Iridium diamine catalyst for the asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1002/anie.201102732

A simple and very efficient chiral aqua iridium(III) diamine complex leads to excellent enantioselectivities in the asymmetric transfer hydrogenation of various α-cyano and α-nitro ketones. The catalyst provides the ortho-substituted aromatic alcohols with especially high ee values. The diamine ligands can be used directly as chiral ligands; conversion into the corresponding sulfamide is not necessary.

Full text of DOI:10.1002/anie.201102732

DOI: 10.1002/anie.201102732
Asymmetric Transfer Hydrogenation
Iridium Diamine Catalyst for the Asymmetric Transfer Hydrogenation
of Ketones**
Henar Vꢀzquez-Villa, Stefan Reber, Martin A. Ariger, and Erick M. Carreira*
Catalytic asymmetric transfer hydrogenation (ATH) of
ketones has emerged as an attractive alternative to the use
of hydrogen for the preparation of optically active secondary
alcohols.[1] The majority of the research carried out in this
area has relied on RuII catalysts bearing optically active
phosphines and amino/sulfonamides.[1] Among the most
widely employed catalytic systems is that of Noyori et al.,
namely the RuII–TsDPEN catalyst (TsDPEN = N-(p-toluene-
reports involving iridium published to date remains scarce
when compared to those using ruthenium(II)-based systems.[7]
Moreover, none of these employ simple secondary C2-
symmetric diamines as chiral ligands.[8–11] Bearing in mind
the complex developed by Ogo, Fukuzumi, and co-workers,
we decided to explore the use of chiral aqua iridium
complexes in ATH.
The chiral aqua iridium(III) complexes [Cp*Ir(ligand)-
(H2O)]SO4 were easily prepared by mixing [Cp*Ir(H2O)3]SO4
with a collection of chiral diamines in water at room
temperature (Scheme 2). These complexes were isolated as
sulfonyl)-1,2-diphenylethylenediamine),
which
displays
broad substrate scope and provides optically active alcohols
in high enantiomeric purity.[2] Herein we report the synthesis,
isolation, and application of a new chiral aqua iridium(III)
complex for the ATH of aromatic a-cyano and a-nitro
ketones, substrates whose reduction has not yet been widely
studied (Scheme 1).[3a–c] The catalytic system described is
based on commercially available, optically active diamines,
which are simplified ligand alternatives to the commonly used
monosulfonylated diamines.
Scheme 1. ATH with iridium diamine complexes.
Ogo, Fukuzumi, and co-workers have documented the
ability of [Cp*Ir(bpy)(H2O)]SO4 (bpy = 2,2’-bypyridine,
Cp* = C5Me5) to effectively reduce ketones through the
action of formate ions in a pH-dependent process.[3,4]
Recently, the Xiao[5] and Deng[6] groups have shown that
chiral iridium(III) catalysts are an attractive alternative to the
use of ruthenium(II) systems in the ATH processes of ketones
in water. These catalytic systems are generated by allowing
[{Cp*IrCl2}2] to react with the monosulfonylated diamine
Scheme 2. Synthesis of iridium(III) complexes.
air- and moisture-stable solids that could be used directly in
the ATH reaction. Screening of the various Ir complexes was
carried out for the reduction of 2-cyanoacetophenone with
formate ion using a 1:1 water/methanol solvent mixture in an
open reaction flask. As shown in Table 1 the reaction with
0.5 mol% of the corresponding complex and 5 equivalents of
sodium formate at 708C led to the expected 2-hydroxynitrile
with variable yields and ee values (Table 1, entries 1–5). The
complexes with ligands 1 and 2 gave low enantiomeric
excesses (47% and 43%, respectively; Table 1, entries 2 and
3); however, the reaction catalyzed by the complex [Cp*Ir(3)-
(H2O)]SO4 yielded the corresponding alcohol in 83% ee
(Table 1, entry 4). At this point, further significant improve-
ment in the enantioselectivity was achieved by introduction of
a trifluoromethyl group into the phenyl rings of the diamine
(4). Using the complex derived from this ligand, we obtained
2-hydroxynitrile in 95% ee (Table 1, entry 5). Finally, the use
CsDPEN
(CsDPEN = N-(camphorsulfonyl)-1,2-diphenyl-
ethylenediamine) and TsDPEN. However, the number of
[*] Dr. H. Vꢀzquez-Villa, Dr. S. Reber, M. A. Ariger,
Prof. Dr. E. M. Carreira
Laboratorium fꢁr Organische Chemie, ETH Zꢁrich, HCI H335
Wolfgang-Pauli-Strasse 10, 8093 Zꢁrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] H.V.-V. thanks the Ministerio de Educaciꢂn y Cienda (Spain) for a
postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102732.
