A convenient asymmetric synthesis of α-1-arylalkylamines through the enantioselective hydrogenation of enamides

Article abstract of DOI:10.1021/ja953872n

We have found that cationic Rh catalysts based on our 1,2-bis(trans-2,5 dimethylphospholano)benzene (Me-DuPHOS) and 1,2-bis(trans-2,5-dimethylphospholano)ethane (Me-BPE) ligands effect the hydrogenation of N-acetyl α-arylenamides (1, R = H) to yield a wid

Full text of DOI:10.1021/ja953872n

5142
J. Am. Chem. Soc. 1996, 118, 5142-5143
and unique feature of our catalysts is the ability to tolerate
â-substituents in both (E)- and (Z)-positions of enamides 1, thus
allowing the production of a diverse array of R-1-arylalkyl-
amines 2 through hydrogenation of isomeric mixtures of
enamide substrates.
A Convenient Asymmetric Synthesis of
r-1-Arylalkylamines through the Enantioselective
Hydrogenation of Enamides
Mark J. Burk,* Yan Ming Wang, and Jeffrey R. Lee
Department of Chemistry, Duke UniVersity
P. M. Gross Chemical Laboratory
Durham, North Carolina 27708
ReceiVed NoVember 17, 1995
Optically active R-1-arylalkylamines constitute an important
class of compounds that have been employed extensively as
resolving agents,1 chiral auxiliaries, and intermediates in the
synthesis of a wide range of biologically active molecules.2 The
broad utility of R-1-arylalkylamine derivatives has stimulated
relentless pursuit of practical asymmetric routes to these valuable
compounds. In this regard, many reliable synthetic methods
have been devised and generally involve optical resolution
procedures, biocatalytic methods, or stoichiometric use of chiral
precursors or chiral auxiliaries.1-5 Asymmetric catalytic reduc-
tion of CdN or CdC double bonds potentially could provide a
very efficient and convenient route to many chiral amine
derivatives, yet only limited success has been achieved along
these lines of research.6,7 While very high enantioselectivities
have been attained in the hydrogenation of R-enamide esters,8
the development of similarly effective catalysts for asymmetric
hydrogenation of R-arylenamides of type 1 has remained a
challenging objective.9 Toward this goal, we have found that
cationic Rh catalysts based on our 1,2-bis(trans-2,5-dimeth-
ylphospholano)benzene (Me-DuPHOS) and 1,2-bis(trans-2,5-
dimethylphospholano)ethane (Me-BPE) ligands effect the hy-
drogenation of N-acetyl R-arylenamides (1, R ) H) to yield a
wide variety of valuable R-1-arylethylamine derivatives with
high enantioselectivities (g90% ee). Moreover, an important
We recently have shown that Rh and Ru catalysts bearing
our DuPHOS or BPE ligands are extremely effective for
enantioselective hydrogenation of a variety of prochiral unsatur-
ated substrates.10 These studies have highlighted an important
advantage of our ligand design; the ability to readily vary the
phospholane 2,5-substituents has allowed us to optimize enan-
tioselectivities by matching the ligand sterics to the steric
demands of substrates of interest. In an effort to develop a
general asymmetric catalytic method for the preparation of R-1-
arylalkylamines, we initially screened a series of Rh and Ru
catalysts for efficacy in the hydrogenation of the model
R-arylenamide 1a (Ar ) C6H5, R ) H). We found that under
a standard set of reaction conditions (MeOH, 22 °C, 60 psi H2,
S/C ) 500, 12 h) cationic Rh complexes of the type
[(COD)Rh(DuPHOS)]+OTf- and [(COD)Rh(BPE)]+OTf- be-
have as efficient catalyst precursors for the reduction of enamide
1a. Moreover, we observed that enantioselectivities tended to
increase with decreasing steric demand of the DuPHOS and
BPE ligands (phospholane 2,5-susbtituents ) Me, Et, Pr, i-Pr,
Cy). This trend suggests that enamides 1 are rather sterically
demanding substrates and in fact, more sterically demanding
than standard R-enamide esters.10c,f Thus, hydrogenation of 1a
using the (S,S)-Me-DuPHOS-Rh catalyst afforded the product,
N-acetyl-R-phenethylamine (2a), in 94.7% ee and (S) absolute
configuration. Within the analogous series of BPE-Rh catalysts,
(R,R)-Me-BPE-Rh provided (R)-2a with the highest enantiose-
lectivity (95.2% ee). By comparision, directly analogous Rh
catalysts bearing other well-known chiral diphosphines led to
significantly lower enantioselectivities in the reduction of 1a
in MeOH under our prototypical conditions: (R)-BINAP (15.1%
ee), (S,S)-CHIRAPHOS (40.7% ee), (R,R)-SKEWPHOS (7.1%
ee), and (R,R)-DIOP (56.6% ee). Similarly, a Ru-BINAP
catalyst derived from (R)-BINAP-RuBr2 produced (S)-2a with
low enantioselectivity (53.7% ee).
