Efficient, microwave-mediated synthesis of benzothiazole- and benzimidazole-based heterocycles Ahmed F. Darweesh 1 • Ahmed E. M. Mekky 1,2 • Amani A. Salman 1 • Ahmad M. Farag 1 Received: 27 May 2015 / Accepted: 12 September 2015 / Published online: 24 September 2015 Ó Springer Science+Business Media Dordrecht 2015 Abstract 1-(Benzothiazol-2-yl)-3-(N,N-dimethylamino)-2-(phenylsulfonyl)prop- 2-en-1-one (3) and 1-(1-methylbenzimidazol-2-yl)-3-(N,N-dimethylamino)-2- (phenylsulfonyl)prop-2-en-1-one (4) were obtained from the reaction of 1-(ben- zothiazothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benz- imidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) with N,N-dimethylformamide dimethyl acetal, respectively. The enaminosulfones 3 and 4 were used as versatile building blocks for the synthesis of novel pyrazolo[1,5-a]pyrimidine and [1,2,4]- triazolo[1,5-a]pyramidine derivatives via their reactions with the appropriate aminopyrazoles and aminotriazole under both microwave and thermal reaction conditions. They have been also utilized as reactive synthons for the construction of novel pyrimido[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole, pyrimidine, isoxazole and pyrazole heterocycles pendent to benzothiazole and benzimidazole ring systems. Keywords Enaminosulfone Á Benzimidazole Á Benzothiazole Á Pyrazolo[1,5-a]pyrimidine Á [1,2,4]-Triazolo[1,5-a]pyramidine Á Pyrimido[1,2-a]benzimidazole Á Pyrido[1,2-a]benzimidazole Introduction Benzothiazole and benzimidazole ring systems are recognized as important heterocycles due to their diverse pharmacological properties [1, 2]. Their derivatives have attracted continued interest because of their varied biological activities [3–11]. & Ahmad M. Farag [email protected]; [email protected]1 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt 2 Chemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203, Jeddah 21589, Saudi Arabia 123 Res Chem Intermed (2016) 42:4341–4358 DOI 10.1007/s11164-015-2279-8
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Efficient, microwave-mediated synthesisof benzothiazole- and benzimidazole-based heterocycles
Ahmed F. Darweesh1 • Ahmed E. M. Mekky1,2 •
Amani A. Salman1 • Ahmad M. Farag1
Received: 27 May 2015 / Accepted: 12 September 2015 / Published online: 24 September 2015
On the other hand, enaminones are considered reactive intermediates that are
versatile for the synthesis of a great variety of heterocycles and aromatic compounds
[12–15]. Their structural features constitute many compounds of anticonvulsive [16]
and anti-histaminergic activities [17]. In addition, b-ketosulfones are readily
available from a variety of precursors and display a broad range of synthetic
versatility [18–21]. In addition, microwave irradiation assists in development and
enhancement of organic synthesis [22–25]. In continuation of a research program
directed towards the synthesis of a variety of heterocycles for biological evaluation
[26–37], we report here on the utility of the enaminosulfone derivatives 3 and 4 as
versatile intermediates, for the synthesis of new heterocyclic derivatives incorpo-
rating benzothiazole and benzimidazole moieties of biological and pharmacological
importance.
Results and discussion
The enaminones 3 and 4 were readily obtained by the reaction of equimolar
quantities of 1-(benzothiazothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) or 1-(1-
methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) with N,N-
dimethylformamide dimethyl acetal in toluene at reflux or under microwave
conditions (Scheme 1). The structures of compounds 3 and 4 were established from
their elemental analyses and spectral data. For example, the proton nuclear magnetic
resonance (1H NMR) spectrum of compound 4 displayed a singlet signal at
3.05 ppm due to N,N-dimethyl protons, a singlet signal at 4.02 ppm due to an N-
methyl group, a singlet at 7.87 ppm due to an olefinic proton, in addition to an
aromatic multiplet in the region 7.35–8.03 ppm.
The reactivity of the enaminosulfones 3 and 4, in general, can be attributed to the
fact that they have two electron-poor centers at C-1 and C-3, in addition to one
electron-rich center at C-2 due to the delocalization of the lone pair of electrons on
the nitrogen atom beside conjugation with the sulfone group.