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Communications
Table 1: ATH reaction of 2-cyanoacetophenone catalyzed by chiral
iridium(III) complexes.
Table 2: ATH reaction of 2-cyanoacetophenones with [Cp*Ir(4)-
(H2O)]SO4.
Entry[a]
Ligand
HCO2X
Yield [%][b]
ee [%]
Entry[a]
Ar
t [h]
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
bpy
1
2
3
4
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2H
87
90
79
63
84
99
–
1
2
3
4
5
6
7
8
C6H5
12
24
18
24
15
20
44
18
18
12
15
20
96
92
93
90
91
90
45
87
85
96
88
92
95
99
92
99
97
90
99
90
87
87
95
73
47
43
83
95
95
o-MeC6H4
p-MeC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
o-IC6H4
p-BrC6H4
p-FC6H4
m-NO2C6H4
2-naphthyl
1-thienyl
4
[a] Reactions were carried out at 708C using 1 mml of ketone in 5 mL of a
1:1 mixture of water/methanol with 0.5 mol% of [Cp*Ir(ligand)H2O]SO4.
[b] Yield and ee were determined by GC.
9
10
11
12
of formic acid instead of sodium formate resulted in improved
catalyst efficiency (> 99% conversion) without detriment to
the enantioselectivity (Table 1, entry 6). The fact that the
reaction may be conducted at pH 2 (formic acid) as well as at
pH 5.5 (sodium formate) without affecting the selectivity
renders it a highly flexible process. This is remarkable as it is
in contrast with the reactivity shown for the RuII–TsDPEN
system, where it has been noted that conducting the reaction
in acidic media leads to a decrease in enantioselectivity.[4c]
The initial results obtained with [Cp*Ir(4)(H2O)]SO4
prompted us to study this system further with a diverse
range of substituted 2-cyanoacetophenones. We chose as
standard conditions those that gave the best conversion
(Table 1, entry 6), wherein the starting 2-cyanoacetophenone
was heated at 708C in the presence of 0.5 mol% of [Cp*Ir(4)-
(H2O)]SO4 and 5 equivalents of HCO2H using a 1:1 mixture
of water/methanol as solvent. The results obtained are shown
in Table 2.
In general, the majority of the substrates tested were
reduced under the standard conditions, affording the b-
hydroxynitriles in good yield and enantiomeric excess (up to
99% ee). Both electron-donating and electron-withdrawing
substituents were well tolerated in the substrates examined in
the ATH reaction; indeed the substitution pattern had no
significant influence on the reaction time needed to achieve
conversions. However, those systems with electron-withdraw-
ing substituents yielded the reduction products with slightly
lower selectivity (Table 2, entries 8–10). It is well worth noting
that ortho-substituted arenes furnished products displaying
higher enantiomeric excess than those obtained from the
corresponding meta and para isomers (Table 2, entries 2–6).
Thus, in the case of methoxy-substituted 2-cyanoacetophe-
nones (Table 2, entries 4–6), the ortho regioisomer was
reduced with 99% ee, and the para isomer delivered the
alcohol in only 90% ee. A similar trend was found also for the
corresponding methyl-substituted 2-cyanoacetophenones
(Table 2, entries 2 and 3, 99% ee (ortho) versus 92% ee
(para)). The beneficial “ortho effect” was also confirmed in
the case of acetophenones bearing electron-withdrawing
substituents such as iodine (99% ee). These results are in
contrast with the widely reported effect found in the ATH
reaction of substituted acetophenones, where ortho-substi-
[a] Reactions were carried out at 708C using 1 mmol of ketone in 5 mL of
a 1:1 mixture of water/methanol with 0.5 mol% of catalyst and
5 equivalents of HCO2H. [b] Yield of isolated product. [c] Determined by
GC or HPLC analysis with a chiral stationary phase. [d] Configuration of
the products were all determined to be S as shown by the optical rotation
values.
