Synthesis of substituted pyrrolidines by reaction of aryl-substituted vinylidenecyclopropanes with aromatic imines catalyzed by BF3· Et2O

Article abstract of DOI:10.1007/s10593-008-0059-8

The reactions of 1,1-diaryl-2-(diphenylvinylidene)cyclopropanes and 1,1-diaryl-2-(2-phenylpropenylidine) cyclopropanes with aromatic amines in the presence of BF₃·Et₂O leads to the formation of pyrrolidine derivatives.

Full text of DOI:10.1007/s10593-008-0059-8

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
SYNTHESIS OF SUBSTITUTED PYRROLIDINES
BY REACTION OF ARYL-SUBSTITUTED
VINYLIDENECYCLOPROPANES WITH
AROMATIC IMINES CATALYZED BY BF3·Et2O
A. V. Stepakov, A. G. Larina, O. V. Radina, V. M. Boitsov, and A. P. Molchanov
The reactions of 1,1-diaryl-2-(diphenylvinylidene)cyclopropanes and 1,1-diaryl-2-(2-phenyl-
propenylidine)cyclopropanes with aromatic amines in the presence of BF3·Et2O leads to the formation
of pyrrolidine derivatives.
Keywords: vinylidenecyclopropanes, imines, pyrrolidines.
Vinylidenecyclopropanes have value as synthons in organic synthesis, in particular in the preparation of
heterocyclic compounds [1-6]. Catalysis by Lewis acids has recently been reported in the reaction of
vinylidenecyclopropanes with acetals to give indene derivatives [7]. It has previously been shown that the
reaction of vinylidenecyclopropanes with aromatic imines or ethyl (arylimino)acetates in the presence of a
Lewis acids gives pyrrolidine or 1,2,3,4-tetrahydroquinoline derivatives depending on the nature of the
substituent on the multiple bond or in the cyclopropane ring [8, 9]. We have found that the reaction of aromatic
imines with vinylidenecyclopropanes containing alkyl substituents in the cyclopropane ring and on the multiple
bond gives only the formation of products which occurs via a cyclopropyl-allyl rearrangement stage, i.e.
substituted pyrrolidines. Vinylidenecyclopropanes containing an aryl and alkyl substituent simultaneously in the
cyclopropane ring and aryl substituents on the double bond gave products the formation of which occurs via an
intramolecular Friedel-Crafts reaction stage, i.e. tetrahydroquinoline derivatives [8]. Vinylidene-cyclopropanes
containing two aryl substituents in the cyclopropane ring have not been included in this reaction hence the aim
of this work was a study of the reaction of vinylidenecyclopropanes containing aryl substituents in the
cyclopropane ring and on the double bond with aromatic imines in the presence of BF3·Et2O.
It was found that treating the 1,1-diaryl-2-(diphenylvinylidene)cyclopropanes 1a,b with the imines 2a,b
in the presence of BF3·Et2O (15 mol %) in methylene chloride gave the 2-aryl-4-diarylmethylene-
3-diphenylmethylene-1-phenylpyrrolidines 3a-d in yields up to 27%. In all cases the target compounds were
separated using preparative TLC. The structure and composition of compounds 3a-d were established from their
spectroscopic and elemental analytical data. The 1H NMR spectra of these compounds show doublet signals for
the methylene group protons at 4.2 and 4.6 ppm (J = 12 Hz) and a methine proton singlet at 5.0 ppm assigned to
the pyrrolidine ring. The 13C NMR spectra show the signals for atoms C-2 and C-5 of the pyrrolidine ring at 66
and 53 ppm respectively.
_________________________________________________________________________________________
St. Petersburg State University, St. Petersburg 198504, Russia, e-mail: alstepakov@yandex.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552-557, April, 2008. Original article
submitted October 12, 2007.
430
0009-3122/08/4404-0430©2008 Springer Science+Business Media, Inc.

R1
Ph
R1
1
R
R3
R2
R3
R1
Ph
R2
.
