Some novel sulfanilyl amino acids and dipeptides derivatives

Article abstract of DOI:10.1080/10426500601144821

3-(N-phenylcarboxamido)-coumarin 1 reacted with chlorosulfonic acid to give the corresponding sulfaniyl chloride 2. However, isonicotinic acid anilide 14, and nicotinic acid anilide 33, reacted with chlorosulfonic acid in a 1:6 molar ratio, only for conve

Full text of DOI:10.1080/10426500601144821

This article was downloaded by: [University of Windsor]
On: 17 November 2014, At: 18:53
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
Some Novel Sulfanilyl
Amino Acids and Dipeptides
Derivatives
Ragab A. El-Sayed a
a Chemistry Department , Al-Azhar University , Nasr
City, Cairo, Egypt
Published online: 19 Apr 2007.
To cite this article: Ragab A. El-Sayed (2007) Some Novel Sulfanilyl Amino Acids and
Dipeptides Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:5, 1153-1162, DOI: 10.1080/10426500601144821
To link to this article: http://dx.doi.org/10.1080/10426500601144821
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, 182:1153–1162, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601144821
Some Novel Sulfanilyl Amino Acids and
Dipeptides Derivatives
Ragab A. El-Sayed
Chemistry Department, Al-Azhar University, Nasr City, Cairo, Egypt
3-(N-phenylcarboxamido)-coumarin 1 reacted with chlorosulfonic acid to give the
corresponding sulfaniyl chloride 2. However, isonicotinic acid anilide 14, and nico-
tinic acid anilide 33, reacted with chlorosulfonic acid in a 1:6 molar ratio, only
for conversion into sulfanilyl chlorides 15 and 34. Treatment with nucleophilic
reagents afforded amino acid derivatives 3–6, 16–20, and 35–37. Some of the cor-
responding methyl esters 7–9, 21, 24, and 38–39 were prepared. Hydrazinolysis of
some methyl esters yielded hydrazides 25–28 and 40–41. Coupling reactions of some
amino acid derivatives with amino acid methyl ester hydrochloride in THF-Et3N
medium using the dicyclohexyl carbodiimide DCC furnished the desired dipeptide
methyl esters 10–13, 29–32, and 42–43. The spectral properties of the compounds
are briefly discussed.
Keywords Chlorosulfonation of 3-(N-phenyl carboxamidocoumarin; nicotinic acid
anilide; isonicotinic acid anilide; and reactions with different essential amino acids
INTRODUCTION
Sulfanilamides are valuable antibacterial drugs.1 Other sulfanilamides
are active as diuretics and against fungal diseases in plants.2 Ear-
lier investigations have shown that various nicotinic acid and isonico-
tinic acid derivatives exhibit powerful antimicrobial and antitubercular
properties.3−5 The compounds from the anilide of isonicotinic acid are
of special interest in view of the use of isonicotinic acid hydrazide as an
antitubercular drug and as a selective herbicide.6 Several coumarins
have biological activities. 3-carboxylic acid derivatives possess sedative
and hypotic properties,7 while 4-hydroxy coumarins are blood anticoag-
ulants, which have been used as rodenticides.8 The work reported here
is a continuation of our general program on the chemistry and reac-
tivity of aryl sulfanilyl amino acid derivatives as candidate pesticides.
Some have been found to possess hypoglycemic, antipyretic, analgesis
Received May 23, 2006; accepted October 17, 2006.
Address correspondence to Ragab A. El-Sayed, Chemistry Department, Faculty of
Science, Al-Azhar University, Nasr City, Cairo, Egypt. E-mail: dr ragabaly@yahoo.com
1153

