Eco-Friendly Microwave-Assisted Scaleable Synthesis of 2-Cyanobenzothiazoles via N-Arylimino-1,2,3-dithiazoles

Article abstract of DOI:10.1081/SCC-120025190

The cyclization procedure of N-aryl iminodithiazoles into 2-cyanobenzothiazoles was re-investigated with the aim to develop original and environmentally friendly procedures. In this article, the benefits associated with the microwave methodology are reported and the opportunity to use solvent-free procedures in order to scale up organic synthesis is studied. The result obtained show that the strong thermal effects due to graphite/microwaves interaction can be efficiently used for the synthesis of heterocyclic molecules for which traditional methods failed or are less attractive.

Full text of DOI:10.1081/SCC-120025190

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Eco-Friendly Microwave-Assisted Scaleable Synthesis
of 2-Cyanobenzothiazoles via N -Arylimino-1,2,3-
dithiazoles
Stéphane Frère a , Valérie Thiéry a & Thierry Besson a
a Laboratoire de Génie Protéique et Cellulaire , Groupe de Chimie Organique , UFR Sciences
Fondamentales et Sciences pour l’Ingénieur , Bâtiment Marie Curie , Université de la
Rochelle , La Rochelle cedex 1, France
Published online: 16 Aug 2006.
To cite this article: Stéphane Frère , Valérie Thiéry & Thierry Besson (2003) Eco-Friendly Microwave-Assisted Scaleable
Synthesis of 2-Cyanobenzothiazoles via N -Arylimino-1,2,3-dithiazoles, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 33:21, 3795-3804, DOI: 10.1081/SCC-120025190
To link to this article: http://dx.doi.org/10.1081/SCC-120025190
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3795–3804, 2003
Eco-Friendly Microwave-Assisted Scaleable
Synthesis of 2-Cyanobenzothiazoles via
N-Arylimino-1,2,3-dithiazolesy
*
´ ´ ´
Stephane Frere, Valerie Thiery, and Thierry Besson
Laboratoire de Ge
Groupe de Chimie Organique, UFR Sciences
Fondamentales et Sciences pour l’Ingenieur, Batiment
Marie Curie, Universite de la Rochelle, La Rochelle
nie Proteique et Cellulaire,
´ ´
´
´
cedex 1, France
ABSTRACT
The cyclization procedure of N-aryl iminodithiazoles into 2-
cyanobenzothiazoles was re-investigated with the aim to develop
original and environmentally friendly procedures. In this article,
the benefits associated with the microwave methodology are reported
and the opportunity to use solvent-free procedures in order to scale
yDedicated to Professor Charles W. Rees on the occasion of his 75th birthday.
*Correspondence: Thierry Besson, Laboratoire de Ge
EA3169, Groupe de Chimie Organique, UFR Sciences Fondamentales et Sciences
pour l’Ingenieur, Batiment Marie Curie, Universite de la Rochelle, F-17042 La
nie Proteique et Cellulaire,
´ ´
´
´
Rochelle cedex 1, France; Fax: (33) (0)5 46 45 82 47; E-mail: tbesson@univ-lr.fr.
3795
DOI: 10.1081/SCC-120025190
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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´
Frere, Thiery, and Besson
3796
up organic synthesis is studied. The result obtained show that the
strong thermal effects due to graphite/microwaves interaction can be
efficiently used for the synthesis of heterocyclic molecules for which
traditional methods failed or are less attractive.
Key Words: Microwave assisted organic chemistry; Benzothiazoles;
Imino-1,2,3-dithiazoles
INTRODUCTION
It is well known that reaction of 4,5-dichoro-1,2,3-dithiazolium
chloride 1 with primary aromatic amines in dichloromethane at room
temperature allows access to stable N-arylimino-4-chloro-5H-1,2,
3-dithiazoles 2.[1] These compounds have proved to be highly versatile
intermediates in heterocyclic synthesis. Among the transformations
studied we published that imino compounds 2 cyclized on vigorous heating
to give sulphur, hydrogen chloride, and 2-cyanobenzothiazoles 3 (Sch. 1).[2]
In a search of new polyheterocyclic systems with potential pharmaco-
logical value, we showed that extension of the aromatic heterocyclic
moiety of the starting imines allowed the preparation of original thiazole
derivatives[3–7] which where inspired by natural marine alkaloids (e.g.,
Dercitine and Kuanoniamines) or by the terrestrial ellipticine. In all of
these synthesis the crucial step was the fusion of the thiazole ring with
various heterocyclic skeletons and the pharmaceutical development of
such promising compounds was limited due to the difficulty to scale up
the key step (this reaction was limited to 0.2 g of starting material). In
connection with our recent work on the utility of microwaves in organic
chemistry,[8–14] we decided to re-investigate the cyclization procedure of
the N-aryl iminodithiazoles into 2-cyanobenzothiazoles with the aim to
develop original and environmentally friendly procedures. In this article,
Cl
Cl
Cl
N
N
µ
w
NH2
N
S
R
+
S
R
+
S
N
-
S
1
Cl
2
CN
N
S
CN
3
R
+
R
Cl
4
Scheme 1. Synthesis of benzothiazoles 3 via N-arylimino-1,2,3-dithiazoles 2
thermolysis.

