A metal-free transfer hydrogenation: Organocatalytic conjugate reduction of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200461816

Impressive tolerance is displayed in the efficient and chemoselective organocatalytic transfer hydrogenation of α,β-unsaturated aldehydes in the presence of a Hantzsch dihydropyridine and a catalytic amount of dibenzylammonium trifluoroacetate (see scheme). Various sensitive functional groups such as the nitro, cyano, alkenyl, and benzyloxy groups survive these reaction conditions.

Full text of DOI:10.1002/anie.200461816

Communications
Reported conjugate reductions of aldehydes are either non-
catalytic and require stoichiometric amounts of an (organo)-
metallic hydride source,[4] require elevated temperatures,[5] or
show only modest selectivity.[6] Clearly, a mild, catalytic, and
highly chemoselective variant is highly desirable.
Recently iminium catalysis emerged as a powerful method
for the asymmetric catalysis of cycloadditions and conjugate
additions to enals and enones.[7] We reasoned that this
catalysis strategy might be applicable to the conjugate
reduction of a,b-unsaturated carbonyl compounds if a
suitable hydride donor could be identified.[8] Such a process
would constitute the first metal-free catalytic transfer hydro-
genation.
We found that several ammonium salts (5 mol%)readily
catalyze the conjugate reduction of o-nitrocinnamaldehyde
(3a)to the corresponding saturated analogue 4a when the
Hantzsch ester 1 (1.1 equiv)is also added at room temper-
ature [Eq. (1), Table 1]. No reduction was observed in the
Organocatalysis
A Metal-Free Transfer Hydrogenation:
Organocatalytic Conjugate Reduction of
a,b-Unsaturated Aldehydes**
Jung Woon Yang, Maria T. Hechavarria Fonseca, and
Benjamin List*
Hydrogenations of double-bond-containing compounds such
as carbonyls, imines, and olefins are crucial for living
organisms as well as for the industrial production of
chemicals. While chemical hydrogenations require metal
catalysts or the use of stoichiometric amounts of metal
hydrides, nature typically relies on organic cofactors such as
nicotinamide adenine dinucleotide (NADH)in combination
with metalloenzymes. Metal-free catalytic hydrogenations of
olefins have been unknown both in nature and in chemical
synthesis.[1] Herein we disclose a highly efficient and remark-
ably chemoselective but completely metal-free catalytic
transfer hydrogenation of a,b-unsaturated aldehydes.
Table 1: Catalyst screening for the iminium catalytic conjugate reduction
of a,b-unsaturated aldehydes.
Entry
Catalyst 2
Yield [%]
1
2
3
2a
94
65
81
92
2b
2c
4
2d
The hydrogenation of a,b-unsaturated carbonyl com-
pounds is a useful but challenging transformation. As both
1,2- and conjugate reductions readily occur, low selectivity for
either of the two pathways is common. Catalytic hydro-
genations of a,b-unsaturated aldehydes are possible, but the
chemoselectivity is often low, and additional functional
groups that are sensitive to hydrogenation conditions such
as the benzyloxy, nitro, and nitrile groups are usually not
tolerated.[2] Alternative conjugate reductions have been
realized with various substrate classes,[3] but a mild, general,
highly chemoselective, and catalytic variant that is applicable
to a,b-unsaturated aldehydes has not been described.
5
6
2e
2 f
90
35
absence of catalyst after 48 h at room temperature. Cyclic as
well as acyclic ammonium salts could be used, and the highest
rate and yield was obtained with dibenzylammonium trifluor-
oacetate (2a). Interestingly, this catalyst was introduced in the
1970s by Corey et al. as an efficient catalyst for intramolecular
aldol reactions of aldehydes.[9] Under our reaction conditions
aldolization did not occur to any measurable extent. In
addition to catalyst 2a, the corresponding pyrrolidinium,
morpholinium, and piperidinium salts as well as the Weinreb
salt 2b can be used as catalysts.[10] Ammonium salt 2b has
been used previously in the iminium catalysis of the Diels–
Alder reaction.[11]
[*] Dr. J. W. Yang, Dr. M. T. Hechavarria Fonseca, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
After identifying an efficient and chemoselective iminium
catalyst for the conjugate reduction of enal 3a, we decided to
explore the scope of this new process with a variety of
[**] We thank Degussa for donations of chemicals, Dr. Nicola Vignola
for technical assistance, and the analytical departments of the Max-
Planck-Institut für Kohlenforschung.
6660 ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200461816
Angew. Chem. Int. Ed. 2004, 43, 6660 –6662

