Highly efficient Rh(I)-catalyzed asymmetric hydrogenation of enamines using monodente spiro phosphonite ligands.
ABSTRACT A highly enantioselective hydrogenation of nonfunctionalized enamines has been developed by using rhodium complexes of chiral spiro phosphonite ligands, providing chiral tertiary amines in excellent enantioselectivities.
Highly Efficient Rh(I)-Catalyzed Asymmetric Hydrogenation of Enamines
Using Monodente Spiro Phosphonite Ligands
Guo-Hua Hou, Jian-Hua Xie, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received June 23, 2006; E-mail: firstname.lastname@example.org
Chiral amines are an important class of compounds in organic
and pharmaceutical synthesis, and a great effort has been made to
develop efficient synthetic methods for chiral amines. In the past
decades, the catalytic asymmetric hydrogenation of functionalized
enamines, such as R- and ?-N-acylamino acrylates, and enamides
have been extensively studied, and a great number of highly
enantioselective protocols for the synthesis of enantiomer-enriched
primary and secondary amines have been documented.1However,
only a limited progress has been achieved in the direct preparation
of chiral tertiary amines, which broadly occurred in the biologically
active molecules and natural products,2by asymmetric hydrogena-
tion of the corresponding N,N-dialkylenamines. This is not surpris-
ing because one substantial drawback in the current approaches to
asymmetric hydrogenation of enamides is the requirement of an
N-acyl group in the substrate.3This N-acyl group is considered
indispensable for the substrate to form a chelate complex with metal
of catalyst in transition state, giving a good reactivity and
enantioselectivity. Up to now, only two groups have tackled the
challenging class of N,N-dialkylenamine substrates in the asym-
metric hydrogenation.4In 1994, Buchwald et al.5reported the first
example of catalytic asymmetric hydrogenation of simple enamines.
By using 5 mol % chiral titanocene catalyst [(S,S,S)-(EBTHI)TiO2-
binaphtho] they achieved excellent enantioselectivities (up to 98%
ee) in the hydrogenation of 1-(dialkylamino)-1-arylethenes. Few
years later, Bo ¨rner and co-workers6used chiral Rh(I)-diphosphine
complexes for this hydrogenation and obtained the chiral tertiary
amines in moderate enantiomeric excesses (up to 72%). These
results are very encouraging and suggested that new efficient
catalysts are necessary for the development of highly enantio-
selective hydrogenation of simple nonfunctionalized enamines to
give chiral tertiary amines in broad scope.
Recently, we demonstrated that the chiral monodentate phos-
phoramidites and phosphonites containing a 1,1′-spirobiindane
scaffold were highly enantioselective ligands for the Rh-catalyzed
asymmetric hydrogenation of N-(R-arylethenyl)-acetamides and
N-acyl R- and ?-dehydroamino acid derivatives.7As a part of our
sustained efforts in this area, we herein wish to report the
asymmetric hydrogenation of N,N-dialkylenamines using chiral
spiro phosphonite ligands 1, providing chiral tertiary amines in
excellent enantiomeric excesses (up to 99.9%).
The chiral tertiary 1,2-diarylethanamine is a very useful unit; it
widely exists in natural products such as benzylisoquinolines.8The
catalytic asymmetric hydrogenation of N,N-dialkylenamines is one
of the most straightforward accesses to the optically active tertiary
1,2-diarylethanamines. In our study, the hydrogenation of (E)-1-
(1-pyrrolidinyl)-1,2-diphenylethene (2a) was initially performed
under 100 atm of H2in THF with the rhodium catalyst generated
in situ from 1 mol % [Rh(COD)2]BF4and 2.2 mol % phosphorus
ligands. A brief screening on the chiral phosphorus ligands available
in our laboratory showed that the diphosphine ligands including
BINAP, SDP, and JosiPhos were inefficient in the reaction (ee e
10%). Most of monophosphorus ligands illustrated in Scheme 1
also gave very low enantioselectivity (ee e 14%) except for spiro
phosphonite ligand (S)-1c, which provided chiral tertiary amine 3a
in 33% ee (Table 1, entry 3).