Thus, treatment of the enaminones 3 and 4 with N-benzoylglycine in acetic
anhydride at reflux temperature or under microwave conditions, led to the formation
of products identified as N-(6-(benzothiazol-2-yl)-2-oxo-5-(phenylsulfonyl)-2H-
pyran-3-yl)benzamide (10) and N-(6-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-5-
(phenylsulfonyl)-2H-pyran-3-yl)benzamide (11), respectively (Scheme 2). The
Scheme 1 Synthesis of the enaminones 3 and 4
4342 A. F. Darweesh et al.
123
infrared (IR) spectra of the isolated products showed, in each case, two strong
absorption bands at 1699 and 1672 cm-1, due to two carbonyl groups and a strong
absorption band at 3410 cm-1 due to the function of NH. Their mass spectra
showed, in each case, a peak corresponding to the molecular ion. The 1H NMR
spectrum of compound 11 revealed a singlet signal at 4.02 ppm due to N-methyl
Scheme 2 Synthetic route to the compounds 10 and 11
Scheme 3 Synthetic routes to pyrazolo[1,5-a]pyrimidine derivatives 17a–d and 18a–d
Efficient, microwave-mediated synthesis of benzothiazole… 4343
123
protons, a singlet signal at 6.30 ppm due a proton of the oxopyran ring and a
multiplet signal in region of 7.51–8.14 ppm due to aromatic protons.
When the enaminone derivatives 3 and 4 were treated with substituted 5-amino-
1H-pyrazole derivatives 12a–d in ethanol (EtOH) in the presence of a catalytic
amount of piperidine at reflux temperature or microwave conditions, they afforded
the corresponding pyrazolo[1,5-a]pyrimidine derivatives 17a–d and 18a–d, respec-
tively, in almost quantitative yields (Scheme 3). The 1H NMR spectrum of
compound 17a showed a singlet signal at 9.25 ppm due to a pyrimidine CH-5
proton in addition to aromatic protons as a multiplet at 7.44–8.38 ppm. The IR
spectrum of the same product revealed no peak due to carbonyl absorption. The IR
spectrum of compounds 17d and 18d revealed, in each case, a band at 2194 cm-1
due to CN absorption (see ‘‘Experimental’’ section). The structures of compounds
17a–d and 18a–d were further supported by their independent synthesis from the
reaction of compounds 1 and 2 with the heterocyclic amines 12a–d and triethyl
orthoformate in the presence of a catalytic amount of piperidine in a one pot
reaction, which afforded products identical in all respects [melting point (m.p.),
mixed m.p., and IR spectra)] with those obtained from the reaction of enaminones 3and 4 with 5-amino-1Hpyrazole derivatives (Scheme 3).
Similarly, the enaminosulfones 3 and 4 reacted with 4-arylazo-3,5-diaminopy-
razoles 19a,b under the same experimental conditions, to afford the corresponding
polysubstituted pyrazolo[1,5-a]pyrimidines 22a,b and 23a,b, respectively
(Scheme 4). The structures of products 22a,b and 23a,b were established on the
basis of their elemental analyses and spectral data (see ‘‘Experimental’’ section).
Scheme 4 Synthesis of pyrazolo[1,5-a]pyrimidines 22a,b and 23a,b
4344 A. F. Darweesh et al.
123
The enaminones 3 and 4 reacted also with 3-amino-1,2,4-triazole (24) in
refluxing pyridine to afford 2-(6-phenylsulfonyl-[1,2,4]-triazolo[1,5-a]pyrimidin-7-
yl)benzothiazole (27) and 7-(1-methyl benzimidazol-2-yl)-6-(phenylsulfonyl)-
[1,2,4]-triazolo[1,5-a]pyrimidine (28), respectively (Scheme 5). The 1H NMR
spectrum of compound 27 revealed a singlet signal at 9.11 ppm due to a pyrimidine
CH-5 proton in addition to aromatic protons as a multiplet in the region of
7.21–8.13 ppm. The IR spectrum of the same compound revealed the absence of a
band corresponding to a carbonyl group. A plausible mechanism for the formation
of compounds 27 and 28 is outlined in (Scheme 5). Compounds 27 and 28 were
assumed to be formed via an initial Michael-type addition of the amino group of
3-amino-1,2,4-triazole (24) to the activated double bond in enaminones 3 and 4followed by elimination of dimethylamine and water molecules from the non-
isolable intermediates 25 and 26 to afford the final products 27 and 28, respectively
(Scheme 5).
In contrast to its behavior towards the aminoheterocycles 12a–d, 19a,b and 24,
the enaminones 3 and 4 reacted with 2-aminobenzimidazole (29) in refluxing
pyridine or under microwave conditions to afford, in each case, only one isolable
Scheme 5 Synthetic routes to fused ring heterocycles 27, 28, 32, 33, 37, and 38
Efficient, microwave-mediated synthesis of benzothiazole… 4345
123
product [as examined by thin-layer chromatography (TLC)]. The reaction products
were identified as 3-(benzothiazol-2-yl)-2-(phenylsulfonyl)pyrimido[1,2-a]benzim-
idazole (32) and 3-(1-methylbenzimidazol-2-yl)-2-(phenylsulfonyl)pyrimido[1,2-
a]benzimidazole (33), respectively (Scheme 5). The spectral data of the isolated
products 32 and 33 were in complete agreement with the assigned structures. For
example, the IR spectra of 32 and 33 revealed no absorption bands due to amino or
carbonyl functions. Moreover, their 1H NMR spectra revealed an aromatic multiplet
in the region 7.45–8.75 ppm and a singlet signal at 9.21 ppm due to a pyrimidine
proton. The formation of compounds 32 and 33 was assumed to take place via an
initial Michael-type addition of the imino function (endocyclic nitrogen) [38, 39] in
compound 29 to the double bond in the enaminones 3 and 4 to give the acyclic non-
isolable intermediates 30 and 31, respectively, which undergo intramolecular
cyclization via the loss of dimethylamine and water molecules to afford the final
products 32 and 33 (Scheme 5).