Angewandte
Chemie
different aldehydes [Eq. (2), Table 2)]. The reduction works
extremely well with a diverse set of unsaturated aldehydes,
including substituted aromatic and aliphatic ones, and the
process. These include the nitro, nitrile, benzyloxy, and
alkenyl functional groups, which all survive the reaction
conditions, illustrating the remarkable chemoselectivity of
this novel organocatalytic reaction.
In terms of the mechanism we assume the reaction to
proceed by the iminium catalysis cycle illustrated in
Scheme 1. Accordingly, after an initial reversible formation
Table 2: Organocatalytic conjugate reduction of a,b-unsaturated alde-
hydes.
Entry
1
Substrate
Product
Yield [%][a]
94
2
3
4
5
96
93
81[b]
92
Scheme 1. Proposed mechanism of iminium catalysis.
of iminium ion 5 (which effectively lowers the LUMO energy
of the substrate), conjugate hydride and proton transfer from
dihydropyridine 1 follows. This step generates pyridine 7
along with iminium ion 6. Hydrolysis then releases saturated
aldehyde product 4 and regenerates catalyst 2a. We suggest
the hydride transfer to proceed via transition state A.
We are also developing an asymmetric variant of this
reaction. For example, treating aldehyde 3i with dihydropyr-
idine 1 in the presence of catalyst 8 furnished (R)-4i in good
yield and in 81% ee [Eq. (3)].
6
7
8
92
92[c]
90
9
94
10
11
90[b,c]
86[b,c]
12
92
In summary, we have developed the first metal-free
catalytic transfer hydrogenation. This novel iminium catalytic
conjugate reduction of a,b-unsaturated aldehydes is highly
efficient and chemoselective. It requires low catalyst loadings
and tolerates various functional groups that are sensitive to
the conditions of standard hydrogenations and alternative
conjugate reductions. Current work in our laboratory focuses
on a)expanding the scope of the reaction even further to
include other substrate classes such as ketones and a-
substituted a,b-unsaturated aldehydes, b)improving the over-
all atom economy, potentially by regeneration of the cofactor
in situ,[12] c)including the reaction in tandem sequences
[a] Yield of isolated product. [b] Reaction time of 15 h. [c] Yield
determined by GC.
yields exceed 90% in almost all cases. Both b-mono- and b,b’-
disubstituted enals can be reduced, although so far we have
been unable to use enals with an additional substituent at the
a-position. Besides the carbonyl group of aldehydes and
ketones, a variety of functional groups that are sensitive to
standard hydrogenation conditions are tolerated in the
Angew. Chem. Int. Ed. 2004, 43, 6660 –6662
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6661

