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T. Inokuma et al.
CLUSTER
(5) (a) Xie, J.; Yoshida, K.; Takasu, K.; Takemoto, Y.
Tetrahedron Lett. 2008, 49, 6910. (b) Inokuma, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413.
(c) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672.
determined to be trans. Then, 7e was deduced to be a C1
epimer of 5e.
(14) We tried the one-pot process of Knoevenagel reaction and
cyclopropanation. But, disappointingly, we obtained the
same product 5e with lower ee (58% yield, 63:37 dr, 17%
ee).
(6) Jones, G. Org. React. 1967, 15, 204.
(7) Knoevenagel Reaction Catalyzed by Thiourea 1
A mixture of 3e (40.2 mg, 0.195 mmol), benzaldehyde 2a
(22 mL, 0.215 mmol), and(rac)-thiourea 1 (8.1 mg, 0.0195
mmol) in toluene (2.0 mL) was stirred at 80 °C for 25 h.
After the reaction mixture was concentrated in vacuo, the
residue was purified by silica gel column chromatography
with hexane–EtOAc (3:1) to afford 4e (41.5 mg, 72%) as
white needles.
(15) General Procedure for the Thiourea-Catalyzed
Nitrocyclopropanation
To a mixture of 4e (29.7 mg, 0.1 mmol) and thiourea 1 (4.7
mg, 10 mol%) in toluene (0.1 M) were added
bromonitromethane (10 mL, 0.15 mmol) and Et3N (20 mL,
0.15 mmol) at –60 °C during the indicated period. The
reaction mixture was directly purified by silica gel column
chromatography with hexane–EtOAc (3:1) to afford 5e (19
mg, 53%, 97% ee) as white amorphous solids and 7e (11 mg,
31%, 90% ee) as a brown oil.
(E)-N-(2-Cyano-3-phenylacryloyl)-2-fluorobenzamide
(4e)
White needles; Rf = 0.54 (hexane–EtOAc, 1:1); mp 186–188
°C. 1H NMR (500 MHz, CDCl3): d = 9.96 (d, J = 16.3 Hz, 1
H) 8.47 (s, 1 H), 8.16 (td, J = 6.3, 1.7 Hz, 1 H), 8.02 (d,
J = 8.0 Hz, 2 H), 7.65–7.60 (m, 2 H), 7.55 (dd, J = 8.0, 7.2
Hz, 2 H), 7.36 (td, J = 7.7, 7.2 Hz, 1 H), 7.25 (dd, J = 12.0,
8.0 Hz). 13C NMR (126 MHz, CDCl3): d = 161.5, 161.0 (2
C), 160.6 (d, J = 249 Hz), 158.3, 156.4, 135.6 (d, J = 9.9
Hz), 133.9, 132.7, 131.3, 129.2, 125.6 (d, J = 3.0 Hz), 116.0
(d, J = 10.2 Hz), 116.5 (d, J = 24.6 Hz), 116.0, 103.4. IR
(KBr): 3364, 1737, 1513, 1289 cm–1. MS–FAB+: m/z (%) =
295(10) [MH+], 154 [100]. Anal. Calcd for C17H11FN2O2C:
69.38, H: 3.77, N: 9.52. Found C: 69.57, H: 3.81, N: 9.55.
(8) Moison, H.; Boullet, F.; Foucaud, A. Tetrahedron 1987, 43,
537.
