X-ray investigation of (E)-2-phenyl-1-chlorocyclopropane-1-carboxylic acid - A convenient synthon for transamine synthesis

Article abstract of DOI:10.1023/B:JORY.0000048892.75811.b9

A method for the synthesis of (E,Z)-2-phenyl-1-chlorocyclopropane-1- carboxylic acid by the addition of ethyl trichloroacetate to styrene in the presence of copper(I) ammine complexes is suggested. The major isomer was isolated as the corresponding acid.

Full text of DOI:10.1023/B:JORY.0000048892.75811.b9

Journal of Structural Chemistry, Vol. 45, No. 2, pp. 352-355, 2004
Original Russian Text Copyright © 2004 by A. A. Karapetyan, R. A. Tamazyan, A. R. Mikaelyan, and N. P. Raganyan
X-RAY INVESTIGATION OF (E)-2-PHENYL-1-
CHLOROCYCLOPROPANE-1-CARBOXYLIC ACID —
A CONVENIENT SYNTHON FOR TRANSAMINE SYNTHESIS
1
A. A. Karapetyan, R. A. Tamazyan, A. R. Mikaelyan,
1
2
UDC 548.737+547.512
2
and N. P. Raganyan
A method for the synthesis of (ȿ,Z)-2-phenyl-1-chlorocyclopropane-1-carboxylic acid by the addition of
ethyl trichloroacetate to styrene in the presence of copper(I) ammine complexes is suggested. The major
isomer was isolated as the corresponding acid. The results of X-ray diffraction (XRD) analysis
unequivocally prove that the benzene ring and the carboxylic group are in the cis-position and that the
molecules form centrosymmetric dimers. (ȿ)-2-phenyl-1-chlorocyclopropane-1-carboxylic acid can serve
as a convenient synthon for transamine synthesis.
Key words: cyclopropane carboxylic acid, transamine, centrosymmetric dimers.
Functionally substituted cyclopropanes are often found as structural units in molecules exhibiting biological activity
1-3]. One of the most popular methods for the design of the cyclopropane unit is 1,3-elimination of halogen atoms in
[
polychlorinated organic compounds, resulting in intramolecular cyclization, forming a new ɋ–ɋ bond [4]. Thus cyclization of
polychlorohexene acids with a Zn/Cu pair in DMF yielded alkenyl-substituted cyclopropane-1-carboxylic acids; the latter
were successfully used in syntheses of pyrethroids [5].
trans-2-Phenylcyclopropylamine (transamine, tranylcipromine, parnate) is an active inhibitor of monoamine oxidase
and is widely used as antidepressant [2, 6, 7]. The most popular method for the synthesis of this compound is interaction of
styrene with ethyl diazoacetate [6].
We suggest the addition of ethyl trichloroacetate to styrene in the presence of copper(I) ammine complexes as a
more accessible method for the synthesis of (ȿ)-2-phenyl-1-chlorocyclopropane-1-carboxylic acid (3) — a convenient
synthon for transamine synthesis.
Scheme 1.
1
2
Molecular Structure Research Center, NAS, Republic of Armenia; harkar@nfsat.am; aramrm@seua.am. Institute
of Organic Chemistry, NAS, Republic of Armenia. Translated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 2, pp. 369-373,
March-April, 2004. Original article submitted April 2, 2003.
3
52
0022-4766/04/4502-0352 © 2004 Springer Science+Business Media, Inc.

