A Practical and Efficient Synthesis of the Selective Neuronal Acetylcholine-Gated Ion Channel Agonist (S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y)

Article abstract of DOI:10.1021/jo971572d

An efficient, high-yielding synthetic procedure for the preparation of the novel neuronal acetylcholinegated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-1508Y] is described. The key steps in the process include the lithium bis(trimethylsilyl)amide-mediated acylation of N-vinylpyrrolidinone with ethyl 5-bromonicotinate, a high-yielding sodium borohydride reduction of imine 5, and a new heteroaryl-alkyne cross-coupling protocol for the introduction of the ethyne moiety in (S)-2. The preparation of enantiomerically pure (S)-2 was accomplished via a combination of enantioselective reduction of imine 5 and crystallization of enantiomerically enriched 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) as the dibenzoyl-L-tartaric acid salt.

Full text of DOI:10.1021/jo971572d

J . Org. Chem. 1998, 63, 1109-1118
1109
A P r a ctica l a n d Efficien t Syn th esis of th e Selective Neu r on a l
Acetylch olin e-Ga ted Ion Ch a n n el Agon ist
(S)-(-)-5-Eth yn yl-3-(1-m eth yl-2-p yr r olid in yl)p yr id in e Ma lea te
(SIB-1508Y)
Leo S. Bleicher, Nicholas D. P. Cosford,* Audrey Herbaut, J . Stuart McCallum, and
Ian A. McDonald
SIBIA Neurosciences Inc., 505 Coast Boulevard South, La J olla, California 92037
Received August 22, 1997
An efficient, high-yielding synthetic procedure for the preparation of the novel neuronal acetylcholine-
gated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-
1508Y] is described. The key steps in the process include the lithium bis(trimethylsilyl)amide-
mediated acylation of N-vinylpyrrolidinone with ethyl 5-bromonicotinate, a high-yielding sodium
borohydride reduction of imine 5, and a new heteroaryl-alkyne cross-coupling protocol for the
introduction of the ethyne moiety in (S)-2. The preparation of enantiomerically pure (S)-2 was
accomplished via a combination of enantioselective reduction of imine 5 and crystallization of
enantiomerically enriched 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) as the dibenzoyl-L-tartaric
acid salt.
In tr od u ction
modulatory compounds. In our own laboratories the
investigation of the therapeutic properties of the novel
NAChR agonist 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)-
pyridine fumarate (2, SIB-1765F)16-18 and the enantio-
merically pure (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolid-
inyl)pyridine maleate [(S)-2, SIB-1508Y]19 led to the
selection of (S)-2 for clinical development to treat Par-
kinson’s disease. Consequently, large quantities of 2 and
(S)-2 were required for biological characterization. Herein
are described our efforts toward the development of an
efficient large scale synthesis of 2 and an enantioselective
synthesis of (S)-2.
The therapeutic potential of drug molecules acting at
neuronal nicotinic acetylcholine receptors (neuronal
NAChRs) is now well established.1,2 Several studies have
demonstrated that the naturally occurring alkaloid nico-
tine (1) and other NAChR agonists may have beneficial
effects in the treatment of Parkinson’s disease (PD),3
Alzheimer’s disease (AD),3-5 attention deficit hyperactiv-
ity disorder (ADHD),6 Tourette’s syndrome,7 and schizo-
phrenia.8,9 Recently a number of drug candidates, such
as ABT-418,4,10,11 ABT-089,12 DMXB (GTS-21),5,13 and
RJ R-240314,15 have been disclosed as a result of ongoing
research aimed at the rational design of neuronal NAChR
(1) McDonald, I. A.; Cosford, N. D. P.; Vernier, J .-M. Annu. Rep.
Med. Chem. 1995, 30, 41-50.
(2) McDonald, I. A.; Vernier, J .-M.; Cosford, N. D. P.; Corey-Naeve,
J . Curr. Pharm. Des. 1996, 2, 357-366.
(3) Newhouse, P.; Potter, A.; Corwin, J . Drug Dev. Res. 1996, 38,
278-289.
(4) Buccafusco, J . J .; Prendergast, M. A.; Terry J r., A. V.; J ackson,
W. J . Drug Dev. Res. 1996, 38, 196-203.
(5) Levin, E. D. Drug Dev. Res. 1996, 38, 188-195.
(6) Levin, E. D.; Conners, C. K.; Sparrow, E.; Hinton, S. C.; Erhardt,
D.; Meck, W. H.; Rose, J . E.; March, J . Psychopharmacology 1996, 123,
55-63.
Resu lts a n d Discu ssion
The synthetic method used initially to produce research
quantities of racemic 2 is shown in Scheme 1. The first
(7) Shytle, R. D.; Silver, A. A.; Philipp, M. K.; McConville, B. J .;
Sanberg, P. R. Drug Dev. Res. 1996, 38, 290-298.
(8) Freedman, R.; Coon, H.; Myles-Worsley, M.; Orr-Urtreger, A.;
Olincy, A.; Davis, A.; Polymeropoulos, M.; Holik, J .; Hopkins, J .; Hoff,
M.; Rosenthal, J .; Waldo, M. C.; Reimherr, F.; Wender, P.; Yaw, J .;
Young, D. A.; Breese, C. R.; Adams, C.; Patterson, D.; Adler, L. E.;
Kruglyak, L.; Leonard, S.; Byerley, W. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 587-592.
(13) De Fiebre, C. M.; Meyer, E. M.; Henry, J . C.; Muraskin, S. I.;
Kem, W. R.; Papke, R. L. Mol. Pharmacol. 1995, 47, 164-171.
(14) Bencherif, M.; Lovette, M. E.; Fowler, K. W.; Arrington, S.;
Reeves, L.; Caldwell, W. S.; Lippiello, P. M. J . Pharmacol. Exp. Ther.
1996, 279, 1413-1421.
(15) Lippiello, P. M.; Bencherif, M.; Gray, J . A.; Peters, S.; Grigoryan,
G.; Hodges, H.; Collins, A. C. J . Pharmacol. Exp. Ther. 1996, 279,
1422-1429.
(9) Levin, E. D.; Wilson, W.; Rose, J . E.; McEvoy, J . Neuropsychop-
harmacology 1996, 15, 429-436.
(16) Sacaan, A. I.; Reid, R. T.; Santori, E. M.; Adams, P.; Correa, L.
D.; Mahaffy, L. S.; Bleicher, L.; Cosford, N. D. P.; Stauderman, K. A.;
McDonald, I. A.; Rao, T. S.; Lloyd, G. K. J . Pharmacol. Exp. Ther. 1997,
280, 373-383.
(10) Buccafusco, J . J .; J ackson, W. J .; Terry, A. V., J r.; Marsh, K.
C.; Decker, M. W.; Arneric, S. P. Psychopharmacology 1995, 120, 256-
266.
(11) Garvey, D. G.; Wasicak, J . T.; Elliott, R. L.; Lebold, S. A.;
Hettinger, A.-M.; Carrera, G. M.; Lin, N.-H.; He, Y.; Holladay, M. W.;
Anderson, D. J .; Cadman, E. D.; Raszkiewicz, J . L.; Sullivan, J . P.;
Arneric, S. P. J . Med. Chem. 1994, 37, 4455-4463.
(12) Lin, N.-H.; Gunn, D. E.; Ryther, K. B.; Garvey, D. S.; Donelly-
Roberts, D. L.; Decker, M. W.; Brioni, J . D.; Buckley, M. J .; Rodriguez,
A. D.; Marsh, K. G.; Anderson, D. J .; Buccafusco, J . J .; Prendergast,
M. A.; Sullivan, J . P.; Williams, M.; Arneric, S. P.; Holladay, M. W. J .
Med. Chem. 1997, 40, 385-390.
(17) Menzaghi, F.; Whelan, K. T.; Risborough, V. T.; Rao, T. S.;
Lloyd, G. K. J . Pharmacol. Exp. Ther. 1997, 280, 384-392.
(18) Menzaghi, F.; Whelan, K. T.; Risborough, V. T.; Rao, T. S.;
Lloyd, G. K. J . Pharmacol. Exp. Ther. 1997, 280, 393-401.
(19) Cosford, N. D. P.; Bleicher, L.; Herbaut, A.; McCallum, J . S.;
Vernier, J .-M.; Dawson, H.; Whitten, J . P.; Adams, P.; Chavez-Noriega,
L.; Correa, L. D.; Crona, J . H.; Mahaffy, L. S.; Menzaghi, L. S.; Rao,
T. S.; Reid, R.; Sacaan, A. I.; Santori, E.; Stauderman, K. A.; Whelan,
K.; Lloyd, G. K.; McDonald, I. A. J . Med. Chem. 1996, 39, 3235-3237.
S0022-3263(97)01572-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

1110 J . Org. Chem., Vol. 63, No. 4, 1998
Bleicher et al.
Sch em e 1
step, based on a published method,20 involved the con-
densation of ester 3 with the sodium enolate of N-
vinylpyrrolidinone (4). The crude reaction mixture con-
taining intermediate 9 was acidified with 6 M HCl and
the solvent removed in vacuo. The resulting aqueous
mixture was heated for 3 h at reflux to effect hydrolysis
and decarboxylation, providing imine 5 upon treatment
with base. Reduction of 5 with sodium borohydride at
-40 °C in MeOH-acetic acid (4:1) provided the secondary
amine 6 which was converted to 7 via reductive amina-
tion using formaldehyde and sodium cyanoborohydride
with a catalytic amount of glacial acetic acid in acetoni-
trile. Cross-coupling of 7 with (trimethylsilyl)acetylene
(TMSA) in the presence of a catalytic amount of pal-
ladium tetrakis(triphenylphosphine) [Pd(PPh3)4] and cop-
per(I) iodide (Sonogashira reaction)21 gave the coupled
product 8a . Deprotection with cesium carbonate in
MeOH provided racemic 2 in an overall yield of 20% from
3.
Unfortunately this procedure suffered from a number
of drawbacks. Several of the reaction steps employed
reagents that were considered either too hazardous, too
unstable, or too expensive to be employed on a large scale.
Also problematic were the five chromatographic purifica-
tions performed during the synthesis. Furthermore, the
process provided racemic material rather than the de-
sired active single enantiomer. Thus several modifica-
tions were necessary to produce an efficient, inexpensive,
and scaleable synthesis of 2 and subsequently (S)-2. To
improve the yield of this process and simplify purification
of the intermediates, each step in the synthesis was
carefully investigated and optimized.
tion, and this material was collected by vacuum filtration
to provide 9 as a solid in 94 to 99% yield. Rinsing solid
9 removed the impurities which led to the formation of
the tarry byproducts produced by the original method.