Communications
utilizing the presumed enamine intermediate,[13] and d)devel-
oping an efficient catalytic asymmetric variant. First results
will be reported shortly.
2003, 125, 1192 – 1194, and references therein; c)B. List, Synlett
2001, 1675 – 1686.
[8] For reported conjugate reductions of preformed a,b-unsaturated
iminium ions with Hantzsch esters, see: a)T. Makino, N. Baba, J.
Oda, Y. Inouye, Chem. Ind. 1977, 277 – 278; b)N. Baba, T.
Makino, J. Oda, Y. Inouye, Can. J. Chem. 1980, 58, 387 – 392.
[9] a)E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret,
G. E. Keck, J.-L. Gras, J. Am. Chem. Soc. 1978, 100, 8031 – 8034;
see also: b)A. Takahashi, M. Shibasaki, Tetrahedron Lett. 1987,
28, 1893 – 1896; c)W. R. Roush, D. A. Barda, Tetrahedron Lett.
1997, 38, 8785 – 8788.
[10] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 – 3818.
[11] J. L. Cavill, J. L. Peters, N. C. O. Tomkinson, Chem. Commun.
2003, 728 – 729.
[12] For an example of an enzymatic process in which the NADH
cofactor can be regenerated in situ, see: M. R. Kula, C. Wandrey,
Methods Enzymol. 1987, 136, 9 – 21.
Experimental Section
General procedure for the transfer hydrogenation reaction: Synthesis
of aldehyde 4a: To a solution of o-nitrocinnamaldehyde (3a, 88.6 mg,
0.5 mmol)and catalyst 2a (7.8 mg, 0.025 mmol, 5 mol%)in dry THF
(2 mL)was added dihydropyridine 1 (140 mg, 0.55 mmol, 1.1 equiv).
The reaction mixture was stirred at room temperature for 5 h under
argon, after which the solvent was removed and the residue was
chromatographed on silica gel (30% diethyl ether/n-hexane)to give
84 mg (94%)of 4a as an oil. All aldehydes 3 and 4 are commercially
available or have been described previously, and their analytical data
match literature values.
À
[13] For elegant catalytic C C coupling reactions that proceed by
Received: August 28, 2004
capture of hydrogenation intermediates, see: H.-Y. Jang, M. J.
Published online: November 12, 2004
Krische, Acc. Chem. Res. 2004, 37, 653 – 661.
Keywords: chemoselectivity · Hantzsch dihydropyridine ·
.
iminium salts · organocatalysis · transfer hydrogenation
[1] For mechanistic studies on the base-catalyzed and transition-
metal-free hydrogenation of ketones, see: a)A. Berkessel,
T. J. S. Schubert, T. N. Müller, J. Am. Chem. Soc. 2002, 124,
8693 – 8698; Also see: b)J. H. Teles, S. Brode, A. Berkessel, J.
Am. Chem. Soc. 1998, 120, 1345 – 1346; c)E. J. Lyon, S. Shima,
G. Buurman, S. Chowdhuri, A. Batschauer, K. Steinbach, R. K.
Thauer, Eur. J. Biochem. 2004, 271, 195 – 204.
[2] See for example: a)V. V. Grushin, H. Alper, Organometallics
1991, 10, 831 – 833; b)J. M. Grosselin, C. Mercier, G. Allmang, F.
Grass, Organometallics 1991, 10, 2126 – 2133; c)M. Sommovigo,
H. Alper, Tetrahedron Lett. 1993, 34, 59 – 62, and references
therein.
[3] For selected examples: a)U. Leutenegger, A. Madin, A. Pfaltz,
Angew. Chem. 1989, 101, 61 – 62; Angew. Chem. Int. Ed. Engl.
1989, 28, 60 – 61; b)M. Misun, A. Pfaltz, Helv. Chim. Acta 1996,
79, 961 – 972; c)D. S. Hays, M. Scholl, G. C. Fu, J. Org. Chem.
1996, 61, 6751 – 6752; d)D. H. Appella, Y. Moritani, R. Shintani,
E. M. Ferreira, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
9473 – 9474; e)Y. Moritani, D. H. Appella, V. Jurkauskas, S. L.
Buchwald, J. Am. Chem. Soc. 2000, 122, 6797 – 6798; f)G.
Hughes, M. Kimura, S. L. Buchwald, J. Am. Chem. Soc. 2003,
125, 11253 – 11258; g)B. H. Lipshutz, J. M. Servesko, Angew.
Chem. 2003, 115, 4937 – 4940; Angew. Chem. Int. Ed. 2003, 42,
4789 – 4792; h)C. Czekelius, E. M. Carreira, Angew. Chem.
2003, 115, 4941 – 4943; Angew. Chem. Int. Ed. 2003, 42, 4793 –
4795.
[4] a)E. Keinan, N. Greenspon, J. Am. Chem. Soc. 1986, 108, 7314 –
7325; b)D. M. Brestensky, J. M. Stryker, Tetrahedron Lett. 1989,
30, 5677 – 5680; c)S. Saito, H. Yamamoto, J. Org. Chem. 1996,
61, 2928 – 2929; d)H.-Y. Lee, M. An, Tetrahedron Lett. 2003, 44,
2775 – 2778.
[5] a)B. E. Norcross, P. E. Klinedinst, Jr., F. H. Westheimer, J. Am.
Chem. Soc. 1962, 84, 797 – 802; b)K. Nakamura, M. Fujii, A.
Ohno, S. Oka, Tetrahedron Lett. 1984, 25, 3983 – 3986; c)S.
Torchy, G. Cordonnier, D. Barbry, J. J Vanden Eynde, Molecules
2002, 7, 528 – 533.
[6] T. Suwa, I. Shibata, A. Baba, Organometallics 1999, 18, 3965 –
3967.
[7] See for example: a)K. A. Ahrendt, C. J. Borths, D. W. C.
MacMillan, J. Am. Chem. Soc. 2000, 122, 4243 – 4244; b)S. P.
Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc.
6662
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6660 –6662