Utility of sulphones in heterocyclic synthesis: Synthesis of some pyridine, chromene and thiophene derivatives

Article abstract of DOI:10.3390/50500701

Phenylsulfonylacetonitrile (1) when reacted with α,β-unsaturated nitriles (2a,b) and/or 2-hydroxynaphthaldehyde yields pyridine derivatives (3a,b) and / or the imino-chromene derivative (4) respectively. The behavior of (1) towards some α-halogenated compounds has been investigated.

Full text of DOI:10.3390/50500701

Molecules 2000, 5, 701-709
molecules
ISSN 1420-3049
http://www.mdpi.org
Utility of Sulphones in Heterocyclic Synthesis: Synthesis
of Some Pyridine, Chromene and Thiophene Derivatives
A. A. Fadda1*, Hala M. Refat2 and M. E. A. Zaki3
1Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
E-mail: sinfac@mum.mans.eun.eg
2Department of Chemistry, Faculty of Education, Suez Canal University, Al-Arish, Egypt
3National Research Cente Dokki, Cairo, Egypt
Fax: 002023370931, E-mail: mzaki@nrc.sci.eg
* Author to whom correspondence should be addressed.
Received: 3 August 1999; revised form: 13 October 1999 / Accepted: 13 October 1999 / Published: 5 May 2000
Abstract: Phenylsulfonylacetonitrile (1) when reacted with a ,b-unsaturated nitriles (2a,b)
and/or 2-hydroxynaphthaldehyde yields pyridine derivatives (3a,b) and / or the imino-
chromene derivative (4) respectively. The behavior of (1) towards some a -halogenated
compounds has been investigated.
Keywords: Phenylsulfonylacetonitrile, pyridine derivatives, chromene derivatives, thio-
phene derivatives.
Introduction
This work is the continuation of a program with the aim to develop new simple methods for the
synthesis of functionally substituted heterocycles with anticipated biological activity. We have recently
extended it to include the investigation of the pharmacological aspects of the newly synthesized he-
terocycles based on the finding that some heterocycles can achieve activity in both the pharmacologi-
cal and pesticidal areas, e.g. thiabenzdazole, the well known human and veterinary anthelmentic, is
also used as a fungicide [1,2].
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
Results and Discussion
Pyridines and chromene derivatives have recently received considerable attention due to their syn-
thetic and pharmaceutical importance and different approaches for their synthesis have been developed
[3,5a-c]. In the last few years the authors have been exploring the synthetic potential, scope, and limi-
tations of activated nitriles in heterocyclic synthesis [6-8]. Several new approaches for the synthesis of
five and six membered rings and their fused heterocyclic derivatives have been developed during this
work [9,10]. In the present work we explore the synthetic potential of phenylsulfonyl-acetonitrile (1) to
form polysubstituted pyridines and chromene heterocycles via the reaction of 1 with a ,b-unsaturated
nitriles (2a,b) and 2-hydroxynaphthaldehyde respectively.
Thus, compound 1 reacts under TEA catalysis with a ,b-unsaturated nitriles (2a,b) in refluxing
ethanol to afford 2-amino-3-phenylsulfonyl-4-aryl-5-carbonitrile pyridines 3a,b as coloured solid
products [11]. The IR spectrum of these products showed in each case, absorption bands at n 3350-
3400, 2220, and 1610 cm-1 corresponding to NH2, CN, and C=N groups respectively. Structures 3a,b
were assigned to these products on the basis of the spectral as well as analytical data (cf. Table 1). The
1H-NMR spectrum of 3a revealed a broad singlet at d 6.5 ppm assigned to the amine protons and a
multiplet at d 7.8- 8.4 ppm assigned to the pyridine-2H and aromatic protons.
O
S
CN
CN
r
A
C
N
Ar
O
a, Ar = C H -NO -P
H N
N
6
4
2
2
( 2 a, b )
b, Ar = C H -2,3,4-triOCH
6 2
3
( 3a, b )
O
S
CH
CN
2
O
O
CH
HCl
O
S
O
O
S
O
( 1 )
OH
O
NH
O
O
( 4 )
Scheme 1.
( )
5
Compound (1) reacts with 2-hydroxy naphthaldehyde in refluxing ethanol in the presence of TEA to
give 2-imino-3-phenylsulfonyl-benzo[f]chromene (4) in high yield. Mass spectral measurements and
analytical data are in complete agreement with structure 4 (M+ 335). Moreover, the resulting coumarin
derivatives have latent functional substituents, which have the potential for further chemical transfor-
mations giving new routes for the preparation of substituted coumarin derivatives with possible bio-
logical activity. 3-Phenylsulfonyl-2H-benzo[f]-2-chromenone (5) was synthesized via hydrolysis of (4)
in a mixture of conc. hydrochloric acid and ethanol. The mass spectrum of (5) showed the expected
molecular formula C19H12O4S (M+ 336).