TABLE 1. Crystal Data, Details of Experiment, and Refinement Parameters for the Structure
Molecular formula C H O Cl
10
9
2
Mol. wt.
196.62
CAD-4
Diffractometer
Radiation, wavelength, Å
Crystal system
Space group
Unit cell parameters:
a(V), Å
MoK , 0.7103
D
Monoclinic
P2 /n
1
6.509(1)
9.032(2)
16.785(3)
94.38(3)
983.9(3), 4
1.327
b(V), Å
c(V), Å
E(V), deg
3
V(V), Å , Z
3
Ucalc, g/cm
–
1
P, mm
0.351
Crystal size, mm
0.15 u 0.20 u 0.30
T range
2.43-27.97
Indices
0 d h d 8, 0 d k d 11, –20 d l d 20
Z/2T
Scan mode
Number of reflections:
Collected
2545
2349
1122
Independent
Used in refinement (I > 2VI)
Refinement method
Refinement approximation:
non-hydrogen atoms
H atoms
2
Full-matrix least squares on F
Anisotropic
Isotropic with B = const
iso
Number of parameters
Goodness-of-fit S (GOOF)
Final R-factors for data with I > 2V(I)
146
0.98
R = 0.0436, wR = 0.0948
1 2
3
Residuals, e/Å :
'
'
Umin
Umax
–0.133
0.133
Gas-liquid chromatography analysis (LKhM-80, 2000u3 mm column, 5% SE-30 on Inerton-Super (0.16 mm-
0
.2 mm), column temperature 180qɋ, helium as carrier gas) of a mixture of stereoisomers 2 revealed that the content of the
1
major isomer is a75%. This conclusion is supported by the H NMR (300 MHz) spectrum of a mixture of (ȿ,Z)-2, but we
failed to assign the signals and to determine the stereoisomer contents unambiguously. Acid 3 was obtained as a crystalline
solid (alkaline hydrolysis of 2 followed by acidification, mp 93qC-95qɋ from CCl ) which contained only one isomer
4
1
according to H NMR data. Taking into account the yield at this stage (a70%) and assuming that under alkaline hydrolysis
conditions the (Z) isomer of ester 2 can experience dehydrochlorination (anti-configuration of eliminated atoms) followed by
tar formation, we assigned the (E) configuration to the major isomer.
To prove unequivocally the structure of acid 3 we performed an X-ray investigation, which showed that the acid
obtained from major isomer 2 has an (E) configuration.
3
53

4
3
TABLE 2. Positional (u10 ) and Equivalent Thermal Parameters (u10 ) of Atoms
Atom
x/a
y/b
z/c
Ueq
Atom
x/a
y/b
z/c
Ueq
Cl(1)
O(1)
O(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
10797(1)
6081(3)
6903(3)
9002(4)
8712(4)
9798(5)
7219(4)
6681(4)
5511(4)
3656(5)
2923(6)
2537(1)
4301(2)
3978(2)
2903(2)
1685(3)
3079(3)
3788(2)
1246(2)
219(3)
5321(1)
4145(1)
5442(1)
4513(1)
3876(2)
3702(2)
4730(2)
3496(1)
3865(2)
3520(2)
2802(2)
99(1)
80(1)
81(1)
70(1)
73(1)
93(1)
63(1)
65(1)
73(1)
88(1)
96(1)
C(9)
C(10)
H(1)
H(2)
H(3)
H(4)
H(5)
H(6)
H(7)
H(8)
H(9)
4040(7)
5914(6)
515(4)
959(4)
1126(4)
901(4)
601(4)
293(4)
168(4)
376(4)
677(4)
1256(4) 2425(2)
1762(3) 2761(2)
108(1)
93(1)
90
90
90
90
90
90
90
482(3)
90(3)
428(2)
404(1)
372(2)
337(2)
437(2)
381(2)
254(2)
198(2)
252(2)
306(3)
378(3)
–12(3)
–101(3)
–6(3)
–271(4)
250(4)
163(3)
245(3)
90
90
TABLE 3. Bond Lengths d(V) (Å) and Angles Z(V) (deg)
Bond
d(V)
Bond
d(V)
Bond
d(V)
Cl(1)–C(1)
C(1)–C(4)
C(2)–C(3)
C(5)–C(6)
C(8)–C(9)
1.753(3)
1.477(3)
1.484(4)
1.377(3)
1.350(5)
O(1)–C(4)
C(1)–C(3)
C(2)–C(5)
C(6)–C(7)
C(9)–C(10)
1.272(3)
1.502(4)
1.478(4)
1.372(4)
1.382(5)
O(2)–C(4)
C(1)–C(2)
C(5)–C(10)
C(7)–C(8)
1.241(3)
1.536(3)
1.376(4)
1.347(4)
Angle
Z(V)
Angle
Z(V)
C(4)–C(1)–C(3)
C(3)–C(1)–C(2)
C(3)–C(1)–Cl(1)
C(5)–C(2)–C(3)
C(3)–C(2)–C(1)
O(2)–C(4)–O(1)
O(1)–C(4)–C(1)
C(10)–C(5)–C(2)
C(7)–C(6)–C(5)
C(7)–C(8)–C(9)
C(5)–C(10)–C(9)
119.9(2)
58.5(2)
117.8(2)
124.5(3)
59.6(2)
124.3(2)
115.4(2)
123.2(3)
121.7(3)
119.2(3)
120.1(3)
C(4)–C(1)–C(2)
C(4)–C(1)–Cl(1)
C(2)–C(1)–Cl(1)
C(5)–C(2)–C(1)
C(2)–C(3)–C(1)
O(2)–C(4)–C(1)
C(10)–C(5)–C(6)
C(6)–C(5)–C(2)
C(8)–C(7)–C(6)
C(8)–C(9)–C(10)
120.1(2)
113.7(2)
116.3(2)
123.5(2)
61.9(2)
120.2(2)
117.2(3)
119.6(2)
120.4(3)
121.5(3)
Fig. 1. Molecular structure with an atomic labeling scheme 1
for non-hydrogen atoms.
3
54

