Regioselective synthesis of a new class of N-arylsulfonylaminated biheterocycles

Article abstract of DOI:10.1080/10426500307914

A novel and efficient method for the synthesis of a new variety of novel N-arylsulfonylamino derivatives of biheterocycles by the reaction of N-cyanoaceto-arylsulphonylhydrazides with α,β-unsaturated nitriles. The synthetic potential of the method is demonstrated.

Full text of DOI:10.1080/10426500307914

This article was downloaded by: [Linnaeus University]
On: 06 October 2014, At: 06:58
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Regioselective Synthesis of a New Class of N -
Arylsulfonylaminated Biheterocycles
Galal Hamza Elgemeie a & Shahinaz Hassan Sayed a
a Helwan University , Ain-Helwan, Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: Galal Hamza Elgemeie & Shahinaz Hassan Sayed (2003) Regioselective Synthesis of a New Class of N -
Arylsulfonylaminated Biheterocycles, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:3, 465-473
To link to this article: http://dx.doi.org/10.1080/10426500307914
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur and Silicon, 2003, Vol. 178:465–473
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390170598
REGIOSELECTIVE SYNTHESIS OF A NEW CLASS
OF N-ARYLSULFONYLAMINATED BIHETEROCYCLES
Galal Hamza Elgemeie and Shahinaz Hassan Sayed
Helwan University, Ain-Helwan, Cairo, Egypt
(Received May 10, 2002; accepted July 21, 2002)
A novel and efficient method for the synthesis of a new variety of novel
N-arylsulfonylamino derivatives of biheterocycles by the reaction of
N-cyanoaceto-arylsulphonylhydrazides with , -unsaturated nitriles.
The synthetic potential of the method is demonstrated.
Keywords: 2-pyridones; N-cyanoaceto-arylsulphonylhydrazides; N-
aminated-2-pyridones; unsaturated nitriles
INTRODUCTION
Recently, we have undertaken a comprehensive study of N-alkylated
pyridines and related compounds and have reported the synthesis of
new N-substitutedamino-2-pyridones.1–3 The synthetic applications of
cyanoacetyl-N-arylsulfonylhydrazides 2 as reaction intermediate for
the synthesis of a variety of interesting N-sulfonatedaminoheterocycles
has aroused considerable interest during the last decade.4–7 Since these
compounds have been shown to constitute a new class of antimetabo-
lites, it was of interest to evaluate synthetic methods for preparation
of their analogues and demonstrate the effects of various structural
Address correspondence to G. H. Elgemeie, Chemistry Department, Faculty of Sci-
ence, Helwan University, Ain-Helwan, Cairo, Egypt. E-mail: elgemeie@hotmail.com
465

466
G. H. Elgemeie and S. H. Sayed
modification on biological activity. To this end, the present investiga-
tion reports the synthesis of novel N-arylsulfonylamino derivatives of
biheterocycles. As far as we know this is the first class of this type to
be reported for N-substituted-aminopyridines.
DISCUSSION
It has been found that cyanoacetohydrazide 1 reacts with arenesul-
fonyl chlorides in ethanol to afford the corresponding cyanoacetyl-N-
arylsulfonylhydrazides 2 in good yields. Compounds 2 reacted with
-(2-furanyl)- and -(2-thienyl)acrylonitrile derivatives 3a–d in reflux-
ing ethanol containing catalytic amounts of piperidine to give the cor-
responding N-arylsulfonylamino-2-pyridones 6a–h. The structures of
6 were established on the basis of elemental analysis and spectral
1
data (MS, IR, H NMR). Thus, structure 6c is supported by its mass
spectrum which showed a molecular ion corresponding to the formula
1
C17H11N5S2O3 (M+ = 397). The H NMR spectrum contained a mul-
tiplet at = 7.27–7.96 ppm assigned to the thiophene and aromatic
protons, a broad band at = 8.5 ppm assigned to an amino function,
and a broad singlet at = 8.84 ppm assigned to the NH group. The
13C NMR spectra were characterized by a signal at = 168.8 ppm cor-
responding to the carbonyl carbon atom. The formation of 6 from 2
and 3a–d is assumed to proceed via addition of the active methylene
group of 2 to the double bond of 3 to give the intermediates 4. This
Michael adduct then cyclizes to give the intermediate dihydropyridines
5, which is oxidized under the reaction conditions to give the novel
N-arylsulfonylamino-2-pyridone derivatives 6. Compounds 6 also could
be prepared by the reaction of the reported N-amino-2-pyridones 88
with arenesulfonyl chlorides in ethanol containing catalytic amounts
of piperidine at room temperature for 24 h. The course of the reaction
between the N-cyanoacetylarylsulphonylhydrazides 2 and 3 prompted
us to investigate this reaction between 2 and 3 under other basic re-
action conditions. In contrast, it has been found that compounds 3
reacted with ethyl furfurylidene- and thiophenylidenecyanoacetates
3c,d in refluxing pyridine for 1 h to yield a product for which the
N-arylsulphonylamino-6-hydroxy-2-pyridones 10a–d were assigned.
Each structure of compounds 10 was established on the basis of ele-
mental analysis and spectral data. The formation of 10 from 2 and 3c,d
is assumed to proceed via addition of the active methylene group of 2 to
the double bond of 3 to give intermediate acyclic adducts, which were
cyclized via ethanol elimination to give the intermediate dihydropy-
ridines 9. The laters are oxidized under the reaction conditions to yield

