Iridium-monodentate phosphoramidite-catalyzed asymmetric hydrogenation of substituted benzophenone N-H imines

Full text of DOI:10.1021/ja909583s

Published on Web 01/27/2010
Iridium-Monodentate Phosphoramidite-Catalyzed Asymmetric Hydrogenation
of Substituted Benzophenone N-H Imines
Guohua Hou,† Ran Tao,‡,§ Yongkui Sun,‡ Xumu Zhang,*,† and Francis Gosselin*,‡
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, and
Department of Chemistry, Rutgers, The State UniVersity of New Jersey, 610 Taylor Road, Piscataway,
New Jersey 08854-8066
Received November 11, 2009; E-mail: xumu@rutgers.edu; francis_gosselin@merck.com
Chiral diarylmethylamines are found in numerous biologically
active compounds of pharmaceutical relevance to human and animal
health.1 As a consequence, several approaches for their asymmetric
synthesis have been devised.2-6 Methodologies have relied upon
stoichiometric, chiral-auxiliary-based additions of arylmetal reagents
to N-aryl imines, oxazolidines, and N-tert-butanesulfinyl imines.2
Significant improvements have been made recently with the
development of rhodium-catalyzed enantioselective additions of
arylstannane, aryltitanium, and arylboron reagents to N-sulfonyl,
N-sulfamoyl, and N-tert-butanesulfinyl imines.3 While these meth-
ods offer moderate to high stereocontrol, they also often involve
use of excess reagents in their key steps as well as unproductive
deprotection schemes to isolate the desired product amines.
Asymmetric hydrogenation of substituted benzophenone imines
would provide a succinct, environmentally sound, and atom-
economical approach to diarylmethylamines. Asymmetric hydro-
genation of benzophenones to produce diarylmethanols has limited
precedent,7 and to the best of our knowledge, the corresponding
asymmetric hydrogenations of benzophenone imines8 are unknown.
The obstacles encountered with the preparation and isolation of
N-substituted benzophenone imines as single isomers have likely
thwarted attempts involving their use as substrates in asymmetric
hydrogenations.9 We have recently reported on the enantioselective
hydrogenation of N-H imines using iridium-f-binaphane as a
catalyst system that provides efficient access to chiral amines
without the requirement of nitrogen protection.10 We present herein
a concise, protection-free approach to the asymmetric synthesis of
diarylmethylamines.
Examination of solvent effects revealed that a 3:1 CH2Cl2/MeOH
combination afforded enantioselectivities of up to 87% ee (entries
13-15). Use of 1 mol % catalyst loading led to decreased reaction
performance (28% conv, 77% ee).15
Scheme 1. Asymmetric Hydrogenation of 2-Chlorobenzophenone
N-H Imine
Table 1. Catalyst Evaluation for Asymmetric Hydrogenation of
2-Chlorobenzophenone N-H Imine 1aa
entry
ligand
% conversionb
% eec
1
2
3
4
5
6
7
8
(S,S)-f-binaphane
(R)-Segphos
(R)-Binap
Josiphos
(S)-SiPhos
(R,R,R)-SiPhos PE
(R)-MonoPhos
(S)-NEt2-MonoPhos
(S)-MorPhos
26
25
47
12
99
20
87
70
85
62
99
99
99 (96)
99
99
64
64
64
52
62
20
66
80
76
83
72
80
83d
9
10
11
12
13
14
15
(S)-PipPhos
(S,R,R)-MonoPhos PE
(S,S,S)-MonoPhos PE
(S)-N-Bn-N-Me-MonoPhos
(S)-N-Bn-N-Me-MonoPhos
(S)-N-Bn-N-Me-MonoPhos
85d e
,
87d f
,
Benzophenone imines 1a-r were synthesized in a single step
on multigram scale, chromatography-free, via organometallic ad-
dition to benzonitriles.11 Initial evaluations of 2-chlorobenzophe-
none imine substrate 1a with [Ir(COD)Cl]2 as the precatalyst and
using chiral bidentate phosphines including f-binaphane, Segphos,
Binap, and Josiphos (Scheme 1 and Table 1, entries 1-4) all gave
low conversions to amine hydrochloride 2a and moderate enanti-
oselectivities at best. It is noteworthy that commercially available,
inexpensive monodentate phosphoramidite ligands (Figure 1) gave
superior results with improved conversion and enantioselectivities
(entries 5-15).12,13 (S,S,S)-MonoPhos PE (3a) gave slightly
improved enantioselectivity over its corresponding (S,R,R) diaste-
reomer 3b (entries 11 and 12). Evaluation of amine substituent
effects on the enantioselectivity led us to select (S)-N-benzyl-N-
methyl-MonoPhos (4) as the ligand of choice for this hydrogenation
(entries 11-15).14 Increasing the H2 pressure to 1500 psi ensured
full conversion and maintained high enantioselectivity (entry 15).
a Screening reaction conditions: [Ir(COD)Cl]2/phosphine/substrate )
2.5:10:100, ligand/metal ) 2:1, MeOH/CH2Cl2 ) 2:1, 10 mg/mL, rt,
500 psi H2, 36 h. b Determined by HPLC analysis; HPLC assay yield in
parentheses. c Determined by chiral HPLC or SFC analysis of the
corresponding acetamides (see the Supporting Information). d Reaction
at 1500 psi. e CH2Cl2/MeOH ) 2:1. f CH2Cl2/MeOH ) 3:1.
Figure 1
The effect of the counterion was evaluated using 2-chlorophenyl
imine 1a. Asymmetric hydrogenation of the corresponding
imine·HBF4 salt afforded decreased enantioselectivity (99% conv,
81% ee) relative to imine ·HCl 1a (Table 2, entry 1). Similarly,
hydrogenation of the imine ·HBF4 salt under chloride-free conditions
† Rutgers, The State University of New Jersey.
‡ Merck Research Laboratories.
§ MRL Summer Intern from the Department of Chemistry, Colorado State
University.
9
2124 J. AM. CHEM. SOC. 2010, 132, 2124–2125
10.1021/ja909583s  2010 American Chemical Society

