Highly enantioselective hydrogenation of enamides catalyzed by chiral phosphoric acids

Article abstract of DOI:10.1021/ol802860u

A highly enantioselective hydrogenation of enamides catalyzed by a dual chiral-achiral acid system was developed. By employing a substoichiometric amount of a chiral phosphoric acid and acetic acid, catalyst loadings as low as 1 mol % of the chiral cataly

Full text of DOI:10.1021/ol802860u

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1075-1078
Highly Enantioselective Hydrogenation
of Enamides Catalyzed by Chiral
Phosphoric Acids
Guilong Li and Jon C. Antilla*
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue
CHE205A, Tampa, Florida 33620
jantilla@cas.usf.edu
Received December 11, 2008
ABSTRACT
A highly enantioselective hydrogenation of enamides catalyzed by a dual chiral-achiral acid system was developed. By employing a
substoichiometric amount of a chiral phosphoric acid and acetic acid, catalyst loadings as low as 1 mol % of the chiral catalyst were sufficient
to provide excellent yield and enantioselectivity of the reduction product.
Enantioselective hydrogenation is one of the key transforma-
tions to produce chiral compounds in academia and in the
chemical industry.1 As a new direction in this research field,
enantioselective hydrogenation catalyzed by organocatalysts
with Hantzsch esters as the reducing agent has emerged as
an attractive strategy due to its environmentally benign
nature.2 Recently, chiral Brønsted acids3 were reported as
highly efficient catalysts for the hydrogenation of ketimines,
R,ꢀ-unsaturated aldehydes, and nitroolefins by the research
groups of Rueping, List, MacMillan, and others.4 Likewise,
our recent interest in chiral phosphoric acid catalysis5
included a report whereby R-imino esters could be reduced
in the presence of a VAPOL phosphoric acid catalyst (A2)
to prepare chiral R-amino acid esters with excellent
enantioselectivities.5a
acids were achieved in high enantioselectivities, these
reactions were limited primarily to reactants derived from
aniline and its analogues. As a result, the deprotection of
the aromatic group to reveal the amino group can be
relatively difficult, requiring somewhat harsh reaction condi-
tions such as those methods that use ceric ammonium nitrate
(CAN), rendering these methods less synthetically appealing
(eq 1, Scheme 1). Attractive features of enamides are their
relative stability and ease in handling. Additionally, when
considering N-acyl enamide substrates, the acyl group of the
reduction product can be easily removed under standard
procedures in good yield. Therefore, due to these consider-
ations, such enamide precursors have become popular
substrates for preparing chiral amines through standard metal-
catalyzed hydrogenation.1 Herein we report our results on
the asymmetric hydrogenation of enamides with high enan-
tioselectivity using chiral phosphoric acid catalysis (eq 2,
Scheme 1).
Although the reductive amination of ketones and the
hydrogenation of ketimines catalyzed by chiral Brønsted
(1) (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (b) Jaekel,
C.; Paciello, R. Chem. ReV. 2006, 106, 2912. (c) Brown, J. M. Mechanism
of enantioselectiVe hydrogenation. Handbook of Homogeneous Hydrogena-
tion; De Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2007.
(2) For reviews, see: (a) Ouellet, G.; Walji, A. M.; Macmillan, D. W. C.
Acc. Chem. Res. 2007, 40, 1327. (b) You, S. -L. Chem. Asian J. 2007, 2,
820. (c) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407.
10.1021/ol802860u CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society