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2-Cyanobenzothiazoles via N-Arylimino-1,2,3-dithiazoles
3797
we report the benefits associated with the microwave methodology and we
study the opportunity to use solvent-free conditions in order to achieve
better yields and cleaner reactions that for the purely thermal processes.
RESULTS AND DISCUSSION
Using a standard method applied for the preparation of various
N-arylimino-1,2,3-dithiazoles, the starting anilines were condensed with
4,5-dichloro-1,2,3-dithiazolium chloride 1 (Appel salt) in dichloro-
methane at room temperature to give the desired imines 2 in good
yields (1, 2). Studying the chemistry of Appel salt 1 and its derivatives,
we previously showed that 5-(N-arylimino)-4-chloro-5H-1,2,3-dithiazoles
2, which are stable crystalline solids, cyclized by vigorous heating to
give sulfur, hydrogen chloride, and 2-cyanobenzothiazoles.[2] It was
also published that electron releasing group favored formation of the
benzothiazole 3 whilst a strongly electron withdrawing group reduced
the yield of 3 dramatically in favor of the cyanoimidoyl chloride 4
which became the major product.
The traditional thermolysis procedure consisted of heating the neat
imines 2 under argon at 200–250ꢀC with a metal bath for 1 or 2 min.[2]
The amount of starting material was limited to 0.2 g and the products
were usually accompanied by complicated mixtures of carbonaceous
compounds and impurities, which were difficult to eliminate.
In the course of our work on the synthesis of heterocyclic compounds
which possess a thiazole ring,[3–8] various methodologies under con-
ventional conditions or microwave (mw) irradiation where also developed
in our group: heating the imines 2 at 200ꢀC in the presence of biphenyl
ether (oil bath or mw),[6] at 140ꢀC (oil bath) for two or three days in sealed
tube in the presence of toluene,[8] exposing the neat imines to microwaves
in a glass vial with a screw-cap lid[8] or heating (oil bath or mw) the imines
in pyridine at reflux in the presence of pyridinium tribromide.[5]
Whatever method were used, the microwave procedures were more
rapid than the purely thermal processes but the amount of the desired
benzothiazoles 3 was constant (under 0.2 g of starting imine) and scaling
up (up to 0.2 g) the quantity of starting material led to lowest yields of
products, accompanied by complicated mixtures of carbonaceous
compounds and impurities which were difficult to eliminate even by
column chromatography or recrystallization.
Our previous experience in the use of microwave in organic
synthesis,[8–14] and our ambition to improve the pharmaceutical develop-
ment of our compounds, led us to check if there was any possibility for

