Transfer hydrogenation in water: Enantioselective, catalytic reduction of (E)-β,β-disubstituted nitroalkenes

Article abstract of DOI:10.1021/ol901332e

A mild catalytic asymmetric transfer hydrogenation of β,β- disubstituted nitroalkenes Is reported. Formic acid Is used as a reductant in combination with an Ir catalyst. The reaction Is conducted in water at low pH and open to air to give adducts In prepa

Full text of DOI:10.1021/ol901332e

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4196-4198
Transfer Hydrogenation in Water:
Enantioselective, Catalytic Reduction of
(E)-ꢀ,ꢀ-Disubstituted Nitroalkenes
Omid Soltani, Martin A. Ariger, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, HCI H335,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received June 14, 2009
ABSTRACT
A mild catalytic asymmetric transfer hydrogenation of ꢀ,ꢀ-disubstituted nitroalkenes is reported. Formic acid is used as a reductant in
combination with an Ir catalyst. The reaction is conducted in water at low pH and open to air to give adducts in preparatively useful
yield and selectivity.
The study of catalytic, asymmetric methods is at the forefront
of research in chemical synthesis. In general, the field is
propelled by the discovery of novel catalysts, by the identifica-
tion of new modes of reactivity, and by enabling simple access
routes to useful building blocks. Enantioselective, catalytic
hydrogenation is the most widely applied catalytic method in
industry. Asymmetric transfer hydrogenation (ATH)1,2 methods
are attractive because of the simplification that can result
from their implementation. In this respect, we were intrigued
some years ago by the development of chiral aqua Ir(III)
complexes3 in enantioselective transfer hydrogenations. The
benefits of such a process can be appreciated on several
fronts, including the cost and ease of using low molecular
weight, organic reductants in aqueous media4 at ambient
temperature and pressure. Herein, we report an efficient and
convenient method for asymmetric reduction of ꢀ,ꢀ-disub-
stituted nitroalkenes with diamine derived iridium(III)
complexes 2 (Scheme 1).5 The method delivers chiral
(1) For recent reviews on ATH see: (a) Ikariya, T.; Blacker, A. J. Acc.
Chem. Res. 2007, 40, 1300. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res.
1997, 30, 97. (c) Samec, J. S. M.; Ba¨ckvall, J. E.; Andersson, P. G.; Brandt,
P. Chem. Soc. ReV 2006, 35, 237. (d) Gladiali, S.; Alberico, E. Chem. Soc.
Scheme 1. Catalyst Formation
ReV. 2006, 35, 226
.
(2) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 2675. (b) Hashiguchi, S.; Fujii, A.; Takehara,
J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (c) Fujii, A.;
Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521. (d) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (e) Hashiguchi, S.; Fujii,
A.; Haack, K. J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. 1997, 36, 288. (f) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem.
Soc. 2000, 122, 1466. (g) Haack, K. J.; Hashiguchi, S.; Fujii, A.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 285
.
10.1021/ol901332e CCC: $40.75
Published on Web 08/26/2009
 2009 American Chemical Society

