Microwave-induced by-products in the synthesis of 2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile

Article abstract of DOI:10.1016/j.tetlet.2009.05.068

The Letter describes the investigation of an industrial reaction of N-methylphenylpiperazine and chloronicotinonitrile, under microwave heating. Besides the formation of the expected 2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile (4), extension o

Full text of DOI:10.1016/j.tetlet.2009.05.068

Tetrahedron Letters 50 (2009) 4502–4505
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-induced by-products in the synthesis of
2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile
a
a
a
a
Christelle Lamazzi a, , Armelle Dreau , Christel Bufferne , Christine Flouzat , Patrick Carlier ,
*
Rob ter Halle a, Thierry Besson b,
*
a Department of Development Chemistry, Centre de Développement Préclinique, Schering-Plough, 22 rue Henri Goudier, 63203 Riom cedex 2, France
b Université de Rouen, UMR CNRS 6014—C.O.B.R.A.—IRCOF, UFR Médecine-Pharmacie, 22 boulevard Gambetta, F-76183 Rouen cedex 1, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The Letter describes the investigation of an industrial reaction of N-methylphenylpiperazine and chloro
nicotinonitrile, under microwave heating. Besides the formation of the expected 2-(4-methyl-2-phe
nylpiperazinyl)pyridine-3-carbonitrile (4), extension of the scale leads to unexpected by-products. A spe-
cific pathway due to the formation of a reactive ‘ionic alkylating intermediate’ formed in situ under
microwave conditions is proposed to explain the results observed.
Received 4 March 2009
Revised 19 May 2009
Accepted 20 May 2009
Available online 25 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Microwave irradiation
Piperazinoazepine derivatives
Piperazines
1. Introduction
pressant mirtazapine.5 This reaction is generally performed with
bases, transition metal-catalyzed processes, phase transfer cata-
The use of adapted reactants and techniques offering opera-
tional, economic, and environmental benefits over conventional
methods, is becoming crucial in the preparation and development
of biologically active molecules. Microwave irradiation has gained
popularity throughout both industry and academia since it was
found to be an effective heating source applicable to a wide range
of reactions.1,2 The main benefits of microwaves are significant rate
enhancements, higher product yields, and easier handling of reac-
tion mixtures. The release of dedicated instruments for organic
synthesis in the market has allowed a rapid development of micro-
wave-assisted organic synthesis. Experiments can be carried out in
monomode or multimode devices using different techniques such
as open or sealed conditions, solvent-less procedures or solvent
conditions.3
lysts or solid phase synthesis.6 Long reaction times and high tem-
peratures are often required. In the current industrial context, we
need to manage well-established procedures and methodologies,
with environmental and safe benefits over conventional methods.
Improving chemistry in a ‘green approach’ suggests exploring
microwave heating. The aim of our work was to reinvestigate un-
der microwaves an industrial reaction in order to identify what
the advantages of these novel conditions are over classical condi-
tions, with expectation for further developments. This down-scal-
ing approach is not common and the main work published in the
literature consists in transferring traditional lab-scale reactions
into microwave reactors or domestic ovens. This Letter describes
our work and the surprising results obtained.
Our research project consisted of developing an easy access to
piperazinoazepines with pharmaceutical interest4 and we were
particularly interested in finding a rapid preparation method of
2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile 4. Tradi-
tional synthetic methods allowing access to this scaffold involve
a preliminary N-alkylation of the piperazine scaffold and a subse-
quent cyclization into the corresponding pyrido-azepine. This
specific alkylation is a key step in the preparation of the antide-
2. Results
The reaction investigated was the synthesis of 2-(4-methyl-2-
phenylpiperazinyl)pyridine-3-carbonitrile 4 via condensation of
chloronicotinonitrile
dimethylformamide (DMF) in the presence of potassium fluoride.
This reaction has been previously optimized and is performed on
industrial scale.5 Using traditional heating, the reaction is com-
pleted after 5 h in refluxing DMF in an isolated yield of 73%. It pro-
ceeds via an intermediate 2-fluoronicotinonitrile 2 (Scheme 1).7,8
During the process, reaction of water with compound 1 (the pres-
ence of water being brought by moist KF) and further condensation
1 and 1-methyl-3-phenylpiperazine 3 in
* Corresponding authors. Tel.: +33 4 73 33 39 16; fax: +33 4 73 33 39 34 (C.L.),
tel.: +33 2 35 14 83 99; fax: +33 2 35 14 84 23 (T.B.).
E-mail addresses: christelle.lamazzi@spcorp.com (C. Lamazzi), thierry.besson@
univ-rouen.fr (T. Besson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.068