Synthesis of N-Arylsulfonylaminated Biheterocycles
467
CHART 1
the novel N-arylsulphonylamino-6-hydroxy-2-pyridone derivatives 10.
In order to investigate the scope of this reaction further we studied
the reaction of 2 with furfurylidene- and thiophenylidene derivatives
of ketonitriles. Thus, it has been found that compounds 2 reacted with

468
G. H. Elgemeie and S. H. Sayed
CHART 2

Synthesis of N-Arylsulfonylaminated Biheterocycles
469
CHART 3

470
G. H. Elgemeie and S. H. Sayed
furfurylidene- and thiophenylidene derivatives of benzoylacetonitrile
3e,f in refluxing pyridine to yield the N-sulphonylaminated pyridones
13. The structures of 13 were established on the basis of their ele-
mental analysis and spectral data. Thus, structure 13a is supported
1
by its H NMR spectroscopy which revealed a multiplet at = 7.00–
7.80 ppm assigned to the furan and aromatic protons and a broad singlet
at = 11.90 ppm assigned to the NH proton.
CONCLUSION
We have achieved a regiospecific synthesis of interesting N-sulfonated
aminopyridines by the reaction of cyanosulphonylhydrazides with , -
unsaturated nitriles. The compounds obtained seem promising for fur-
ther chemical transformations and biological evaluation studies.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were obtained (KBr disc)
1
on a Pye Unicam instrument. H NMR spectra were measured on a
Varian 400 or Wilmad 270 MHz spectrometer for solutions in (CD3)2SO
using SiMe4 as internal standard. Mass spectra were recorded on a
Varian MAT 112 spectrometer. The analytical data were obtained from
the Microanalytical Data Center at Cairo University. Compounds 3
were prepared through a Knoevenagel condensation of 2-furfuraldehde
or 2-thiophenaldehyde with malononitrile, ethyl cyanoacetyate or ben-
zoylacetonitrile, respectively. Compounds 8 were prepared following
literature procedures.8
Cyanoacetyl-N-arylsulfonylhydrazides (2a,b)
A mixture of cyanoacetohydrazide 1 (0.99 g, 0.01 mmol) and arenesul-
fonyl chloride (0.01 mmol) in ethanol (30 ml) was stirred at room tem-
perature for 24 h. The resulting solid product was collected by filtration
and recrystallized from the appropriate solvent.
2a: white, m.p. 170 C (from EtOH) yield (80%); IR (KBr disc)
1
1
max/cm 3407, 3284 (NH, NH), 2215 (CN), and 1672 cm (CO);
1H NMR 3.63 (s, 2H, CH2), 7.56–7.86 (m, 5H, C6H5), 10.11 (s, br, 1H,
NH), and 10.40 (s, br, 1H, NH); C9H9N3O3S (293) (M+ = 239), Calcd: C,
45.2; H, 3.8; N, 17.6. Found: C, 45.0; H, 3.5; N, 17.3%.
2b: white, m.p. 180 C (from EtOH) yield (85%); C10H11N3O3S, Calcd:
C, 47.4; H, 4.3; N, 16.6. Found: C, 47.0; H, 4.1; N, 16.3%.

