Highly enantioselective borane reduction of heteroaryl and heterocyclic ketoxime ethers catalyzed by novel spiroborate ester derived from diphenylvalinol: Application to the synthesis of nicotine analogues

Article abstract of DOI:10.1021/jo800204n

(Chemical Equation Presented) An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from (S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10°C. (S)-N-ethylnornicotine (3) was also successfully synthesized from the TIPS-protected (S)-2-amino-2-pyridylethanol in 97% ee.

Full text of DOI:10.1021/jo800204n

Highly Enantioselective Borane Reduction of Heteroaryl and
Heterocyclic Ketoxime Ethers Catalyzed by Novel Spiroborate Ester
Derived from Diphenylvalinol: Application to the Synthesis of
Nicotine Analogues
Kun Huang, Francisco G. Merced, Margarita Ortiz-Marciales,* Héctor J. Meléndez,
Wildeliz Correa, and Melvin De Jesús
Department of Chemistry, UniVersity of Puerto Rico—Humacao, CUH Station,
Humacao, Puerto Rico 00791
margarita.ortiz1@upr.edu
ReceiVed January 26, 2008
An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic
rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded
by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived
from (S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The
optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers
was achieved using 30% of catalytic loading in dioxane at 10 °C. (S)-N-ethylnornicotine (3) was also
successfully synthesized from the TIPS-protected (S)-2-amino-2-pyridylethanol in 97% ee.
Introduction
Nicotinic acetylcholine receptors (nAChRs) are a group of
ligand-gated ion channel receptors that play a vital role in
different biological processes, in particular, those related to the
electrical transmission at the neuromuscular junction and central
nervous system (CNS) functions.1–6 Several studies have
demonstrated that (S)-nicotine (2 in Figure 1) and analogues
* To whom correspondence should be addressed. Tel.: 787-852-3222. Fax:
787-850-9422.
(1) (a) Sine, S. M. Neurobiology 2002, 53, 431–446. (b) Tonder, J. E.; Olesen,
P. H. Curr. Med. Chem. 2001, 8, 651. (c) Jensen, A. A.; Frolund, B.; Liljefors,
T.; Krogsgaard-Larsen, P. J. Med. Chem. 2005, 48, 4705.
(2) (a) Lloyd, G. K.; Williams, M. J. Pharm. Exp. Ther. 2000, 292, 461. (b)
Cosford, N. D. P.; Blecher, L.; Herbaut, A.; Mccallum, J. S.; Venier, 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, S. I.; Santori,
E.; Stauderman, K. A.; Whelan, K.; McDonald, I. A. J. Med. Chem. 1996, 39,
3235. (c) Galzi, J. L.; Changeux, J. P. Neuropharmacology 1995, 34, 563.
FIGURE 1. Nicotine and analogues.
display potent biological activity in mammals by modulation
of nAChRs2 which, in addition, regulate the release of other
important neurotransmitters, such as catecholamines (dopamine,
10.1021/jo800204n CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4017–4026 4017

Huang et al.
norepinephrine), glutamate, γ-aminobutyric acid (GABA), and
serotonin (5-hydroxytriptamine). In the past decade, intense
research efforts in the area of neurobiology and pharmacology
of nicotine and related nAChR agonists and antagonists have
led to exciting developments in drug discovery for the treatment
of Parkinson’s and Alzheimer’s (AD) diseases, schizophrenia,
attention deficit/hyperactivity, and Tourette’s syndrome.3,4 Ago-
nist SIB-1508Y (5) and ABT-418 (6), as well as other potentially
active drugs, are presently in clinical trial for AD and Parkin-
son’s diseases.5 Several nicotine-derived drug candidates are
also being developed for the treatment of nicotine addition, as
analgesic and anesthetic agents.1c,6 Novel competitive antagonist
N-n-nicotinium analogues (7) have been, recently, found to
possess selective binding to nAChR subtypes depending on the
lipophilicity of the alkyl groups, opening a new area of selective
antagonists.7 Moreover, (S)-nicotine has been, recently, dem-
onstrated to inhibit amyloid formation by ꢀ-peptides.5a,8 Con-
sequently, new nonaddictive nicotine analogues that can prevent
or retard the development of Alzheimer’s disease will be of
interest in the future. (S)-Nicotine is more bioactive than the
(R) enantiomer,9 as it is also observed for related alkaloid
compounds. Surprisingly, appropriate methods for the enanti-
oselective synthesis of nicotinic derivatives are scarce,3e,f and
usually, the desired enantiomer is obtained by costly resolution
methods.2a Hence, convenient and versatile asymmetric synthetic
methods that permit the introduction of a chiral pyrrolidine-
based ring skeleton, offering diverse structural features in the
design of new enantiopure nicotinic compound, are needed.
In general, enantioenriched compounds with a stereogenic
carbon center R to the amino group are being extensively used
as key intermediaries in the synthesis of a large variety of
pharmaceuticals,10 chiral auxiliaries,11 catalysts,12 and resolving
agents.13 Accordingly, the development of facile and efficient
synthetic strategies that provide highly enantiopure amines at
low cost has received, recently, an increasing amount of
attention.14 Organoborane reagents, especially oxazaborolidine-
borane complexes, have achieved wide recognition for the
asymmetric reduction of ketones due to their outstanding
enantioselectivity, predictable absolute stereochemistry, and low
environmental impact.12 Noteworthy, the use of these chiral
boron-based reagents for the CdN reduction under catalytic
conditions remains limited due to their relatively modest
enantioselectivity and lack of reproducibility in some cases.12–17
Although the asymmetric reduction of oxime ethers with borane-
based catalysts offers a facile and direct approach to obtain
enantioenriched primary amines, more than an stoichiometric
amount of in situ prepared oxazaborolidine has been employed
to obtain a high degree of enantioselectivity.12,14–17 Itsuno et
al.16 described the first catalytic reduction of acetophenone
O-benzyl oxime using the B-H oxazaborolidine-borane com-
plex prepared in situ by the reaction of 10 mol % of (S)-
diphenylvalinol with 1 equiv of borane, achieving only 52% ee
of (S)-1-phenylethanamine. Fontaine et al.17c used 2.5 equiv of
diphenylvalinol-B-H oxazaborolidine for the reduction of
arylalkyl ketoxime O-benzyl ethers, achieving excellent enan-
tioselectivity and good yield. When the amount of diphenylvali-
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4018 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of Nicotine Analogues
TABLE 1. Catalyzed Asymmetric Reduction of Acetophenone
O-Substituted Oxime Ethers
yield (%)a b
ee (%)c
,
entry
oxime
R
1
2
3
4
5
a
b
c
d
e
Me
Bn
4-MeOBn
4-CF3Bn
2-NO2Bn
85
77
70
60
95
95
97
97
99
97
FIGURE 2. Spiroborate esters derived from nonracemic amino alcohols
and ethylene glycol.
a Borane was stabilized with <0.005
M N-isopropyl N-methyl
tert-butylamine. b Isolated yield after purification by column
chromatography. c The ee was analyzed using a Crompack Chirasil-Dex-CB
GC column.
nol was lowered to 1 equiv in the reduction of p-fluoro-2-
cyclopropylacetophenone O-benzyl oxime, the yield of the
corresponding amine decreased to 52%. In addition, previous
reports in the literature have demonstrated that the in situ
prepared B-H oxazaborolidines present unusual side products
that can affect the enantioselectivity of the catalyst.18 Recently,
stable spiroborate esters, derived from (R)- or (S)-1,1′-bi-2-
naphthol and (S)-proline, were employed as chirality transfer
agents in the borane-mediated reduction of arylalkyl ketoxime
ethers.17e Nevertheless, 1 equiv of the expensive chiral reagents
was necessary to achieve a high degree of stereoselectivity.
