Enantioselective hydrogenation of N-H imines

Article abstract of DOI:10.1021/ja903319r

(Figure Presented) N-H ketoimines 3a-3v are readily prepared in high yield via organometallic addition to nitriles and isolated as corresponding bench-stable hydrochloride salts. Homogeneous asymmetric hydrogenation of unprotected N-H ketoimines 3a-3v usi

Full text of DOI:10.1021/ja903319r

Published on Web 07/01/2009
Enantioselective Hydrogenation of N-H Imines
Guohua Hou,† Francis Gosselin,*,‡,§ Wei Li,† J. Christopher McWilliams,‡ Yongkui Sun,‡
Mark Weisel,‡ Paul D. O’Shea,§ Cheng-yi Chen,‡ Ian W. Davies,‡ and Xumu Zhang*,†
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065,
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Trans-Canadienne,
Kirkland, Que´bec, Canada H9H 3L1, and Department of Chemistry, Rutgers, The State UniVersity of New Jersey,
610 Taylor Road, Piscataway, New Jersey 08854-8066
Received May 1, 2009; E-mail: francis_gosselin@merck.com; xumu@rutgers.edu
Scheme 1. Synthesis of N-H Iminesa
Chiral amines are ubiquitous structural elements of small-
molecule pharmaceuticals and agrochemicals that improve human
life. While several approaches have been developed to prepare chiral
amines, decades of research have evolved catalytic hydrogenation
into a technology ideally suited for their stereoselective synthesis.1
a Conditions: (a) R2MgX or R2Li, in MTBE or THF; MeOH quench.
Although success has been achieved with enantioselective hydro-
(b) HCl in Et2O.
genation of protected enamides, enamines, and imines, many
catalysts fail to deliver the same levels of control and efficiency
Scheme 2. Asymmetric Hydrogenation of N-H Imines
demonstrated with ketones and olefins.1-3 Diminished enantiose-
lectivities may be observed because of ambiguous catalyst-substrate
interactions complicated by imine-enamine tautomerization and
interconversion of imine E/Z stereoisomers.1 Furthermore, available
methods often require cumbersome protecting group manipulations
to provide a substrate suited for hydrogenation and subsequent
release of the desired amine products.
Table 1. Asymmetric Hydrogenation of 3a (R1 ) 4-Tolyl, R2 )
Methyl)a
We report herein the first examples of efficient, atom-economical,
entry
ligand
solvent
% convb
% eec
enantioselective hydrogenations of unprotected N-H imines,4
a
1
2
3
4
5
6
7
8
TangPhos
DuanPhos
BINAP
Me-DuPhos
(S,S)-5
(S,S)-5
(S,S)-5
TFEd
TFE
TFE
TFE
TFE
99
41
40
20
31
60
15
60
37
30
99
99
99
99
99
99
98
99
0
8
fundamental step in the development of an ideal direct asymmetric
reductive amination of ketones. To the best of our knowledge, N-H
ketoimines have been completely overlooked as substrates for
enantioselective hydrogenation. This is possibly because they have
been considered difficult to synthesize and isolate and often exist
as complex mixtures of E/Z isomers and imine-enamine tautomers.
Multigram amounts of N-H ketoimines 3a-3v were readily
prepared via organometallic addition to nitriles 1 followed by
quenching with anhydrous MeOH and isolation of the corresponding
hydrochloride salts as single isomers, free-flowing, bench-stable
solids (Scheme 1).
14
20
52
80
70
32
38
20
9
10
20
89
95f
95g
95h
73i
CH2Cl2
Toluene
(S,S)-5
(S,S)-5
DCEe
9
EtOAc
THF
MeOH
MeOH/TFE (2:1)
MeOH/DCE (2:1)
MeOH/CH2Cl2 (1:2)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
10
11
12
13
14
15
16
17
18
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
(S,S)-5
Inspired by a number of imine hydrogenation studies,5,6 we
anticipated that rigid electron-rich ligands could lead to high
enantioselectivities with N-H ketoimines (Scheme 2). Our initial
evaluation began with hydrogenation of N-H imine 3a as the model
substrate with a series of catalysts. Few promising results were
obtained using Rh-phosphine catalysts. A number of electron-rich
chiral Ir-phosphine complexes were also evaluated (Table 1, entries
1-4). While poor results were obtained using TangPhos,7a
DuanPhos,7b BINAP,7c and Me-DuPhos,7d we were gratified to find
that axially chiral Ir-(S,S)-f-binaphane7e (Figure 1) was a promising
candidate for further optimization. Only moderate conversion was
observed in most solvents (Table 1, entries 5-8). Use of MeOH
as solvent gave complete conversion albeit with poor enantiose-
lectivity (Table 1, entry 11). We found that the best enantioselec-
tivity was obtained using CH2Cl2 as solvent (80% ee, Table 1, entry
6). We optimized the solvent combination and ratio with MeOH
to achieve complete conversion and high enantioselectivity (Table
a Reaction conditions: [Ir(COD)Cl]2/phosphine/substrate ) 2.5:5:100,
1:1 ligand/metal, rt, 100 atm of H2, 18 h. b Determined by GC analysis.
c Determined by chiral GC analysis of the corresponding acetamides (see
Supporting Information). d 2,2,2-Trifluoroethanol. e 1,2-Dichloroethane.
f 30 atm of H2. g 10 atm of H2. h 5 atm of H2. i 10 atm of H2, S/C )
100, 48 h.
1, entries 12-18). Interestingly, under these optimized conditions
