Job/Unit: O43313
/KAP1
Date: 28-11-14 11:40:56
Pages: 7
Organocatalytic α-Addition of Isocyanides to Aldehydes
Scheme 4. Possible reaction mechanism.
resubmitted to standard conditions. However, compound 7
was not hydrolyzed at all to give the α-hydroxyamide 1b.
El Kaïm and co-workers described an O-arylative
Passerini reaction with 5-nitro-2-pyridone (2a), as an acid
component.[10] Accordingly, we prepared the α-aryloxy-
amide 10,[7] a possible intermediate for our pyridone-cata-
lyzed reaction. Although the α-aryloxyamide 10 was treated
Experimental Section
General Procedure: Isocyanide (0.11 mmol) was added to a solution
of aldehyde (0.1 mmol, 1.0 equiv.), 3,5,6-trifluoro-2-pyridone
(1.6 mg, 10 mol-%), and H2O (3.6 μL, 0.2 mmol) in benzene
(0.1 mL) at room temperature. The reaction mixture was stirred at
room temperature for 40–120 h. The reaction mixture was concen-
trated under reduced pressure. The residue was purified by silica
under our standard conditions, hydrolysis of 10 did not gel column chromatography to give the α-hydroxyamide.
occur. This result indicates the Smiles rearrangement is not
involved in our catalytic cycle.
Acknowledgments
The possible reaction mechanism is described in
Scheme 4. 3,5,6-Trifluoro-2-pyridone (2b) acts as
a
This work was supported by a Grant for the 21st Century COE
program; a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocatalysts”
(Grant number 23105012) to T. S. from MEXT; a Grant-in-Aid for
Young Scientists B to T. Y. from a JSPS KAKENHI Grant (Grant
number 25860010); and a Kitasato University Research Grant for
Young Researchers to T. Y. We thank Dr. Kenichiro Nagai and Ms.
Noriko Sato (School of Pharmacy, Kitasato University) for their
contributions.
Brønsted acid to provide the nitrilium cation intermediate
D. The nitrilium cation intermediate D is trapped by the
generated pyridinylalkoxide 11 to give an imidate E that is
hydrolyzed in situ to provide the imidic acid F, along with
recycling of the catalyst 2b. The imidic acid F is isomerized
to α-hydroxyamide 1. Trapping of the nitrilium intermedi-
ate D by water is also possible to provide α-hydroxyamide
1 directly, together with recycling of the catalyst 2b.
¯
[1] a) Y. Konda, M. Onda, A. Hirano, S. Omura, Chem. Pharm.
Bull. 1980, 28, 2987–2993; b) H. Suda, T. Takita, T. Aoyagi,
H. Umezawa, J. Antibiot. 1976, 29, 100–101; c) K. Yokoi, K.
Nagaoka, T. Nakashima, Chem. Pharm. Bull. 1986, 34, 4554–
4561; d) N. B. Perry, J. W. Blunt, M. H. G. Munro, J. Am.
Chem. Soc. 1988, 110, 4850–4851.
Conclusions
In this report, we demonstrated the organocatalytic
multicomponent reaction of aldehydes, isocyanides, and
water to provide α-hydroxyamides 1. The 3,5,6-trifluoro-2-
pyridone (2b) was an effective catalyst for this reaction. The
reaction did not require any special conditions, such as tem-
perature control, inert atmosphere, or dry solvent. Various
aldehydes and isocyanides performed well in this reaction to
provide the α-hydroxyamides. Notably, even very sterically
hindered aliphatic aldehydes reacted very well with isocyan-
ides, providing the corresponding α-hydroxyamides in excel-
lent yield. Considering the ease with which catalyst ana-
logues can be prepared,[13] this will enable the development
of a new asymmetric organocatalytic reaction system. De-
velopment of the organocatalytic asymmetric α-addition of
isocyanide is in progress.
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Eur. J. Org. Chem. 0000, 0–0
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