Iridium-catalyzed asymmetric hydrogenation of 2-pyridyl cyclic imines: A highly enantioselective approach to nicotine derivatives

Article abstract of DOI:10.1021/ja511422q

A highly efficient asymmetric hydrogenation of cyclic imines containing a pyridyl moiety was established by using iridium catalysts with chiral spiro phosphine-oxazoline ligands. This process will facilitate the development of new nicotine-related pharmaceuticals. The introduction of a substituent at the ortho position of the pyridyl ring to reduce its coordinating ability ensures the success of the hydrogenation and excellent enantioselectivity.

Full text of DOI:10.1021/ja511422q

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Asymmetric Hydrogenation of 2‑Pyridyl Cyclic
Imines: A Highly Enantioselective Approach to Nicotine Derivatives
Cui Guo, Dong-Wei Sun, Shuang Yang, Shen-Jie Mao, Xiao-Hua Xu,* Shou-Fei Zhu,* and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
perfect atom economy, operational simplicity, and environ-
ABSTRACT: A highly efficient asymmetric hydrogena-
tion of cyclic imines containing a pyridyl moiety was
established by using iridium catalysts with chiral spiro
phosphine-oxazoline ligands. This process will facilitate the
development of new nicotine-related pharmaceuticals. The
introduction of a substituent at the ortho position of the
pyridyl ring to reduce its coordinating ability ensures the
success of the hydrogenation and excellent enantioselec-
tivity.
mental friendliness. Thus, this reaction has attracted increasing
research attention over the past several decades.8 However, the
transition-metal-catalyzed enantioselective hydrogenation of
pyridyl-containing unsaturated compounds remains a great
challenge because the strong coordinating ability of the pyridine
moiety tends to deactivate transition-metal catalysts.9 For
example, although a chiral titanocene catalyst shows good to
high enantioselectivity for the asymmetric hydrogenation of
various cyclic imine substrates, the reaction of 2-(3-pyridyl)-
pyrroline does not proceed.10
To overcome the challenge posed by transition-metal-
catalyzed enantioselective hydrogenation of pyridyl-containing
unsaturated N-heterocycles, we have developed a strategy we
refer to as the “substituent-control strategy”. Specifically, by
introducing, at the position adjacent to the pyridine N atom, a
substituent that either is present in the desired product or can be
removed after the hydrogenation reaction, we can greatly reduce
the coordination ability of the pyridine moiety and thus facilitate
the asymmetric hydrogenation of pyridyl-containing unsaturated
N-heterocycles. Here, we report the first highly enantioselective
hydrogenation of pyridyl-containing cyclic imines catalyzed by
iridium complexes with chiral spiro phosphine-oxazoline ligands.
Initially, we attempted to hydrogenate 2-(3-pyridyl)pyrroline
under 50 atm of hydrogen in the presence of 10 mol % I2 and 1
mol % chiral spiro iridium complexes (Sa,S)-3, which is known to
catalyze the asymmetric hydrogenation of acyclic N-aryl
ketimines,11 but no reaction took place under any of the reaction
conditions we investigated. In contrast, substrate 1a,12 which has
a bromine substituent adjacent to the pyridine N atom,
underwent hydrogenation catalyzed by (Sa,S)-3a to afford the
desired amine product (2a) in 96% yield, although the
enantiomeric excess (ee) was only 5% (Table 1, entry 1). We
then systematically modified the catalyst by changing the
substituent on the oxazoline ring and the P-aryl moieties of the
spiro phosphine-oxazoline ligands (entries 2−6). Catalyst (Sa,S)-
3d,13 which has a phenyl group on the oxazoline ring and two 3,5-
tert-butylphenyl groups on the P atom, proved to be the best
catalyst, giving full conversion, a 98% yield of the desired
product, and an ee of 96% (entry 4). Catalyst (Sa,R)-3d, a
diastereoisomer of (Sa,S)-3d, was inactive (entry 7), indicating
that the chiralities of (Sa,S)-3d were well matched. Various
solvents could be used for this hydrogenation (entries 8−12),
with 1,4-dioxane giving the best results (full conversion, 98%
hiral N-heterocycles, such as pyrrolidine and piperidine
Cderivatives, are very common in alkaloid natural products
and pharmaceuticals.1 The list of the top 200 prescription drugs
in the United States in 2010 included more than 30 pyrrolidine
and piperidine derivatives.2 Nicotine, nornicotine, anabasine, and
other nicotine-related alkaloids have shown potential for the
treatment of Parkinson’s disease, Alzheimer’s disease, and
various other conditions.3 However, these compounds are highly
toxic and have the potential for abuse, so the development of low-
toxicity nicotine analogues for use as drugs, pesticides, and other
bioactive compounds is highly desirable. Examples of such
analogues include ABT-418, a prototypical cholinergic channel
activator for the potential treatment of Alzheimer’s disease;4 SIB-
1508Y, a novel anti-Parkinsonian agent with selectivity for
neuronal nicotinic acetylcholine receptors;5 A-85380, a novel,
highly potent nicotinic acetylcholine receptor ligand;6 and
imidacloprid, one of the most commonly used insecticides
worldwide (Figure 1).7
Transition-metal-catalyzed asymmetric hydrogenation of
cyclic imines is an ideal method for preparing chiral pyrrolidines,
piperidines, and other unsaturated N-heterocycles because of its
Received: November 6, 2014
Figure 1. Nicotine and its analogues.
