Asymmetric Hydrogenation of Pyridinium Salts with an Iridium Phosphole Catalyst

Article abstract of DOI:10.1002/anie.201406762

Iridium-catalyzed asymmetric hydrogenation of N-alkyl-2-alkylpyridinium salts provided 2-aryl-substituted piperidines with high levels of enantioselectivity. Simple benzyl and other alkyl groups successfully activated the challenging pyridine substrates toward hydrogenation. The use of the unusual chiral-phosphole-based MP²-SEGPHOS was the key to the success of this approach which provides a versatile and practical procedure for the synthesis of chiral piperidines. Ring to ring: Simple N-benzyl and N-alkyl groups successfully activated pyridine substrates toward hydrogenation. The use of the unusual chiral phosphole-based ligand L was the key to the success of this approach, which provides a versatile and practical procedure for the synthesis of chiral piperidines. cod=1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.201406762

Angewandte
Chemie
DOI: 10.1002/anie.201406762
Asymmetric Catalysis
Asymmetric Hydrogenation of Pyridinium Salts with an Iridium
Phosphole Catalyst**
Mingxin Chang, Yuhua Huang, Shaodong Liu, Yonggang Chen,* Shane W. Krska,
Ian W. Davies, and Xumu Zhang*
Abstract: Iridium-catalyzed asymmetric hydrogenation of N-
alkyl-2-alkylpyridinium salts provided 2-aryl-substituted piper-
idines with high levels of enantioselectivity. Simple benzyl and
other alkyl groups successfully activated the challenging
pyridine substrates toward hydrogenation. The use of the
unusual chiral-phosphole-based MP2-SEGPHOS was the key
to the success of this approach which provides a versatile and
practical procedure for the synthesis of chiral piperidines.
have been explored to circumvent this issue.[6,7] Charette and
co-workers have employed N-iminopyridinium ylides to
improve the reactivity of the pyridine ring and achieve
efficient asymmetric hydrogenation.[8] Most recently, Zhou
and co-workers have reported the successful asymmetric
hydrogenation of N-(2-CO2iPr)benzylpyridinium salts where
the ester is believed to act as a directing group for the catalyst
[Eq. (1); Boc = tert-butoxycarbonyl].[9] Extra steps are
H
ydrogenation of readily available substituted pyridines is
a straightforward and atom-economical approach for the
preparation of substituted piperidines.[1] These piperidines are
ubiquitous structural motifs in natural products as well as key
pharmacophores in many active pharmaceutical ingredients
(Figure 1).[2]
Despite the advances made in the asymmetric hydro-
genation of other nitrogen-containing heterocycles such as
quinolines and isoquinolines,[1c,3] examples of direct asym-
metric hydrogenations of pyridines remain scarce. In 2000,
Studer and co-workers reported the asymmetric reduction of
pyridines in 27% ee using rhodium bis(phosphine) com-
plexes.[4] Zhouꢀs [{Ir(cod)Cl}2]/(S)-MeO-Biphep system re-
duced the related 7,8-dihydroquinolin-5(6H)-one substrates
with good enantioselectivities. However, the system was not
general for pyridines.[5]
Figure 1. Selected pharmaceutical targets.
required for removing the activating groups to obtain the
desired piperidine product. Given that simple N-alkylpiper-
idines themselves are valuable synthons, an asymmetric
hydrogenation method which utilizes simple N-alkylpyridi-
nium salts would increase the scope and utility of this
approach. Herein, we report a highly efficient asymmetric
hydrogenation of simple N-alkyl-2-arylpyridinium salts with
excellent reactivity and enantioselectivity using an iridium
phosphole catalyst [Eq. (2)].
Recognizing that the major obstacle to achieving highly
efficient asymmetric hydrogenations of pyridines is over-
coming the thermodynamic stability associated with the
aromaticity of the pyridine ring, a number of approaches
[*] Dr. M. Chang, Y. Huang, S. Liu, Prof. X. Zhang
Department of Chemistry and Chemical Biology and Department of
Medicinal Chemistry, Rutgers, The State University of New Jersey
610 Taylor Road, Piscataway, New Jersey, 08854 (USA)
E-mail: xumu@rci.rutgers.edu
For our initial studies, an N-benzyl group was chosen to
activate 2-phenylpyridine because of its ubiquity in protect-
Y. Huang, Dr. Y. Chen, Dr. S. W. Krska, Dr. I. W. Davies
Department of Process Chemistry and
Department of Discovery Chemistry, Merck & Co., Inc.