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Molecules 2000, 5
Previously, we investigated the reaction of phenyl isothiocyanate with active methylene compounds
in alkaline medium, which has proved to be a convenient route for the synthesis of thiazole, pyrazole,
oxazine and pyrimidine ring systems[7]. Now, we have extended our synthetic program to the synthe-
sis of otherwise inaccessible heterocyclic ring systems, utilizing phenyl isothiocyanate as a key starting
material. It is known that a great variety of reactants bearing the N=C=S fragment undergo cyclization
on reaction with a -halocarbonyl compounds to afford thiazoles, 2,3-dihydrothiazoles and thiazolidines
[12], which have been shown to exhibit local anaesthetic [13], antiprotozoal [14] and fungicidal pro-
perties [15]. In this paper, we describe a generally applicable extension of this synthetic approach, first
reported by Hantzsch and Weber [16]. Thus, the base-prompted reaction of the acidic methylene com-
pound 1 with phenyl isothio-cyanate in dry DMF at room temperature yields the non-isolable interme-
diate 6. Treatment of 6 with a -chloroacetamide in boiling DMF yielded a product (8), which analyzed
correctly for C17H15N3O3S2. The structure 8 was inferred from its spectral data. Thus, the IR spectrum
showed absorption bands at n 3450, 3150, 1661, 1550, 1270 and 1180 cm-1 corresponding to NH2, NH,
1
C=O, Ph and SO2 functions and the absence of a CN stretching band. Its H-NMR spectrum showed a
broad singlet at d 5.5- 6.2 ppm (4H), two multiplet signals integrated for (10 H) centered at 7.4 and 8.0
(aromatic protons) and a singlet (1H) at 8.6. On shaking the compound with D2O, the broad band sig-
nals at d 5.5- 6.2 ppm and 8.6 disappeared . Based on the foregoing data, structure 8 was assigned to
this product. The structure of 8 was further confirmed by its alternative synthesis. Thus, it was found
that, treatment of 6 with a -chloroacetamide in refluxing ethanol produced the acyclic intermediate 7.
Structure 7 was suggested for the reaction product on the basis of both elemental and spectral analysis.
The IR spectrum showed the presence of a cyano absorption band at n 2220 cm-1, NH2, NH and C=O
(amidic) functions at n 3340, 3150 and 1680 cm-1 respectively. Refluxing 7 in ethanol with a few drops
of TEA led to the formation of a product identical in all respects (m.p., mixed m.p., IR, 1H-NMR) to 8.
O
S
O
S
O
S
/
ClCH CONH
2
2
CN
NaOEt/DMF
room temp.
NH
2
CH2
CN
+
Ph-N=C=S
O
O
DMF
O
S
CONH
2
Ph
Ph
HN
Na
S
HN
( 1 )
( 6 )
(
)
8
ClCH CONH
2
EtOH
2
EtOH,
TEA
O
S
C = N
O
CONH
2
S
Ph
HN
( 7 )
Scheme 2.
The intermediate 6 also undergoes in-situ cyclization upon the reaction with equimolar amounts of
phenacyl bromide in boiling ethanol and a catalytic amount of TEA, giving a yellow colored product
(10). The phenylsulfonyl thiophene structure 10 was suggested for this product on the basis of analyti-
cal and spectral data (cf. Table 1). The mass spectrum of 10 showed molecular formula C23H18N2O3S2