(1) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and
Resolutions; John Wiley and Sons: New York, 1981.
(2) No´gra´di, M. StereoselectiVe Synthesis, 2nd Ed.; VCH: Weinheim,
Germany, 1995.
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1986, 25, 1109. (b) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J. Am.
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Tetrahedron: Asymmetry 1995, 6, 1507.
(4) Representative optical resolution procedures: (a) Newman, P. Optical
Resolution Procedures for Chemical Compounds; O.R.I.C., Manhattan
College Press: New York, 1978; Vol 1. (b) Hoeve, W. T.; Wynberg, H. J.
Org. Chem. 1985, 50, 4508. (c) Westley, J. W.; Evans, R. H., Jr.; Blount,
J. F. J. Am. Chem. Soc. 1977, 99, 6057. (d) Gharpure, M. M.; Rao, A. S.
Synthesis 1988, 410.
(5) For enzymatic resolution procedures, see: (a) Stirling, D. I. In
Chirality in Industry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.;
John Wiley and Sons: New York, 1992; pp 209-222. (b) Rossi, D.;
Calcagni, A.; Romeo, A. J. Org. Chem. 1979, 44, 2222.
(6) (a) Landor, S. R.; Chan, Y. M.; Sonola, O. O.; Tatchell, A. R. J.
Chem. Soc., Perkin Trans. 1 1984, 493. (b) Itsuno, S.; Nakano, M.;
Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc.,
Perkin Trans 1 1985, 2039. (c) Cho, B. T.; Chun, Y. S. J. Chem. Soc.,
Perkin Trans. 1 1990, 3200. (d) Kawate, T.; Nakagawa, M.; Kakikawa, T.;
Hino, T. Tetrahedron: Asymmetry 1992, 3, 227. (e) Sreekumar, R.; Pillai,
C. N. Tetrahedron: Asymmetry 1993, 4, 2095.
(7) (a) Chan, Y. N.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400.
(c) Spindler, F.; Pugin, B.; Blaser, H.-U. Angew. Chem., Int. Ed. Engl. 1990,
29, 558. (c) Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.;
Kang, G.-J.; Rettig, S. J. Inorg. Chem. 1991, 30, 5002. (d) Bakos, J.; Orosz,
A.; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou, D. J. Chem. Soc., Chem.
Commun. 1991, 1684. (e) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 8952. (f) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford,
N. Tetrahedron 1994, 50, 4399.
Enantioselectivities attained in the present hydrogenations
were found to be relatively insensitive to solvent. For example,
similar ee’s were achieved in the Me-DuPHOS-Rh-catalyzed
reduction of 1a: MeOH (94.7% ee), C6H6 (94.3% ee), EtOAc
(95.7% ee), i-PrOH (95.8% ee), THF (91.4% ee), and CF3CH2-
OH (91.8% ee). In general, high ee’s were achieved consistently
in either the protic solvent MeOH or the aprotic EtOAc, thus
allowing the reaction to be conducted in two solvents with rather
different properties. Likewise, minor pressure variations had
little effect on selectivities in the hydrogenation of 1a using
the Me-DuPHOS-Rh catalyst in MeOH; ee’s varied by e1.5%
ee over the pressure range 10-90 psi.
The general utility of the Me-DuPHOS-Rh and Me-BPE-Rh
catalysts was revealed through production of a panoply of R-1-
(8) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH Publishers:
Weinheim, 1993;, Chapter 2. (b) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley & Sons: New York, 1994; Chapter 2.
(9) (a) Kagan, H. B.; Langlois, N.; Dang, T. P. J. Organomet. Chem.
1975, 90, 353. (b) Sinou, D.; Kagan, H. B. J. Organomet. Chem. 1976,
114, 325. (c) Morimoto, T.; Chiba, M.; Achiwa, K. Chem. Pharm. Bull.
1992, 40, 2894. (d) See also: Lee, N. E.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 5985.
(10) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M.
J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266. (c) Burk, M. J.; Feaster,
J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125.
