Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3. 2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands

Article abstract of DOI:10.1021/jo800028q

(Chemical Equation Presented) In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the α4β2 and α7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(

Full text of DOI:10.1021/jo800028q

Synthesis of 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(Pyridin-3-yl)-
1-azabicyclo[2.2.2]octane, and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a
Class of Potent Nicotinic Acetylcholine Receptor–Ligands
Balwinder S. Bhatti,*,† Jon-Paul Strachan,† Scott R. Breining,† Craig H. Miller,† Persida Tahiri,†
Peter A. Crooks,‡ Niranjan Deo,‡, Cynthia S. Day,§ and William S. Caldwell†
Targacept, Inc., 200 East 1st Street, Suite 300, Winston-Salem, North Carolina 27101-4165, College of
Pharmacy, Department of Pharmaceutical Sciences, UniVersity of Kentucky, Rose Street,
Lexington, Kentucky 40536-0082, and Department of Chemistry, Wake Forest UniVersity,
Winston-Salem, North Carolina 27109
bhattib@targacept.com
ReceiVed January 4, 2008
In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the R4ꢀ2 and R7
subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR
ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of
their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same
basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-
yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily
elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via
a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane
via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective
syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-
pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography
was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All
compounds synthesized exhibited high affinity for the R4ꢀ2 nAChR subtype (Ki e 0.5–15 nM), a subset
bound with high affinity for the R7 receptor subtype (Ki e 110 nM), selectivity over the R3ꢀ4 (ganglion)
receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle
(R1ꢀγδ) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.
Introduction
abundant in the mammalian central nervous system (CNS) and
peripheral nervous system (PNS). The two most prevalent
nAChR subtypes in the CNS are R4ꢀ2 and R7.1 Ligands for
these receptors have been recognized as possessing potential
for treatment of a variety of conditions and disorders with
substantial unmet medical needs, including schizophrenia,
Nicotinic acetylcholine receptors (nAChRs) are a family of
ligand-gated ion channels, and are widely distributed and
† Targacept, Inc.
‡ University of Kentucky.
Present address: BASF Corporation, 100 Campus Drive, Florham Park, NJ
07932.
§ Wake Forest University.
(1) Schmitt, J. D. Curr. Med. Chem. 2000, 7 (8), 749–800.
J. Org. Chem. 2008, 73, 3497–3507 3497
10.1021/jo800028q CCC: $40.75
Published on Web 03/26/2008
2008 American Chemical Society

Bhatti et al.
SCHEME 1. Retrosynthetic Analysis of
2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octanes and
2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonanes
FIGURE 1. Design of constrained analogues.
effects. The lack of available crystal structures of the nicotinic
receptors necessitated ligand-based design, in which compounds
possessing pharmacophoric elements consistent with nicotinic
activity serve as the basis for creation of new ligands.22
various pain states, neurodegenerative diseases, and cognitive
disorders.2–19
S-(-)-Nicotine (1), Figure 1, the principal alkaloid in tobacco
and the prototypical nAChR ligand, possesses high affinity for
the R4ꢀ2 nAChR (Ki ∼ 2nM).20 It is also recognized as a non-
selective agonist, with activity at multiple nAChR subtypes.20,21
This lack of selectivity, particularly with respect to ganglionic
R3ꢀ4 nAChR subtypes, is assumed to be responsible for
undesirable side effects associated with nicotine substitution
therapy (in smoking cessation medications).21 Our goal was
therefore to create ligands with enhanced selectivity over the
ganglionic nAChRs to minimize the potential for adverse side
Introduction of conformational constraint is an often used
technique in medicinal chemistry to enhance selectivity. Ana-
basine (2) and 2-pyridinylazepane (5), close structural relatives
to nicotine, were both reported to have Ki values at R4ꢀ2
nAChRs of 20 nM or less,23 and appeared to be suitable candi-
dates for this strategy. In addition, the 1-azabicyclo[2.2.2]octane
moiety appears in numerous nicotinic ligands, particularly those
with high affinity and selectivity at R7 nAChRs.17,18 We became
interested in exploring the pharmacological profile of 2-(pyri-
dine-3-yl)-1-azabicyclo[2.2.2]octane (3) and 2-(pyridine-3-yl)-
1-azabicyclo[3.2.1]octane (4), which we envisioned as con-
strained analogues of 2, wherein the piperidine ring is incorporated
into a bridged azabicycle. Also of interest was the related
2-(pyridine-3-yl)-1-azabicyclo[3.2.2]nonane 6.
A literature survey revealed that target compounds 3 and 6
had been previously claimed in patents24,25 or reported in the
literature,26,27 albeit without pharmacological data. We felt that
the reported syntheses were cumbersome, lengthy, or not suitable
for our needs. We therefore designed syntheses of these targets
which were facile and straightforward. We now report the results
of our racemic and enantioselective synthetic approaches to
2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane (3), 2-(pyridin-3-yl)-
1-azabicyclo[3.2.2]nonane (6), 2-(pyridin-3-yl)-1-azabicyclo-
[3.2.1]octane (4) and a number of other novel derivatives bearing
substituents on the pyridinyl ring.
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N. D.; McDonald, L. A. Life Sci. 1998, 62 (17–18), 1601–1606.
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Retrosynthetic analysis (Scheme 1) of compounds 3 and 6
suggested that they could be synthesized via an intramolecular
bis-aminocyclization of a dibromide (14 or 16), which should
be readily available from the HBr-promoted ring opening of
64.(16) Suto, M. J.; Zacharias, N. Expert Opin. Ther. Targets 2004, 8 (2), 61–
(17) Toma, L.; Barlocco, D.; Gelain, A. Expert Opin. Ther. Pat. 2004, 14
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L. G. Drug DeV. Res. 1998, 45, 10–16.
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Acetylcholine Receptor Modulators: Recent Advances and Therapeutic Potential.
In Annual Reports in Medicinal Chemistry; Annette, M. D., Ed.; Academic Press:
New York, 2005; Vol. 40, pp 3–16.
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(10), 3417–3420.
3498 J. Org. Chem. Vol. 73, No. 9, 2008

Potent Nicotinic Acetylcholine Receptor–Ligands
SCHEME 2. Synthesis of 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane (3) and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane (6)
SCHEME 3. Synthesis of N-(Diphenylmethylene)-1-(5-bromopyridin-3-yl)methanamine (8)
the tetrahydropyran rings in 11 or 13, respectively.28,29 It was
anticipated that the desired tetrahydropyrans could be prepared
by alkylation of the imine 7 via abstraction of the benzylic
proton with LDA, an approach that has been successfully
employed by others30–32 as well as in our own laboratories.33–35
EtOH at 60 °C to give alcohol 1939 in 52% yield. Reaction of
this alcohol with phthalimide under Mitsunobu conditions gave
phthalimide 20 in 85% yield. This was subsequently deprotected
with methylamine under aqueous conditions at 60 °C to give
the desired 5-bromo-3-aminomethylpyridine (21)40 in 60% yield.
Condensation of 21 with benzophenone under standard condi-
tions gave imine 8 in quantitative yield (Scheme 3). Alkylation
of imine 8, to give compound 12, and subsequent ring opening
Discussion
Alkylation of imine 735 (available from condensation of
benzophenone and 3-aminomethylpyridine) was accomplished
in good yield by treatment with LDA and the appropriate
bromide (936,37 or 10,38 Scheme 2). The resulting tetrahydro-
pyrans (11 and 13) were reacted with concentrated HBr in the
presence of excess HBr gas at 120 °C in a sealed tube for 8 h,
affording dibromides 14 and 16 as the dihydrobromide salts.
Subsequent heating of the crude reaction products in EtOH in
the presence of K2CO3 gave the desired cyclized compounds
(3 and 6) in good yield.
(28) Ullrich, T.; Binder, D.; Pyerin, M. Tetrahedron Lett. 2002, 43 (2), 177–
179.
(29) Dekimpe, N. G.; Keppens, M. A.; Stevens, C. V. Tetrahedron Lett. 1993,
34 (29), 4693–4696.
(30) Ferrari, B.; Gougat, J.; Muneaux, Y.; Perraut, P.; Sarran, L. PCT Int.
Appl. WO2002076964-A1, 2002.
(31) Ullrich, T.; Binder, D.; Pyerin, M. Tetrahedron Lett. 2002, 43 (2), 177–
179.
(32) Upadhyaya, P.; McIntee, E. J.; Villalta, P. W.; Hecht, S. S. Chem. Res.
Toxicol. 2006, 19 (3), 426–435.
(33) Strachan, J. P.; Whitaker, R. C.; Miller, C. H.; Bhatti, B. S. J. Org.
Chem. 2006, 71 (26), 9909–9911.
(34) Crooks, P. A.; Deo, N. M. PCT Int. Appl. WO 9951601-A1. 1999.