704
Molecules 2000, 5
(M+ = 434). The reaction may occur through the non-isolable intermediacy of a cyclic derivative (9).
Attempts to isolate 9 by refluxing phenacyl bromide with the intermediate 6 in ethanol were unsuc-
cessful. Compound 10 is assumed to be formed via the acyclic intermediate 9.
Compound 6 reacted readily with chloroacetone in boiling ethanol to afford the acyclic intermediate
11 by NaCl elimination. Refluxing 11 in ethanol with a catalytic amount of TEA, gave the thiophene
derivative 12 whose structure was confirmed by elementary analysis and spectral data. (cf. Table 1).
The structure of 12 was further confirmed by its alternative synthesis. Thus, refluxing 6 with chloro-
acetone in DMF affords the thiophene derivative 12 in reasonably good yield. Similarly, when the in-
termediate 6 is treated with chloroacetonitrile in refluxing ethanol the corresponding acyclic interme-
diate 13 is exclusively isolated in good yield. The structure of 13 has been confirmed on the basis of
elemental and spectral data. e.g. the IR spectrum exhibits bands at n 3200 (NH), 2220, 2195 cm-1 (two
cyano). Its 1H-NMR spectrum reveals a CH2 signal at d 3.23 ppm. Furthermore, heating of the interme-
diate 13 in ethanol containing a catalytic amount of TEA affords the thiophene derivative 14. The thio-
phene structure 14 was established based on its IR spectrum which showed bands related to NH2, NH
1
and CN functions. Its H-NMR spectrum reveals a multiplet at (d ppm) 7.31-7.56 (10 H, aromatic),
broad signals at d 6.5 (2H, NH2) and d 8.7 ppm (1H, NH). On the other hand, it has been found that it
is directly formed by refluxing 6 and chloroacetonitrile in DMF.
O
S
O
S
C = N
S
NH
PhCOCH Br
2
2
O
O
EtOH, TEA
S
COPh
COPh
Ph
Ph
Ph
Ph
HN
HN
( 9 )
( 10 )
O
O
S
C = N
S
S
NH
2
ClCH COCH
2
3
EtOH
TEA
O
O
EtOH
.
OCH
C
S
3
COCH
HN
Ph
3
HN
( 11 )
( 12 )
( 6 )
O
S
O
S
C = N
S
ClCH CN
2
NH
CN
EtOH
TEA
2
O
O
EtOH
S
CN
HN
Ph
HN
( 13 )
( 14 )
or
ClCH COCl
2
O
S
O
S
C = N
S
NH
EtOH
TEA
COOC H
2 5
ClCH COOH or
2
2
O
O
BrCH COOC H /
2
2 5
S
COOEt
Ph
HN
Ph
HN
EtOH
(
)
15
( 16 )
Scheme 3.

705
Molecules 2000, 5
When 6 was treated with an equimolar amount of chloroacetyl chloride or with chloroacetic acid in
boiling ethanol, a product that analyzed for C19H18N2O4S 2 was isolated in each case in good yield. The
acyclic structure 15 was established based on its IR spectrum that showed bands related to NH, CN
1
and CO functions. Its H-NMR spectrum reveals a multiplet at (d ppm) 7.5- 8.56 (10 H, aromatic), a
triplet signal at d 1.3 (3H, CH3), singlet at d 3.7 ( 2H ), quartet at d 4.3 ( 2H, CH2) and a D2O exchange-
able NH at 8.91 ppm. Alternatively, treatment of 6 with ethyl bromoacetate in refluxing ethanol gives a
single product, which is identical in all respects to 15 (m.p., mixed m.p. and IR spectrum). The mass
spectrum of 15 showed a molecular formula C19H18N2O4S2 (M+ = 402). Refluxing of 15 in ethanol with a
catalytic amount of TEA afforded the corresponding thiophene derivative 16 [16] (cf. Table 1).
Conclusion
We report a facile route for the formation of pyridines, chromenes and thiophene derivatives based
on sulfones.
Experimental
General
All melting points are uncorrected. FTIR spectra (KBr disk) were recorded on a Nicolet Magna-IR
1
model 550 spectrophotometer, H NMR spectra in CDCl3 were determined on a Brucker WPSY 200
MHZ spectrometer with TMS as internal standard, and the chemical shifts are in d ppm. Mass spectra
were recorded at 70 ev with a Varian MAT 311
Synthesis of pyridine derivatives (3a,b). General procedure
A mixture of phenylsulfonylacetonitrile (1) (0.01 mol), a ,b-unsaturated nitriles 2a,b (0.01 mol) and
catalytic amounts of TEA in ethanol (15 mL) were refluxed for 6 h. The solid product obtained after
cooling was filtered off and recrystallized from ethanol to give the pyridine derivatives 3a,b (cf. Table
1).
Synthesis of 2- imino-3-phenylsulfonyl-2H-benzo[ f ]chromene (4)
A mixture of phenylsulfonylacetonitrile (1) (0.01 mol), 2-hydroxy-1-naphthaldehyde (0.01 mol) and
a catalytic amount of TEA in ethanol (15 mL) was refluxed for 2 h. The solid product iminochromene
4 obtained after cooling was recrystallized from ethanol. (cf. Table 1).