(d) Burk, M. J.; Harper, T. G. P.; Kalberg, C. S. J. Am. Chem. Soc. 1995,
117, 4423-4424. (e) Burk, M. J.; Feng, S.; Gross, M. F.; Tumas, W. J.
Am. Chem. Soc. 1995, 117, 8277. (f) Burk, M. J.; Gross, M. F.; Martinez,
J. P. J. Am. Chem. Soc. 1995, 117, 9375.
S0002-7863(95)03872-8 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 21, 1996 5143
Table 1. Rh-Catalyzed Asymmetric Hydrogenation of
R-Arylenamides 1 (R ) H)a
entry
AR in 1 (R ) H)
optimum ligand
% eeb (confign)c
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C6H5
(R,R)-Me-BPE
(R,R)-Me-BPE
(S,S)-Me-DuPHOS
(R,R)-Me-BPE
(S,S)-Me-DuPHOS
(R,R)-Me-BPE
(R,R)-Me-BPE
(R,R)-Me-BPE
(S,S)-Me-DuPHOS
(S,S)-Me-DuPHOS
(R,R)-Me-BPEf
(R,R)-Me-BPE
(R,R)-Me-BPE
(R,R)-Me-BPE
(S,S)-Me-DuPHOS
(S,S)-Me-DuPHOS
(S,S)-Me-DuPHOS
(S,S)-Me-DuPHOS
95.2 (R)
96.5 (R)
95.6 (S)e
95.3 (R)e
96.2 (S)e
95.8 (R)
95.0 (R)e
96.3 (R)e
96.8 (S)e
94.9 (S)e
89.0 (R)e,g
95.7 (R)e
74.8 (R)e
97.8 (R)e
95.6 (S)
95.6 (S)
96.1 (S)e
97.5 (S)
p-CH3-C6H4
p-CF3-C6H4
p-CH3O-C6H4
p-CF3O-C6H4
p-Br-C6H4
p-F-C6H4
p-MeS-C6H4
m-Br-C6H4
m-CH3-C6H4
o-Br-C6H4
Figure 1. Asymmetric catalytic synthesis of R-arylalkylamine deriva-
tives. (R)- (S)-amines derived from (R,R)-Me-BPE-Rh and (S,S)-Me-
DuPHOS-Rh catalysts, respectively.
o-F-C6H4
(entry 11). These results further indicate the sterically demand-
ing nature of enamide substrates 1.
o-CH3-C6H4
2,6-F2C6H3
3,4,5-(MeO)3C6H2
2-naphthyl
2-furanyl
We next examined whether our catalysts could effectively
hydrogenate R-arylenamides possessing â-substituents (i.e., 1;
R * H). The ability to hydrogenate such substrates would vastly
expand the types of chiral amine derivatives available through
this methodology. We were pleased to find that a variety of
â-substituted enamides could be reduced to the corresponding
R-1-arylalkylamine derivatives 2 with high enantioselectivities
(Figure 1). Importantly, we have found that isomeric mixtures
of (E)- and (Z)-enamides 1 (E/Z isomer ratios varied from ca.
1:1 to 4:1) may be employed in these hydrogenation reactions,
with no apparent detrimental effect on the selectivity. This
finding was critical for development of a useful route to R-1-
arylalkylamines, as we have been unable to prepare or purify
the separate (E)- and (Z)-enamide isomers. Thus, an array of
isomeric enamides 1 possessing both linear and branched â-alkyl
substituents and an assortment of different R-aryl groups were
hydrogenated with enantioselectivities g95% ee using either
the Me-DuPHOS-Rh or the Me-BPE-Rh catalysts. A rational
for why the Me-BPE-Rh and Me-DuPHOS-Rh catalysts are
capable of tolerating â-substituents in both (E)- and (Z)-positions
of enamides 1 awaits further mechanistic study. Preliminary
deuteration studies suggest that neither isomerization to N-
acylimines nor interconversion of geometric enamides is
involved in enamide hydrogenation reactions.10c,f,12
In conclusion, our Me-DuPHOS-Rh and Me-BPE-Rh cata-
lysts have been found to allow efficient hydrogenation of
R-arylenamides 1, thus providing practical access to a broad
range of valuable R-1-arylalkylamine derivatives in highly
enantiomerically-enriched form. A unique feature of this system
is the ability of our catalysts to hydrogenate mixtures of (E)-
and (Z)-enamides with high enantioselectivities, hence obviating
the need to prepare isomerically pure substrates. The present
study further demonstrates the versatility and utility of our
DuPHOS-Rh and BPE-Rh hydrogenation catalysts for the
production of chiral building blocks of medicinal and biological
interest. Future studies will attempt to decipher the effects
(steric and/or electronic)13 responsible for the high enantiose-
lectivities we observe in these hydrogenation reactions.
