Molecules 2010, 15
) are reported in parts per million (ppm) relative to the residual solvent signal. Coupling constant
8151
(δ
values (J) are given in Hertz (Hz) and refer to apparent multiplicities, indicated as follows: s (singlet);
d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of doublets). ESI+ mass spectra were
recorded on a Trace 200 chromatograph with a capillary column CPSIL5CB/MS (l = 25 m,
Ø = 0.25 mm, df = 0.12 µm). Characterization data of the coupling products matched the data reported
in the literature [31-33].
General procedure for the synthesis of 2-chlorophenyzinc bromide (2). A 25 mL round-bottom flask
was flushed with argon and charged with acetonitrile (7 mL). Dodecane (0.04 mL), zinc dust (1.2 g,
18 mmol), trifluoroacetic acid (0.04 mL) and 1,2-dibromoethane (0.1 mL) were added and the solution
was heated under vigorous stirring until gas was evolved. Heating was stopped and the solution
allowed to cool for 15 min. 2-Bromochlorobenzene (1, 0.7 mL, 6 mmol) and cobalt bromide (0.13 g,
0.6 mmol) were added to the mixture which was stirred at ambient temperature for additional 30 min,
resulting in the formation of 2-cholorophenyl zinc bromide (2) in ~75 % yield [34].
Multicomponent synthesis of ethyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetate (6). To a 25 mL round-bottom flask, flushed with argon, was added acetonitrile (2 mL) and
ethyl glyoxylate (4, ~50 % w/w solution in toluene, 0.4 mL, 2 mmol). The resulting solution was
heated at 60 °C for 20 minutes then cooled down to room temperature. The amine 3 (0.14 g) and the
solution of organozinc 2 were successively added and the mixture was stirred for 30 minutes. A
saturated ammonium chloride solution (30 mL) was added and the organic products were extracted
with dichloromethane (2
X
50 mL). The organic fraction was washed with water (30 mL), dried over
MgSO4 then concentrated under reduced pressure. The remaining crude oil was purified by silica gel
chromatography using a 89/9/2 pentane/Et2O/NEt3 mixture as an eluant to furnish 6 as a pale yellow oil
(0.262 g, 78 %). 1H-NMR: δ 7.71 (dd, J = 7.6, J = 2.0 Hz, 1H), 7.41 (dd, J = 7.6, J = 2.0 Hz, 1H), 7.28
(dd, J = 5.6, J = 1.6 Hz, 1H), 7.28-7.25 (m, 1H), 7.06 (d, J = 5.1 Hz, 1H), 6.67 (d, J = 5,1 Hz, 1H),
4.88 (s, 1H), 4.22-4.14 (m, 2H), 3.75 (d, J = 14.1 Hz, 1H), 3.63 (d, J = 14.1 Hz, 1H), 2.88-2.89 (m,
4H), 1.22 (t, J = 7.1 Hz, 3H); 13C-NMR: δ 171.0, 134.8, 134.1, 133.5, 133.4, 130.0, 129.9, 129.4,
127.2, 125.4, 122.8, 68.1, 61.2, 50.7, 48.4, 25.6, 14.3; MS (ESI+): m/z = 335 (1), 264 (37), 263 (18),
262 (100), 207 (10), 154 (14), 152 (46), 138 (14), 125 (22).
Multicomponent synthesis of methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetate [(±)-clopidogrel (7)]. To a 25 mL round-bottom flask, flushed with argon, was added
acetonitrile (2 mL) and methyl glyoxylate 5 (0.18 g, 2 mmol). The flask was placed in the microwave
oven and heated for 30 min at 50 W. The amine 3 (0.14 g) was added and the resulting solution was
submitted to the action of an additional 50 W over 10 min program. The solution of organozinc 2 was
added to the flask and the resulting mixture was heated for additional 30 minutes at 50 W. A saturated
ammonium chloride solution (30 mL) was added and the organic products were extracted with
dichloromethane (2 50 mL). The organic fraction was washed with water (30 mL), dried over MgSO4
X
then concentrated under reduced pressure. The remaining crude oil was purified by silica gel
chromatography using a 89/9/2 pentane/Et2O/NEt3 mixture as an eluant to furnish 7 as a pale yellow oil
(0.103 g, 32 %). 1H-NMR: δ 7.70 (dd, J = 8.0, J = 1.0 Hz, 1H), 7.41 (dd, J = 8.0, J = 1.6 Hz, 1H), 7.25-