Transfer hydrogenation in water: Enantioselective, catalytic reduction of α-cyano and α-nitro substituted acetophenones

Article abstract of DOI:10.1021/ol1008894

Catalytic reduction of α-substituted acetophenones under conditions involving asymmetric transfer hydrogenation in water is described. The reaction is conducted in water and open to air, and formic acid is used as reductant.

Full text of DOI:10.1021/ol1008894

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2893-2895
Transfer Hydrogenation in Water:
Enantioselective, Catalytic Reduction of
r-Cyano and r-Nitro Substituted
Acetophenones
Omid Soltani, Martin A. Ariger, Henar Va´zquez-Villa, and Erick M. Carreira*
Laboratorium fu¨r organische Chemie, ETH Zu¨rich, Ho¨nggerberg, Switzerland
carreira@org.chem.ethz.ch
Received April 19, 2010
ABSTRACT
Catalytic reduction of r-substituted acetophenones under conditions involving asymmetric transfer hydrogenation in water is described. The
reaction is conducted in water and open to air, and formic acid is used as reductant.
The number of catalytic asymmetric methods has increased
dramatically in recent years, and these have proven invalu-
Scheme 1. Reduction of Acetophenones
able for the synthesis of natural products, chiral starting
materials, and intermediates. In the past decade, asymmetric
transfer hydrogenation (ATH)1 has flourished as a result of
the pioneering studies of Noyori and co-workers.2 We wish
to report a convenient and efficient method for enantiose-
lective reduction of R-cyanoketones and R-nitroketones with
iridium(III) diamine aqua complexes 3 (Scheme 1).3 The
(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.
ReV. 2006, 35, 226.
methodology described herein delivers functionalized chiral
alcohols in good to excellent selectivities and conversions.
Also, the products derived from these reductions have
(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.
(3) (a) Li, Y.; Li, Z.; Li, W.; Wang, Q.; Tao, F. Org. Biomol. Chem.
2005, 3, 2513. (b) Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Q. Org. Lett. 2004,
6, 169. (c) Hamada, T.; Torii, T.; Izawa, K.; Ikariya, T. Tetrahedron 2004,
60, 7411. (d) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002,
67, 1712. (e) Florey, P.; Smallridge, A. J.; Ten, A.; Trewhella, M. A. Org.
Lett. 1999, 1, 1879.
10.1021/ol1008894  2010 American Chemical Society
Published on Web 06/01/2010

