Regioselective synthesis and ab initio calculations of fused heterocycles thermally and under microwave irradiation

Article abstract of DOI:10.1016/j.saa.2015.03.102

Pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-(thiophen-2-yl)-2-(phenylsulfo

Full text of DOI:10.1016/j.saa.2015.03.102

Accepted Manuscript
Regioselective Synthesis and ab initio Calculations of Fused Heterocycles Ther-
mally and under Microwave Irradiation
Mostafa E. Salem, Ashour A. Ahmed, Mohamed R. Shaaban, Mohamed F.
Shibl, Ahmad M. Farag
PII:
S1386-1425(15)00417-5
http://dx.doi.org/10.1016/j.saa.2015.03.102
SAA 13517
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomo-
lecular Spectroscopy
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Received Date:
Revised Date:
Accepted Date:
11 June 2014
16 March 2015
27 March 2015
Please cite this article as: M.E. Salem, A.A. Ahmed, M.R. Shaaban, M.F. Shibl, A.M. Farag, Regioselective
Synthesis and ab initio Calculations of Fused Heterocycles Thermally and under Microwave Irradiation,
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2015), doi: http://dx.doi.org/10.1016/j.saa.
2015.03.102
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Regioselective Synthesis and ab initio Calculations of Fused Heterocycles
Thermally and under Microwave Irradiation
Mostafa E. Salema, Ashour A. Ahmeda,b,c, Mohamed R. Shaabana,d, Mohamed F.
∗
Shible,f , Ahmad M. Faraga
a Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt.
b Institute of Physics, Rostock University, 18051 Rostock, Germany
c Steinbeis GmbH & Co. KG für Technologietransfer, 70174 Stuttgart, Germany
d Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah,
Saudi Arabia.
e Department of Materials Science and Engineering (MSE), Cornell University, Ithaca, NY 14853, USA
f Gas Processing Center, College of Engineering, Qatar University, P.O. Box 2713, Doha, Qatar
Abstract
Pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole,
pyrido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were
synthesized
via
the
reaction
of
3-(N,N-dimethylamino)-1-(thiophen-2-yl)-2-
(phenylsulfonyl)prop-2-en-1-one derivatives with the appropriate aminoazoles as 1,3-
binucleophiles and 1H-benzimidazol-2-ylacetonitrile using conventional methods as well as
microwave irradiation. The regioselectivity of the cyclocondensation reactions was confirmed
both experimentally by alternative synthesis of reaction products and theoretically using ab
initio quantum chemical calculations namely the Density Functional Theory (DFT). The
theoretical work was carried out using the Becke, three parameter, Lee-Yang-Parr hybrid
functional (B3LYP) combined with the 6-311++G(d,p) basis set. It was found that the final
cyclocondensation reaction product depends mainly on the initial addition to the activated
∗
Corresponding author: Mohamed Shibl
E-mail: mfshibl@cornell.edu
1

double bond by the nitrogen atom of the 1,3-binucleophiles that has the higher electron
density.
Keywords: Regioselectivity; DFT calculations; Cyclocondensation; Sulfones; Alterative
synthesis
Introduction
Sulfones1-2 are a versatile class of compounds due to their applications in many
pharmaceutical fields.3-9 They have attracted the attention of many authors and great efforts
have been made to develop new approaches to a variety of heterocycles incorporating
phenylsulfonyl moiety for biological screening. Moreover, sulfone moiety is usually
incorporated as an active part in many analgesic anti-inflammatory molecules available as
drugs in the market such as celecoxib,2,10 valdecoxib,11 rofecoxib,12 parecoxib,13 etoricoxib,14
tenoxicam,15 piroxicam,16 meloxicam,17 lornoxicam,18 ampiroxicam,19 and nimesulide.20,21-23
On the other hand, α-aminoazoles as 1,3-binucleophiles are quite important reagents in
modern heterocyclic synthesis, and their reactions with electrophiles are the most widespread
and facile synthetic approach to obtain diverse fused heterocyclic systems containing azole
moiety.24-26 In addition, aminoazoles and their ambident properties make them challenging
objectives for studying mechanisms of organic reactions and then tuning their
regioselectivity. The mostly investigated area of aminoazoles chemistry is their two
component reactions with ketoesters, β-dicarbonyls, α,β-unsaturated aldehydes/ketones and
enaminones yielding fused azoloazines.24-31 Moreover, multicomponent reactions (MCRs)
based on aminoazole building-blocks were covered in literature which are very promising for
combinatorial and medicinal chemistry as well as for diversity-oriented synthesis.32 In
continuation of our recent work aiming at the synthesis of heterocyclic systems with
remarkable biological importances,33-38 the utility of β-keto-β-sulfonylenamines as building
blocks for the synthesis of pyrazolo[1,5-a]pyrimidines, 1,2,4-triazolo[1,5-a]pyrimidines,
2

