Scheme 4. Cannizzaro-Type Reaction (Nu ) OH, OR,
Table 3. Kinetic Resolution of (()-1 by HB Cleavage with
(1R,2R)-Dilithium Amide 7a
NR4R5)
produced by hydride transfer to aldehydes. To our knowl-
edge, this is the first example of a Cannizzaro-type reaction4
to give carboxamides and alcohols.
The effects of bases were investigated for the Cannizzaro-
type reaction of a nonenolizable benzaldehyde with metal
N-hexylamide in THF (Table 4). Sodium N-hexylamide was
ee (%) of
yieldb (%)
yielda (%) and eeb (%)
entry
reactant 1
of 8
of 1 recovered
1
2
3
0
40
<11
69
35, 66 (R)c
71, 83 (R)c
10, 11 (S)c
91 (R)c,d
92 (S)c,d
a Isolated yield. b Determined by HPLC (Daicel OD-H column). c Ab-
solute configuration of 1 is shown in parentheses. d For the preparation of
optically active 1, see: Ishihara, K; Kaneeda, M.; Yamamoto, H. J. Am.
Chem. Soc. 1994, 116, 11179.
Table 4. Cannizzaro-Type Reaction of Benzaldehyde with
Metal N-Hexylamide
HB cleavage and the partial epimerization of 1. This reaction
did not proceed at all with the corresponding monolithium
amide under the same conditions. These results were
mechanistically interesting.
The observed kinetic resolution can be understood in terms
of the difference in the differing stereoelectronic effect
operating in bicyclic intermediates 9 and 10, as shown in
Figure 1. These intermediates are expected to be furnished
catalyst
(mol %)
conditions
(°C, h)
yielda,b
(%)
entry
MNHC6H13
1
2
3
4
5
NaNHC6H13
LiNHC6H13
LiNHC6H13
LiNHC6H13
LiNHC6H13
0, 0.5 to rt, 5
0, 0.5 to rt, 5
0, 0.5 to rt, 5
0, 0.5 to rt, 5
0, 0.5 to 40, 5
82 (76)
64 (70)
71 (75)
73 (73)
80 (75)
LDA, 10
NaH, 10
LDA, 10
a Isolated yield of N-hexylbenzamide. b Isolated yield of benzyl alcohol
is shown in parentheses.
reactive enough at room temperature for the Cannizzaro
reaction, and N-hexylbenzamide and benzyl alcohol were
obtained in respective yields of 82% and 76% yields (method
A; entry 1). On the other hand, lithium N-hexylamide, which
was less reactive than sodium N-hexylamide, gave N-
hexylbenzamide in 64% yield (entry 2). Although LDA and
NaH slightly accelerated the reaction with lithium N-
hexylamide (entries 3 and 4), sodium N-hexylamide was still
more reactive than lithium N-hexylamide-LDA. The reac-
tivity of lithium N-hexylamide was further improved under
heating at 40 °C in the presence of 10 mol % of LDA
(method B; entry 5).
To explore the generality and scope of the above reaction,
the Cannizzaro-type reaction was examined with various
aldehydes and amines using method A or B (Table 5). Most
aromatic aldehydes exhibited good reactivity, while aliphatic
aldehydes were less reactive. Notably, carboxamides were
obtained from not only lithium N-alkylamides but also from
relatively less hindered lithium N,N-dialkylamides. Dilithium
anilide was also a useful nucleophile.5
Figure 1. Bicyclic intermediates 9 and 10 via path A.
by the preferential equatorial attack3 of 7 with (R)- and (S)-
1, respectively, through path A. The Li-O bond in 10 can
adopt an antiperiplanar position to a C-C bond to be cleaved,
while the Li-O bond in 9 is conformationally restricted to
be in a synclinal position. Therefore, the reaction rate of (S)-1
would be much faster than that of its (R)-enantiomer. In
contrast, there do not appear to be any striking differences
between the steric stabilities of intermediates 9 and 10.
While studying the HB reaction, we found that N-alkyl
carboxamides and N,N-dialkyl carboxamides were directly
obtained in good yield from 2 equiv of aldehyde and 1 equiv
of the corresponding lithium amide by a C-H bond cleavage
reaction (Scheme 4). In this reaction, alcohols were also
The present methods A and B were successfully applied
to the Cannizzaro reaction of anhydrous phenylglyoxal6 with
(3) Several examples of the preferential equatorial attack of alkyllithium
to 2-substituted cyclohexanones have been reported: (a) Maruoka, K.; Itoh,
T.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 4573. (b) Maruoka, K.;
Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. J. Am. Chem. Soc.
1988, 110, 3588.
(4) Cannizzaro, S. Justus Liebigs Ann. Chem. 1853, 88, 129.
(5) Ooi, T.; Tayama, E.; Yamada, M.; Maruoka, K. Synlett 1999, 729.
(6) An anhydrous solution of phenylglyoxal in toluene was used. For its
preparation, see the Supproting Information.
Org. Lett., Vol. 6, No. 12, 2004
1985