We recently disclosed a series of air- and moisture-stable
crystalline spiroborate esters, derived from nonracemic 1,2-
amino alcohols and ethylene glycol, for the enantioselective
reduction of ketones that were fully characterized by optical
and spectroscopic methods.19 Catalysts 8-12 (Figure 2) provide
a high degree of enantioselectivity in the borane-DMS reduc-
tion of aromatic and aliphatic prochiral ketones, at room
temperature, in less than 1 h.19b In a related study, enantiopure
alcohols containing pyridyl and other heterocyclic fragments
were obtained with an excellent yield in up to 99% ee using, in
some cases, only 1 mol % of catalyst 12.19c
A preliminary study of catalysts 8-12 (Figure 2) in the
borane-mediated reduction of aryl ketoximes as catalytic systems
for the synthesis of enantiopure primary amines was recently
reported.20 After several optimization studies using different
equivalents of borane and borane sources, in addition to a variety
of solvents and different temperatures, the asymmetric reduction
of (E)-acetophenone O-benzyl oxime ether was accomplished,
with only 10 mol % of catalyst 10 and 4 equiv of borane-THF
in dioxane at 0 °C, affording R-methylbenzylamine with an
excellent yield and 97% ee. After screening the catalysts
presented in Figure 2, it was observed that the reactivity of
catalysts 8, 9, and 11 was rather low at 0 °C. At room
temperature, complete reduction was achieved with catalysts 8
and 9 but provided only 59 and 65% ee, respectively, while
catalyst 11 derived from 1-amino-2-indanol afforded the (R)-
benzylamine enantiomer in 88% ee. Interestingly, 10% of
spiroborate 12 derived from diphenylprolinol offers outstanding
enantioselectivity for acetophenone reduction, affording the
1-phenylethanol in 99% ee, while it provides modest enanti-
oselectivity (77% ee) for the reduction of its corresponding
benzyl oxime ether to the primary amine. Substituents at the
ketoxime oxygen play a key role in the reduction stereoselec-
tivity, as illustrated in Table 1. The (E)-acetophenone O-4-
(trifluoromethy)benzyl oxime imparts outstanding enantiose-
lectivity (99% ee), although with a modest yield (entry 4).
Excellent enantioselectivity and good chemical yield (entry 5)
were achieved for the 2-nitrobenzyl oxime. Unfortunately, N-2-
nitrobenzyl diphenylvalinol was also isolated from the reaction
mixture, possibly formed by the reaction of the 2-nitrobenzylic
borate intermediate with the amino group, destroying the
expensive amino alcohol. Consequently, benzylic oximes were
selected as more adequate substrates since they can also provide
excellent enantioselectivity (entry 2) and their synthesis affords
pure products using the less expensive benzyl bromide. Besides,
the diphenylvalinol can be recovered almost quantitatively after
the reduction process. Other representative aromatic and cyclic
O-benzyl oximes were prepared and reduced, giving excellent
enantioselectivities (up to 99% ee) and demonstrating the
capability of our developed spiroborate-borane method for an
effective asymmetric catalytic reduction of oxime ethers.
(18) (a) Stepanenko, V.; Ortiz-Marciales, M.; Barnes, C. E.; Garcia, C.
Tetrahedron Lett. 2006, 47, 7603. (b) Ortiz-Marciales, M.; De Jesus, M.;
Gonzales, E.; Raptis, R. G.; Baran, P. Acta Crystallogr. 2004, C60, 173. (c)
Lang, A.; Noth, H.; Schmidt, M. Chem. Ber. 1997, 130, 241. (d) Mathre, D. J.;
Thompson, A. S.; Douglas, A. W.; Carroll, J. D.; Corley, E. G.; Grabowski,
E. J. J. J. Org. Chem. 1993, 58, 2880. (e) Tlahuext, H.; Santiesteban, F.; García-
Báez, E.; Contreras, R. Tetrahedron: Asymmetry 1994, 5, 1579. (f) Santiesteban,
F.; Mancilla, T.; Klaébe, A.; Contreras, R. Tetrahedron Lett. 1983, 24, 759. (g)
Brown, J. M.; Guy, C.; Lloyd-Jones, G. C.; Layzell, T. P. Tetrahedron:
Asymmetry 1993, 4, 2151.
As mentioned previously, asymmetric synthesis of nonracemic
amines with heterocyclic and heteroaromatic fragments is a key
step in the preparation of many biological active compounds.
Optically active pyridine-derived amines have attracted a strong
interest,1–9 primarily, due to their existence in naturally occurring
compounds, such as tobacco alkaloids,3a or as potential drug
candidates.4 To our knowledge, there is a lack of direct methods
for the enantioselective synthesis of these compounds. Herein,
we describe the first catalytic asymmetric reduction of pyridyl
alkyl and heterocyclic O-benzyl oxime ethers to obtain amino
derivatives with a high degree of enantiopurity and good yield
using a simple and convenient process and a further application
of the method to the stereoselective synthesis of N-ethylnorni-
cotine.
(19) (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De-Jesús, M.;
Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry 2006, 17, 112–115. (b) Ortiz-
Marciales, M.; Stepanenko, V.; Correa, W.; De Jesús, M.; Espinosa, S. U.S.
Patent Application 11/512,599, Aug 30, 2006. (c) Stepanenko, V.; Ortiz-
Marciales, M.; De Jesús, M.; Correa, W.; Vázquez, C.; Ortiz, L.; Guzmán, I.;
De la Cruz, W. Tetrahedron: Asymmetry 2007, 18, 2738.
(20) (a) Huang, X.; Ortiz-Marciales, M.; Huang, K.; Stepanenko, V.; Merced,
F. G.; Ayala, A. M.; De Jesús, M. Org. Lett. 2007, 9, 1793. (b) Ortiz-Marciales,
M.; Huang, X.; Huang, K.; Stepanenko, V.; De Jesús, M.; Merced, F. G. PCT/
US07/76195 Aug 17, 2007.
J. Org. Chem. Vol. 73, No. 11, 2008 4019

Huang et al.
SCHEME 1. Stereoselectivity in the Borane Reduction of
Oxime Ethers with (S)-Norephedrine
thiochroman-4-amine (entry 5), and with good to high yields
of the isolated pure amides.
Pyridyl Ethanone O-Benzyl Oximes Reduction. Initially,
the reduction of (E)-1-(3-pyridyl)ethanone O-benzyl oxime (16a)
in THF with 0.1 mol % of catalyst 10 and 5 equiv of BH3 ·THF
for 72 h at 0 °C was carried out according to our previously
developed protocol.20 One equivalent of borane was required
for the boron coordination to the pyridyl nitrogen. The extraction
of (S)-1-(3-pyridyl)ethylamine (21a) in ether was unsuccessful,
due to the high solubility of the amine in water, and hence the
workup procedure was modified. The reaction was first quenched
with methanol at 0 °C and then refluxed overnight to hydrolyze
the boron amino complex. The desired product 21a was obtained
by a simple solvent removal under vacuum and purification by
column chromatography. However, the amine’s chemical yield
and optical purity were assessed from the acetylated derivative
due to the amides’ stability and facile resolution by GC. Initially,
the corresponding amide (22a) was obtained in 92% ee, but
the isolated yield was low (entry 1, Table 3). This result
encouraged us to further optimize the reaction conditions to
improve both the enantioselectivity and chemical yield. Dioxane
was the best solvent, although THF and t-butyl methyl ether
afforded also good selectivity (entries 1–4). By increasing the
amount of catalyst to 0.3 equiv and the temperature at 10 °C in
dioxane, the reaction time decreased and, fortunately, the amine
22a was obtained with 75% yield and 98% ee (entry 6). Under
similar conditions, the reduction of the 1-(4-pyridyl)ethanone
O-benzyl oxime (18a) gave excellent enantioselectivity (99%
ee), with 84% yield of amine 24a (entry 10). A larger catalytic
load did not improve the enantioselectivity or the chemical yield
(entry 11).
