The formation of cyclopropane 3a can be explained by
the following mechanism: at low temperature, the dianion
chemoselectively attacked the carbon attached to the bromine
atom. Warming of the mixture to 20 °C resulted in attack of
the monoanion onto the central carbon atom of the epoxide.
The epoxide was activated by the Lewis acid LiClO4.
Alternatively, the formation of 3a can be explained by attack
of 1a onto the epoxide, Payne rearrangement and subsequent
cyclization. The regioselectivity (formation of a three- rather
than a four-membered ring) can be explained on the basis
of stereoelectronic considerations.10-12 The diastereoselec-
tivity can be explained by steric interaction of the phenyl
and the hydroxymethyl group during the cyclization (Scheme
1).
Table 1. Optimization of the Reaction of Dilithiated 1a with
Functionalized Epoxides
To study the preparative scope of the reaction, the
substituents of the arylacetonitrile were systematically varied
(Scheme 2, Table 2). Cyclopropanes 3b and 3c were prepared
Scheme 2. Cyclization of Dilithiated Arylacetonitriles with
Epibromohydrin
a Reaction time at -35 °C + reaction time at 20 °C. b Isolated yield of
nonseparable diastereomeric mixtures.
Lewis acid lithium perchlorate and when an excess of the
dianion was used (Table 1).9 A thorough tuning of the
temperature also proved important for the optimization. The
reaction mixture was stirred for 10 h at -35 °C and
subsequently for 8 h at 20 °C. The use of epichlorohydrin
was less effective than that of 2. Cyclopropane 3a was
formed with good diastereoselectivity (cis/trans ) 8:1).
However, the isomeric mixture could not be separated by
chromatography. The configuration was established by
NOESY experiments carried out on the diastereomeric
mixture of 3a. The diagnostic NOE effects are depicted in
Scheme 1.
with good diastereoselectivity from 4-tolyl- and 4-methoxy-
phenylacetonitrile, respectively. The reaction of 2 with
3-tolyl- and 3-methoxyphenylacetonitrile afforded cyclopro-
panes 3d and 3e, respectively, in good yields and with good
diastereoselectivity. The use of 2-tolylacetonitrile 1f resulted
in formation of the expected product 3f, but only in a low
(9) Representative experimental procedure: To a THF solution (20
mL) of phenylacetonitrile (0.58 g, 5.00 mmol) was added n-BuLi (10.48
mmol, 4.23 mL, solution in n-hexane) at 0 °C. The solution was stirred for
1 h, and subsequently a THF solution (20 mL) of LiClO4 (0.34 g) and of
epibromohydrin (0.33 g, 2.40 mmol) was added at -78 °C. The temperature
was increased to -35 °C during 2 h, and the solution was stirred at this
temperature for 10 h. The solution was warmed to ambient during 1 h and
stirred for 8 h. To the solution was added a saturated aqueous solution of
NH4Cl (40 mL) and ether (50 mL). The organic layer was separated, and
the aqueous layer was extracted with ether (2 × 50 mL) and dichloromethane
(2 × 50 mL). The combined organic layers were extracted with a saturated
aqueous solution of brine, dried (Na2SO4), and filtered and the solvent of
the filtrate was removed in vacuo. The residue was purified by column
chromatography (silica gel, petroleum ether/ether ) 4:1 f 1:1) to give 3a
as a colorless oil (330 mg, 79%, Z/E ) 8:1). Spectroscopic data for 3a: 1H
NMR (CDCl3, 250 MHz) δ ) 1.55 (m, 1 H, CH2), 1.91 (m, 1 H, CH), 3.34
(br, 1 H, OH), 3.76 (dd, J ) 12 Hz, J ) 5 Hz, CH2OH), 3.98 (dd, J ) 12
Hz, J ) 5 Hz, CH2OH), 7.28 (m, 5 H, Ph); 13C NMR (CDCl3, 75 MHz) δ
) 16.08 (C), 21.23 (CH2), 31.30 (CH), 62.62 (CH2OH), 120.57 (C, CN),
125.82, 127.56, 128.73 (CH, Ph), 135.52 (C); MS (EI, 70 eV) 173 (M+,
18), 143 (24), 129 (100), 115 (26), 103 (34); the exact molecular mass m/z
) 173.0841 ( 2 mD (M+) for C11H11NO was confirmed by HRMS (EI,
70 eV). Anal. Calcd for C11H11NO: C 76.28, H 6.40. Found: C 76.46, H
6.28. All compounds were prepared as racemic material and gave satisfactory
spectroscopic and analytical and/or high-resolution mass data. The diaster-
eomers of 3a-g and 5 could not be separated.
Scheme 1. Cyclization of Dilithiated Phenylacetonitrile with
Epibromohydrin
(10) For comparison, see: (a) Corbel, B.; Decesare, J. M.; Durst, T. Can.
J. Chem. 1978, 56, 505. (b) Benedetti, F.; Berti, F.; Risaliti, A. Tetrahedron
Lett. 1993, 6443.
(11) For the synthesis of hydroxycyclobutanes, see: Jeffery, J. E.;
Kerrigan, F.; Miller, T. K.; Smith, G. J.; Tometzki, G. B. J. Chem. Soc.,
Perkin Trans. 1 1996, 2583.
(12) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749.
3904
Org. Lett., Vol. 3, No. 24, 2001