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Molecules 2000, 5
Synthesis of 3-phenylsulfonyl-2H-benzo[ f ]-2-chromenone (5)
3-Phenylsulfonyliminochromene (4) (0.01 mol) was heated in a mixture of conc. HCl and ethanol
(1:1, 20 mL) for 15 min. The reaction mixture was left to stand at room temperature overnight, and the
solid product was filtered and recrystallized from ethanol to give (5).
Preparation of compound (6)
To a stirred suspension of sodium ethoxide (0.23 g, from 0.01 mol sodium and 10 mL ethanol) in
DMF (20 mL), phenylsulfonyl acetonitrile (0.01 mol) was added. To the resulting solution the phenyl
isothiocyanate (0.01 mol) was added and the reaction mixture stirred for 24 h. at room temperature.
Synthesis of the acyclic intermediates 7, 11, 13 and 15. General procedure
Equimolecular quantities of 6 in ethanol and a a -chloroacetamide and/or chloroacetone and/or chlo-
roacetonitrile and/or ethyl bromoacetate were stirred for 6 hr. at room temperature, then left to stand at
the same temperature for 24 h. The reaction mixture was washed with water, dried and crystallized
from ethanol to give 7, 11, 13 and 15 respectively (cf. Table 1).
Synthesis of thiophene derivatives (10)
A mixture of equimolecular amounts of 6 and phenacyl bromide (0.01 mol) was refluxed in ethanol
(20 mL) containing a catalytic amount of TEA for 6 h. The reaction mixture was cooled, filtered and
recrystallized from ethanol to give 10 (cf. Table 1).
Synthesis of thiophene derivatives ( 8, 12, 14 and 16 )
Method A
A mixture of equimolecular amounts of 6, and a -halo compounds (0.01 mol) was refluxed in DMF
(20 mL) for 6 h. The reaction mixture was cooled, filtered and recrystallized from ethanol to give the
corresponding thiophene derivatives. (cf. Table 1).
Method B
Refluxing the acyclic intermediate (7, 11, 13 and/or 15) in ethanol (20 mL) containing a catalytic
amount of TEA for 3 h. afforded the corresponding substituted thiophene derivatives 8, 12, 14 and 16
respectively.

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Molecules 2000, 5
Table 1. Characterization of the newly prepared compounds.
No.
3a
Yld
%
Mol.
formula
Analysis
Calcd. ( Found %)
Characterization
mp°
C
C
56.71
H
3.14
(56.84) (3.15)
N
180
78
C18H12N4O4S
(380.38)
14.71
(14.73)
IR: 3350- 3450 (NH2), 2220 (CN),
1610cm-1 (C=N); 1H-NMR (CDCl3) d
6.5 (s, 2H, NH2 exchangeable with
D2O,), 7.8-8.4 (m, 9H, Ar-H), 8.5 (s,
1H, o-Py-H); MS: (m/z) 380 M+.
IR: 3350- 3450 (NH2), 2220 (CN),
1610cm-1 (C=N); 1H-NMR (CDCl3) d
3.8 (s, 3H, OCH3), 3.9 (s, 3H, OCH3),
4.0 (s, 3H, OCH3), 7.1 (d, 2H, NH2,
exchangeable with D2O), 7.7-8.0 (m,
6H, Ar-H), 8.5 (s, 1H, o-Py-H); MS:
(m/z) 425 M+ .
125
83
C21H19N3O5S
(425.47)
59.10
4.43
(59.29) (4.47)
9.87
(9.88)
3b
225
267
219
90
98
85
C19H13NO3S
(335.38)
68.00
3.84
(68.05) (3.88)
4.15
(4.17)
IR: 3150 (NH), 1650 (C=N), 1561cm-
1 (Ph); 1H-NMR (CDCl3) d 7.3- 8.5
(m, 11H, Ar-H), 8.8 (s, 1H, NH ex-
changeable with D2O), 9.2 (s, 1H, C4-
H); MS: (m/z) 335 M+ .
4
5
7
IR: 1700 (g-Lactone), 1555cm-1 (Ph);
1H-NMR (CDCl3) d 7.55- 8.25 (m,
9H, Ar-H), 8.4 (d, J=8.1 Hz, 1H, C9-
H), 8.45 (d, J=8.1 Hz,1H, C10-H), 9.2
(s, 1H, C4-H); MS: (m/z) 336 M+ .
IR: 3340 (NH2), 3150(NH), 2220
C19H12O4S
(336.37)
67.69
3.56
(67.85) (3.57)
C17H15N3O3S2
(373.46)
54.55
4.00
(54.69) (4.02)
11.24
(11.26) (CN), 1680cm-1 (C=O, amidic); 1H-
NMR (CDCl3) d 3.7(s, 2H, CH2), 6.2
(br, 2H, CONH2 exchangeable with
D2O), 7.2-7.98 (m, 10H, Ar-H), 9.25
(s, 1H, NH exchangeable with D2O);
MS: (m/z) 373 M+ .
145
154
62
88
C17H15N3O3S2
(373.46)
45.51
(45.50) (4.02)
4.01
11.23
IR: 3450 (NH2), 3150(NH), 1661
8
(11.26) (CO), 1550 (Ph), 1270, 1180cm-1
(SO2); 1H-NMR (CDCl3) d 5.5 (br,
2H, NH2 exchangeable with D2O), 6.2
(br, 2H, CONH2 exchangeable with
D2O), 7.4-8.0 (m, 10H, Ar-H), 8.6 (s,
1H, NH exchangeable with D2O);
MS: (m/z) 373 M+
C23H18N2O3S2
(434.54)
63.50
(63.59) (4.14)
4.12
6.43
(6.45)
IR: 3463 (NH2), 3194(NH), 1720
(CO), 1587cm-1 (Ph); 1H-NMR
(CDCl3) d 6.5 (br, 2H, NH2 ex-
changeable with D2O), 7.3-8.1 (m,
15H, Ar-H), 9.22 (s, 1H, NH ex-
changeable with D2O); MS: (m/z)
434 M+ .
10