Results and Discussion
It is well-known that the enantioselectivity in the reduction
of CdN bonds depends not only on the chirality’s transfer agent
but also on the E/Z isomeric purity.14,15 In a comparative study,
Sakito and co-worker15i studied the borane-mediated reduction
of E and Z aromatic and aliphatic ketoxime ethers in the
presence of (-)-norephedrine, demonstrating that each geometric
isomer affords the chiral amine with the opposite absolute
configuration (Scheme 1). Since (E)-ketoximes are easier to
purify by crystallization or column chromatography than their
benzylated ethers, our first aim was to prepare pure (E)-oximes.
Most ketoximes were initially prepared using Na2CO3 in EtOH/
water at 60–70 °C (method A), affording, mainly, the E isomer
(>99%). However, in the case of certain pyridyl ketoximes, a
significant amount of the Z isomer was observed, about 25%
for oxime of compound 19 (Scheme 2), possibly formed by
E/Z isomerization under the heating conditions. To obtain
enriched (E)-pyridyl ketoxime isomers, pyridine was used as
base at room temperature, attaining high yields of the product
(90% for oxime of 19) in a relative short time (3 h) (method
B).21 These oximes were carefully purified by recrystallization
or column chromatography to obtain only the E isomer.
Excellent yields of the desired (E)-oxime benzyl ethers
(Scheme 2) were obtained after oxime treatment with NaH and
benzyl bromide at low temperature (0 °C) and purified by
column chromatography on silica. We have observed that some
benzylic oximes isomerize or decompose under vacuum distil-
lation at temperatures over 150 °C.22,23 Oxime and benzyl oxime
isomeric purity was carefully assessed by TLC, NMR, and GC/
MS analysis.
(E)-Heteroaryl and Heterocyclic O-Benzyl Oxime Reduc-
tion. The heteroaryl and heterocyclic benzyl oximes (15a-f,
Table 2) were reduced at 0 °C with 0.1 equiv of catalyst 10
and 4 equiv of borane in dioxane until the conversion was
completed. After an acidic work up, the corresponding (S)
primary amines were acetylated with acetic anhydride in the
presence of triethylamine and DMAP in dichloromethane. All
of the products (20a-f) were purified by column chromatog-
raphy, and the enantiomeric excess was determined by GC with
a Crompack Chirasil-Dex-CB column, using the optimal condi-
tion established with the racemic amide derivative. The enan-
tioselectivity of the reactions was excellent, up to 99% ee for
Our attention was directed to the synthesis of 2-pyridylalky-
lamine. Initially, 1-(2-pyridyl)ethanone O-benzyl oxime was
reduced in the presence of 10 mol % of catalyst and THF as
solvent, with 5 equiv of BH3 ·THF, but the reaction provided a
low enantioselectivity (entry 1, Table 4), due to the uncatalyzed
reaction that takes place by hydrogen transfer from the borane
coordinated to the pyridine nitrogen (Scheme 3). Increasing the
amount of borane and catalyst produced modest results. In the
presence of 1.0 equiv of catalyst and 4.0 equiv of borane-THF
in dioxane at 10 °C, compound 27 was achieved in 73% ee and
79% yield. Attempts to protect the pyridine nitrogen with BEt3
provided unsatisfactory results (entry 6), and protection with
BF3 afforded only 54% ee, although the yield increased to 73%
(entry 7).
Under optimized conditions, a variety of other pyridylalkyl
and pyridylphenyl O-benzyl oxime ethers were tested to
investigate the generality of the reaction. The asymmetric
reduction of 16–19 was conducted with 30 mol % of catalyst
and 5 equiv of borane in dioxane at 10 °C for 2 days. As
illustrated in Table 5, excellent enantioselectivities (95–99% ee)
were obtained with good to excellent yields of isolated pure
products by column chromatography. The enantiomeric excess
values of the amine or their acetylated derivatives were
determined by GC or HPLC analysis, using suitable chiral
stationary phases. The (S)-cyclopropyl 3- and 4-pyridyl meth-
anamines (entries 4 and 8) were afforded in 96 and 98% ee,
respectively. Noteworthy, the reduction of the 3-pyridyl phenyl
oxime ether provided the (S)-amine 31 (entry 5) in excellent
enantiopurity (95% ee), with the pyridine ring being the larger
group and the phenyl the smaller group in the face selectivity.
In addition, both E and Z isomers of cyclopropyl-4-pyridyl
(21) Benjahad, A.; Croisy, M.; Monneret, C.; Bisagni, E.; Mabire, D.; Coupa,
S.; Poncelet, A.; Csoka, I.; Guillemont, J.; Meyer, C.; Andries, K.; Pauwels, R.;
de Be´thune, M. P.; Himmel, D. M.; Das, K.; Arnold, E.; Nguyen, C. H.; David,
S.; Grierson, D. S. J. Med. Chem. 2005, 48, 1948.
(22) Purification of oxime benzyl ethers by vacuum distillation should be
avoided since they isomerize and decompose under heating by a reverse radical
disproportionation.23
(23) Blake, J. A.; Ingold, K. U.; Lin, S.; Mulder, P.; Pratt, D. A.; Sheeller,
B.; Walton, J. C. Org. Biomol. Chem. 2004, 2, 415.
4020 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of Nicotine Analogues
SCHEME 2. Synthesis of (E)-O-Benzyl Ketoxime Ethers
O-benzylketoxime (18c) were separated by chromatography on
a silica column and reduced by our established protocol. The E
isomer produced the (S)-amine in 98% ee (entry 8); however,
the minor Z isomer afforded the (R)-amine in only 71% ee.
To demonstrate the capability of our methodology for the
synthesis of (S)-nicotine analogues, we decided to prepare (S)-
N-ethylnornicotine (3) for its biological activity as a potential
selective nAChR agonist. Initially, an attempt was made to
synthesize racemic nornicotine (4) from amine 35 by first
removing the protecting TIPS group using TBAF in THF at 0
°C to obtain the amino alcohol 36, followed by an intramolecular
Mitsunobu24 reaction, as indicated in Scheme 4. However, the
cyclization step gave a complex mixture of products. As an
alternative, (S)-N-ethylnornicotine (3) was successfully prepared
from compound (S)-34, previously synthesized in 95% ee
(HPLC analysis). The amino alcohol (S)-37 was afforded in 89%
yield, after deprotection with TBAF in THF at 0 °C and
subsequent reduction with borane providing N-ethylamine 38
in 86% yield. The desired pyrrolidine derivative 3 was furnished
in 84% yield after a successful intramolecular cyclization of
(S)-38 with Ph3P/DIAD.25 In summary, the synthesis of (S)-N-
ethylnornicotine was achieved with excellent enantiopurity (97%
ee determined by GC) and 64% overall yield. This approach
opens the door to the highly enantioselective synthesis of other
important biological targets in a facile and efficient way.
heterocyclic and heteroaryl rings with a high degree of enan-
tioselectivity with only 10% of spiroborate 10 was developed.
After several optimization studies, the first borane reduction of
a variety of pyridyl benzyl oximes afforded enantiopure amines
in up to 99% ee, using 30% of 10 at 10 °C. The (S)-nicotine
analogue 3 was prepared in 97% ee from enantiopure 34 with
64% overall yield. Considering the convenience and generality
of the method and the abundance of natural products that contain
the heterocyclic amine functionality, this method should find
wide interest in both academic research and industry.
Experimental Section
19
Catalyst, (R)-2-amino-1,1,2-triphenylethanol,26 (S)-2-amino-
1,1,2-triphenylethanol, 26 (S)-2-amino-3-methyl-1,1-diphenylbutan-
1-ol,27 cyclopropylpyridin-3yl methanone,28 cyclopropylpyridin-
4yl methanone,28 and 4-hydroxy-1-pyridin-3-yl butan-1-one29 were
synthesized according to literature procedures. BH3 ·THF (1 M
solution in THF, stabilized with <0.005 M NaBH4) and other
starting materials and chemical reagents were purchased and used
without purification unless otherwise noted.