BF3 Et2O
+
C
N
CH2Cl2
R4
N
2a–d
R4
1a–d
3a–j
1 a R1 = R2 = Ph; b R1 = 4-MeC6H4, R2 = Ph; c R1 = Ph, R2 = Me; d R1 = 4-MeC6H4, R2 = Me;
2 a R3 = R4 = Ph; b R3 = 4-ClC6H4, R4 = Ph; c R3 = 4-ClC6H4, R4 = 4-MeOC6H4CH2;
d R3 = Ph, R4 = 1-naphtyl; 3 a R1 = R2 = R3 = R4 = Ph; b R1 = R2 = R4 = Ph, R3 = 4-ClC6H4;
c R1 = 4-MeC6H4, R2 = R3 = R4 = Ph; d R1 = 4-MeC6H4, R2 = R4 = Ph, R3 = 4-ClC6H4;
e R1 = R2 = Ph, R3 = 4-ClC6H4, R4 = 4-MeOC6H4CH2; f R1 = R3 = R4 = Ph, R2 = Me;
g R1 = R4 = Ph, R2 = Me, R3 = 4-ClC6H4; h R1 = 4-MeC6H4, R2 = Me, R3 = R4 = Ph;
i R1 = 4-MeC6H4, R2 = Me, R3 = 4-ClC6H4, R4 = Ph; j R1 = 4-MeC6H4, R2 = Me, R3 = Ph,
R4 = 1-naphtyl
The reaction of the vinylidenecyclopropane 1a with imine 2c in the presence of BF3·Et2O (15 mol %)
1
yielded only 8% of the pyrrolidine 3e from the reaction mixture. The H NMR spectrum of compound 3e
showed doublet signals for the methylene group at 2.8 and 4.1 ppm (J = 13 Hz) and methine proton singlet at 4.4
ppm for the pyrrolidine ring and doublet signals for the benzyl substituent methylene protons at 3.3 and 3.6 ppm
(J = 15 Hz). The shift of the signal for one of the methylene group protons of the pyrrolidine ring to the high
field region (2.8 ppm) occurs as a result of the shielding effect of the benzyl group.
The reactions of the 1,1-diaryl-2-(2-phenylpropenylidene)cyclopropanes 1c,d with the N-arylidene-
anilines 2a,b in the presence of BF3·Et2O (15 mol %) in methylene chloride gives a complex mixture from
which the 2-aryl-4-diarylmethylene-1-phenyl-3-[(E)-1-phenylethylidene]pyrrolidines 3f-i could be separated in
yields up to 30%. The structure and composition of compounds 3f-i were proved using spectroscopic and
1
elemental analytical data. The H NMR spectra of these compounds show doublet signals for the methylene
group protons at 4.1 and 4.5 ppm (J = 12 Hz) and methine proton at 5.5 ppm, the signal for the phenylethylidene
methyl group being at 2.1 ppm. Through a comparison of the values of the chemical shift of the methyl group
with literature data the phenylethylidene fragment at position 3 is assigned the E-configuration. It has previously
been shown that, in similarly structured pyrrolidines 3f-i with an E-configured phenylethylidene fragment, the
methyl signal occurs in the range 1.9-2.3 ppm while in the Z-configuration it is shifted to 1.4-1.5 ppm as a result
of the shielding effect of an aryl substituent in the diarylmethylene fragment at position 4 [10, 11]. The 13C
NMR spectra of compounds 3f-i show signals for the pyrrolidine ring C-2 and C-5 atoms at 65 and 53 ppm
respectively.
R1
R1
R1
Ph
Ph
Ph
R2
R3
1
R
1
R
R1
R2
R3
R2
R3
R3
+
.
+
BF3 Et2O
3
1
–
2
+
R4
N
N
–
R4
R4
–
R4
.
N
BF3 Et2O
N
.
.
BF3 Et2O
BF3 Et2O
.
BF3 Et2O
4
5
6
H
Ph
R2
R3
H
R1
R1
N
R4
7
431

Treatment of the vinylidenecyclopropane 1d with N-(1-naphthyl)imine 2d in the presence of BF3·Et2O
1
(15 mol %) gives the pyrrolidine 3j in 16% yield. The H NMR spectrum of the compound shows doublet
signals for methylene group protons at 4.2 and 4.4 ppm (J = 12 Hz) and methine proton singlet at 5.7 ppm from
the pyrrolidine ring and the methyl group signal of the phenylethylidene fragment at 2.0 ppm.
The mechanism of formation of the pyrrolidines 3a-j can be represented by the following scheme: in the
first stage formation of the imine-Lewis acid complex 4 which then reacts with the starting
vinylidenecyclopropane, while electrophilic attack occurs at the central carbon atom of the cumulated system to
form the cyclopropyl cation 5 which subsequent undergoes cyclopropyl-allyl rearrangement to form
intermediante 6 then cyclizing to the substituted pyrrolidine 3. Formation of the isomeric pyrrolidines 7 was not
observed.
EXPERIMENTAL
Elemental analysis was carried out using a Hewlett-Packard 185B CHN-analyzer. Melting points were
determined on a Boetius block. 1H and 13C NMR spectra were recorded on a Bruker DPX-300 (300 and 75 MHz
1
respectively) using CDCl3. Chemical shifts are given relative to the residual solvent signal at 7.26 for H NMR
and 77.16 ppm for 13C NMR [12].