C. Lamazzi et al. / Tetrahedron Letters 50 (2009) 4502–4505
4503
CN
N
6
N
H
N
Ph
DMF
Heat
N
3
CN
Ph
CN
F
CN
Cl
KF
N
N
N
N
N
2
4
1
Hydrolysis
Heat
CN
OH
CN
CN
O
1 or 2
O
CN
N
N
N
N
H
5
Scheme 1. Synthesis of 4, 5, and 6 from 1 (or 2).
Table 1
Investigation of microwave-assisted synthesis of 4 from chloronicotinonitrile 19,18
of the hydrolyzed intermediate on nicotinonitrile derivative 1 lead
to low quantities of a by-product characterized as 1-(2-cyano-
phenyl)-2-oxohydropyridine-3-carbonitrile (5 in Scheme 1).9,10
In the case studied, apart from some general microwave-as-
sisted N-alkylations,11 only one method of preparation of mono-
N-substituted piperazines combining solid phases synthesis and
microwave heating has been reported.12 The preparation of N-aryl-
piperazinones has also been described via microwave-enhanced
Goldberg reactions.13
S.M.a
Microwave reaction conditionsb
Product 4c (%)
1+3
1+3
1+3
NMP,150 °C, 30 min
NMP, 180 °C, 30 min
NMP, 200 °C, 15 min
73
88
99
a
S.M.: starting material.
Performed on 1 mmol scale on monomode system (300 W), under sealed vials.
Product conversion (%) based on the GC and GC/MS analysis after work-up.
b
c
Initial microwave experiments were performed at 150 °C in
DMF on 1 mmol scale on a monomode system and a control of
temperature by infrared pyrometer. After optimization, the reac-
tion reached completion after 1 h of irradiation and the desired
product 4 was isolated in 78% yield. As expected, an enhancement
in the reaction rate and a shorter reaction time were observed.
Experiments carried out in the presence of DMF at higher temper-
atures (>150 °C) were not successful. Another by-product was
detected and identified as the 2-(N,N-dimethylamine)-3-pyridine-
carbonitrile 6.9 Formation of this product probably results from
reaction of 1 (or 2) with dimethylamine generated by micro-
wave-accelerated thermal degradation of DMF into the mixture
(Scheme 1). This phenomenon was recently reported for reactants
like DMSO,14 formamide,15 and DMF which has been yet utilized as
a liquid source of carbon monoxide and dimethylamine in micro-
wave-accelerated aminocarbonylations of aryl halides.16
N-Methylpyrrolidone (NMP), another polar aprotic solvent, is
now a common replacement for DMF in pharmaceutical industry.
It allows working at 200 °C and is known for its efficiency to trans-
form electromagnetic energy into thermal energy.17 Investigating
various parameters (time, temperature, and power input) we
observed that the reaction time decreased by increasing the tem-
perature (200 °C). Under these conditions, completion of the reac-
tion was possible within 15 min, as indicated in Table 1.
Large-scale experiments (15 mmol scale) were carried out in
sealed vials in a multimode microwave device.18 Various tempera-
tures (180, 190, and 200 °C) were attempted and the results com-
pared with data obtained in the previous monomode trials. Besides
formation of the expected compound 4, and the usual carbonitrile
5, four novel by-products 8–119 were detected in all cases (Table 2
and Fig. 1).
Table 2
Extension of the scale of microwave experiments18 starting from 1 and 1-methyl-3-phenylpiperazine 3 or salt derivative 12a
S.M.
Reactor
Temperature and time
Product 3b (%)
Product 4b (%)
Side-products: 8,10,11b (%)
Side-products: 5/9b (%)
1+3
1+3
1+3
1+3
1+3
1+12
1+12
Sealed
Sealed
Sealed
Open
200 °C, 15 min
190 °C, 15 min
180 °C, 15 min
190 °C, 15 min
180 °C, 120 min
190 °C, 15 min
200 °C, 15 min
2
4
3
<1
4
37
51
50
84
85
64
58
5, 10, 16
3, 4, 6
2, 3, 4
/
8
8
7
2 (5 only)
2 (5 only)
4
7
Sealedc
Open
/
<1
<1
1, <1, 3
1, 3, 6
Sealed
a
Performed on 15 mmol scale from 1+3 or 1+12 on multimode system.
% Based on the GC/MS analysis after work-up, residual of 1 and 2 not included, retention times of 5 and 9 were identical in GC analysis.
Autoclave, use of traditional heating.
b
c