It was reported that the additives might play a crucial role for
the high reactivity and enantioselectivity in the hydrogenations of
simple olefins,9ketones,10and imines.11To improve the enantio-
Table 1. Rh(I)-Catalyzed Asymmetric Hydrogenation of Enamine
2a, Optimizing Reaction Conditionsa
aReaction conditions: 1 mol % [Rh(COD)2]BF4, 2.2 mol % ligand,
[substrate] ) 0.125 M, room temperature, 100% conversion.bDetermined
by chiral HPLC using a chiralcel OD-H column.cWith 0.5 mol % catalyst,
Published on Web 08/19/2006
11774 9 J. AM. CHEM. SOC. 2006, 128, 11774-11775
10.1021/ja0644778 CCC: $33.50 © 2006 American Chemical Society
selectivity in the hydrogenation of enamine 2a catalyzed by Rh/
(S)-1c complex, we investigated the effect of additives. When
o-phthalimide, HOAc, or H2SO4 were added, the catalyst was
strongly deactivated and only very low conversions were obtained.
However, a promising result was obtained when I2was added. In
the presence of 5 mol % I2, the enantioselectivity of reaction was
dramatically increased to 71% ee (entry 4). Adjusting the amount
of I2, we found that 2 mol % I2was suitable for achieving a high
enantioselectivity (83% ee) (entry 5). Different solvents were then
compared in the presence of 2 mol % I2. A full conversion was
obtained in all tested solvents. In addition to THF, the solvents
including Et2O, dioxane, CH2Cl2, and toluene also could be
employed, albeit the enantioselectivities were slightly lower (60-
78% ee). However, the reactions in MeOH and chelate solvent DME
(1,2-dimethoxyethane) had very low enantioselectivities (entries 11
and 12). Although the addition of I2significantly improved the
enantioselectivity of hydrogenation of enamine 2a, the reaction rate
was still too low.
Acid was often utilized to accelerate the reaction rate in the Ir(I)-
catalyzed asymmetric hydrogenation of imines by preventing
deactivation of the catalyst caused by the amine products.12It was
mentioned above that the use of acetic acid alone in this Rh(I)-
catalyzed hydrogenation of enamines strongly lowered the conver-
sion. Surprisingly, when the acetic acid was used together with 2
mol % of I2in the hydrogenation of enamine 2a, the reaction rate
was remarkably increased. In the presence of 20-50 mol % of
acetic acid the reaction time was shortened from 48 to 12 h without
losing enantioselectivity. A more significant improvement brought
about by the addition of I2and acetic acid was that the hydrogena-
tion could proceed under a much lower pressure of H2, which was
beneficial to high enantioselectivity. For example, employing 2 mol
% I2and 20 mol % acetic acid as additives, the hydrogenation of
2a was completed in 12 h under 10 atm of hydrogen, affording the
amine 3a in 87% ee (entry 15). The comparison of ligands 1 under
the optimized conditions showed that the enantioselectivity of
catalyst was constantly enhanced as the size of R group in the
ligands 1 became larger. The ligand 1c, which contained a tert-
butyl gave the best result. Other ligands listed in Scheme 1 were
also evaluated in combination with iodine/acetic acid. Most of them
showed no enantioselectivity, with ligands 4 (56% ee) and ShiP
(33% ee) being exceptions.
A variety of (E)-1-(1-pyrrolidinyl)-1,2-diarylethenes 2 can be
successfully hydrogenated using [Rh(COD)2]BF4/(S)-1c catalyst to
produce the corresponding tertiary amines 3 in good to excellent
ee values (Table 2). The electronic nature of the aryl groups of
enamines 2 had a strong influence on the enantioselectivity of the
reaction. The substrates with a Ar1connecting electron-donating
groups such as Me or MeO have higher enantioselectivity (entries
2-6). However, on the Ar2side, a reverse effect was observed.