Scheme 1
Figure 1. Phosphorus-based acid catalysts.
We initiated our studies on the hydrogenation of enamide
1a by using the achiral phenylphosphinic acid (A1) as the
catalyst, with 1.1 equiv of Hantzsch ester dihydropyridine 2
as the reducing agent. We were pleased to find that in the
presence of 10 mol % of A1, at ambient temperature, the
reaction took place smoothly in an argon atmosphere to
provide a 95% isolated yield of the desired product amide
3a (entry 1, Table 1). However, when we replaced the
(3) For reviews with considerable chiral phosphoric acid coverage, see:
(a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999.
(b) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (c) Akiyama, T.
Chem. ReV. 2007, 107, 5744. (d) Terada, M. Chem. Commun. 2008, 4097.
For recent reports, see: (e) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.;
Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593. (f) Wang, X.; List, B.
Angew. Chem., Int. Ed. 2008, 47, 1119. (g) Akiyama, T.; Honma, Y.; Itoh,
J.; Fuchibe, K. AdV. Synth. Catal. 2008, 350, 399. (h) Jiao, P.; Nakashima,
D.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 2411. (i) Jiang, J.;
Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008,
47, 2458. (j) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew.
Chem., Int. Ed. 2008, 47, 2840. (k) Chen, X.-H.; Zhang, W.-Q.; Gong,
L.-Z. J. Am. Chem. Soc. 2008, 130, 5652. (l) Enders, D.; Narine, A. A.;
Toulgoat, F.; Bisschops, T. Angew. Chem., Int. Ed. 2008, 47, 5661. (m)
Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. AdV. Synth. Catal. 2008, 350,
1457. (n) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246.
(o) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.; Hu, J.; Yang, L.;
Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (p) Rueping, M.;
Antonchick, A. P. Org. Lett. 2008, 10, 1731. (q) Giera, D.; Sickert, M.;
Schneider, C. Org. Lett. 2008, 10, 4259. (r) Cheng, X.; Goddard, R.; Buth,
G.; List, B. Angew. Chem., Int. Ed. 2008, 47, 5079. (s) Sickert, M.;
Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631. (t) Itoh, J.; Fuchibe,
K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016. (u) Terada, M.;
Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122. (v)
Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47, 5836.
(w) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew.
Chem., Int. Ed. 2008, 47, 6798. (x) Kang, Q.; Zheng, X.-J.; You, S.-L.
Chem.sEur. J. 2008, 14, 3539. (y) Cheng, X.; Vellalath, S.; Goddard, R.;
List, B. J. Am. Chem. Soc. 2008, 130, 15786. (z) Rueping, M.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2008, 47, 10090.
Table 1. Reaction Conditions for the Asymmetric Reduction of
Enamides
catalyst
(mol%)
T
time yield ee
(h)
entry
solvent (°C)
(%)a (%)
1
A1 (10)
toluene
toluene
toluene
toluene
Et2O
rt
17
36
36
15
22
22
48
48
41
117
15
17
95
0
2
A2 (5)
A3 (5)
A4 (5)
A4 (5)
A4 (5)
A4 (5)
A4 (5)
A4 (2)
A4 (1)
50
50
50
50
50
50
50
50
50
50
50
<15b
<10b
92
nd
nd
91
nd
nd
nd
nd
91
90
91
nd
3
4
5
<13b
<5b
<15b
<5b
85
6
THF
7
EtOAc
MeOH
toluene
toluene
8
9
10
11
12
39
A4 (1) + AcOH (10) toluene
AcOH (10) toluene
97
0b
a Isolated yields. b Yield determined by 1H NMR. c Ee values determined
by Chiral-HPLC (see the Supporting Information).
(4) For chiral phosphoric acid catalyzed reduction reactions, see: (a)
Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett.
2005, 7, 3781. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem.,
Int. Ed. 2005, 44, 7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (d) Martin, N. J. A.; List, B.
J. Am. Chem. Soc. 2006, 128, 13368. (e) Hoffmann, S.; Nicoletti, M.; List,
B. J. Am. Chem. Soc. 2006, 128, 13074. (f) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (g) Mayer, S.; List,
B. Angew. Chem., Int. Ed. 2006, 45, 4193. (h) Rueping, M.; Antonchick,
A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751. (i) Zhou, J.;
List, B. J. Am. Chem. Soc. 2007, 129, 7498. (j) Rueping, M.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2007, 46, 4562. (k) Guo, Q.-S.; Du, D.-M.;
Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759. (l) Rueping, M.; Theissmann,
T.; Raja, S.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 1001. (m) Kang, Q.;
Zhao, Z.-A.; You, S.-L. AdV. Synth. Catal. 2007, 349, 1657. (n) Kang, Q.;
Zhao, Z.-A.; You, S.-L. Org. Lett. 2008, 10, 2031. (o) Martin, N. J. A.;
Cheng, X.; List, B. J. Am. Chem. Soc. 2008, 130, 13862.
achiral catalyst A1 with chiral phosphoric acids (A2-A4)
under similar conditions (5 mol % catalyst, rt), the
reactions were sluggish and no product was detected by
TLC after 24 h (not shown in Table 1). However, when
we raised the temperature to 50 °C, we were pleased to
find that catalyst A3 allowed for a 92% isolated yield of
amine 3a with 91% ee (entry 4), while acids A2 and A3
gave very low yields of the desired product (<15% yield
by 1H NMR, entries 2 and 3). Further screening of solvents
showed that noncoordinating solvents like toluene were
ideal (entry 4), while other coordinating solvents such as
ether, THF, and the protic solvent methanol gave very
sluggish reactions (entries 5-8).
Efforts toward decreasing the catalyst loading led to lower
yields but no loss in ee was found. For example, with 2 mol
% of catalyst A3, the yield of 3a was 85% (entry 9), but
with a catalyst loading of 1 mol %, the yield of 3a decreased
to 39% even with a longer reaction time (entry 10). Believing
that a reactive iminium was the intermediate of this reaction
(5) (a) Li, G.; Liang, Y.; Antilla, J. C J. Am. Chem. Soc. 2007, 129,
5830. (b) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (c)
Rowland, G. B.; Rowland, E. B.; Liang, Y.; Antilla, J. C. Org. Lett. 2007,
9, 2609. (d) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org.
Lett. 2007, 9, 4065. (e) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman,
J. A.; Antilla, J. C. Chem. Commun. 2007, 43, 4477. (f) Rowland, E. B.;
Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 12084. (g) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc.
2008, 130, 12216.
1076
Org. Lett., Vol. 11, No. 5, 2009