4504
C. Lamazzi et al. / Tetrahedron Letters 50 (2009) 4502–4505
formed in situ from the reaction of free HCl (liberated during the
CN
N
N
Ph
course of the reaction and trapped into the closed vessel). The ionic
character of this salt seems to induce its high capacity to transform
electromagnetic energy into thermal energy at the temperature
and frequency used in this study (Scheme 2).
Ph
NH
N
N
The monohydrochloride salt 12 was prepared from commercial
N-methylphenylpiperazine and experiments were performed un-
der microwaves, in open and closed vessels. Formation of the pre-
vious impurities 8–11 was observed in both cases (Table 2); it
confirms the importance of a synergic effect of microwaves and
pressure into the appearance of salt 12, methylating agent 7, and
consequently of by-products 8–11.
8
9
CN
Ph
CN
Ph
N
N
N
N
N
N
N
To complete our study, chloronicotinonitrile was replaced by
fluoronicotinonitrile as the starting compound. The reaction was
complete and clean and whatever the conditions used, none of
the by-products (5, 8–11) were detected (Scheme 3, Table 3).
In the aforementioned case, we rationalize that HF must be less
absorbent to microwave irradiation than HCl and thus none of the
by-products are formed indicating that ionic interactions between
the starting materials and the selected reagents can indeed influ-
ence product distribution. It is noteworthy that product 5 is not
observed under these conditions, this result confirms the hypothe-
sis of its formation from 1 (see Scheme 1).9
NC
10
11
Figure 1. Four main by-products.
The reaction (same concentration and scale of starting material)
conducted in an open vessel under microwave irradiation at 190 °C
or in an autoclave using traditional heating at 180 °C, was com-
plete and cleaner since only compound 5 (2%) was observed as a
by-product besides formation of the substituted pyridine 4 (Table
2).
4. Conclusion
3. Discussion
We studied the reaction of N-methylphenylpiperazine and chlo-
ronicotinonitrile under a microwave field with various conditions
of pressure, times, and temperatures. Compared to a traditional
heating mode, microwaves allowed reduction in reaction time
and preserved good yields. Our work also demonstrated the diffi-
culty to transpose a large-scale reaction performed at atmospheric
pressure to a lab-scale microwave-assisted process carried out in a
In a large number of the microwave-assisted reactions investi-
gated here, the yields for the expected product 4 were similar to
the yields described for the industrial-scale reaction, but time
was considerably reduced (from 5 h to 15 min).
The formation of by-products 8-11 could be explained via an
intermediate 7 itself resulting from a non selective attack of 1-
methyl-3-phenylpiperazine 3 on chloronicotinonitrile 1. A possible
pathway is described in Scheme 2: formation of methylated com-
pound 8 and demethylated product 9 could be directly initiated
from intermediate 7. Further alkylation of compound 9 could lead
to compound 10 (regio-isomer of 4) and a second reaction of chlo-
ronicotinonitrile 1 with compound 9 could lead to the tricyclic
product 11.
H
N
CN
Ph
Ph
MW
CN
F
+
N
N
N
200ºC, 20 min
> 99%
N
N
2
3
4
Formation of the methylating reagent 7 and its by-products 8–
11 can be explained via an ionic monohydrochloride salt (12)
Scheme 3. Synthesis of 4 from 2.
H
N
Ph
.HCl
CN
H
N
CN
N
3
Cl -
Ph
1
N
N
8
Ph
Ph
Ph
1
+
3
+
N
N+
N
N
N
NH
NH
12
formed "in situ"
7
9
KF
"Alkylating intermediate"
1 or 2
7
CN
CN
Ph
Ph
CN
N
N
N
N
N
N
N
Ph
N
N
N
NC
Scheme 2. Suggested mechanism for the formation of 8–11.
10
4
11