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(36) Burger, A.; Turnbull, L. B.; Dinwiddic, J. G., Jr. J. Am. Chem. Soc.
1950, 72, 5512–5515.
Bolstered by this initial success, we next applied this
methodology to the preparation of the analogous 2-(pyridin-3-
yl)-1-azabicyclo[2.2.2]octanes and 2-(pyridin-3-yl)-1-azabicyclo-
[3.2.2]nonanes bearing a bromine substituent at the 5-position
of the pyridine ring (17), believing that the bromine substituent
could subsequently serve to introduce other functionalities at
that position. Preparation of the required imine 8 began with
reduction of ethyl 5-bromo-3-nicotinate (18) with NaBH4 in
(37) Bhatti, B. S.; Gatto, G. J.; Klucik, J. PCT Int. Appl. WO2006023630-
A2, 2006.
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532, 69–82.
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A. J.; Griffin, S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. J. Med.
Chem. 1995, 38 (10), 1608–1628.
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US5002949.
J. Org. Chem. Vol. 73, No. 9, 2008 3499

Bhatti et al.
SCHEME 4. Synthesis of Analogues of 17
SCHEME 5. Synthesis of 2-(Pyridin-3-yl)-1-azabicyclo[3.2.1]octane (4) and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane (6)
(producing 15) and cyclization, utilizing chemistry previously
described, produced compound 17.
17 with phenylboronic acid under Suzuki41 conditions gave 26
in 65% yield.
We next chose to apply a slight modification of this
methodology to the preparation of 4, in which the azabicyclic
ring system is constrained by a one-carbon bridge (Scheme 5).
It was recognized that both 4 and the previously prepared 6
could be obtained via a modification of the initial route. In this
case, choice of either a halomethyltetrahydrofuran or a halo-
methyltetrahydropyran alkylating species would determine the
product ring system. A similar sequence was envisioned to that
in Scheme 1, but in this instance, imine 34,42 derived from
3-acetylpyridine, would be utilized.
SAR around the pyridinyl-quinuclidine scaffold of 3 could
be explored if there was a convenient synthetic handle that could
be elaborated readily. This was achieved in one instance by
converting 17 into a number of analogues by using the Br at
the 5′-position of pyridine as the synthetic handle for elaboration
(Scheme 4). Heating bromide 17 in 30% aqueous NH4OH
containing catalytic CuI in a sealed tube at 120 °C for 8 h
afforded 2-(5-aminopyridin-3-yl)-1-azabicyclo[2.2.2]octane (22).
Diazotization with isoamyl nitrite in the presence of ethanol or
2-propanol gave aryl ethers 24 and 25, respectively, in moderate
yield (∼50%). Hydrolysis of the intermediate diazonium ion
(22 + NaNO2 and H2SO4, then heat) gave the pyridinol 23,
which was subsequently reacted with 4-fluorobenzonitrile (27)
or 4-fluoronitrobenzene (28), in the presence of K2CO3, to give
29 and 30, respectively (synthesis and spectral data for 29 and
30 can be found in the Supporting Information). Reaction of
Alkylation42 of imine 34 with 3-(bromomethyl)tetrahydro-
furan (35),43 followed by aqueous workup to hydrolyze the
imine, gave 1-(pyridin-3-yl)-3-(tetrahydrofuran-3-yl)propan-1-
(41) Ohe, T.; Miyauri, N.; Suzuki, A. J. Org. Chem. 1993, 58 (8), 2201.
(42) DeKimpe, N. G.; Keppens, M. A.; Stevens, C. V. Tetrahedron Lett.
1993, 34 (29), 4693–4696.
3500 J. Org. Chem. Vol. 73, No. 9, 2008

Potent Nicotinic Acetylcholine Receptor–Ligands
SCHEME 6. Enantioselective Synthesis of Azabicyclo[3.2.2]octanes and Azabicyclo[3.2.2]nonanes (59-64)
one (32) in good yield (Scheme 5). Oxime formation under
standard conditions, followed by reduction with zinc and acetic
acid, afforded 31 in high yield (90%). The tetrahydrofuran ring
was cleaved by heating with HBr, as described previously, to
give the dibromo intermediate 36. Subsequent heating with
K2CO3 in EtOH gave the desired 4, as an inseparable mixture
of exo and endo diastereomers, in good yield. When bromide 9
was used to alkylate 34, ketone 33 was produced in ∼90% yield
after purification. Conversion of 33 to the oxime and reduction
as before afforded intermediate 13, thus completing a formal
synthesis of 6.
The Enantioselective Synthesis of 2-(Pyridin-3-yl)-1-aza-
bicyclo[2.2.2]octanes and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]-
nonanes. It has been well established in the field of drug
design that the enantiomers of a given racemate often
differentiate from one another on the basis of potency,
selectivity, or efficacy at biologic targets. This is exemplified
by nicotine itself. (S)-Nicotine (1) has high affinity for R4ꢀ2
(Ki ) 2 nM) and moderate affinity for R7 receptors (Ki >
700 nM), whereas (R)-nicotine possesses much lower affinity
(Ki ) 38 nM) for R4ꢀ2 and virtually no affinity for R7.44–46
Since a similar possibility existed for enhanced affinity and/
or selectivity residing in a single enantiomer of the 2-(pyridin-
3-yl)-1-azabicyclo[2.2.2]octanes and 2-(pyridin-3-yl)-1-
azabicyclo[3.2.2]nonanes, we were interested in developing
enantioselective versions of the syntheses in Schemes 2
and 5.
There are several examples in the literature where alkylation
of imines derived from enantiomerically pure chiral ketones has
afforded acyclic quaternary R-amino acids with high
enantioselectivities,47–49 and Crooks et al. have used this
technique to synthesize anabasine analogues and derivatives.50
Recognizing the potential of this modification to control the
stereochemical outcome in the key alkylation step, we chose to
use the (+)- and (-)-antipodes of 2-hydroxy-3-pinanone to
synthesize the desired imines. Imine 37 was synthesized in 52%
yield from (-)-2-hydroxy-3-pinanone and 3-aminomethylpyr-
idine, by refluxing the mixture in the presence of BF3 ·Et2O in
(44) Daly, J. W. Cell Mol. Neurobiol. 2005, 25 (3–4), 513–552.
(45) Badio, B.; Shi, D.; Garaffo, M. H.; Daly, J. W. Drug DeV. Res. 1995,
46–59.
(46) Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E. P.;
Huang, J.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.; Shrikhande, A.;
Heym, J. H.; Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers,
L. K.; Rovetti, C. C.; Schulz, D. W.; Tingley, F. D., III; O’Neill, B. T. J. Med.
Chem. 2005, 48, 3473–3477.
(47) Laue, K. W.; Kroger, S.; Wegelius, E.; Haufe, G. Eur. J. Org. Chem.
2000, (22), 3737–3743.
(48) Cativiela, C.; az-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11
(3), 645–732.
(49) Cativiela, C.; az-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18
(5), 569–623.
(43) Kodaka, K.; Kinoshita, K.; Wakita, T.; Shiraishi, S.; Ohnuma, K.;
Yamada, E.; Yasui, N.; Nakaya, M.; Matsuno, H. EP649845.
(50) Ayers, J. T.; Xu, R.; Dwoskin, L. P.; Crooks, P. A. AAPS J. 2005, 7
(3), E752–E758.
J. Org. Chem. Vol. 73, No. 9, 2008 3501

Bhatti et al.
SCHEME 7. Proposed Mechanism Involving Pyridyne Intermediate
TABLE 1. In Vitro Activity of nAChR Ligands
R4ꢀ2 Ki
R7 Ki
R4ꢀ2 Emax
R4ꢀ2 EC50
(nM)
R3ꢀ4 Emax
R1ꢀγδ EC50
R1ꢀγδ Emax
R1ꢀγδ EC50
compd
(nM)a
(nM)b
(%)c
(%)d
(nM)
(%)e
(nM)
3
1.0
0.5
3.0
15.0
0.3
2.0
1.0
0.5
10.0
2.0
3.0
2.5
0.7
0.5
3.0
24.3
105
40
40
297
3890
3
85
125
110
108
1100
375
8000
2000
130
169
226
116
55
50
362
650
59
61
17
63
64
24
25
26
29
30
4
S.P. <20f
55000
26
66
400000
3900
4900
410
40
45
52
55
10000
10000
161
110
400
3000
22
47
100
6
60
62
10.9
19.8
5.0
97
63
1000
4620
13
12
10
100000
100000
100000
120000
b
a [3H]Nicotine; R4ꢀ2 nAChR in rat cortex. Inhibtion of radiolabeled [3H]MLA binding to rat hippocampus receptors. c Transfected SH-EP 1 cells,
d
e
86Rb2+ efflux. PC12 cells, 86Rb2+ efflux. TE-671 cells, 86Rb2+ efflux. f S.P. ) single-point response.
benzene for 16 h (Scheme 6). The (+)-2-hydroxy-3-pinanone
was likewise used to make imine 39. Deprotonation of imines
37 and 39 with LDA and alkylation with bromides 9 or 10 at
-78 °C in THF gave imines 41–44 in 60–70% yield. Imines
41–44 were treated with hydroxylamine in ethanol to cleave
the chiral auxiliary, affording amines 47–50 in good yield.