pyrimido[1,2-a]benzimidazole, and pyrido[1,2-a]benzimidazole under microwave irradiation
is reported. In this work, several aminoazoles as 1,3-binucleophiles, namely; 5-amino-1H-
pyrazoles 1, 3-amino-1,2,4-triazole (2), and 2-aminobenzimidazole (3) are used in
construction of the corresponding fused ring systems via their cyclocondensation with
enaminosulfone, (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)-prop-2-en-1-
one (5) as well as their MCR with the sulfone, 2-phenylsulfonyl-1-(thiophen-2-yl)-ethan-1-
one (4) and triethyl orthoformate as a CH-acid.
R1
NH2
NH2
N
N
N
NH2
N
N
N
H
R2
H
N
H
1
2
3
O
O
S
O
O
S
S
O
O
S
Me2N
4
5
The regioselectivity in such cyclocondensation reaction was examined using DFT
quantum chemical calculations. Geometry optimizations have been performed for
heterocyclic amines 1, 2, 3, and the enaminosulfone 5. The molecular geometries were fully
optimized using the gradient minimization technique. The minima are characterized by
having zero gradient norms and by diagonalizing the matrix of the second derivatives to give
positive harmonic vibrational frequencies. This was done using the Becke, three parameter,
Lee-Yang-Parr hybrid functional (B3LYP)39 combined with the 6-311++G(d,p) basis set.40
These calculations have been performed using the Gaussian09 program package.41 The partial
atomic charges on the first nucleophilic center N of NH2 and the second nucleophilic center
3

N of NH are calculated using Mulliken population analysis, atomic polar tensor (APT), and
electrostatic potential (ESP).
Results and discussion
The versatile, hitherto unreported (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-
2-yl)-prop-2-en-1-one (5) was readily obtained by refluxing equimolar quantities of 2-
phenylsulfonyl-1-(thiophen-2-yl)-ethan-1-one (4) and dimethylformamide dimethylacetal
(DMF-DMA), without solvent under microwave irradiation or in benzene under conventional
method as shown in scheme 1.
OCH3
Me2N
O
O
O
O
S
OCH3
MW/ solvent free
∆ /
S
S
O
O
S
or
Benzene
Me2N
5
4
Thermal Yield 80%
MW Yield 95%
Scheme 1
The structure of the enaminosulfone 5 was confirmed by its elemental analysis and
1
spectral data. For example, its H NMR spectrum displayed a singlet signal at δ 3.33 due to
N,N-dimethyl protons, a singlet signal at δ 7.91 due to olefinic proton, in addition to an
aromatic and thiophene ring multiplets in the region δ 7.15-7.96.
The reactivity of the enaminosulfone 5, in general, can be attributed to the delocalization
of the lone pair of electrons on NMe2 nitrogen (N) with the carbonyl carbon (C) as well as the
conjugation with the sulfone group, see Fig. 1. These delocalization and conjugation effects
result in two electron poor centers at N and C between which an electron rich carbon atom.
4

O
O
O
O
S
S
O
O
S
S
Me2N
Me2N
O
O
O
O
O
O
S
S
S
O
O
O
S
S
S
Me2N
Me2N
Me2N
Fig. 1. The tautomeric forms of the enaminosulfone (5).
When (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)-prop-2-en-1-one (5)
was treated with substituted 5-amino-1H-pyrazole derivatives 1a-c, either under refluxing
ethanol in the presence of a catalytic amount of piperidine or in pyridine under MW
irradiation, it afforded, the corresponding 6-(phenylsulfonyl)-7-(thien-2-yl)pyrazolo[1,5-
a]pyrimidine derivatives 7a-c (Scheme 2) in a good yield as shown in Table 1. In general, the
yields of the microwave synthesis are higher than the conventional heating as expected. The
structures of 7a-c were established on the basis of their elemental analyses and spectral data.
For example, the mass spectrum of compound 7a, revealed a molecular ion peak at m/z 451.
1
Its H NMR spectrum revealed a singlet signal at δ 7.52 due to pyrazole CH-3 proton and a
singlet signal at δ 9.18 (pyrimidine-CH-5), in addition to aromatic protons as a multiplet at δ
7.25-8.02. The formation of 7a-c is assumed to take place via an initial Michael-type addition
of the exocyclic amino group in aminopyrazoles 1a-c to α,β-unsaturated moiety in the
enaminosulfone 5, to yield the corresponding acyclic non-isolable intermediates 6a-c which
undergo intramolecular cyclization and aromatization into the final products 7a-c under the
reaction conditions (Scheme 2). The other expected product 8a-c was ruled out on the basis
of alternative synthesis of compounds 7a-c theoretical investigations. Thus, solvent free one-
pot, three component reaction of the sulfone 4, aminopyrazoles 1b (taken as a typical
5