Heating 9 in 6 M HCl at reflux (12 h) effected the removal
of the N-vinyl group, amide bond hydrolysis, and decar-
boxylation. Subsequent basic workup produced the crude
imine 5 with no observable byproducts. While 5 prepared
in this way was of sufficient purity to proceed, material
of higher purity could be obtained by the addition of
activated charcoal and simple filtration through a silica
gel pad. The yield of imine 5 from ester 3 ranged from
65 to 75% over the two steps.
The sodium borohydride reduction of 5 to racemic 6
was investigated next. It was found that reducing the
amount of HOAc employed from 8 to 5 equiv did not affect
the reaction adversely, but greatly simplified the workup.
Sodium borohydride was still employed, but the excess
used in the original procedure was found to be unneces-
sary. By maintaining the reaction temperature at -40
°C during the addition of the solid NaBH4, complete
conversion could be effected with only 0.5 equiv of
reducing agent, giving a 90% yield of amine 6. If the
reaction was allowed to warm to 0 °C as the NaBH4
dissolved, more than 2 equiv of the reducing agent was
required to drive the reaction to completion, resulting in
the formation of byproducts. While the precise nature
of the active reductant in this reaction is not known, it
is noteworthy that the reaction of 5 with 2 equiv NaBH-
(OAc)3 in THF was slow and resulted in incomplete
reduction of the imine. These observations would appear
to preclude in situ formation of sodium triacetoxyboro-
hydride as the active reductant in the formation of 6.
The introduction of the pyrrolidine N-methyl function-
ality was the next step to be studied. To eliminate the
need for NaBH3CN on a large scale, N-methylation using
an Eschweiler-Clarke reductive amination procedure
was investigated.11 It was found that heating 6 at 80 °C
with formaldehyde (37%, aqueous) in the presence of
formic acid as the reducing agent greatly simplified the
isolation of the product, avoided the generation of HCN,
and allowed the preparation of 7 in 92% yield with
minimal purification.
The palladium catalyzed cross-coupling to introduce
the ethyne moiety and provide 8 suffered from several
problems. The reaction of 7 with TMSA catalyzed by
Pd(PPh3)4 and copper(I) iodide did not go to completion
and afforded the product 8a as an oil which was difficult
to separate from unreacted starting material. The
homogeneous catalyst Pd(PPh3)4, is not only expensive,
The conditions reported by J acob20 for the first step
(conversion of 3 to 5) resulted in the generation of tarry
material which necessitated the chromatograpic purifica-
tion of 5. Furthermore, the reaction had an induction
period, was highly exothermic, and evolved hydrogen gas.
The first modification, therefore, was to replace NaH with
LiHMDS in the formation of the enolate. This allowed
the enolate acylation reaction to proceed at ambient
temperature and eliminated the induction period, the
evolution of hydrogen gas, and the exotherm. Thus, 4
was treated with LiHMDS (2 equiv) in THF at -22 °C,
a solution of ester 3 in tBuOMe was added, and the
mixture was then stirred at ambient temperature for 18
h. Dilution of the reaction mixture with water caused
the intermediate ketoamide 9 to precipitate out of solu-
(20) J acob, P., III J . Org. Chem. 1982, 47, 4165-4167.
(21) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467-4470.

Synthesis of Acetylcholine-Gated Ion Channel Agonist
J . Org. Chem., Vol. 63, No. 4, 1998 1111
Ta ble 1. Cr oss Cou p lin g of Su bstitu ted Ar yl Ha lid es
w ith Su bstitu ted Alk yn esa
but also air and temperature sensitive and difficult to
remove from the crude product. Furthermore, the method
required an excess of TMSA, a comparatively expensive
reagent. It was clear, therefore, that this critical step
in the process required considerable refinement. Sono-
gashira aryl-alkyne cross coupling reactions typically
employ a homogeneous source of Pd(0), a catalytic
amount of a copper(I) salt, and an organic amine base
as the solvent or cosolvent.22 Our strategy for optimizing
the transformation of 7 to 8 consequently focused on the
modification of three components of the reaction condi-
tions: the catalyst system, the alkyne coupling partner,
and the solvent/base combination.
A number of recent studies pointed to the utility of
heterogeneous palladium on carbon (Pd/C) as an alterna-
tive to the standard homogeneous catalysts for carbon-
carbon bond formation. Of particular interest to us was
an article reporting the use of a catalytic amount of Pd/C
in the presence of PPh3 and CuI to promote coupling of
aryl bromides and phenylacetylene in anhydrous triethy-
lamine-acetonitrile,23 and another disclosing a Pd/C-
catalyzed Suzuki cross-coupling reaction.24 Thus we
envisioned that a catalytic system consisting of Pd/C in
combination with PPh3 might replace Pd(PPh3)4 in the
coupling reaction.
entry compound
X
Y
R
% isolated yield
1
2
3
4
5
6
7
10
11
12
13
14
15
16
Br m-CHO C(CH3)2OH
Br p-NO2 C(CH3)2OH
m-NH2 C(CH3)2OH
98b
92b
78b
89b
92c
50d
80d,e
I
Br o-CN
Br o-CN
C(CH3)2OH
CH2N(CH3)2
1-cyclohexenyl
I
I
p-OH
p-CO2H 1-cyclohexenyl
a
Reactions performed using a 1:4:2 ratio of 10% Pd/C:PPh3:
CuI, 2.5 equiv of K2CO3, and 2.5 equiv of alkyne in DME:water
1:1 at 80 °C. a: 2 mol % Pd/C. b: 2.5 mol % Pd/C. c: 3.3 mol %
Pd/C. d: Reaction performed in DME with 5 equivalents water.
Ta ble 2. Cou p lin g of Heter ocyclic Ha lid es w ith
Su bstitu ted Alk yn es
A survey of the literature revealed a potentially viable
replacement for TMSA as the ethyne equivalent in the
reaction. 2-Methyl-3-butyn-2-ol (mebynol) has been em-
ployed previously as a protected ethynyl moiety, although
reports of its use are less common than the analogous
reactions with TMSA.25,26 This is quite surprising con-
sidering the low cost of mebynol and the generally
crystalline nature of the resulting coupled products.
The beneficial effect of water in some palladium-
mediated processes has also been noted recently.27-30 In
light of these observations it seemed likely that a mixture
of 1,2-dimethoxyethane (DME) and water would be a
viable solvent system. While organic amine bases are
commonly employed in Sonogashira coupling protocols,
there was concern that the presence of triethylamine in
a reaction mixture which also contained 8b, a tertiary
amine, would complicate the workup and purification.
Since similar problems were envisioned with the use of
a phase transfer catalyst,31 we elected to use an inorganic
base without additives. K2CO3 was selected as the
reagent of choice for its high water solubility and mild-
ness compared with NaOH which has been reported to
induce the in situ deprotection of mebynol-coupled prod-
ucts.31
Reactions performed using a 1:4:2 ratio of 10% Pd/C:PPh3:CuI,
2.5 equiv of K2CO3, and 2.5 equiv of alkyne in DME:water 1:1 at
80 °C. 2 mol % Pd/C. 3.3 mol % Pd/C.
a
b
ratio of 1:4:2), and K2CO3 (2.5 equiv) in a DME-water
mixture (1:1) cross-coupling proceeded to afford 8b in
high yield. The product was isolated as a solid which
was readily recrystallized from cyclohexane or heptane
in purified yields ranging from 92 to 98%. Deprotection
to afford 2 was accomplished by simply heating 8b in
toluene in the presence of a catalytic quantity of NaH
(10 mol %) at a high enough temperature to distill a
portion of the solvent.32 Racemic 2, an oil at ambient
temperature, was converted to the monofumaric acid salt
(SIB-1765F) for biological evaluation.
To define the scope and limitations of the new cross-
coupling conditions, experiments were performed on a
variety of readily available substrates. The results of
these experiments are presented in Tables 1 and 2 and
were the subject of a recent communication from this
laboratory.33 The coupling partners were selected to
When 7 was heated with mebynol in the presence of
catalytic amounts of 10% Pd/C, PPh3 and CuI (in a molar
(22) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Int. 1995,
129-160.
(23) De la Rosa, M.; Velarde, E.; Guzman, A. Synth. Commun. 1990,
20, 2059-2064.
(24) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett. 1994,
35, 3277-3280.
(25) Mal′kina, A. G.; Brandsma, L.; Vasilevsky, S. F.; Trofimov, B.
A. Synthesis 1996, 589-590.
(26) Melissaris, A.; Litt, M. H. J . Org. Chem. 1994, 59, 5818-5821.
(27) Bumagin, N. A.; Sukhomlinova, L. I.; Luzikova, E. V.; Tolstaya,
T. P.; Beletskaya, I. P. Tetrahedron Lett. 1996, 37, 897-900.
(28) Roshchin, A. I.; Bumagin, N. A.; Beletskaya, I. P. Tetrahedron
Lett. 1995, 36, 125-128.
(29) Genet, J . P.; Linquist, A.; Blart, E.; Mouries, V.; Savignac, M.
Tetrahedron Lett. 1995, 36, 1443-1446.
(30) Rai, R.; Aubrecht, K. B.; Collum, D. B. Tetrahedron Lett. 1995,
36, 3111-3114.
(32) Havens, S. J .; Hergenrother, P. M. J . Org. Chem. 1985, 50,
1763-1764.
(31) Carpita, A.; Lessi, A.; Rossi, R. Synthesis 1984, 571-572.

1112 J . Org. Chem., Vol. 63, No. 4, 1998
Bleicher et al.
Ta ble 3. Requ ir ed Rea gen t Stu d y
properties. At the outset, two basic approaches to the
preparation of (S)-2 were available: classical resolution
of 2 or one of its precursors (6, 7, or 8b) or enantioselec-
tive synthesis.