General Procedure for the Preparation of O-Benzyl Oximes:
To a suspension of NaH (1.1 equiv) in DMF was added dropwise a
(26) (a) Lawrence, S. A. In Amines: Synthesis, Properties and Applications;
Cambridge University Press: Cambridge, U.K., 2004. (b) Breuer, M.; Ditrich,
K.; Habicher, T.; Hauer, B.; Keâeler, M.; Sturmer, R.; Zelinski, T. Angew. Chem.,
Int. Ed. 2004, 43, 788. (c) Hieber, G.; Ditrich, K. Chim. Oggi 2001, 19, 16. (d)
Franchini, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M. M.; Corbo, F.; Lentini,
G.; Scilimati, A.; Tortorella, P.; Camerino, D. C.; Luca, A. J. Med. Chem. 2003,
46, 5238. (e) Abreo, M. A.; Lin, N. H.; Garvey, D. S.; Gunn, D. E.; Hettinger,
A. M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y. C.; Donnelly-Roberts, D. L.;
Anderson, D. J.; Sullivan, J. P.; Stephen, M. W.; Arneric, S. P.; Holladay, M. W.
J. Med. Chem. 1996, 39, 817.
Conclusion
We have investigated the effect of heteroaryl and heterocyclic
groups in the asymmetric borane reduction of O-benzyl oxime
ethers with the novel spiroborate 10 derived from diphenylvali-
nol and ethylene glycol as catalyst. A true catalytic and practical
synthesis of a variety of chiral primary amines containing
(27) (a) Henderson, K. W. Chem. Commun. 2000, 479. (b) Denolf, B.;
Mangelinckx, S.; Tornroos, K. W.; Kimpe, N. D. Org. Lett. 2006, 8, 3129. (c)
Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2007, 72, 626.
(28) Edwards, William, B. J. Heterocycl. Chem. 1975, 12, 413.
(24) Mitsunobu, O. Synthesis 1981, 1.
(29) Ohkawa, S.; Terao, J. S.; Terashita, Z. I.; Shibouta, Y.; Nishikawat, K.
J. Med. Chem. 1991, 34, 267.
(25) Bernotas, R. C.; Cube, R. V. Tetrahedron Lett. 1991, 32, 161.
J. Org. Chem. Vol. 73, No. 11, 2008 4021

Huang et al.
TABLE 2. Asymmetric Reduction of (E)-Heteroaryl and Heterocyclic O-Benzyl Oximes
a The reactions were carried out using 4 equiv of borane stabilized with NaBH4. b Isolated yield of amides purified by column chromatography.
c Determined by GC of acetyl derivatives on chiral column (CP-Chirasil-Dex-CB).
solution of hydroxyl oxime (1.0 equiv) and maintaining the
temperature at 0 °C. After the addition, the reaction mixture was
stirred for 1 h. Then, BnBr (1.05 equiv) in DMF was added
dropwise at 0 °C. The resulting mixture was stirred overnight at rt
and then quenched with saturated aqueous NH4Cl solution and
extracted with ether. The organic phases were combined and dried
over anhydrous Na2SO4. The solvents were evaporated under
vacuum, and the residue was purified by flash silica gel column
chromatography.
734, 755; GC-MS m/z 231.0 (M+). Anal. Calcd for C13H13NOS:
C, 67.50; H, 5.66; N, 6.06. Found: C, 67.67; H, 5.71; N, 6.17.
(E)-1-(2,5-Dimethylthiophen-3-yl)ethanone O-Benzyl Oxime
(15b). Purified by column chromatography on silica gel/hexane:
AcOEt (30:1) as a colorless oil; yield 92% (2.10 g); 1H NMR (400
MHz, CDCl3) δ 2.24 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 5.24 (s,
2H), 6.72 (s, 1H), 7.3–7.5 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3) δ 15.0, 15.1, 15.2, 75.9, 125.5, 127.7, 128.1, 128.3, 133.3,
135.4, 135.8, 138.5, 153.0 ppm; IR ν (cm-1) 3031, 2919, 2857,
1604, 1496, 1454, 1364, 1266, 1208, 1181, 1143, 1081, 1048, 1012,
985, 924, 882, 833, 733, 696; GC-MS m/z 259.0 (M+). Anal. Calcd
for C15H17NOS: C, 69.46; H, 6.61; N, 5.40. Found: C, 69.71; H,
6.66; N, 5.41.
(E)-1-(Thiophen-3-yl)ethanone O-Benzyl Oxime (15a). Purified
by column chromatography on silica gel/hexane: AcOEt (30:1) as
1
a colorless oil; 94% (6.1 g); H NMR (400 MHz, CDCl3) δ 2.30
(s, 3H), 5.27 (s, 2H), 7.3–7.5 (m, 8H) ppm; 13C NMR (100 MHz,
CDCl3) δ 13.2, 76.7, 123.4, 125.4, 126.1, 127.8, 128.2, 128.4, 138.2,
139.0, 151.3 ppm; IR ν (cm-1) 3031, 2922, 1601, 1454, 1363, 1015,
(E)-6-Chlorochroman-4-one O-Benzyl Oxime (15d). Purified
by column chromatography on silica gel/hexane: AcOEt (9:1) as
4022 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of Nicotine Analogues
TABLE 3. Optimization Studies for the Asymmetric Reduction of
Pyridyl Ethanone O-Benzyl Oximes
TABLE 5. Asymmetric Reduction of Representative Pyridyl
O-Benzyl Oxime Ethers
benzyl cat 10
entry oxime (equiv) T (°C)
yield
ee
solvent
THF
time (h) (%)a (%)b
1
2
3
4
5
6
7
8
16a
16a
16a
16a
16a
16a
18a
18a
18a
18a
18a
0.1
0.1
0.1
0.1
0.3
0.3
0.1
0.2
0.1
0.3
0.5
0
25
0
0
0
10
0
10
25
10
10
72
48
72
72
72
48
72
72
48
48
48
46
53
42
38
50
75
38
64
63
84
79
92
89
93
98
99
98
99
94
90
99
98
THF
t-BuOMe
dioxane
dioxane
dioxane
THF
dioxane
THF
dioxane
dioxane
9
10
11
a The reactions were carried out using 5 equiv of borane stabilized
with NaBH4. Isolated yield of amides by column chromatography.
b Determined by GC of acetyl derivatives on
(CP-Chirasil-Dex-CB).
a chiral column
TABLE 4. Asymmetric Reduction of 25 under Different Reaction
Conditions
cat 10 BH3-THF
T
isolated
ee
entry (equiv) (equiv)a (°C) solvent time (h) yield (%)b (%)c
1
2
3
4
5
6
7
0.1
1.0
1.0
1.0
1.0
0.3
1.0
5.0
5.0
2.0
3.0
4.0
5.0
2.0
0
0
THF
THF
72
96
72
48
48
72
48
50
46
57
71
79
34
73
8
13
60
57
73
10 dioxane
10 dioxane
10 dioxane
10 dioxane
10 dioxane
4d
54e
a Stabilized with NaBH4. b Isolated yield of amide. c Determined by
GC of acetyl derivatives on a chiral column (CP-Chirasil-Dex-CB).
d Triethyl borane (1.0 equiv) was added. e BF3 (1.0 equiv) was added.
a The reactions were carried out using 1 equiv of oxime ether, 0.3
equiv of catalyst 10 and 5 equiv of borane stabilized with NaBH4 in
dioxane at 10 °C until 100% amine conversion. b Isolated yield of
products after column chromatography. c Determined by GC of acetyl
derivatives on a chiral column (CP-Chirasil-Dex-CB). d Determined by
chiral HPLC (Chiralcel OD-H column). e Determined by chiral HPLC
(Chiralcel IB column).
