Reaction of dimethyl (s)-2-(p-tolyl)cyclopropane-1,1-dicarboxylate with acetonitrile

Full text of DOI:10.1007/s10593-012-1062-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
REACTION OF DIMETHYL (S)-2-(p-TOLYL)CYCLOPROPANE-
1,1-DICARBOXYLATE WITH ACETONITRILE
A. O. Chagarovskiy1,2, K. L. Ivanov1, E. M. Budynina1,2,
O. A. Ivanova1, and I. V. Trushkov1,2*
Keywords: donor-acceptor cyclopropanes, nitriles, 1-pyrrolines, cycloaddition.
The Lewis acid-activated reactions of donor-acceptor cyclopropanes with nitriles are the basis of a
convenient method for the synthesis of 1-pyrrolines and pyrroles [1-5]. The use of 1,2,3-substituted donor-
acceptor cyclopropanes leads to the formation of 1-pyrrolines with high diastereoselectivity. Depending on the
type of substrate and the reaction conditions, either reversal [5] or retention [1] of the configuration of the
cyclopropane carbon atom bearing donor substituent and taking part in the interaction with the nitrile nitrogen
atom is observed. In order to determine the stereoselectivity of nitrile reactions with 2-arylcyclopropane-1,1-di-
carboxylates without a substituent at the C-3 atom [4], we have prepared the optically pure donor-acceptor
cyclopropane (S)-1 and studied its reaction with acetonitrile.
The synthesis of enantiomerically pure cyclopropane (S)-1 includes the hydrolysis of the racemic diester
(rac)-1 to the 2-(p-tolyl)cyclopropane-1,1-dicarboxylic acid, its conversion to (S)-1-phenylethylamine salt as
two diastereomers and recrystallization. We have modified the previously reported method [6] for the synthesis
of enantiomerically pure 2-phenylcyclopropane-1,1-dicarboxylates. In particular, shorter hydrolysis time for the
compound (rac)-1 and two successive crystallizations of the salt allowed us to avoid lactonization and gave the
diester (S)-1 with ee > 98%.
1) KOH, MeOH
20°С, 11 h
CO2Me
CO2Me
CO2Me
CO2Me
0
Me
2)
Me
Me
NH2
(S)-1
> 98% ee
(rac)-1
3) crystallization
4) MeI, K2CO3, DMF
In a study of the cyclopropane (S)-1 reaction with acetonitrile using previously reported conditions (2
equiv. of SnCl4, nitromethane, 55ºC) [4], we found that it occurs with a total loss of optical activity to give the
pyrroline 2 as a racemic mixture. A similar result was obtained when the reaction was carried out in 1,2-di-
chloroethane (1 equiv. of SnCl4, room temperature). Previously it was observed that under these conditions a
_______
*To whom correspondence should be addressed, e-mail: trush@phys.chem.msu.ru, Igor.Trushkov@fccho-
moscow.ru.
1M. V. Lomonosov State University, 1 Build. 3 Leninskie Gory, Moscow 119991, Russia.
2D. Rogachev Federal Research Center of Pediatric Hematology, Oncology, and Immunology, 1 Samora Mashel
St., Moscow 117198, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 886-888, May, 2012. Original
article submitted March 19, 2012.
0009-3122/12/4805-0825©2012 Springer Science+Business Media, Inc.
825

