A comparative study on some diaryl azines amino acid derivatives

Article abstract of DOI:10.1080/10426500601142155

Benzaldehydeazines, p-anisaldehydeazines, and thiophene-2-carboxaldehyde azines react with excess chlorosulfonic acid to give corresponding disulfonyl chlorides 1,13, and 24. These were condensed with nucleophiles to give disulfonyl amino acid derivatives

Full text of DOI:10.1080/10426500601142155

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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A Comparative Study on Some
Diaryl Azines Amino Acid
Derivatives
Ragab A. El-Sayed a
a Chemistry Department , Al-Azhar University , Nasr
City, Cairo, Egypt
Published online: 20 Apr 2007.
To cite this article: Ragab A. El-Sayed (2007) A Comparative Study on Some Diaryl
Azines Amino Acid Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:5, 1131-1142, DOI: 10.1080/10426500601142155
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Phosphorus, Sulfur, and Silicon, 182:1131–1142, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601142155
A Comparative Study on Some Diaryl Azines Amino
Acid Derivatives
Ragab A. El-Sayed
Chemistry Department, Al-Azhar University, Nasr City, Cairo, Egypt
Benzaldehydeazines, p-anisaldehydeazines, and thiophene-2-carboxaldehyde
azines react with excess chlorosulfonic acid to give corresponding disulfonyl
chlorides 1,13, and 24. These were condensed with nucleophiles to give disulfonyl
amino acid derivatives, 2–4, 14–16, and 25–27. Some of the corresponding methyl
esters were prepared: 5–6, 17–18, and 28–29. Hydrazinolysis of these methyl esters
yielded hydrazides 7–8, 19–20, and 30–31. Coupling reactions of some amino acid
derivatives, in THF-Et3N medium using the dicyclohexylcarbodiimide method
DCC, furnished dipeptide methyl esters 9–12, 21–23, and 32–34. Attemped
chlorosulfonation of furan-2-carboxaldehyde azine were unsuccessful. Some
spectra data are briefly discussed.
Keywords Benzaldehyde azines; chlorosulfonation of diarylazines; p-anisaldehyde
azines; thiophene-2-carboxyaldehyde azines; and their reactions with essential amino
acids
INTRODUCTION
The work reported here is a continuation of our general program on
the chemistry and reactivity of aryl sulfonyl derivatives as candidate
pesticides, which are found to possess hypoglycemic, antipyretic, anal-
gesic diuretic, bacteriostatic, and other pharmacological activities. The
compounds mentioned were found to have these activities.1−12
Diarylazines are known13 to be readly formed by condensation of the
appropriate aryl aldehyde and hydrazine hydrate. However, the chloro-
sulfonation of these compounds has been previously reported. In view of
the known ability of diaryl azines to undergo 1,3-dipolar cycloaddition
reactions with maleic acid derivatives.
Received May 4, 2006; accepted October 17, 2006.
The author is grateful to Prof. Dr. Mohamed H. El-Nagdi, Chemistry Department,
Faculty of Science, Cairo University, for helping me during my research.
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
1131