© XXXX American Chemical Society
A
DOI: 10.1021/ja511422q
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Communication
Table 1. Enantioselective Ir-Catalyzed Hydrogenation of 2-
(6-Bromo-pyridin-3-yl)-1-pyrroline 1a: Optimization of
Reaction Conditions
Table 2. Ir-Catalyzed Asymmetric Hydrogenation of 2-
a
(Pyridin-3-yl) Cyclic Imines
a
entry
R
n
conv (%)
yield (%)
ee (%)
1
6-Br (1a)
1
1
1
1
1
1
1
1
1
2
2
2
3
100
100
100
98
98 (2a)
97 (2b)
95 (2c)
91 (2d)
90 (2e)
98 (2f)
95 (2g)
92 (2h)
95 (2i)
93 (2j)
91 (2k)
90 (2l)
85 (2m)
98
96
94
>99
96
96
94
90
94
88
81
91
75
2
6-Cl (1b)
3
6-F (1c)
4
6-Me (1d)
6-OMe (1e)
5-Me-6-Br (1f)
5-Me-6-Cl (1g)
5-Me-6-F (1h)
5,6-Cl2 (1i)
6-Br (1j)
5
95
6
100
100
100
97
7
b
c
d
entry
catalyst
solvent
THF
conv (%)
yield (%)
ee (%)
8
1
(Sa,S)-3a
(Sa,S)-3b
(Sa,S)-3c
(Sa,S)-3d
(Sa,S)-3e
(Sa,S)-3f
(Sa,R)-3d
(Sa,S)-3d
(Sa,S)-3d
(Sa,S)-3d
(Sa,S)-3d
(Sa,S)-3d
100
100
100
100
100
100
0
96
97
96
98
95
93
−
98
85
96
87
55
5
9
2
THF
6
10
11
100
100
100
93
3
THF
29
96
93
91
−
98
90
95
88
89
6-Cl (1k)
4
THF
b
12
6-OMe (1l)
6-Br (1m)
5
THF
c
13
6
THF
a
Reaction conditions and analysis were similar to those in Table 1,
7
THF
b
c
entry 8 unless otherwise noted. 1.5 mol % catalyst was used. (Sa,S)-
3e was used as catalyst.
8
1,4-dioxane
Et2O
100
90
9
10
11
12
EtOAc
CH2Cl2
toluene
100
89
Scheme 1. Asymmetric Hydrogenation of 1n and 1o
60
a
Reaction conditions: 0.2 mmol of 1a, [substrate] = 0.05 M, substrate/
catalyst = 100, H2 (50 atm), and 0.1 equiv of I2 as additive. BArF is
b
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. Determined by 1H
c
d
NMR. Isolated yield. Determined by chiral HPLC analysis.
yield, and 98% ee; entry 8). I2 was indispensable for the
hydrogenation reaction, although its function is not clear.14 The
iodide additives, such as HI, KI, and LiI, are ineffective in this
reaction. The absolute configuration of 2a was determined as S
by means of X-ray diffraction analysis of a single crystal.13
Various pyridine-containing pyrroline compounds were
evaluated using the optimized reaction conditions (Table 2).
In addition to the bromo substituent, other halogen substituents
and methyl and methoxy substituents at the position adjacent to
the N atom of the pyridine ring (1b−1e) also promoted the
hydrogenation; the desired products were obtained with high
yields and excellent enantioselectivities (entries 2−5). The
presence of a second substituent on the pyridine ring had little
effect on the yield or enantioselectivity (entries 6−9). This
substituent-control strategy was also applicable for the
asymmetric hydrogenation of 6- and 7-membered-ring cyclic
imines; the corresponding N-heterocyclic compounds were
obtained in high yields with good to excellent enantioselectivities
(entries 10−13). Moreover, 2-(2-chloro-pyridin-4-yl)-1-pyrro-
line (1n) could also be hydrogenated with excellent yield (99%)
and enantioselectivity (96% ee, Scheme 1). In contrast, 2-(6-
bromo-pyridin-2-yl)-1-pyrroline (1o) was inert to the hydro-
genation reaction; the two N atoms of 1o may strongly
coordinate the iridium to form a chelating complex and
deactivate the catalyst.