example), and triethyl orthoformate, afforded product identical in all respects (m.p., mixed
m.p. and IR spectra) with the product obtained from the stepwise synthesis (Scheme 2).
R2
N
N
R1
O
N
S
S
O
8a-c
R1
H
N
R2
Me2N
Me2N
O
S
N
HN
R1
O
S
NH2
O
S
O
∆
Method A:EtOH/
+
O
Method C
: pyridine/ MW
N
O
H
R2
N
S
1a-c
5
6a-c
-Me2NH
-H2O
R1
N
O
R2
O
O
R1
NH2
N
S
N
S
S
∆
Method B: CH(OEt)3/
O
O
N
+
H
R2
S
N
R1 = H, R2 = Me, Yield =75%
7a-c
1a-c
4
MW Yield %
∆
Yield %
7
R1
H
R2
80
81
87
7a
7b
7c
C6H4Cl-p
CH3
65
67
68
H
Me
C6H5
Scheme 2
6

DFT calculations show that the electron density on the first nucleophilic center, N of NH2
(Nexocyclic), is more than that on the second nucleophilic center, N of NH (Nendocyclic), for the
optimized structure of aminopyrazole 1 (Fig. 2). This is valid for the three different types of
the population analyses, which have charges ratios of Nexocyclic to Nendocyclic nucleophilic
centers range from 2.0 to 4.9 (see Table 1). This leads the aminopyrazole 1 to attack the
enaminosulfone 5 (Fig. 3) via Nexocyclic nucleophilic center producing 6-(phenylsulfonyl)-7-
(thien-2-yl)pyrazolo[1,5-a]pyrimidine derivatives 7a-c. This can be elucidated through
analyzing the highest occupied molecular orbital (HOMO) of aminopyrazoles 1 (Fig. 2)
where the electron density on Nexocyclic nucleophilic center is more than that on Nendocyclic
.
Fig. 2. The optimized three-dimensional structure (A) and HOMO (B) for the compound 1.
7

Fig. 3. The optimized three-dimensional structure (A) and the lowest unoccupied molecular
orbital (LUMO), (B), for the compound 5.
Table 1: Different types of partial atomic charges, for compounds 1, 2, and 3, of the first and
second nucleophilic centers and their ratios.
atomic charge
APT
Nexocyclic/Nendocyclic charges ratio
Mulliken
-0.353
-0.100
-0.327
-0.301
-0.340
-0.276
ESP
Mulliken
APT
ESP
Nexocyclic
Nendocyclic
Nexocyclic
Nendocyclic
Nexocyclic
Nendocyclic
-0.586
-1.034
-0.210
-0.882
-0.520
-0.872
-0.706
compound 1
compound 2
compound 3
3.530
1.086
1.232
1.993
4.924
1.696
1.235
-0.294
-0.607
1.412
1.369
-0.430
-0.771
-0.563
8

Reaction of enaminosulfone 5 with 3-amino-1,2,4-triazole (2), in refluxing pyridine or
under microwave irradiation, afforded the corresponding 6-(phenylsulfonyl)-7-(thien-2-yl)-
1,2,4-triazolo[1,5-a]pyrimidine (10) (Scheme 3). The 1H NMR spectrum of the latter revealed
a singlet signal at δ 10.00 (triazole-CH-2) and a singlet signal at δ 8.91 (pyrimidine-CH-5), in
addition to aromatic protons as a multiplet in the region δ 7.12-7.87. The IR spectrum of the
same compound showed the absence of a band corresponding to carbonyl absorption. A
plausible mechanism for the formation of 10 is outlined in Scheme 3.
9