we reasoned that decreasing the catalyst loading probably
lead to a low concentration of iminium, and thus a slow
reaction. Our working hypothesis assumed therefore that this
iminium formation was the rate determining step (eq 3,
Scheme 2). In order to develop an efficient hydrogenation
Table 2. Studies on the Substrate Scope
time yieldb
catalysta
(h)
(%)
eec (%)
Scheme 2. Function of a Dual-Acid Catalyst System
entry
R
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
4-MeC6H4 (1b)
4-MeC6H4 (1b)
4-ClC6H4(1c)
4-ClC6H4(1c)
4-FC6H4 (1d)
4-FC6H4 (1d)
4-CF3C6H4 (1e)
4-CF3C6H4 (1e)
4-MeOC6H4 (1f)
ꢀ-naphthyl (1g)
ꢀ-naphthyl (1g)
R-naphthyl (1h)
R-naphthyl (1h)
3-MeOC6H4 (1i)
3-MeOC6H4 (1i)
2-MeOC6H4 (1j)
2-MeOC6H4 (1j)
t-Butyl (1k)
A
B
A
B
A
B
A
B
A
B
A
A
B
A
B
A
117
15
72
24
48
17
72
17
69
40
15
48
14
94
44
47
18
40
15
48
39
97
53
93
71
88
90
96
74
96
96
91
99
31
43
90
98
90
96
NRd
91 (R) (+)
91 (R) (+)
91 (R) (+)
90 (R) (+)
92 (R) (+)
91 (R) (+)
90 (R) (+)
89 (R) (+)
87 (R) (+)
87 (R) (+)
95 (R) (+)
94 (R) (+)
92 (R) (+)
89 (S) (-)
78 (S) (-)
74 (R) (+)
71 (R) (+)
42 (S) (-)
41 (S) (-)
NDe
9
10
11
12
13
14
15
16
17
18
19
20
reaction with a low catalyst loading, we considered the use
of a dual catalytic chiral-achiral acid system. We believed
that a suitable achiral acid should be able to facilitate iminium
formation, while being inactive in the hydrogenation step,
where our chiral phosphoric acid, which had already
demonstrated enantioselectivity, could remain active (eq 4,
Scheme 2).
B
A
B
As expected, with 1 mol % of catalyst (S)-A4 and 10 mol
% of acetic acid as a cocatalyst, the reaction was completed
within 15 h to provide the desired product 3a in 97% isolated
yield and with 91% ee (entry 11, Table 1). A study on the
background reaction with acetic acid as the only catalyst
further confirmed our hypothesis that the acetic acid was
inactive for the hydrogenation of enamide 1a (entry 12). We
would like to note that a similar strategy was also reported
by Rueping’s group. Rueping and co-workers successfully
utilized two Brønsted acids as the catalyst for the asymmetric
synthesis of isoquinuclidines.6
A or B
a Catalyst A ) A4 (1 mol %); catalyst B ) A4 (1 mol %) + AcOH (10
mol %). b Isolated yield. c Determined by chiral HPLC; see the Supporting
Information for details. d No desired product was detected. e Not analyzed.
trifluoromethyl groups (entries 9 and 10) proVided similar
rate acceleration with good enantioselectiVities (87-92%
ee). Likewise, the p-methoxy (95% ee; entry 11) and
ꢀ-naphthyl enamide substrates (92% ee; entry 13) were
excellent reaction partners.
Our optimized reaction conditions for the enantioselective
organocatalytic hydrogenation of enamides were determined
to be the following: 1 mol % of chiral phosphoric acid A4,
10 mol % of AcOH, 50 °C, with a ratio of enamide 1 and
Hantzsch ester 2 set at 1/1.1 equiv and toluene as the solvent.
Under the general conditions above, we evaluated various
enamide substrates, and the results are summarized in Table
2. In order to demonstrate the advantages of the dual-acid
catalytic system, we also conducted the corresponding
reactions catalyzed by the single chiral phosphoric acid (S)-
A4. As shown in Table 2, the dual-acid catalytic system
significantly accelerated the hydrogenation reaction. For
example, enamide 1b bearing a p-methyl group on the phenyl
ring gave only 53% yield and 91% ee of the product 3b
even when the reaction was run for 3 days (entry 3), while
with the addition of 10 mol % of acetic acid, the reaction
provided a 93% isolated yield and 90% ee of the product in
24 h (entry 4). In other cases, the dual-acid catalytic system
was also highly efficient; for instance, with aromatic ena-
mides bearing electron-withdrawing groups such as p-chloro
(entries 5 and 6), p-fluoro (entries 7 and 8), and p-
A lower enantioselectivity was noted with the R-naphthyl
enamide 1h (78% ee; entry 15). It is interesting that in this
case the addition of the cocatalyst resulted in a slightly
diminished ee. This phenomenon suggested that steric
hindrance is an important factor in this hydrogenation
reaction, and it was further confirmed by other examples.
Enamides 1i and 1j, meta- and ortho-substituted arenes, gave
even lower enantioselectivities as the steric hindance in-
creased (71% ee and 41% ee, entries 17 and 19, respectively.
Finally, it should be noted that while these conditions allow
for the highly selective hydrogenation of aromatic enamides
they are ineffective for aliphatic enamides, such as enamide
1k (entry 20). The absolute stereochemistries of all the
products were assigned by comparing the optical rotation
with the corresponding known amides (see the Supporting
Information for details).
In order to support our hypothesis that the iminium is an
important intermediate of this reduction, a series of 1H NMR
experiments was performed. To a solution of 1a in C6D6
was added catalyst A4. It was apparent that new NMR signals
grew in after 5 min at room temperature. These peaks were
assigned to the following species: acetophenone, acetamide,
(6) Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832.
Org. Lett., Vol. 11, No. 5, 2009
1077