tuted systems lead to products with lower enantiomeric
excess. For example, ATH of 1-(p-methoxyphenyl)ethanone
catalyzed by Ir–CsDPEN yielded the corresponding alcohol
with 97% ee, while the enantiomeric excess for the ortho
isomer was 85% ee.[5a] The same effect was also observed
when the system Ru–TsCYDN (TsCYDN = N-(p-toluenesul-
fonyl)-1,2-cyclohexanediamine) was used as the catalyst, and
1-p-tolylethanone was reduced with 92% ee while 80% ee
was obtained for 1-o-tolylethanone.[5b]
The reductions of 2-nitroacetophenones were also exam-
ined with the catalytic system described herein, [Cp*Ir(4)-
(H2O)]SO4 and HCO2H, and the results are summarized in
Table 3. When the reaction was examined using the standard
conditions described above for the reduction of 2-cyanoace-
tophenones, the corresponding 2-nitroalcohols were obtained
with good enantiomeric excesses (up to 98% ee) and moder-
ate to good yields (Table 3, entries 1–5). The reduction of
meta-bromo-2-nitroacetophenone was better achieved with a
slight modification of the standard reaction conditions. Thus,
when the solvent was changed from water/methanol to a 1:1
mixture of water/formic acid, which caused a drop in the pH
from 5.5 to 2.0, both the reaction time and the yield were
improved (Table 3, entry 5 versus entry 6), without a signifi-
cant change in the enantioselectivity. These latter conditions
were successfully applied to the reduction of meta-chloro-2-
nitroacetophenone (Table 3, entry 7). The heteroaromatic
system 2-nitro-1-(thiophen-2-yl)ethanone was also reduced
using these modified conditions with moderate yield and
enantioselectivity (Table 3, entry 9).
In summary, we have developed a new, simple, and highly
efficient chiral aqua iridium(III) complex for ATH. This
catalytic system has shown high reactivity, leading to excellent
enantioselectivities (up to 99% ee) for various aromatic a-
cyano and a-nitro ketones. An additional advantage of this
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[2] a) K. Matsumura, S. Sashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1997, 119, 8738; b) A. Fujii, N. Hashiguchi, N.
Uematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118,
2521; c) S. Hashiguchi, A. Fujii, J. Takehara, T. Akariya, R.
Noyori, J. Am. Chem. Soc. 1995, 117, 7562.
Table 3: ATH reaction of 2-cyanoacetophenones with [Cp*Ir(4)-
(H2O)]SO4.
[3] For recent reactions catalyzed by ruthenium complexes, see for
example a) Y. Li, Z. Li, W. Li, Q. Wang, F. Tao, Org. Biomol.
Chem. 2005, 3, 2513; b) P. N. Liu, P. M. Gu, F. Wang, Y. Q. Tu,
Org. Lett. 2004, 6, 169; c) M. Watanabe, K. Murata, T. Ikayriya, J.
Org. Chem. 2002, 67, 1712; d) D. S. Matharu, D. J. Morris, G. Y.
Clarkson, M. Wills, Chem. Commun. 2006, 3232; e) A. Zaitsev,
H. Adolfsson, Org. Lett. 2006, 8, 5129 – 5132; f) X. Wu, X. Li, F.
King, J. Xiao, Angew. Chem. 2005, 117, 3473; Angew. Chem. Int.
Ed. 2005, 44, 3407; g) J. Hannedouche, G. Y. Clarkson, M. Wills,
Entry[a,b]
Ar
t [h]
Yield [%][b]
ee [%][d]
1[a]
2[a]
3[a]
4[a]
5[a]
6[b]
7[b]
8[a]
9[b]
C6H5
5
18
8
12
15
3
2
10
9
85
51
77
75
35
78
81
78
50
95
99
92
98
94
93
92
93
76
o-MeC6H4
p-tBuC6H4
o-MeOC6H4
m-BrC6H4
m-BrC6H4
m-ClC6H4
2-naphthyl
2-thienyl
ˇ
J. Am. Chem. Soc. 2004, 126, 986; h) D. Sterk, M. S. Stephan, B.
Mohar, Tetrahedron Lett. 2004, 45, 535; i) X. Li, X. Wu, W. Chen,
F. E. Hancock, F. King, J. Xiao, Org. Lett. 2004, 6, 3321; j) Y. Ma,
H. Liu, L. Chen, X. Cui, J. Zhu, J. Deng, Org. Lett. 2003, 5, 2103.
[4] a) S. Ogo, K. Uehara, T. Abura, S. Fukuzumi, J. Am. Chem. Soc.
2004, 126, 3020; b) T. Abura, S. Ogo, Y. Watanabe, S. Fukuzumi,
J. Am. Chem. Soc. 2003, 125, 4149; c) S. Ogo, N. Makihara, Y.
Kaneko, Y. Watanabe, Organometallics 2001, 20, 4903; d) S.
Ogo, N. Makihara, Y. Watanabe, Organometallics 1999, 18, 5470.
[5] a) X. Li, J. Blacker, I. Houson, X. Wu, J. Xiao, Synlett 2006, 1155;
b) W. Wu, D. Vinci, T. Ikariya, J. Xiao, Chem. Commun. 2005,
4447; For an example of iridium (III) catalyst for the TH of
aldehydes, see: c) X. Wu, J. Liu, X. Li, A. Zanotti-Gerosa, F.