SCHEME 3. Intramolecular Uncatalyzed Reduction of 25
1
oil with a slight yellow color; yield 84% (1.89 g); H NMR (400
an oil with a slight yellow color; yield: 84% (1.62 g);1H NMR
(400 MHz, CDCl3) δ 2.98 (t, 2H, J ) 6.0 Hz), 4.24 (t, 2H, J ) 6.0
Hz), 5.29 (s, 2H), 6.9 (m, 1H), 7.39 (m, 1H), 7.43 (m, 5H), 7.92
(s, 1H) ppm; 13C NMR (CDCl3) δ 24.0, 65.1, 76.7, 119.1, 119.8,
123.8, 126.6, 128.0, 128.2, 128.4, 130.7, 137.6, 147.7, 155.1 ppm;
IR ν (cm-1) 3031, 2928, 1618, 1475, 1452, 1425, 1364, 1284, 1250,
1216, 1094, 1068, 1039, 1014, 962, 814, 732; GC/MS m/z 287.0
(M+), 91.1 (PhCH2+). Anal. Calcd for C16H14ClNO2: C, 66.79; H,
4.90; N, 4.87. Found: C, 67.03; H, 4.89; N, 4.85.
MHz, CDCl3) δ 2.99 (t, 2H, J ) 6.0 Hz), 3.21 (t, 2H, J ) 6.0 Hz),
5.32 (s, 2H), 7.2 (m, 1H), 7.3 (m, 2H), 7.44 (m, 5H), 8.0 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 26.0, 26.9, 76.6, 25.4, 126.2,
127.9, 128.2, 128.3 128.4, 129.1, 129.8, 135.9, 137.9, 152.3 ppm;
IR ν (cm-1) 3059, 2921, 1598, 1495, 1468, 1433, 1364, 1330, 1286,
1245, 1208, 1007, 931, 907, 751, 695; GC/MS m/z 269.0 (M+),
91.1 (PhCH2+). Anal. Calcd for C16H15NOS: C, 71.34; H, 5.61; N,
5.21. Found: C, 71.45; H, 5.66; N, 5.30.
(E)-6-Chlorothiochroman-4-one O-Benzyl Oxime (15f). Puri-
fied by column chromatography on silica gel/hexane: AcOEt (9:1)
as an oil with a slight yellow color; yield 82% (2.82 g);1H NMR
(E)-Thiochroman-4-one O-Benzyl Oxime (15e). Purified by
column chromatography on silica gel/hexane: AcOEt (9:1) as an
J. Org. Chem. Vol. 73, No. 11, 2008 4023

Huang et al.
SCHEME 4. Enantioselective Synthesis of the (S)-Nicotine
Analogue
MS m/z 240.2 (M+). Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71;
N, 11.66. Found: C, 75.21; H, 6.78; N, 11.65.
(E)-Cyclopropyl(pyridine-4-yl)methanone O-Benzyl Oxime
(18cE). Purified by column chromatography on silica gel/hexane:
1
AcOEt (2:1) as a colorless oil; yield 94% (1.32 g); H NMR (400
MHz, CDCl3) δ 0.73 (m, 2H), 1.0 (m, 2H), 2.2 (m, 1H), 5.29 (s,
2H), 7.3–7.5 (m, 7H), 8.6 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 6.1, 9.4, 77.0, 122.5, 127.9, 128.1, 128.4, 137.7, 142.6,
149.8, 158.1 ppm; IR ν (cm-1) 3066, 3031, 2930, 2876, 1588, 1541,
1496, 1454, 1408, 1365, 1210, 1083, 984, 940, 909, 820, 697; GC-
MS m/z 252.2 (M+). Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39;
N, 11.10. Found: C, 76.08; H, 6.40; N, 11.04.
(E)-1-(Pyridine-3-yl)-4-(triisopropylsilyloxy)butan-1-one O-
Benzyl Oxime (19). Purified by column chromatography on silica
gel/hexane: AcOEt (2:1) as a colorless oil; yield 93% (1.98 g); 1H
NMR (400 MHz, CDCl3) δ 1.04–1.14 (m, 21H), 1.85 (m, 2H),
2.93 (m, 2H), 3.77 (t, 2H, J ) 6.4 Hz), 5.29 (s, 2H), 7.3–7.5 (m,
6), 8.02 (m, 1H), 8.63 (m, 1H), 8.96 (d, 1H, J ) 2.0 Hz) ppm; 13
C
NMR (100 MHz, CDCl3) δ 12.0, 18.0, 23.2, 29.7, 62.8, 76.3, 123.2,
127.8, 128.2, 128.4, 131.6, 133.6, 137.9, 147.8, 149.9, 156.5 ppm;
IR ν (cm-1) 3065, 3031, 2928, 2877, 1619, 1475, 1455, 1425, 1283,
1250, 1216, 1095, 1040, 1014, 962, 815, 696. Anal. Calcd for
C25H38N2O2Si: C, 70.38; H, 8.98; N, 6.57. Found: C, 70.11; H,
9.02; N, 6.38.
(400 MHz, CDCl3) δ 2.98 (t, 2H, J ) 6.0 Hz), 3.18 (t, 2H, J ) 6.0
Hz), 5.32 (s, 2H), 7.32 (m, 2H), 7.41 (m, 5H), 8.06 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 25.9, 26.4, 77.0, 125.8, 128.1, 128.2,
128.5, 129.0, 129.4, 131.1, 131.2, 134.2, 137.6, 151.2 ppm; IR ν
(cm-1) 2922, 1573, 1496, 1455, 1394, 1364, 1305, 1240, 1099,
1048, 1009, 940, 889, 796, 725, 695; GC/MS m/z 303.0 (M+), 91.1
(PhCH2+). Anal. Calcd for C16H14ClNOS: C, 63.25; H, 4.64; N,
4.61. Found: C, 63.50; H, 4.66; N, 4.67.
General Procedure for Asymmetric Reduction of Thio-
furanyl and Heterocyclic O-Benzyl Oximes with Spiroborate
10. To a 25 mL two-necked flask under N2 was added catalyst 10
(33 mg, 0.1 mmol). Then, anhydrous dioxane (10 mL) was
introduced, and BH3 ·THF (4 mL, 1 M in THF stabilized with
<0.005 M NaBH4) was added in one portion. The resulting mixture
was stirred at rt for 30 min until a transparent solution was observed.
The solution was cooled at 0 °C, and the benzyl oxime (1 mmol)
in dioxane (5 mL) was added dropwise during 1.5 h by a syringe
pump. The resulting mixture was stirred at 0 °C until the conversion
was completed in about 48 h. Then, the reaction was quenched
with 6 N HCl and then 6 N NaOH until the solution was basic.
It was extracted with ether, and the combined organic phase was
washed with a saturated NaCl solution and dried over anhydrous
Na2SO4. The solvent was removed under vacuum, and the residue
was analyzed by GC for amine conversion and then used directly
to form the acetylated derivatives for GC analysis on a chiral
column. The acetamide derivatives of racemic amines were first
prepared by reduction of the benzyl oximes with borane and used
as standard samples for chiral GC analysis. Generally, the ee was
determined using a Crompack Chirasil-Dex-CB GC column (30 m
× 0.25 mm × 0.25µm), with a He flow at a 1.0 mL/min rate and
an initial temperature of 70 °C for 10 min, followed by a 5 °C/min
ramp until 190 °C, and maintaining this temperature for about 25
min, depending on the particular compound.