1132
R. A. El-Sayed
Sulfonyl chlorides 1,13, and 24 by condensation with nucleophiles,
e.g., amino acids residue, can be converted into sulfonylamino acid
derivatives for biological evaluation as candidate biocides.
DISCUSSION
In diaryl azines, the C N group is a deactivating substituent with re-
gard to electrophilic substitution. In agreement, (Comp. 1, R = X =
H) were prepared by reaction of chlorosulfonic acid with benzaldehyde
azine in a 68% yield.
The N N bond does not undergo fission under the reaction condi-
tions adopted, and the imino group was deactivated to electrophilic
1
attack. The H NMR spectrum contained an unsymmetrical aromatic
region.
Other azines were treated with chlorosulfonic acid, p-anisaldehyde
azines, and (Comp. 13, R = P-OMe, X = H) accured under milder condi-
tions than for benzaldehyde azine (Comp. 1, R = X = H). In thiophene
carboxaldehyde azines, (Comp. 24, Y = S, X = H) the more electron
rich azines react with chlorosulfonic acid, the greater reactivity of the
thiophene ring as a result from electron donation from the hetero sul-
fur atom, which is known.14 Generally, an electron–donner substituent
gives direct electrophilic substition at 5-position of the thiophene ring.
The 1H NMR spectrum of disulfonylamino acids derivatives showed an
AB pattern in the aromatic resonance at (δ 7.8, 7.7).
In the case of furan-2-carboxyladehydeazines (Comp. 35, Y = O,
X = H) powerful electron donation from the hetero oxygen atom. The
1H NMR spectrum showed a complex series of aromatic resonace at (δ
7.3–6.8).
Furan is well known15, to decompose with highly acidic sulfonation
reagents, chlorosulfonic and sulfuric acid; the electron-withdrawing
C N group might sufficiently stabilize the furan ring to allow
sulfonation, as was observed with furan-2-carboxamide,16 and
carboxanilide.17
EXPERIMENTAL
Melting points were taken on a Griffin melting point apparatus and are
uncorrected. Infrared solid samples were run as a KBr disc on a Schi-
madzu model 440 spectrophotometer. 1H NMR spectra were measured
in DMSO-d6 as a solvent unless otherwise stated using Fx 90 Q Furier
1
Transform HNMR. Mass spectra were obtained using a Schimadzu
(Japan). GC. M.S. QP 1000 Ex spectrometer using the direct inlet sys-
tem. TLC analyses were carried out on Merek silica gel plates and

Diaryl Azines Amino Acid Derivatives
1133
developed with n-butanol-acetic acid-water (4:1:1) using iodine, nin-
hydrin, and benzidine as spraying agents.
Diaryl azines disulfonyl chloride 1,13, and 24 were prepared accord-
ing to the procedure described earlier.18
Coupling Reaction 2–4, 14–16, and (25–27): General Procedure
To an amino acid (0.2 mol) in a water (25 mL) THF (15 mL) mixture
was added triethylamine (5 mL), followed by the portionwise addition
of disulfonyl chlorides (0.11 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, and wa-
ter (50 mL) was added and acidified with 2M HCl to pH5. The crude
products were filtered and recrystallized (ethanol-water). All products
CHART 1 (Continued)

1134
R. A. El-Sayed
CHART 1 (Continued)
2–4, 14–16, and 25–27 were chromatographically homogeneous by io-
dine and benzidine development (cf. Charts 1, 2, and 3 and Table I).
IR of 2:
ν3350 cm−1 (NH), ν1660 cm−1 (C O), ν 1580 cm−1
(C N), ν 1600 cm−1 (Ar C C), ν1380, 1170 cm−1
(SO2)
IR of 14: ν 3270 cm−1 (NH), ν 1640 cm−1 (Co), ν 1590 cm−1
(SO2), ν 1270, 1030 cm−1 (Ar O CH3)

Diaryl Azines Amino Acid Derivatives
1135
CHART 2
IR of 25:
ν 1610 cm−1 (Ar.C C), ν 1360, 1160 cm−1 (SO2)
1H NMR of 2: (DMSO-d6): δ 1.2 (s, 6H, 2CH3-alalyl), δ 4.2 (s, 2H,
2CH), δ 8.8 (s, 2H, 2CH N), δ 7.8 (s, 2H, 2NH), δ
8.4-7.6 (s, 8H, Ar H), δ 9.8, (s, 2H, 2COOH), MS of
4 : m/z 594 (M+)

1136
R. A. El-Sayed
CHART 3
1H NMR of 15: (DMSO-d6): δ 0.98 [s, 12H, (CH3)2], δ 1.97 (s, 2H,
2β CH Valyl), δ 4.26 (s, 2H, α CH Valyl), δ 4.33 (s,
6H, 2O-CH3), δ 7.88 (s, 2H, 2NH), δ 8.4–7.6 (s, 8H,
ArH), δ 8.8 (s, 2H, CH N), δ 11.3 (s, 2H, COOH)
MS of 15 : m/z 626 (M+)