The classical resolution of 6 has been reported by
J acob.20 After several unsuccessful attempts using in-
expensive resolving agents, such as (+)-tartaric acid,
J acob found that resolution with the appropriate enan-
tiomer of Mosher’s acid provided either (S)- or (R)-6. To
date, the resolution of racemic 7 has not been reported,39
while 8b and 2 were hitherto unknown compounds. It
was envisioned that an alternative approach to the
problem via the enantioselective reduction of imine 5
might be effective. While there are numerous procedures
in the literature for the enantioselective reduction of
ketones, there are comparatively few methods for the
analogous transformation of imines.40 Among those
reported are the asymmetric hydrogenation protocols
developed separately by Noyori,41 Buchwald,42 and Burk.43
While these methods provide a variety of amines in high
enantiomeric excess a number of limitations have been
noted. For example, Buchwald reported that while
2-phenyl-1-pyrroline (22) underwent enantioselective
hydrogenation at very high pressure to give 23 in >99%
ee, the corresponding pyridyl imine 24 failed to reduce
under these conditions.42
entry
Pd/C
PPh3
CuI
K2CO3
% yieldb
1
2
3
4
5
0.05a
0.05
0.0
0.05
0.05
0.2
0.0
0.2
0.2
0.2
0.0
0.1
0.1
0.1
0.1
2.5
2.5
2.5
0.0
2.5
2.5
0
0
3
80
a
Amounts are equivalents relative to 1-bromo-4-fluorobenzene,
b
using 2.5 equiv of mebynol in all cases. Yields determined by GC/
MS.
assess the applicability of the reaction conditions to a
wide range of unprotected functional groups. In addition
to the observations noted in the earlier publication, an
interesting aspect of the cross-coupling of aniline deriva-
tives has been noted. While iodoanilines cross-couple in
high yield at both the meta (Table 1, entry 3) and ortho
positions,34 the corresponding bromoanilines are com-
pletely unreactive. The likely reason for this is that the
increased reactivity of the iodo- versus bromoaryl sub-
strates offsets the deactivating effect of the arylamine
functional group.35
To determine the necessity of each component of the
catalyst-base system for successful coupling, a series of
experiments, each lacking one of the components, was
performed (Table 3). Thus, when cross-coupling of
1-bromo-4-fluorobenzene with mebynol was attempted in
the absence of either Pd/C or PPh3 from the reaction
mixture, no coupled product was observed. In the
absence of CuI or K2CO3, only traces of product could be
detected by GC/MS. These results clearly indicate that
cycling of the catalyst for this reaction requires all four
of the components. Furthermore, while it has been
reported that alkynes couple with aryl iodides in the
absence of a copper(I) source, our results are in ac-
cordance with others who have demonstrated the ben-
eficial effect of copper(I) salts in this22 and other palladium-
catalyzed coupling reactions.36 Indeed, prolonged reaction
times in the absence of CuI resulted in byproducts
evidently derived from the coupling of mebynol with
product, forming the corresponding enyne, a result which
has been utilized synthetically by Trost.37 Another
observation concerns the degassing of the reaction mix-
ture solvents. In many cases where the reaction condi-
tions failed to give cross-coupled product, prior degassing
of the reaction mixture allowed cross-coupling to proceed.
Having optimized the preparation of large amounts of
racemic 2, we next considered the synthesis of the
individual enantiomers (S)-2 and (R)-2. Nicotine (1)
exhibits stereoselectivity in biological assays, the natural
(S)-(-)-isomer being a more potent agonist than the (R)-
(+)-isomer.38 It appeared likely, therefore, that the (S)-
enantiomer of 2 would possess the desired biological
We were intrigued, however, by a report which de-
scribed the enantioselective reduction of imines employ-
ing a reagent formed from the reaction of sodium
borohydride (1 equiv) with CBZ-L-proline 25 (3 equiv).44
While the reported enantioselectivities were not spec-
tacular (up to 86% ee) the simplicity of the procedure and
the ready availability of the reagents made this meth-
odology attractive. Furthermore the authors reported
successful reduction of a cyclic imine 27 to give the
enantiomerically enriched amine 28.
In the event, application of this methodology to our
substrate proved to be fruitful. Stirring a solution of the
preformed chiral (acyloxy)borohydride reagent 26 with
imine 5 provided secondary amine 6, after workup and
purification, in 98% yield and 30% ee. The ee of 6 was
determined by recording the 1H NMR spectrum of the
enantiomerically enriched material in the presence of
Mosher’s acid as a chiral shift reagent. The resonance
due to the methine proton at C-2′, an apparent triplet,
appears as two signals and the ratio of the integrated
peaks provided an estimate of the ee (Figure 1). Predict-
(38) Aceto, M. D.; Martin, B. R.; Uwaydah, I. M.; May, E. L.; Harris,
L. S.; Izazola-Conde, C.; Dewey, W. L.; Bradshaw, T. J .; Vincek, W. C.
J . Med. Chem. 1979, 22, 174-177.
(39) Rondahl, L. Act. Pharm. Suec. 1977, 14, 113-118.
(40) Gawley, R. E.; Aube, J . Principles of Asymmetric Synthesis; 1st
ed.; Elsevier: Oxford, 1996; Vol. 14.
(33) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115-1116.
(34) Edwards, J . P., personal communication.
(35) Tsuji, J . Palladium Reagents and Catalysis; Wiley: Chichester,
1996.
(36) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905-5911.
(37) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G.
J . Am. Chem. Soc. 1997, 119, 698-708.
(41) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J . Am. Chem. Soc. 1996, 118, 4916-4917.
(42) Willoughby, C. A.; Buchwald, S. L. J . Am. Chem. Soc. 1994,
116, 8952-8965.
(43) Burk, M. J .; Martinez, J . P.; Feaster, J . E.; Cosford, N. D. P.
Tetrahedron 1994, 50, 4399-4428.
(44) Yamada, K.; Takeda, M.; Iwakuma, T. J . Chem. Soc., Perkin
Trans. 1 1983, 265-270.

Synthesis of Acetylcholine-Gated Ion Channel Agonist
J . Org. Chem., Vol. 63, No. 4, 1998 1113
be resolved using this GC method. Determination of the
ee of 2 showed that the asymmetric center was not
sensitive to the conditions of the N-methylation, pal-
ladium-catalyzed aryl-alkyne cross coupling, or the
NaH-catalyzed deprotection, as no loss of stereochemical
integrity could be detected. Finally, conversion of (S)-2,
an oil at ambient temperature, to its mono maleic acid
salt gave the desired product SIB-1508Y, in 93% yield.
The absolute stereochemistry of the enantiomers of 7,
and by analogy 2, was established by hydrogenation of
(S)-7 to afford a compound which was identical in all
respects to (S)-(-)-nicotine. It was thus proven that
reduction with the (acyloxy)boroborohydride reagent (29)
derived from CBZ-D-proline ultimately provided (S)-2, the
more active enantiomer, while using CBZ-L-proline re-
sulted in the formation of (R)-7 and ultimately (R)-2.
Fortunately, extraction of the acidic aqueous phase with
i-PrOAc during workup following the reduction of 5
allowed recovery of the CBZ-D-proline which could be
purified by chromatography and reused, offsetting the
expense of using the reagent derived from the unnatural
amino acid.
F igu r e 1. Resonances (1H NMR) due to the C-2′ proton of 6
(30% ee) in the presence of Mosher’s acid.
Con clu sion
Practical and efficient syntheses of 2 and (S)-2 have
been described. Each step in the process was examined
individually, optimized and incorporated into the final
synthetic scheme. Novel palladium chemistry was de-
veloped for the transformation of 7 to 8b, and this
methodology was shown to be general. The yield of the
conversion of 3 to 2 was improved by a factor of 2 (from
20 to 40% overall), while concurrently improving the
scaleability, economy, and safety of each step. The
preparation of enantiopure (S)-2 was accomplished using
a combination of enantioselective reduction, providing
material with 30% ee, coupled with resolution via crys-
tallization of a diastereomeric salt with >99% ee. Fi-
nally, these improvements and the development of an
enantioselective route to (S)-2 have contributed to the
efficient production of multikilogram quantities of (S)-2
required for the preclinical and clinical study of its
therapeutic properties.
ably, reduction of 5 with the (acyloxy)borohydride reagent
29 derived from CBZ-D-proline gave 6 enriched in the
other enantiomer with a 30% ee (Scheme 2).
Exp er im en ta l Section
Gen er a l. All reactions, unless otherwise noted, were
conducted under an inert atmosphere. Purchased reagents
and solvents were used as received. Solvents designated as
anhydrous were purchased in an anhydrous state (pre-pack-
aged under nitrogen) and stored over activated 3 Å molecular
sieves. Analytical thin-layer chromatography was carried out
on precoated silica gel plates (0.25 mm, 60 F254) with detection
by UV, phosphomolybdic acid solution, or iodine vapor. Col-
umn chromatography was performed on silica gel (35-70 µm).
Melting points were obtained in unsealed capillaries and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded in the indicated solvents, and the
chemical shifts are reported in ppm downfield from tetram-
ethylsilane. Solvent (CDCl3 δC ) 77.00, δH ) 7.25; DMSO-d6
δC ) 39.43, δH ) 2.5; CD3OD δC ) 49.05, δH ) 3.30) or added
tetramethylsilane served as internal references. Infrared
spectra are reported in wavenumbers and were measured as
KBr pellets. Low resolution mass spectra were recorded in
EI mode at 70 EV with a quadrupole instrument. Optical
rotations were obtained at 589 nm (sodium D line) using a
1.9 dm cell at 20 °C. Chiral gas chromatographic separations
were conducted on a 20 m × 0.25 mm capillary column coated
with permethylated hydroxypropyl â-cyclodextrin phase at the
Racemic nicotine has been resolved by sequential
crystallizations with d-tartaric acid and di-p-toluoyl-L-
tartaric acid.38 This approach appeared more attractive
than using the expensive Mosher’s acid to resolve 5-bro-
monornicotine (6), as in J acob’s method, and it was
therefore decided to N-methylate the enantiomerically
enriched 6 and complete the resolution with nicotine
analogue 7. After some experimentation, it was found
that crystallization of the salt formed from enantiomeri-
cally enriched 7 (30% ee) with the correct stoichiomeric
quantity of dibenzoyl-L-tartaric acid in a mixture of EtOH
and EtOAc provided (S)-7 with >99% ee over two
crystallizations (Scheme 2).
The determination of ee for 7 and 2 was accomplished
using a chiral capillary GC column. Interestingly, while
baseline separation was achieved for the key intermedi-
ate 7 and final product 2, neither 8b nor nicotine (1) could

1114 J . Org. Chem., Vol. 63, No. 4, 1998
Bleicher et al.
Sch em e 2
indicated temperatures under isothermal conditions with a
flow rate of 3.0 mL/min, using flame ionization detection.