To demonstrate the utility of this asymmetric hydrogenation
reaction, we synthesized four natural alkaloids, namely, (S)-
nicotine, (S)-pyridylnicotine, (S)-anabasine, and (S)-noranabas-
mine, from the corresponding hydrogenation products (Scheme
2). Specifically, 6-bromonicotine (4) was obtained in 75% yield
by methylation of 2a with formaldehyde and formic acid.
Scheme 2. Total Synthesis of Chiral Pyrrolidine and
a
Piperidine Alkaloids
This asymmetric hydrogenation reaction could be performed
at the gram scale, which is advantageous for practical
applications. For instance, the asymmetric hydrogenation of
1.08 g of imine 1a ran smoothly in the presence of 1 mol % (Sa,S)-
3d under 100 atm of H2 in 18 mL of THF, producing (S)-2a in
95% yield with 93% ee.
a
(a) HCHO/HCOOH, 80 °C; (b) Pd/C (2 mol %), H2 (1 atm),
MeOH, rt; (c) 3-PyB(OH)2 (1.1 equiv), Pd(PPh3)4 (2.5 mol %), aq.
Na2CO3 (2 M), DME/EtOH.
B
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Journal of the American Chemical Society
Communication
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Compound 4 was then transformed into (S)-nicotine with 96%
ee by means of Pd-catalyzed debromination under hydro-
genation conditions.15 (S)-Pyridylnicotine,16 an alkaloid isolated
from a Colombian dendrobatid frog, was prepared by means of
Pd-catalyzed cross-coupling between 4 and pyridin-3-yl boronic
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noranabasmine. In these syntheses, the bromo substituent on
the pyridine ring of the substrates not only promoted the
asymmetric hydrogenation of the pyridyl-containing cyclic
imines but also provided a locus for the highly efficient synthesis
of nicotine analogues via simple transformations. Given that
several nicotine analogues exhibit attractive bioactivities,18 this
asymmetric hydrogenation reaction may facilitate the develop-
ment of nicotine-related pharmaceuticals.
(7) Yamamoto, I. In Nicotinoid Insecticides and the Nicotinic
Acetylcholine Receptor; Yamamoto, I., Casida, J. E., Eds.; Springer-
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In conclusion, we achieved the first highly enantioselective
hydrogenation of cyclic imines bearing a pyridyl group by using
iridium catalysts with a chiral spiro phosphine-oxazoline ligand.
The reaction provides a direct catalytic route to the synthesis of
chiral nicotine analogues. The key to successful hydrogenation is
the inclusion of an ortho substituent on the pyridyl ring of the
substrates to reduce the coordinating ability of the pyridine N
atom. Concise syntheses of the natural pyrrolidine and piperidine
alkaloids (S)-nicotine, (S)-pyridylnicotine, (S)-anabasine, and
(S)-noranabasmine demonstrated the potential applications of
this asymmetric hydrogenation in organic synthesis, and the
strategy can be expected to facilitate the exploration of nicotine-
derived bioactive compounds.
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ASSOCIATED CONTENT
* Supporting Information
(9) Another possible pathway for quenching catalytic activity is the
■
́
formation of carbene species; see: Alvarez, E.; Conejero, S.; Lara, P.;
Lopez, J. A.; Paneque, M.; Petronilho, A.; Poveda, M. L.; del Río, D.;
S
́
CIF data for (S)-2a and (Sa,S)-3d, experimental procedures, and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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spiro ligands for transition-metal catalysis in this laboratory, see:
(b) Zhu, S.-F.; Zhou, Q.-L. In Privileged Chiral Ligands and Catalysts;
Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, 2011; Chapter 4, p 137.
(c) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. (d) Xie, J.-H.;
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(12) The substrate 1a was readily prepared according to literature
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Org. Chem. 1989, 54, 228 and SI.
(13) CCDC 1027452 [(Sa,S)-3d] and CCDC 1027453 [(S)-2a]
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. See SI
for details.
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AUTHOR INFORMATION
■
Corresponding Authors
xiaohuaxu@nankai.edu.cn
sfzhu@nankai.edu.cn
qlzhou@nankai.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China and
the National Basic Research Program of China
(2012CB821600), the “111” project (B06005) of the Ministry
of Education of China, and the National Program for Support of
Top-notch Young Professionals for financial support.
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