N
N
N
O
N
S
O
S
12
N
N
N
Me2N
NH2
O
S
O
O
Me2N
S
O
S
NH2
O
S
∆
Method A: Pyridine/
11
N
+
O
N
N
or
Method B: iPrOH/ MW
H
H
N
N
Me2N
N
2
5
O
S
HN
O
O
S
9
-Me2NH
-H2O
NH2
N
N
N
N
N
O
H
O
S
N
N
O
S
2
S
O
O
Method C: CH(OEt)3/ MW
S
4
10
Method A: Yield = 60 %
Method B:
Method C:
Yield = 83 %
Yield = 75 %
Scheme 3
The product 10 is assumed to be formed via an initial Michael-type addition of the amino
group of 2 (Nexocyclic) to the activated double bond in the enaminosulfone 5 followed by
elimination of dimethylamine and water molecules, from the non-isolable intermediate (9), to
afford the final product 10 as shown in Scheme 3. This proposed mechanism is in agreement
10

with the theoretical findings, where, according to ESP, the electron density on Nexocyclic
nucleophilic center is more than that on Nendocyclic nucleophilic center for the optimized
structure of (2) (charges ratio of first nucleophilic center to second one is 1.7), see Table 1
and Fig. 4. This directs aminotriazole 2 to bind the enaminosulfone 5 through Nexocyclic
nucleophilic center yielding 6-(phenylsulfonyl)-7-(thien-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine
(10).
Fig. 4. The optimized three-dimensional structure (A) and HOMO for aminotriazole (2).
In order to confirm this regioselectivity through alternative synthesis, the sulfone 4 was
allowed to react with aminotriazole 2, and triethyl orthoformate as one pot solvent free
reaction. The obtained product was found to be identical in all respects (m.p., mixed m.p. and
IR spectrum) with the product 10 obtained from the stepwise synthesis (Scheme 3).
In contrast to its behavior towards the aminopyrazole derivatives 1a-c and 3-amino-1,2,4-
triazole (2), the enaminosulfone 5 reacts with 2-aminobenzimidazole (3) in refluxing pyridine
under microwave irradiation or under conventional heat to afford only one isolable product
(as examined by TLC). The reaction product was identified as 3-(thiophen-2-yl)-2-
phenylsulphonylpyrimido[1,2-a]benzimidazole (13) (Scheme 4).
11

1
N
N
Method B
: CH(OEt)3/
∆
NH2
Yield = 65%
H
3
H
N
N
O
N
S
O
S
N
N
14
NH2
H
H
3
N
H
N
-Me2NH
-H2O
O
N
S
O
Me2N
∆
Method A: pyridine/ , yield = 52%
S
O
S
O
S
Method C
: pyridinel MW, yield = 72%
13
O
H
N
H
N
5
CN
N
N
O
S
CN
O
H
S
15
-Me2NH
-H2O
16
∆,
Method A: pyridine/ yield = 46%
CN
Method C:pyridinel MW, yield = 63%
H
S
N
O
N
O
S
17
N
N
Method B
∆
: CH(OEt)3/
CN
Yield = 57%
H
15
4
Scheme 4
12

The spectral data of the isolated product 13 are in complete agreement with the assigned
structure. For example, its IR spectrum revealed no bands due to amino or carbonyl
1
functions. Moreover, its H NMR spectrum revealed an aromatic multiplet in the region δ
7.11-8.63, in addition to a singlet signal at δ 10.30 due to pyrimidine-CH-1.
The formation of compound 13 is assumed to take place via an initial Michael-type
addition of the imino function (Nendocyclic) in compound 3 to the double bond in the
enaminone 5 as shown is (Scheme 4). Theoretical calculations show that the electron density
on the first nucleophilic center is comparable to that on the second nucleophilic center for the
optimized structure of 2-aminobenzimidazole 3. For ESP, charges ratio of first nucleophilic
center to second one is 1.2. This small atomic partial charges difference between the first and
the second nucleophilic centers, disable our decision for the direction of the reaction.
Therefore, it is important to look deeply for the HOMO of 2-aminobenzimidazole 3, which is
responsible for electron donation. Fig. 5 shows that the electron density is close to the second
nucleophilic center (NH) than the first one (NH2). This enhances the attack via the second
nucleophilic center of 2-aminobenzimidazole (3) to the enaminosulfone 5 yeilding 3-
(thiophen-2-yl)-2-phenylsulphonyl pyrimido[1,2-a]benzimidazole (13).
13

