A versatile catalyst for reductive animation by transfer hydrogenation

Article abstract of DOI:10.1002/anie.201002944

An iridium catalyst enables the reductive amination of carbonyl groups with unprecedented substrate scope, selectivity, and activity using formic acid as the hydrogen source (see scheme) The catalyst system provides significant improvement over commonly used boron hydrides.

Full text of DOI:10.1002/anie.201002944

Communications
DOI: 10.1002/anie.201002944
Transfer Hydrogenation
AVersatile Catalyst for Reductive Amination by Transfer
Hydrogenation**
Chao Wang, Alan Pettman, John Bacsa, and Jianliang Xiao*
Reductive amination (RA), the coupling of ketones or
aldehydes with amines in the presence of a reducing reagent,
is one of the most studied and useful reactions in synthetic
chemistry.[1] Applications of the reaction are widespread in
the pharmaceutical, agrochemical, and chemical industries,
materials science, and biotechnology.[1,2] In both academic
research and commercial-scale preparations, RA is effected
mainly with stoichiometric boron hydrides and heterogeneous
hydrogenation.[2] Apart from generating copious waste, the
use of boron hydrides is associated with other problems, such
as the high toxicity of NaBH3CN and the inability to aminate
aromatic ketones with NaBH(OAc)3, two most widely used
hydrides in RA.[1c,2a] RA by heterogeneous hydrogenation has
long been practiced,[2b] but its application is limited by its
(0.5 mol%),[10] 30% conversion to the corresponding amine
in 13% ee was observed by using an azeotropic mixture of
formic acid/triethylamine (F/T) in MeOH at 408C in 3 h.
Surprisingly, when the catalyst was prepared in situ by
treating [{Cp*IrCl2}2] with Tsdpen, the conversion rose to
95%, but the resulting amine was racemic. Of yet further
interest is that when [{Cp*IrCl2}2] (0.25 mol%) was used
without any added ligand, the reaction proceeded to afford
the same result as that obtained with the in situ catalyst.
These observations prompted us to ponder what the real
catalytic species might be. One possibility is a cyclometalated
iridium complex with the substrate ketimine acting as ligand
[11,12]
À
through C H activation.
This hypothesis was quickly
supported by the fact that by simply stirring [{Cp*IrCl2}2] and
the imine substrate in MeOH at 408C for 1 h, the iridium
dimer was converted into a cyclometalated imido complex in
greater than 99% conversion.[13]
=
relatively poor chemoselectivity, for example, reduction of C
O, C C, and -NO2 over C N bonds.[1,2b] In the past decade or
so, a small number of homogeneous catalysts and enzymes
have been developed, allowing for enantioselective RA.[3–7]
However, the substrate scope remains to be improved. Herein
we disclose a class of air-stable cyclometalated imido IrIII
complexes that catalyze transfer hydrogenative RA with safe,
inexpensive formate, providing high chemoselectivity and
activity along with wide substrate scope.
=
=
Encouraged by the results above, we then explored
cyclometalated IrIII complexes of aromatic ketimines for the
reduction of an aliphatic ketimine, which itself is difficult to
undergo cyclometalation and indeed showed no activity in the
[{Cp*IrCl2}2]-catalyzed reduction (Figure 1). Dramatic accel-
Transfer hydrogenation has enjoyed a huge success in the
reduction of ketones. However, its application in the reduc-
tion of imines, the key intermediate in RA, is less devel-
oped;[8,9] examples of transfer hydrogenative RA are even
rarer.[7] In our effort to develop an asymmetric transfer
hydrogenation system for RA, we initially examined reaction
conditions for the transfer hydrogenation of a model imine
prepared from acetophenone and p-anisidine, which was not
reduced under asymmetric transfer hydrogenation condi-
tions.[9] With a previously prepared [Cp*IrCl(Tsdpen-H)]
catalyst [Cp* = pentamethylcyclopentadienyl; Tsdpen =
(1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]
[*] C. Wang, Dr. J. Bacsa, Prof. J. Xiao
Liverpool Centre for Materials & Catalysis
Department of Chemistry, University of Liverpool
Liverpool L69 7ZD (UK)
Fax: (+44)151-794-3588
E-mail: j.xiao@liv.ac.uk
Homepage: http://pcwww.liv.ac.uk/~jxiao
Dr. A. Pettman
Chemical R&D, Global Research&Development, Pfizer
Sandwich, Kent CT13 9NJ (UK)
[**] We are grateful to Pfizer for funding (C.W.), AstraZeneca for
support, Dr. J. W. Ruan for assistance in NMR spectroscopy, and M.