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Frere, Thiery, and Besson
3798
improvement in the thermolysis reaction of the imines 2. Two routes were
investigated: the first one involved the use of polar solvents that by
themselves are good candidates for microwave heating. The second
solvent-free approach includes the use of a support, which may allow a
rapid a safe heating of the starting imines 2.
Microwave Experiments in the Presence of Solvent
Although the use solvents are not recommended for Eco-friendly
procedures and that hazards were associated with microwave heating
of organic solutions, we have previously showed that the use of homo-
geneous starting mixtures, in polar solvent, may have a benefit effect on
the scale up of various reactions under atmospheric pressure.[9] In order
to avoid release of flammable and toxic vapours our strategy consisted to
use a polar solvent which possess a high boiling point and may be rapidly
heated under microwave irradiation. Among all the solvents tested (N,N-
dimethylformamide: DMF, N,N-dimethylacetamide: DMA, sulfolane,
and tetrahydrofuran), N-methylpyrrolidin-2-one (NMP, bp: 204ꢀC) was
defined as the best candidate: it is less toxic than DMF and DMA and, in
comparison with sulfolane which is difficult to eliminate, it can be easily
removed from the reaction mixture by washing with water. The purifica-
tion of the crude product was then facilitated and it gave the attempted
compound in good yields (Table 1).
We have shown that 1 g of the imino-1,2,3-dithiazoles may be heated
in one step using this process. It allowed obtaining homogeneous
solutions, which may avoid the presence of carbonaceous compounds,
Table 1. Microwave synthesis of benzothiazoles 3.
Method A: 3 (1 g), N-methylpyrrolidin-2-one, mw (150ꢀC, 90 W )a
Reaction
time (min)
Yield of
product (%)
Starting imine 2 (R)
Product 3 (R)
(H)
(6-CH3)
a
b
c
d
e
(H)
(4-CH3)
1
2
1
1
3
49
55
48
58
64
(4-OCH3)
(2,5-diCH3)
(2,5-diOCH3)
(6-OCH3)
(4,7-diCH3)
(4,7-diOCH3)
aIn these experiments the amount of 4 was very low and the product difficult to
isolate.

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2-Cyanobenzothiazoles via N-Arylimino-1,2,3-dithiazoles
3799
and an interesting scaling up was expected. Unfortunately, enhancement
(up to 1 g) of the quantity of starting material gave worse results
(yields around 30%) and do not allowed to prepare the expected ben-
zothiazoles in good yields.
Microwave Experiments in Solvent-Free Conditions
The solvent-free technique has been claimed to be particularly
environmentally friendly, since it avoid the use of solvents, and an
easier work-up can be claimed if the support can be removed from the
reaction mixture simply by filtration. Graphite is one of the solids most
efficiently heated by microwave[15] and is also known for its adsorbing
properties of organic molecules. Inspired by a recent work on Friedel-
Crafts acylation reactions[16] with carbon graphite as support, we recently
showed that the strong thermal effect due to graphite/microwaves inter-
action can be efficiently use for the synthesis of various polyheterocyclic
molecules for which traditional methods failed or are less attractive.[10,11]
Our first approach was to adsorb the starting material on an excess of
graphite (3 equiv. by wt.) and to expose the powder obtained to micro-
waves at various times and power. The best conditions were performed at
150ꢀC by a strict power control (150 W) of the focused microwave
irradiation (Table 2).
We have observed that 1 g of the imino-1,2,3-dithiazoles may be
heated in one step using this process. Although it may avoid the presence
Table 2. Microwave synthesis of benzothiazoles 3.
Method B: 3 (5 g), graphite (0.5 g, 10% by wt.), mw (150ꢀC, 150 W )
Timea
Starting imine 2 (R) (min)
Product
3 (R)
Yield of
3 (%)
Product
4 (R)
Yield of
4
a
b
c
d
e
(H)
(4-CH3)
3
5
5
2
5
(H)
(6-CH3)
42
50
(H)
(6-CH3)
2
4
(4-OCH3)
(2,5-diCH3)
(2,5-diOCH3)
(6-OCH3)
(4,7-diCH3)
(4,7-diOCH3)
50b,c (6-OCH3)
3
49
52
(4,7-diCH3)
(4,7-diOCH3)
6
—
aReaction time.
bThe yield decreased (35%) in the presence of an excess of graphite (3 equiv.
by wt.), in 5 min with 1 g of starting material.
cNo modification of the yield (50–54%) with longer reaction times (20 or 30 min).