P.O. Box 2000, Rahway, New Jersey, 07065 (USA)
E-mail: Yonggang.chen@merck.com
[**] This research was supported by the National Institutes of Health
(GM58832). We thank Jerry Hill, Mathew Maust, and Mark Weisel of
the Merck High Pressure Laboratory for their experimental support.
Xiaodong Bu, Leo Joyce, Alex Makarov, Zainab Pirzada, Wes Schafer,
Van Truong, Rong-Sheng Yang, Heather Wang, and Wendy Zhong of
the Merck Analytical Chemistry team are thanked for their analytical
support. Finally, we thank LC Campeau, Matthew T. Tudge, and
Michael Shevlin of the Merck Catalysis & Automation team for their
useful discussions and support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406762.
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with more electron-rich doubly oxygenated ligand frame-
works. When the phosphole-containing MP2-SEGPHOS
(L12) was employed, the chiral piperidine 2 (Ar= Ph) was
obtained in 96% ee. High ee values were also observed for
two other structurally diverse N-benzylpyridinium bromides
(Ar= 2-MeCO2C6H4 and 4-MeOC6H4), thus suggesting that
a general protocol might be achievable. The size of the
phosphole substituents was found to be critical (L12 and L13),
as evidenced by the increased selectivity when a less sterically
encumbered phosphole was employed.
It is worth noting that to the best of our knowledge the
results obtained with L12 represent the first reported
examples of the use of MP2-SEGPHOS in a highly efficient
asymmetric reaction.[11] A number of unique features of
phospholes may contribute to the observed high efficiency
and enantioselectivity in the reactions employing MP2-
SEGPHOS as a ligand. Firstly, the previously noted relation-
ship between the selectivity of the asymmetric hydrogenation
and donor capacity of the ligand would be further enhanced
by the phosphole functionality of MP2-SEGPHOS
(Scheme 1).[12] Secondly, the rigidity[13] and planarity[14] of
the phosphole unit would be expected to provide a well-
defined chiral pocket[15] around the reactive site which is
substantially different from those seen with other C2-sym-
metric bis(phosphine) ligands.
Scheme 1. Order of electron-donating ability of phosphorus ligands.
[a] Infrared data for [LMo(CO)5] complexes.[12] Only the highest energy
u(CO) is given.
Figure 2. Selected results of ligand screen for asymmetric hydrogena-
tion of N-alkyl-2-phenylpyridium bromide substrates using iridium
catalysts. Reactions were carried out using 0.01 mmol of substrate in
0.12 mL of mixed solvent. Absolute enantiomeric excesses were
determined by SFC using a chiral stationary phase. Ar1=2-
MeCO2C6H4 and Ar2=4-MeOC6H4 for the Ar group in 1. cod=1,5-
cyclooctadiene.
Having identified MP2-SEGPHOS as the most selective
ligand of those examined, we next explored the influence of
solvent (Table 1). While many single solvents led to excellent
enantioselectivity for 1a, acceptable reactivity was only
observed for THF, acetone, and 1,2-dichloroethane (DCE)
with 2 mol% of the iridium catalyst. The combination of
acetone and DCE proved optimal (Table 1, entry 10), thus
allowing the iridium catalyst loading to be lowered to
0.5 mol%.
ing-group chemistry (Figure 2).[10] While simple N-benzylpyr-
idinium salts have been demonstrated to be very challenging
substrates in asymmetric hydrogenation, we envisioned that
an in depth evaluation of ligand architecture with respect to
reaction selectivity might result in the identification of an
efficient catalyst. A library of 240 chiral phosphine ligands
was evaluated. While the majority of phosphine ligands
screened gave less than 60% ee, several active and selective
ligands were discovered. Doubly oxygenated atropisomeric
C2-symmetric bis(phosphine) ligands, such as SynPhos, SEG-
PHOS, and GarPhos, in conjunction with [{Ir(cod)Cl}2] as
a precatalyst showed good enantioselectivities in the asym-
metric hydrogenation of 1a (L7–L11; Figure 2). The fine-
tuning of the GarPhos and SEGPHOS ligands structure also
had notable impact on their enantioselectivities, with more
sterically encumbered and electron-rich phosphine aryl sub-
stituents giving higher enantioselectivities (L8, L9, and L10,
L11). In addition, generally higher selectivities were observed
To explore the utility of the newly developed Ir/MP2-
SEGPHOS catalytic system, a range of N-benzyl-2-substi-
tuted pyridium bromide substrates were synthesized and
studied under the optimized reaction conditions. The results
are summarized in Table 2. For all chosen 2-arylpyridinium
substrates (entries 1–15), the chiral products 2a–m were
obtained in excellent yield and selectivity (90% to 96% ee).