we observed a negative impact on enantioselectivities when the
chloride counterion in 3a was replaced with noncoordinating
-
counterions: methanesulfonate (75% conversion, 51% ee), PF6
-
(90% conversion, 91% ee), BF4 (99% conversion, 88% ee).
A variety of N-H imine substrates 3a-3v were then examined
using the Ir-f-binaphane catalyst system (Table 2). The bulkiness
of the R2 group in substrates had an influence on the enantiose-
lectivities. As the R2 group changed from Me to tert-Bu, the
enantioselectivity of the product gradually decreased from 93% to
80% ee (entries 2-5). Substrates bearing both electron-donating
† Rutgers, The State University of New Jersey.
‡ Merck Research Laboratories.
§ Merck Frosst Centre for Therapeutic Research.
9
9882 J. AM. CHEM. SOC. 2009, 131, 9882–9883
10.1021/ja903319r CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Isotopic Labeling of 3a
toimines. This method allows the enantioselective synthesis of chiral
amines without use of protecting groups. Further studies are
underway and will be reported in due course.
Figure 1
Table 2. Enantioselective Hydrogenation of N-H Iminesa
yield (%)b
ee (%)c
Acknowledgment. X.Z. and G.H. thank the National Institutes
entry
R1
R2
product
of Health (GM58832) for financial support.
1
2
3
4
5
6
7
8
4-MeC6H4 (3a)
C6H5 (3b)
C6H5 (3c)
C6H5 (3d)
C6H5 (3e)
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
93
92
92
90
95
95
95
94
93
95
94
92
93
92
93
92
95
94
90
91
95
95 (R)d
93 (R)
86 (R)
88 (R)
80 (R)
93 (R)
92 (R)
94
93 (R)
93 (R)
92
94
92
91
81
92 (R)
81
93
92 (R)
17 (R)
73 (R)
23 (R)
Supporting Information Available: Experimental procedures,
characterization, analysis of enantioselectivities of hydrogenation
products (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
n-Bu
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4-MeOC6H4 (3f)
4-FC6H4 (3g)
4-ClC6H4 (3h)
4-BrC6H4 (3i)
4-CF3C6H4 (3j)
3-MeC6H4 (3k)
3-MeOC6H4 (3 L)
3-ClC6H4 (3m)
3-BrC6H4 (3n)
2-MeC6H4 (3o)
2-MeOC6H4 (3p)
2-ClC6H4 (3q)
1-naphthyl (3r)
2-naphthyl (3s)
t-Bu (3t)
References
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
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4m
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4t
4u
4v
cyclohexyl (3u)
4-MeC6H4 (3v)
a Conditions: [Ir(COD)Cl]2/(S,S)-f-binaphane/substrate
)
2.5:5:100,
10 atm of H2, rt, 20 h, >99% conversion. b Isolated yields of
hydrochloride salts. c Determined by chiral GC analysis of the
corresponding acetamides (see Supporting Information). d Absolute
configuration determined by comparison with literature (see Supporting
Information for other entries).8
and -withdrawing substituents on the aromatic ring in R1 were
hydrogenated with uniformly high enantioselectivities (entries
6-14). Both the 1- and 2-naphthyl N-H imines afforded product
amines in 92 and 93% ee, respectively (entries 18 and 19). We
found that the presence of either a methyl or chloro substituent at
the ortho-position resulted in a slightly reduced ee (entry 15 and
17). The reduction of enantioselectivity may be attributed to the
steric hindrance of the ortho-substituents in the substrates. However,
an ortho-methoxy group did not exhibit a similar effect (entry 16).
Significant erosion in enantioselectivity was observed when the aryl
substituent was replaced with a sterically hindered tert-butyl group
(entry 20). Finally, the Ir catalyst showed promising enantioselec-
tivities on dialkyl imine 3u and diaryl imine 3v, substrates with a
more limited steric and electronic bias (entries 21-22).
Preliminary mechanistic information was garnered through
isotopic labeling of imine 3a with D2 in MeOH/CH2Cl2 (Scheme
3). 1H NMR analysis of the crude product showed exclusive
formation of R-deuterio-amine hydrochloride 4a, suggesting a
pathway consistent with reduction of the imine tautomer.3 In
addition, enantioface selection of imine 3a by the Ir-f-binaphane
catalyst was found to be identical to that of 4′-methylacetophenone.9
In conclusion, we have developed an unprecedented, operation-
ally simple, and mild asymmetric hydrogenation of N-H ke-
(7) (a) TangPhos: (1S,1S′,2R,2R′)-1,1′-di-tert-butyl-(2,2′)-diphospholane. (b)
DuanPhos: (1S,1′S,2R,2′R)-2,2′-di-tert-butyl-2,3,2′,3′-tetrahydro-1H,1′H-
(1,1′)-biisophosphindolyl. (c) BINAP: (R)-2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl. (d) MeDuPhos: 1,2-bis[(2R,5R)-2,5-dimethylphospholano]ben-
zene. (e) (S,S)-f-binaphane: 1,1′-bis[(S)-4,5-dihydro-3H-binaphtho[2,1-c:1′,2′-
e]phosphepino]ferrocene.
(8) Smith, H. E.; Neergard, J. R.; de Paulis, T.; Chen, F.-M. J. Am. Chem. Soc.
1983, 105, 1578.
(9) Hydrogenation of 4′-methylacetophenone with Ir-f-binaphane gave (R)-R-
4-dimethylbenzenemethanol (30% conversion, 64% ee, [R]20 +27.4° (c
589
) 0.2, MeOH); lit.: [R]20589 +43.8° (c ) 0.914, MeOH) for 99.8% ee: Mathre,
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JA903319R
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