1H), 7.23 (d, J ) 8.3 Hz, 1H), 7.75 (dd, J ) 8.3, 2.5
Hz, 1H), 8.26 (d, J ) 2.6 Hz, 1H).
7-(ter t-Bu t oxyca r b on yl)-2-exo-(6-ch lor o-3-p yr id yl)-3-
en d o-ca r beth oxy-7-a za bicyclo[2.2.1]h ep ta n e (28). Yellow
viscous oil. Yield 55%. IR (neat) 1727, 1708, 1460, 1227, 1056
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.25 (t, J ) 7.21 Hz, 3H),
1.42 (s, 9H), 1.50-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.70-1.95
(m, 2H), 3.0 (t, J ) 4.89 Hz, 1H), 3.30 (d, J ) 5.46 Hz, 1H),
4.2 (q, J ) 7.31 Hz, 2H), 4.30 (bs, 1H), 4.60 (bs, 1H), 7.25 (d,
J ) 8.44 Hz, 1H), 7.65 (dd, J ) 2.43, 8.27 Hz, 1H), 8.30 (d, J
) 2.44 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 24.5, 28.0,
29.3, 47.0, 56.8, 58.1, 61.0, 62.3, 80.2, 124.0, 137.0, 138.4, 148.4,
154.57, 170.9; mass (m/z, relative intensity) 380 (M+, 3), 280
(25), 212 (60), 142 (10), 69 (100).
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-3-exo-ca r beth oxy-
7-a za bicyclo[2.2.1]h ep ta n e (33). Yellow viscous oil. Yield
62%. IR (CHCl3) 1731, 1455, 1215, 1106 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 0.8 (t, J ) 6.95 Hz, 3H), 1.60-1.45 (m,
2H), 2.1-2.2 (m, 2H), 2.90 (d, J ) 10.12 Hz, 1H), 3.1 (d, J )
10.13 Hz, 1H), 3.25 (d, J ) 4.03 Hz, 1H), 3.73-3.5 (m, 4H),
3.75 (m, 1H), 7.20 (d, J ) 8.38 Hz, 1H), 7.45-7.25 (m, 4H),
7.5 (m, 1H), 8.05 (dd, J ) 8.35 Hz, 1H), 8.35 (d, J ) 2.7 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.3, 25.3, 26.2, 49.1, 51.4,
54.8, 59.5, 59.7, 65.3, 122.9, 126.6, 127.9, 128.2, 136.7, 138.5,
139.0, 149.0, 170.6; mass (m/z, relative intensity) 370 (M+, 8),
159 (100), 130 (15), 91 (87), 68 (18).
7-Ben zyl-2-en do-(6-ch lor o-3-pyr idyl)-3-en do-car beth oxy-
7-a za bicyclo[2.2.1]h ep ta n e (34). Yellow viscous oil. Yield
7%. IR (CHCl3) 1720, 1216, 1108 cm-1; 1H NMR (CDCl3, 200
MHz) δ 1.00 (t, J ) 7.1 Hz, 3H), 1.60-1.80 (m, 2H), 1.85-2.0
(m, 1H), 2.10-2.20 (m, 1H), 3.45 (m, 2H), 3.60 (t, J ) 4.45 Hz,
1H), 3.75 (s, 2H), 3.80 (m, 1H), 3.80-4.06 (m, 2H), 7.25-7.42
(m, 7H), 8.10 (d, J ) 2.19 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 13.7, 21.3, 22.7, 29.4, 44.6, 47.9, 51.1, 60.0, 62.2, 64.5, 122.9,
126.9, 128.2, 133.5, 138.7, 139.1, 149.0, 150.0, 171.6; mass (m/
z, relative intensity) 370 (M+, 3.5), 159 (100), 131 (13.5), 91
(89).
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-3-exo-cya n o-7-a za -
bicyclo[2.2.1]h ep ta n e (40). Viscous oil. Yield 55%. IR
1
(Nujol) 2400, 1461, 1046 cm-1; H NMR (CDCl3, 200 MHz) δ
1.55-1.75 (m, 2H), 2.05-2.15 (m, 2H), 3.0 (s, 2H), 3.38 (d, J
) 4.17 Hz, 1H), 3.67 (s, 2H), 3.8 (d, J ) 4.08 Hz, 1H), 7.25-
7.50 (m, 6H), 8.05 (dd, J ) 2.45, 8.30 Hz, 1H), 8.26 (d, J )
2.45 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.3, 24.0, 34.9,
44.7, 51.5, 63.0, 63.9, 119.3, 123.7, 127.4, 128.3, 128.5, 130.9,
138.4, 139.4, 150.4, 150.5; mass (m/z, relative intensity) 323
(M+, <1), 159 (61), 131 (25), 91 (100).
7-Ben zyl-2-en d o-(6-ch lor o-3-p yr id yl)-3-en d o-cya n o-7-
a za bicyclo[2.2.1]h ep ta n e (41). Yellow oil. Yield 13%. IR
1
(CHCl3) 2400, 1522, 1463, 1217, 1046 cm-1; H NMR (CDCl3,
200 MHz) δ 1.80-1.95 (m, 2H), 2.05-2.15 (m, 2H), 3.55 (m,
2H), 3.75 (m, 4H), 7.3-7.45 (m, 6H), 7.47 (dd, J ) 2.45, 8.23
Hz, 1H), 8.26 (d, J ) 2.44 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 21.3, 24.0, 34.9, 44.7, 51.4, 63.0, 63.9, 119.3, 123.7, 127.4,
128.3, 128.5, 128.8, 130.9, 138.4, 139.4, 150.4, 150.5; mass (m/
z, relative intensity) 323 (M+, 1), 189 (26), 159 (73), 91 (100).