Checking the purity and homogeneity of the compounds and monitoring the reaction course was carried
out by TLC on Silufol UV-254 plates. Preparative TLC separations were performed on LSL254 5/40 silica gel.
The vinylidenecyclopropanes 1a-d were prepared by the method reported in [13].
3,4-Bis(diphenylmethylene)-1,2-diphenylpyrrolidine (3a). The vinylidenecyclopropane 1a (170 mg,
0.46 mmol), imine 2a (91 mg, 0.5 mmol), and absolute methylene chloride (3 ml) were placed in a 10 ml round
bottomed flask in an argon stream. BF3·Et2O (13 mg, 0.096 mmol) was added dropwise with stirring to the
mixture obtained and it was stirred at room temperature under an argon atmosphere for 3 days. Solvent was
evaporated and the residue was separated by preparative TLC using hexane and ethyl acetate (40: 1 by volume)
1
as eluent. Yield 59 mg (23%); mp 160-162ºC (methanol). H NMR spectrum, δ, ppm (J, Hz): 4.20 (1H, d,
J = 12.4, CH2); 4.66 (1H, d, J = 12.4, CH2); 5.07 (1H, s, CH); 6.45-7.53 (30H, m, Harom). 13C NMR spectrum, δ,
ppm: 53.1 (C-5), 66.4 (C-2); 111.9, 116.6, 126.6, 126.7, 127.7, 127.95, 127.96, 128.1, 128.37, 128.38, 128.59,
128.63, 129.4, 129.5, 129.8, 130.3, 133.3, 139.6, 139.8, 141.6, 142.06, 142.09, 143.1, 143.8, 146.1. Found, %:
C 91.29; H 5.97; N 2.36. C42H33N. Calculated, %: C 91.43; H 6.03; N 2.54.
2-(4-Chlorophenyl)-3,4-bis(diphenylmethylene)-1-phenylpyrrolidine (3b) was prepared similarly to
compound 3a from the vinylidenecyclopropane 1a and imine 2b in 24% yield with mp 124-126ºC (methanol).
1H NMR spectrum, δ, ppm (J, Hz): 4.20 (1H, d, J = 12.4, CH2); 4.65 (1H, d, J = 12.4, CH2); 5.04 (1H, s, CH);
6.38-7.60 (29H, m, Harom). 13C NMR spectrum, δ, ppm: 53.0 (C-5), 65.7 (C-2), 111.9, 116.8, 126.8, 126.9,
128.0, 128.1, 128.2, 128.5, 128.6, 128.8, 129.4, 129.5, 129.7, 129.8, 130.1, 132.9, 133.3, 139.96, 140.0, 140.2,
141.5, 141.9, 142.0, 142.6, 143.0, 145.9. Found, %: C 85.94; H 5.41; N 2.17. C42H32ClN. Calculated, %:
C 86.06; H 5.50; N 2.39.
3-Diphenylmethylene-4-di(4-methylphenyl)methylene-1,2-diphenylpyrrolidine (3c) was prepared
similarly to compound 3a from the vinylidenecyclopropane 1b and imine 2a in 27% yield with mp 154-156ºC
1
(methanol). H NMR spectrum, δ, ppm (J, Hz): 2.17 (3H, s, CH3); 2.41 (3H, s, CH3); 4.17 (1H, d, J = 12.4,
CH2); 4.61 (1H, d, J = 12.4, CH2); 5.02 (1H, s, CH); 6.32-6.71 (9H, m, Harom); 6.83-6.97 (5H, m, Harom);
7.02-7.29 (14H, m, Harom). Found, %: C 91.07; H 6.32; N 2.31. C44H37N. Calculated, %: C 91.15; H 6.43;
N 2.42.
2-(4-Chlorophenyl)-4-di(4-methylphenyl)methylene-3-diphenylmethylene-1-phenylpyrrolidine
(3d) was prepared similarly to compound 3a from the vinylidenecyclopropane 1b and imine 2b in 20% yield. 1H
NMR spectrum, δ, ppm (J, Hz): 2.17 (3H, s, CH3); 2.41 (3H, s, CH3); 4.18 (1H, d, J = 12.4, CH2); 4.61 (1H,
432

d, J = 12.4, CH2); 5.05 (1H, s, CH); 6.40-6.69 (9H, m, Harom); 6.81-6.96 (5H, m, Harom); 7.05-7.31 (13H, m,
Harom). Found, %: C 86.19; H 6.03; N 2.11. C44H36ClN. Calculated, %: C 86.04; H 5.91; N 2.28.
