Proline-Catalyzed Asymmetric R-Aminoxylation
ketones.18 At the same time Zhong19 and MacMillan et
al.20 have reported the R-aminoxylation of aldehydes, and
Cordova et al.21 have discovered the R-aminoxylation of
ketones independently. J ust recently Yamamoto and co-
workers have reported the R-aminoxylation of aldehydes
and ketones catalyzed by pyrrolidine-2-yl-1H-tetrazole.22
The conditions employed by Zhong,19 MacMillan et
al.,20 and ourselves18a for this R-aminoxylation reaction
of aldehydes are slightly different: Zhong employed 1.2
equiv of the aldehyde to nitrosobenzene in the presence
of 20 mol % of proline in DMSO at room temperature for
10-20 min,19 whereas MacMillan and co-workers used
2-3 equiv of the aldehyde in the presence of 5 mol % of
proline in CHCl3 at 4 °C for 2-4 h and a catalyst loading
that can be reduced as low as 0.5 mol %.20 In our reported
procedure,18a 3 equiv of an aldehyde was used in the
presence of 30 mol % of proline in CH3CN at -20 °C for
24 h, and we proposed that use of a low temperature (-20
°C) is suitable for suppressing the self-aldol reaction of
aldehydes, which is known to proceed at 4 °C.13m Al-
though we can reproduce the excellent enantioselectivity
they obtained using Zhong and MacMillan’s procedures,
we have been unable to obtain a high yield at room
temperature or under low catalyst loading. To clarify the
discrepancy between the work performed by other groups
and our own work and to propose robust, easily repro-
ducible reaction conditions, we have carried out several
detailed experiments at various temperatures and under
several different catalyst loadings, which will be de-
scribed in this full paper.
Concerning the R-aminoxylation of ketones, the reac-
tion conditions of Cordova and co-workers21 are also
different from ours:18b Cordova used a large excess of
ketone (10 equiv) to nitrosobenzene in the presence of
20 mol % of proline in DMSO at room temperature for
2-3 h, with one example of a cyclic ketone,21 whereas
we used 2 equiv of ketones in the presence of considerably
lower catalyst loading (10 mol %) in DMF at 0 °C, using
slow addition of the nitrosobenzene, and with several
examples of cyclic ketones including asymmetric desym-
metrization.18b As chiral R-hydroxyketones are syntheti-
cally useful building blocks, the generality of the present
reaction has been investigated in detail, and these results
will also be presented here. In this paper we will disclose
the full details of our direct asymmetric R-aminoxylation
of aldehydes and ketones using nitrosobenzene as oxidant
and proline as catalyst.23
(13) (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623,
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Asym m etr ic r-Am in oxyla tion of Ald eh yd es. The
reaction of propanal and nitrosobenzene was selected as
a model, and the effect of solvent was examined with the
results summarized in Table 1. As the R-aminoxy alde-
hyde product 1 is rather labile, isolation and character-
ization was performed after conversion to the correspond-
ing R-aminoxy alcohol 2 by treatment of the reaction
mixture with NaBH4. Although the R-aminoxylation
reaction is readily accomplished with very high enanti-
oselectivity in most of the solvents employed, the yield
is dependent on the solvent. Acetonitrile was the best of
the solvents examined, the reaction proceeding at -20
°C, to afford the R-aminoxylated aldehyde quantitatively
in 98% ee.24 In this reaction, no R-hydroxyamino aldehyde
was formed at all, and R-hydroxyamino ketones are major
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(18) Preliminary communications of this work have been reported;
see: (a) Hayashi, Y.; Yamaguchi, J .; Hibino, K.; Shoji, M. Tetrahedron
Lett. 2003, 44, 8293. (b) Hayashi, Y.; Yamaguchi, J .; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112.
(22) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5374.
(19) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
(20) Brown, S. P.; Brochu, M. P.; Sinz, C. J .; MacMillan, D. W. C. J .
Am. Chem. Soc. 2003, 125, 10808.
(21) Bøgevig, A.; Sundeen, H.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 1109.
(23) Review: Merino, P.; Tejero, T. Angew. Chem., Int. Ed. 2004,
43, 2995.
(24) Though CHCl3 is reported to be a suitable solvent by MacMillan
et al.,20 CH3CN is found to be superior in our hands.
J . Org. Chem, Vol. 69, No. 18, 2004 5967