Synthesis of N-Arylsulfonylaminated Biheterocycles
471
N-Arylsulfonylamino-2-pyridones (6a–h)
Method A. A mixture of compounds 2a,b (0.01 mmol) and -(2-
furanyl)- or -(2-thienyl)acrylonitrile derivatives 3a–d (0.01 mmol) in
ethanol (30 ml) containing a few drops of piperidine is refluxed for 3 h.
The resulting product precipitates from the hot solution is collected by
filtration and then recrystallized from the appropriate solvent.
Method B. To a mixture of 8 (0.01 mmol) and an arenesulfonyl chlo-
ride (0.01 mmol) in ethanol (50 ml) was added piperidine (0.05 ml). The
reaction mixture was stirred at room temperature until the reaction
was complete (TLC) and then set aside overnight. The resultant pre-
cipitate was filtered off and crystallized from the appropriate solvent.
6a: reddish brown, m.p. 302–304 C (from EtOH) yield (94%); IR (KBr
disc) max/cm 1 3320, 3280 (NH, NH2), 2214 (CN), 1690 (CO); 1H NMR
(DMSO) ; 7.15–7.90 (m, 8H, furan H-3,4,5 and C6H5), 8.90 (s, br, 2H,
NH2), 11.50 (s, br, 1H, NH); C17H11N5O4S (381), Calcd: C, 53.54; H,
2.88; N, 18.37. Found: C, 53.1; H, 2.1; N, 18.3%.
6b: red, m.p. > 300 C (from EtOH) yield (86%); IR (KBr disc)
1
max/cm 3320, 3300 (NH, NH2); 2220 (CN), 1670 (CO); 1H NMR
(DMSO) , 2.51 (s, 3H, CH3), 7.25–7.94 (m, 7H, furan H-3,4,5 and C6H4),
8.50 (s, br, 2H, NH2), 11.80 (s, br, 1H, NH); C18H13N5O4S (395), Calcd:
C, 54.68; H, 3.29; N, 17.70. Found: C, 55.0; H, 3.3; N, 17.5%.
6c: white, m.p. 240–242 C (from EtOH) yield (90%); IR (KBr disc)
1
max/cm 3380, 3271 (NH, NH2); 2259 (CN), 1680 (CO); 1H NMR
(DMSO) , 7.00–7.70 (m, 8H, thiophene H-3,4,5 and C6H5), 7.78 (s, br,
2H, NH2), 11.77 (s, br, 1H, NH); C17H11N5O3S2 (397) (M+ = 397), Calcd:
C, 51.38; H, 2.77; N, 17.63. Found: C, 51.1; H, 3.0; N, 17.9%.
6d: white, m.p. 158–160 C (from EtOH) yield (95%); IR (KBr disc)
max/cm 1 3450, 3390, 3197 (NH, NH2), 2214 (CN), 1690 (CO); 1H NMR
(DMSO) , 2.68 (s, 3H, CH3), 7.18 (s, br, 2H, NH2), 7.73–8.21 (m, 7H,
thiophene H-3,4,5 and C6H4), 11.65 (s, br, 1H, NH), C18H13N5O3S2
(411), Calcd: C, 52.55; H, 3.16; N, 17.93. Found: C, 53.0; H, 2.9; N, 16.8%.
6e: reddish brown, m.p. > 300 C (from EtOH) yield (85%); IR (KBr
1
disc) max/cm 3350, 3190 (NH2), 1720 (CO), 1632 (CO); 1H NMR
(DMSO) , 0.99 (t, 3H, CH3), 3.90 (q, 2H, CH2), 7.12–7.88 (m, 8H, fu-
ran H-3,4,5 C6H5), 8.56 (s, br, 2H, NH2), 10.3 (s, 1H, NH); C19H16N4O6S
(428), Calcd: C, 53.27; H, 3.73; N, 13.08. Found: C, 52.9; H, 3.9; N, 13.9%.
6f: reddish brown, m.p. > 300 C (from EtOH) yield (95%); IR (KBr
1
disc) max/cm 3307 (NH, NH2), 2225 (CN), 1737 (CO), 1680 (CO);
1H NMR (DMSO) , 0.75 (t, 3H, CH3), 2.42 (s, 3H, CH3), 3.72 (q, 2H,
CH2), 7.25–7.8 (m, 7H, furan H-3,4,5 C6H4), 8.18 (s, br, 2H, NH2), 9.20
(s, 1H, NH); C20H18N4O6S (442), Calcd: C, 54.29; H, 4.07; N, 12.66.
Found: C, 54.4; H, 3.8; N, 13.0%.