(E)-1-(Pyridine-3-yl)propan-1-one O-Benzyl Oxime (16b). Pu-
rified by column chromatography on silica gel/hexane: AcOEt (2:
1
1) as a colorless oil; yield 80% (0.96 g); H NMR (400 MHz,
CDCl3) δ 1.19 (t, 3H, J ) 7.6 Hz), 2.86 (q, 2H, J ) 7.6 Hz), 5.29
(s, 2H), 7.3–7.5 (m, 6H), 7.98 (m, 1H), 8.6 (m, 1H), 8.9 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 10.9, 19.9, 76.5, 123.3, 127.9,
128.2, 128.4, 131.3, 133.5, 137.9, 147.7, 150.0, 157.6 ppm; IR ν
(cm-1) 3032, 2972, 2937, 2877, 1604, 1454, 1412, 1365, 1018,
982, 951, 905, 876, 808, 747; GC-MS m/z 240.2 (M+). Anal. Calcd
for C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C, 75.06; H,
6.76; N, 11.63.
(E)-1-(6-Methoxypyridin-3-yl)ethanone O-Benzyl Oxime
(16c). Purified by column chromatography on silica gel/hexane:
1
AcOEt (2:1) as a colorless oil; yield 90% (1.41 g); H NMR (400
MHz, CDCl3) δ 2.29 (s, 3H), 4.00 (s, 3H), 5.27 (s, 2H), 6.8 (m,
1H), 7.4–7.5 (m, 5H), 7.97 (m, 1H), 8.4 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 12.4, 53.6, 76.0, 110.7, 125.9, 127.8, 128.2,
128.4, 136.2, 138.0, 144.8, 152.4, 164.6 ppm; IR ν (cm-1) 3026,
2947, 2897, 1726, 1601, 1499, 1452, 1376, 1285, 1020, 928, 900,
833, 738, 698; GC-MS m/z 256.1 (M+). Anal. Calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.01; H, 6.27;
N, 10.56.
(S)-N-(1-(Thiophen-3-yl)ethyl)acetamide (20a). Purified by
(E)-Cyclopropyl(pyridine-3-yl)methanone O-Benzyl Oxime
column chromatography on silica gel/hexane: AcOEt (1:1) as a
(16d). Purified by column chromatography on silica gel/hexane:
white solid; yield 85% (144 mg); mp 69–71 °C; 98% ee; [R]20
)
D
1
AcOEt (2:1) as a colorless oil; yield 88% (0.89 g); H NMR (400
–120° (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.56 (d, 3H
J ) 6.8 Hz), 2.03 (s, 3H), 5.3 (m, 1H), 5.73 (s, 1H), 7.19 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 21.3, 23.5, 44.1, 120.7, 126.3,
126.5, 144.4, 169.0 ppm; IR ν (cm-1) 3285, 3095, 3079, 2968,
1629, 1545, 1446, 1417.18, 1367, 1274, 1214, 1167, 1121, 1050
971, 862, 784, 731, 693; GC/MS m/z 169.0 (M+); HRMS m/z
170.0631 (M + H)+.
MHz, CDCl3) δ 0.69 (m, 2H), 1.0 (m, 2H), 2.3 (m, 1H), 5.28 (s,
2H), 7.3–7.5 (m, 6H), 7.8 (m, 1H), 8.6 (m, 1H), 8.7 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 5.8, 9.77, 76.3, 122.9, 127.9, 128.1,
128.4, 130.5, 135.6, 137.8, 149.3, 149.7, 158.2 ppm; IR ν (cm-1
)
3087, 3031, 2924, 2869, 1592, 1564, 1497, 1475, 1455, 1412, 1365,
1327, 1083, 1022, 981, 938, 808,734; GC-MS m/z 252.1 (M+).
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found:
C, 76.02; H, 6.39; N, 11.00.
(S)-N-(1-(2,5-Dimethylthiophen-3-yl)ethyl)acetamide (20b). Pu-
rified by column chromatography on silica gel/hexane: AcOEt (1:
(E)-1-(Pyridine-4-yl)propan-1-one O-Benzyl Oxime (18b).
1) as a white solid; yield 92% (169 mg); mp 102–104 °C; 96% ee;
1
Purified by column chromatography on silica gel/hexane: AcOEt
[R]20 ) –117.5° (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ
D
1
(2:1) as a colorless oil; yield 90% (1.08 g); H NMR (400 MHz,
1.46 (d, 3H, J ) 6.8 Hz), 1.99 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H),
5.1 (m, 1H), 5.58 (s, 1H), 6.62 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 12.8, 15.2, 21.7, 23.4, 43.0, 123.1, 132.7, 136.4, 138.3,
168.7; IR ν (cm-1) 3278, 3064, 2972, 2919, 2869, 1635, 1544,
1442, 1368, 1334, 1311, 1274, 1222, 1132, 1108, 1035, 968, 824,
733; GC-MS m/z 197.0 (M+). HRMS m/z 198.0944 (M + H)+.
CDCl3) δ 1.19 (t, 3H, J ) 7.6 Hz), 2.8 (q, 2H, J ) 7.6 Hz), 5.31
(s, 2H), 7.4–7.5 (m, 5H), 7.6 (m, 2H), 8.7 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) δ 10.9, 19.5, 76.7, 120.4, 128.0, 128.2, 128.4,
137.7, 142.9, 150.2, 157.7 ppm; IR ν (cm-1) 3031, 2976, 2936,
2877, 1591, 1454, 1409, 1366, 1015, 992, 979, 922, 824, 740; GC-
4024 J. Org. Chem. Vol. 73, No. 11, 2008

Synthesis of Nicotine Analogues
(S)-N-(6-Chlorochroman-4-yl)acetamide (20d). Purified by
1.88 (m, 2H, J ) 7.6 Hz), 2.05 (s, 3H), 4.95 (m, 1H, J ) 7.6 Hz),
6.10 (s, 1H), 7.29 (m, 1H), 7.6 (m, 1H), 8.5 (m, 1H), 8.60 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 10.7, 23.3, 28.8, 53.0, 123.5,
134.5, 137.8, 148.4, 148.7, 169.5; IR ν (cm-1) 3259, 3060, 2968,
2933, 2877, 1647, 1544, 1373, 1301, 1137, 1027, 795, 693 ppm;
GC-MS m/z 178.1 (M+); HRMS m/z 179.1175 (M + H)+.
(S)-N-(1-(6-Methoxypyridine-3-yl)ethyl)acetamide (29). Puri-
fied by column chromatography on silica gel/CH2Cl2: CH3OH (10:
column chromatography on silica gel/hexane: AcOEt (1:1) as a
white solid; yield 73% (0.161 g); mp 188–190 °C; 95% ee; [R]20
D
) –56.4° (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.0–2.1
(m, 1H), 2.09 (s, 3H), 2.1 (m, 2H), 4.2–4.3 (m, 2H), 5.2 (m, 1H),
5.80 (s, 1H), 6.8 (m, 1H), 7.2 (m, 1H), 7.19 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 23.4, 28.8, 43.6, 63.6, 118.7, 123.6, 125.6,
128.6, 129.3, 153.8, 169.4 ppm; IR ν (cm-1) 3265, 3083, 2984,
1634, 1537, 1483, 1411, 1370, 1261, 1222, 1193, 1107, 1022, 993,
878, 814, 751, 677; GC/MS m/z 225.1 (M+), 167.0 (M+ - NHAc);
HRMS m/z 226.0627 (M + H)+.
1) as a white solid; yield 88% (85 mg); mp 66–67 °C; 98% ee;
1
[R]20 ) –63.5° (c 1.85, CHCl3); H NMR (400 MHz, CDCl3) δ
D
1.50 (d, 3H, J ) 6.8 Hz), 2.01 (s, 3H), 3.95 (s, 3H), 5.1 (m, 1H),
5.92 (s, 1H), 6.7 (m, 1H), 7.6 (m, 1H), 8.16 (d, 1H, J ) 2.0 Hz)
ppm; 13CNMR (100 MHz, CDCl3) δ 21.3, 23.4, 46.3, 53.5, 110.9,
131.4, 137.2, 144.6, 163.6, 169.2 ppm; IR ν (cm-1) 3277, 2988,
1629, 1539, 1500, 1430, 1384, 1293, 1258, 1120, 1019, 972, 826,
744; GC-MS m/z 194.1 (M+); HRMS m/z 195.1123 (M + H)+.
