C O M M U N I C A T I O N S
Table 2. The Asymmetric Hydrogenation of Enamines Catalyzed
by Ir/(Ra,S,S)-4a
hydrogenation of tricyclic enamine 7 yielded the corresponding
amine 8 with 82% ee (Figure 1). This result prompted us to utilize
this asymmetric hydrogenation reaction to synthesize the isoquino-
line alkaloid crispine A,15 which was isolated from Carduus crispus,
Linn. (welted thistle) and has a significant cytotoxic activity.16 The
tricyclic enamine 11 was conveniently synthesized from 2-(3,4-
dimethoxyphenyl)ethamine in 72% yield by a literature method.15b
The asymmetric hydrogenation of enamine 11 was performed under
the optimized conditions using the catalyst Ir/(Sa,R,R)-4 to produce
crispine A in 97% yield with 90% ee (Scheme 2).
entry
R1
R2
product
ee (%)b
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-MeOC6H4
3-FC6H4
2-MeC6H4
2-ClC6H4
4-MeOC6H4
4-FC6H4
Me
Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
94 (S)
95
96
91
94
92
95
97
89
93
92
87
82
90
97
94
94
72
iPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
9
10
11
12
13
14
15
16
17
18c
Scheme 2
Et
Et
Et
Me
4-ClC6H4
4-BrC6H4
nC4H9
a Reaction conditions are the same as those of Table 1, entry 9,
yields >90%. b Determined by chiral GC (see Supporting Information).
c (Sa,R,R)-Monophos-Pe gave 66% ee. Very low ee values were obtained
with other monodentate phosphorus ligands listed in Table 1.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant No. 20532010, 20572049, 20721062),
the Major Basic Research Development Program (Grant No.
2006CB806106), and the “111” project (B06005) of the Ministry
of Education of China for financial support.
tried to detect if there is a secondary interaction between iridium
and ligands (Ra,S,S)-4 and (Ra,S,S)-Monophos-Pe. However, 1H and
31P NMR analyses in the beginning or the end of the reaction
showed no cyclometallated Ir-complex generated by cyclometalation
at the methyl group of phosphoramidite ligand like in the Ir-
catalyzed substitution reaction.14a,b
Supporting Information Available: Experimental procedures, the
characterizations of substrates and products, and the analysis of ee
values of hydrogenation products. This material is available free of
Encouraged by the promising result obtained in the hydrogenation
of enamine 1a, a variety of dihydropyrrole substrates 1 were
examined using catalyst Ir/(Ra,S,S)-4. The alkyl group R2 on the
nitrogen atom in the substrates has no obvious influence on the
reactivity and enantioselectivity of the reaction. The hydrogenations
of enamines with N-Me (1a), N-Et (1b), and N-iPr (1c) produced
the corresponding tertiary amines with comparable enantiomeric
excesses (94-96% ee, Table 2, entries 1-3). The aryl group (R1)
on the R-position of substrates 1 is necessary for obtaining high
enantioselectivity. When the R1 group was phenyl or a substituted
phenyl, the hydrogenated products were isolated with high yields
(>90%) with 82-97% ee (entries 1-17). However, the hydrogena-
tion of substrate 1r, when R1 was nBu, afforded the amine 2r with
a lower ee value (72%, entry 18). The electronic property of
substituents on the aryl ring of the substrate has very little effect
to the enantiomeric excess of the product. The substituent at the
ortho-position of the aryl ring of the substrate slightly diminished
the enantioselectivity of the reaction. For example, the hydrogena-
tions of 1-methyl-5-o-tolyl-2,3-dihydropyrrole (1l) and 1-methyl-
5-(o-chlorophenyl)-2,3-dihydropyrrole (1m) yielded the cyclic
amines 2l and 2m in 87% ee and 82% ee, respectively (entries 12
and 13).
References
(1) For reviews, see: Tang, W.-J.; Zhang, X.-M. Chem. ReV. 2003, 103, 3029.
(2) For reviews, see: Halpern, J. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic Press: Orlando, FL, 1985; p 41.
(3) (a) Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985. (b)
Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Bo¨rner, A.
Tetrahedron Lett. 2000, 41, 2351. For asymmetric hydrogenation of
unsubstituted enamines and N-arylenamines, see: (c) Hsiao, Y.; Rivera,
N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong,
J. D., III; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am.
Chem. Soc. 2004, 126, 9918. (d) Dai, Q.; Yang, W.; Zhang, X. Org. Lett.
2005, 7, 5343.
(4) Hou, G.-H.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2006,
128, 11774.
(5) For Ir-catalyzed asymmetric hydrogenation of enamides, see: (a) Bunlak-
sananusorn, T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42,
3941. (b) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Bo¨hler, C.; Ru¨egger,
H.; Scho¨nberg, H.; Gru¨tzmacher, H. Chem. Eur. J. 2004, 10, 4198. (c)
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(6) (a) Elliott, R. L.; Ryther, K. B.; Anderson, D. J.; Raszkiewicz, J. L.;
Campbell, J. E.; Sullivan, J. P.; Garvey, D. S. Bioorg. Med. Chem. Lett.
1995, 5, 991. (b) Dunsmore, C. J.; Carr, R.; Fleming, T.; Tumer, N. J.
J. Am. Chem. Soc. 2006, 128, 2224.
(7) Monophos-Pe ) O,O′-(1,1′-dinaphthyl-2,2′-diyl)-N,N′-di(1-phenylethyl)-
phosphoramidite.
(8) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
(9) SDP ) 7,7′-bis(diphenylphosphino)-1,1′-spirobiindane.
(10) Me-Duphos ) 1,2-bis(2,5-dimethylphospholano)benzene.
(11) Josiphos ) 1-[2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine.
(12) Synphos ) (5,6),-(5′,6′)-bis(ethylenedioxy)-2,2′-bis(diphenylphosphino)-
1,1′-biphenyl.
(13) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425.
(14) (a) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 14272. (b) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Du¨bon,
P.; Helmchen, G. Org. Lett. 2005, 7, 1239. (c) Mikhel, I. S.; Ru¨egger, H.;
Butti, P.; Camponovo, F.; Huber, D.; Mezzetti, A. Organometallics 2008,
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Figure 1
The catalyst Ir/(Ra,S,S)-4 was also applied to the hydrogenation
of enamines having a six-membered ring or a fused ring. In the
hydrogenation of 1-methyl-6-phenyl-1,2,3,4-tetrahydropyridine (5),
the cyclic tertiary amine 6 was provided in 21% ee. Other available
monodentate phosphorus ligands listed in Table 1 were also tested
and no more than 20% ee were obtained. In contrast, the
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