2-(4-Chlorophenyl)-3,4-bis(diphenylmethylene)-1-(4-methoxybenzyl)-pyrrolidine (3e) was prepared
similarly to compound 3a from the vinylidenecyclopropane 1a and imine 2c in 8% yield with mp 183-184ºC
1
(methanol). H NMR spectrum, δ, ppm (J, Hz): 2.75 (1H, d, J = 13.1, CH2); 3.30 (1H, d, J = 17.4, CH2); 3.58
(1H, d, J = 17.4, CH2); 3.68 (3H, s, OCH3); 4.05 (1H, d, J = 13.1, CH2); 4.40 (1H, s, CH); 6.45 (4H, dd, J = 7.3,
J = 8.0, Harom); 6.79 (2H, d, J = 8.7, Harom); 6.90-7.18 (6H, m, Harom); 7.21-7.66 (14H, m, Harom); 7.79 (2H, d,
J = 7.3, Harom). Found, % C 83.87; H 6.04; N 2.01. C46H40ClNO. Calculated, %: C 83.93; H 6.12; N 2.13.
1,2-Diphenyl-4-diphenylmethylene-3-[(E)-1-phenylethylidene]pyrrolidine (3f) was prepared
similarly to compound 3a from the vinylidenecyclopropane 1c and imine 2a in 21% yield with mp 162-164ºC
1
(methanol). H NMR spectrum, δ, ppm (J, Hz): 2.14 (3H, s, CH3); 4.11 (1H, d, J = 11.6, CH2); 4.52 (1H, d,
J = 11.6, CH2); 5.55 (1H, s, CH); 6.18 (2H, d, J = 6.5, Harom); 6.58-7.55 (23H, m, Harom). 13C NMR spectrum, δ,
ppm: 22.6 (CH3), 53.3 (C-5); 65.5 (C-2); 111.9, 116.6, 126.2, 127.1, 127.4, 127.6, 127.8, 127.9, 128.1, 128.4,
128.6, 129.1, 129.4, 129.6, 129.8, 130.3, 132.4, 132.9, 135.9, 139.4, 141.7, 143.3, 143.6, 146.7. Found, %:
C 90.59; H 6.29; N 2.65. C37H31N. Calculated, %: C 90.76; H 6.38; N 2.86.
2-(4-Chlorophenyl)-4-diphenylmethylene-1-phenyl-3-[(E)-1-phenylethylidene]pyrrolidine (3g) was
prepared similarly to compound 3a from the vinylidenecyclopropane 1c and imine 2b in 24% yield with mp
169-170ºC (methanol). 1H NMR spectrum, δ, ppm (J, Hz): 2.10 (3H, s, CH3); 4.08 (1H, d, J = 11.6, CH2); 4.48
(1H, d, J = 11.6, CH2); 5.49 (1H, s, CH); 6.16 (2H, d, J = 7.3, Harom); 6.53-6.83 (7H, m, Harom); 6.84-7.10 (6H,
m, Harom); 7.13-7.50 (9H, m, Harom). 13C NMR spectrum, δ, ppm: 22.6 (CH3); 53.2 (C-5); 65.0 (C-2); 111.9,
117.0, 126.3, 126.5, 127.91, 127.93, 128.1, 128.2, 128.4, 128.5, 128.8, 129.3, 129.5, 129.6, 129.8, 132.0, 133.3,
135.4, 139.8, 141.6, 142.1, 143.2, 143.4, 146.5. Found, %: C 84.73; H 5.84; N 2.61. C37H30ClN. Calculated, %:
C 84.79; H 5.77; N 2.67.
4-Di(4-methylphenyl)methylene-1,2-diphenyl-3-[(E)-1-phenylethylidene]pyrrolidine
(3h)
was
prepared similarly to compound 3a from the vinylidenecyclopropane 1d and imine 2a in 22% yield with mp
1
191-192ºC (methanol). H NMR spectrum, δ, ppm (J, Hz): 2.11 (3H, s, CH3); 2.22 (3H, s, CH3); 2.41 (3H, s,
CH3); 4.12 (1H, d, J = 11.6, CH2); 4.49 (1H, d, J = 11.6, CH2); 5.49 (1H, s, CH); 6.07 (2H, d, J = 7.3, Harom);
6.50-6.78 (7H, m, Harom); 6.85-7.05 (5H, m, Harom); 7.08-7.32 (5H, m, Harom); 7.40 (2H, d, J = 8.0, Harom); 7.46
(2H, d, J = 8.0, Harom). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 21.7 (CH3); 22.6 (CH3); 53.3 (C-5); 65.0 (C-2);
111.9, 116.9, 126.3, 127.9, 128.0, 128.5, 129.1, 129.2, 129.4, 129.6, 129.8, 131.1, 132.6, 133.2, 135.7, 135.9,
137.7, 138.8, 139.7, 140.4, 142.2, 143.5, 146.6. Found, %: C 90.32; H 6.67; N 2.53. C39H35N. Calculated, %:
C 90.48; H 6.81; N 2.71.