3-(5-Br om o-3-p yr id oyl)-N-vin ylp yr r olid in on e (9). A 5
L reaction vessel equipped for overhead stirring and fitted with
a temperature probe was charged with lithium bis(trimethyl-
silyl)amide (1600 mL of a 1 M solution in THF, 1.6 mol, 2
equiv) and was cooled to an internal temperature of -22 °C
(CaCl2/H2O cooling bath). N-Vinylpyrrolidinone (103 mL, 0.96
mol, 1.2 equiv) was added in one portion, and the solution was
stirred for 0.5 h at -22 °C. Ethyl 5-bromo-3-pyridinecarboxy-
late (184 g, 0.8 mol) was added to the mixture via cannula as
a solution in tert-butyl methyl ether (800 mL), and the reaction
mixture was allowed to warm to 25 °C. After stirring for 18
h at 25 °C, the reaction was quenched with water (400 mL)
and stirring was continued. After 5-10 min a yellow precipi-
tate appeared which was collected by filtration, rinsed with
CH2Cl2, and dried under vacuum at 65 °C to afford 3-(5-bromo-
3-pyridoyl)-N-vinylpyrrolidinone (9) (235 g, 99%). 1H NMR
(DMSO-d6) apparent rotamers; major: δH 8.68 (d, J ) 2 Hz, 1
H), 8.63 (d, J ) 3 Hz, 1 H), 8.05 (m, 1 H), 7.06 (dd, J ) 16, 9
Hz, 1 H), 4.11 (m, 2 H), 3.33 (t, J ) 8 Hz, 2 H), 2.18 (t, J ) 8
Hz, 2 H); minor: δH 8.53 (m, 1 H), 8.45 (m, 1 H), 7.94 (m, 1
H), 6.94 (dd, J ) 16, 9 Hz, 1 H), 3.87 (m, 2 H), 3.23 (t, J ) 7
Hz, 2 H), 2.68 (t, J ) 8 Hz, 2 H). IR (KBr) 3418, 2923, 2869,
1651, 1629, 1525, 1422, 1281, 1020 cm-1; LRMS (EI) m/e 297
(C12H11N281Br + H+), 296 (C12H11N281Br), 295 (C12H11N279Br
+ H+), 294 (C12H11N279Br); HRMS calcd for C12H1179BrN2O2
+ Li+ 301.0164 found 301.0155.
resulting solution was further diluted with water (200 mL) to
provide a solution of pH 4. Concentrated HCl (30 mL) was
added to afford a solution of pH 3 and this was then extracted
with CH2Cl2 (3 × 100 mL). The aqueous phase was basified
with solid NaOH and extracted with CH2Cl2 (3 × 200 mL).
The combined basic organic extracts were washed with brine
(100 mL) and stirred with MgSO4 and charcoal for 18 h.
Filtration through Celite and concentration in vacuo gave 6
as an oil (44.8 g, crop 1). The acidic organic extracts, shown
by TLC to contain product, were extracted with 1 M HCl (2 ×
200 mL). The combined extracts were washed with CH2Cl2
(2 × 50 mL) and then basified with solid NaOH to pH 12. The
basic aqueous layer was then extracted with CH2Cl2 (3 × 100
mL). The combined organic phase was washed with brine (50
mL) and then stirred with MgSO4 and charcoal for 18 h.
Filtration through Celite and concentration in vacuo gave 6
as an oil (6 g, crop 2). The basic aqueous fractions were
combined and concentrated in vacuo (2-propanol azeotrope)
giving a reduced volume which was extracted with CH2Cl2 (3
× 150 mL). The combined organic extracts were stirred with
MgSO4 and charcoal for 18 h. Filtration through Celite and
concentration in vacuo gave 6 as an oil (10.5 g, crop 3). Total
yield of product 61.3 g, 90%. LRMS (EI) m/e 228 (C9H11N2-
81Br), 227 (C9H11N281Br - H+), 226 (C9H11N279Br), 225
(C9H11N279Br - H+); HRMS calcd for C9H1179BrN2 + H+
1
227.0184 found 227.0193; H NMR (CDCl3) δH 8.53 (d, J ) 2
Hz, 1 H), 8.49 (d, J ) 2 Hz, 1 H), 7.91 (t, J ) 2 Hz, 1 H), 4.17
(t, J ) 7.5 Hz, 1 H), 3.18 (m, 1 H), 3.06 (m, 1 H), 2.30 (s, 1 H),
2.24 (m, 1 H), 1.80-2.00 (m, 2 H), 1.63 (m, 1 H); 13C NMR
(CDCl3) δC 149.0, 146.6, 142.6, 136.6, 120.7, 59.1, 46.9, 34.5,
25.4.
5-Br om o-3-(2-p yr r olin -1-yl)p yr id in e (5). 3-(5-Bromo-3-
pyridoyl)-N-vinylpyrrolidinone (9) (230 g, 0.78 mol) was dis-
solved in a mixture of water (1.25 L), 12 M HCl (1.25 L), and
charcoal (125 mL) in a 5 L reaction vessel equipped for
overhead stirring and fitted with an internal temperature
probe and a reflux condenser. The mixture was gradually
heated to 98 °C over 2 h and then held at this temperature
for 2 h. The reaction flask was allowed to cool to 25 °C
overnight (HPLC analysis indicated completion). The reaction
mixture was filtered through Celite and the pad thoroughly
washed with CH2Cl2 (3 × 300 mL). The aqueous solution was
basified with solid NaOH to pH 11, the layers were separated,
and the aqueous was extracted with CH2Cl2 (5 × 500 mL). The
combined organic extracts were stirred with MgSO4 and
charcoal prior to filtration through a pad consisting of layers
of silica gel, Florisil, and Celite. This was flushed through
with more CH2Cl2 (4 L) followed by EtOAc (4 L). The combined
eluants were concentrated in vacuo to afford 5-bromo-3-(2-
pyrrolin-1-yl)pyridine (5) (124.8 g, 71%) as a solid. Mp 98-
5-Br om o-3-(1-m et h yl-2-p yr r olid in yl)p yr id in e (7).
A
three-necked 2L round-bottomed flask equipped for overhead
stirring and fitted with an internal temperature probe and a
reflux condenser was charged with 5-bromo-3-(1-H-2-pyrro-
lidinyl)pyridine (6) (50 g, 0.22 mol), 98% formic acid (400 mL),
and 37% aqueous formaldehyde solution (200 mL). The
mixture was heated for 18 h at 80 °C. After cooling to 25 °C,
the mixture was concentrated in vacuo to a volume of ap-
proximately 200 mL and water (200 mL), and concentrated
HCl (10 mL) were added giving a solution of pH 3. CH2Cl2
(100 mL) was added and the mixture filtered through a pad
of Celite to destroy the emulsion. The organic phase was
separated and the aqueous layer extracted with CH2Cl2 (2 ×
50 mL). The aqueous phase was basified with solid NaOH to
pH 12, and the mixture was again filtered through Celite. The
basic aqueous phase was extracted with CH2Cl2 (3 × 200 mL),
and the combined basic organic extracts were stirred with
MgSO4 and charcoal for 1 h. The mixture was filtered through
Celite and concentrated in vacuo to afford 7 as an oil (44 g,
crop 1). The basic aqueous fractions were combined and
concentrated in vacuo (2-propanol azeotrope) giving a reduced
volume which was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were stirred with MgSO4 and
charcoal for 18 h. Filtration through Celite and concentration
in vacuo gave 7 as an oil (4.7 g, crop 2). Total yield 48.7 g,
92%. LRMS (EI) m/e 242 (C10H13N281Br), 241 (C10H13N281Br
- H+), 240 (C10H13N279Br), 239 (C10H13N279Br - H+); 1H NMR
(CDCl3) δH 8.56 (d, J ) 2.5 Hz, 1 H), 8.47 (d, J ) 2.5 Hz, 1 H),
7.90 (t, J ) 2.5 Hz, 1 H), 3.22 (bt, J ) 8.5 Hz, 1 H), 3.10 (t, J
) 8.0 Hz, 1 H), 2.30 (app dd, J ) 8.5, 8.5 Hz, 1 H), 2.20 (m, 1
H), 2.17 (s, 3 H), 1.93 (m, 1 H), 1.80 (m, 1 H), 1.68 (m, 1 H);
13C NMR (CDCl3) δC 149.0, 146.9, 140.6, 136.7, 120.4, 67.4,
56.2, 39.8, 34.8, 22.1.
1
99 °C (EtOAc) (lit.19 mp 97.5-98.5 °C); H NMR (CDCl3) δH
8.88 (d, J ) 2 Hz, 1 H), 8.71 (d, J ) 2 Hz, 1 H), 8.36 (app t, J
) 2 Hz, 1 H), 4.10 (app tt, J ) 8, 2 Hz, 2 H), 2.94 (app tt, J )
8, 2 Hz, 1 H), 2.09 (app quintet, J ) 8 Hz, 2 H); 13C NMR
(CDCl3) δC 169.8, 152.1, 147.0, 137.2, 131.6, 120.9, 61.7, 34.8,
22.5.
5-Br om o-3-(1-H-2-p yr r olid in yl)p yr id in e (6). A three-
necked, 2L, round-bottomed flask equipped for overhead
stirring and fitted with an internal temperature probe was
charged with 5-bromo-3-(2-pyrrolin-1-yl)pyridine (5) (67.5 g,
0.3 mol) and dissolved in a mixture of MeOH (560 mL) and
glacial acetic acid (140 mL). The solution was cooled to -42
°C (CaCl2/H2O cooling bath), causing the imine to precipitate,
and solid sodium borohydride (1.96 g, 0.052 mol) was slowly
added in portions over 1 h, maintaining the internal temper-
ature below -40 °C. The reaction was stirred at -40 °C for 3
h and then at 0 °C for 18 h, the course of the reaction being
monitored by TLC. Water (200 mL) was added, and the
mixture was concentrated to a volume of about 200 mL. The

Synthesis of Acetylcholine-Gated Ion Channel Agonist
J . Org. Chem., Vol. 63, No. 4, 1998 1115
A portion of this material was converted to the dihydrobro-
mide salt and characterized as follows. Mp 225-226 °C
(EtOH-Et2O); IR (KBr) 3429, 2934, 2635, 2559, 2499, 1537,
second crop (14.2 g). The total yield of racemic 2 fumarate
was 31.5 g, 62%. Mp 149-150 °C (EtOH); IR (KBr) 3438, 3194,
1
2939, 2658, 2510, 2103, 1680, 1614, 1454, 984, 643 cm-1; H
1
1439, 1319, 1254, 851, 672 cm-1; H NMR (CD3OD): δH 9.23
NMR (DMSO-d6): δH 8.57 (d, J ) 2 Hz, 1 H), 8.54 (d, J ) 2
Hz, 1 H), 7.83 (app t, J ) 2 Hz, 1 H), 6.61 (s, 2 H), 4.44 (s, 1
H), 3.25 (app dd, J ) 16, 8 Hz, 1 H), 3.19 (dd, J ) 8, 3 Hz, 1
H), 2.33 (app dd, J ) 16, 8 Hz, 1 H), 2.20 (m, 1 H), 2.12 (s, 3
H), 1.6-1.9 (m, 3 H); 13C NMR (DMSO-d6) δC 166.4, 151.1,
148.9, 137.8, 137.0, 134.2, 118.6, 84.1, 80.3, 67.4, 56.0, 39.5,
34.0, 22.1. Anal. Calcd for C12H14N2‚C4H4O4: C, 63.58; H,
5.96; N, 9.27%. Found: C, 63.47; H, 6.03; N, 9.17%.