472
G. H. Elgemeie and S. H. Sayed
6g: yellow, m.p. over 300 C (from EtOH) yield (89%); IR (KBr disc)
1
1
max/cm 3213 (NH, NH2), 1722 (CO), 1670 (CO); H NMR (DMSO)
, 0.90 (t, 3H, CH3), 4.00 (q, 2H, CH2), 7.00–7.80 (m, 8H, thiophene
H-3,4,5 C6H5), 9.50 (s, br, 2H, NH2), 10.0 (s, 1H, NH); C19H16N4O5S2
(444), Calcd: C, 51.35; H, 3.60; N, 12.61. Found: C, 50.8; H, 3.5; N,
13.1%.
6h: yellow, m.p. 182–184 C (from EtOH) yield (87%); IR (KBr disc)
1
max/cm 3400, 3194 (NH, NH2), 1621 (CO), 1720 (CO); 1H NMR
(DMSO) , 1.10 (t, 3H, CH3), 2.34 (s, 3H, CH3), 3.98 (q, 2H, CH2), 7.25–
7.8 (m, 7H, thiophene H-3,4,5 C6H4), 8.90 (s, br, 2H, NH2), 9.55 (s, 1H,
NH); C20H18N4O5S2 (458), Calcd: C, 52.40; H, 3.93; N, 12.23. Found: C,
52.6; H, 4.2; N, 12.5%.
N-Arylsulphonylamino-3,5-dicyano-2-pyridones (10a–d)
General Procedure
Method (1). A mixture of ethyl 2-furfurylidene- (3c) or 2-thio-
phenylidenecyanoacetate (3d) (0.01 mmol) and arylsulphonylcyanoace-
tohydrazide 2a,b (0.01 mmol) was heated under refulx in pyridine
(30 ml) for 1 h. The solution mixture was poured over an ice-water
mixture and neutralized with dil. HCl to precipitate the solid product.
The performed product isolated by suction and recrystallized from the
appropriate solvent.
10a: white, m.p. 260–262 C (from EtOH) yield (78%); IR (KBr disc)
1
max/cm
3420, 3300 (OH, NH); 2220 (CN); 1690 (CO); 1H NMR
(DMSO) 7.00–7.80 (m, 8H, furan H-3,4,5 and C6H5); 7.99 (s, br, 1H,
OH), 8.30 (s, br, 1H, NH); C17H10N4O5S (382), Calcd: C, 53.40; H, 2.62;
N, 14.65. Found: C, 53.4; H, 2.4; N, 15.1%.
10b: white, m.p. 218–220 C (from EtOH) yield (75%); IR (KBr disc)
1
max/cm
3330, 3260 (OH, NH); 2220 (CN); 1680 (CO); 1H NMR
(DMSO) 2.21 (s, 3H, CH3); 7.20–7.50 (m, 7H, furan H-3,4,5 and C6H4);
7.80 (s, br, 1H, OH), 8.22 (s, br, 1H, NH); C18H12N4O5S (396), Calcd: C,
54.54; H, 3.03; N, 14.14. Found: C, 54.6; H, 3.1; N, 14.3%.
10c: yellow, m.p. 245–247 C (from EtOH) yield (89%); IR (KBr disc)
1
max/cm 3340, 3300 (OH, NH); 2220 (CN); 1660 (CO); C17H10N4O4S2
(398), Calcd: C, 51.26; H, 2.51; N, 14.70. Found: C, 50.3; H, 2.7; N,
14.7%.
10d: yellow, m.p. > 300 C (from EtOH) yield (81%); IR (KBr disc)
1
max/cm
3440–3250 (OH, NH); 2220 (CN); 1660 (CO); 1H NMR
(DMSO) 2.44 (s, 3H, CH3); 7.15–7.58 (m, 7H, thiophene H-3,4,5 and
C6H4); 7.99 (s, br, 1H, OH), 8.77 (s, br, 1H, NH); C18H12N4O4S2 (412),
Calcd: C, 52.42; H, 2.91; N, 13.59. Found: C, 52.3; H, 3.0; N, 13.8%.