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-3-en d o-n itr o-7-a za -
bicyclo[2.2.1]h ep ta n e (42). Viscous oil. Yield 65%. IR
7-Ben zyl-2-exo-(6-ch lor o-3-p yr id yl)-7-a za bicyclo[2.2.1]-
h ep ta n e (35). Yellow viscous oil. Yield 55%. 1H NMR
(CDCl3, 200 MHz) δ 1.60-1.80 (m, 2H), 1.85-2.00 (m, 2H),

768 J . Org. Chem., Vol. 63, No. 3, 1998
Pandey et al.
1
(CHCl3) 1550, 1470, 1230, 1120, 770 cm-1; H NMR (CDCl3,
200 MHz) δ 1.60-1.75 (m, 2H), 2.0-2.2 (m, 2H), 3.35 (d, J )
4.5 Hz, 1H), 3.45 (d, J ) 5.36 Hz, 1H), 3.63 (s, 2H), 4.02 (m,
1H), 4.75 (m, 1H), 7.28 (d, J ) 8.45 Hz, 1H), 7.35-7.45 (m,
5H), 7.78 (dd, J ) 2.45, 8.3 Hz, 1H), 8.5 (d, J ) 2.46 Hz, 1H);
13C NMR (CDCl3, 75 MHz) gd 20.3, 26.5, 48.4, 51.8, 62.8, 66.9,
93.0, 124.0, 127.5, 128.5, 128.6, 137.2, 137.9, 138.1, 148.9,
150.1; mass (m/z, relative intensity) 221 (6), 191 (14), 140 (9),
83 (100).
Hz, 1H), 4.2 (q, J ) 7.2 Hz, 2H), 7.27 (d, J ) 8.24 Hz, 1H),
7.88 (dd, J ) 2.73, 8.25 Hz, 1H), 8.42 (d, J ) 2.75 Hz, 1H); 13
C
NMR (CDCl3, 200 MHz) δ 14.1, 16.7, 19.5, 23.2, 34.6, 45.9,
57.1, 60.5, 62.0, 66.1, 123.9, 137.2, 142.2, 148.4, 149.1, 171.9;
mass (m/z, relative intensity) 308 (M+, 3), 166 (10), 97 (100),
83 (72).
8-Meth yl-2-exo-(6-ch or o-3-p yr id yl)-3-exo-ca r beth oxy-8-
a za bicyclo[3.2.1]octa n e (47). Viscous liquid. Yield 61%. IR
1
(CHCl3) 1728, 1106 cm-1; H NMR (CDCl3, 200 MHz) δ 0.80
N-Meth yl-2,6-bis(tr im eth ylsilyl)p ip er id in e (43). 19b (4
g, 12.1 mmol) was deprotected using trifluoroacetic acid (9.70
g, 85.1 mmol) in an identical fashion as described for 19a . To
a stirring solution of crude amine (2.54 g, 11.09 mmol) in
CH3CN (120 mL) were added a 37% aqueous solution of HCHO
(4 mL) and NaBH3CN (0.836 g, 13.30 mmol). The reaction
mixture was stirred for an additional 15 min. Neutralization
of the reaction mixture by adding glacial acetic acid followed
by basification by the slow addition of concentrated NH4OH
and extraction with hexane (3 × 50 mL) followed by concen-
tration and purification of the residue by silica gel column
chromatography, eluting with EtOAc:hexane (3:97), gave 43
(2.15 g, 80% yield) as a colorless viscous liquid. 1H NMR
(CDCl3, 200 MHz) gd 0.06 (s, 18H), 1.52-1.67 (m, 6H), 2.2-
2.3 (m, 2H), 2.55 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ -1.2,
20.7, 24.3, 42.4, 54.1; mass (m/z, relative intensity) 243 (M+,
<1), 170 (100).
(t, J ) 7.21 Hz, 3H), 1.10-1.22 (m, 2H), 1.62-1.75 (m, 2H),
1.92-2.05 (m, 2H), 2.58 (s, 3H), 3.08 (m, 1H), 3.25 (d, J ) 10.2
Hz, 1H), 3.42 (m, 2H), 3.68 (m, 2H), 7.12 (d, J ) 3.37 Hz, 1H),
7.92 (dd, J ) 2.76, 8.34 Hz, 1H), 8.24 (d, J ) 2.78 Hz, 1H); 13
C
NMR (CDCl3, 200 MHz) δ 13.4, 17.4, 20.5, 21.2, 32.6, 47.7,
53.5, 59.5, 60.0, 66.2, 123.5, 138.1, 138.5, 149.2, 149.7, 171.8;
mass (m/z, relative intensity) 308 (M+, 16), 235 (37), 194 (18),
97 (100), 82 (14).
Ack n ow led gm en t. T.D.B. and A.K.S. thank CSIR
and DST, New Delhi, for the award of research fellow-
ship, respectively. Financial support from DST is also
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of new compounds (59 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
8-Meth yl-2-en do-(6-ch lor o-3-p yr idyl)-3-exo-ca r beth oxy-
8-a za bicyclo[3.2.1]octa n e (45). Yellow oil. Yield 64%. IR
(neat) 1724, 1582, 1241, 1103 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 1.25 (t, J ) 7.21 Hz, 3H), 1.50-1.75 (m, 3H), 1.85-2.05 (m,
3H), 2.52 (s, 3H), 3.17 (m, 2H), 3.55 (m, 1H), 3.65 (d, J ) 6.65
J O971728+