SnCl4
O
O
CO2Me
CO2Me
p-MeC6H4
MeO
+
SnCl4
MeCN
(S)-1
N
CH3NO2, 55°C
OMe
Me
(rac)-2
or
p-MeC6H4
A
ClCH2CH2Cl, 20°C
reaction of nitriles with analogs of compound 1 (with an acyl substituent at atom C-3) gave complete reversal of
the configuration of the carbon atom bound to the aryl substituent [5].
We consider that the reason for the racemization is the occurrence of the reaction via the achiral
zwitterionic intermediate A, which is formed as the result of heterolysis of the C(1)–C(2) bond of the
cyclopropane via coordination of the SnCl4 at the ester groups. This proposal agrees with the previously
obtained data for the reactions of donor-acceptor cyclopropanes of type 1, which are induced by SnCl4 and other
strongly activating Lewis acids in polar solvents [7, 8].
Subsequent study of the detailed mechanism of the formal [3+2] cycloaddition of donor-acceptor cyclo-
propanes to nitriles and the possibility of obtaining optically active 1-pyrrolines from type 1 cyclopropanes and
Lewis acid complexes with chiral ligands will be the subject of our future investigations.
1
IR spectra were recorded on a UR-20 instrument using vaseline oil. H and 13C NMR spectra were
recorded on a Bruker Avance 600 spectrometer (600 and 150 MHz respectively) using CDCl3, and chemical
1
shifts were determined relative to the solvent signal at  7.26 ppm for H and 77.13 ppm for 13C. The
enantiomeric purity was determined chromatographically using an AmyCoat chiral support column (1504.6
mm) and heptane–2-PrOH (95:5) as eluent.
Dimethyl (S)-2-(4-tolyl)cyclopropane-1,1-dicarboxylate ((S)-1)) was prepared by two successive
crystallizations of the diastereomeric salts of (S)-1-phenylethylamine with (rac)-2-(p-tolyl)cyclopropane-
1,1-dicarboxylic acid and subsequent alkylation of the optically pure diacid using the method reported
20
20
previously for 2-phenylcyclopropane-1,1-dicarboxylate [6]. ee > 98º. []D -135º (c 2.0, CH2Cl2) ([]D -141º
(c 0.9, C6H6) [9]). The spectroscopic data agreed with the literature [10].
Dimethyl 2-Methyl-5-(4-tolyl)-4,5-dihydropyrrole-3,3-dicarboxylate (2). A. SnCl4 (300 mg, 0.13 ml,
1.15 mmol) in MeNO2 (2 ml) was added to a solution of the cyclopropane (S)-1 (150 mg, 0.6 mmol) and MeCN
(123 mg, 0.16 ml, 3 mmol) in MeNO2 (15 ml). The reaction mixture was stirred under an argon atmosphere for
3 h at 55ºC, poured into aqueous NaHCO3 solution (50 ml) and extracted with CH2Cl2 (340 ml). The combined
organic extracts were washed with a solution of Trilon B (320 ml), water (320 ml) and dried over anhydrous
Na2SO4. The solvent was evaporated, and compound 2 was isolated by column chromatography on silica using
petroleum ether–EtOAc (4: 1) as eluent.
B. SnCl4 (166 mg, 0.07 ml, 0.6 mmol) in ClCH2CH2Cl (2 ml) was added to a solution of the
cyclopropane (S)-1 (150 mg, 0.6 mmol) and MeCN (123 mg, 0.16 ml, 3 mmol). The reaction mixture was
stirred under argon for 12 h at 20ºC and then treated as in method A.
Yield 149 mg (86%, method A), 134 mg (77%, method B). Colorless oil. Rf 0.55 (petroleum ether–
EtOAc, 2:1). IR spectrum, , cm-1: 3020, 2970, 1740 (C=O), 1665 (C=N), 1520, 1440, 1380, 1290, 1095, 1030,
1
5
830. H NMR spectrum, , ppm (J, Hz): 2.29 (3Н, d, J = 2.2, 2-CH3); 2.33 (3Н, s, CH3C6H4); 2.36 (1Н, dd,
2J = 13.4, 3J = 8.3) and 3.14 (1Н, dd, 2J = 13.4, 3J = 7.2, 4-CH2); 3.78 (3H, s, OCH3); 3.82 (3H, s, OCH3); 5.12
(1H, ddq, 3J = 8.3, 3J = 7.2, 5J = 2.2, 5-CH); 7.14-7.17 (4H, m, H Ar). 13C NMR spectrum, , ppm: 18.1 (CH3);
21.0 (CH3); 42.6 (4-CH2); 53.0 (ОCH3); 53.1 (ОCH3); 72.2 (C-3); 73.4 (5-СН); 126.4 (2CH Ar); 129.2 (2CH
Ar); 136.8 (C Ar); 139.3 (C Ar); 168.2; 168.3; 169.2. Found, %: С 66.45; Н 6.71; N 5.00. C16H19NO4.
Calculated, %: C 66.42; H 6.62; N 4.84.
826

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