The substrates with a Ar2connecting electron-withdrawing groups
such as Cl, Br, and F on para-position gave higher enantioselectivity.
The highest enantioselectivity (99.9% ee) was achieved in the
hydrogenation of enamine 2n, which has a 4-F on Ar2(entry 14).
The effect of N-alkyl groups of enamine substrates on the
enantioselectivity of reaction was also examined. When the
pyrrolidine moiety was changed to piperidine and morpholine the
ee values of hydrogenation products were lowered to 75% and 77%,
In summary, a highly enantioselective hydrogenation of simple
N-unprotected enamines catalyzed by a Rh(I) complex of chiral
spiro phosphonite ligand (S)-1c has been developed, which provided
a straightforward method for the synthesis of chiral tertiary amines
with excellent ee values. Further investigation will focus on the
reaction mechanism and the extension of this novel catalytic system
to a broader rang of enamines.
Acknowledgment. We thank the National Natural Science
Foundation of China, and the Ministry of Education of China for
Supporting Information Available: Experimental procedures, the
characterizations of substrates and products, the analysis of ee values
of hydrogenation products (PDF), and the crystal data and structure
refinement for (R)-3m. This material is available free of charge via
the Internet at http://pubs.acs.org.
(1) For a review, see: Tang, W.-J.; Zhang, X.-M. Chem. ReV. 2003, 103,
(2) (a) Keay, J. D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8. (b) ComprehensiVe
Natural Products Chemistry; Barton, D. H. R., Nakanishi, K., Meth-Cohn,
O., Eds.; Elsevier: Oxford, 1999; Vols. 1-9.
(3) For a review, see: Halpern, J. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic Press: Orlando, FL, 1985; p 41.
(4) For the examples of asymmetric hydrogenation of N-unprotected ?-
aminoesters and amides, see: (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. (b) Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005,
(5) Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985.
(6) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Bo ¨rner, A.
Tetrahedron Lett. 2000, 41, 2351.
(7) (a) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L.
Chem. Commun. 2002, 480. (b) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.;
Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348. (c) Fu,
Y.; Hou, G.-H.; Xie, J.-H.; Xing, L.; Wang, L.-X.; Zhou, Q.-L. J. Org.
Chem. 2004, 69, 8157.
(8) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic: Am-
sterdam, The Netherlands, 1998; p 255.
(9) (a) Ohta, T.; Ikegami, H.; Miyake, T.; Takaya, H. J. Organomet. Chem.
1995, 502, 169. (b) Buriak, J. M.; Klein, J. C.; Herrington, D. G.; Osborn,
J. A. Chem. Eur. J. 2000, 6, 139.
(10) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed.
1998, 37, 1100.
(11) (a) Spindler, F.; Pugin, B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.; Blaser,
H.-U. Chem. Ind. (Dekker) 1996, 68, 153. (b) Spindler, F.; Blaser, H.-U.;
Enantiomer 1999, 4, 557. (c) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed.
2001, 40, 3425. (d) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.;
Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536.
(12) Blaser, H. U.; Buser, H. P.; Coers, K.; Hanreich, R.; Jalett, H. P.; Jelsch,
E.; Pugin, B.; Schneider, H. D.; Spindler, F.; Wegmann, A. Chimia 1999,
Table 2. The Asymmetric Hydrogenation of Enamines 2
Catalyzed by Rh(I)/(S)-1c Complexa
a[Rh(COD)2]BF4/(S)-1c/I2/HOAc/substrate ) 1:2.2:2:20:100, [substrate]
) 0.125 M, THF, rt, 10 atm H2, 12 h, 100% conversion.bDetermined by
HPLC using chiral columns (see Supporting Information).cDetermined by
X-ray diffraction analysis (see Supporting Information).
C O M M U N I C A T I O N S
J. AM. CHEM. SOC. 9 VOL. 128, NO. 36, 2006 11775