1154
R. A. El-Sayed
diuretic, bacteriostatic, and other pharmacological activities. It has
been reported that such compounds have biological activity.9−21 We de-
cided to prepare some coumarins amino acid derivatives. Coumarin was
first sulfonated by Perkin,22 and Rubtzov and Fedossova,23 showed that
treatment with hot chlorosulfonic acid caused electrophilic substitution
to occur preferentially in sulfanilyl chloride.
DISCUSSION
3-(N-phenylcarboxamido)-coumarin (1) was prepared by heating ethyl-
3-coumarin carboxylate with aniline or by the action of thionyl chloride
and aniline on 3-coumarin carboxyhlic acid. When (1) was reacted with
an excess of chlorosulfonic acid for 7 days at r.t., an excellent yield (85%)
of the p-sulfanilyl chloride (2) was isolated. The anilino ring was more
susceptible to sulfonation than the coumarin nucleus due to a combina-
tion of the electron donating effect of the nitrogen lone pair of electrons
and the with drawing effect of the amido group. The mass spectra of
compound (2) showed the molecular ions (M+, 365, 363) with no trace
of higher molecular mass ions confirming the absence of disulfonation.
Isonicotinic acid anilide (14) required a large excess of chlorosulfonic
acid (6 mol) to obtain a good yield of sulfanilyl chloride 15 due to the
presence of the basic pyridyl nitrogen atom; on the other hand, nicotinic
acid anilide (33) with chlorosulfonic acid, under the same conditions,
gave a lower yield.
The lower yield of sulfanilyl chloride obtained from nicotinic acid
anilide as compared with that obtained from isonicotinic acid anilide
is probably due to the more basic character of the nitrogen atom in
nicotinic acid anilide, which tends to form a hydrochloride salt in the
presence of chlorosulfonic acid.
Compounds 2,15, and 34 reacted with nucleophilic reagents under
anhydrous conditions in the case of coumarin reactions. The correspond-
ing sulfanilylamino derivatives 3–13, 16–32, and 35–43 were obtained.
Coumarin derivatives 3–13 showed the IR spectra of NH and SO2 ab-
sorption bands, which appeared in the normal positions,24 and showed
the carbonyl stretching absorption band in the region 1740–1715 and
the C O C band at 1110–1105 cm−1. In the 3(N-p-sulfanilylphenyl
carboxamido)- coumarin (Table I), the frequency of the carbonyl band
was slightly lower (1710–1700), while that of C O C absorption was
significantly higher (1210–1205).25,26
EXPERIMENTAL
Melting points were taken on a Griffin melting point apparatus and
were uncorrected. Infrared analysis of solid samples were run as a KBr

Sulfanilyl Amino Acids and Dipeptides Derivatives
1155
1
disc on a Schimadzu model 440 spectrophotometer. H NMR spectra
were measured in DMSO-d6 as a solvent unless otherwise stated using
Fx 90 Q Furier Transform 1H NMR. Mass spectra were obtained using a
Schimadzu GC MS QP 1000 Ex spectrometer using the direct inlet sys-
tem. TLC analyses were carried out on Merek (Darmstadt, Germany)
silica gel plates and were developed with n-butanol-acetic acid-water
(4:1:1) using iodine, ninhydrin, and benzidine as spraying agents.
Compounds 2,15, and 34 were prepared according to the procedures
described earlier.27,28
Coupling Reactions: 3–6, 16–20, and 35–37: General Procedure
To an amino acid (0.1 mol) in a water (25 mL) THF (15 mL) mix-
ture was added triethylamine (5 mL), followed by a portionwise ad-
dition of sulfonyl chlorides (0.1 mol) during 30 min. The temperature of
the reaction mixture during the process of addition was kept at 10◦C.
Stirring continued for 4 h at 20◦C. Tetrahydrofuran was removed by
concentration of the reaction mixture under reduced pressure. Water
(50 mL) was added, and the solution acidified with 2M HCl to pH5.
The crude products were filtered and recrystallized (ethanol-water).
All the products 3–6, 16–20, and 35–37 were chromatographically ho-
mogeneous by iodine and benzidine development in TLC (cf. Chart 1,
Table I).
IR of 4:
ν3250 cm−1 (NH), ν1700 cm−1 (C O), ν1610,
1590 cm−1 (Ar–C C), ν1365, 1150 cm−1 (SO2),
ν1200 cm−1 (C O C).
IR of 6c:
ν3250 cm−1 (NH), ν1705 cm−1 (C C), ν1615,
1590 cm−1 (ArC C), ν1355, 1165 cm−1 (SO2),
ν1200 cm−1 (C O C).
IR of 19:
ν3300 cm−1 (NH), ν1690 cm−1 (C O), ν1590 cm−1
(Ar-C C), ν1320, 1160 cm−1 (SO2).
1H NMR of 4:
(DMSO-d6): δ1.2(s, CH3-alalyl), δ4.1(s, H, CH ala-
lyl), δ8.1–7.3(s, 9H, Ar H), δ8.9(s, H, SO2-NH),
δ11.3, (s, H, COOH), δ11.7(s, H, CONH). MS of 4:
m/z 416 (M+).
1H NMR of 6b: (DMSO-d6): δ8.1–7.2[s, 9H, Ar H), δ8.5 (s, 2H,
NH2), δ8.8(s, H, SO2 NH), δ11.6(s, H, CONH). MS
of 6b: m/z 12 359 (M+).
1H NMR of 6c: (DMSO-d6): δ1.9[s, 6H, (CH3)2], δ8.5–7.3(s, 9H,
Ar H), δ10.1(s, H, SO2 NH), δ11.9(s, H, CONH),
δ11.9(s, H, CONH). MS of 6c: m/z 399 (M+).