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Molecules 2000, 5
Continuation of the Table 1.
No.
11
Yld
%
Mol.
formula
Analysis
Calcd. ( Found %)
Characterization
mp°
C
C
58.00
H
4.29
(58.06) (4.30)
N
7.50
(7.52)
190
94
C18H16N2O3S2
(372.47)
IR: 3287(NH), 2220 (CN), 1730
(CO), 1603 cm-1 (Ph); 1H-NMR
(CDCl3) d 2.3 (s, 3H, CH3), 3.7 (s,
2H, CH2), 7.16-7.97 (m, 10H, Ar-H),
9.25 (s, 1H, NH exchangeable with
D2O); MS: (m/z) 372 M+ .
165
88
C18H16N2O3S2
(372.47)
58.10
(58.06) (4.30)
4.28
7.51
(7.52)
IR: 3456 (NH2), 3288 (NH), 1730
(CO), 1603cm-1 (Ph); 1H-NMR
(CDCl3) d 2.14 (s, 3H, CH3), 5.3 (br,
2H, NH2 exchangeable with D2O),
7.26-7.96 (m, 10H, Ar-H), 9.25 (s,
1H, NH exchangeable with D2O);
MS: (m/z) 372 M+
12
188
158
80
66
C17H13N3O2S2
(355.44)
57.33
(57.46) (3.66)
3.65
11.82
(11.83)
IR: 3200 (NH), 2220, 2195 (two CN),
1603 cm-1 (Ph); 1H-NMR (CDCl3) d
3.23 (s, 2H, CH2), 7.12-7.87 (m, 10H,
Ar-H), 9.25 (s, 1H, NH exchangeable
with D2O); MS: (m/z) 355M+ .
IR: 3456 (NH2), 3266 (NH), 2220
13
14
C17H13N3O2S2
(355.44)
57.29
(57.46) (3.66)
3.63
11.81
(11.83) (CN), 1603cm-1 (Ph); 1H-NMR
(CDCl3) d 6.5 (br, 2H, NH2 ex-
changeable with D2O), 7.31-7.96 (m,
10H, Ar-H), 8.7 (s, 1H, NH ex-
changeable with D2O); MS: (m/z)
355M+ .
248
152
93
86
C19H18N2O4S2
(402.49)
56.66
(56.71) (4.47)
4.46
6.95
(6.96)
IR: 3278(NH), 2220 (CN), 1730 cm-1
(CO); 1H-NMR (CDCl3) d 1.3 (t,
J=2.5 Hz, 3H, CH3), 3.7 (s, 2H, CH2),
4.3 (q, J=2.5Hz, 2H, CH2), 7.5- 8.56
(m, 10H, Ar-H), 9.25 (s, 1H, NH ex-
changeable with D2O); MS: (m/z)
402 M+ .
IR: 3448 (NH2), 3243(NH), 1730
(CO), 1603cm-1 (Ph); 1H-NMR
(CDCl3) d 1.26 (t, J= 2.5 Hz, 3H,
CH3), 4.22 (q, J=2.5Hz, 2H, CH2),
6.55 (br, 2H, NH2 exchangeable with
D2O), 7.18-7.96 (m, 10H, Ar-H), 9.25
(s, 1H, NH exchangeable with D2O);
MS: (m/z) 402 M+ .
15
16
C19H18N2O4S2
(402.50)
56.70
(56.71) (4.47)
4.45
6.94
(6.96)

709
Molecules 2000, 5
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Samples Availability: available from the authors.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.