C O M M U N I C A T I O N S
Table 2. 1,4-Addition Reaction of Various Conjugated
Nitroalkenes (2) with Dimethyl Malonate (3a) Catalyzed by (R)-1h
(eq 1)a
In conclusion, we have developed axially chiral guanidine 1 as
a remarkably active organocatalyst that facilitates the highly
enantioselective 1,4-addition reaction of 1,3-dicarbonyl compounds
with a broad range of conjugated nitroalkenes to provide various
types of optically active nitroalkane derivatives of synthetic and
biological importance. We also found a significant effect of Ar
substitution at the 3,3′-positions of the binaphthyl ring. Further
studies are in progress to elucidate the substituent effect and the
origin of the enantioselectivity.
entry
R1of 2
product
time (h)
yield (%)b
ee (%)c
1
2
3
5
4
6
7
8
9
10
11d
12d
13d
2-MeOC6H4-
2-BrC6H4-
2-NO2C6H4-
3-MeOC6H4-
3-BrC6H4-
4-MeOC6H4-
4-ClC6H4-
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
2
2
4
2
2
4
2
4
2
98
>99
86
94
90
97
98
91
94
95
94
95
93
94
96
86
87
91
96
>99
>99
90
>99
>99
87
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and The Sumitomo
Foundation.
4-BrC6H4-
2-furyl-
R-naphthyl-
(CH3)2CHCH2-
(CH3)2CH-
cyclohexyl-
2
10
15
10
79
Supporting Information Available: Representative experimental
procedure including the results of 1h reused and moisture tolerance of
the catalysis, spectroscopic data for axially chiral guanidine catalyst
(1) and the 1,4-addition products (4) (PDF), and stereochemical proof.
This material is available free of charge via the Internet at http://
pubs.acs.org.
a Unless otherwise noted, all reactions were carried out with 0.002 mmol
of (R)-1h (2 mol %), 0.1 mmol of 2, and 0.15 mmol of 3a (1.5 equiv) in
1 mL of diethyl ether at -40 °C. b Isolated yield. c Enantiomeric excess
was determined by chiral HPLC analysis. See Supporting Information for
details. d A total of 0.005 mmol of (R)-1h (5 mol %) was employed in 1
mL of diisopropyl ether at -40 °C.
References
1h exhibited excellent performance for a broad range of nitroalkenes
(2) in terms of catalytic activity and enantioselectivity. In the
reactions of a variety of aromatic-substituted nitroalkenes (2) with
3a, uniformly high chemical yields and enantioselectivities were
obtained (entries 1-10). 1h also displayed high catalytic efficiency
for aliphatic nitroalkenes, which are challenging substrates in terms
of reactivity and selectivity (entries 11-13).8,9 Although slightly
lower enantioselectivities than that of their aromatic counterparts
were observed, the reactions proceeded within a reasonable period
by increasing the catalyst loading to 5 mol %.10 Various types of
1,3-dicarbonyl compounds (3) were also applicable to the present
catalytic system (eq 2). Excellent yields and high enantioselectivities
at the â-position to the nitro group were obtained for R-substituted
malonate (3d), 1,3-diketone (3e), and â-ketoester (3f).
(1) (a) Hannon, C. L.; Anslyn, E. V. Bioorganic Chemistry Frontiers;
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The high catalytic efficiency of 1h was further evaluated by a
gram-scale experiment with low catalyst loading. As highlighted
in eq 3, 0.4 mol % of 1h was sufficient for the completion of the
reaction within 2 h, and a single recrystallization gave the optically
pure product (4d) in 83% yield. Furthermore, 1h was recovered in
a nearly quantitative manner (96%) as an HCl salt by acidic workup
following column purification. The HCl salt of 1h was readily
neutralized by a basic resin and reusable for subsequent runs without
any detrimental effects on the catalytic activity and the enantiose-
lectivity.
(10) During the preparation of this paper, Connon et al. (ref 8f) reported the
enantioselective 1,4-addition reactions catalyzed by (thio)urea derivatives
of cinchona alkaloids as a highly active organocatalyst. Even by using 5
mol % of this (thio)urea catalyst, more than 6 days are required for
conversion of the hindered cyclohexyl-substituted nitroalkene to 4p in an
acceptable yield.
JA057848D
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