McCarron and J. Ellis for mass spectral analysis.
Figure 1. Reduction of aliphatic ketimine (above) with cyclometalated
iridium complexes and [{Cp*IrCl2}2]. Reactions were carried out on a
1 mmol scale at S/C=4000 with 1 mL F/T in 3 mL CF3CH2OH. 1 (*),
2 (&), 3 (!), and [{Cp*IrCl2}2] (~).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002944.
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Chemie
Table 1: Reduction of imines with complex 1.
eration in the reaction rate was observed by using cyclo-
metalated iridium complexes. As is shown in Figure 1, at a
substrate/catalyst (S/C) ratio of 4000, complex 1 afforded
greater than 99% conversion in 30 min in trifluoroethanol,
providing an initial turnover frequency (TOF) of 1.9 ꢀ 104 hÀ1,
the highest TOF value ever reported for transfer hydro-
genation of imines.[7] The more electron-rich catalyst 2
displayed somewhat lower activity. In sharp contrast, complex
3, derived from the saturated amine, showed much lower
activity (Figure 1).[12a,b] The crystal structure of 1 was con-
firmed by X-ray diffraction; details are given in the Support-
ing Information. Various mono- and bidentate amine and
phosphine ligands, for example, PPh3, 1,3-bis(diphenylphos-
phino)propane (dppp), 2,2’-bis(diphenylphosphino)-1,1’-
binathpthyl (binap), dpen, and Tsdpen, were also tested;
however, they all failed to provide more than 10% conversion
at S/C = 1000 in 15 min.
Entry[a]
1
Product
Time [h]
0.5
Yield [%][b]
97
2
3
2
2
94
91
Subsequent examination of various imine substrates
demonstrated that complex 1 is indeed both highly active
and very versatile (Table 1). At an S/C ratio of 1000, both
aromatic and aliphatic ketone-derived imines were reduced
quickly, with the latter being reduced in 0.5–2 h (Table 1,
entries 1–3). Aromatic ketimines tend to be less reactive; but
full conversion was still reached in 5 h (Table 1, entries 4–7).
The amine part of the imines can be either aromatic or
aliphatic. Aldimines are particularly active under the con-
ditions developed. Thus, even at S/C = 10000, the amine
shown was isolated in 65% yield in 2 h (Table 1, entry 8).
RA was then investigated, initially using 2-heptanone and
p-anisidine as substrates. A quick screening revealed that
complex 2 was, somewhat surprisingly, more active than
complex 1 in the cheaper solvent MeOH; the former showed
conversion of 85% for the ketone while the latter showed
42% at S/C = 1000 in 20 min. The chemoselectivity is
excellent in both cases; ketone reduction was scarcely
4
5
5
5
93
92
6
7
8
5
5
97
95
0.5
96/65[c]
1
detectable by H NMR spectroscopy.