Fig. 5. The optimized three-dimensional structure (A) and HOMO for compound 2-
aminobenzimidazole (3).
The cyclocondensation product 14 could be obtained by solvent free one pot three
component reaction of the sulfone 4, 2-aminobenzimidazole (3) and triethyl orthoformate as
shown in Scheme 4. The reaction product was identified as 3-(phenylsulfonyl)-2-(thiophen-2-
yl) pyrimido[1,2-a]benzimidazole (14) (Scheme 4). The spectral data of the isolated product
14 are in complete agreement with the assigned structure. For example, its IR spectrum
1
revealed no bands due to amino or carbonyl functions. Moreover, its H NMR spectrum
revealed an aromatic multiplet in region δ 5.88-8.10, in addition to a singlet signal at δ 9.41
(pyrimidine-CH-1). The difference between the structures 13 and 14 is distinguishable from
the values of the chemical shifts of the pyrimidine-CH where the structure 14 showed higher
value (δ 10.30) than that of other possible regioisomer 13 which may be attributed to the
magnetic anisotropy effect of the adjacent benzene ring as shown in the Fig. 6.
14

Fig.6. Aromatic region of the 1H NMR spectra of regioisomers 13 and 14.
In similar manner, the enaminosulfone 4 reacts with 1H-benzimidazol-2-yl acetonitrile
(15), in refluxing pyridine, to afford only one isolable product identified as 3-(thiophen-2-yl)-
2-phenylsulphonylpyrido[1,2-a]benzimidazole-4-carbonitrile (16) and not the other possible
regioisomer 17 (Scheme 4).
The structure of reaction product 16 was assigned on the basis of its elemental analysis
and spectral data. For example, its IR spectrum exhibited a characteristic absorption band at
2130 cm-1 due to a nitrile function and revealed the absence of absorption band corresponding
to carbonyl group. Moreover, its 1H NMR spectrum revealed an aromatic multiplet in region
δ 5.89-8.07, in addition to a singlet signal at δ 8.93 (pyridine-CH-4). These results ruled out
the existence of the other isomeric product which contain pyridine-CH-2. The latter expected
to resonate at higher chemical shifts as shown in Fig. 7.
15

CN
δ
8.6 ppm
H
N
N
H
N
4
δ
> 10.0 ppm
N
CN
17
16
Fig. 7. Comparison between pyridine-2-CH and pyridine-4-CH protons chemical shifts in the
regioisomers 16 and 17.
Also, the other expected product 17 was ruled out on the basis of an alternative synthesis
of compound 16. Thus, solvent free one pot three component reaction of the sulfone 1, 1H-
benzimidazol-2-ylacetonitrile (15), and triethyl orthoformate, afforded product identical in all
respects (m.p., mixed m.p. and IR spectra) with the product 15 obtained from the stepwise
synthesis (Scheme 4).
Experimental
All melting points were measured on a Gallenkamp melting point apparatus. The infrared
spectra were recorded in potassium bromide discs on a Pye Unicam SP 3–300 and Shimadzu
FT IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded on a Varian
Mercury VXR-300 NMR spectrometer (1H NMR (300 MHz) and 13C NMR (75.46 MHz))
were run in deuterated chloroform (CDCl3) or dimethyl sulfoxide (DMSO-d6). Chemical
shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-
QP1000 EX mass spectrometer at 70 eV. Elemental analyses were carried out at the Micro-
analytical Centre of Cairo University, Giza, Egypt and recorded on Elementar-Vario EL
automatic analyzer. Microwave irradiation was performed using the Discover system of
CEM.
16

Synthesis of (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-
on (5)
Thermal method
To a solution of 2-(Phenylsulfonyl)-1-(thiophen-2-yl)ethanone (4) (26.6 g, 100 mmole) in
dry benzene (150 ml) was added dimethylformamide-dimethylacetal (DMF-DMA) (11.9 g,
100 mmol) and the mixture was refluxed for 8 h. The solvent was distilled off under reduced
pressure and the residual reddish brown viscous liquid was taken in petroleum ether (20 ml)
and the resulting orange crystal was collected by filtration, washed thoroughly with ether,
dried and finally recrystallized from dry benzene to afford the (E)-3-(dimethylamino)-2-
(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-one (5) in (80% yield), m.p 150°C.
Microwave method (MW)
To a solution of 2-(Phenylsulfonyl)-1-(thiophen-2-yl)ethanone (4) (2.66 g, 10 mmole) was
added dimethylformamide-dimethylacetal (DMF-DMA) (11.9 g, 100 mmol) and the mixture
was mixed in a process vial. The vial was capped properly and irradiated by microwaves
o
under pressurized conditions (17.2 bar, 110 C) for 20 min. The reaction mixture was
evaporated in vacuo and the residual solid was taken in ether, washed with ether and dried
and finally recrystallized from dry benzene to afford the (E)-3-(dimethylamino)-2-
(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-one (5) in (95% yield), m.p 150°C, The
physical and spectral data of the synthesized compound are listed below.
IR (KBr) νmax/cm–1: 1655 (C=O), 1585 (C=N). 1H NMR (DMSO-d6): δ 3.33 (s, 6H,
N(CH3)2), 7.15 (d, 1H), 7.48-7.57 (m, 4H, ArH’s), 7.78 (d, 2H, ArH’s), 7.91 (s, 1H, =CH-
N), 7.96 (d, 1H, ArH), . MS (m/z): 321 (M+). Analysis for C15H15NO3S2: Calcd: C, 56.05; H,
4.70; N, 4.36. Found: C, 56.19; H, 4.51; N, 4.20%
17