C. Lamazzi et al. / Tetrahedron Letters 50 (2009) 4502–4505
4505
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2
and 1-
methyl-3-phenylpiperazine 318
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7, 803–810; (b) Boudakian, M.; Olin, M. J. Heterocycl. Chem. 1967, 4, 381–
384.
S.M.
Reactor
Reaction conditionsa
4b (%)
2+3
2+3
2+3
Sealedc
Sealedd
Sealede
200 °C (MW), 20 min
200 °C (MW), 20 min
190 °C, 20 min
>99
>99
>99
a
Performed on 6 mmol scale.
Product conversion (%) and selectivity based on the GC and GC/MS analysis after
work-up.
Performed on monomode system.
Performed on multimode system.
b
c
d
e
Preheated oil bath, preheating time not included: 30 min.
8. Briner, G. P.; Miller, J.; Liveris, M.; Lutz, P. G. J. Chem. Soc. 1954, 1265.
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6633–6636.
sealed vessel. The presence of unexpected by-products was specif-
ically observed under these microwave conditions and not in usual
thermal processes. In contrast, working under microwaves at
atmospheric pressure gave very satisfactory results and data col-
lected in this study show the real interest to use microwave for
enhancing processes. In our case, the use of microwaves suggests
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important role in the mechanism of the reaction and therefore, into
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Acknowledgments
We wish to thank Dr F. Kaspersen (Schering Plough) for his ad-
vice and helpful discussions, and I. Bourgeois, F. Ranoux-Julien, G.
Martin for their contribution to the analytical data. T. Besson
thanks Milestone S.r.l. (Italy) for financial and technical support.
from Biotage) with
multimode cavity (Ethos MicroSynth from Milestone) with
power delivery system ranging from to 1000 W. Experiments in the
a
power output ranging from
0
to 300W and one
a
microwave
0
single mode were performed in 2–5 mL glass vials. The temperature was
monitored via an IR sensor located on the side of the vessel. The vessel
contents were stirred by means of
a rotating magnetic plate located
Supplementary data
below the microwave cavities and Teflon-coated magnetic stir bars
inside the vessel. Experiments in multimode systems were carried out in
closed 10 or 25 mL reactors made of quartz or glass. Open vessel
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.068.
experiment was carried out in
with reflux condenser. The temperature was monitored via
optic contact thermometer protected in Teflon-coated ceramic gain
a
250 mL round bottomed flask fitted
a
a
fiber-
a
References and notes
inserted directly into the reaction mixture. The vessel contents were
stirred by means of an adjustable rotating magnetic plate located below
the floor of the microwave cavity and
a Teflon-coated magnetic stir bar
1. For a recent book see: Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH Verlag Gmbh & Co. KGaA: Weinhein, 2006.
2. For recent reviews see: (a) Lidström, P.; Tierney, J.; Wathey, B.; Westmam, J.
Tetrahedron 2001, 57, 9225–9283; (b) Bogdal, D.; Penczek, P.; Pielichowski, J.;
inside the vessel. Temperature, pressure, and power profiles were
monitored using commercially available softwares provided by the
manufacturers.