2-Chlorophenyl zinc bromide: A convenient nucleophile for the mannich-related multicomponent synthesis of clopidogrel and ticlopidine

Article abstract of DOI:10.3390/molecules15118144

A methodological study devoted to the Mannich-like multicomponent synthesis of the antiplatelet agent (±)-clopidogrel (7) and the ethyl ester analogue 6 is described. The process involves the formation of 2-chlorophenyl zinc bromide (2) and its subsequent reaction with an alkyl glyoxylate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3). We demonstrate that the organozinc reagent 2 also constitutes a very convenient nucleophile for the multicomponent synthesis of the benzylamine core of ticlopidine (9).

Full text of DOI:10.3390/molecules15118144

Molecules 2010, 15, 8144-8155; doi:10.3390/molecules15118144
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
2-Chlorophenyl Zinc Bromide: A Convenient Nucleophile for
the Mannich-Related Multicomponent Synthesis of
Clopidogrel and Ticlopidine
Isabelle Aillaud 1, Caroline Haurena 1, Erwan Le Gall 1,*, Thierry Martens 1 and Gino Ricci 2
1
Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris Est, ICMPE, UMR
7182 CNRS - Université Paris-Est Créteil Val-de-Marne, 2-8 rue Henri Dunant, 94320 Thiais,
France; E-Mails: iaillaud@cpe.fr (I.A.); haurena@glvt-cnrs.fr (C.H.); martens@glvt-cnrs.fr (T.M.)
2
Sanofi-Aventis, Process Development, 45 Chemin de Mételine, BP 15, 04201 Sisteron cedex,
France; E-Mail: gino.ricci@sanofi-aventis.com (G.R.)
* Author to whom correspondence should be addressed; E-mail: legall@glvt-cnrs.fr;
Tel.: +33-1-49781135; Fax: +33-1-49781148.
Received: 8 October 2010; in revised form: 2 November 2010 / Accepted: 9 November 2010 /
Published: 11 November 2010
Abstract: A methodological study devoted to the Mannich-like multicomponent synthesis
of the antiplatelet agent (±)-clopidogrel (7) and the ethyl ester analogue 6 is described. The
process involves the formation of 2-chlorophenyl zinc bromide (2) and its subsequent
reaction with an alkyl glyoxylate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3). We
demonstrate that the organozinc reagent 2 also constitutes a very convenient nucleophile
for the multicomponent synthesis of the benzylamine core of ticlopidine (9).
Keywords: multicomponent reactions, organozinc reagents, amino acids, cobalt, zinc
Introduction
The development of new or improved methods for the straightforward preparation of
pharmaceuticals has been the subject of great interest over the last few years, e.g. for the production of
generics. In this context, the synthesis of the antiplatelet agent clopidogrel, which was the second top
selling drug in the mid 2000s, has been extensively investigated [1]. Curiously, in spite of their high

Molecules 2010, 15
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synthetic interest, the use of multicomponent procedures [2-11] for the synthesis of (±)-clopidogrel (7)
has been only scarcely reported. For instance, as this compound can be regarded as the ester derivative
of a non-natural
α-amino acid, some well-established multicomponent procedures allowing the
formation of this core unit have been used as the key step of its preparation. Accordingly, the synthesis
of 7 has been reported recently by Kalinski and co-workers [12], either by using the Petasis [13-15] or
the Ugi [16, 17] reaction. Compared to the original patented Sanofi multi-step synthesis of clopidogrel
[18], the use of these multicomponent procedures allows the preparation of 7 both in a more
straightforward manner and with better overall yields (Scheme 1).
Scheme 1. Some representative examples of (±)-clopidogrel syntheses.
Conditions and yields: i. 1. MeOH, HCOOH, 60 °C, MW; 2. THF-HClaq (9:1), r.t., 81%; ii.
DMF, r.t., 49%; iii. MeOH, H2SO4, heat, 92%; iv. HCl, MeOH, reflux, 5 h, 84%; v. SOCl2,
heat, 83%; vi. K2CO3, MDF, 90 °C, 4 h, 45%.
In previous papers, we reported a straightforward synthesis of various nitrogen-containing
compounds by using a Mannich-type multicomponent reaction between aromatic organozinc reagents,
amines, and carbonyl derivatives [19, 20]. It was noticed that a wide range of structural units are
accessible using this methodology, but we did not investigate the potential use of this procedure for the
preparation of pharmaceuticals. Consequently, we intended herein to apply this methodology to the
synthesis of some famous drugs such as the antiplatelet agents (±)-clopidogrel (7) and ticlopidine (9).

