Communications
Table 3: The generality of the one-pot, oxidative asymmetric Michael
The reaction is thought to proceed via two reaction paths
(Scheme 2). The first oxidation path is rather fast (within 1 h;
Table 1), while the second addition reaction of nitromethane
is slow (within 3–20 h; Table 3). Organocatalyst 1a reacts with
the aldehyde to afford enamine 2 along with the generation of
water. Enamine 2 reacts with DDQ, which abstracts a
hydride, to provide iminium ion 3, and 3 reacts with water
to afford a,b-unsaturated aldehyde 4 with the regeneration of
catalyst 1a. a,b-Unsaturated aldehyde 4 reacts with catalyst
1a to generate iminium ion 5, which reacts with nitromethane
to afford enamine 6. Enamine 6 reacts with water to give the
product 7 with regeneration of catalyst 1a. Iminium ion 5 is
also generated directly from iminium ion 3 by reaction with
NaOAc. 4,5-Dichloro-3,6-dihydroxy-1,2-benzenecarbonitrile
is too acidic and addition of NaOAc is essential for the
conversion of iminium ion 3 into 5, with the elimination of the
sodium salt of hydroquinone derivative from the reaction
mixture by the precipitation.
reaction.[a]
Entry
1
Product
t [h][b]
Yield [%][c]
75
ee [%][d]
12
92
2
3
4
12
12
12
77
66
65
95
95
94
When DDQ reacts with the enamine 2, single electron
transfer[4e,15] from enamine 2 would occur to afford a radical
cation, from which hydrogen transfer would proceed to
provide iminium ion 3. To check the intermediacy of a radical
cation, we performed the reaction of 3-phenylpropanal and
DDQ in the presence of several equivalents of the radical trap
reagent TEMPO. Although the yield of cinnamaldehyde was
dependant on the amount of TEMPO,[16] the hydride abstrac-
tion proceeded to afford cinnamaldehyde with the recovery of
3-phenylpropanal, in which no addition product of 3-phenyl-
propanal and TEMPO was formed. We also conducted the
experiment with allyltrimethylsilane as a radical trap, as it is
reported to be a suitable SOMOphile by MacMillan and co-
workers.[17] When 3-phenylpropanal, DDQ, allyltrimethylsi-
lane (2.5 equiv), and 1a (20 mol%) were stirred in THF,
cinnamaldehyde was obtained in 95% yield without forma-
tion of the addition product with the allyl moiety. These
results indicate that a radical cation might be involved, but the
irreversible hydrogen transfer would be very rapid.
5
6
7
20
12
4
62
70
78
94
92
91
8
3
80
92
9
4
8
71
64
90
85
10
In summary, we have developed a one-pot, oxidative and
enantioselective cross-coupling reaction of aldehydes and
nitromethane catalyzed by diphenylprolinol silyl ether. There
are several noteworthy features in the present reaction.
1) The proton at the b-carbon atom of an aldehyde was
substituted with nitromethyl (CH2NO2) enantioselectively.
[a] Reaction conditions: aldehyde (0.4 mmol), DDQ (0.4 mmol), catalyst
1a (0.08 mmol), THF (1.6 mL), MeNO2 (4.0 mmol), NaOAc
(0.96 mmol), MeOH (0.8 mL). [b] The reaction time for the addition
reaction of nitromethane. [c] Yield of isolated product. [d] For the
determination of enantiomeric excess, see the Supporting Information.
Bn=benzyl.
À
2) This reaction is a synthetic equivalent of C H activation at
the b-carbon atom of an aldehyde. 3) b-Substituted g-nitro
aldehyde, an important synthetic intermediate, can be syn-
À
were suitable (Table 3, entries 2–4), where hydride abstrac-
tion and subsequent asymmetric Michael reaction proceeded
efficiently to afford the product with excellent enantioselec-
tivity. In addition to the aromatic group, heteroaromatic
groups such as furyl and indole were successfully employed as
a b substituent of a,b-unsaturated aldehyde (Table 3, entries 5
and 6). Moreover, b-aryl and b-heteroaryl substituted a,b-
unsaturated aldehydes, pent-4-enal derivatives were also
suitable substrates. As for the substituents at the 5-position
of pent-4-enal, aromatic groups with both electron-rich and
electron-deficient substituents were used to afford the
products with excellent enantioselectivity (Table 3,
entries 7–10).
thesized with excellent enantioselectivity. 4) Oxidative C C
bond-forming reactions can be successfully performed with-
out a metal by the use of organic oxidizing reagent. 5) The
secondary amine catalyst 1a plays two different roles: one is
the generation of an enamine and the other is the generation
of an a,b-unsaturated iminium ion. 6) This is the first,
À
enantioselective one-pot transformation of a C H bond at
À
the b-carbon atom of aldehyde into a new C C bond.
Received: November 3, 2010
Revised: February 22, 2011
Published online: March 25, 2011
3922
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3920 –3924