Amines 47–50 were then reacted with concentrated HBr in the
presence of excess HBr gas at 120 °C in a sealed tube for 8 h,
affording dibromides 53-56 as the dihydrobromide salts.
Subsequent heating of the crude reaction products with K2CO3
in EtOH gave the desired cyclized compounds 59–64. We did
not determine the enantioselectivity of the alkylation reaction
or the enantiomeric excess for intermediates in the sequence.
Instead, evidence of the extremely high enantioselectivity of
the key alkylation step was made by inference, as the final
products 59–64 were shown to be essentially single enantiomers
by chiral LC analysis. Since minimal purification was performed
on intermediates, it is unlikely that the enantiomeric ratio was
significantly enhanced in steps subsequent to the alkylation.
Although the chemistry proved to be relatively straightforward
when the 5-position of pyridine was unsubstituted, the presence
of a bromo substituent in 38 and 40 complicated matters. The
yields observed for alkylation products 45 and 46 were
approximately 10%, with the majority of the isolated product
66 and 67 arising from a side reaction involving LDA (Scheme
7). These presumably arise via the pyridyne intermediate 65.
The absolute configurations for products 59-64 were as-
signed on the basis of X-ray crystallographic analysis. Com-
pounds 59-62 exhibited two crystallographically independent
anion/cation pairs in the asymmetric unit along with a single
water molecule. The crystal structures can be found in the
Supporting Information (Figures S2, S3, S4, and S5).
A summary of biological data for our targeted compounds is
shown in Table 1. All compounds tested had R4ꢀ2 Ki < 15nM.
Several compounds, 3, 6, 59–62, and 64, also bound to the R7
receptor with high affinity. Unfortunately only the 2-(pyridin-
3-yl)-1-azabicyclo[3.2.2]nonane series (6, 60, and 62) had little
or no efficacy at R1ꢀγδ (muscle). In sharp contrast the
2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series is extremely
potent at R1ꢀγδ, the reason for this difference between these
two series is unknown. However, we do see selectivity within
the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series for R3ꢀ4
(ganglion) with compound 59 (R isomer) >10 times the potency
of compound 61 (S isomer). Binding at the R7 receptor within
the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series drops off
quickly with susbstitution at the 5′-position on the pyridine (17,
24, 25, 26, 29, and 30) presumably due to unfavorable
interactions with the receptor.
Summary
In summary, we have developed facile methods for the synthesis
of a class of high-affinity nAChR ligands, the 2-(pyridin-3-yl)-1-
azabicyclo[3.2.2]nonanes, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]oc-
tanes, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octanes. The general
approach of alkylation of a pyridine-containing imine, cyclic
3502 J. Org. Chem. Vol. 73, No. 9, 2008

Potent Nicotinic Acetylcholine Receptor–Ligands
1
determined by GC-MS. H NMR (300 MHz, CDCl3) δ 8.57–8.56
ether cleavage, and bis-aminocyclization was also tolerant to
the incorporation of a bromo substituent in the 5-pyridinyl
position, allowing elaboration to a number of novel analogues.
All compounds have been evaluated for activity at nAChRs,
and displayed high affinity at the R4ꢀ2 receptor (<15 nM).
Pharmacological data for several of these analogues have been
previously reported as well as in this paper.51,52 Compounds
60 and 62 exhibit high affinity for both the R4ꢀ2 and R7
receptors. The R-enantiomer (60) shows some preference for
R4ꢀ2 over R7, while the S-enantiomer (62) binds with equal
affinity (<10 nM) to the two receptor subtypes. However, more
pertinent to a possible side effect profile, compound 60 is
significantly less active than compound 62 at human muscle
and ganglionic nAChR subtypes. Data for other compounds will
be reported in due course.
(d, J ) 2.1 Hz, 1H), 8.45–8.44 (d, J ) 2.1 Hz, 1H), 7.86–7.84 (t,
J ) 2.1 Hz, 1H), 4.09–4.06 (t, J ) 6.8 Hz, 1H), 3.95–3.90 (m,
2H), 3.36–3.29 (t, J ) 11.7 Hz, 2H), 2.19 (br, 2H), 1.66–1.27 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 149.8, 146.6, 133.0, 136.6,
121.1, 67.7, 50.3, 46.1, 33.3, 32.8, 31.8.
Alkylation Procedure B (Preparation of Amines 13 and 31).
1-(Pyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-amine (13).
A solution of LDA [prepared from diisopropylamine (1.0 mL; 7.3
mmol) and n-BuLi (2.9 mL of a 2.5 M solution in hexane, 7.25
mmol) at 0 °C in dry THF (10 mL) under N2] was added dropwise
to a solution of isopropyl(1-pyridin-3-ylethylidene)amine 3442 (1.2
g, 7.3 mmol) in dry THF (10 mL) at 0 °C under N2. After 45 min,
4-(2-bromomethyl)tetrahydropyran (9, 1.3 g, 7.3 mmol) in 10 mL
dry THF, was added to the reaction mixture. The reaction mixture
was warmed to ambient temperature, stirred for another 12 h,
quenched with 10 mL of saturated aqueous NH4Cl solution, and
stirred for a further 45 min. The mixture was extracted with CH2Cl2
(3 × 25 mL), and the combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to give a
light brown residue. This was purified by column chromatography
eluting with acetone in CHCl3 (3:7), to yield 1-(pyridin-3-yl)-3-
(tetrahydro-2H-pyran-4-yl)propan-1-one (33, 1.4 g, 90%) as a color-
less oil. 1H NMR (300 MHz, CDCl3) δ 9.19 (m, 1H), 8.76–8.84 (m,
1H), 8.20–8.28 (m, 1H), 7.40–7.45 (m, 1H), 3.90–4.15 (m, 2H),
3.30–3.45 (m, 2H), 3.02–2.92 (m, 2H), 1.20–1.80 (m, 7H); 13C NMR
(75 MHz, CDCl3) δ 198.9, 153.5, 149.6, 135.3, 132.1, 123.6, 67.9,
35.6, 34.5, 32.9, 30.7.
Experimental Section
Alkylation Procedure A (Preparation of Amines 11, 12, and
13). 1-(Pyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-amine
(13). To a stirred solution of 7 (2.0 g, 7.3 mmol) in 50 mL of dry
THF at -78 °C was added a solution of LDA [prepared from
diisopropylamine (0.96 g, 9.6 mmol) and n-BuLi (3.8 mL of 2.5
M solution in hexanes, 9.5 mmol) at 0 °C in dry THF (10 mL)
under N2] dropwise via cannula over 5 min. After stirring for 10
min at -78 °C, the reaction mixture was warmed to -40 °C, and
4-(2-bromoethyl)tetrahydropyran (10, 1.56 g, 8.08 mmol) in 15 mL
of dry THF was added. The reaction mixture was stirred for an
additional 12 h, and then quenched with 20 mL of 2 N HCl. The
reaction mixture was stirred for an additional 45 min and extracted
with EtOAc (4 × 25 mL) to remove the liberated benzophenone.
The acidic solution was then basified by the addition of solid
NaHCO3 (pH 8–9) and extracted with CHCl3 (5 × 25 mL). The
combined organic extracts were dried over anhydrous K2CO3,
filtered, and concentrated under reduced pressure to afford a viscous
brown liquid, which was purified by column chromatography
(MeOH/CHCl3, 9:1) to afford compound 13 as a viscous, light
Solid K2CO3 (4.4 g, 32 mmol) was added to a stirred suspension
of hydroxylamine hydrochloride (2.2 g, 32 mmol) in 20 mL of
MeOH at 0 °C. Intermediate 33 (1.4 g, 6.4 mmol) in MeOH (5
mL) was added and the reaction mixture was stirred for 2 h, then
filtered and concentrated in vacuo. Zinc dust (6.50 g, 100 mmol)
was added, over a 15 min period, to a suspension of the crude oxime
(obtained as a mixture of cis- and trans-isomers) in 20 mL of EtOH
(95%) and 8 mL of acetic acid. The reaction was stirred for 4 h,
then filtered through a pad of diatomaceous earth, washing with
EtOH (50 mL). The filtrate was evaporated under reduced pressure
to afford a white solid, which was basified with NaOH (∼10 mL,
50% aqueous, pH 9–10) and extracted with CHCl3 (6 × 25 mL).