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Results and Discussion
It was anticipated that both targets should be accessible through a three-component reaction between
2-chlorophenylzinc bromide (2), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3), and methyl glyoxylate (5)
[for the synthesis of (±)-clopidogrel (7)] or paraformaldehyde (8) [for the synthesis of ticlopidine (9)].
The projected syntheses are outlined in Scheme 2.
Scheme 2. Projected multicomponent synthesis of clopidogrel and ticlopidine.
As a starting point of the study, we turned our attention to the synthesis of methyl 2-(2-
chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate [(±)-clopidogrel (7)]. As indicated
above, with our multicomponent process in hands, the synthesis of 7 might be achievable in one step
by using methyl glyoxylate as the carbonyl-containing compound. However, due to its ready
commercial availability, we envisaged carrying out an optimization study starting from ethyl glyoxylate
[21] instead of methyl glyoxylate. It was anticipated that methyl glyoxylate should possess a similar
reactivity and therefore, we planed to make the use of this compound only after the optimization step.
Alternatively, (±)-clopidogrel (7) should also be reachable by a simple transesterification of its ethyl
ester analogue 6. The synthesis of this latter was envisaged as follows: 2-bromochlorobenzene (1)
would be converted into 2-chlorophenyl zinc bromide (2), which would be allowed to react with
4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3) and ethyl glyoxylate (4) to furnish the clopidogrel ethyl
ester analogue 6 (Scheme 3).
Scheme 3. Synthesis of the clopidogrel ethyl ester analogue 6.
S
S
Cl
Cl
N
H
Br
ZnBr
3
Zn, CoBr2
Cl
N
CH3CN
r.t.
O
OEt
H
1
2
OEt
O
O
4
6
We then tried to define accurate reaction conditions for the preparation of 6 by assessing a broad
range of reaction parameters like the amounts of reagents, the medium temperature, the reaction scale,
the concentration of reagents, etc. In a first series of experiments, we turned our attention to evaluating
the effect of different amounts of organozinc reagent on the three-component coupling efficiency. To

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this end, an initial set of conditions had to be defined. In a previous study dealing with the
multicomponent synthesis of α-amino esters, it was noticed that a range of arylzinc halides react
efficiently at room temperature with amines and ethyl glyoxylate, provided that the latter is used in
excess. Thus, in a typical experiment, 2-chlorophenylzinc bromide (2) was prepared in acetonitrile
from the corresponding aryl bromide 1 according to the general procedure, closely related to the
original procedure of Gosmini and coworkers [22-24]. Various amounts [25] of this organometallic
reagent were then allowed to react with the amine 3 (1 mmol) in the presence of 2.5 equiv. [26] of
ethyl glyoxylate (4) [27], for 0.5-1 h at room temperature [28]. Results are presented in Table 1.
Table 1. Influence of organozinc amount. a
Entry
Organozinc 2 (equiv.)b Time (h)
Conversion (%)c Yield (%)
1
2
3
4
5
6
1
1
0
-
2
1
0
-
2.5
3
1
<5
100
100
100
-
0.5
0.5
0.5
82d (>95e)
>95e
>95e
3.5
4
a Experiments were typically conducted with 7 mL of acetonitrile, 0.14 g (1 mmol) of the amine 3,
b
0.5 mL (~2.5 mmol) of ethyl glyoxylate in toluene and 1.2 g (19 mmol) of zinc dust. Relative to
the amine 3. c Consumption of the amine 3, monitored by GC. d Isolated yield. e GC yield.
These experiments revealed that at least 2.5 equiv. of 2 are required for the reaction to start
(Table 1, entry 3). The minimum value for the completion of the reaction is 3 equiv. of the organozinc
(Table 1, entry 4). In that case, a 100% conversion is observed after only 30 min at room temperature,
along with a very good isolated yield (82 %) [29]. It is worth noting that beyond 3 equiv., the reaction
proceeds quantitatively (GC monitoring, Table 1, entries 5 and 6). However, in a general manner, since
comparable isolated yields should be obtained when quantitative GC yields are observed, it was not
intended to systematically extract the coupling products.
In another set of experiments, we examined the influence of amount of ethyl glyoxylate on the three-
component coupling. Having previously demonstrated that the organozinc species 2 has to be used in
sufficient excess to obtain efficient couplings, the following experiments were realized on a 1 mmol
scale (amine 3) with a large excess of 2 in the reaction medium. Results are summarized in Table 2.
Table 2. Influence of glyoxylate amount. a
Entry
Glyoxylate 4 (equiv.)b Time (h)
Conversion (%)c Yield (%)d
1
2
3
4
1.25
2
2.5
5
1.5
0.5
0.5
0.5
43
-
100
100
100
78 (>95e)
82 (>95e)
75 (>95e)
a
Experiments were typically conducted with 7 mL of acetonitrile, 0.7 mL (6 mmol) of 2-
bromochlorobenzene, 0.14 g (1 mmol) of the amine 3, 1.2 g (19 mmol) of zinc dust, 0.13 g
(0.6 mmol) of CoBr2. b Relative to the amine 3. c Consumption of the amine 3, monitored by GC. d
Isolated yield. e GC yield.