2-thienyl
a Reactions were conducted at 22 °C and an initial H2 pressure of
60 psi using 0.10-0.25 M methanol solutions of substrate and the
catalyst precursors [(S,S)-Me-DuPHOS-Rh(COD)]+OTf- or [(R,R)-Me-
BPE-Rh(COD)]+OTf- (0.2 mol %), unless otherwise noted. Reaction
time was 15 h, and complete (100%) conversion was observed in all
cases. b Enantiomeric excesses were determined by chiral capillary GC
using Chrompack’s Chirasil-L-Val column (25 m). c Absolute configu-
rations were confirmed by comparing the sign of optical rotation of 2,
or hydrolyzed product, with that of known N-acetylamines or free
amines, respectively (see supporting information). d Enamide 1a (entry
1) was prepared following the procedure outlined by Kagan and co-
workers in ref 9a,b. To our knowledge, all other enamides in Table 1
are new and were prepared via the same method as that employed for
1a. The procedure used and characterization data for all new enamides
are provided as supporting information. e Absolute configurations for
these products were assigned by analogy, through comparison of sign
of optical rotation and chiral GC elution order with configurationally
defined products (see supporting information). f Reaction performed in
ethyl acetate. g Enantiomeric excess determined by HPLC (CHIRAL-
CEL OJ; 15:85 2-propanol/hexane).
arylethylamine derivatives with high enantioselectivities. Table
1 lists selectivities achieved using the optimum catalyst identi-
fied for each individual enamide substrate 1.11 Overall, Me-
DuPHOS-Rh and Me-BPE-Rh catalysts performed comparably
with the substrates listed in Table 1 and generally furnished
products with enantioselectivities differing by e2% ee. More-
over, the Et-DuPHOS-Rh catalyst afforded similarly high
enantioselectivities in certain cases but did not display the
substrate generality enjoyed by the Me-DuPHOS-Rh and Me-
BPE-Rh catalysts. Thus, our asymmetric hydrogenation process
provides a convenient route to a variety of highly enantiomeri-
cally-enriched ring-substituted R-phenethylamine derivatives.
Substitution at the meta or para positions of the parent enamide
1a did not greatly influence the enantioselectivites. No
significant substituent electronic effects on the ee’s were
observed. Hydrogenation of enamide 1 possessing a p-
thiomethyl substituent (entry 8) demonstrated tolerance to
potentially detrimental sulfur-bearing groups. Substitution at
the ortho position of 1a did affect selectivities. Hydrogenation
with (R,R)-Me-BPE-Rh under our standard conditions yielded
2-fluoro- and 2,6-difluoro-R-phenethylamine derivatives with
high enantioselectivities (95.7% and 97.8% ee, respectively).
A minimal increase in the steric nature of the ortho substituent
to 2-methyl or 2-bromo, however, led to a significant decrease
in selectivity, wherein the products were obtained in 74.8% and
81.3% ee, respectively. The more rigid Me-DuPHOS-Rh
catalyst provided these products in only 58.0% and 62.1% ee,
respectively. Varying the solvent to EtOAc allowed the
2-bromophenethylamine derivative to be obtained in 89.0% ee
Acknowledgment. We thank Dr. G. Dubay for obtaining HRMS
data. M.J.B. gratefully acknowledges the National Institutes of Health
(GM-51342), Boehringer Ingelheim Pharmaceuticals, Union Carbide
(Innovative Recognition Award, 1994-96), Eli Lilly (Grantee Award,
1995-97), and The DuPont Company (1995 Educational Aid Grant)
for financial support of this work.
Supporting Information Available: Experimental details, including
preparation of R-arylenamides (1), hydrogenation procedure, spectral
and analytical data, and ee determinations for amine derivatives 2 (25
pages). Ordering information is given on any current masthead page.
JA953872N
(12) (a) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee,
J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37. (b) Burk, M. J.;
Martinez, J. P.; Straub, J. A.; Gross, M. F. Manuscript in preparation.
(13) Miyashita, A.; Karino, H.; Shimamura, J.; Chiba, T.; Nagano, K.;
Nohira, H.; Takaya, H. Chem. Lett. 1989, 1849.
(11) For the preparation of R-arylenamides, see ref 9 and the following:
(a) Lenz, G. R. Synthesis 1978, 489 and references therein. (b) Tsachen,
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.