Hancock, D. Vinci, J. Ruan, J. Xiao, Angew. Chem. 2006, 118,
6870; Angew. Chem. Int. Ed. 2006, 45, 6718.
[a] Reactions were carried out at 708C using 1 mmol ketone in 5 mL of a
1:1 mixture of water/methanol with 0.5 mol% of catalyst and 5 equiv-
alents of HCO2H. [b] Reactions were carried out at 708C using 1 mmol of
ketone in 5 mL of a 1:1 mixture of water/HCO2H with 0.5 mol% of
catalyst. [c] Yield of isolated product. [d] Determined by HPLC analysis
with a chiral stationary phase. [e] Configuration of the products were all
determined to be R as shown by the optical rotation values.
catalyst is the “ortho effect” observed, which leads to ortho-
substituted aromatic alcohols with high enantioselectivity. Of
particular importance is the fact that the diamines can be used
as the chiral ligands without conversion to the corresponding
monosulfonylated diamines. This leads to a significant
simplication of the ligand and its synthesis. Moreover, it
opens up new opportunities for ligand design which have
otherwise focused on monosulfonamides of diamines. Further
exploration of these iridium(III) catalytic systems is under-
way and results will be reported in due course.
[6] a) F. Wang, H. Liu, L. Cun, J. Zhu, J. Deng, Y. Jiang, J. Org.
Chem. 2005, 70, 9424.
[7] For other examples of iridium-based catalysts, see: a) Z.-R.
Dong, Y.-Y. Li, J.-S. Chen, B.-Z. Li, Y. Xing, J.-X. Gao, Org. Lett.
2005, 7, 1043; b) T. Thorpe, J. Blacker, S. M. Brown, C. Bubert, J.
Crosby, S. Fitzjohn, J. P. Muxworthy, J. M. J. Williams, Tetrahe-
dron Lett. 2001, 42, 4041; c) K. Murata, T. Ikariya, R. Noyori, J.
Org. Chem. 1999, 64, 2186; d) K. Mashima, T. Abe, K. Tani,
Chem. Lett. 1998, 1199; e) O. Soltani, M. A. Ariger, E. M.
Carreira, Org. Lett. 2009, 11, 4196; f) O. Soltani, M. A. Ariger,
H. Vꢁzquez-Villa, E. M. Carreira, Org. Lett. 2010, 12, 2893; g) S.
Arita, T. Koike, Y. Kayaki, T. Ikariya, Angew. Chem. 2008, 120,
2481; Angew. Chem. Int. Ed. 2008, 47, 2447.
Received: April 20, 2011
Published online: August 25, 2011
[8] For a review of recent advances in asymmetric hydrosilylation,
transfer hydrogenation, and hydrogenation of ketones catalyzed
by iridium complexes, see: R. Malacea, R. Poli, E. Manouri,
Coord. Chem. Rev. 2010, 254, 729.
[9] For a discussion of asymmetric transfer hydrogenation in water
with Pt group metal catalysts, see: X. Wu, C. Wang, J. Xiao,
Platinum Met. Rev. 2010, 54, 3.
[10] Amino alcohols have been examined in asymmetric transfer
hydrogenation of acetophenones, affording phenethyl alcohols
in 35 – 87% ee, see: X. Wu, X. Li, M. McConville, O. Saidi, J.
Xiao, J. Mol. Catal. A 2006, 247, 153.
[11] Aminosulfoxides have been reported as ligands for Ir in
asymmetric transfer hydrogenation of acetophenone, see:
D. G. I. Petra, P. C. J. Kramer, A. L. Spek, H. E. Schoemaker,
P. W. N. M. van Leeuwen, J. Org. Chem. 2000, 65, 3010.
Keywords: asymmetric catalysis · hydrogen transfer · iridium ·
ketones · water
.
[1] For recent reviews on ATH, see: a) T. Ikariya, K. Murata, R.
Noyori, Org. Biomol. Chem. 2006, 4, 393; b) S. Gladiali, E.
Alberico, Chem. Soc. Rev. 2006, 35, 226; c) J. S. M. Samec, J.-E.
Bꢀckvall, G. G. Andersson, P. Brandt, Chem. Soc. Rev. 2006, 35,
237; d) K. Everaere, A. Mortreux, J.-F. Carpentier, Adv. Synth.
Catal. 2003, 345, 67; e) H.-U. Blaser, C. Malan, B. Pugin, F.
Spindler, H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345,
103; f) C. Wang, X. Wu, J. Xiao, Chem. Asian J. 2008, 3, 1750. For
a recent review on Ir-catalyzed ATH see: g) O. Saidi, M. J.
Williams, Topics in Organometallic Chemistry, Vol. 34 (Ed.: P. G.
Andersson), Springer, Heidelberg, 2011, 77.
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8981