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These experiments indicate that a quantitative consumption of the amine 3 (and a 78 % yield) could
be achieved, after 30 min reaction time, starting from 2 equiv. of ethyl glyoxylate (Table 2, entry 2). It
can be noted that the use of larger amounts of ethyl glyoxylate gave similar results (Table 2, entries 3
and 4). Taken together, the results presented in Tables 1 and 2 indicate that both reagents other than the
amine 3 have to be used in excess. Consequently, the amine might be used as the limiting reagent and a
rise of its amount should result in the decrease of the reaction efficiency. This hypothesis could be
verified as following: starting from the optimum conditions defined in entry 2 of Table 2, the amine
amount was increased from 1 to 2 mmol, resulting in the important decrease of its consumption from
100 to 15 %, even after 2 h at room temperature. Starting from the optimized conditions (Table 2,
entry 2), we next envisaged to assess the influence of the reaction temperature. Results are presented in
Table 3.
Table 3. Influence of the reaction temperature. a
Entry
Temperature (°C) Time (h) Conversion (%)b Yield (%)
1
2
3
0
2
25
-
25
60
0.5
0.3
100
100
78c (>95d)
>95d
a
Experiments were typically conducted with 7 mL of acetonitrile, 0.7 mL (6 mmol) of 2-
bromochlorobenzene, 0.14 g (1 mmol) of the amine 3, 0.4 mL (~2 mmol) of ethyl glyoxylate in
b
toluene, 1.2 g (19 mmol) of zinc dust, 0.13 g (0.6 mmol) of CoBr2. Consumption of the amine 3,
monitored by GC. c Isolated yield. d GC yield.
It can be noted that while the reaction substrates do not undergo coupling at 0 °C (Table 3, entry 1),
a moderate rise of the temperature to 25°C already provides efficient conversions in short reaction
times (Table 3, entry 2), while at 60°C, the reaction goes to completion in less than 20 min (Table 3,
entry 3).
All previously-described experiments were realized on a 1 mmol scale (of amine 3). Thus, we next
tried to change the reaction scale by using increased amounts of the amine 3 in the presence of 2 equiv.
of glyoxylate 4 and at least 3 equiv. of the organozinc 2. Results are presented in Table 4.
Table 4. Scale-Up. a
Entry
Amine 3 (mmol)
Time (h)
Conversion (%)b
Yield (%)c
1
2
3
1
0.5
1
100
100
100
78
89
75
5
30
1.5
a
Experiments with 1 mmol of 3 were typically conducted with 7 mL of acetonitrile, 0.7 mL
(6 mmol) of 2-bromochlorobenzene, 0.4 mL (~2 mmol) of ethyl glyoxylate in toluene, 1.2 g
(19 mmol) of zinc dust, 0.13 g (0.6 mmol) of CoBr2. For scale-up, all amounts were increased
proportionally to maintain similar concentrations. b Consumption of the amine 3, monitored by GC.
c Isolated yield.
A scale-up of the reaction appears feasible. Indeed, similar conversions and yields are obtained with
an amine amount ranging from 1 to 30 mmol. However, for technical reasons, we did not try to raise
the amine amount above this latter quantity.