The combined CHCl3 extracts were dried over anhydrous K2CO3,
filtered, and concentrated under reduced pressure to afford a viscous
1
brown oil (1.2 g, 75%). H NMR (300 MHz, CDCl3) δ 8.46–8.58
(m, 2H), 7.64–7.72 (m, 1H), 7.22–7.32 (m, 1H), 3.80–4.00 (m, 3H),
3.34–3.48 (t, J ) 14.1 Hz, 2H), 1.00–1.80 (m, 11H); 13C NMR (75
MHz, CDCl3) δ 148.6, 141.4, 133.7, 123.5, 67.9, 54.1, 36.3, 34.9,
33.5, 33.1, 33.0.
1
oil (0.70 g, 93% yield). H 13C NMR spectra were identical with
those generated from 13 from the Alkylation Procedure A.
1-(Pyridin-3-yl)-3-(tetrahydrofuran-3-yl)propan-1-amine (31).
By using the procedure described above for 13, amine 31 was syn-
thesized from 32, hydroxylamine, and Zn dust in 90% yield as a pair
1-(Pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine (11).
By using the procedure described above and replacing 10 with
4-(bromomethyl)tetrahydropyran (9),36,37 1-(pyridin-3-yl)-2-(tet-
rahydro-2H-pyran-4-yl)ethanamine (11) was obtained from imine
1
of diastereomers and was taken as such to the next step. H NMR
1
7 in 90% yield. Purity was determined to be g95% by H NMR
(300 MHz, CDCl3) δ 8.58–8.48 (m, 2H), 7.68–7.64 (m, 1H), 7.30–7.24
(m, 1H), 3.96–3.66 (m, 3H), 3.33–3.22 (m, 1H), 2.18–21.95 (m, 2H),
1.75–1.20 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 148.6, 148.5, 141.3,
133.8, 123.6, 73.2, 67.8, 54.1, 39.2, 38.3, 32.3, 29.9.
1
spectroscopy. H NMR (300 MHz, CDCl3) δ 8.52–8.53 (d, J )
4.0 Hz, 1H), 8.50–8.52 (dd, J ) 6.0 Hz, 1H), 7.62–7.65 (m, 1H),
7.26–7.70 (m, 1H), 4.52–4.57 (t, J ) 14.0 Hz, 1H), 3.80–4.00 (m,
2H), 3.34–3.48 (m, 2H), 1.00–1.80 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 149.1, 147.7, 138.9, 122.9, 56.3, 49.4, 41.9, 32.4, 26.8,
26.0, 21.0, one quaternary carbon was not observed.
1-(Pyridin-3-yl)-3-(tetrahydrofuran-3-yl)-propan-1-one (32). By
using the procedure described above for 33, ketone 32 was
synthesized from 34 and 3-(bromomethyl)tetrahydrofuran (35).43
1H NMR (300 MHz, CDCl3) δ 9.14–9.18 (m, 1H), 8.74–8.80 (m,
1H), 8.14–8.24 (m, 1H), 7.38–7.44 (m, 1H), 3.82–3.96 (m, 2H),
3.70–3.80 (m, 1H), 3.82–4.20 (m, 1H), 2.98–3.24 (m, 2H),
2.20–2.34 (m, 1H), 2.02–2.16 (m, 1H), 1.78–1.87 (m, 2H),
1.50–1.62 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 198.0, 153.5,
149.5, 135.3, 131.9, 123.6, 73.1, 67.8, 38.7, 37.5, 32.2, 27.2.
Procedures for Ether Cleavage and Amine Cyclization (Com-
pounds 3, 6, 17, and 4). 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane
(6). HBr gas was passed through a solution of amine 13 (1.80 g,
8.73 mmol) in 48% HBr (10 mL) in a high-pressure reaction tube
until the solution was saturated. The pressure tube was then sealed
and heated in an oil bath at 120 °C for 12 h. The reaction mixture
was cooled in an ice–water bath, and the contents transferred to a
round-bottomed flask. Repeated azeotropic distillation with EtOH
1-(5-Bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)etha-
namine (12). Alkylation of imine 8 (1.0 g, 2.9 mmol) with
4-(bromomethyl)tetrahydropyran (9)36,37 (0.5 g, 2.9 mmol) afforded
1-(5-bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine 12
1
(0.74 g, 90%). This material was 85% pure by H NMR and was
used crude in subsequent reactions. Further purification could be
achieved by distillation of the crude product under reduced pressure
in a Kugelrohr apparatus, resulting in material of g99% purity as
(51) Bencherif, M.; Schmitt, J. D.; Bhatti, B. S.; Crooks, P.; Caldwell, W. S.;
Lovette, M. E.; Fowler, K.; Reeves, L.; Lippiello, P. M. J. Pharmacol. Exp.
Ther. 1998, 284 (3), 886–894.
(52) Caldwell, W. S.; Bencherif, M.; Dull, G. M.; Crooks, P. A.; Lippiello,
P. M.; Bhatti, B. S.; Deo, N. M.; Ravard, A. PCT Int. Appl., WO A1 9900385,
1999.
J. Org. Chem. Vol. 73, No. 9, 2008 3503

Bhatti et al.
under reduced pressure removed the HBr, leaving a yellow solid
(17). This was taken up in EtOH (150 mL), and the solution was
heated under reflux in the presence of solid K2CO3 (5 g) for 10 h.
The reaction mixture was filtered through a diatomaceous earth plug,
which was washed with 50 mL of EtOH. The EtOH filtrates were
combined and concentrated under reduced pressure to give a white
solid, which was then dissolved in 100 mL of CHCl3. The resulting
solution was passed through a pad of silica gel, eluting with
additional CHCl3. The light brown liquid obtained after the removal
of CHCl3 was distilled under reduced pressure (110–112 °C at 4
mmHg), using a Kugelrohr distillation apparatus. This afforded
2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane (6) as a colorless liquid
2-(Pyridin-3-yl)-1-azabicyclo[3.2.1]octane (4). By using the pro-
cedure described above, 4 (1.37 g, 88%) was synthesized from
1-pyridin-3-yl-3-(tetrahydrofuran-3-yl)propylamine (31, 1.7 g, 8.2
mmol) as an approximately 1:1 mixture of diastereomers. 1H NMR
1
1
(300 MHz, CDCl3) δ 8.72–8.74 (m, /2H), 8.60–8.63 (m, /2H),
8.42–8.48 (m, 1H), 7.82– 7.85 (m, 1/2H), 7.72–7.78 (m, 1/2H),
7.20–7.30 (m, 1H), 3.90–3.98 (m, 1H), 3.00–3.20 (m, 2H),
1
2.52–2.86 (m, 2H), 1.50–2.31 (m, 7H). Dihydrochloride salt: H
NMR (300 MHz, D2O) δ 8.52–8.60 (m, 1H), 8.42–8.48 (m, 1H),
7.85–7.88 (m, 1H), 7.38–7.46 (m, 1H), 4.70–4.7.45 (m, 1H),
3.20–3.80 (m, 3H), 2.60–3.20 (m, 1H), 2.60–2.80 (m, 1H), 1.6–2.48
(m, 6H); 13C NMR (75 MHz, D2O) δ 152.9, 152.4, 151.8, 141.1,
140.6, 133.5, 127.7, 127.6, 67.0, 65.1, 63.3, 56.0, 55.1, 49.2, 36.3,
35.8, 30.6, 29.6, 29.3, 29.2, 23.3, 21.2; GC-MS M+ 188. GC-MS
of the free base regenerated from the salt confirms the presence of
two diastereomers in the ratio of 26:74, which indicates that during
the crystallization of the salt, differential solubility resulted in
enrichment in one of the diastereomers. Anal. Calcd for
C12H16N2 ·2HCl: C, 54.43; H, 7.00; N, 10.58. Found C, 54.44; H,
7.09; N, 10.47. (Consistent with correction for 0.2 mol equiv of
H2O.)
1
(1.3 g, 79%). H NMR (300 MHz, CDCl3) δ 8.62–8.64 (d, J ) 6
Hz, 1H), 8.42–8.50 (m, 1H), 7.72–7.82 (m, 1H), 7.22–7.30 (m, 1H),
3.98–4.08 (dd, J ) 15 Hz, 1H), 3.22–3.98 (m, 1H), 3.08–3.21 (m,
1H), 2.82–3.08 (m, 2H), 1.60–2.10 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 144.7, 143.9, 142.3, 132.5, 127.6, 66.8, 50.3, 40.9, 32.3,
25.8, 24.7, 24.3, 20.6; GC-MS M+ 202. The free base was dissolved
in HCl-saturated EtOH and sonicated for 5 min. Solvent was
removed in vacuo to yield a solid residue that was recrystallized
from 2-propanol to afford the di-HCl salt monohydrate as a brown
1
Procedures for Preparation of Analogues 22–26, 29, and 30.