Synthesis of pyrazolo[1,5-a]pyrimidine derivatives (7a-c)
Thermal methods:
Method A
General procedure:
To a mixture of (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-
one (5) (3.21 g, 10 mmol) and the appropriate aminopyrazole derivative 1a-c (10 mmol), in
absolute ethanol (25 ml), few drops of piperidine was added and the reaction mixture was
refluxed for 6h then left to cool. The solid product was filtered off, washed with ethanol and
recrystallized from EtOH/DMF to afford the corresponding pyrazolo[1,5-a]pyrimidine
derivatives 7a-c in 65-68% yield.
Method B
General procedure:
A solution of sulfone (4) (3.21 g, 10 mmol) and an equivalent molar ratio of the
appropriate aminopyrazole derivative 1a-c and triethyl orthoformate (10 mL), was heated
under reflux for 4 h. The excess triethyl orthoformate was removed by distillation under
reduced pressure and the residue was left to cool. The precipitated solid product was
collected by filtration, washed with ethanol, dried and finally recrystallized from DMF/EtOH
to afford the corresponding pyrazolo[1,5-a]pyrimidine derivatives 7a-c, respectively.
Microwave method (MW):
Method C
General procedure:
A mixture of the enaminosulfone 5 (3.21 g, 10 mmol) and the appropriate aminopyrazole
derivative 1a-c (10 mmol) in pyridine (10 ml) was mixed in a process vial. The vial was
capped properly and irradiated with microwaves under pressurized conditions (17.2 bar, 130
oC) for 20 min. The reaction mixture was evaporated in vacuo and the residual solid was
18

taken in ethanol, filtered off and dried and finally recrystallized from DMF/EtOH to afford
the corresponding pyrazolo[1,5-a]pyrimidine derivatives 7a-c in 80-87% yield.
2-(4-Chlorophenyl)-6-(phenylsulfonyl)-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine
(7a)
1
–1
Yield 70%; mp. 248-250˚C. IR (KBr) νmax /cm : 1607 (C=N). H NMR (DMSO-d6): δ
7.25 (d, 1H, ArH), 7.44 (t, 2H, ArH’s), 7.51-7.62 (m, 5H, ArH’s), 7.52 (s, 1H, pyrazole-3-
CH), 7.95 (d, 2H, ArH’s), 8.02 (d, 2H, ArH’s), 9.18 (s, 1H, pyrimidine-5-CH). MS (m/z):
451 (M+, 100%), 453 (M++2, 45%). Analysis for C22H14ClN3O2S2: Calcd: C, 58.47; H, 3.12;
N, 9.30 % Found: C, 58.24; H, 3.01; N, 9.65%
2-Methyl-6-(phenylsulfonyl)-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine (7b)
1
–1
Yield 68%; mp. 251-253˚C. IR (KBr) νmax /cm : 1620 (C=N). H NMR (DMSO-d6): δ
2.36 (s, 3H, CH3), 6.79 (s, 1H, pyrazole-3-CH), 7.20 (d, 1H, ArH), 7.39-7.49 (m, 5H,
ArH’s), 7.58 (t, 1H, ArH), 7.95 (d, 1H, ArH), 9.11 (s, 1H, pyrimidine-5-CH). MS (m/z):
355 (M+, 100%). Analysis for C17H13N3O2S2: Calcd: C, 57.45; H, 3.69; N, 11.82. Found: C,
57.39; H, 3.61; N, 11.68%
3-Methyl-2-phenyl-6-(phenylsulfonyl)-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine
(7c)
1
–1
Yield 69%; mp. 220-221˚C. IR (KBr) νmax /cm : 1604 (C=N). H NMR (DMSO-d6): δ
2.48 (s, 3H, CH3), 7.22 (d, 1H, ArH), 7.37-7.53 (m, 9H, ArH’s), 7.62 (t, 1H, ArH), 7.70 (d,
1H, ArH), 7.98 (d, 1H, ArH), 9.16 (s, 1H, pyrimidine-5-CH). MS (m/z): 431 (M+, 100%).
Analysis for C23H17N3O2S2: Calcd: C, 64.02; H, 3.97; N, 9.74. Found: C, 64.19; H, 3.81; N,
9.68%
19

