Chiral counteranion-aided asymmetric hydrogenation of acyclic imines

Article abstract of DOI:10.1021/ja807188s

When combined with a chiral phosphate counteranion, a chiral diamine-ligated Ir(III) catalyst displayed excellent enantioselectivities in the asymmetric hydrogenation of a wide range of acyclic imines, affording chiral amines in up to 99% ee. Copyright

Full text of DOI:10.1021/ja807188s

Published on Web 10/08/2008
Chiral Counteranion-Aided Asymmetric Hydrogenation of Acyclic Imines
Chaoqun Li, Chao Wang, Barbara Villa-Marcos, and Jianliang Xiao*
Department of Chemistry, LiVerpool Centre for Materials and Catalysis, UniVersity of LiVerpool, LiVerpool L69
7ZD, U.K.
Received September 10, 2008; E-mail: j.xiao@liv.ac.uk
Table 1. Optimization of Conditions for the Hydrogenation of 1aa
Asymmetric hydrogenation of imines provides direct access to chiral
amines, one of the most important functionalities in fine chemical,
agrochemical, and pharmaceutical products.1,2 However, in terms of
both enantioselectivity and substrate scope, this transformation remains
challenging, particularly in the case of acyclic imines.1b,c The vast
majority of the transition metal catalysts reported thus far employ
phosphorus-containing ligands, and it is generally believed that the
reduction proceeds via imine nitrogen coordination to the metal
center.1c However, Norton recently showed that imines can be reduced
through an ionic pathway, where a Ru(II)-H2 complex is deprotonated
by an amine and the resulting Ru(II)-H reduces preformed iminium
salts.3 In more recent studies in organocatalysis,4 the groups of
Rueping, List, and MacMillan reported highly enantioselective transfer
hydrogenation with Hantzsch ester of imines4b,c or imines in situ
generated from ketones and amines;4d the reduction is catalyzed by
chiral phosphoric acids, which protonate the imines while the anion
of which directs the facial attack of the hydride. Inspired by these
discoveries, we envisioned that if a heterolitically hydrogen-activating
catalyst5 is associated with a chiral counteranion, the latter may be
exploited to influence the enantiodiscrimination of the chiral ligands
by ion pairing with the resulting iminium cation (Scheme 1).6 We
report herein that when combined with a chiral phosphate anion,
diamine-ligated Ir(III) catalysts indeed enable highly enantioselective
asymmetric hydrogenation of acyclic imines, affording up to 99% ee.
entry
catalyst
additive
conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3b
(S,S)-3c
(R,R)-3a
(R,R)-3c
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
none
0
-
5a (6%)
5b (6%)
5c (6%)
5d (6%)
5e (6%)
5e (6%)
5e (6%)
5e (6%)
5e (6%)
none
5e (0.5%)
5e (1%)
5e (3%)
5e (7%)
5e (10%)
5e (5%)
53
57
40
43
60
76
30
47
27
76
90
92
84
69
60
83
17(R)
26(R)
20(S)
38(S)
97(S)
92(S)
81(S)
38(R)
3(R)
9
10
11
12
13
14
15
16
17d
97(S)
97(S)
97(S)
97(S)
96(S)
96(S)
99(S)
a Reaction conditions: 0.5 mmol of 1a, 1 mol% catalyst, 2 mL of
toluene, 20 bar of H2, 20 °C, 12 h. b Determined by 1H NMR analysis
of the crude product. c Determined by HPLC analysis; configuration
assigned by comparison with the literature.2,4 d 10 °C, 18 h.
Scheme 1
chirality of the diamine ligand, i.e. from (S,S)-3a,c to (R,R)-3a,c, a
dramatic decrease in ee’s (entries 6, 8 vs 9, 10) was recorded, showing
the chirality of the catalyst needs to match that of its counteranion.
We recently found that the complex [Cp*Rh(TsDPEN-
H)(H2O)][SbF6] acts as an excellent catalyst for asymmetric hydro-
genation of cyclic imines.7-9 However, disappointing results were
obtained with acyclic imines. Thus, in the reduction of the model imine
4-methoxy-N-(1-phenylethylidene)benzenamine 1a at 20 bar H2 in
toluene, an ee of only 3% was observed at 20 °C. In contrast, the
analogous Ir(III) complex led to encouraging results, affording a 22%
ee. This prompted us to search for Cp*Ir(III) catalysts containing chiral
