Highly enantioselective hydrogenation of cyclic enamides catalyzed by a Rh-PennPhos catalyst

Full text of DOI:10.1021/jo9824605

1774
J . Org. Chem. 1999, 64, 1774-1775
phenylenebis(endo-2,5-dialkyl-7-phosphabicyclo[2.2.1]hep-
tane,8 Me-PennPhos, Figure 1) and are exploring their
synthetic utility. High enantioselectivities have been achieved
for the hydrogenation of acyclic enamides with a Rh-BICP
catalyst.4c However, only modest enantioselectivities (60-
70% ee) were obtained for the hydrogenation of cyclic
enamides derived from R-tetralone and R-indanone. Encour-
aged by the excellent results observed upon asymmetric
hydrogenation of simple ketones catalyzed by a Rh-Penn-
Phos complex,8 we have now extended our study of the
asymmetric hydrogenation of enamides to include this
unique catalytic system.
High ly En a n tioselective Hyd r ogen a tion of
Cyclic En a m id es Ca ta lyzed by a
Rh -P en n P h os Ca ta lyst†
Zhaoguo Zhang, Guoxin Zhu, Qiongzhong J iang,
Dengming Xiao, and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University,
University Park, Pennsylvania 16802
Received December 17, 1998
Chiral amines are often critical components of pharma-
ceutical agents. For example, about 15-25% of the single-
enantiomer products in development contain this unit
according to a recent analysis.1 The development of practical
methods for the synthesis of enantiomerically pure amines
is therefore of great interest. Traditional resolution methods
and enzymatic transaminase technology are frequent choices
in industry for making chiral amines. However, recent
attention has been devoted to asymmetric hydrogenation of
imines and enamides as potentially more competitive syn-
thetic routes.2 A variety of transition-metal catalysts have
been explored to date for asymmetric hydrogenation of
imines, albeit with either low enantioselectivity, limited
substrate scope, or low activity.3 Alternatively, asymmetric
hydrogenation of simple enamides is a more useful strategy.
Several Rh-bisphosphine compounds have been developed
as efficient catalysts for asymmetric hydrogenation of acyclic
enamides,4 and some can even tolerate Z/E mixtures of
â-substituted enamides as substrates.4a,c However, only
limited success has been achieved in the hydrogenation of
cyclic enamides despite the potential importance of this
process for the synthesis of biologically active chiral ami-
notetralins and aminoindanes.5 Herein we report the highly
enantioselective hydrogenation of cyclic enamides catalyzed
by a Rh-PennPhos compound.
N-(3,4-Dihydro-1-naphthyl)acetamide was chosen as a
typical enamide substrate. This enamide can be easily
prepared by reduction of the corresponding oxime with iron
powder in the presence of acetic anhydride (Scheme 1).9a,b
This facile synthesis of enamides9 combined with an efficient
asymmetric hydrogenation step provides a practical protocol
for the synthesis of chiral amines from ketones. Table 1 lists
asymmetric hydrogenation results under different conditions
and with a variety of chiral bisphosphine systems. The
catalyst was generally prepared in situ by mixing a solution
of a Rh precursor and a phosphine ligand. The reaction was
carried out under an initial H2 pressure of 40 psi at room
temperature with a ratio of substrate/Rh/Me-PennPhos of
100:1:1.1. Different Rh catalytic precursors led to large
variations in enantioselectivities (entries 1-3). Higher enan-
tioselectivities were observed with cationic Rh precursors
(entry 2, 97% ee; entry 3, 98% ee), while the ee is lower with
a neutral Rh system (entry 1, 92% ee). Changing solvents
and/or H2 pressure have only a small effect on enantiose-
lectivity, although reaction conversions vary to a large
extent. The catalytic hydrogenation goes to completion in
methylene chloride, methanol, and 2-propanol under 40 psi
of H2 in 20 h, while only 24% conversion was achieved under
the same conditions in toluene. Reactions performed under
15 psi H2 and 500 psi H2 in MeOH give similar enantiose-
lectivities (>98% ee) but gave different conversions (6%
under 15 psi H2 and 100% under 500 psi H2 after 20 h).
