Studies from these laboratories4 and others5,6 have shown
that primary4,6 and secondary5 acyclic enamines derived from
ꢀ-ketoesters and amides are viable substrates for asymmetric
hydrogenation, although no examples of asymmetric hydro-
genation of cyclic secondary enamines have been reported.
Exocyclic N-alkyl imines have been reduced with good
enantioselectivity using Ru-catalyzed transfer hydrogenation7
and Ti-catalyzed hydrosilylation.8 However, the enantiose-
lective hydrogenation of acyclic imines remains a significant
challenge, and no general catalyst systems have been
reported.9
directly exposed to DBU to afford a mixture of imines
(5a-5b) and enamine (5c) (ratio of 5a:5b:5c ca. 66:21:13)12
as a light yellow crystalline solid in 88% isolated yield.
Attempts to reduce the mixture of isolated imines (5a-5b)/
enamine (5c) using chiral Ru, Rh, and Ir transfer hydrogena-
tion catalysts gave low levels of enantioselectivity (<30%
ee). However, screening this substrate mixture against a
library of chiral bis(phosphine) Rh and Ir complexes in a
variety of solvents yielded a catalyst system consisting of
Josiphos 8 in conjunction with (COD)2RhBF4 that gave the
desired product in reasonable conversion and enantioselec-
tivity (Table 1, entry 1). Interestingly, the substitution pattern
Thus, treatment of compound 210 with hydrogen chloride
in dry ethyl acetate led to ammonium chloride 3, which was
directly crystallized from the reaction mixture in 99% yield
(Scheme 2). Subsequent treatment of 3 with 2.5 N sodium
Table 1. Optimization of Asymmetric Hydrogenation Conditions
Scheme 2. Preparation of Imines and Enamine
TFAd
entry precursora S/Cb [SM]c (equiv) convne 6:7e
%
erf
1
2
3
4
5
6
7
BF4
BF4
Cl
37
50
0
>99
99
47:1 94:6
49:1 95:5
100:0 94:6
85:1 95:5
31:1 95:5
8:1 95:5
63
100
100
100
100
100
200
0
185
185
185
185
250
0
72
Cl
0.2
0.5
0.8
0.5
86
Cl
99
Cl
99
Cl
98
23:1 95:5
a The Rh catalysts were preformed by stirring the metal precursor and
the ligands at ambient temperature in TFE. b Sustrate to catalyst ratio.
c Concentration of 5a/5b/5c in mg/mL. d Equivalents of trifluoroacetic acid
(TFA) relative to substrate. e HPLC area percent, uncorrected for absorption
factor. f Enantiomeric ratio of desired:undesired product, determined by
chiral HPLC analysis.
hydroxide aqueous solution in isopropyl acetate and water,
followed by addition of 10 mol % of tert-butanol, acetic acid,
and sodium hypochlorite,11 gave a quantitative assay yield
of N-Cl intermediate 4. Without isolation, compound 4 was
of the best ligand 8 was very similar to that of the two ligands
(9 and 10) found to be effective in the asymmetric hydro-
genation of ꢀ-enamine amides and esters.4a In addition, as
was observed in certain cases for the hydrogenations of
unprotected primary and secondary enamines,4,5 the use of
2,2,2-trifluoroethanol (TFE) was found to be key to achieving
high reactivity and enantioselectivity in this reaction. Inter-
estingly, product 7, formally derived from hydrogenolytic
cleavage of a mesylate group from 6, was detected as a
byproduct in most of the screening reactions. The other major
byproduct of the reaction, the corresponding alcohol derived
from hydrolysis of 5a/5b/5c to the ketone followed by
reduction, could be minimized by rigorous drying of the
reaction mixture with 4 Å molecular sieves.
(4) (a) 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, 9918–9919. (b)
Hansen, K. B.; Rosner, T.; Kubryk, M.; Dormer, P. G.; Armstrong, J. D.,
III Org. Lett. 2005, 7, 4935–4938. (c) Kubryk, M.; Hansen, K. B.
Tetrahedron: Asymmetry 2006, 17, 205–209.
(5) Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343–5345
(6) Bunlaksananusorn, T.; Rampf, F. Synlett 2005, 2682–2684
(7) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916–4917.
.
.
(8) (a) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 6784–6785. (b) Willoughby, C. A.; Buchwald,
S. L. J. Am. Chem. Soc. 1994, 116, 11703–11714. (c) Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952–8965.
(9) For a recent example, see: (a) Cheemala, M. N.; Knochel, P. Org.
Lett. 2007, 9, 3089–3092. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim,
2000; p 1.
Although the Josiphos/Rh catalyst system gave the
desired chiral amine in useful enantioselectivity, it ex-
(10) For the preparation of compound 2, please see ref 1.
(11) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R., Jr.; Lee, J.; Askin, D.;
Dolling, U. H.; Volante, R. P. Tetrahedron Lett. 2005, 46, 1099.
(12) The ratio of 5a:5b:5c varied from 66:21:13 to 14:21:65 depending
on the temperature and solvents. It was subsequently found that this ratio
had no impact on the performance of the asymmetric hydrogenation.
370
Org. Lett., Vol. 11, No. 2, 2009