(d, J ) 2 Hz, 1 H), 9.21 (d, J ) 2 Hz, 1 H), 9.11 (app t, J ) 2
Hz, 1 H), 4.85 (app dd, J ) 10, 8 Hz, 1 H), 3.97 (m, 1 H), 3.43
(m, 1 H), 2.92 (s, 3 H), 2.65-2.77 (m, 1 H), 2.31-2.53 (m, 3
H); 13C NMR (CD3OD) δC 148.8, 148.0, 144.8, 134.8, 123.9, 69.8,
57.6, 39.5, 32.5, 22.9. Anal. Calcd for C10H15Br3N2: C, 29.78;
H, 3.72; N, 6.95%. Found: C, 30.03; H, 3.70; N, 6.82%.
5-(2-Hyd r oxy-2-m eth ylbu t-3-yn yl)-3-(1-m eth yl-2-p yr r o-
lid in yl)p yr id in e (8b). A 1 L three-necked flask fitted with
an overhead stirrer and reflux condenser was charged with
5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) (44.0 g, 182
mmol), K2CO3 (52.4 g, 455 mmol), copper(I) iodide (3.47 g, 18.2
mmol), 10% palladium on carbon (4.86 g, 4.56 mmol Pd), and
triphenylphosphine (4.78 g, 18.2 mmol) in DME (220 mL) and
water (220 mL). This mixture was stirred at 25 °C for 0.5 h
before 2-methyl-3-butyn-2-ol (37.8 g, 450 mmol) was added.
The mixture was heated under reflux for 16 h, allowed to cool
to 25 °C, filtered through a pad of Celite, and concentrated in
vacuo. The aqueous residue (approximately 250 mL) was
slowly added to 2 M HCl (400 mL) and extracted with toluene
(600 mL). The aqueous layer was basified to pH 11 with solid
K2CO3 and extracted with EtOAc (3 × 500 mL). The organic
layers were washed with saturated Na2CO3 (300 mL) and brine
(300 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo to afford 8b as a light brown oil. This material
was crystallized from hot cyclohexane (400 mL). The colorless
solid (8b) which precipitated was collected (32.4 g, 72%). The
mother liquors were concentrated to approximately 200 mL,
allowing the precipitation of a second crop of 8b (4.2 g, 9%).
The remaining mother liquors were concentrated in vacuo and
purified by flash column chromatography on silica gel, eluting
with hexane:EtOAc (1:1) followed by CH2Cl2:MeOH (95:5), to
give a further 4.5 g of 8b (10%). The total yield of 8b was
41.0 g, 92%. Mp 79-81 °C (cyclohexane); IR (KBr) 3233, 2972,
En a n tiom er ica lly En r ich ed 5-Br om o-3-(1H-2-p yr r o-
lid in yl)p yr id in e (6). A single neck 500 mL round-bottomed
flask was charged with CBZ-D-proline (42.9 g, 172 mmol) and
DME (120 mL). The stirred solution was cooled to -10 °C
and sodium borohydride (2.08 g, 55 mmol) was added in
portions as a solid. After the addition, the cooling bath was
removed and the stirring continued at 25 °C for 2 h. The
colorless solution was concentrated in vacuo to afford a syrup
which was dissolved in CH2Cl2 (50 mL). 5-Bromo-3-(2-pyrro-
lin-1-yl)pyridine (5) (8.00 g, 35.6 mmol) in CH2Cl2 (50 mL) was
added to the solution of CBZ-D-Pro/NaBH4 and the mixture
stirred at 25 °C for 48 h. The solvents were removed in vacuo,
and 6 M HCl (240 mL) and i-PrOAc (240 mL) were added. The
aqueous phase was extracted with i-PrOAc (2 × 240 mL), and
the combined i-PrOAc extracts were concentrated in vacuo to
afford CBZ-D-proline (essentially quantitative recovery). The
aqueous phase was made basic (pH 13) with solid NaOH and
extracted with CH2Cl2 (3 × 150 mL). The combined CH2Cl2
extracts were washed with brine (100 mL), dried (MgSO4),
filtered, and concentrated in vacuo to afford enantiomerically
enriched 6 as an oil (7.95 g, 98%). LRMS (EI) m/e 228
(C9H11N281Br), 227 (C9H11N281Br - H+), 226 (C9H11N279Br),
1
225 (C9H11N279Br - H+); H NMR (CDCl3) δH 8.53 (d, J ) 2
Hz, 1 H), 8.49 (d, J ) 2 Hz, 1 H), 7.91 (t, J ) 2 Hz, 1 H), 4.17
(t, J ) 7.5 Hz, 1 H), 3.18 (m, 1 H), 3.06 (m, 1 H), 2.30 (s, 1 H),
2.24 (m, 1 H), 1.80-2.00 (m, 2 H), 1.63 (m, 1 H). This product
was carried on to the next step without further purification.
The enantiomeric purity of this material was determined in
the following manner. An NMR tube was charged with
2787, 1450, 1417, 1373, 1313, 1215, 1178, 1150, 900, 704 cm-1
;
1H NMR (CDCl3): δH 8.65 (d, J ) 2 Hz, 1 H), 8.41 (d, J ) 2
Hz, 1 H), 7.80 (t, J ) 2 Hz, 1 H), 4.71 (bs, 1 H), 3.24 (app dt,
J ) 7, 2 Hz, 1 H), 3.07 (app t, J ) 8.5 Hz, 1 H), 2.31 (app dd,
J ) 8.5, 8.5 Hz, 1 H), 2.19 (m, 1 H), 2.16 (s, 3 H), 1.90-2.10
(m, 1 H), 1.77-1.90 (m, 1 H), 1.65-1.77 (m, 1 H), 1.62 (s, 6
H); 13C NMR (CDCl3) δC 150.6, 147.8, 138.6, 137.8, 120.1, 98.2,
78.3, 68.3, 64.7, 56.9, 40.3, 35.1, 31.3, 31.0, 22.5. Anal. Calcd
for C15H20N2O: C, 73.77; H, 8.20; N, 11.48%. Found: C, 73.86;
H, 8.21; N, 11.47%.
1
enantiomerically enriched 6 and the H NMR was recorded in
CDCl3. Into the same NMR tube was added (S)-(-)-R-
methoxy-R-(trifluoromethyl)phenylacetic acid (S-Mosher’s acid)
(1.5-2 equiv). The 1H NMR was again recorded and the
integral ratio of the pair of 1H resonances at δH 4.12 and 4.32
(app t or dd) corresponding to the C2′-H signal of each
stereoisomer was measured. This analysis showed the ee of
6 produced in this manner to be 30%.
5-Eth yn yl-3-(1-m eth yl-2-pyr r olidin yl)pyr idin e (2). 5-(2-
Hydroxy-2-methylbut-3-ynyl)-3-(1-methyl-2-pyrrolidinyl)pyri-
dine (8b) (40.8 g, 0.167 mol) and NaH as a 60% dispersion in
mineral oil (680 mg, 17.0 mmol) were dissolved in dry toluene
(700 mL) in a 1 L round-bottom flask. The mixture was heated
to an internal temperature of 111 °C, and a portion of the
toluene/acetone mixture (approximately 250 mL) was removed
by distillation. The mixture was allowed to cool to 25 °C and
then washed with 1 M K2CO3 (100 mL), water (100 mL), and
brine (100 mL). The organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to afford 2 (30.4
g, 97%) as a light brown oil. LRMS (EI) m/e 187 (M+ + H),
E n a n t iom er ica lly E n r ich ed 5-Br om o-3-(1-m et h yl-2-
p yr r olid in yl)p yr id in e (7). Enantiomerically enriched 6
(7.95 g, 35 mmol) was dissolved in a mixture of 98% formic
acid (74 mL) and 37% aqueous formaldehyde (37 mL). The
solution was heated with stirring for 3 h at 80 °C. After being
cooled to 25 °C, the mixture was concentrated in vacuo and
water (30 mL) added. The mixture was basified with solid
NaOH to pH 12 and extracted with CH2Cl2 (4 × 100 mL). The
combined organic extracts were washed with brine (100 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The crude
material was chromatographed on silica gel with EtOAc:
hexane (1:3 to 1:1) as the eluant to afford enantiomerically
enriched 7 as an oil (6.0 g, 71%). LRMS (EI) m/e 242
(C10H13N281Br), 241 (C10H13N281Br - H+), 240 (C10H13N279Br),
239 (C10H13N279Br - H+); 1H NMR (CDCl3) δH 8.56 (d, J )
2.5 Hz, 1 H), 8.47 (d, J ) 2.5 Hz, 1 H), 7.90 (t, J ) 2.5 Hz, 1
H), 3.22 (bt, J ) 8.5 Hz, 1 H), 3.10 (t, J ) 8.0 Hz, 1 H), 2.30
(app dd, J ) 8.5, 8.5 Hz, 1 H), 2.20 (m, 1 H), 2.17 (s, 3 H), 1.93
(m, 1 H), 1.80 (m, 1 H), 1.68 (m, 1 H).
(S)-(-)-5-Br om o-3-(1-m et h yl-2-p yr r olid in yl)p yr id in e
[(S)-7]. A flask was charged with enantiomerically enriched
(30% ee) 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) (6.0
g, 24.9 mmol) and dibenzoyl-L-tartaric acid (5.9 g, 16.4 mmol).
Absolute EtOH (80 mL) and EtOAc (540 mL) were added, and
the mixture was warmed to afford a solution. Heating was
continued until the solvent distilled. After removal of part of
the solvent the solution started to become cloudy, and the
1
186 (M+), 185 (M+ - H); H NMR (CDCl3): δH 8.58 (d, J ) 2
Hz, 1 H), 8.48 (d, J ) 2 Hz, 1 H), 7.80 (app t, J ) 2 Hz, 1 H),
3.23 (bt, J ) 8 Hz, 1 H), 3.18 (s, 1 H), 3.08 (app t, J ) 8.5 Hz,
1 H), 2.32 (app dd, J ) 9, 9 Hz, 1 H), 2.21 (m, 1 H), 2.16 (s, 3
H), 1.65-2.00 (m, 3 H).