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Frere, Thiery, and Besson
3800
of carbonaceous compounds, the scale up of such a procedure was
rapidly limited. As described in the use of NMP, enhancement of the
quantity of starting material (up to 1 g) gave worse results and do not
allowed to prepare the expected benzothiazoles: the yields became low
and various impurities were detected in the final mixture. These results
may be linked with the difficulty to obtain a good temperature control at
the surface of the solid phase. In some of our experiments, we observed
that large quantity of graphite may lead to technical problems (hazardous
electric arcs and important local elevation of temperature) regarding
controllability and reproductibility (an other problem concern the
sublimation of one of the reactants which may be observed in some
experiments).
Following the strategy which consist to vary the ratio between the
quantity of the reactant and the support (graphite) and in connection
with our recent work on heterocyclic reactions with carbon graphite as
support[10,11] we discovered that a short (2–5 min) microwave irradiation
(150 W) of the starting imino-1,2,3-dithiazoles at 150ꢀC in the presence of
a small amount of graphite (10% by weight) afforded the attempted
2-cyanobenzothiazoles. Under similar experimental conditions (with
same quantity of starting material, graphite, and same reaction time), a
conventional heating allowed the products in very long time.
To our knowledge the use of graphite as fusion accelerator (which
assists the initial heating but does not react with other reactants) under
microwave irradiation was very rarely described. The yields calculated
are quite good, the process is reproducible and mutigrams quantity
(5–10 g) of the N-arylimino-1,2,3-dithiazoles can be heated in good
conditions.
The main interest to use small quantities of graphite is to facilitate
the work up procedures, avoiding filtration step (which avoid also the use
of solvents). The crude products obtained can be directly purified by
column chromatography, or, in some favorable cases, recrystallized in
the appropriate solvent.
N-Arylcyanoimidoyl Chlorides 4
In all the experiments performed, the yield of cyanoimidoyl chlorides
4 was quite constant (2–6%, see table). Working with highest quantity
(5 g) of the starting material allowed us to isolate and characterize
these by-products, a strategy that is particularly useful in research and
development activities.

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2-Cyanobenzothiazoles via N-Arylimino-1,2,3-dithiazoles
3801
CONCLUSION
In conclusion we have described a novel and productive eco-friendly
methodology of the synthesis of 2-cyanobenzothiazoles via the starting
N-arylimino-1,2,3-dithiazoles. In connection with our previous results,
we show that the strong thermal effect due to graphite/microwaves inter-
action can be efficiently use for the synthesis of heterocyclic molecules for
which traditional methods failed or are less attractive. This work also
confirm that working under focused microwave irradiation need a special
attention: (a) the ratio between the quantity of the material and the
support (e.g., graphite) may be very important, (b) the use of adapted
reactants offer operational, economical, and environmental benefits over
conventional methods.
The strategy described in this article is actually developed in our
group. Scale-up and technical transposition to various multi-step
synthesis are actually in course and will be published later.
EXPERIMENTAL SECTION
General
Commercial reagents were used as received without additional
purification. Melting points were determinate on a Kofler melting
¨
point apparatus and are uncorrected. Infrared spectra were obtained
on a Perkin-Elmer Paragon 1000PC FT-IR. 1H and 13C NMR were
recorded on a JEOL JNM LA 400 (400 MHz) spectrometer (Centre
´
Commun d’Analyses, Universite de La Rochelle). The mass spectra
(HRMS) were recorded on a Varian MAT 311 in the Centre Regional
´
´
de Mesures Physiques de l’Ouest (CRMPO, Universite de Rennes).
Analytical thin layer chromatography (tlc) was performed on Merck
60F-254 silica gel plates. Column chromatography was performed by
using Merck silica gel (70–230 mesh).
Focused microwave irradiations were carried out with
SynthewaveTM S402 (Prolabo) or CEM DiscoverTM focused micro-
wave reactor (300W, 2450 MHz, monomode system) which has in
situ magnetic variable speed rotation, irradiation monitored by PC
computer, infrared measurement and continuous feedback tempera-
ture control. Experiments may be performed at atmospheric pressure
or under pressure in pressure-rated reaction tubes with continuous
pressure measurement.