the cocatalyst acetic acid, the enamide 1 was tautomerized
to the corresponding imine, which was activated by the acid
via an iminium intermediate. In the following step, only
chiral phosphoric acid A4 was active enough to catalyze the
hydrogenation of the imine, while the acetic acid role was
probably only to help keep a sufficient concentration of
iminium intermediate present since A4 was used in such
small quanitities.
Scheme 3. Proposed Mechanism for the Asymmetric
Hydrogenation of Enamides Catalyzed by a Dual Acid System
In conclusion, we have developed a highly enantioselective
hydrogenation reaction of enamides catalyzed by a dual-acid
catalyst system. By using a chiral phosphoric acid combined
with a catalytic amount of acetic acid as the catalyst, the
loading of the chiral phosphoric acid can be as low as 1 mol
% but still provide excellent yield and enantioselectivity for
the process. Additionally, we confirmed that the iminium is
the intermediate generated and that the achiral coacid can
be used to generate a suitable concentration of iminium for
a facile reaction.
and the corresponding iminium. It was therefore apparent
that catalyst A4 can tautomerize the enamide 1a to its imine
and then partially decompose this imine. In a separate
experiment using acetic acid instead of catalyst A4, nothing
happened at room temperature. However, at 50 °C, the
corresponding iminium was observed after 3 h, and only a
very small amount of enamide 1a was decomposed. These
experiments comfirmed the hypothesis in Scheme 2. Based
on the experiments above, a reasonable dual-activation
mechanism similar to that reported recently by Goodman is
proposed in Scheme 3.7 In the presence of catalyst A4 and
Acknowledgment. We thank the University of South
Florida for generous start-up funds and a New Researcher
Award. J.C.A. also thanks the Petroleum Research Fund
(PRF 45899-G1) and the National Institutes of Health (NIH
GM-082935) for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization, chiral HPLC conditions, and
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(7) For an excellent theoretical study on a related mechanism, see:
Simon, L.; Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741.
OL802860U
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Org. Lett., Vol. 11, No. 5, 2009