2-(5-Aminopyridin-3-yl)-1-azabicyclo[2.2.2]octane (22). 2-(5-Bro-
mopyridin-3-yl)-1-azabicyclo[2.2.2]octane 17 (1.0 g, 3.8 mmol) and
concentrated aqueous NH4OH (150 mL) were added to a pressure
tube containing CuI (75 mg, 10 mol %). The tube was sealed and
heated at 120 °C for 16 h. The tube was cooled to room temperature,
and the reaction mixture was concentrated by rotary evaporation
at 60 °C (bath temperature). The resulting solid was dissolved in
CH3OH and filtered through diatomaceous earth to remove copper
salts. The solvent was removed by rotary evaporation, and the
residue was purified on silica gel, eluting with a CH3OH-CHCl3
gradient (0–20% CH3OH) to give 22 as an orange solid (0.74 g,
crystalline solid (mp 270–272 °C). H NMR (300 MHz, D2O) δ
8.82 (s, 1H), 8.76–8.78 (d, J ) 6 Hz, 1H), 8.60–8.63 (d, J ) 9 Hz,
1H), 7.96–8.00 (t, J ) 12 Hz, 1H), 4.80–4.84 (d, J ) 12 Hz, 1H),
3.40–3.80 (m, 2H), 3.20–3.40 (m, 1H), 3.10–3.23 (m, 1H),
2.20–2.50 (m, 2H), 1.92–2.26 (m, 6H), 1.74–1.88 (m, 1H); 13C
NMR (75 MHz, d6-DMSO) δ 169.4, 147.3, 136.1, 132.4, 124.5,
67.2, 49.1, 41.7, 31.8, 25.2, 24.1, 23.8, 20.1; GC-MS M+ 202. Anal.
Calcd for C13H18N2 ·2HCl: C, 56.25; H, 7.27; N, 10.18. Found: C,
53.63; H, 7.12; N, 9.59. (Consistent with 1 mol equiv of water.)
The following conditions were used to determine retention times
for each enaniomer: Chiralpack AD 0.46 × 25 cm column, 85%
hexane, 15% EtOH, flow rate 1.0 mL/min, 210–400 nm detector
wavelength; retention times 7.4 and 8.4 min.
1
99%). H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.96–7.97 (d,
J ) 2.7 Hz, 1H), 7.09 (m, 1H), 3.97–3.91 (t, J ) 8.7 Hz, 1H), 3.62
(m, 2H), 3.20–2.98 (m, 2H), 2.82–2.68 (m, 2H), 2.20–2.05 (m, 1H),
1.85–1.40 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 139.2, 135.6,
120.9, 56.2, 49.4, 42.0, 32.3, 26.8, 25.9, 21.8, two quaternary
carbons were not observed; mp 165 °C. The free base was dissolved
in HCl-saturated EtOH (20 mL) and sonicated for 10 min. Solvent
was removed in vacuo to yield a solid that was recrystallized from
2-propanol to afford the di-HCl salt as a yellow crystalline solid.
1H NMR (300 MHz, D2O) δ 8.15 (s, 1H), 8.02 (s, 1H), 7.80 (s,
1H), 4.84–4.78 (t, J ) 6.6 Hz, 1H), 3.62–3.51 (m, 1H), 3.40–3.24
(m, 1H), 3.20–3.10 (m, 2H), 2.30–2.11 (m, 3H), 2.00–1.79 (m, 4H);
13C NMR (75 MHz, D2O) δ 147.5, 134.0, 129.5, 129.1, 127.9, 57.4,
48.9, 41.9, 27.2, 22.1, 21.5, 19.8; mp 276–279 °C; GC-MS M+
203. Anal. Calcd for C12H17N3 ·2HCl: C, 51.35; H, 7.00; N, 14.97;
Cl, 25.26. Found C, 51.30; H, 6.98; N, 14.70; Cl, 25.10. (Consistent
with 0.25 mol equiv of H2O.)
2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane (3). Compound 3 (0.94
g, 86% yield) was obtained by using the above sequence, starting
with amine 11 (1.2 g, 5.8 mmol). H NMR (300 MHz, CDCl3) δ
1
8.67–8.66 (d, J ) 2.0 Hz, 1H), 8.47–8.49 (m, 1H), 7.73–7.77 (m,
1H), 7.24–7.28 (m, 1H), 3.99–4.04 (t, J ) 9.0 Hz, 1H), 2.89–3.20
(m, 2H), 2.75–3.20 (q, J ) 7.5 Hz, 2H), 2.15–2.23 (m, 1H),
1.90–1.98 (m, 1H), 1.40–1.80 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 149.1, 147.1, 138.9, 134.9, 122.9, 56.3, 49.4, 42.0, 32.4, 26.8,
25.9, 21.8; GC-MS M+ 188. Dihydrochloride salt, monohydrate
1
(mp 197–200 °C): H NMR (300 MHz, D2O) δ 9.00 (s, Hz, 1H),
8.80–8.83 (d, J ) 9.0 Hz, 1H), 8.60–8.84 (m, 1H), 7.88–8.24 (m,
1H), 4.98–5.06 (t, J ) 9.0 Hz, 1H), 3.68–3.80 (m, 1H), 3.45–3.52
(m, 2H), 3.15–3.23 (m, 1H), 2.30–2.50 (m, 3H), 1.92–2.22 (m, 4H);
13C NMR (75 MHz, D2O) δ 150.0, 149.7, 144.8, 134.7, 129.0, 61.3,
51.8, 44.7, 30.4, 25.2, 24.7, 23.0 (one more than theoretical); GC-
MS M+ 188. Anal. Calcd for C12H16N2 ·2HCl: C, 55.17; H, 6.89;
N, 10.72. Found: C, 50.91; H, 7.12; N, 9.80. (Consisent with 1
mol equiv of water.) The following conditions were used to
determine retention times for each enatiomer: Chiralpack AD 0.46
× 25 cm column, 85% hexane, 15% EtOH, flow rate 1.0 mL/min,
210–400 nm detector wavelength; retention times 7.8 and 10.9 min.
2-(5-Bromopyridin-3-yl)-1-azabicyclo[2.2.2]octane (17). By using
the procedure described above, 17 (132 mg, 75%) was synthesized
from 1-(5-bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)etha-
namine (12, 0.19 g, 0.66 mmol). The free base was converted to
the dihydrobromide salt, which was obtained as white needles
2-(5-Ethoxypyridin-3-yl)-1-azabicyclo[2.2.2]octane (24). To a
stirred solution of 22 (25 mg of di-HCl salt, 0.091 mmol) in dry
EtOH (3 mL) was added isoamyl nitrite (0.1 mL, 0.74 mmol) and
the mixture was heated at reflux for 2 h. The mixture was then
cooled to ambient temperature, and the solvent was removed in
vacuo to yield a viscous, brown oil, which solidified upon addition
of dry ether. The product thus obtained was dissolved in CHCl3
and kept overnight at 4 °C to induce crystallization. The resulting
solids were filtered, washed with ether, and dried under vacuum to
1
yield 24 as its di-HCl salt (10 mg, 51%), as colorless needles. H
NMR (300 MHz, CD3OD) δ 8.78 (s, 1H), 8.58 (s, 1H), 8.42 (s,
1H), 5.08–5.02 (m, 1H), 4.35 (m, 2H), 3.75–3.65 (m, 1H), 3.42–3.35
(m, 1H), 3.20–3.14 (m, 2H), 2.38–2.30, (m, 3H), 2.15–1.80 (m,
4H), 1.42–1.38 (m, 3H); 13C NMR (75 MHz, CD3OD) δ 158.6,
136.9, 135.5, 132.8, 132.3, 67.3, 58.7, 49.6, 42.8, 28.4, 23.3, 22.9,
21.7, 14.6; GC-MS M+ 232.
2-(5-Isopropoxypyridin-3-yl)-1-azabicyclo[2.2.2]octane (25). By
using the procedure described above for 24, compound 25 (as its
di-HCl salt) was synthesized from 22 (28 mg, 55%). 1H NMR (300
1
(sublimed at 198–200 °C, dec at 210 °C). H NMR (300 MHz,
D2O) δ 8.75 (d, J ) 1.8 Hz, 1H), 8.67 (d, J ) 1.8 Hz, 1H),
8.44–8.42 (t, J ) 1.8 Hz, 1H), 4.84–4.78 (t, J ) 6.8 Hz, 1H),
3.62–3.51 (m, 1H), 3.40–3.24 (m, 1H), 3.20–3.10 (m, 2H),
2.30–2.11, (m, 3H), 2.00–1.79 (m, 4H); 13C NMR (75 MHz, D2O)
δ 148.7, 147.1, 141.3, 137.5, 120.7, 55.9, 49.4, 42.0, 32.6, 26.7,
25.9, 21.8. Anal. Calcd for C12H15N2Br·2HBr: C, 33.60; H, 3.99;
N, 6.53; Br, 55.88. Found: C, 33.70; H, 4.21; N, 6.25; Br, 55.60.