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-
fluorobenzamide (5e; Major Diastereomer)
White amorphous solids; Rf = 0.48 (hexane–EtOAc, 1:1);
[a]D26 –19.01 (c 0.71, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 9.41 (d, J = 16.3 Hz, 1 H), 8.14 (dt, J = 6.0, 1.7 Hz, 1 H),
7.64–7.67 (m, 1 H), 7.48–7.40 (m, 5 H), 7.36 (dd, J = 7.7,
7.4 Hz, 1 H), 7.23 (dd, J = 12.3, 8.4 Hz, 1 H), 5.41 (d, J = 6.4
Hz, 1 H), 4.34 (d, J = 6.4 Hz, 1 H). 13C NMR (126 MHz,
CDCl3): d = 161.9, 161.8, 160.8 (d, J = 241 Hz), 159.7,
136.4 (d, J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz),
128.0, 125.6 (d, J = 3.6 Hz), 118.1 (d, J = 9.9 Hz), 116.7 (d,
J = 24.6 Hz), 112.2, 68.4, 37.7, 35.9. IR (CHCl3): 3400
(NH), 2247 (CN), 1699 (C=O), 1617 (NO2), 1559 (C=O).
MS–FAB–: m/z (%) = 352(100) [M – H]. HRMS–FAB–: m/z
calcd for C18H11FN3O4 [M – H]: 352.0733; found: 352.0699.
HPLC: Daicel Chiralcel AS-H; hexane–i-PrOH (90:10), 1
mL min–1, 254 nm: tR(minor) = 67.8 min; tR(major) = 76.1
min.
(9) Hayashi, T. J. Org. Chem. 1966, 31, 3253.
(10) o-Fluorobenzimide is a better substrate for asymmetric
Michael addition than nonsubstituted benzimide due to the
intramolecular hydrogen bond between imide proton and
fluoro atom, see: Inokuma T., Nagamoto Y., Sakamoto S.,
Miyabe H., Takasu K., Takemoto Y.; Heterocycles; 2009, in
press
(11) CCDC 717740 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
(12) The methanolysis [cat. Er(OTf)3, MeOH, 60 °C] of 4d and
4e provided the same product 4a. Therefore, we concluded
that the compounds 4a, 4d, and 4e have the same relative
configuration. In addition, the minor product 6e was
converted into 5e by the treatment with a catalytic amount of
Et3N. The result suggests that 6e was a C2 epimer of 5e.
(13) The relative configuration of 7e was assigned as follows:
From the coupling constant of C2 and C3 protons (5e: 6.4
Hz, 7e: 6.6 Hz) in 1H NMR, the relative configuration
between the phenyl and nitro group of both 5e and 7e was
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-
fluorobenzamide (7e; Minor Diastereomer)
Brown oil; Rf = 0.40 (hexane–EtOAc, 1:1); [a]D26 +91.9 (c
0.19, CHCl3). 1H NMR (500 MHz, CDCl3): d = 9.35 (d,
J = 15.8 Hz, 1 H), 8.10 (dt, J = 6.6, 1.4 Hz, 1 H), 7.61–7.65
(m, 1 H), 7.27–7.36 (m, 5 H), 7.26 (dd, J = 10.1, 6.0 Hz, 1
H), 7.19 (dd, J = 8.3, 4.0 Hz, 1 H), 5.79 (d, J = 6.6 Hz, 1 H),
4.45 (d, J = 6.6 Hz, 1 H). 13C NMR (126 MHz, CDCl3):
d = 161.6, 161.8, 159.4 (d, J = 263 Hz), 158.7, 136.5 (d,
J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz), 128.0,
125.6 (d, J = 3.6 Hz), 118.4 (d, J = 9.9 Hz), 116.6 (d,
J = 24.6 Hz), 112.5, 65.1, 41.1, 34.1. IR (CHCl3): 3400
(NH), 2244 (CN), 1699 (C=O), 1615 (NO2), 1563 (C=O).
MS–FAB–: m/z (%) = 352(20) [M – H]. HRMS–FAB–: m/z
calcd for C18H11FN3O4 [M – H]: 352.0733; found: 352.0722.
HPLC: Daicel Chiralcel AS-H; hexane–i-PrOH (90:10), 1
mL min–1, 254 nm: tR(minor) = 91.0 min; tR(major) = 103.9
min.
Synlett 2009, No. 10, 1627–1630 © Thieme Stuttgart · New York