COMMUNICATION
RhI-catalyzed aldol-type reaction of organonitriles under mild
conditionsw
Akihiro Goto,a Kohei Endo,ac Yu Ukai,a Stephan Irleb and Susumu Saito*ab
Received (in College Park, MD, USA) 14th January 2008, Accepted 27th February 2008
First published as an Advance Article on the web 26th March 2008
DOI: 10.1039/b800634b
An aldol-type reaction of organonitriles with aldehydes was
catalyzed by a RhI(OR) species under ambient conditions, and
the reaction displayed a broad substrate scope with respect to
both organonitrile and aldehyde components.
suspension was kept at 50 1C with stirring for 24 h, during
which time the mixture became a clear solution, giving the b-
hydroxynitrile 3aa in an isolated yield of 61% after column
chromatography on silica gel. The use of Cy3P alone (0.04
molar equiv.) resulted in complete recovery of 1a. In addition,
when [RhCl(cod)]2 was used in place of [Rh(OH)(cod)]2, no
reaction was observed, suggesting that the hydroxyl group of
Rh worked as a base. In contrast, a slightly better yield of 3aa
was obtained with [Rh(OMe)(cod)]2 (70%). Two molar
equivalents of Cy3P per Rh ([Rh(OMe)(cod)]2 : Cy3P =
1 : 4) was most appropriate, as equal amounts decreased the
yield considerably (40%) and a three-fold excess gave a
comparable result (66%). For reference, less basic phosphines
(Ph3P, (o-Tol)3P and n-Bu3P) and a phosphite ((PhO)3P) were
tested but shown to be far less effective than Cy3P under
otherwise identical conditions (3aa: o16% with n-Bu3P, and
B1% with the others). The use of bidentate phosphines such
as dppe, dppp, dppb, and (R)-BINAP resulted consistently
in lower conversions (o23%). The solvent screening with
[Rh(OMe)(cod)]2–4Cy3P (Rh: 0.01 M; 50 1C, 24 h) suggested
that aprotic polar solvents including DMSO, DMF, DMA,
NMP and DMI were more promising (3aa: 77–84%). In
t-BuOH the reaction proceeded more sluggishly (61%), but
better than in MeOH (31%).
The nitrile functionality is synthetically versatile for many
functional group conversions.1 Incorporation of a nitrile
fragment into a carbon framework provides rapid access to
a number of useful chemicals such as a-amino and a-hydroxy
carboxylic acid derivatives as well as nitrile-branching poly-
mers. Concerned with this goal, cyanation strategies2 have
been most widely employed so far. In contrast, aldol-type
reactions of alkylnitriles are those in which nitriles serve as
enolate equivalents incorporating aldehyde directly. This
alternative strategy for introducing the nitrile functionality is
an attractive process, providing b-hydroxynitriles, which are
potential precursors for pharmaceutically important sub-
stances.2 Although pioneering achievements related to this
end have been reported recently by Murahashi,3 Verkade,4
Knochel,5 Shibasaki and Kanai6 and others,7 some drawbacks
resulting from concomitant dehydration,3 high catalyst load-
ing (B0.05 molar equiv.) and alkylnitrile loading (ca. 20 molar
equiv.)4–6 need improvement in order to increase catalytic
efficiency and atom economy. We report here on the first
example of the RhI-catalyzed aldol-type reaction of unacti-
vated alkylnitriles under mild conditions, employing lower
catalyst and substrate loading, thereby expanding substrate
scope with respect to both aldehyde and organonitrile compo-
nents (Scheme 1).
Finally, [Rh(OMe)(cod)]2 was tested further, and after an
additional set of experiments this was proven to be the best
surrogate for [Rh(OH)(cod)]2, affording the highest produc-
tivity (99% of 3aa with [Rh(OMe)(cod)]2 (0.01 molar equiv.)
and Cy3P (0.04 molar equiv.); Rh: 0.01 M in DMSO, 25 1C,
6 h). We chose DMSO as a representative solvent and further
screened additional phosphine ligands (Fig. 1). Among the
ones tested we found that R3P ligands or the 2-(1,10-biphe-
nyl)PR2 ligands 5a (R = Cy) and 5b (R = i-Pr) were the most
potent, affording the highest conversion of 2a (495%).
Surprisingly, t-Bu3P or other ArCy2P- and Ar(t-Bu)2P-based
phosphines 5c–e were totally unsatisfactory (3aa: o5%),
suggesting that the reaction is strongly structure-demanding
and sensitive to the steric bulk around the outer sphere of Rh.
Given the above optimal conditions,z the substrate scope
was then investigated (Tables 1 and 2). Aromatic, heteroaro-
matic, a,b-unsaturated and aliphatic aldehydes 1a–u were all
suitable substrates (Table 1), although a somewhat lower yield
The Rh catalyst was prepared by treatment of [Rh(OH)-
(cod)]2 (0.01 molar equiv.) with Cy3P (0.04 molar equiv.) in
toluene at 25 1C for 0.5 h under argon (Cy = c-hexyl). After
the solvent and cod were removed by evaporation in vacuum,
MeCN (2a: 19 molar equiv.) and benzaldehyde (1a: 1 molar
equiv.) were added sequentially to the resulting yellowish
viscous oil containing the Rh complex at 25 1C. The resulting
a Department of Chemistry, Graduate School of Science, Nagoya
University, Chikusa, Nagoya, 464-8602, Japan. E-mail:
susumu@chem.nagoya-u.ac.jp; Fax: +81 52 789 5945; Tel: +81 52
789 5945
b Institute for Advanced Research, Nagoya University, Chikusa,
Nagoya, 464-8601, Japan. E-mail: susumu@chem.nagoya-u.ac.jp;
Fax: +81 52 788 6140; Tel: +81 52 788 6140
c Department of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Ohkubo, Shinjuku,
Tokyo, 169-8555, Japan
w Electronic supplementary information (ESI) available: General
experimental information and spectral data of new compounds. See
DOI: 10.1039/b800634b
Scheme 1 General scheme of the Rh-catalyzed nitrile aldol reaction.
ꢀc
This journal is The Royal Society of Chemistry 2008
2212 | Chem. Commun., 2008, 2212–2214