Optimal reaction conditions with the Rh-Me-PennPhos
catalyst use MeOH as the solvent and an initial H2 pressure
of 40 psi. Under these conditions, we have investigated the
Rh-catalyzed asymmetric hydrogenation of N-(3,4-dihydro-
1-naphthyl)acetamide with several commercially available
chiral bisphosphines. Compared with the Rh-Me-PennPhos
catalyst, significantly lower enantioselectivities (10% ee,
entry 4; 24% ee, entry 5) were observed with Rh-DIOP and
Rh-BINAP catalysts. The most surprising result is the low
enantioselectivity (1% ee, entry 6) achieved with the Rh-
Me-DuPhos complex, which is in sharp contrast to its
effective asymmetric hydrogenation of acyclic enamides.4a
Our results are in agreement with the investigation by
Burk,9b who found that under similar conditions hydrogena-
tion of N-(3,4-dihydro-1-naphthyl)acetamide gave 0% ee with
a Rh-Me-DuPhos complex and 69% ee with a Rh-Me-BPE
catalyst. However, up to 92% ee was reported with a Rh-
Me-BPE catalyst if the reaction was done at 0 °C.9b To the
best of our knowledge, Rh-Me-PennPhos-catalyzed asym-
metric hydrogenation of N-(3,4-dihydro-1-naphthyl)aceta-
mide gives the highest enantioselectivity reported to date.
In our continuing work on catalytic asymmetric reactions,
we have developed conformationally rigid chiral bisphos-
phines (e.g., BICP ) bis(diphenylphosphino)dicyclopentane;6
phosphinobicyclo[2.2.1]heptanes;7 PennPhos ) P,P′-1,2-
† Dedicated to Professor Xiyan Lu on the occasion of his 70th birthday.
(1) Cannarsa, M. S. Proceedings of the Chiral USA’97 Symposium;
Matrix, 1997; and a related report of Technol. Catal. Int.
(2) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York,
1993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994.
(3) (a) Spinder, F.; Pugin, B.; Blaser, H.-U. Angew. Chem., Int. Ed. Engl.
1990, 29, 558. (b) Chan, Y. Ng C.; Osborn, J . A. J . Am. Chem. Soc. 1990,
112, 9400. (c) Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; J ames, B. R.;
Kang, G. J .; Rettig, S. J . Inorg. Chem. 1991, 30, 5002. (d) Lensink, C.; Vries,
J . G. Tetrahedron: Asymmetry 1992, 3, 235. (e) Willoughby, C. A.; Buchwald,
S. L. J . Am. Chem. Soc. 1992, 114, 7562. (f) Willoughby, C. A.; Buchwald,
S. L J . Am. Chem. Soc. 1994, 116, 8952. (g) Chan, A. S. C.; Chen, C. C.;
Lin, C. W..; Lin, Y. C.; Cheng, M. C. J . Chem. Soc., Chem. Coummn. 1995,
1767. (h) Verdaguer, X.; J ange, U. E. W.; Reding, M. T.; Buchwald, S. L. J .
Am. Chem. Soc. 1996, 118, 6784. (i) Togni, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 14575. (j) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J . Am. Chem. Soc. 1996, 118, 4916. (k) Schnider, P.; Koch, G.;
Pretot, R.; Wang, G.; Bohnen, F. M.; Kruger, C.; Pfaltz, A. Chem. Eur. J .
1997, 3, 887.
(4) For recent advances, see: (a) Burk, M. J .; Wang, Y. M.; Lee, R. J . J .
Am. Chem. Soc. 1996, 118, 5142. (b) Zhang, F.-Y.; Pai, C.-C.; Chan, A. S.
C. J . Am. Chem. Soc. 1998, 120, 5808. (c) Zhu, G.; Zhang, X. J . Org. Chem.
1998, 63, 9590.
(5) One example was reported on asymmetric hydrogenation of N-(6-
bromo-1,2,3,4-tetrahydronaphthalene)yl benzamide using
a Ru-BINAP
catalyst: Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-
H.; Frey, L.; Karady, S.; Shi, Y.-J .; Verhoeven, T. R. J . Org. Chem. 1995,
60, 4324.
(6) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997, 119,
1799.
(7) (a) Zhu, G.; Chen, Z.; J iang, Q.; Xiao, D.; Cao, P.; Zhang, X. J . Am.
Chem. Soc. 1997, 119, 3836. (b) Chen, Z.; J iang, Q.; Zhu, G.; Xiao, D.; Cao,
P.; Guo, C.; Zhang, X. J . Org. Chem. 1997, 62, 4521.
(8) J iang, Q.; J iang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1100.
(9) (a) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J . Org. Chem. 1998, 63,
8100. (b) Burk, M. J .; Casey, G.; J ohnson, N. B. J . Org. Chem. 1998, 63,
6084. For the origin of this Fe/Ac2O method, see: (c) Boar, R. B.; McGhie,
J . F.; Robonson, M.; Barton, D. H. R.; Horwell, D. C.; Stick, R. V. J . Chem.
Soc., Perkin Trans. 1 1975, 1237. (d) Laso, N. M.; Quiclet-Sire, B.; Zard, S.