2-(4-Chlorophenyl)-4-di(4-methylphenyl)methylene-1-phenyl-3-[(E)-1-phenylethylidene]pyrroli-
dine (3i) was prepared analogously to compound 3a from the vinylidenecyclopropane 1d and imine 2b in 30%
1
yield with mp 206-207ºC (methanol). H NMR spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH3); 2.21 (3H, s, CH3);
2.41 (3H, s, CH3); 4.13 (1H, d, J = 11.6, CH2); 4.53 (1H, d, J = 11.6, CH2); 5.53 (1H, s, CH); 6.07 (2H, d,
J = 7.3, Harom); 6.56 (2H, d, J = 8.0, Harom); 6.65 (2H, d, J = 8.0, Harom); 6.70 (2H, d, J = 7.3, Harom); 6.93-7.52
(14H, m, Harom). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 21.7 (CH3); 22.6 (CH3); 53.3 (C-5); 65.5 (C-2); 111.9,
116.6, 126.1, 127.1, 127.5, 127.9, 128.0, 128.4, 129.1, 129.5, 129.8, 131.4, 132.2, 135.8, 136.1, 137.6, 138.9,
139.4, 140.6, 143.5, 143.7, 146.8. Found, %: C 84.71; H 6.71; N 2.39. C39H34ClN. Calculated, %: C 84.4;
H 6.21; N 2.54.
4-Di(4-methylphenyl)methylene-1-(1-naphthyl)-2-phenyl-3-[(E)-1-phenylethylidene]pyrrolidine
(3j) was prepared similarly to compound 3a from the vinylidenecyclopropane 1d and imine 2d in 16% yield
1
with mp 139-140ºC (methanol). H NMR spectrum, δ, ppm (J, Hz): 2.00 (3H, s, CH3); 2.25 (3H, s, CH3); 2.31
(3H, s, CH3); 4.24 (1H, d, J = 12.4, CH2); 4.38 (1H, d, J = 12.4, CH2); 5.72 (1H, s, CH); 6.37 (2H, d, J = 6.5,
433

Harom); 6.65 (2H, d, J = 8.0, Harom); 6.78-7.51 (16H, m, Harom); 7.54 (1H, d, J = 7.3, Harom); 7.63 (2H, d, J = 7.3,
arom); 7.81 (1H, d, J = 8.0, Harom); 8.24 (1H, d, J = 8.7, Harom). Found, %: C 90.82; H 6.53; N 2.39. C43H37N.
H
Calculated, %: C 90.96; H 6.57; N 2.47.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
M. L. Poutsma and P. A. Ibarbia, J. Am. Chem. Soc., 93, 440 (1971).
W. Smadja, Chem. Rev., 83, 263 (1983).
M. E. Hendrick, J. A. Hardie, and M. Jones, J. Org. Chem., 36, 3061 (1971).
H. Sugita, K. Mizuno, T. Saito, K. Isagawa, and Y. Otsuji, Tetrahedron Lett., 33, 2539 (1992).
L. K. Sydnes, Chem. Rev., 103, 1133 (2003).
A. Brandi, S. Cicchi, F. M. Cordero, and A. Goti, Chem. Rev., 103, 1213 (2003).
J. –M. Liu and M. Shi, Org. Lett., 8, 5317 (2006).
A. V. Stepakov, A. G. Larina, A. P. Molchanov, L. V. Stepakova, G. L. Starova, and R. R. Kostikov, Zh.
Org. Khim., 43, 41 (2007).
9.
10.
11.
J.-M. Liu and M. Shi, Org. Lett., 9, 1805 (2007).
D. J. Pasto, A. F.-T. Chen, and G. Binsch, J. Am. Chem. Soc., 95, 1553 (1973).
D. J. Pasto, J. K. Borchardt, T. P. Fehlner, H. F. Baney, and M. E. Schwartz, J. Am. Chem. Soc., 98, 526
(1976).
12.
13.
H. E. Gotlieb, V. Kotlyar, and A. Nudelman, J. Org. Chem., 62, 7512 (1997).
K. Isagawa, K. Mizuno, H. Sugita, and Y. Otsuji, J. Chem. Soc., Perkin Trans. 1, 2283 (1991).
434