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Frere, Thiery, and Besson
3802
Synthesis of N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)
derivatives 2: General Procedure
Appel salt 1 (1.1 equiv.) was added to a solution of aniline derivative
(1 g) in dichloromethane (20 mL). The mixture was stirred at room tem-
perature for 2h and then washed twice with water (20 mL). The organic
layer was dried over MgSO4 and concentrated in vacuum. Purification by
column chromatography with light petroleum-dichloromethane as the
eluent afforded the title compounds 2a–e as stable yellow solids.
Synthesis of 2-Cyanobenzothiazoles: General Procedures
Method A: in the presence of solvent (NMP). N-Arylimino-1,2,
3-dithiazole 2 (1 g) was irradiated with N-methylpyrrolidin-2-one
(10 mL) as the solvent. The irradiation was programmed to maintain a
constant temperature (150ꢀC) with a maximal power output of 90 W. After
cooling, dichloromethane was added, the organic layer washed with water,
dried over MgSO4, and the crude product was purified by column
chromatography (silica gel) with light petroleum-dichloromethane as the
eluent.
Method B: with carbon graphite as fusion accelerator. Benzothiazoles
(5 g) were irradiated in the presence of graphite (0.5 g, 10 wt% to the
reactants). The irradiation was programmed to obtain a constant tem-
perature (150ꢀC) with a maximal power output of 150 W. After cooling,
the mixture was dissolved in dichloromethane and purified by column
chromatography (silica gel). Elution with light petroleum-ethyl acetate
gave the corresponding cyanoimidoyle chloride 4 followed by the
attempted benzothiazole 3.
Spectral data for N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) deriva-
tives 2 and benzothiazoles 3 and N-arylcyanoimidoyl chlorides 4 were
consistent with the assigned and previously published structures.[8,17]
Benzothiazole-2-carbonitrile (3a). White needles. M.p.: 80ꢀC (Lit.[1b]
78ꢀC). ꢀ/cmꢁ1 3080, 2230, 1684, 1550, 1460, 1318, 874, 763. H NMR
1
(CDCl3): ꢁ 8.24 (dd, 1H, J ¼ 7.0, 2.2 Hz), 8.00 (dd, 1H, J ¼ 7.0, 2.2 Hz),
7.65 (m, 2H). HRMS (EI): calcd. for C8H4N2S (Mþ): 160.0095. Found:
160.0091.
6-Methylbenzothiazole-2-carbonitrile (3b). Yellow needles. M.p.: 92ꢀC
(Lit.[1b] 88ꢀC). ꢀ /cmꢁ1 2940, 2228, 1607, 1560, 1474, 1316, 1244, 816.
1H NMR (CDCl3): ꢁ 8.10 (d, 1H, J ¼ 8.6 Hz), 7.76 (d, 1H, J ¼ 1.6 Hz),
7.46 (dd, 1H, J ¼ 8.6, 1.6 Hz). HRMS (EI): calcd. for C9H6N2S (Mþ):
174.0251. Found: 174.0252.

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2-Cyanobenzothiazoles via N-Arylimino-1,2,3-dithiazoles
3803
6-Methoxybenzothiazole-2-carbonitrile (3c). Yellow needles. M.p.:
126ꢀC (Lit.[8] 130ꢀC).ꢀ/cmꢁ1 3063, 3026, 2983, 2949, 2228, 1600, 1268,
833. 1H NMR (CDCl3): ꢁ 8.08 (d, 1H, J ¼ 9.2 Hz), 7.36 (d, 1H,
J ¼ 2.4 Hz), 7.24 (dd, 1H, J ¼ 9.2, 2.4 Hz). HRMS (EI): calcd for
C9H6N2OS (Mþ): 190.0201. Found: 190.0198.
4,7-Dimethylbenzothiazole-2-carbonitrile (3d). Yellow needles. M.p.:
90ꢀC. ꢀ/cmꢁ1 3018–2928, 2236, 1904, 1476, 1146, 836. 1H NMR (CDCl3):
ꢁ 7.35 (d, 1H, J ¼ 8.0 Hz), 7.30 (d, 1H, J ¼ 8.0 Hz), 2.75 (s, 3H). HRMS
(EI): calcd for C8H10N2S (Mþ): 188.0408. Found: 188.0414.
4,7-Dimethoxybenzothiazole-2-carbonitrile (3e). Yellow needles. M.p.:
174ꢀC (Lit.[4] 174ꢀC). ꢀ/cmꢁ1 2229, 1595, 1501, 1454, 1280, 1140, 1094,
1
1046, 969. H NMR (CDCl3): ꢁ 6.93 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H).
HRMS (EI): calcd for C10H8N2OS (Mþ): 220.0306. Found: 220.0303.
ACKNOWLEDGMENTS
We thank CEM Corp. (USA) for financial and technical support. We
´
also thank the Comite de Charente-Maritime de la Ligue Nationale contre
le Cancer for financial support. S. F. is thankful to the Communaute
´
´
d’Agglomeration de la Ville de La Rochelle for a research fellowship.
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Received in Poland March 18, 2003