3504 J. Org. Chem. Vol. 73, No. 9, 2008

Potent Nicotinic Acetylcholine Receptor–Ligands
MHz, D2O) δ 8.38–8.35 (m, 2H), 7.60 (s, 1H), 4.88–4.76 (m, 2H),
3.72–3.60 (m, 1H), 3.56–3.42 (m, 1H), 3.36–3.14 (m, 2H),
2.40–2.31, (m, 3H), 2.15–1.92 (m, 4H), 1.40 (d, J ) 3.6 Hz, 6H);
GC-MS M+ 246. Anal. Calcd for C15H22N2O·2HCl: C, 56.43; H,
37.58; N, 8.77; Cl, 22.21. Found: C, 56.39; H, 7.65; N, 8.62; Cl,
22.05.
for 16 h. Saturated aqueous NH4Cl (100 mL) was added, and the
mixture was stirred for 30 min. The layers were separated, and the
aqueous layer was extracted with CHCl3 (2 × 50 mL). The
combined organic layers were dried over anhydrous K2CO3, filtered,
and concentrated. The resulting material was purified via chroma-
tography eluting with 25% acetone/CHCl3 to yield 42 (1.85 g, 65%).
1H NMR (300 MHz, CDCl3) δ 8.60 (m, 2H), 8.18 (br, 1H),
7.38–7.42 (m, 1H), 4.56–4.66 (t, J ) 6.6 Hz, 1H), 3.88–4.00 (m,
2H), 3.30–3.44 (dt, J ) 6.6 Hz, 2H), 2.88–2.92 (d, J ) 24 Hz,
1H), 2.56–2.60 (d, J ) 24 Hz, 1H), 2.22–2.38 (m, 2H), 2.02–2.12
(m, 3H), 1.80–1.92 (m, 3H), 1.40–1.65 (m, 3H), 1.15–1.38 (m, 8H),
0.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.6, 148.3, 138.9,
134.5, 123.6, 67.9, 60.9, 49.9, 38.2, 38.2, 35.6, 34.8, 33.5, 33.5,
2-(5-Phenylpyridin-3-yl)-1-aza-bicyclo[2.2.2]octane (26). DME
(5.0 mL) and H2O (2.0 mL) were added to a vial containing 17
(100 mg, 0.375 mmol), phenylboronic acid (92 mg, 0.75 mmol),
Pd(PPh3)4 (22 mg, 5 mol %), and Na2CO3 (80 mg, 0.75 mmol).
The vial was purged with argon (evacuated and filled 3 times),
capped, and then heated under reflux for 12 h. The vial was cooled
to ambient temperature, and the solvent was removed in vacuo.
The crude residue was suspended in saturated NH4Cl solution (25
mL) and extracted with CHCl3 (3 × 25 mL). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated in vacuo
to afford a viscous oil. Purification on an ISCO Combiflash silica
gel column, eluting with a CH2Cl2:EtOAc gradient (0–100%),
33.4, 33.1, 33.0, 28.4, 27.9, 27.2, 22.9; [R]25 +30.0 (c 1.02,
D
MeOH).
(2S,Z)-3-((R)-1-(5-Bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-
4-yl)ethylimino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (45). Fol-
lowing the procedure described above for 42, LDA (2.1 mol equiv),
9 (1.8 mol equiv), and 38 (3.0 g, 8.9 mmol) in 50 mL of dry THF
afforded 45 (1.73 g, 45%). 1H NMR (300 MHz, CDCl3) δ 8.52–8.51
(d, J ) 3.0 Hz, 1H), 8.42–8.41 (d, J ) 3.0 Hz, 1H), 7.84–7.82 (d,
J ) 0.6 Hz, 1H), 4.32–4.40 (dd, J ) 12.0 Hz, 1H), 3.84–3.80 (m,
4H), 3.18–3.33 (m, 2H), 2.62–2.58 (m, 1H), 2.30–2.38 (m, 1H),
2.10–2.20 (m, 1H), 1.98–1.92 (t, J ) 9.0 Hz, 1H), 1.92–1.82 (m,
1H), 1.80–1.62 (m, 4H), 1.52–1.00 (m, 9H), 0.78 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 148.9, 147.2 139.0, 136.0, 120.6, 68.0, 67.9,
67.7, 61.5, 39.4, 38.3, 38.2, 35.6, 34.8, 33.3, 33.1, 32.2, 30.7, 28.4,
1
afforded 26 as a yellow oil (65 mg, 65%). H NMR (300 MHz,
D2O) δ 9.05 (s, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 7.70–7.65, (m,
2H), 7.58–7.50 (m, 3H), 5.02–4.96 (t, J ) 6.6 Hz, 1H), 3.60–3.50
(m, 1H), 3.38–3.32 (m, 1H), 3.22–3.14 (m, 2H), 2.40–2.31 (m, 3H),
2.05–1.89 (m, 4H); 13C NMR (75 MHz, D2O) δ 150.0, 149.7, 144.9,
134.7, 128.9, 61.3, 51.9, 44.7, 30.5, 25.2, 24.7, 23.0. Anal. Calcd
for C18H20N2: C, 81.77; H, 7.62; N, 10.59. Found: C, 81.50; H,
7.20; N, 10.87; LC-MS (M + H)+ 265.2.
5-(1-Azabicyclo[2.2.2]oct-2-yl)pyridin-3-ol (23). To a solution of
compound 22 (87 mg of di-HCl salt, 0.32 mmol) in 2 mL of 3 M
sulfuric acid, cooled in an ice bath, was added sodium nitrite (33
mg, 0.47 mmol) in two portions over several minutes. The mixture
was stirred for 30 min, then placed in a hot-water bath at 55 °C for
45 min. The mixture was cooled, adjusted to pH ∼8, and con-
centrated under reduced pressure. The residue was triturated with
hot CH3OH (2 × 10 mL), and the extracts filtered and concentrated
to give ∼50 mg (82%) of crude product 23. This material was not
characterized, but used directly to produce compounds 29 and 30.
Typical Procedure for the Enatioselective Synthesis of
Azabicyclo[3.2.2]nonanes and Azabicyclo[2.2.2]octanes. Typi-
cal Procedure for Formation of Imines 37–40. 2,6,6-Trimethyl-
3-(pyridine-3-ylmethylimino)bicycle[3.1.1]heptan-2-ol (37).53,54 To
a stirred solution of (-)-2-hydroxy-3-pinanone (10.0 g, 59.4 mmol)
in 500 mL of benzene was added pyridinylmethylamine (6.66 mL,
65.4 mmol) in one portion. Boron trifluoride diethyl etherate (0.70
mL, 5.90 mmol) was added in one portion and the reaction was
heated at reflux for 5 h under N2 and then stirred at room
temperature for an additional 16 h. The solvents were then removed
in vacuo, and the resulting residue was stirred in 100 mL of
saturated aqueous NaHCO3 for 1 h and extracted with CHCl3 (3 ×
100 mL). The extracts were combined, dried over Na2SO4,
filtered, and concentrated. The resulting dark brown oil was
purified via chromatography, eluting with a gradient of CHCl3
to 20% MeOH-CHCl3. The yellow oil was dissolved in 50 mL
of hot EtOAc and placed in the freezer at -4 °C for 16 h. The
resulting solid was filtered, washed with cold EtOAc, and dried
under high vacuum to yield off-white crystals 37 (8.0 g, 53%).
Typical Procedure for Alkylation of Imines 37–40. (1′R,2S)-
2,6,6-Trimethyl-3-[1-pyridin-3-yl-3-(tetrahydropyran-4-yl)propyl-
imino]bicyclo[3.1.1]heptan-2-ol (42). LDA was prepared from BuLi
(2.5 M, 6.23 mL, 15.6 mmol) and diisopropylamine (2.19 mL, 15.6
mmol) in dry THF (20 mL) at 0 °C. The solution was warmed to
room temperature and stirred for 30 min. The LDA solution was
added dropwise via cannula to a solution of 37 (2.0 g, 7.8 mmol)
in dry THF (80 mL) at -78 °C and stirred for 60 min, at which
point 4-(2-bromoethyl)tetrahydropyran (10, 2.69 g, 14.0 mmol) was
added. The solution was warmed to ambient temperature and stirred
27.9, 27.2, 22.9; [R]20 +15 (c 1.0,CHCl3).
D
(2R,Z)-3-((S)-1-(5-Bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-
4-yl)ethylimino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (46). Fol-
lowing the procedure described above for 42, LDA (2.1 mol equiv),
9 (1.8 mol equiv), and 40 (3.0 g, 8.9 mmol) in 50 mL of dry THF
afforded 45 (1.6 g, 42%). [R]20 -15 (c 1.0, CHCl3).