The catalytic system worked well for ortho-substituted,
sterically hindered substrates such as 1d, 1k, and 1m
(entries 4, 12, and 15), thus highlighting the enhanced
reactivity of this system. The enantioselectivities in these
cases were only slightly less than those where the 2-aryl group
bore substituents in the meta or para positions. Significantly,
the electronic properties of the 2-aryl group did not exert any
noticeable effect on the reaction selectivity. Both the elec-
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Table 1: Solvent screening for asymmetric hydrogenation of N-benzyl-2-
phenylpyridium bromide using an Ir/(R)-MP2-SEGPHOS catalyst.[a]
adjustment of the solvent ratio to achieve higher reactivity
(entries 10 and 11, and 14 and 15). For 2-alkylpyridinium
substrates, chiral products were obtained with only low to
moderate levels of enantioselectivity (entries 16–19). While
improved enantioselectivity was observed with a sterically
bulky substrate (1o versus 1n), the yield of the isolated
product fell significantly because of the lower reactivity
(entries 16 and 17). Notably, tuning the phosphole ligand
structure had some impact on the levels of enatioselectivity
for the 2-benzylpyridinium substrate (1p) (entries 18 and 19).
When using L13, the desired product 2p was obtained in 42%
ee.
To evaluate the practical utility of the newly developed
method, the asymmetric hydrogenation of N-benzyl-2-phe-
nylpyridium bromide (1a) was carried out on a .5 mmol scale.
The desired product 2a was obtained in 98% yield and 94%
ee [Eq. (3)], and the catalyst loading could be reduced to
0.25 mol% (S/C = 400) at this scale. The facile removal of the
N-benzyl group was demonstrated through a one-pot asym-
metric hydrogenation followed by deprotection, thus giving 2-
phenylpiperidine in 91% overall yield and 92% ee [Eq. (4)].
Having established a robust reaction with N-benzyl
derivatives, we wished to explore the substrate scope with
Entry
Solvent
Conversion [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
DCE
EtOAc
acetone
1,4-dioxane
toluene
THF
53
>99
57
>99
62
22
>99
32
93
94
94
94
93
89
89
63
86
93
95
MeOH
9[c]
10[c]
11[c]
acetone
DCE/acetone (1:1)
DCE
91
>99
78
[a] Reaction conditions: 1a 0.083m, [Ir]/ligand/N-benzyl-2-phenylpyri-
dium bromide=2:2.2:100, 20 h. [b] Conversions and enantiomeric
excesses were determined by SFC using a chiral stationary phase. [c] 1a
0.025m, [Ir]/ligand/N-benzyl-2-arylpyridium bromide=0.5:0.55:100,
20 h.
Table 2: Iridium-catalyzed asymmetric hydrogenation of the N-benzyl-2-
substituted pyridinium salts 1.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5 (1a)
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2j
2k
2l
2m
2m
2n
2o
2p
2p
97
99
93
90
99
95
97
96
96
86
96
94
95
12
88
81
24
92
94
96
96
93
90
96
94
95
93
95
90
95
90
96
93
94
33
69
24
42
3-MeC6H4 (1b)
4-MeC6H4 (1c)
2-MeOC6H4 (1d)
3-MeOC6H4 (1e)
4-MeOC6H4 (1 f)
4-Ac(H)NC6H4 (1g)
4-tBuC6H4 (1h)
4-ClC6H4 (1i)
4-PhC6H4 (1j)
4-PhC6H4 (1j)
2,4-Cl2C6H3 (1k)
3,5-F2C6H3 (1l)
2-naphthyl (1m)
2-naphthyl (1m)
Me (1n)
other N-alkyl substituents. As shown in Scheme 2, the iridium
phosphole catalyst delivered remarkably high conversion and
enantioselectivity with N-alkyl substituents as small as Et
(5e), and even an N-methylpyridinium salt gave the resulting
N-methylpiperidine product in good yield and 81% ee (5d).