(S)-N-(Cyclopropyl(pyridine-3-yl)methyl)acetamide (30). Puri-
fied by column chromatography on silica gel/CH2Cl2: CH3OH (10:
(S)-N-(Thiochroman-4-yl)acetamide (20e). Purified by column
chromatography on silica gel/hexane: AcOEt (1:1) as a white solid;
yield 71% (0.150 g); mp 186–188 °C; 99% ee; [R]20 ) –134.6°
D
(c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.04 (s, 3H), 2.15
(m, 1H), 2.4 (m, 1H), 3.0-3.14 (m, 2H), 5.22 (s, 1H), 5.91, (s,
1H), 7.1 (m, 1H), 7.26 (m, 2H), 7.2 (m, 1H) ppm; 13C NMR
(CDCl3) δ 22.7, 23.4, 28.1, 46.8, 124.5, 125.5, 126.8, 130.5, 132.6,
133.5, 169.1 ppm; IR ν (cm-1) 3191, 3034, 2944, 2837, 1632,
1532, 1476, 1431, 1369, 1322, 1277, 1199, 1095, 944, 796, 753;
GC/MS 207.0 (M+), 149.0 (M+ - NHAc); HRMS m/z 208.0788
(M + H)+.
1) as a white solid; yield 83% (157 mg); mp 122–123 °C; 96% ee;
1
[R]20 ) -32.5° (c 1.5, CHCl3); H NMR (400 MHz, CDCl3) δ
D
0.41 (m, 1H), 0.52 (m, 1H), 0.69 (m, 2H), 1.19 (m, 1H), 2.07 (s,
3H), 4.4 (m, 1H, CH), 6.2 (s, 1H), 7.3 (m, 1H), 7.7 (m, 1H), 8.5
(d, 1H, J ) 3.6 Hz), 8.68 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 3.9, 4.2, 16.4, 23.3, 55.5, 123.4, 134.4, 137.7, 148.3, 148.6, 169.4
ppm; IR ν (cm-1) 3244, 3062, 3004, 2928, 2849, 1630, 1546, 1426,
1372, 1298, 1194, 1162, 1104, 1091, 1020, 948, 845, 807, 715;
GC-MS m/z 190.1 (M+); HRMS m/z 191.1174 (M + H)+.
(S)-N-(1-(Pyridine-4-yl)propyl)acetamide (32). Purified by
column chromatography on silica gel/CH2Cl2: CH3OH (10:1) as a
colorless oil; yield 85% (76 mg); 96% ee; [R]20D ) –114° (c 1.15,
(S)-N-(6-Chlorothiochroman-4-yl)acetamide (20f). Purified by
column chromatography on silica gel/hexane: AcOEt (1:1) as a
white solid; yield 70% (0.167 g); mp 190–192 °C; 94% ee; [R]20
D
) –107.6° (c 1.00, CHCl3);1H NMR (400 MHz, CDCl3) δ 2.07
(s, 3H), 2.1–2.3 (m, 1H), 3.0 (m, 2H), 5.2 (m, 1H), 5.91 (s,
1H), 7.1(m, 1H), 7.14 (m, 1H), 7.3 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 22.9, 23.4, 28.1, 46.6, 76.7, 128.1, 128.3, 129.9,
132.1, 134.2, 169.2; IR ν (cm-1) 3269, 3048, 2940, 1635, 1532,
1463, 1427, 1367, 1186, 1098, 1054, 944, 887, 811, 730; GC/
MS m/z 241.1 (M+), 183.0 (M+ - NHAc); HRMS m/z 242.0399
(M + H)+.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J ) 7.6 Hz),
1.84 (m, 2H, J ) 7.6 Hz), 2.08 (s, 3H), 4.93 (m, 1H, J ) 7.6 Hz),
5.87 (s, 1H), 7.23 (dd, 2H, J ) 1.6, 6.0 Hz), 8.6 (dd, 2H, J ) 1.6,
6.0 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 10.5, 23.3, 28.6,
54.0, 121.7, 150.1, 169.8 ppm; IR ν (cm-1) 3259, 3056, 2968, 2936,
2877, 1648, 1601, 1543, 1415, 1372, 1299, 1178, 999, 825, 789;
GC-MS m/z 178.1 (M+); HRMS m/z 179.1175 (M + H)+.
(S)-N-(Cyclopropyl(pyridine-4-yl)methyl)acetamide (33). Puri-
fied by column chromatography on silica gel/CH2Cl2: CH3OH (10:
General Procedure for Asymmetric Reduction of Pyridyl
O-Benzyl Oximes with Catalyst 10: To a dried 50 mL reaction
tube under N2 was added catalyst 10 (50 mg, 0.15 mmol, 0.3 equiv)
at room temperature. Then, anhydrous dioxane (4 mL) was
introduced, and BH3 ·THF (2.5 mL, 1.0 M in THF stabilized with
<0.005 M NaBH4) was added. The resulting mixture was stirred
at room temperature for 1 h until a clear solution formed. The oxime
benzyl ether (0.5 mmol, 1.0 equiv) in 4 mL of dioxane was added
dropwise by syringe pump for 1 h. The resulting mixture was stirred
for 2 days at 10 °C under nitrogen. The reaction mixture was
quenched with methanol (5 mL) at 0 °C and then refluxed overnight.
The solvents were evaporated under vacuum, and the residue was
directly acetylated, in most cases, to form the amide derivatives.
To a solution of crude amine in anhydrous CH2Cl2 (10 mL) were
added DMAP (13 mg, 10%), Et3N (0.2 mL, 1 mmol, 2.0 equiv)
and acetic anhydride (0.11 mL, 1.0 mmol, 2.0 equiv). The resulting
mixture was stirred for 3 h. The solvent was removed under water
pump and then under high vacuum. The residue was purified directly
by flash chromatography on a silica gel column, eluted first by ether
and then by CH2Cl2/CH3OH (10/1), giving the corresponding
products. As indicated previously, the enantiomeric excess was
determined by GC with a chiral column, using a Crompack Chirasil-
Dex-CB GC column (30 m × 0.25 mm × 0.25 µm), with He flow
at a 1.0 mL/min rate isothermal at 140-160 °C or with a gradient
at an initial temperature of 80-120 °C for 5–15 min, followed by
a 2–5 °C/min ramp until 130-170 °C, and maintaining this
temperature for about 35–100 min, depending on the particular
compound. Generally, the HPLC enantiomeric analysis was carried
out with a Chiralcel-IB or OD-H columns (0.46 cm × 25 cm) with
a 0.5 mL/min flow of 90% hexane/10% 2-propanol for 100 min or
at 0.4 mL/min flow with 95% hexane/5% 2-isopropanol for 60 min,
using a UV detector at 254 nm.
1) as a white solid; yield 91% (176 mg); mp 78–80 °C; 98% ee;
1
[R]20 ) -15.6° (c 1.25, CHCl3); H NMR (400 MHz, CDCl3) δ
D
0.49 (m, 2H), 0.72 (m, 2H), 1.14 (m, 1H), 2.10 (s, 3H), 4.37 (m,
1H), 6.20 (s, 1H), 7.32 (d, 2H, J ) 6.0 Hz), 8.60 (dd, 2H, J ) 1.6,
6.0 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 3.77, 4.42, 16.3,
23.3, 56.7, 121.7, 150.0, 151.0, 169.5 ppm; IR ν (cm-1) 3276, 3080,
3006, 1649, 1598, 1542, 1432, 1410, 1371, 1312, 1289, 1221, 1200,
1105, 1052, 1023, 957, 850, 820, 808, 737; GC-MS m/z 190.2 (M+);
HRMS m/z 191.1174 (M + H)+.