5-Eth yn yl-3-(1-m eth yl-2-p yr r olid in yl)p yr id in e F u m a -
r a te. 5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (2) (31.2
g, 0.167 mol) was dissolved in MeOH (150 mL), and solid
fumaric acid (19.4 g, 0.167 mol) was added. After 0.5 h the
solids had dissolved completely. Charcoal was added, and the
mixture was stirred for 18 h at 25 °C, filtered through Celite,
and concentrated in vacuo to afford a solid. Crystallization
was accomplished using the minimum of hot absolute EtOH
to dissolve the fumarate; the product crystallized at 25 °C to
afford a first crop (17.3 g). The mother liquors were concen-
trated and recrystallized from EtOH as before to provide a

1116 J . Org. Chem., Vol. 63, No. 4, 1998
Bleicher et al.
heating was stopped. The mixture was allowed to stand at
25 °C and the product crystallized as a colorless solid. After
18 h the crystals were collected and dried in vacuo to give (S)-
(-)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine, dibenzoyl-L-
tartaric acid salt [(S)-7] (9.15 g, 93% based on dibenzoyl-L-
tartaric acid used). The enantiomeric enrichment of this
material was 87% as determined by chiral GC (oven temper-
ature 120 °C, retention time 11.5 min major peak, 12.0 min
minor peak). A second crystallization provided (S)-7 with
>99% ee as determined by chiral GC under the same condi-
tions. Mp 160-161 °C (EtOH-EtOAc); IR (KBr) 3429, 2967,
tube was charged with (5-10 mg) enantiomerically enriched
1
5-bromo-3-(1H-2-pyrrolidinyl)pyridine, and the H NMR was
recorded in CDCl3. Into the same NMR tube was added (R)-
(-)-R-methoxy-R-(trifluoromethyl)phenylacetic acid (R-Mosh-
er’s acid), 1.5-2 times the molar quantity of the amine. The
1H NMR was again recorded and the integral ratio of the pair
of 1H resonances at δH 4.04 and 4.23 (app t or dd) correspond-
ing to the C2′-H signal of each stereoisomer was measured.
This analysis showed the ee of 6 produced in this manner to
be 30%.
E n a n t iom er ica lly E n r ich ed 5-Br om o-3-(1-m et h yl-2-
p yr r olid in yl)p yr id in e (7). Enantiomerically enriched 5-bro-
mo-3-(1H-2-pyrrolidinyl)pyridine (6) (1.82 g, 8 mmol) was
dissolved in a mixture of 98% formic acid (16 mL) and 37%
aqueous formaldehyde (8 mL). The solution was heated with
stirring for 3 h at 80 °C. After being cooled to 25 °C the
mixture was concentrated in vacuo and water (30 mL) added.
The mixture was basified with solid NaOH to pH 12 and
extracted with CH2Cl2 (3 × 40 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4),
filtered, and concentrated in vacuo. The crude material was
chromatographed on silica gel with EtOAc:hexane (1:3) as
eluant to afford enantiomerically enriched 7 as an oil (1.63 g,
84%). LRMS (EI) m/e 242 (C10H13N281Br), 241 (C10H13N281Br
- H+), 240 (C10H13N279Br), 239 (C10H13N279Br - H+); 1H NMR
(CDCl3) δH 8.56 (d, J ) 2.5 Hz, 1 H), 8.47 (d, J ) 2.5 Hz, 1 H),
7.90 (t, J ) 2.5 Hz, 1 H), 3.22 (bt, J ) 8.5 Hz, 1 H), 3.10 (t, J
) 8.0 Hz, 1 H), 2.30 (app dd, J ) 8.5, 8.5 Hz, 1 H), 2.20 (m, 1
H), 2.17 (s, 3 H), 1.93 (m, 1 H), 1.80 (m, 1 H), 1.68 (m, 1 H).
(R)-5-Br om o-3-(1-m eth yl-2-p yr r olid in yl)p yr id in e [(R)-
7]. Enantiomerically enriched 5-bromo-3-(1-methyl-2-pyrro-
lidinyl)pyridine (482 mg, 2.00 mmol) was treated with di-p-
toluoyl-D-tartaric acid monohydrate (534 mg, 1.32 mmol) and
recrystallized from EtOH-EtOAc (1:4) to afford (R)-5-bromo-
3-(1-methyl-2-pyrrolidinyl)pyridine di-p-toluoyl-D-tartrate [(R)-
7] (659 mg, 80%). This material had an 88% ee as determined
by chiral GC (oven temperature 120 °C, retention time 11.9
min major peak, 11.4 min minor peak). A second crystalliza-
tion provided material with 95% ee as determined by chiral
GC under the same conditions. Mp 161-162 °C (EtOH-
EtOAc); IR (KBr) 3429, 2956, 1721, 1612, 1270, 1178, 1112,
2929, 1721, 1607, 1449, 1264, 1112, 715 cm-1 1H NMR
;
(DMSO-d6): δH 8.68 (d, J ) 2 Hz, 1 H), 8.59 (d, J ) 2 Hz, 1
H), 8.14 (app t, J ) 2 Hz, 1 H), 8.00 (d, J ) 7 Hz, 4 H), 7.69
(app t, J ) 7 Hz, 2 H), 7.56 (app t, J ) 7 Hz, 4 H), 5.79 (s, 2
H), 3.75 (m, 1 H), 3.41 (m, 1 H), 2.65 (app t, J ) 9 Hz, 1 H),
2.31 (s, 3 H), 2.23 (m, 1 H), 1.73-1.94 (m, 3 H); 13C NMR
(DMSO-d6) δC 167.8, 164.9, 150.2, 148.2, 138.1, 136.5, 133.9,
129.4, 129.0, 128.5, 120.5, 72.1, 67.3, 55.6, 38.8, 32.8, 21.7.
Anal. Calcd for C10H13BrN2‚C18H14O8: C, 56.09; H, 4.51; N,
4.67%. Found: C, 56.02; H, 4.55; N, 4.63%. A portion of this
material was converted to the free amine by treatment with
base, providing (S)-7 with [R]D -124° (c ) 14.5, EtOH).
(S)-(-)- 5-Eth yn yl-3-(1-m eth yl-2-p yr r olid in yl)p yr id in e
Ma lea te. Free base (S)-2 (5.25 g, 28.2 mmol) was dissolved
in MeOH (150 mL), and solid maleic acid (3.3 g, 28.2 mmol)
was added. After 0.5 h the solids had dissolved completely.
The mixture was stirred for 1 h at 25 °C and concentrated in
vacuo to afford a light yellow powder. Crystallization was
accomplished using the minimum of hot absolute EtOH to
dissolve the (S)-2 maleate; the product crystallized at 8 °C to
afford (S)-2 maleate, 7.95 g, 93% as an off-white solid. This
product possessed a >99% ee as determined by chiral GC (oven
temperature 125 °C, retention time 10.0 min major peak, peak
due to other enantiomer not detected). Mp 152.5-153.5 °C
(EtOH); IR (KBr) 3433, 3219, 2918, 2652, 2510, 2102, 1586,
1500, 1382, 1367, 1199, 1005, 877, 867, 709 cm-1 1H NMR
;
(DMSO-d6): δH 8.74 (d, J ) 2 Hz, 1 H), 8.70 (d, J ) 2 Hz, 1
H), 8.11 (app t, J ) 2 Hz, 1 H), 6.07 (s, 2 H), 4.56 (s, 1 H), 4.34
(bt, J ) 8 Hz, 1 H), 3.68 (dd, J ) 8, 3 Hz, 1 H), 3.14 (app dd,
J ) 16, 8 Hz, 1 H), 2.63 (s, 3 H), 2.45-2.35 (m, 1 H), 2.25-
2.05 (m, 3 H); 13C NMR (DMSO-d6) δC 167.2, 152.8, 149.8,
138.9, 135.4, 130.1, 118.9, 85.0, 79.9, 68.0, 55.6, 39.5, 30.8, 21.5.
Anal. Calcd for C12H14N2‚C4H4O4: C, 63.58; H, 5.96; N, 9.27%.
Found: C, 63.61; H, 5.95; N, 9.17%. A portion of this material
was converted to the free amine by treatment with base,
providing [(S)-2] with [R]D -164° (c ) 5, EtOH).
1
1025, 753 cm-1; H NMR (DMSO-d6): δH 8.66 (d, J ) 2 Hz, 1
H), 8.57 (d, J ) 2 Hz, 1 H), 8.08 (bt, J ) 2 Hz, 1 H), 7.88 (d,
J ) 8 Hz, 4 H), 7.38 (d, J ) 8 Hz, 4 H), 5.76 (s, 2 H), 3.6 (bm,
1 H), 3.34 (bm, 1 H), 2.58 (dd, J ) 9, 9 Hz, 1 H), 2.39 (s, 6 H),
2.27 (s, 3 H), 2.24 (m, 1 H), 1.70-1.95 (m, 3 H). Anal. Calcd
for
C10H13BrN2‚C20H18O8: C, 57.42; H, 4.94; N, 4.47%.
Found: C, 57.46; H, 5.01; N, 4.39%.
