C O M M U N I C A T I O N S
between the Cp* methyl group and the imine aromatic ring,11 the more
electron-rich 4g and 4h might be expected to give rise to stronger
interactions and so higher ee’s.
Table 1. Asymmetric Hydrogenation of Imines 4 To Give Amines
5a
The applicability of 2 was also demonstrated in the hydrogenation
of imine precursors to tetrahydro-ꢀ-carbolines (Table 2). Unlike the
reduction of 4, the reactions were performed in methanol, in which 6
is more soluble. In contrast to 4a-4d, all the alkyl substituted imines
6 gave rise to excellent ee’s, including those having cyclohexyl and
tBu groups, although 6e necessitated a longer time. The catalyst loading
could be lowered to 0.1% without compromising the ee (entry 5).
Remarkably, the electronic properties of the aryl substituents appear
to impact significantly on the enantioselectivity (entries 8 vs 10). In
line with this, when the electronic effect is mitigated with a spacer, a
high ee of 99% was obtained (entry 11). However, when switching to
a similar Ir(III) catalyst, a high ee of 97% was obtained in hydrogenat-
ing 6g (entry 9).
entry
R1/R2/R3
time (h)
yield (%)b
ee (%)c
1
2
3
H/H/Me 4a
1
8
4
94
95
90
90
85
90
95
90
95
94
95
99d
97
40
65
83
91
96
93
93
95
99
H/H/Et 4b
H/H/iPr 4c
4
H/H/Cy 4d
4
5e
6e
7
H/H/iPr 4c
24
24
4
4
4
H/H/Cy 4d
MeO/MeO/Me 4e
MeO/MeO/Et 4f
MeO/MeO/iPr 4g
MeO/MeO/Cy 4h
MeO/MeO/R 4if
8
9
10
11
4
5
In conclusion, an efficient Rh(III)-diamine catalyst has been
identified, which affords excellent enantioselectivities in asymmetric
hydrogenation of imines to give bioactive tetrahydroisoquinolines and
tetrahydro-ꢀ-carbolines. The cationic nature and the bulky noncoor-
dinating counteranion appear to be the key to the success of 2.
a Reaction conditions: 0.5 mmol 4, 1 mol% 1, 4 mol% AgSbF6, 2 mL
of DCM, 30 µL of water, 20 bar of H2 at room temperature. b Isolated
yields. c S product, determined by HPLC with
a Chiralcel OD-H
column. d Determined by GC (Table S1). e iPrOH as solvent; 50 bar of
H2. f R ) 3,4-(MeO)2C6H3CH2CH2.
Acknowledgment. We gratefully acknowledge EPSRC for a
Dorothy Hodgkin Postgraduate Award to C.L. We also thank Drs.
R. Cosstick and A. Carnell for suggestions and Dr. A. Mills for
collecting MS spectra.
Table 2. Asymmetric Hydrogenation of Imines 6 To Give Amines
7a
Supporting Information Available: Experimental details and
spectroscopy data (1H, 13C NMR, and HPLC). This material is available
entry
R
time (h)
yield (%)
ee (%)b
References
1
2
3
Me 6a
Et 6b
3
3
3
95
96
94
95
91
97
94
96
97
95
95
99
99
98
98
98
>99
99
20
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iPr 6c
Cy 6d
Cy 6d
tBu 6e
4
3
5c
6
24
12
4
3
4
7
C6H5 6f
8
4-MeOC6H4 6g
4-MeOC6H4 6g
4-CF3C6H5 6h
R′ 6if
9d
10
11
97
5
5
96e
99
a The conditions were the same as those in Table 1 except with
MeOH as solvent. b S product. c 0.1 mol% 1 and 0.4 mol% AgSbF6 at
50 bar of H2. d A similar Ir(III) catalyst was used. e Determined using a
Chiralpak AD column. f R′ ) 3,4-(MeO)2C6H3CH2CH2.
active catalyst 2.8 Unlike asymmetric transfer hydrogenation,5a,b
the Ru(II) analogue of 2 was less effective in the asymmetric
hydrogenation (Table S1).
(3) de Vries, J. G., Elsevier, C. J., Eds. Handbook of Homogeneous Hydrogena-
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Using the optimized conditions, Viz. with 2 being generated in situ
from 1 (1 mol%), a range of imines were hydrogenated. The results
on 3,4-dihydroisoquinolines and 3,4-dihydro-6,7-dimethoxyisoquino-
lines are given in Table 1. As can be seen, 4a was completely reduced,
affording 5a in 99% ee and 94% isolated yield after 1 h (entry 1).
(5) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
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X. F.; Xiao, J. L. Chem. Commun. 2007, 2449.
i
However, replacing the methyl with the bulkier Et, Pr, and Cy
(7) (a) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C.;
Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724. (b) Sandoval, C. A.;
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R.; Murata, K. Org. Lett. 2007, 9, 255. (d) Ohkuma, T.; Utsumi, N.;
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(9) Water presumably helps dissolve the silver salt. When the presynthesized
2 was used, water was not required for the reduction.
substituents necessitated longer reaction times, and the enantioselec-
tivity decreased significantly in the case of 4c and 4d (entries 3 and
4). On the other hand, when the solvent was changed to isopropanol,
the ee’s were improved to 83% and 91% for 5c and 5d, respectively
(entries 5 and 6). Delightfully, excellent yields and ee’s were observed
for 3,4-dihydro-6,7-dimethoxyisoquinolines. Thus, the compounds
4e-4i were all fully reduced in 4-5 h, with ee’s up to 99% being
obtained. These results suggest that the poor behavior of 4c and 4d
cannot simply be ascribed to steric effects. Since the enantioselectivity
of the hydrogenation may be determined by weak C-H π interactions
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37, 2897. (b) Macchioni, A. Chem. ReV. 2005, 105, 2039.
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