phosphate anions. A quick way for accessing such catalysts is to
protonate the 16e complex 3 with the phosphoric acid 5,10 which is
expected to in situ generate the catalyst 4.11 As can be seen from Table
1, while 3a was inactive in hydrogenating 1a, the combination of 3a
and 5a-e delightfully led to conversions and enantioselectivities, which
vary with the phosphoric acid used, with 5e promoting an excellent
ee of 97% (entry 6). The 3b-5e and 3c-5e couples were less
enantioselective, however (entries 7-8). Remarkably, the phosphoric
acids 5a,b afforded the amine with the configuration opposite to that
observed with 5c-e (entries 2-3 vs 4-6), revealing the directing effect
of phosphates on enantioselection. Still further, on changing the
Having identified the bulky 5e to be the best promoter for
enantioselectivity among 5a-e, we prepared the complex 4a, which
has the conjugate base of 5e as the counteranion. Using 4a as catalyst
with no additional phosphoric acid, the hydrogenation of 1a afforded
the same ee as when the catalyst was in situ prepared from 3a and 5e
(entries 6 vs 11). However, additional 5e was found to affect the
catalytic activity, with the highest conversion being observed at ca. 1
mol% 5e (entries 12-16). A higher ee of 99% was obtained when
the hydrogenation was performed at a lower temperature of 10 °C.
As with reactions that involve ion-pairing intermediates,6 the hydro-
genation is solvent-sensitive. Thus, lower ee’s were observed in more
polar solvents such as THF (92%) and MeCN (10%).
9
14450 J. AM. CHEM. SOC. 2008, 130, 14450–14451
10.1021/ja807188s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Imines 1 to Amines 2a
Using the optimized conditions, i.e. 1 mol% 4a or the analogous
4b in the presence of 1 mol% 5e, a range of acyclic imines were
hydrogenated.12 The results are given in Table 2. As can be seen, a
wide spectrum of imines are hydrogenated with 4, affording excellent
yields and ee’s in almost all the cases. Notably, the catalyst tolerates
functional groups of diverse electronic properties (-OMe, -Br, -Cl,
-CN, -NO2, alkenyl, and cyclopropyl). Furthermore, it allows N-aryl
ketimines with aryl ethyl groups (entries 17, 18) and with dialkyl
substituents (entries 20-22) to be reduced with 90-97% ee’s. In both
metallo- and organocatalysis,1,2,4 such substrates have rarely proved
to be viable. MacMillan,4d List4c and co-workers recently reported
ee’s of 81-94% for dialkyl-substituted N-aryl ketimines in organo-
catalytic reduction, but for related aryl alkyl ketimines with high
enantioselectivities, the alkyl group appears to be restricted to a
methyl.4d Much lower enantioselectivities were reported for the dialkyl
ketimines with homogeneous metal catalysts; in fact, none seems to
give ee’s higher than 80%.13,14
In conclusion, we have developed an efficient catalytic system
for asymmetric hydrogenation of the often-problematic acyclic
imines. The catalyst is viable for a wide variety of imines and
appears to operate via cooperative catalysis between a chiral metal
catalyst and its chiral counteranion.
Acknowledgment. We gratefully acknowledge the Research
Councils UK for a Dorothy Hodgkin Postgraduate Award (C.L.).
Supporting Information Available: Experimental details and
spectroscopy data (1H, 13C NMR, and HPLC). This material is available
free of charge via the Internet at http://pubs.acs.org.
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a Reaction conditions: 0.5 mmol of 1a, 1 mol% 4a, 1 mol% 5e, 2 mL
of toluene, 20 bar of H2, 20 °C, 15-20 h. b Determined by HPLC
analysis; S configuration, assigned by comparison with the literature.2,4
c S,S)-4b as catalyst. With 4a, the ee’s were ca. 6% lower.
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JA807188S
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J. AM. CHEM. SOC. VOL. 130, NO. 44, 2008 14451