En a n tiom er ica lly En r ich ed 5-Br om o-3-(1H-2-p yr r o-
lid in yl)p yr id in e (6). (Carbobenzyloxy)-L-proline (37.4 g, 150
mmol) was dissolved in DME (100 mL) and cooled to 0 °C with
stirring. Sodium borohydride (1.89 g, 50 mmol) was added in
portions (gas evolution), and the resulting mixture was stirred
for 2 h at 25 °C to afford a colorless solution. The solvents
were removed in vacuo, and the resulting gum was dissolved
in CH2Cl2 (50 mL). To this solution was added a mixture of
5-bromo-3-(2-pyrrolin-1-yl)pyridine (5.63 g, 25 mmol) and
(carbobenzyloxy)-L-proline (6.23 g, 25 mmol) in CH2Cl2 (50
mL). The resulting solution was stirred at 25 °C for 36 h. The
solvent was removed in vacuo, and 6 M HCl (200 mL) was
added to the residue. The resulting solution was extracted
with i-PrOAc (200 mL), and the phases were separated. The
acidic aqueous phase was basified with solid NaOH to pH 14
and then extracted with CH2Cl2 (3 × 200 mL). The combined
CH2Cl2 extracts were washed with brine (150 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The crude
product was chromatographed on silica gel with EtOAc and
then MeOH:EtOAc (1:19 to 1:9) as eluants to afford 5-bromo-
3-(1H-2-pyrrolidinyl)pyridine (6) (4.1 g, 72%) as a pale yellow
oil. LRMS (EI) m/e 228 (C9H11N281Br), 227 (C9H11N281Br -
H+), 226 (C9H11N279Br), 225 (C9H11N279Br - H+); 1H NMR
(CDCl3, 300 MHz) δH 8.53 (d, J ) 2 Hz, 1 H), 8.49 (d, J ) 2
Hz, 1 H), 7.91 (t, J ) 2 Hz, 1 H), 4.17 (t, J ) 7.5 Hz, 1 H), 3.18
(m, 1 H), 3.06 (m, 1 H), 2.30 (s, 1 H), 2.24 (m, 1 H), 1.80-2.00
(m, 2 H), 1.63 (m, 1 H). The enantiomeric purity of this
material was determined in the following manner. An NMR
(R)-5-Eth yn yl-3-(1-m eth yl-2-p yr r olid in yl)p yr id in e Di-
p-tolu oyl-D-ta r tr a te. Enantiomerically enriched 5-ethynyl-
3-(1-methyl-2-pyrrolidinyl)pyridine [(R)-2] (248 mg, 1.3 mmol)
was treated with di-p-toluoyl-D-tartaric acid monohydrate (485
mg, 1.2 mmol) and recrystallized from EtOH to afford (R)-5-
ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine di-p-toluoyl-D-tar-
trate [(R)-2] (452 mg, 66%). This product possessed a 97% ee
as determined by chiral GC (oven temperature 130 °C,
retention time 8.07 min major peak, 7.8 min minor peak). Mp
163-164 °C (EtOH); IR (KBr) 3434, 2929, 2363, 2341, 1727,
1618, 1270, 1180, 1106, 758 cm-1 1H NMR (DMSO-d6): δH
;
8.64 (d, J ) 2 Hz, 1 H), 8.61 (d, J ) 2 Hz, 1 H), 7.95 (t, J ) 2
Hz, 1 H), 7.88 (d, J ) 8 Hz, 4 H), 7.37 (d, J ) 8 Hz, 4 H), 5.75
(s, 2 H), 4.49 (s, 1 H), 3.6 (bm, 1 H), 3.37 (bm, 1 H), 2.62 (app
t, J ) 9 Hz, 1 H), 2.39 (s, 6 H), 2.29 (s, 3 H), 2.24 (m, 1 H),
1.75-1.95 (m, 3 H); 13C NMR (DMSO-d6) δC 168.2, 165.1, 152.3,
149.6, 144.3, 138.8, 132.7, 129.6, 126.6, 119.0, 84.7, 80.2, 72.4,
67.7, 55.5, 38.4, 32.1, 21.5, 21.4. Anal. Calcd for
C
12H14N2‚C20H18O8: C, 67.13; H, 5.59; N, 4.90%. Found: C,
67.22; H, 5.64; N, 4.86%.
Esta blish m en t of Absolu te Ster eoch em istr y. (-)-5-
Bromo-3-(1-methyl-2-pyrrolidinyl)pyridine [(S)-7] (2.0 g, 8.3
mmol) as the free amine was dissolved in absolute EtOH (20
mL), and 10% palladium on carbon (107 mg, 0.1 mmol Pd) was
added. This was hydrogenated at 40 psi in a Parr hydrogena-
tion apparatus for 3 h. The slurry was then filtered through
Celite and concentrated in vacuo. This material was chro-

Synthesis of Acetylcholine-Gated Ion Channel Agonist
J . Org. Chem., Vol. 63, No. 4, 1998 1117
1
matographed on silica gel with CH2Cl2:MeOH (95:5) as eluant
to afford a light yellow oil. Spectral data indicated that the
isolated material was nicotine hydrobromide. This was taken
up in CH2Cl2 and washed with aqueous K2CO3. The organic
phase was dried over Na2SO4 and concentrated to afford (S)-
(-)-nicotine (850 mg, 63%) as an oil. [R]D -154° (c ) 4, EtOH);
lit.3 -169° (neat); LRMS (EI) m/e 163 (M+ + H), 162 (M+), 161
to yield 330 mg of a white powder 81%. Mp 117-118 °C; H
NMR (CDCl3) δH 7.31 (d, J ) 9 Hz, 2 H), 6.76 (d, J ) 9 Hz, 2
H), 6.17 (m, 1 H), 5.22 (br s exch, 1 H), 2.19 (m, 2 H), 2.12 (m,
2 H), 1.64 (m, 4 H); 13C NMR (CDCl3) δC 155.2, 134.6, 133.0,
120.7, 116.0, 115.4, 89.8, 86.5, 29.3, 25.7, 22.3, 21.5. Anal.
Calcd for C14H14N2‚C4H4O4: C, 63.99; H, 5.37; N, 9.33%.
Found: C, 63.89; H, 5.38; N, 9.33%.
1
(M+ - H); H NMR (CDCl3): δH 8.56 (app t, J ) 2 Hz, 1 H),
4-[2-(Cycloh ex-1-en yl)eth yn yl]p h en ol (15). The proce-
dure described for 10 was employed using 4-iodophenol (660
mg, 3.0 mmol), K2CO3 (1.03 g, 7.5 mmol), CuI (38 mg, 0.20
mmol), PPh3 (106 mg, 0.40 mmol), 10% Pd/C (107 mg, 0.10
mmol Pd), and cyclohex-1-enylacetylene (0.88 mL, 7.5 mmol).
8.53 (d, J ) 2 Hz, 1 H), 7.88 (dt, J ) 8, 2 Hz, 1 H), 7.31 (dd,
J ) 8, 5 Hz, 1 H), 3.41 (bt, J ) 8 Hz, 1 H), 3.29 (app t, J ) 8
Hz, 1 H), 2.46 (app t, J ) 8 Hz, 1 H), 2.28 (m, 1 H), 2.26 (s, 3
H), 2.07 (m, 1 H), 1.80-2.00 (m, 2 H); 13C NMR (CDCl3) δC
149.5, 149.1, 136.7, 135.3, 123.9, 69.1, 56.8, 39.9, 34.5, 22.3.
3-(2-Hyd r oxy-2-m et h ylbu t -3-yn yl)b en za ld eh yd e (10).
3-Bromobenzaldehyde (0.35 mL, 3.0 mmol), K2CO3 (1.03 g, 7.5
mmol), CuI (23 mg, 0.12 mmol), PPh3 (64 mg, 0.24 mmol), and
10% Pd/C (63 mg, 0.06 mmol Pd) were mixed in DME (5 mL)
and H2O (5 mL) at 20 °C. This was stirred for 30 min, and
2-methyl-3-butyn-2-ol (0.73 mL, 7.5 mmol) was added. The
mixture was heated at 80 °C for 16 h, cooled to room
temperature, and filtered through Celite, and the filtrate was
extracted with EtOAc (35 mL). The organic layer was washed
with H2O (25 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. This material was purified by flash
column chromatography eluting with 3:2 hexane:EtOAc to
yield 550 mg of 10 as a colorless oil 97%. 1H NMR (CDCl3) δH
9.98 (s, 1 H), 7.91 (m, 1 H), 7.82 (d, J ) 8 Hz, 1 H), 7.65 (d, J
) 8 Hz, 1 H), 7.47 (t, J ) 8 Hz, 1 H), 2.52 (br s exch, 1 H); 1.64
(s, 6 H); 13C NMR (CDCl3) δC 191.7, 137.2, 136.3, 133.0, 129.0,
124.0, 95.4, 80.6, 65.5, 31.3. Anal. Calcd for C12H12O: C,
76.57; H, 6.43%. Found: C, 76.34; H, 6.48%.
4-(2-H yd r oxy-2-m et h ylb u t -3-yn yl)n it r ob en zen e (11).
The procedure described for 10 was employed using 4-bro-
monitrobenzene (606 mg, 3.0 mmol), K2CO3 (1.03 g, 7.5 mmol),
CuI (23 mg, 0.12 mmol), PPh3 (62 mg, 0.24 mmol), 10% Pd/C
(63 mg, 0.06 mmol Pd), and 2-methyl-3-butyn-2-ol (0.73 mL,
7.5 mmol). Yield 92% (570 mg) as a colorless oil; 1H NMR
(CDCl3) δH 8.18 (d, J ) 9 Hz, 2 H), 7.56 (d, J ) 9 Hz, 1 H),
2.28 (s exch, 1 H), 1.64 (s, 6 H); 13C NMR (CDCl3) δC 147.0,
132.4, 129.7, 123.5, 99.0, 80.4, 65.6, 60.5, 31.2. Anal. Calcd
for C11H11NO3: C, 64.38; H, 5.40; N, 6.83%. Found: C, 64.45;
H, 5.42; N, 6.82%.
1
Yield 290 mg, 49%, as an off-white solid. Mp 95-97 °C; H
NMR (CDCl3) δH 7.31 (d, J ) 9 Hz, 2 H), 6.76 (d, J ) 9 Hz, 2
H), 6.17 (m, 1 H), 5.22 (br exch, 1 H), 2.19 (m, 2 H), 2.12 (m,
2 H), 1.64 (m, 4 H); 13C NMR (CDCl3) δC 155.2, 134.6, 133.0,
120.7, 116.0, 115.4, 89.8, 86.5, 29.27, 25.7, 22.3, 21.5. Anal.
Calcd for C14H14O: C, 84.81; H, 7.12%. Found: C, 84.56; H,
7.11%.
4-[2-(Cycloh ex-1-en yl)eth yn yl]ben zoic Acid (16). The
procedure described for 10 was employed using 4-iodobenzoic
acid (744 mg, 3.0 mmol), K2CO3 (1.03 g, 7.5 mmol), CuI (38
mg, 0.20 mmol), PPh3 (106 mg, 0.40 mmol), 10% Pd/C (107
mg, 0.10 mmol Pd), and cyclohex-1-enylacetylene (0.88 mL,
7.5 mmol) in 10 mL of DME and 0.5 mL of H2O. Purification
was accomplished by trituration with a mixture of toluene:
EtOAc:acetic acid (1:1:0.06), and recrystallization from EtOAc:
MeOH 97:3. Yield 81% as translucent yellow flakes. Mp 228-
230 °C; 1H NMR (CDCl3) δH 7.90 (d, J ) 8 Hz, 2 H), 7.51 (d, J
) 8 Hz, 2 H), 6.24 (m, 1 H), 2.13 (m, 4 H), 1.58 (m, 4 H); 13C
NMR (CDCl3) δC 136.9, 131.5, 129.8, 127.5, 120.0, 94.4, 86.5,
28.9, 25.5, 22.0, 21.2. Anal. Calcd for C15H14O2‚0.5 H2O: C,
76.58; H, 6.43%. Found: C, 76.57; H, 6.13%.