In a similar manner, the enaminones 3 and 4 reacted with 1H-benzimidazol-2-yl-
acetonitrile (34) in refluxing pyridine to afford, in each case, only one isolable
product (as examined by TLC). The reaction products were identified as
(Scheme 6). The IR spectra of the reaction products showed two absorption bands
near 3367 and 3120 cm-1 due to an amino group. Plausible mechanisms for the
formation of compounds 42 and 43 are outlined in Scheme 6. When the enaminones 3and 4 were treated with hydroxylamine at reflux or under microwave conditions, they
afforded, in each case, only one isolable product. The isolated products were identified
as 3-(benzothiazol-2-yl)-4-(phenylsulfonyl)isoxazole (46) and 3-(1-methylbenzimi-
azol-2-yl)-4-(phenylsulfonyl)isoxazole (47), respectively (Scheme 6). The IR spectra
of the isolated products revealed, in each case, no bands due to amino or carbonyl
functions. Moreover, the 1H NMR spectra of compounds 46 and 47 revealed, in each
case, a singlet signal at 8.87 ppm due to an isoxazole proton, in addition to an aromatic
multiplet in the region 7.38–8.14 ppm.
Similarly, the enaminones 3 and 4 underwent cyclocondensation upon treatment
with hydrazine hydrate or phenylhydrazine in acetic acid at room temperature (rt),
or under microwave conditions to afford 2-(1H-pyrazol-3-yl)-4-(phenysulfonyl)ben-
idazole (34) [42] were prepared following procedures in the literature.
Reactions of 1-(benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2)with N,N-dimethylformamide dimethyl acetal
Method A (thermal)
General procedure To a solution of 1-(benzothiazothiazol-2-yl)-2-phenylsulfonyl-
1-ethanone (1) or 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-etha-
none (2; 100 mmol), in dry toluene (150 mL), was added N,N-dimethylformamide
dimethyl acetal (13.4 g, 100 mmol) and the mixture was refluxed for 8 h. The solvent
was removed at reduced pressure and the residual reddish-brown viscous liquid was
taken in petroleum ether (bp. 60–80 �C, 20 mL). The resulting golden-yellow crystal
was collected by filtration, washed thoroughly with ether, dried and finally
recrystallized from dry benzene to afford the 1-(benzothiazol-2-yl)-3-(N,N-dimethy-
lamino)-2-(phenylsulphonyl)prop-2-en-1-one (3) and 1-(1-methylbenzimidazol-
General procedure An ethanolic solution of the appropriate enaminones 3 or 4(10 mmol) and N-benzoylglycine (1.7 g, 10 mmol) was mixed in a process vial. The
vial was capped properly and irradiated with microwave under 17.2 bar, at 80 �Cfor 20 min, The reaction mixture was concentrated in vacuo and the solid product,
obtained upon cooling, was filtered off, washed with EtOH, dried and recrystallized
from DMF to afford the corresponding 2H-pyran-3-yl-benzamide derivatives 10 and
General procedure A solution of guanidine nitrate (1.73 g, 14.2 mmol) in
absolute EtOH (15 mL) was added to a solution of the appropriate enaminones 3or 4 (11.3 mmol) in boiling absolute EtOH (10 mL) with stirring for 20 min. To this
mixture, was added sodium ethoxide solution (22.6 mmol) in absolute EtOH
(10 mL) and the reaction mixture was refluxed for 16 h. The solution was allowed
to cool to rt and the precipitated solid was removed by filtration. The filtrate was
concentrated under reduced pressure. The solid product was collected by filtration,
washed with water, dried and finally recrystallized from DMF to afford the
2-aminopyrimidine derivatives 42 and 43, respectively.
Method B (microwave)
General procedure The appropriate enaminones 3 or 4 (2 mmol), guanidine
nitrate (2.3 mmol) in EtOH (3 mL), and anhydrous potassium carbonate (4 mmol)
were mixed in a process vial. The vial was capped properly and irradiated with
microwaves under conditions of 17.2 bars, at 130 �C for 20 min. The reaction
mixture was allowed to cool to rt then diluted with water (20 mL). The formed solid
product was collected by filtration, washed with water and dried. Recrystallization
from DMF afforded 2-aminopyrimidine derivative 42 and 43, respectively.