Z. Tetrahedron Lett. 1996, 37, 1605.
10.1021/jo9824605 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/27/1999

Communications
J . Org. Chem., Vol. 64, No. 6, 1999 1775
Ta ble 2. Asym m etr ic Hyd r ogen a tion of En a m id es
Ca ta lyzed by a Me-P en n P h os-Rh Com p lex
F igu r e 1.
Sch em e 1
Ta ble 1. Rh -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of a n
En a m id ea
entry
Rh(I) species
ligand
% eeb
1
2
3
4
5
6
[Rh(COD)Cl]2
Rh(COD)2BF4
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
(R,S,R,S)-Me-PennPhos
(R,S,R,S)-Me-PennPhos
(R,S,R,S)-Me-PennPhos
(+)-DIOP
92 (R)
97 (R)
98 (R)
10 (S)
24 (R)
1c (R)
(R)-BINAP
(R,R)-Me-DuPhos
a
The reaction was complete in quantitative yield at room
a
The reaction was complete in quantitative yield at room
temperature under an initial hydrogen pressure of 40 psi after 20
h using MeOH as the solvent. The catalyst was made in situ by
stirring a solution of Rh precursor and phosphine ligand in MeOH
for 30 min [[substrate (0.5 mmol, 0.17 M)/Rh cat./ligand ) 1:0.01:
temperature under an initial hydrogen pressure of 40 psi after 20
h using MeOH as the solvent. The catalyst was made in situ by
stirring a solution of [Rh(COD)2]PF6 and Me-PennPhos in MeOH
for 30 min [[substrate (0.5 mmol, 0.17 M)/[Rh(COD)2]PF6/ligand
b
) 1:0.01:0.011]]. Enantiomeric excesses were determined by
b
0.011]]. Enantiomeric excesses were determined by chiral GC
chiral GC using a Supelco Chiral Select 1000 (0.25 mm × 15 m)
using a Supelco chiral Select 1000 (0.25 mm × 15 m) column. c 57%
column.
conversion.
However, these enantioselectivities are lower than those
obtained with Rh-DuPhos, Rh-BICP, and other catalytic
systems.4 Since there is as yet no universal catalyst to
handle such a diverse set of substrates, the Rh-PennPhos
complex serves to compliment other efficient catalysts4 for
hydrogenation of simple acyclic enamides.
To demonstrate that this is a potentially practical method
for the synthesis of R-aminotetralins, we increased the ratio
of N-(3,4-dihydronaphthalen-1-yl)acetamide/ Rh-Me-Penn-
Phos to 2000:1 and the reaction was still complete in 20 h
with 98% ee.
In summary, we have developed a highly enantioselective
Rh-PennPhos catalyst for asymmetric hydrogenation of
cyclic enamides. The high reactivity and ease of operation
combined with an efficient method for the synthesis of
substrates make this reaction an attractive synthetic pro-
cedure for the synthesis of enantiomerically pure R-ami-
notetralins and R-aminoindanes.
Using these optimal conditions, several cyclic and acyclic
enamides were investigated (Table 2). Hydrogenation of
several cyclic enamides derived from R-tetralones and R-in-
danones (entries 1-5) gives high enantioselectivities (>97%
ee) regardless of the substituents on the aromatic ring.10
Interestingly, a tetrasubstituted five-membered cyclic ena-
mide gives high enantioselectivity (98% ee, entry 8). How-
ever, the ee with the corresponding six-membered cyclic
enamide (73% ee, entry 9) is significantly lower. Only
moderate ee was observed for the enamide made from
â-tetralone (entry 7). Burk et al. reported excellent results
(>98% ee) for the asymmetric hydrogenation of an indanone-
derivated enamide using a Rh-Me-DuPhos catalyst.9b The
profile of their catalytic systems has not yet been completely
established for a variety of cyclic enamides. Using the Rh-
Me-PennPhos catalyst, several acyclic enamides were hy-
drogenated with moderate to good ee’s (entries 10-12).
Ack n ow led gm en t. This work was supported by a
Camille and Henry Dreyfus New Faculty Award and
Teacher Scholar Award, an ONR Young Investigator
Award, a DuPont Young Faculty Award, Catalytica Phar-
maceuticals, and DuPont Agricultural Products. We ac-
knowledge a generous loan of precious metals from J ohnson
Matthey, Inc. and a gift of chiral GC columns from Supelco
and thank Dr. Albert L. Casalnuovo of DuPont Agricultural
Products for useful suggestions for enamide synthesis.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data and
experimental details.
(10) The absolute configuration was determined by comparing the GC
trace and optical rotation of the acetamide derived from (R)-R-aminoindane
and (R)-R-aminotetralin purchased from Lancaster, Inc.
J O9824605