Synthesis of N-Arylsulfonylaminated Biheterocycles
473
N-Arylsulphonylamino-6-aryl-3,5-dicyano-
2-pyridones (13)
General Procedure
A mixture of 2-furfurylidene- (3e) or 2-thiophenylidene derivatives
of benzoylacetonitrile (3f) (0.01 mmol) and arylsulphonyl cyanoaceto-
hydrazide 2a,b (0. 01 mmol) was heated under refulx in pyridine (30 ml)
for 1 h. The solution mixture was poured over an ice-water mixture and
neutralized with dil. HCl to precipitate the solid product. The performed
product was isolated by suction and recrystallized from the appropriate
solvent.
13a: white, m.p. 271–273 C (from EtOH) yield (72%); 1H NMR
(DMSO) 7.52–7.99 (m, 13H, furan H-3,4,5 and 2C6H5), 12.55 (s, br,
1H, NH); C23H14N4O4S (442), Calcd: C, 62.44; H, 3.16; N, 12.66. Found:
C, 62.3; H, 3.2; N, 12.8%.
13b: white, m.p. 290–292 C (from EtOH) yield (75%); IR (KBr disc)
1
1
max/cm 3350, 3250 (NH); 2220 (CN); 1690 (CO); H NMR (DMSO)
2.25 (s, 3H, CH3); 7.65–8.00 (m, 12H, furan H-3,4,5, C6H5,C6H4), 8.27
(s, br, 1H, NH); 13C NMR (DMSO) 21.22 (CH3), 98.34 (CN), 101.15
(CN), 119.21–140.00 (furan and phenyl-C), 149.59 (C-3), 152.33 (C-5),
153.18 (C-4), 159.69 (C-6), 163.36 (C-2); C24H16N4O4S (456), Calcd: C,
63.15; H, 3.51; N, 12.28. Found: C, 62.9; H, 3.8; N, 12.6%.
13c: yellow, m.p. 253–255 C (from EtOH) yield (86%); 1H NMR
(DMSO) 7.00–7.80 (m, 13H, thiophene H-3,4,5 and 2C6H5), 12.00 (s,
br, 1H, NH); C23H14N4O3S2 (458), Calcd: C, 60.26; H, 3.05; N, 12.22.
Found: C, 60.3; H, 3.2; N, 12.6%.
13d: yellow, m.p. 280–282 C (from EtOH) yield (80%); 1H NMR
(DMSO) 2.34 (s, 3H, CH3); 7.22–8.04 (m, 12H, thiophene H-3,4,5,
C6H50, C6H4), 8.55 (s, br, 1H, NH); C24H16N4O3S2 (472), Calcd: C, 61.01;
H, 3.38; N, 11.86. Found: C, 60.0; H, 3.3; N, 12.0%.
REFERENCES
[1] E. V. Stoyanov, I. C. Ivanov, and D. Heber, Molecules, 5, 19 (2000).
[2] G. E. H. Elgemeie, S. R. El-Ezbawy, H. A. Ali, and A. K. Mansour, Org. Prep. Proced.
International, 26, 465 (1994).
[3] G. E. H. Elgemeie and B. A. Hussein, J. Chem. Research (S), 87 (1993).
[4] G. E. H. Elgemeie, A. H. Elghandour, A. M. Elzanate, and W. A. Masoud, J. Chem.
Research (S), 164 (1998).
[5] G. E. H. Elgemeie and N. Hanfy, J. Chem. Res. (S), 385 (1999).
[6] G. E. H. Elgemeie, A. H. Elghandour, A. M. Elzanate, and W. A. Masoud, Phosphurs,
Sulfur, and Silicon, 163, 91 (2000).
[7] M. R. H. Elmoghayar, A. A. El-Agamay, N. M. Abed, and M. K. A. Ibrahim, An. Quim.,
81, 286 (1983).