Fig. 2. Crystal packing.
Experimental. Crystal data, details of the diffraction experiment, and refinement parameters of the structure are
given in Table 1. The structure was solved by direct methods. All hydrogen atoms were located in difference electron density
synthesis. All calculations were performed with SHELXTL Version 6.10. Atomic coordinates are presented in Table 2.
Molecular structure. The projection of the molecule providing reasonably small atomic overlap is given in Fig. 1.
Bond lengths and angles for the structure are reported in Table 3.
The geometrical parameters of the molecule have expected values. In particular, substantial deformation of the
cyclopropane ring agrees with the substituent effect on the geometry of the cyclopropane fragment found experimentally [8,
9
]. The C(4)–O(2) bond is elongated to 1.241(3) Å; this is apparently caused by the fact that the O(2) atom accepts the
hydrogen of the substantially strong [9] intermolecular hydrogen bond O(1)–H…O(2) (O–H 0.81(3), H…O 1.81(3), O…O
.622(2) Å, O–H–O 178(3)q), forming molecular dimers around the (0.5, 0.5, 0.5) inversion center. Crystal packing is given
in Fig. 2.
The C(4)C(1)–C(2)C(5) torsion angle is –4.9(4)q, indicating that the benzene ring and the carboxyl group have a cis
2
arrangement and providing a clue to the problem posed in this study.
This work was supported by ANSEF and the Open Society Institute (OCI) grant No. NS 75-01 (2002).
REFERENCES
1
2
3
4
. D. Arlt, M. Jautelat, and R. Lantzsch, Angew. Chem., B93, No. 9, 719-840 (1981).
. C. J. Suckling, ibid., B100, No. 4, 555-570 (1988).
. M. Boeykens, N. De Kimpe, and K. A. Tehrani, J. Org. Chem., 59, No. 23, 6973-6985 (1994).
. R. Kh. Freidlina, F. K. Velichko, S. S. Zlotskii, et al., Radical Isomerization [in Russian], Khimiya, Moscow (1988),
pp. 244-257.
5
6
7
8
9
. Sh. O. Badanyan, A. N. Stepanyan, A. R. Mikaelyan, et al., Zh. Org. Khim., 33, No. 1, 44-52 (1997).
. M. V. Rubtsov and A. G. Baichikov, Synthetic Pharmaceuticals [in Russian], Meditsina, Moscow (1971), pp. 30-32.
. D. A. Kharkevich, Pharmacology [in Russian], Geotar Meditsina, Moscow (1999), pp. 96, 217, 222.
. F. H. Allen, Tetrahedron, 38, No. 18, 2843-2847 (1982).
. F. H. Allen, Acta Crystallogr., B36, No. 1, 81-83 (1980).
1
0. Yu. V. Zefirov, Kristallografiya, 44, 1091-1094 (1999).
3
55