The (carboethoxy)methyl substituent (5g) was also tolerated,
thus giving enantioselectivities comparable to those seen with
benzyl substituents (5a). This substituent is particularly
interesting because of its utility as a functional group for
further elaboration. The nature of the pyridinium counterion
had some impact on both the activity and enantioselectivity of
the reaction (5a and 5d). The counterion effect is not yet
understood,[16] and we are currently investigating its origin.
In summary, we have developed a highly efficient
enantioselective hydrogenation of N-alkyl-2-arylpyridinium
salts. This protocol represents a significant advance over
previous methods in that a directing group is not required.
With this constraint removed, this new method tolerates
a variety of N-benzyl as well as simple N-alkyl groups, which
greatly increases the scope and applicability of this approach
in synthesis. In addition, this work provides the unique
example of using a chiral-phosphole-based ligand for highly
9
10
11[d]
12
13
14
15[e]
16[e]
17[e]
18[f]
19[f,g]
iPr (1o)
CH2OAc (1p)
Bn (1p)
[a] Reaction conditions: 1 0.025m, [Ir]/ligand/N-benzyl-2-arylpyridium
bromide=0.5:0.55:100, 20 h. [b] Yield of isolated product. [c] Enantio-
meric excesses were determined by SFC or HPLC using a chiral
stationary phase. [d] DCE/acetone=5:1 as solvent. [e] Acetone as
solvent. [f] DCE as solvent. [g] L13 was used as ligand.
tron-donating 4-MeO (1 f) and electron-withdrawing 4-Cl
(1i), and 3,5-F2-phenyl-substituted (1l) substrates provided
similarly high enantioselectivities (entries 6, 9, and 13).
During our study, we observed that some substrates were
quite sensitive to the solvent composition, thus requiring
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[1] For selected reviews, see: a) P. D. Bailey, P. A. Millwood, P. D.
Smith, Chem. Commun. 1998, 633; b) F. Glorius, Org. Biomol.
Chem. 2005, 3, 4171; c) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G.
Zhou, Chem. Rev. 2012, 112, 2557.
[2] For a review and selected examples, see: a) Chiral Amine
Synthesis (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010;
b) Y. Zhang, Y.-B. Liu, Y. Li, S.-G. Ma, L. Li, J. Qu, D. Zhang, X.-
G. Chen, J.-D. Jiang, S.-S. Yu, J. Nat. Prod. 2013, 76, 1058; c) Z.
Peng, J. W. Wong, E. C. Hansen, A. L. A. Puchlopek-Dermenci,
H. J. Clarke, Org. Lett. 2014, 16, 860; d) Y. Liu, H. Du, J. Am.
Chem. Soc. 2013, 135, 12968.
[3] a) D. Zhao, F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 9616;
Angew. Chem. 2013, 125, 9794; b) Z. Wu, M. Perez, M. Scalone,
T. Ayad, V. Ratovelomanana-Vidal, Angew. Chem. Int. Ed. 2013,
52, 4925; Angew. Chem. 2013, 125, 5025; c) A. Iimuro, K. Yamaji,
S. Kandula, T. Nagano, Y. Kita, K. Mashima, Angew. Chem. Int.
Ed. 2013, 52, 2046; Angew. Chem. 2013, 125, 2100; d) Z.-S. Ye,
R.-N. Guo, X.-F. Cai, M.-W. Chen, L. Shi, Y.-G. Zhou, Angew.
Chem. Int. Ed. 2013, 52, 3685; Angew. Chem. 2013, 125, 3773;
e) N. Ortega, D.-T. D. Tang, S. Urban, D. Zhao, F. Glorius,
Angew. Chem. Int. Ed. 2013, 52, 9500; Angew. Chem. 2013, 125,
9678; f) T. Wang, F. Chen, J. Qin, Y.-M. He, Q.-H. Fan, Angew.
Chem. Int. Ed. 2013, 52, 7172; Angew. Chem. 2013, 125, 7313.
[4] M. Studer, C. Wedemeyer-Exl, F. Spindler, H.-U. Blaser,
Monatsh. Chem. 2000, 131, 1335.
Scheme 2. Iridium-catalyzed asymmetric hydrogenation of the 2-phe-
nylpyridinium salts 4.[a] [a] Reaction conditions: 4 0.025m, [Ir]/ligand/
N-alkyl-2-phenylpyridium bromide=0.5:0.55:100, 20 h. [b] Yield of the
isolated product. [c] Enantiomeric excesses were determined by either
SFC or HPLC using a chiral stationary phase. [d] DCE as solvent.
