Organocatalytic asymmetric transfer hydrogenation of nitroolefins

Article abstract of DOI:10.1021/ja074045c

We describe a highly efficient and highly enantioselective Hantzsch ester mediated conjugate transfer hydrogenation of β,β-disubstituted nitroolefins that is catalyzed by a Jacobsen-type thiourea catalyst. Copyright

Full text of DOI:10.1021/ja074045c

Published on Web 06/28/2007
Organocatalytic Asymmetric Transfer Hydrogenation of Nitroolefins
Nolwenn J. A. Martin, Lidia Ozores, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received June 4, 2007; E-mail: list@mpi-muelheim.mpg.de
Table 1. Catalyst Developmenta
Catalytic enantioselective conjugate reductions of â,â-disubsti-
tuted nitroolefins are useful for the synthesis of chiral â-branched
nitroalkanes.1 The approach is particularly attractive because
nitroolefins are relatively easy to synthesize either by condensing
ketones with nitroalkanes or via nitration of olefins. Furthermore,
the resulting nitroalkanes are valuable intermediates, such as for
further reduction to chiral amines. So far, only one biocatalytic
and one transition-metal-catalyzed variant have been realized.
Carreira et al. developed an elegant chiral copper complex-catalyzed
version using a silane as stoichiometric reductant,2 and Ohto et al.
used fermenting bakers’ yeast in the presence of glucose.3 Recently,
Hantzsch esters have been introduced to asymmetric catalysis as
convenient reagent for a number of transfer hydrogenations.4 We
have now explored their utility in conjugate reductions of nitroole-
fins. Here we report the preliminary results of this investigation
culminating in a highly enantioselective, organocatalytic transfer
hydrogenation of â,â-disubstituted nitroolefins using a Jacobsen-
type thiourea catalyst.
Because acetic acid is a known catalyst of Hantzsch ester
mediated conjugate reductions of nitroolefins,5 and because chiral
urea derivatives have recently been used to activate nitroolefins
for conjugate additions,6 we reasoned that chiral Brønsted acids4g,i,7
and hydrogen-bonding catalysts would be particularly promising
for the development of an organocatalytic transfer hydrogenation
of nitroolefins. As a model reaction, we investigated the transfer
hydrogenation of (E)-1-nitro-2-phenyl-1-propene (1a) with com-
mercially available Hantzsch esters 3 (Table 1). Chiral binol-derived
phosphoric acid catalyst 4, which we have recently used in a number
of reactions4d,f,h,j,8 proved to be an active catalyst for this reaction
but gave the desired product with poor enantioselectivity (entry
1). More promising results were obtained using hydrogen-bonding
or general acid-type thiourea catalysts. Bisthiourea catalyst 5 gave
nitroalkane 2a with moderate conversion and 40:60 er (entry 2).9
Takemoto catalyst 6 proved to be essentially inactive for the
reaction, even at elevated temperature (entry 3).6a,b We also
investigated thiourea derivatives 7-11, identical or similar to those
pioneered by Jacobsen and co-workers (entries 4-10).10 In
particular, catalysts 7 and 10 turned out to be active and highly
enantioselective catalysts (entries 4-6 and 9). Further structural
fine-tuning of thiourea 10 (see Supporting Information) led to
catalyst 11, which proved optimal in terms of reactivity and
enantioselectivity (entry 10). Running the reaction at slightly
elevated temperature (40 °C) improved the reaction rate presumably
by increasing the solubility of the Hantzsch ester (entries 4 and 5).
After optimizing solvent, substrate concentration, Hantzsch ester
structure, and catalyst loading, the following protocol was subse-
quently used: Treating nitroolefins 1 (1.3 M) with commercially
available Hantzsch ester 3b (1.1 equiv) in the presence of thiourea
catalyst 11 (5 mol %) at 40 °C in toluene for 24-48 h gave the
saturated â,â-disubstituted nitroalkane 2 in high yields and enan-
tioselectivities (Table 2).
Hantzsch
esterb
T
conv.
(%)
entry
catalyst
(
°
C)
er
1
2
3
4
5
6
7
8
9
4
5
6
7
7
7
8
9
10
11
3a
3a
3a
3a
3a
3b
3a
3b
3b
3b
rt
rt
40
rt
40
40
40
40
40
40
85
55
6
10
85
94
47
66
94
95
45:55
40:60
48:52
95:5
93:7
97:3
81:19
83:17
97:3
10
98:2
a For additionally studied catalysts, see Supporting Information. b 3a:
R3 ) Et, 3b: R3 ) t-Bu.
The reaction has a broad substrate scope and gives products with
high yields and enantioselectivities with a number of â-alkyl-
substituted nitrostyrenes (entries 1-3). Various substituents at the
phenyl ring and other aromatic groups are tolerated (entries 4-10).
Aliphatic nitroalkenes are equally suitable. tert-Butyl-substituted
nitroolefin 1k gave the corresponding product in good yield and
excellent enantioselectivity (entry 11). Aliphatic nitroolefin 1l is
also reduced in high yields (entries 12 and 13). Remarkably, the
enantioselectivity is strongly dependent on the olefin geometry. We
partially separated the two olefin diastereomers by HPLC and found
that (E)-1l gave nitroalkane 2l with significant enantioselectivity
(entry 12). A sample enriched in the (Z)-isomer gave the opposite
enantiomer but in much lower selectivity (entry 13). The absolute
configuration of compound 2c was determined by measuring its
known optical rotation.2
9
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J. AM. CHEM. SOC. 2007, 129, 8976-8977
10.1021/ja074045c CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preliminary Scope of the Transfer Hydrogenation
general support, Degussa and BASF for donating chemicals, Jutta
Rosentreter for GC measurements, and Marianne Hannappel and
Esther Bo¨ss for technical assistance. We thank our excellent HPLC
department (Georg Breitenbruch, Alfred Deege, and Heike Hinrichs)
for carefully separating the isomers of nitroolefin 1l.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC and GC traces
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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We speculate the reaction to proceed via a hydrogen-bonding
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Acknowledgment. We thank the DFG (Priority Program
Organocatalysis SPP1179) for funding this work. Generous support
by the Max-Planck-Society, by Novartis (Young Investigator Award
to B.L.), and by the Fond der Chemischen Industrie is gratefully
acknowledged. We also thank Merck, Saltigo, and Wacker for
JA074045C
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