(S)-N-(1-(Pyridine-3-yl)-4-(triisopropylsilyloxy)butyl)ace-
tamide (34). Purified by column chromatography on silica gel/
CH2Cl2: CH3OH (10:1) as a colorless oil; yield 91% (331 mg);
95% ee by HPLC; [R]20D ) –109.7° (c 1.9, CHCl3); 1H NMR (400
MHz, CDCl3) δ 1.07–1.18 (m, 21H), 1.56 (m, 2H), 1.94 (m, 2H),
2.04 (s, 3H), 3.75 (m, 2H), 5.04 (m, 1H), 6.15 (s, 1H), 7.3 (m,
1H), 7.6 (m, 1H), 8.53 (t, 1H), 8.6 (d, 1H, J ) 2.0 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ 12.0, 18.0, 23.3, 29.3, 32.1, 51.4, 62.5,
123.5, 134.3, 138.0, 148.3, 148.6, 169.4 ppm; IR ν (cm-1) 3278,
3054, 2942, 2865, 1648, 1546, 1463, 1428, 1372, 1292, 1099, 1068,
1012, 995, 881, 796, 714, 680; GC-MS m/z 364.2 (M+); HRMS
m/z 365.2614 (M + H)+, calcd for C20H37O2N228Si m/z 365.2619.
(S)-N-(4-Hydroxy-1-(pyridine-3-yl)butyl)acetamide (37). To
a round-bottom flask was added a solution of 34 (364 mg, 1.0
mmol) in THF (10 mL). The solution was cooled with an ice-bath,
and Bu4NF (1.5 mL, 1.0 M in THF) was added dropwise. The
mixture was stirred for 2 h until 37 was consumed. Solvents were
removed under vacuum, and the residue was purified by chroma-
tography on a silica gel column, eluted with CH2Cl2: CH3OH (5:
(S)-N-(1-(Pyridine-3-yl)propyl)acetamide (28). Purified by
column chromatography on silica gel/CH2Cl2: CH3OH (10:1) as a
colorless oil; yield 89% (80 mg); 99% ee; [R]20D ) –109.7° (c 1.30,
1). The product was obtained as a colorless oil; yield 89% (186
1
1
CHCl3); H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J ) 7.6 Hz),
mg); [R]20 ) –92° (c 1.2, CHCl3); H NMR (400 MHz, CDCl3)
D
J. Org. Chem. Vol. 73, No. 11, 2008 4025

Huang et al.
δ 1.56 (m, 2H), 1.92 (m, 2H), 1.99 (s, 3H), 3.41 (br, 1H), 3.67 (m,
2H), 5.01 (m, 1H), 7.28 (m, 2H), 7.68 (d, 1H, J ) 7.6 Hz), 8.47
(d, 1H, J ) 4.0 Hz), 8.57 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 23.1, 29.0, 32.5, 51.3, 61.7, 123.7, 134.8, 138.5, 148.0, 148.2,
170.2 ppm; IR ν (cm-1) 3265, 3056, 2931, 2861, 1647, 1543, 1479,
1428, 1372, 1299, 1102, 1058, 1041, 806, 747, 713; GC-MS m/z
208.1 (M+); HRMS m/z 209.1281 (M + H)+, calcd for C11H17O2N2
m/z 209.1284.
(S)-4-(N-Ethylamino)-4-(pyridin-3-yl)butan-1-ol (38). To a
dried two-neck flask at room temperature under nitrogen was added
37 (180 mg, 0.87 mmol) in 10 mL of THF and BH3 ·THF (2.6
mL, 1.0 M in THF, stabilized with <0.005 M NaBH4). The solution
was refluxed for 3.5 h. Then, the mixture was cooled with an ice-
bath, and 5 mL of MeOH was added dropwise to quench the borane.
The resulting mixture was refluxed overnight. The solvents were
evaporated under reduced pressure, and the residue was directly
purified by chromatography on a silica gel column eluted with
CH2Cl2:CH3OH (4:1). The product was obtained as a colorless oil;
yield 86% (145 mg); [R]20D ) –37° (c 2.2, CHCl3); 1H NMR (400
MHz, CDCl3) δ 1.09 (t, 3H, J ) 7.2 Hz), 1.67 (m, 2H), 1.85 (m,
2H), 2.53 (q, 2H, J ) 7.2 Hz), 3.0 (br, 1H), 3.7 (m, 3H), 7.32 (m,
1H), 7.6 (m, 1H), 8.5 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
δ 15.0, 30.5, 36.2, 41.6, 60.9, 62.7, 123.6, 134.3, 139.3, 148.7,
148.9 ppm; IR ν (cm-1) 3268, 2932, 2861, 1655, 1578, 1426, 1379,
1320, 1268, 1104, 1060, 1027, 928, 808, 715; GC-MS
m/z 194.0 (M+); HRMS m/z 195.1490 (M + H)+, calcd for
C11H19O1N2 195.1492.
reaction was monitored by TLC until the starting material was
totally consumed (around 3 h). When the reaction was completed,
water (15 mL) was added and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were dried
over anhydrous Na2SO4. The solvents were removed under vacuum,
and the residue was purified by chromatography on silica gel eluted
with CH2Cl2:CH3OH (95:5). The product was obtained as a
colorless oil; yield 84% (110 mg); 97% ee by GC; [R]20D ) –139°
(c 2.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.04 (t, 3H, J ) 7.2
Hz), 1.73 (m, 1H), 1.85 (m, 1H), 2.0 (m, 1H), 2.12 (m, 1H), 2.25
(m, 2H), 2.64 (m, 1H), 3.27 (m, 1H), 3.4 (m, 1H), 7.28 (m, 1H),
7.7 (m, 1H), 8.5 (m, 1H), 8.6 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 13.8, 22.5, 35.1, 48.2, 53.2, 67.5, 123.5, 134.9, 139.6,
148.5, 149.6 ppm; GC-MS m/z 176.1 (M+).
Acknowledgment. Financial support by the National Insti-
tutes of Health through their MBRS-SCORE (GM 08216) and
PR-AABRE-INBRE (NC P20 RR-016470) grant is greatly
appreciated. We express our special gratitude to the NSF-MRI
(01–07) and NIH-MBRS programs to have made possible the
acquisition of a 400 MHz NMR spectrometer. The NSF-
ADVANCE (SBE-0123645), NIH-INBRE and NIH-RISE, NIH-
MARC, NSF-AMP undergraduate student’s support is also
gratefully acknowledged.
(S)-3-(1-Ethylpyrrolidin-2-yl)pyridine30 (3). To a dried three-
neck round-bottom flask containing PPh3 (393 mg, 1.5 mmol),
Et3N·HCl (104 mg, 0.75 mmol), and compound 38 (145 mg, 0.75
mmol) in anhydrous CH2Cl2 (30 mL) under nitrogen was added a
solution of diisopropyl azodicarboxilato (DIAD) (303 mg, 1.5
mmol) in anhydrous CH2Cl2 (10 mL) dropwise at –20 °C. The
Supporting Information Available: Experimental proce-
dures, physical properties and spectral data for all oximes, data
characterization for known benzyl oximes and acetamides, and
enantiomeric determination by chromatography for all racemic
and nonracemic acetamides. This material is available free of
charge via the Internet at http://pubs.acs.org.
(30) Damaj, M. I.; Glassco, W.; Dukat, M.; May, E. L.; Richard, A.; Martin,
B. R. Drug DeV. Res. 1996, 38, 177.
JO800204N
4026 J. Org. Chem. Vol. 73, No. 11, 2008