D
Typical Procedure for Hydrolysis of Imines 41–46 To Yield
Amines 47–52. (R)-1-Pyridin-3-yl-3-(tetrahydropyran-4-yl)propyl-
amine (48). A solution of 42 (1.85 g, 5.0 mmol) and hydroxylamine
hydrochloride (2.00 g, 28.8 mmol) in EtOH (20 mL) was heated at
reflux for 16 h. The mixture was then cooled to room temperature,
filtered through diatomaceous earth, washed with EtOH, concen-
trated, and purified via chromatography, using 10–20% MeOH/
CHCl3 with 1% NH4OH, to yield 48 (0.88 g, 80%). 1H NMR (300
MHz, CDCl3) δ 8.73 (s, 1H), 8.55 (d, J ) 5 Hz, 1H), 7.93 (d, J )
10 Hz, 1H), 7.33–7.43 (m, 1H), 4.23–4.30 (m, 1H), 3.90–3.94 (dd,
J ) 10 Hz, 2H), 3.64–3.70 (m, 1H). 3.33–3.43 (t, J ) 10 Hz, 2H),
2.22 (m, 2H), 2.02 (m, 3H), 1.65 (m, 4H), 1.05 (m, 1H); [R]25
+5.0 (c 1.0, MeOH).
D
Compounds 47 and 49–52 were synthesized following the
procedure outlined above and the desired material for each reaction
was isolated and used directly in the cyclization reaction described
in detail below.
(R)-1-(Pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine (47).
A solution of 41 (1.40 g, 3.92 mmol) and 20 mL of ethanolic
hydroxylamine hydrochloride solution were reacted together as
1
described for 48 to give 47 (650 mg, 80%). H NMR (300 MHz,
CDCl3) δ 8.56–8.55, d (d, J ) 3.0 Hz, 1H), 8.51–8.49 (dd, J )
2.4, 7.2 Hz, 1H), 7.71–7.64, (m, 1H), 7.32–7.24, (m, 1H), 4.10–4.02
(t, J ) 7.5 Hz, 1H), 3.98–3.88, (m, 2H), 3.38–3.28 (dt, J ) 2.1,
12.6 Hz, 2H), 1.90–1.22, (m, 9H); 13C NMR (75 MHz, CDCl3) δ
148.7, 148.5, 133.7, 123.6, 67.8, 50.7, 46.6, 33.3, 32.9, 31.9; [R]20
+3.50 (c 1.0, CHCl3).
D
(S)-1-Pyridin-3-yl-3-(tetrahydropyran-4-yl)propylamine (50). A
solution of 44 (1.5 g, 4.0 mmol) and 20 mL of ethanolic
hydroxylamine hydrochloride solution were reacted together as
described for 48 to give 50 (0.67 g, 75%).
(S)-1-(Pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine (49).
A solution of 43 (1.20 g, 3.37 mmol) and 20 mL of ethanolic
hydroxylamine hydrochloride solution were reacted together as
(53) Swango, J. H.; Bhatti, B. S.; Qureshi, M. M.; Crooks, P. A. Chirality
1999, 11 (4), 316–318.
1
described for 48 to give 49 (520 mg, 75%). H NMR (300 MHz,
(54) Ayers, J. T.; Sonar, V. N.; Parkin, S.; Dwoskin, L. P.; Crooks, P. A.
Acta Crystallogr., Sect. E 2005, 61, o2682–o2684.
CDCl3) δ 8.56–8.55 (d, J ) 2.0 Hz, 1H), 8.51–8.49 (dd, J ) 1.7,
J. Org. Chem. Vol. 73, No. 9, 2008 3505

Bhatti et al.
6.6 Hz, 1H), 7.70–7.64 (m, 1H), 7.32–7.24 (m, 1H), 4.10–4.02 (t,
J ) 7.2 Hz, 1H), 3.98–3.88 (m, 2H), 3.38–3.28 (dt, J ) 2.0, 11.5
Hz, 2H), 1.70–1.22 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 149.1,
147.7, 138.9, 134.9, 122.9, 56.3, 49.5, 41.9, 32.4, 26.8, 25.9, 21.8;
was no detectable compound 61. (R)-2-(Pyridin-3-yl)quinuclidine
(59) (free-base): 1H NMR (300 MHz, CDCl3) δ 8.67–8.66 (t, J )
1.0 Hz, 1H), 8.49–8.47 (dd, J ) 3.0 Hz, 1H), 7.77–7.73 (m, 1H),
7.28–7.24 (m, 1H), 4.06–4.00 (t, J ) 9.0 Hz, 1H), 3.19–2.99 (m,
2H), 2.76–2.71 (q, J ) 7.5 Hz, 2H), 2.05 (s, 1H), 1.96–1.92 (m,
1H), 1.77–1.39 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 149.1,
147.7, 138.9, 134.8, 122.9, 56.3, 49.4, 41.9, 32.4, 26.7, 25.9, 21.8;
[R]20 -5.18 (c 1.35, CHCl3).
D
(R)-1-(5-Bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-
amine (51). A solution of 45 (1.3 g, 3.0 mmol) and 20 mL of
ethanolic hydroxylamine hydrochloride solution were reacted
together as described for 48 to give 51 (640 mg, 75%).1H NMR
(300 MHz, CDCl3) δ 8.57–8.56 (d, J ) 6 Hz, 1H), 8.45–8.44 (d,
J ) 6 Hz, 1H), 7.85–7.84 (m, 1H), 4.08–4.03 (t, J ) 7.5 Hz, 1H),
3.96–3.95 (m, 1H), 3.92–3.90 (m, 1H), 3.38–3.30 (m, 2H),
1.72–1.28 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 149.7, 146.5,
[R]25 +59.8 (c 0.97, CHCl3).
D
(S)-2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane dihydrochloride
(61). By using the procedure described above for compound 60,
compound 61 (213 mg of di-HCl salt, 84%) was synthesized from
49 (0.20 g, 0.97 mmol). 1H NMR (300 MHz, D2O) δ 9.00 (s, 1H),
8.80–8.83 (d, J ) 9 Hz, 1H), 8.60–8.84 (m, 1H), 7.88–8.24 (m,
1H), 4.98–5.06 (t, J ) 18 Hz, 1H), 3.68–3.80 (m, 1H), 3.45–3.52
(m, 2H), 3.15–3.23 (m, 1H), 2.30–2.50 (m, 3H), 1.92–2.22 (m, 4H);
13C NMR (75 MHz, D2O) δ 150.0, 149.7, 144.8, 134.7, 129.0, 61.3,
51.8, 44.7, 30.4, 25.2, 24.7, 23.0; mp 203–205 °C; [R]25D -49.2 (c
1.18, MeOH). Anal. Calcd for C12H16N2.2HCl: C, 55.17; H, 6.89;
N, 10.72. Found: C, 51.50; H, 7.20; N, 9.97. (Consistent with 1
mol equiv of water.) The following conditions were used to
determine enatiomeric purity: Chiralpack AD 0.46 × 25 cm column,
85% hexane, 15% EtOH, flow rate 1.0 mL/min, 210–400 nm
detector wavelength; retention times t61 ) 10.9. There was no
detectable compound 59.
143.6, 136.5, 121.0, 67.7, 50.3, 50.2, 46.5, 33.3, 32.7, 31.3; [R]20
+4.5 (c 1.0, CHCl3).
D
(S)-1-(5-Bromopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-
amine (52). A solution of 46 (1.4 g, 3.2 mmol) and 20 mL of
ethanolic hydroxylamine hydrochloride solution were reacted
together as described for 48 to give 51 (0.74 g, 80%). [R]20D -4.5
(c 1.0, CHCl3).