nitroalkanes in good to excellent selectivity under operation-
ally straightforward conditions.
withdrawing groups on mono-N-tosylated diamines led to
remarkable improvement in selectivity and reactivity. In
particular, stilbene diamine ligands derivatized as perfluori-
nated sulfonamides were notable (Table 1, entries 2-7).
Finetuning of the aryl-groups and re-examination of the
sulfonyl-group led to a modest but significant increase in
selectivity (Table 1, entry 7). Interestingly, this reactivity
trend stands in sharp contrast to what is observed with
the typical Ru(II) based catalyst systems and molecular
hydrogen as well as the Ir(III) based catalysts in water
and formic acid.2b,6
There is ample precedence for the use of diamine derived
Ru complexes in transfer hydrogenation reactions, as exem-
plified by the catalyst systems developed by Noyori and
Ikariya.1b,2 In contrast, there was little precedence available
to guide our initial investigations with Ir catalysts in water.
Recent studies by Ogo and Fukuzumi document water-
soluble [Cp*Ir(bpy)(H2O)](SO4) catalysts that perform achiral
reductions of simple ketones in water at pH 5.3 Yet, whether
the ligands in the parent complex could be replaced by chiral
donors without altering the stability or reactivity of the Ir
complex was unclear at the time that we commenced our
studies.6 Initial screening and optimization studies relied upon
preparation of iridium(III) complexes derived from optically
active diamines.7 To our delight, the corresponding com-
plexes 3 are simply prepared by combining the known Ir(III)
trihydrate complex 1 with a donor ligand 2 of choice in
aqueous methanol at ambient temperature. Solvent evapora-
tion furnished aqua Ir complexes as air stable solids in
quantitative yields (Scheme 1).
We then proceeded to examine the scope of nitroalkenes
which would undergo selective and efficient reduction. As
displayed in Table 2, reduction with catalyst 5 provided
Table 2. Substrate Scope
Since many of the studies about asymmetric transfer
hydrogenations are limited to the reduction of acetophe-
nones and related compounds,1,2,6 we were interested in
expanding the scope of this powerful methodology to other
substrate classes, such as conjugate reduction of activated
double bonds. We choose nitroalkenes8 as valuable targets
since these substrates have only been studied to a limited
extent, namely in enzymatic,5a-c metal-catalyzed,5d-f and
organocatalytic5g reductions. Our initial studies commenced
with nitroolefin 4 as a test substrate and a broad range of
ligands, with aqua Ir(III) complexes in water. Monotosylated
1,2-diphenyldiamines provided a leading result and warranted
closer scrutiny (Table 1, entry 1). The use of strongly electron
entrya b
R
mol % cat.
yield,c %
ee,d e
%
,
,
1
2
3
4
5
6
7
8
C6H5
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.5
90
82
92
92
94
78
94
87
77
56
90
94
90
92
91
90
92
92
89
92
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
m-Cl-C6H4
p-CH3-C6H4
p-CH3O-C6H4
p-CN-C6H4
p-tBu-C6H4
2-naphthyl
Table 1. Initial Catalyst Screening
9
10f
a Reactions carried out with 0.5 mmol of nitroalkene. b 1.0 M formic
acid solutions were utilized. c Isolated yields. d Determined by chiral HPLC.
e Absolute configuration established by correlation to known compounds,
see the Experimental Section in the Supporting Information. f 40 °C.
excellent yields and good selectivity for a variety of
nitroalkenes, including those substituted with electron with-
drawing and donating groups (Table 2, entries 6-8). A series
entrya
R1
R2
pH
convn,b
%
ee,c %
(3) (a) Ogo, S.; Makihara, N.; Watanabe, Y. Organometallics 1999, 18,
5470. (b) Ogo, S.; Makihara, N.; Kaneko, Y.; Watanabe, Y. Organometallics
2001, 20, 4903. (c) Abura, T.; Ogo, S.; Watanabe, Y.; Fukuzumi, S. J. Am.
Chem. Soc. 2003, 125, 4149. (d) Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi,
S. J. Am. Chem. Soc. 2004, 126, 3020.
1
2
3
4
5
6
7
H
H
H
H
H
Tol
2.0
2.0
3.5
2.0
3.5
3.5
2.0
72
95
91
100
100
94
50
82
86
79
82
85
89
1
CF3
CF3
C6F5
C6F5
C6F5
CF3
(4) For discussions of water as a reaction medium see: (a) Lindstro¨m,
U. M. Chem. ReV. 2002, 102, 2751. (b) Li, C. J. Chem. ReV. 2005, 105,
3095. For examples of ATH in water see: (c) Wu, X.; Liu, J.; Li, X.; Zanotti-
Gerosa, A.; Hancock, F.; Vinci, D.; Ruan, J.; Xiao, J. Angew. Chem., Int.
Ed. 2006, 45, 6718. (d) Li, X.; Blacker, J.; Houson, I.; Wu, X.; Xiao, J.
Synlett 2006, 8, 1155. (e) Wu, X.; Li, X.; King, F.; Xiao, J. Angew. Chem.,
Int. Ed. 2005, 44, 3407. (f) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J.
Org. Biomol. Chem. 2004, 2, 1818. (g) Wu, J.; Wang, F.; Ma, Y.; Cui, X.;
Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766.
2,4-di-F
2,4-di-F
93
b
a Reactions carried out with 0.1 mmol of ketone. Determined by H
NMR of unpurified product. c ee was determined by chiral HPLC.
Org. Lett., Vol. 11, No. 18, 2009
4197

of substrates with halogens underwent clean reduction with
excellent yield and selectivity (Table 2, entries 2-5).
In conclusion, we have developed a mild and convenient
method for the selective reduction of ꢀ,ꢀ-disubstituted
nitroalkenes. The catalyst developed is readily prepared, air
stable, and utilizes formic acid as an inexpensive, safe, and
readily available reductant. The operational simplicity of this
reaction is an attractive advantage over existing methods
since additional precautions with regard to degassing of
solvents and moisture are not necessary. The reaction
provides good selectivities and yields of chiral nitroalkanes
within reasonable reaction time (24 h). Ongoing studies in
this arena look to gain a better understanding of the factors
affecting the reactivity and selectivity of these catalysts such
that more efficient and selective systems may be developed.
Acknowledgment. This research was supported through
generous support in the form of a grant by Sumitomo
Chemicals, Japan.
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Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J. Chem.sEur. J. 2008, 14,
2209.
OL901332E
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