Using catalyst 2, various aliphatic ketones were first
reductively aminated in MeOH at S/C = 1000. As shown in
Table 2, aliphatic ketones, including those that are a-
branched, all reacted well with p-anisidine (Table 2,
entries 1–6). In the case of 2-heptanone, a higher S/C ratio
of 10000 was examined, affording the amine in 73% yield of
the isolated product in 12 h (Table 2, entry 1). Benzylic,
aliphatic, electron-deficient, and various secondary amines
are also viable substrates, albeit requiring a higher catalyst
loading or longer reaction time in some cases (Table 2,
entries 7–13). To our delight, isolated and conjugated carbon–
carbon double bonds are well tolerated (Table 2, entries 14,
15, and 20). Cyclic ketones are very reactive (Table 2,
entries 16 and 17). However, b-ketoesters are less so, entailing
an S/C ratio of 200 to give a satisfactory yield in 24 h (Table 2,
entries 18 and 19); enamines were detected in the crude
products. a,b-Unsaturated aldehyde was also reductively
aminated with retention of the carbon–carbon double bond
(Table 2, entry 20). Amino alcohols and amino acids are both
suitable amine sources (Table 2, entries 21 and 22). Interest-
ingly, amino acids coupled with d-glucose at either high or
body temperature, and the product, which precipitated out of
the reaction medium, could be readily isolated by simple
[a] Reaction conditions: imine (0.5 mmol), 1 (0.5 mmol), F/T (0.5 mL),
CF3CH2OH (3 mL), 808C. [b] Yield of isolated product. [c] S/C=10000 at
1 mmol scale for 2 h.
filtration, albeit with some product loss (Table 2, entries 23
and 24). This type of RA reaction may find applications in
drug synthesis as well as biotechnology.[2]
Aromatic ketones were targeted next. These are less
active substrates and indeed show low activity in RA with
boron hydrides.[1c] Imine formation seems to be turnover
limiting, as water scavengers or strong Lewis acids are usually
employed to promote the condensation of an amine with a
carbonyl substrate.[4b,g,5] Although the acidic environment in
our system is expected to accelerate this first step of RA,
aromatic ketones were still less reactive than their aliphatic
counterparts. Hence, a lower S/C ratio of 200 was used. The
results are presented in Table 3. Substituents on different
positions of the aromatic ring of the ketones appear to have
little influence on the yield (Table 3, entries 1–3). Both
electron-withdrawing and -donating groups on the ring are
tolerated (Table 3, entries 4–6), and there is no reduction of
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Table 2: (Continued)
Table 2: RA of aliphatic ketones and aldehydes with amines.
Entry[a]
Ketones/
aldehydes
Amines
Time
[h]
Yield
[%][b]
Entry[a]
Ketones/
aldehydes
Amines
Time
[h]
Yield
[%][b]
21
22
23
1
2
5
93
1
2
1
1
98/73[c]
77/80[i]
65/63[i]
98
3
4
5
5
5
5
95
24
5
73/70[i]
91[d]
92
[a] Reaction conditions: ketone/aldehyde (0.5 mmol), amine
(0.6 mmol), 2 (0.5 mmol), F/T (0.5 mL), MeOH (3 mL), 808C. [b] Yield
of isolated product. [c] S/C=10000 at 1 mmol scale for 12 h. [d] d.r. =
1.1:1. [e] S/C=200 for 12 h. [f] S/C=200 for 24 h. [g] trans/cis ratio.
[h] cis/trans ratio. [i] The second number refers to the yield of isolated
product at 378C for 12 h.
6
7
8
5
5
5
96
90
94
-CN and -NO2 groups, which is a common problem faced in
heterogeneous hydrogenation (Table 3, entries 4 and 5).[1,2b]
Aromatic, benzylic, and aliphatic primary amines and cyclic
secondary amines all served as good amine sources (Table 3,
entries 8–11). However, an example of an electron-deficient
amine proved less reactive, and some ketone reduction was
noted (Table 3, entry 7). Acylic secondary amines are also less
reactive, with less than 50% conversion observed in the
amination of acetophenone under the standard conditions.
Tetralone reacted well with both aromatic and benzylic
amines (Table 3, entries 12 and 13). Both a- and b-ketoesters
could be used to afford good yields (Table 3, entries 14 and
15). However, an unreacted enamine was again detected in
the case of the b-ketoester. Although excellent diastereose-
letivities were obtained with chiral amines, the yields were
relatively low, possibly because of steric effects (Table 3,
entries 16 and 17).