Synthesis of triazolo[1,5-a]pyrimidine derivative (10)
Thermal method:
Method A
To a mixture of (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-
one (5) (3.21 g, 10 mmol) and 3-amino-l,2,4-triazole (2) (10mmol) in pyridine (25 ml) was
refluxed for 12 h, then left to cool. The excess pyridine was evaporated in vacuo and the
residual solid was taken in ethanol then collected by filtration, washed several times with
water, dried and finally recrystallized from DMF/H2O to afford the corresponding
triazolo[1,5-a]pyrimidine (10).
Microwave methods (MW):
Method B
A mixture of the enaminosulfone 5 (3.21g, 10 mmol) and 3-amino-l,2,4-triazole (2) in
isopropyl alcohol (10 ml) was mixed in a process vial. The vial was capped properly and
o
irradiated with microwaves under pressurized conditions (17.2 bar, 90 C) for 20 min. The
reaction mixture was evaporated in vacuo and the residual solid was taken in ethanol, filtered
off and dried and finally recrystallized from ethanol to afford the corresponding triazolo[1,5-
a]pyrimidine (10).
Method C
A mixture of the sulfone 4 (3.21g, 10 mmol) and 3-amino-l,2,4-triazole (2) and triethyl
orthoformate (10 mL) was mixed in a process vial. The vial was capped properly and
o
irradiated with microwaves under pressurized conditions (17.2 bar, 100 C) for 20 min. The
reaction mixture was evaporated in vacuo and the residual solid was taken in ethanol, filtered
off and dried and finally recrystallized from ethanol to afford the corresponding triazolo[1,5-
a]pyrimidine (10).
6-(Phenylsulfonyl)-7-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (10)
20

1
–1
Yield 74%; mp. 280-282 ˚C. IR (KBr) νmax /cm : 1612 (C=N). H NMR (DMSO-d6): δ
7.12 (d, 1H, ArH), 7.44(t, 2H, ArH’s), 7.74 (m, 4H, ArH’s), 7.87 (d, 1H, ArH), 8.91 (s, 1H,
pyrimidine-5-CH),10.00 (s, 1H, triazole-2-CH). MS (m/z): 342 (M+, 100%). Analysis for
C15H10N4O2S2: Calcd: C, 52.62; H, 2.94; N, 16.36. Found: C, 52.42; H, 2.99; N, 16.47%
Synthesis of pyrimido[1,2-a]benzimidazoles 13, 14 and pyrido[1,2-a]benzimidazole
derivative (17)
(A)-Thermal method:
Method A
General procedure:
To a mixture of (E)-3-(dimethylamino)-2-(phenylsulfonyl)-1-(thiophen-2-yl)prop-2-en-1-
one (5) (3.21 g, 10 mmol) and the appropriate 2-aminobenzimidazole (3) or 2-cyano-
methylbenzimidazole (15) (10mmol) in pyridine (25 ml) was refluxed for 12 h, then left to
cool. The solvent was evaporated in vacuo and the residual solid was taken in ethanol then
collected by filtration, washed with water, dried and finally recrystallized from DMF/H2O to
afford the corresponding pyrimido[1,2-a]benzimidazole or pyrido[1,2-a]benzimidazole
derivatives (13) and (17), respectively.
Method B
A solution of and 2-aminobenzimidazole (3) or 2-cyano-methylbenzimidazole (15)
(10mmol) in triethyl orthoformate (10 mL) and sulfone (4) (10 mmol) was heated under
reflux for 6 h. The excess triethyl orthoformate was removed by distillation under reduced
pressure and the residue was left to cool. The precipitated solid product was collected by
filtration, washed with ethanol, dried and finally recrystallized from DMF/ H2O to afford the
corresponding pyrimido[1,2-a]benzimidazole and pyrido[1,2-a]benzimidazole derivatives
(14) and (17), respectively.
21