C O M M U N I C A T I O N S
using cationic Ir(COD)2BF4 as the precatalyst resulted in poor
performance (27% conv, 47% ee). The ability of the iridium-phos-
phoramidite catalyst system to perform under acidic reaction
conditions and its tolerance to excess chloride ions is rather
remarkable. In particular, the improved reaction outcome in the
presence of chloride ion is somewhat counterintuitive since halide
ions are known transition-metal-catalyst poisons.9c,16
Acknowledgment. The authors thank the members of the Merck
High Pressure Laboratory for support and Dr. Fanyu Meng for
HRMS analyses. X.Z. and G.H. thank the National Institutes of
Health (GM58832) for financial support.
Supporting Information Available: Experimental procedures,
characterization data for new compounds, and analysis of enantiose-
lectivities of hydrogenation products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Table 2. Asymmetric Hydrogenation of Substituted Benzophenone
N-H Iminesa
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c d
,
entry
R1
R2
2
yield (%)b
ee (%)
1
2
3
4
5
6
7
8
2-Cl (1a)
2-Br (1b)
2-Me (1c)
2-OMe (1d)
2-F (1e)
2-CF3 (1f)
3-Cl (1g)
3-OMe (1h)
4-Me (1i)
2,3-Me2 (1j)
2-Cl (1k)
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
94
96
82
88
80
95
89
93
96
91
96
93
94
91
93
90
89
87
87
91
82 (R)
76
36
98
31
46
9
31 (S)
86
10
11
12
13
14
15
16
17
18
4-Me
4-OMe
4-Me
4-OMe
4-Me
4-Me
92
93
91
94
92
72
81
74
2-Cl (1l)
2-Me (1m)
2-Me (1n)
2-Cl-3-CF3 (1o)
2,5-Cl2 (1p)
2,6-Cl2 (1q)
2-Me-5-Cl (1r)
4-Me
4-OMe
a Conditions: [Ir(COD)Cl]2/ligand 4/substrate ) 2.5:10:100, 0.04 M,
1500 psi H2, rt, 36 h. b Isolated yields. c Determined by chiral HPLC or
SFC analysis of the corresponding acetamides (see the Supporting
Information). d Absolute configuration determined by comparison with
refs 3e and 10.
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(15) Inferior results were obtained with metal/ligand ratios of 1:1 (76% conv,
56% ee) and 1:3 (11% conv, 41% ee) using imine 1a. Single monodentate
phosphoramidite-iridium complexes can afford high enantioselectivities;
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The hydrogenation appears to be sensitive to the steric and
electronic nature of the substituent at the ortho position of the
aromatic ring (Table 2). Chloro, bromo, and methyl substituents at
the 2-position gave high enantioselectivities (82-91% ee; entries
1-3). Decreased reaction enantioselectivities were observed with
coordinating 2-methoxy and smaller 2-fluoro substituents (entries
4 and 5). Asymmetric hydrogenation of 2-trifluoromethylbenzophe-
none imine 1f gave up to 98% ee (entry 6). The increased
enantioselectivity may be a consequence of the larger van der Waals
hemispheric volume of a CF3 group (42.6 Å3) in comparison with
a methyl group (16.8 Å3).17 Moving substituents to the meta position
led to a significant decrease in enantioselectivity (entries 7-8).
Similarly, a p-methyl substituent gave 31% ee (entry 9). A slight
increase in enantioselectivity was observed when electron-donating
4-methyl or 4-methoxy groups were introduced as R2 substituents
(see entries 1, 11, and 12 and 3, 13, and 14, respectively).
Benzophenone imines having more than one aromatic ring sub-
stituent gave enantioselectivities in the range 72-94% ee (entries
11-18).
In conclusion, we have developed an asymmetric hydrogenation
of benzophenone N-H imines where ortho substitution is a key
feature for high enantioselectivity. The reaction provides efficient
access to diarylmethylamines without nitrogen protection. The
highly modular and inexpensive nature of chiral phosphoramidite
ligands coupled with the ease of preparation of N-H imines bodes
well for further practical applications of this methodology.
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