9[e]
12
5
98
96
83
86
95
10
11
5
12[e]
13[e]
12
12
The use of ammonia as the amine source to generate
primary amines without deprotection is highly desirable. To
our delight, both ammonium formate and ammonia in MeOH
could be used as viable amine sources. Table 4 shows
examples obtained with ammonium formate. Aromatic
ketones, including an a-branched one, worked very well,
affording full conversions at S/C = 200 in 5–24 h (Table 4,
entries 1–5). Reminiscent of the observations above, aliphatic
ketones are more reactive. For example, Table 4, entry 6
shows full conversion with the more favorable S/C ratio of
1000 in 5 h. a- and b-Ketoesters again reacted well, thus
allowing direct access to amino acids (Table 4, entries 7 and
8).
14
15
16
1
1
1
96
97
99
99
17
1
(>16:1)[g]
80
18[f]
19[f]
24
24
(>99:1)[h]
71
90
These RA reactions probably proceed via an ionic
20
1
À
pathway, in which an Ir H hydride is transferred to a
=
protonated imine without coordination of the C N moiety
to the metal. The Noyori metal–ligand bifunctional mecha-
nism is less likely.[14] We detected no reduction of the imino
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Table 3: RA of aromatic ketones with amines.
Table 4: RA with ammonium formate as amine source.
Entry[a]
1
Ketones
Time [h]
5
Yield [%][b]
85
Entry[a]
Ketones
Amines
Yield
[%][b]
1
2
3
92
90
87
2
24
12
12
12
5
83
88
80
90
95
93
90
3
4
4
5
6
95
90
88
5
6[c]
7
5
7
71
90
89
91
92
88
80
81
75
8
12
8
[a] Reaction conditions: ketone (0.5 mmol), HCOONH4 (5 mmol), 2
(2.5 mmol), F/T (0.5 mL), MeOH (3 mL), 808C. [b] Yield of isolated
product. [c] S/C=1000.
9
bond in 1 when 1 (15 mg) was subjected to heating (808C) in
the presence of F/T (0.5 mL) in CF3CH2OH (0.5 mL) for
15 min, and as mentioned above, 3 is much less active
(Figure 1).
In conclusion, cyclometalated iridium complexes have
been identified as versatile catalysts, allowing the efficient
RA of a wide variety of carbonyl compounds with a diverse
range of amines and safe, inexpensive formate. We believe
this is the first catalytic system that rivals boron hydrides in
chemoselectivity, activity, and substrate scope. Further advan-
tages include the modular nature of ligands and easy
preparation of catalysts. Chiral versions of these catalysts
are being developed in our laboratory.
10
11
12
13
14
15
16
17
65
(>20:1)[c]
Experimental Section
Typical procedure for RA: A carousel reaction tube was charged with
a magnetic stir bar and p-anisidine (0.6 mmol). The tube was degassed
and recharged with nitrogen three times. 2-Heptanone (0.5 mmol)
was then introduced with syringe, followed by 1 mL of a solution of
catalyst 2 in MeOH (5 ꢀ 10À4 molLÀ1). To the mixture was injected
another 2 mL of distilled MeOH and finally 0.5 mL of HCOOH/Et3N
azeotrope. The resulting mixture was stirred at 808C for 1 h. The
reaction mixture was cooled to room temperature, quenched with
73
(>99:1)[c]
[a] Reaction conditions: ketone (0.5 mmol), amine (0.6 mmol),
(2.5 mmol), F/T (0.5 mL), MeOH (3 mL), 808C, 12 h. [b] Yield of isolated
product. [c] The d.r. value is given in parentheses.
2
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Received: May 15, 2010
Published online: August 31, 2010
Keywords: amination · amines · cyclometalation ·
.
hydrogenation · iridium
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Synlett 1999, 867; b) Y. Chi, Y. G. Zhou, X. Zhang, J. Org. Chem.
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[13] This cyclometalated complex was also prepared according to
reference [11]. See the Supporting Information for character-
ization data.
[14] R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66,
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H. E. Schoemaker, O. May, Acc. Chem. Res. 2007, 40, 1260;
b) M. Hꢁhne, U. T. Bornscheuer, ChemCatChem 2009, 1, 42.
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mura, D. Lee, S. Hayashi, S. Tanaka, M. Yoshimura, J. Org.
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