(B)-Microwave method (MW):
General procedure:
A mixture of the enaminosulfone 5 (3.21 g, 10 mmol) and the appropriate 2-
aminobenzimidazole (3) or 2-cyano-methylbenzimidazole (15) (10 mmol) in pyridine (10 ml)
was mixed in a process vial. The vial was capped properly and irradiated with microwaves
o
under pressurized conditions (17.2 bar, 130 C) for 20 min. The reaction mixture was
evaporated in vacuo and the residual solid was taken in ethanol, filtered off and dried and
finally recrystallized from ethanol to afford the corresponding pyrimido[1,2-a]benzimidazole
or pyrido[1,2-a] benzimidazole derivatives (13) and (17), respectively. The physical and
spectral data of the synthesized compounds (13), (14) and (17) are listed below
3-(Phenylsulfonyl)-4-(thiophen-2-yl)pyrimido[1,2-a]benzimidazole (13)
1
–1
Yield 81%; mp. 225 ˚C. IR (KBr) νmax /cm : 1620 (C=N). H NMR (DMSO-d6): δ 7.11
(d, 1H, ArH), 7.43 (t, 2H, ArH’s), 7.51-7.89 (m, 6H, ArH’s), 7.90 (d, 1H), 7.92 (d, 1H,
ArH), 8.64 (d, 1H, ArH), 10.30 (s, 1H, pyrimidine-1-CH). MS (m/z): 391 (M+, 99%).
Analysis for C20H13N3O2S2: Calcd: C, 61.36; H, 3.35; N, 10.73. Found: C, 61.52; H, 3.22; N,
10.57%
3-(phenylsulfonyl)-2-(thiophen-2-yl) pyrimido[1,2-a]benzimidazole (14)
1
–1
Yield 81%; mp. 268 ˚C. IR (KBr) νmax /cm : 1622 (C=N). H NMR (DMSO-d6): δ 5.88
(d, 1H), 7.10 (t, 1H, ArH), 7.13 (d, 1H, ArH), 7.34 (t, 1H, ArH), 7.48 (t, 2H, ArH’s), 7.60 (d,
1H, ArH), 7.67 (t, 2H, ArH’s), 7.89 (d, 1H, ArH), 8.10 (d, 1H, ArH), 9.41 (s, 1H,
pyrimidine-1-CH). MS (m/z): 391 (M+, 99%). Analysis for C20H13N3O2S2: Calcd: C, 61.36;
H, 3.35; N, 10.73. Found: C, 60.12; H, 3.32; N, 10.57%
2-(Phenylsulfonyl)-3-(Thiophen-2-yl)pyrido[1,2-a]benzimidazole-4-carbonitrile (17)
22

1
–1
Yield 85%; mp. 240 ˚C. IR (KBr) νmax/cm : 2130 (C≡N), 1615 (C=N). H NMR
(DMSO-d6): δ 5.89 (d, 1H), 7.11-7.13 (m, 4H, ArH’s), 7.32 (t, 1H, ArH), 7.50-7.59 (m, 2H,
ArH’s), 7.66 (t, 1H, ArH), 7.81 (d, 1H, ArH), 7.97 (t, 1H, ArH), 8.07 (d, 1H, ArH) 8.93 (s,
1H, pyridine-1-CH). MS (m/z): 415 (M+, 100%). Analysis for C22H13N3O2S2: Calcd: C,
63.60; H, 3.15; N, 10.11. Found: C, 63.62; H, 3.02; N, 10.33%
Conclusions
In conclusion we synthesized a variety of fused heterocyclic systems consolidating
phenylsulfonyl moiety via the reaction of 3-(N,N-dimethylamino)-1-(thiophen-2-yl)-2-
(phenylsulfonyl)prop-2-en-1-one derivatives with the suitable 1,3-binucleophiles using
conventional methods as well as microwave irradiation. Furthermore, a theoretical account on
the regioselectivity of the cyclocondensation reactions was carried out using DFT concerted
with B3LYP/6-311++G(d,p) combination. The newly synthesized fused heterocycles
encompass the advantage that they can be easily synthesized on large scales from inexpensive
starting materials and we believe that they are useful compounds with potentially high
pharmacological and biological activities. This contribution pinpoints that the final
cyclocondensation reaction product relied essentially on the nitrogen electron density of the
1,3-binucleophiles that initially attacks the activated double bond.
Supporting information (SI)
Electronic Supporting Information (SI) is available including the original NMR charts of
compounds 5, 7a-c, 10, 13, 14 and 17.
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25

Highlights
• Biologically important heterocyclic systems have been synthesized from inexpensive
starting materials.
• Microwave irradiation in addition to the conventional methods have been used in the
synthesis.
• The regioselectivity of this cyclocondensation reaction has been revealed by DFT
calculations.
• The reaction product is dependent on the nitrogen electron density of the 1,3-
binucleophiles.
26

27