[e] DCE/acetone=5:1 as solvent.
[5] X.-B. Wang, W. Zeng, Y.-G. Zhou, Tetrahedron Lett. 2008, 49,
4922.
[6] For the use of a chiral auxiliary controlled hydrogenation
example, see: F. Glorius, N. Spielkamp, S. Holle, R. Goddard,
C. W. Lehmann, Angew. Chem. Int. Ed. 2004, 43, 2850; Angew.
Chem. 2004, 116, 2910.
[7] For the stepwise reduction of ethyl nicotinate example, see: A.
Lei, M. Chen, M. He, X. Zhang, Eur. J. Org. Chem. 2006, 4343.
[8] a) C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127,
8966; b) C. Y. Legault, A. B. Charette, P. G. Cozzi, Heterocycles
2008, 76, 1271.
efficient asymmetric catalysis. The unique electronic and
structural aspects of the phosphole unit should inform future
ligand design for asymmetric catalysis. Further applications of
chiral phosphole-based complexes for the asymmetric hydro-
genation of heteroarenes and imines are under investigation
within our laboratories, and the results will be reported in due
course.
[9] Z.-S. Ye, M.-W. Chen, Q.-A. Chen, L. Shi, Y. Duan, Y.-G. Zhou,
Angew. Chem. Int. Ed. 2012, 51, 10181; Angew. Chem. 2012, 124,
10328.
Experimental Section
Representative procedure for the asymmetric hydrogenation of
pyridinium salts 1: In a nitrogen-filled glovebox, MP2-SEGPHOS
(4.58 mg, 0.0099 mmol) and [{Ir(cod)Cl}2] (3.07 mg, 0.00457 mmol)
were placed into a vial and stirred for 30 min in acetone (7.2 mL). The
pyridinium salts 1 (0.05 mmol) were placed into 4 mL hydrogenation
vials. About 0.2 mL of the catalyst solution and remaining solvent
were added. The vials were placed in a parallel hydrogenation block
and after three hydrogen purges, pressurized to 600 psi at 308C for
20 h. After carefully releasing the hydrogen, ee values were deter-
mined by direct sampling of the reaction mixture on SFC or HPLC.
Then saturated sodium carbonate was added and the mixture was
stirred for 15–30 min. The organic layer was separated and extracted
with CH2Cl2 twice, and the combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification was performed by
a silica gel column and eluted with hexanes /EtOAc to give desired
product 2 or 5.
[10] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley-Interscience, New York, 1999.
[11] For the only reported use of MP2-SEGPHOS was for asymmetric
hydrogenation of N-acetamidocinnamic acid, which gave the
product in 60% ee, see: H. Shimizu, T. Saito, I. Nagasaki, EP
1419815A1, 2004.
[12] a) W. Schꢁfer, A. Schweig, G. Markl, H. Hauptmann, F. Mathey,
Angew. Chem. Int. Ed. Engl. 1973, 12, 145; Angew. Chem. 1973,
85, 140; b) W. Schaefer, A. Schweig, F. Mathey, J. Am. Chem.
Soc. 1976, 98, 407.
[13] The value of the intracyclic CPC angle of phosphole (90.78 for
phenylphosphole) is much smaller than normal CPC angles
(1008) and indicates that the system is very strained and rigid.
See: P. Coggon, A. T. McPhail, J. Chem. Soc. Dalton Trans. 1973,
1888.
[14] W. Egan, R. Tang, G. Zon, K. Mislow, J. Am. Chem. Soc. 1971,
93, 6205.
[15] For a recent example, see: G. Liu, X. Liu, Z. Cai, G. Jiao, G. Xu,
W. Tang, Angew. Chem. Int. Ed. 2013, 52, 4235; Angew. Chem.
2013, 125, 4329.
Received: July 1, 2014
Revised: August 25, 2014
Published online: October 8, 2014
[16] For a review of halide effects in transition-metal catalysis, see: K.
Fagnou, M. Lautens, Angew. Chem. Int. Ed. 2002, 41, 26; Angew.
Chem. 2002, 114, 26.
Keywords: asymmetric catalysis · heterocycles · hydrogenation ·
iridium · stereoselectivity
.
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