3-(1-Hyd r oxy-p r op -2-yn yl)p yr id in e (17). The procedure
described for 18 was employed using 3-bromopyridine (1.91
mL, 20.0 mmol), K2CO3 (6.90 g, 50.0 mmol), CuI (342 mg, 1.8
mmol), PPh3 (628 mg, 2.4 mmol), 10% Pd/C (640 mg, 0.60 mmol
Pd), and propargyl alcohol (2.92 mL, 50.0 mmol). Purification
was effected by flash column chromatography on silica eluting
with CH2Cl2:MeOH 95:5. Yield 2.40 g 90% as a white solid.
Mp 99-100 °C. 1H NMR (CDCl3) δH 8.80 (d, J ) 2 Hz, 1 H),
8.51 (dd, J ) 2, 5, 1 H), 7.74 (dt, J ) 8, 2 Hz, 1 H), 7.28 (m, 1
H), 4.72 (m, 1 H), 4.52 (m, 2 H); 13C NMR (CDCl3) δC 151.9,
148.1, 139.1, 123.4, 120.3, 92.4, 81.3, 50.8. Anal. Calcd for
C8H7NO: C, 72.21; H, 5.29; N, 10.41%. Found: C, 72.22; H,
5.29; N, 10.41%.
2-(2-Hyd r oxy-2-m eth ylbu t-3-yn yl)p yr id in e (18). 2-Py-
ridyl trifluoromethanesulfonate (0.46 mL, 3.0 mmol), K2CO3
(1.03 g, 7.5 mmol), CuI (23 mg, 0.12 mmol), PPh3 (64 mg, 0.24
mmol), and 10% Pd/C (64 mg, 0.06 mmol Pd) were mixed in
DME (5 mL) and H2O (5 mL) at 20 °C. This solution was
stirred for 30 min and 2-methyl-3-butyn-2-ol (0.73 mL, 7.5
mmol) was added. The mixture was heated at 80 °C for 16 h,
cooled to room temperature, filtered through Celite, and
acidified with 1 M HCl. The organic solvents were removed
in vacuo, and the solution was extracted with toluene, and the
aqueous phase basified with K2CO3. The aqueous layer was
then extracted with EtOAc. The organic layer was washed
with water, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The crude material was purified by
flash column chromatography on silica gel eluting with 1:1
hexane:EtOAc. Yield 95% (458 mg) as an off white solid. Mp
82-84 °C; 1H NMR (CDCl3) δH 8.57 (d, J ) 4 Hz, 2 H), 7.67 (t,
J ) 8 Hz, 1 H), 7.40 (d, J ) 8 Hz, 1 H), 7.22 (m, 1 H), 1.65 (s,
6 H); 13C NMR (CDCl3) δC 149.7, 142.9, 136.3, 132.0, 127.1,
122.9, 94.4, 81.2, 65.1, 60.4. Anal. Calcd for C10H11NO: C,
74.50; H, 6.88; N 8.69%. Found: C, 74.45; H, 6.92; N, 8.61%.
5-[1-(N,N-Dim eth yla m in o)p r op -2-yn yl]p yr im id in e F u -
m a r a te (19). The procedure described for 18 was employed
using 5-bromopyrimidine (477 mg, 3.0 mmol), K2CO3 (1.03 g,
7.5 mmol), CuI (48 mg, 0.25 mmol), PPh3 (105 mg, 0.40 mmol),
10% Pd/C (107 mg, 0.10 mmol Pd), and N,N-dimethylpropar-
gylamine (0.81 mL, 7.5 mmol). The crude material was
purified by flash column chromatography on silica eluting with
95:5 EtOAc:MeOH. Yield 50% as a pale yellow oil. 1H NMR
3-(2-Hyd r oxy-2-m eth ylbu t-3-yn yl)a n ilin e (12). The pro-
cedure described for 18 was employed using 3-bromoaniline
(657 mg, 3.0 mmol), K2CO3 (1.03 g, 7.5 mmol), CuI (23 mg,
0.12 mmol), PPh3 (62 mg, 0.24 mmol), 10% Pd/C (63 mg, 0.06
mmol Pd), and 2-methyl-3-butyn-2-ol (0.73 mL, 7.5 mmol).
Yield 78% as a off white solid. Mp 119-20 °C; 1H NMR
(DMSO-d6) δH 6.97 (t, J ) 8 Hz, 1 H), 6.57 (m, 1 H), 6.50 (m,
2 H), 5.42 (s, 1 H), 5.17 (s, 2 H), 1.43 (s, 6 H); 13C NMR (DMSO-
d6) δC 148.7, 129.0, 122.8, 118.5, 116.2, 114.0, 94.5, 81.1, 63.5,
31.6. Anal. Calcd for C11H13NO: C, 75.40; H, 7.47; N, 8.00%.
Found: C, 75.50; H, 7.61; N, 7.78%.
2-(2-Hydr oxy-2-m eth ylbu t-3-yn yl)ben zon itr ile (13). The
procedure described for 10 was employed using 2-bromoben-
zonitrile (5.0 g, 27.5 mmol), K2CO3 (9.5 g, 68.7 mmol), CuI (209
mg, 1.1 mmol), PPh3 (576 mg, 2.2 mmol), 10% Pd/C (587 mg,
0.55 mmol Pd), and 2-methyl-3-butyn-2-ol (6.7 mL, 68.7 mmol).
1
Yield 89% as a clear oil; H NMR (CDCl3) δH 7.62 (d, J ) 8
Hz, 1 H), 7.51 (m, 2 H), 3.48 (s, 1 H), 1.67 (s, 6 H); 13C NMR
(CDCl3) δC 132.4, 132.1, 128.3, 127.8, 117.6, 115.2, 100.8, 78.3,
65.4, 31.1. Anal. Calcd for C12H11NO: C, 77.81; H, 5.98; N,
7.56%. Found: C, 77.57; H, 6.00; N, 7.52%.
2-[1-(N,N-Dim eth ylam in o)pr op-2-yn yl]ben zon itr ile Fu -
m a r a te (14). The procedure described for 18 was employed
using 2-bromobenzonitrile (910 mg, 5.0 mmol), K2CO3 (1.725
g, 12.5 mmol), CuI (48 mg, 0.25 mmol), PPh3 (126 mg, 0.48
mmol), 10% Pd/C (134 mg, 0.12 mmol Pd), and N,N-dimeth-
ylpropargylamine (1.35 mL, 12.5 mmol). Yield 850 mg, 92%.
1H NMR (CDCl3) δH 7.65 (d, J ) 8 Hz, 1 H), 7.54 (m, 2 H),
7.40 (m, 1 H), 3.58 (s, 2 H), 2.42 (s, 6 H). 2-[1-(N,N-
Dimethylamino)prop-2-ynyl]benzonitrile (250 mg, 1.35 mmol)
was dissolved in MeOH (100 mL), and fumaric acid (160 mg,
1.35 mmol) was added. This mixture was concentrated in
vacuo, triturated with Et2O, and recrystallized from EtOAc

1118 J . Org. Chem., Vol. 63, No. 4, 1998
Bleicher et al.
(CDCl3) δH 9.13 (s, 1 H), 8.78 (s, 2 H), 3.52 (s, 2 H), 2.38 (s, 6
H). 5-[1-(N,N-Dimethylamino)prop-2-ynyl]pyrimidine (141 mg,
0.9 mmol) was mixed with fumaric acid (101 mg, 0.9 mmol)
and dissolved in 30 mL of MeOH. This mixture was concen-
trated to give a light yellow solid which was triturated with
Et2O and recrystallized from hot EtOAc to give, 19 158 mg,
42%, as a hemifumarate, white needles. Mp 155-156 °C (dec);
1H NMR (DMSO-d6) δH 9.17 (s, 1 H), 8.92 (s, 2 H), 6.61 (s, 4
H), 3.61 (s, 1 H), 2.31 (s, 6 H); 13C NMR (DMSO-d6) δC 166.2,
158.9, 156.8, 134.1, 118.7, 91.4, 79.2, 47.3, 43.3. Anal. Calcd
for C9H11N3‚C8H8O8: C, 51.90; H, 4.87; N 10.68%. Found: C,
52.00; H, 4.89; N, 10.74%.
2-(1-Hyd r oxy-1-ph en ylp r op-2-yn yl)th iop h en e (20). The
procedure described for 10 was employed using 2-iodot-
hiophene (0.38 mL, 3.0 mmol), K2CO3 (1.03 g, 7.5 mmol), CuI
(38 mg, 0.2 mmol), PPh3 (106 mg, 0.4 mmol), 10% Pd/C (107
mg, 0.10 mmol Pd), and 1-phenyl-2-propyn-1-ol (990 mg, 7.5
mmol). Purification was effected by flash column chromatog-
raphy on silica eluting with 9:1 CH2Cl2:MeOH. Yield 95% as
a dark brown oil. 1H NMR (CDCl3) δH 7.59 (d, J ) 7 Hz, 2 H),
7.38 (m, 3 H), 7.25 (m, 2 H), 6.98 (m, 1 H), 5.69 (d, J ) 6 Hz,
1 H), 2.39 (d, J ) 6 Hz, 1 H); 13C NMR (CDCl3) δC 140.2, 132.5,
128.7, 128.5, 127.6, 127.0, 126.7, 122.2, 92.4, 80.0, 65.2. Anal.
Calcd for C8H7NO: C, 72.87; H, 4.70; S, 14.96%. Found: C,
72.98; H, 4.68; S, 14.84%.
4-(1-Hyd r oxy-bu t-3-yn yl)p yr a zole (21). The procedure
described for 18 was employed using 4-iodopyrazole (582 mg,
3.0 mmol), K2CO3 (1.03 g, 7.5 mmol), CuI (38 mg, 0.20 mmol),
PPh3 (105 mg, 0.40 mmol), 10% Pd/C (107 mg, 0.10 mmol Pd),
and 3-butynol (0.57 mL, 7.5 mmol). Purification was effected
by flash column chromatography on silica eluting with EtOAc.
Yield 85% (348 mg) as an off white solid. Mp 102-104 °C; 1H
NMR (DMSO-d6) δH 12.99 (br s, 1H), 7.89 (br s, 1 H), 7.58 (br
s, 1 H), 4.89 (t, J ) 5 Hz, 1 H), 3.54 (m, 2 H), 2.50 (m, 2 H);
13C NMR (DMSO-d6) δC 143.5, 133.6, 104.3, 90.3, 78.7, 75.6,
62.4, 25.9. Anal. Calcd for C7H8N2O: C, 61.75; H, 5.92; N
20.58%. Found: C, 61.86; H, 5.98; N, 20.37%.
J O971572D