1156
R. A. El-Sayed
Chart 1
1H NMR of 18:
(DMSO-d6): δ 1.8[s, 6H, (CH3)2], δ1.97(s, H βCH va-
lyl), δ4.33, (s, H, α CH valyl), δ7.8–7.2 (s, 6H, Ar-H),
δ8.8–8.7(s, 2H, 2HA), δ9.9(s, H, SO2-NH), δ10.9(s,
H, CONH), δ11.6(s, H, COOH). MS of 18: m/z 377
(M+).
1H NMR of 20b: (DMSO-d6): δ 1.9[s, 6H, (CH3)2], δ7.8–7.2 (s, 6H,
Ar-H), δ8.8–8.7(s, 2H, 2HA), δ9.7(s, H, SO2−NH),
δ10.8(s, H, CONH). MS of 20b: m/z 305 (M+).

1157

1158

1159

1160
R. A. El-Sayed
Synthesis of Sulfanilylamino Acid Methyl Esters 7–9, 21–24,
and 38–39: General Procedure
A suspension of coupling reaction products 3, 4,6a, 16–19, and 36–37
(0.2 mole) in absolute methanol (100 mL) was cooled to −10◦C, and
pure thionyl chloride (2.2 mL) was added dropwise during 1 h. The re-
action mixture was stirred for an additional 3–4 h at r.t. after standing.
Overnight, the solvent was removed by vacuum distillation. The resid-
ual solid material was recrystallized (methanol-water) (Table I).
IR of 8:
ν3460,cm−1 (NH), ν1370, 1170 cm−1 (SO2−NH),
ν1440, 1360 cm−1 (COOCH3), ν1710 cm−1 (C O),
ν1310, 1610 cm−1 (SO2).
1H NMR of 23: (DMSO-d6): δ8.8–7.2(s, 8H, Ar H), δ3.87–3.81(s, 3H,
COOCH3), and disappear of OH protons, and other
peaks in support of their structures. MS of 23: m/z
391 (M+).
Synthesis of Sulfanilyamino Acid Hydrazides 25–28 and
40–41: General Procedure
The methyl esters 21–24 and 38–39 (0.2 mol) were dissolved in ethanol
(100 mL), and hydrazine hydrate 85% (0.2 mol) was added. The reaction
mixture was stirred for 3 h at 20◦C and left 24 h at r.t. The crystalline
products 25–28 and 40–41 were filtered off, washed with water, and
recrystallized (ethanol–water).
Hydrazides 25–28 and 40–41 were shown to be chromatographically
to be homogeneous (Table I).
IR of 28:
ν3200 cm−1 (NH), ν1690 cm−1 (C O), ν1580 cm−1
(ArC C), ν1320, 1160 cm−1 (SO2).
1H NMR of 27: δ5.61(s, 2H, NH2), δ5.51(s, H, NH), δ7.8–7.1 (s,
6H, Ar H), δ8.7–8.6 (s, 2H, HA), δ9.2 (s, H,
SO2 NH). MS of 27: m/z 391 (M+).
Synthesis of Sulfanilyl Dipeptide Methyl Esters 10–13, 29–32,
and 42–43: General Procedure
To a solution of amino acid methyl ester hydrochloride (0.11 mol) in
THF (100 ml) was added triethylamine (5 mL). The solution was stirred
at 20◦C for 30 min and cooled to 0◦C, where the sulfanilyl amino acid
(0.005 mol) and dicyclohexylcarbodiimide DCC (1.62 g) were added to
the mixture. The reaction mixture was stirred for 2 h at 0◦C and for an-
other 2 h at r.t. The precipitated dicyclohexylurea was filtered off, and