substantial flexibility for further transformations. Finally, the
operational convenience of these reactions is noteworthy as
they are carried out at ambient temperature, in water, and
open to air.
Table 1. Initial Catalyst Screening
Scheme 2. Catalyst Formation
entrya
R
R1, R2
conversion %b
ee %c
1
2
3
4
5
6
p-Tol
F5C6
F5C6
p-Tol
CF3
-(CH2)4-
Cy
-(CH2)4-
Ph
Ph
Ph
46
0
<5
81
>90
>90
15
ND
ND
84
90
94
F5C6
a Reactions were carried out with 0.5 mmol of ketone. b Determined by
1H NMR of crude reaction after workup. c Enantiomeric excess was
determined by chiral HPLC.
Recent studies by Ogo, Fukuzumi, and colleagues have
yielded water-soluble pH-dependent catalysts that perform
achiral reductions in aqueous medium.4 We were intrigued
at the prospect of utilizing chiral aqua complexes derived
from iridium(III) trihydrate precatalysts4a for the catalytic,
enantioselective reduction of ketones (Scheme 2). Asym-
metric reductions with such catalysts would be beneficial
on several fronts, including both cost of reductant (HCO2H)
and solvent (H2O), as well as ease of operation. The advantage
with regard to safety of formic acid as compared to molecular
hydrogen is also apparent when considering conducting large-
scale reactions. The benefits of working with water as a reaction
medium is also noteworthy, and processes utilizing water as a
reaction medium are on the rise.5
leads for further optimization (Table 1, entry 4). A screen
of sulfonamides with a broad range of steric and electronic
properties proved fruitful. Ligands bearing strong electron-
deficient sulfonamides yielded catalysts with improved
selectivity and reactivity. Perfluorinated sulfonamides in
particular displayed remarkable reactivity, which is in
contrast to what has been observed with Ru(II) based
catalysts (Table 1, entries 5 and 6).2b
Examination of the scope of R-cyano ketones indicated a
well-tolerated reaction at pH ) 3.5 (Table 2). In many cases
catalyst loadings as low as 0.25 mol % proved sufficient for
Initial catalyst screening and optimization relied upon
preparation of chiral iridium(III) complexes such as 3
(Scheme 2). These catalysts are prepared by combining
the known Ir(III) trihydrate complex 1 with a ligand of
choice in a water/methanol solution at ambient tempera-
ture. Removal of the solvent yielded aqua complexes as
air-stable solids in quantitative yields. After screening a
broad selection of bidentate ligands for the reduction of
a standard R-cyano ketone 3-oxo-3-phenylpropanenitrile
4, it was clear that monosulfonylated 1,2-diphenyl di-
amines,6 such as Noyori’s Ts-DPEN ligand, served as
Table 2. Scope of R-Substituted Ketones
entrya b
Ar
X
mol % cat. yield %c ee %d
,
1
2
3
4
C6H5
m-Cl-C6H4
m-CH3O-C6H4 CN
p-F-C6H4
p-CH3-C6H4
2-naphthyl
2-furyl
2-thiophenyl
p-CN-C6H4
C6H5
p-tBu-C6H4
m-Br-C6H4
m-Cl-C6H4
2-naphthyl
o-CH3O-C6H4
C6H5
CN
CN
0.25
0.25
0.25
0.50
0.50
0.5
0.25
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.25
96
90
96
95
96
95
83
94
97
94
92
54
95
53
93
93
94
90
95
91
93
96
96
92
86
93
99
91
95
93
83
91
(4) (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.
CN
CN
CN
CN
CN
5
6e
7
(5) 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) Soltani, O.; Ariger, M. A.;
Carreira, E. M. Org. Lett. 2009, 11, 4196. (d) Wu, X.; Liu, J.; Li, X.; Zanotti-
Gerosa, A.; Hancock, F.; Vinci, D.; Ruan, J.; Xiao, J. Angew. Chem., Int.
Ed. 2006, 45, 6718. (e) Li, X.; Blacker, J.; Houson, I.; Wu, X.; Xiao, J.
Synlett 2006, 8, 1155. (f) Wu, X.; Li, X; King, F.; Xiao, J. Angew. Chem.,
Int. Ed. 2005, 44, 3407. (g) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J.
Org. Biomol. Chem. 2004, 2, 1818. (h) Wu, J.; Wang, F.; Ma, Y.; Cui, X.;
Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766.
(6) (a) Pederson, S. F.; Roskamp, E. J. J. Am. Chem. Soc. 1987, 109,
3152. (b) Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.
-T.; Winter, S. B. D.; Choi, J. Y. J. Org. Chem. 1999, 64, 1958. (c) Busacca,
C. A.; Grossbach, D.; Campbell, S. C.; Dong, Y.; Eriksson, M. C.; Harris,
R. E.; Jones, P. J.; Kim, J. Y.; Lorenz, J. C.; McKellop, K. B.; O’Brien,
E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli, E. M.; Vitous,
J.; Zavattaro, C. J. Org. Chem. 2004, 69, 5187. (d) Kim, H.; Nguyen, Y.;
Yen, C. P-H.; Chagal, L.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem.
Soc. 2008, 130, 12184.
8
9
CN
10
11
12
13
14e
15
16
NO2
NO2
NO2
NO2
NO2
NO2
Cl
a Reactions were carried out with 0.5 mmol of ketone. b For X ) CN,
Cl, pH ) 3.5; for X ) NO2, pH ) 2.0. c Isolated yield, d Enantiomeric
excess was determined by chiral HPLC. e Addition of 10 mol %
hexafluoroisopropanol.
2894
Org. Lett., Vol. 12, No. 13, 2010

complete conversion.7 Electron-donating and -withdrawing
groups at the meta and para positions did not adversely affect
the selectivity or conversion (Table 2, entries 2-5). Het-
eroaromatic substrates such as the furan and thiophene
substituted ketones proved to be outstanding substrates (Table
2, entries 7 and 8). Also worth noting, complete reduction
of 2-naphthyl ketone required addition of 10 mol % hexa-
fluoroisopropanol as a cosolvent, presumably because of poor
interaction between the catalyst and substrate in the aqueous
medium employed.
Examining the scope of R-nitroketones in this reduction
led to similarly fruitful results. A modest increase in catalyst
loading (0.5 mol %), as compared to the reduction of R-cyano
ketones, was required for full conversion. Also, a slightly
more acidic medium (pH ) 2.0) was necessary to minimize
side reactions. Enhancement in selectivity was observed with
a substrate containing a bulky group at the para positon
(entry 11). As it was observed with R-cyano ketones,
substitution of the aryl ring with bulky electron-withdrawing
halogens at the meta position was tolerated (entries 12 and
13). Finally, R-chloroketone was shown to undergo reduction
in excellent yield and selectivity (entry 17). Such chloro-
alcohols are accessible precursors to terminal epoxides.5c
In summary, we have documented a catalytic method for
the enantioselective reduction of R-cyanoketones and R-ni-
troketones. The designed catalysts are readily prepared and
are stable to moisture and air. Furthermore, the use of formic
acid as reductant underlines the convenience of the method
because it is inexpensive, readily available, and operationally
simple to employ. Low catalyst loadings (0.25-0.5 mol %)
provide excellent yields of chiral cyanoketones and nitroke-
tones.
Acknowledgment. This research was supported through
generous support in the form of a grant by Sumitomo
Chemicals, Japan. H.V.-V. thanks the Ministerio de Educa-
cio´n y Ciencia (Spain) for a postdoctoral fellowship.
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.
(7) Repeating the reaction of 4 with 0.1 mol % catalyst after 72 h gives
83% yield and 94% ee in addition to unreacted starting material.
OL1008894
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