Although these hydrogenations with transition metal catalysts
often proceed efficiently, there are important limitations. When
using heterogeneous catalysts, hydrogenolysis3 of benzylic,
allylic, and propargylic alcohols and amines is often inevitable,
and an important drawback when the corresponding benzyl, Cbz,
and Alloc protecting groups are present.4 In addition, several
functional groups such as nitro groups, benzylic ketones, and
aryl halides are rapidly reduced as well.
A less recognized feature of transition metals is their tendency
to isomerize double bonds.5 This holds for all commonly used
transition metals both in heterogeneous and in homogeneous
catalysis. Although often overlooked in cases in which the
isomerized product is subsequently reduced without conse-
quence, this process can lead to epimerization, ring opening of
cyclopropanes, and, most difficult to detect, racemization.
Several studies in natural product synthesis have explicitely
reported epimerization or racemization in the course of the
synthetic route.6 Mori et al. observed partial racemization in
the synthesis of 6-acetoxy-19-methylnonacosane.7 Curran et al.
observed, upon careful analysis during the synthesis of the
pinesaw fly sex pheromones, epimerization due to hydrogenation
with Pd/C and Ra Ni.8 Very recent examples include the
synthesis of the mating hormone of Phythophthera infestans,
which was hampered by the same problem,9 whereas in the
course of an absolute configuration determination, Hayashi et
al. observed a small amount of racemization upon the hydro-
genation of a terminal alkyn.10
Reduction of Carbon-Carbon Double Bonds
Using Organocatalytically Generated Diimide
Christian Smit,† Marco W. Fraaije,‡ and
Adriaan J. Minnaard*,†
Stratingh Institute for Chemistry, Nijenborgh 4,
9747 AG, Groningen, The Netherlands, and Laboratory of
Biochemistry, Groningen Biomolecular Sciences and
Biotechnology Institute, Nijenborgh 4, 9747 AG, Groningen,
The Netherlands
ReceiVed August 8, 2008
An efficient method has been developed for the reduction
of carbon-carbon double bonds with diimide, catalytically
generated in situ from hydrazine hydrate. The employed
catalyst is prepared in one step from riboflavin (vitamin B2).
Reactions are carried out in air and are a valuable alternative
when metal-catalyzed hydrogenations are problematic.
One of the few alternatives to transition metal catalyzed
hydrogenation for the reduction of carbon-carbon double bonds
is the use of diimide (diazene, HNdNH), generated from
hydrazine hydrate or its derivatives. With diimide, nonpolarized
double bonds are reduced via a cycloaddition mechanism and
therefore hydrogenolysis, reduction of polarized bonds, or
isomerization do not take place.11
Diimide itself is unstable and a large number of methods for
its in situ generation have been reported. The most well-known
among these methods are the generation of diimide from a large
excess of hydrazine hydrate with oxygen, generally in the
presence of Cu(II) and/or a carboxylic acid, the oxidation of
The reduction of carbon-carbon double bonds is a central
reaction in organic synthesis, although in principle it lowers
the complexity of the molecule.1 Nevertheless, carbon-carbon
double bonds are often used in the synthesis of natural products
and pharmaceutical compounds either to introduce chirality via
asymmetric hydrogenation or as a consequence of the strategy
applied to connect molecular fragments. Established methods
to form carbon-carbon double bonds are the Wittig and related
reactions, the Julia-Kocienski, Ramberg-Ba¨cklund, aldol, and
Knoevenagel reactions, and more recently olefin metathesis and
allylic substitution reactions.
(3) Wilkinson, H. S.; Hett, R.; Tanoury, G. J.; Senanayake, C. H.; Wald,
S. A. Org. Proc. Res. DeV. 2000, 4, 567–570.
(4) Galletti, A. M. R.; Bonaccorsi, F.; Calvani, F.; Di Bugno, C. Catal.
Commun. 2006, 7, 896–900.
(5) (a) Smith, G. V.; Roth, J. A.; Desai, D. S.; Kosco, J. L. J. Catal. 1973,
30, 79–85. (b) Smith, G. V.; Wang, Y.; Song, R.; Jackson, M. Mol. Catal. Today
1998, 44, 119–127.
(6) (a) Nakai, T.; Yajima, A.; Akasaka, K.; Kaihoku, T.; Ohtaki, M.; Nukada,
T.; Ohrui, H.; Yabuta, G. Biosci. Biotechnol. Biochem. 2005, 69, 2401–2408.
(b) Schwartz, B. D.; Hayes, P. Y.; Kitching, W.; De Voss, J. J. J. Org. Chem.
2005, 70, 3054–3065. (c) Rakoff, H.; Rohwedder, W. K. Lipids 1992, 27, 567–
569.
(7) Mori, K.; Ohtaki, T.; Ohrui, H.; Berkebile, D. R.; Carlson, D. A. Eur. J.
Org. Chem. 2004, 1089–1096.
(8) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70, 9447–
9462.
(9) Yajima, A.; Qin, Y.; Zhou, X.; Kawanishi, N.; Xiao, X.; Wang, J.; Zhang,
D.; Wu, Y.; Nukada, T.; Yabuta, G.; Qi, J.; Asano, T.; Sakagami, Y. Nature
Chem. Biol. 2008, 4, 235–237.
(10) Nishimura, T.; Guo, X.-X.; Uchiyama, N.; Katoh, T.; Hayashi, T. J. Am.
Chem. Soc. 2008, 130, 1576–1577.
(11) Pasto, D. J.; Taylor, R. T. Reductions with Diimide in Organic Reactions;
V Paquette L. A., Ed.; J. Wiley & Sons: New York, 1991; Vol. 40, pp 91-
150.
Reduction of nonpolarized carbon-carbon double bonds is
normally accomplished by using hydrogen and heterogeneous
transition metal catalysts, e.g. Rh/C, Pd/C, Raney Nickel, or
Adams catalyst (PtO2). Alternatively, homogeneous transition
metal complexes such as Wilkinson’s catalyst are applied,
whereas enantioselective hydrogenation is mostly based on
homogeneous catalysis as well.2
† Stratingh Institute for Chemistry.
‡ Groningen Biomolecular Sciences and Biotechnology Institute.
(1) Corey E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New
York, 1989.
(2) Handbook of Homogeneous Hydrogenation; de Vries J. G., Elsevier, C. J.,
Eds.; Wiley-VCH: New York, 2007.
9482 J. Org. Chem. 2008, 73, 9482–9485
10.1021/jo801588d CCC: $40.75 2008 American Chemical Society
Published on Web 11/01/2008