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In a second part of the study, we tried to extend the method to the synthesis of (±)-clopidogrel 7, by
simply exchanging ethyl glyoxylate (4) for methyl glyoxylate (5). Unfortunately, preliminary
experiments realized using (neat) methyl glyoxylate resulted in failure as no conversion of the amine 3
was detected, even after several hours under heating. Two hypotheses were envisaged to explain these
failures: methyl glyoxylate is supplied as a mixture of the aldehyde and the corresponding hydrate. In
that case, a part of the organozinc might be lost instantly through acid-base reaction with the hydrate.
However, the chromatographic monitoring of a test reaction did not reveal a significant loss of the
organozinc reagent upon mixing, thus allowing us to discard this hypothesis. Another possibility lies in
the lack of reactivity of the polymeric form(s) of methyl glyoxylate. The well-known tendency of this
compound to polymerize rapidly, following a strong exothermic reaction, may account for a difficult
reverse reaction. We thus envisaged a depolymerization step by applying a vigorous heating to 5 prior
to the three-component coupling. Unfortunately, conventional heating using an oil bath did not allow
obtaining 7, even in trace amounts.
We then turned our attention to the microwave (MW) activation of the reaction. Thus, in a
preliminary step, methyl glyoxylate was subjected to a focused microwave irradiation (50 W for
20 min). After addition of both other reagents 2 and 3, a 40 % conversion and a 32 % isolated yield
were obtained (Scheme 4).
Scheme 4. Synthesis of (±)-clopidogrel (7).
S
1. MW 50W, 20 min
O
CH3CN
32 %
MeO
H
Cl
N
S
O
2.
Cl
OMe
ZnBr
5
O
7
N
H
2
3
Even though this result could not be further improved [30], it indicates that the synthesis of
(±)-clopidogrel (7) from methyl glyoxylate (5), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3) and
2-chlorophenyl zinc bromide (2) following a Mannich-like multicomponent procedure is
clearly possible.
We then tried to obtain (±)-clopidogrel (7) through transesterification of its ethyl analogue 6. In this
purpose, some common methods were evaluated. Results are summarized in Table 5. The first point to
note concerns the overall difficulty of transesterifying 6, probably due to the presence of a nitrogen
atom close to the ester function. Consequently, an acid catalysis of the reaction is not efficient (Table 5,
entry 1) and the acid has to be used in excess (Table 5, entry 2). This is also the case with iodine (alone
or in conjunction with indium) which must be used in excess to obtain a significant conversion of the
starting amine (Table 5, entries 4 and 5). Best results are obtained with methylate ions as a
transesterification agent, with a quasi-quantitative conversion of 6 into (±)-clopidogrel (7), after a
30 minutes heating period.

Molecules 2010, 15
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Table 5. Transesterification of clopidogrel analogue 6a
Entry Conditions
Time (h)
Conversion (%)b
Yield (%)
1
2
3
4
5
H2SO4, cat.
H2SO4, excess
MeONa, excess
I2, cat.
18
18
0,5
18
18
<5
88
90
<5
72
-
85c
86c (52d)
-
68c
In + I2, excess
a
b
Experiments were typically conducted with 2 mL of methanol and 0.68 g (2 mmol) of 6.
Consumption of Clopidogrel analogue 6, monitored by GC. c GC yield. d Isolated yield.
In a third part of the study, we attempted to synthesize ticlopidine (9) by a three-component reaction
between 2-chlorophenylzinc bromide (2), paraformaldehyde (8) and 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine (3). Thus, the organozinc 2 (> 3 equiv.) was allowed to react with the amine 3 and
paraformaldehyde (8) (1.8 equiv., depolymerized prior to use by a 2 h heating period at 60 °C) for 1 h
at 60 °C. This experiment resulted in the formation of the expected target in 95 % yield, thus pointing-
out the relevance of this strategy for the synthesis of the benzylamine backbone (Scheme 5).
Scheme 5. Synthesis of ticlopidine 9.
S
S
N
H
3
Cl
Cl
N
+
ZnBr
CH3CN
95%
9
(CH2O)n
2
8
Experimental
General
Solvents and reagents were purchased from commercial suppliers and used without further
purification. All reactions were monitored by gas chromatography (GC) using a Varian 3400
chromatograph with a capillary DB1 column (l = 5 m, Ø = 0.32 mm, df = 0.4 µm). Reactions involving
microwave heating were realized using a CEM Discover system. NMR spectra were recorded in
CDCl3, at 400 MHz (1H) and 100 MHz (13C) on a Bruker Avance II 400 spectrometer. Chemical shifts