Sulfanilyl Amino Acids and Dipeptides Derivatives
1161
acetic acid (2 mL) was added to the solution, which was left standing
overnight. The precipitate was filtered off, and the remaining solution
was distilled under vacuum. The remaining solid was recrystallized
from (ethanol-water). The products were to be chromatographically ho-
mogeneous.
IR of 11:
ν3300, 3100 cm−1 (NH, CONH), ν1700 cm−1
(C O), ν1360 cm−1 (COOCH3).
1H NMR of 31: δ3300 cm−1 (NH), ν1370, 1170 cm−1 (SO2 · NH),
ν1445, 1350 cm−1 (COOCH3), ν1760, cm−1 (C O),
ν1610, cm−1 (ArC C), ν1380, 1180 cm−1 (SO2).
1H NMR of 12: (DMSO-d6): δ1.8[s, 6H, (CH3)2 valyl], δ1.94(s, H
βCH valyl), δ4.31, (s, H, αCH valyl), δ3.80 (s,
3H, COOCH3), δ8.0–7.2(s, 9H, Ar-H), δ8.7(s, H,
SO2 NH), δ11.4(s, 2H, CONH). MS of 12: m/z 515
(M+).
1H NMR of 30: (DMSO-d6): δ1.27(s, 3H, CH3-alalyl), δ3.80(s, H,
COOCH3), δ4.31(s, H, αCH alalyl), δ7.60(s, H,
SO2 NH), δ8.8–7.8 (s, 8H, Ar H), δ8.03(s, 2H,
2CONH). MS of 30: m/z 420 (M+).
The remaining dipeptides methyl esters 10–13, 29–32, and 42–43
gave analogous peaks in support of their structures.
REFERENCES
[1] A. Burger, ed., Medicinal Chemistry, Part 1, p. 255 (Wiley, London, 1970).
[2] Medicinol Chemistry, Part 2, p. 987 (Wiley, London, 1970).
[3] M. K. Prasad, B. H. Iyere, and M. Sirs, Indian J. Appl. Chem., 32, 181 (1969).
[4] M. K. Prasad, B. H. Iyere, and M. Sirs, Ind. Chem. Soc., 43, 784 (1966).
[5] R. E. Lyle, J. Pharm. Sci., 61, 477 (1972).
[6] H. H. Fox and T. J. Gibas, J. Org. Chem., 17, 1653 (1952).
[7] S. Wawzonek, Coumarins in Elderfield, Heterocyclic Compounds, vol. 2, p. 213
(Wiley, New York, 1951).
[8] R. J. Cremlyn, F. J. Swinbourne, J. G. Bloy, K. Pathak, and O. O. Shode, Pesticides:
Preparation and Mode of Action, p. 179 (Wiley, Chichester, 1978).
[9] R. A. El-Sayed, J. Serb. Chem. Soc., 56, 311 (1991).
[10] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and Y. A. Abbas, Pak. J. Sci. Industrial
Research, 34, 369 (1991).
[11] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. F. Badie, J. Chem. Soc. Pak., 14, 49
(1992).
[12] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. H. El-Hakim, Proc. Ind. Nat. Sci.
Acad, 58, 389 (1992).
[13] R. A. El-Sayed, J. Ind. Chem. Soc., 69, 618 (1992).
[14] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. A. El-Gazzar, J. Serb. Chem. Soc.,
59, 727 (1994).
[15] R. A. El-Sayed, Ind. Chem. Soc., 75, 53 (1998).
[16] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 131, 207 (1997).

1162
R. A. El-Sayed
[17] R. A. El-Sayed, Chemistry of Heterocyclic Compounds, 7, 821 (1998).
[18] R. A. El-Sayed, Chemistry of Heterocyclic Compounds, 1, 95 (2001).
[19] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 179, 237 (2004).
[20] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 181, (2006).
[21] R. A. El-Sayed, J. Serb. Chem. Soc., 63, 371 (1998).
[22] W. H. Perkin, J. Chem. Soc., 24, 37 (1873).
[23] M. V. Rubtzov and V. M. Fedossova, J. Gen. Chem. (USSR), 14, 857 (1944); C. A. 40,
1804 (1946).
[24] L. J. Bellamy, The Infra-Red Spectra of Complex Molecules, 2nd ed. (Methuen,
London, 1958).
[25] H. Budzikiewicz, C. Djerassi, and D. H. Williams, Structural Elucidation of Natural
Products by Mass Spectrometry, p. 254 (Holden–Day, San Francisco, 1964).
[26] C. Pretsch and S. Simon, Tables of Spectral data for the Structure Determination of
Organic Compounds, p. 1140 (Springer–Verlag, Berlin, 1983).
[27] R. J. Cremlyn and F. J. Swinbourne, Ind. J. Chem., 22, 1029 (1983).
[28] R. J. Cremlyn and S. M. Clowes, J. Chem. Soc., 10, 79 (1988).