Typical Cyclization Reaction for Formation of 59–64. (R)-2-
(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane dihydrochloride (60). HBr
gas was passed through a solution of amine 48 (0.88 g, 4.0 mmol)
in 48% HBr (20 mL) in a high-pressure reaction tube until the
solution was saturated. The pressure tube was sealed and heated in
an oil bath at 120 °C for 8 h. The reaction mixture was cooled in
an ice–water bath, and the contents transferred to a round-bottomed
flask. Repeated azeotropic distillation with EtOH under reduced
pressure removed the HBr, leaving a yellow solid (54). This was
taken up in ethanol (250 mL) and heated under reflux in the
presence of solid K2CO3 (20 g) for 16 h. The reaction mixture was
filtered through a diatomaceous earth plug, which was washed with
50 mL of EtOH. Rotary evaporation of the EtOH from the filtrates
left a white solid, which was purified via column chromatography,
eluting with 10% MeOH/CHCl3 with 1% NH4OH, followed by
Kugelrohr distillation (110–112 °C at 4 mmHg), to yield 528 mg
of the desired free base as a yellow oil (65%). The free base was
dissolved in HCl-saturated ethanol and sonicated for 5 min. Solvent
was removed in vacuo to yield a solid residue that was recrystallized
from 2-propanol to afford the di-HCl salt monohydrate as a brown
(S)-2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane dihydrochloride
(62). By using the procedure described above for compound 60,
compound 62 (123 mg of di-HCl salt, 45%) was synthesized from
1
50 (0.65 g, 4.0 mmol). H NMR (300 MHz, D2O) δ 8.82 (s, 1H),
8.76–8.78 (d, J ) 6.0 Hz, 1H), 8.60–8.63 (d, J ) 9.0 Hz, 1H),
7.96–8.00 (t, J ) 6.0 Hz, 1H), 4.80–4.84 (d, J ) 12.0 Hz, 1H),
3.40–3.80 (m, 2H), 3.20–3.40 (m, 1H), 3.10–3.23 (m, 1H),
2.20–2.50 (m, 2H), 1.92–2.26 (m, 6H), 1.74–1.88 (m, 1H); mp
258–260 °C; [R]25 -4.0 (c 1.0, MeOH). Anal. Calcd for
D
C13H18N2.2HCl: C, 56.25; H, 7.27; N, 10.18. Found: C, 53.53; H,
7.02; N, 9.69. (Consistent with 1 mol equiv of water.) The following
conditions were used to determine enatiomeric purity: Chiralpack
AD 0.46 × 25 cm column, 85% hexane, 15% EtOH, flow rate 1.0
mL/min, 210–400 nm detector wavelength; retention time t60
7.4, t62 ) 8.4 min, ratio (0.3:99.7), ee 99.4%.
)
(R)-2-(5-Bromopyridin-3-yl)-1-azabicyclo[2.2.2]octane dihydro-
bromide (63). By using the procedure described above for compound
60, compound 63 (43 mg of di-HBr salt, 80%) was synthesized from
51 (50 mg, 0.17 mmol). 1H NMR (300 MHz, D2O) δ 8.75 (d, J ) 1.8
Hz, 1H), 8.67 (d, J ) 1.8 Hz, 1H), 8.44–8.42 (t, J ) 1.8 Hz, 1H),
4.84–4.78 (t, J ) 6.8 Hz, 1H), 3.62–3.51 (m, 1H), 3.40–3.24 (m, 1H),
3.20–3.10 (m, 2H), 2.30–2.11, (m, 3H), 2.00–1.79 (m, 4H); mp
1
crystalline solid (mp 258–260 °C). H NMR (300 MHz, D2O) δ
8.82 (s, 1H), 8.76–8.78 (d, J ) 6 Hz, 1H), 8.60–8.63 (d, J ) 9 Hz,
1H), 7.96–8.00 (t, J ) 12 Hz, 1H), 4.80–4.84 (d, J ) 12 Hz, 1H),
3.40–3.80 (m, 2H), 3.20–3.40 (m, 1H), 3.10–3.23 (m, 1H),
2.20–2.50 (m, 2H), 1.92–2.26 (m, 6H), 1.74–1.88 (m, 1H); 13C
NMR (75 MHz, d6-DMSO) δ 169.4, 147.3, 136.1, 132.4, 124.5,
67.2, 49.1, 41.7, 31.8, 25.2, 24.1, 23.8, 20.1; GC-MS M+ 202. Mp
196–201 °C; [R]25 + 39.0 (c 1.02, MeOH). Anal. Calcd for
D
211–215 °C; [R]25 + 4.0 (c 1.0, MeOH). Anal. Calcd for
C12H15N2Br ·2HBr: C, 33.60; H, 3.99; N, 6.53; Br, 55.88. Found: C,
33.82; H, 4.07; N, 6.48; Br, 55.71.
D
C13H18N2 ·2HCl: C, 56.25; H, 7.27; N, 10.18. Found: C, 53.63; H,
7.12; N, 9.59. (Consistent with 1 mol equiv of water.) The following
conditions were used to determine enatiomeric purity: Chiralpack
AD 0.46 × 25 cm column, 85% hexane, 15% EtOH, flow rate 1.0
mL/min, 210–400 nm detector wavelength, tetention time t60 ) 7.4
min. There was no detectable compound 62.
(R)-2-(5-Bromopyridin-3-yl)quinuclidine (63) (free-base). 1H
NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.54 (s, 1H), 7.93–7.92
(d, J ) 0.9 Hz, 1H), 4.04–3.98 (t, J ) 9.0 Hz 1H), 3.19–2.98 (m,
2H), 2.81–2.70 (m, 2H), 1.99–1.90 (m, 1H), 1.71–1.39 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 148.1, 147.0, 140.9, 137.6, 120.7,
55.9, 49.3, 42.0, 32.4, 26.6, 25.8, 21.7; [R]25 +49.8 (c -1.27,
(R)-2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane Dihydrochloride
(59). By using the procedure described above for compound 60,
compound 59 (223 mg of di-HCl salt, 88%) was synthesized from
D
CHCl3). Anal. Calcd for C12H15N2Br·2HBr: C, 33.60; H, 3.99; N,
6.53; Br, 55.88. Found: C, 33.58; H, 4.05; N, 6.47; Br, 55.93. The
following conditions were used to determine enatiomeric purity:
Chiralpack AD 0.46 × 25 cm column, 85% hexane, 15% EtOH,
flow rate 1.0 mL/min, 210–400 nm detector wavelength; retention
times t63 ) 11.0 min. There was no detectable compound 64.
(S)-2-(5-Bromopyridin-3-yl)-1-azabicyclo[2.2.2]octane dihydro-
bromide (64). By using the procedure described above for com-
pound 60, compound 64 (58 mg, 85%) was synthesized from 52
1
compound 47 (0.20 g, 0.97 mmol). H NMR (300 MHz, D2O) δ
9.00 (s, 1H), 8.80–8.83 (d, J ) 9 Hz, 1H), 8.60–8.84 (m, 1H),
7.88–8.24 (m, 1H), 4.98–5.06 (t, J ) 18 Hz, 1H), 3.68–3.80 (m,
1H), 3.45–3.52 (m, 2H), 3.15–3.23 (m, 1H), 2.30–2.50 (m, 3H),
1.92–2.22 (m, 4H); 13C NMR (75 MHz, D2O) δ 152.8, 152.5, 141.2,
133.1, 127.7, 61.7, 51.7, 44.4, 30.4, 25.2, 24.7, 23.1; mp 211–215
°C; [R]25D + 59.8 (c 0.98, MeOH). Anal. Calcd for C12H16N2.2HCl:
C, 55.17; H, 6.89; N, 10.72. Found: C, 51.07; H, 7.24; N, 9.94.
(Consistent with 1 mol equiv of water.) The following conditions
were used to determine enatiomeric purity: Chiralpack AD 0.46 ×
25 cm column, 85% hexane, 15% EtOH, flow rate 1.0 mL/min,
210–400 nm detector wavelength; retention time t59 ) 7.8. There
1
(65 mg, 0.23 mmol). H NMR, (300 MHz, D2O) δ 8.63 (d, J )
1.8 Hz, 1H), 8.56 (d, J ) 1.8 Hz, 1H), 4.84–4.78 (t, J ) 6.8 Hz,
1H), 3.62–3.51 (m, 1H), 3.40–3.24 (m, 1H), 3.20–3.10 (m, 2H),
2.30–2.11, (m, 3H), 2.00–1.79 (m, 4H); 13C NMR (75 MHz, D2O)
δ 148.7, 147.1, 141.3, 137.5, 120.7, 55.9, 49.4, 42.0, 32.6, 26.7,
3506 J. Org. Chem. Vol. 73, No. 9, 2008

Potent Nicotinic Acetylcholine Receptor–Ligands
25.9, 21.8; mp 207 °C; [R]25D -39.2 (c 1.01, MeOH). Anal. Calcd
for C12H15N2Br·2HBr: C, 33.60; H, 3.99; N, 6.53; Br, 55.88. Found:
C, 33.82; H, 4.07; N, 6.48; Br, 55.71. The following conditions
were used to determine enatiomeric purity: Chiralpack AD 0.46 ×
25 cm column, 85% hexane, 15% EtOH, flow rate 1.0 mL/min,
210–400 nm detector wavelength; retention times t64 ) 18.7 min.
There was no detectable compound 63.
Supporting Information for complete details of the X-ray crystal-
lographic studies.
Supporting Information Available: General information and
experimental procedures for preparation of starting materials;
1H NMR and 13C NMR spectra for all new compounds; X-ray
crystallographic data for 59–62. This material is available free
of charge via the Internet at http://pubs.acs.org.
Solid-State Structure Analysis. Crystals of 59–62 suitable for
X-ray analysis were obtained as previously described. See the
JO800028Q
J. Org. Chem. Vol. 73, No. 9, 2008 3507