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-

Molecules 2010, 15
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7.15 (m, 2H), 7.00 (d, J = 4.0 Hz, 1H), 6.61 (d, J = 4.0 Hz, 1H), 4.85 (s, 1H), 3.70 (d, J = 12.0 Hz, 1H),
13
3.64 (s, 3H), 3.57 (d, J = 12.0 Hz, 1H), 2.82 (s, 4H); C-NMR: δ 171.3, 134.7, 133.7, 133.2, 130.0,
129.8, 129.5, 127.2, 125.3, 122.8, 67.8, 52.2, 50.7, 48.3, 25.5; MS (ESI+): m/z = 320 (1), 264 (41), 263
(18), 262 (100), 154 (14), 152 (44), 138 (16), 125 (20).
Synthesis
of
methyl
2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate,
[(±)-clopidogrel (7)] from 6: A 10 mL round-bottom flask was flushed with argon and charged with
methanol (2 mL). Small portions of sodium (0.2 g, 8.7 mmol) were added at 0 °C and the mixture was
stirred until complete dissolution. The α-amino ester 6 (0.68 g, 2 mmol) was added and the resulting
solution was refluxed for 30 minutes then cooled down to ambient temperature. Water (10 mL) was
added and the organic products were extracted with dichloromethane (2 20 mL). The organic fraction
X
was washed with water (10 mL), dried over MgSO4 and concentrated to dryness. The 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 (0.340 g, 52 %).
Synthesis of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ticlopidine (9)]. To a 25 mL
round-bottom flask, flushed with argon, was added acetonitrile (3 mL) and paraformaldehyde (0,17 g,
4 mmol). The resulting solution was heated at 60 °C for 2 h and the amine 3 (0.31 g, 2.2 mmol) was
added. A solution of organozinc 2 (~10 mL, containing ~7.5 mmol ArZnBr) obtained following the
general procedure but starting from 10 mmol of 2-bromochlorobenzene (1) was then added and the
resulting mixture was stirred for an additional 1 h at 60 °C. A saturated ammonium chloride solution
(60 mL) was added and the organic products were extracted with dichloromethane (3 100 mL). The
X
organic fraction was washed with water (100 mL), dried over Na2SO4 then concentrated under reduced
pressure. The remaining crude oil was purified by silica gel chromatography using a 93/5/2
pentane/CH2Cl2/NEt3 mixture as an eluant to furnish 9 as a pale yellow oil (0.55 g, 95 %). 1H-NMR: δ
7.54 (dd, J = 7.4, J = 1.9 Hz, 1H), 7.38 (dd, J = 7.6, J = 1.6 Hz, 1H), 7.40-7.25 (m, 2H), 7.10 (d, J =
7.5 Hz, 1H), 6.72 (d, J = 5,1 Hz, 1H), 3.86 (s, 2H), 3.68 (s, 2H), 2.89-2.94 (m, 4H); 13C-NMR: δ 135.9,
134.3, 133.7, 133.4, 130.7, 129.5, 128.3, 126.8, 125.3, 122.7, 58.3, 53.0, 50.7, 25.4; MS (ESI+): m/z =
265 (42), 264 (45), 263 (100), 262 (78), 228 (51), 125 (31), 110 (77), 89 (13).
Conclusions
In conclusion, the results presented in this study indicate that a three-component Mannich-type
reaction involving an arylzinc reagent as the nucleophile can constitute a very reliable methodology for
the synthesis of commercial drugs displaying a α-amino ester or a benzylamine core. Indeed,
(±)-clopidogrel (7) and its ethyl analogue 6, as well as ticlopidine (9) were obtained in satisfactory to
high yields through this practical and straightforward procedure. A current research interest concerns
the application of this methodology as a key step for the preparation of a larger range of pharmaceutical
drugs and synthetically useful scaffolds.
Acknowledgements

Molecules 2010, 15
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The financial support of this work by Sanofi-Aventis (in the form of a post-doctoral fellowship to I.
A.) and the gift of the amine 3 are gratefully acknowledged.
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usable organozinc reagent. Increased amounts of the organozinc reagent should be obtained with
similar yields by using proportional amounts of the starting reagents and solvent.
Sample Availability: Samples of the compounds are available from the authors.
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(http://creativecommons.org/licenses/by/3.0/).