1137

1138

1139

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R. A. El-Sayed
1H NMR of 26: (DMSO-d6): δ 4.1 [s, 2H, 2CH], δ 4.5 (s, 4H, 2CH2),
δ 4.0 (s, 6H, 2O CH3), δ 7.8–7.7 (s, 4H, 2 thiphene),
δ 8.3–7.17 (s, 6H, 2Ar H), δ 8.68 (s, 2H, 2CH N), δ
11.3 (s, 2H, 2COOH), MS of 27 : m/z 606 (M+)
Synthesis of Disulfonylamino Acid Methyl Esters 5, 6, 17, 18,
28, and 29: General Procedure
A suspension of coupling reaction products 2–4, 17, 18, and 28 and 29
(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 reaction
mixture was stirred for an additional 3–4 h at r.t. It was kept overnight,
and the solvent was removed by vacuum distillation. The residual solid
material was recrystallized (methanol-water) (cf. Table I, and Charts 1,
2, and 3).
IR of 17:
ν 3460cm−1 (NH), ν3250, 1370, 1170 cm−1
(SO2-NH), ν 1445, 1360 cm−1 (COOCH3),
ν 2960 cm−1 (O–CH3), ν 1760 cm−1 (Co), ν 1310,
1160 cm−1 (SO2)
1H NMR of 18: (DMSO-d6): δ 8.34–7.17 (s, 8H, Ar-H), δ 3.81–3.87
(s, 6H, 2COOCH3), and disappear of OH protons,
and other peaks in support of their structures.
Synthesis of Disulfonylamino Acid Hydrazides 7, 8, 19, 20 and
30, 31: General Procedure
The methyl esters 5, 6, 17, 18 and 28, 29, (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 room
temperature. The crystalline products 7, 8, 19, 20 and 30, 31 were
filtered off, washed with water and recrystallized (ethanol–water).
The hydrazides 7, 8, 19, 20, 30 and 31 were shown to be chromoato-
graphically to be homogeneous. cf. Table 1, Chart 1, 2 and 3.
IR of 7:
ν 3340, 3125 cm−1 (NH), ν 1640, cm−1 (Co), ν 1600,
1550 cm−1 (Ar C C), ν 1340, 1180 cm−1 (SO2)
1H NMR of 20: (DMSO-d6): δ 9(s, H, SO2NH), δ 8.2–7.5 (Ar-H), δ
5.52 (s, 2NH), δ 5.61 (s, 4H, 2NH2)
Synthesis of Disulfonyl Dipeptide Methyl Esters 9–12, 21–23,
and 32–34: General Procedure
To a solution of amino acid methyl ester hydrochloride (0.01 mol) in THF
(100 mL) was added triethylamine (5 mL). The solution was stirred at

Diaryl Azines Amino Acid Derivatives
1141
20◦C for 30 min and cooled to 0◦C, where the disulfonyl amino acid
(0.005 mol) and dicyclohexylcarbodiimide DCC (1.62 g) were added to
the above mixture. The reaction mixture was stirred for 2 h at 0◦C
and for another 2 h at r.t. The precipitated dicyclohexylurea was fil-
tered off, and acetic acid (2 mL) was added to the solution and was left
standing overnight. The precipitate was filtered off, and the remaining
solution was distilled under vacuum. The remaining solid was recrystal-
lized from ethanol-water. The products were to be chromatographically
homogeneous.
IR of 10:
IR of 12:
ν 3300, 3100 cm−1 (NH, CONH), ν 1750 cm−1 (Co),
ν 1320 cm−1 (COOCH3)
ν 3390 cm−1 (NH), ν 1370, 1170 cm−1 (SO2-NH), ν
1665, 1530, 1280 cm−1 (CONH), ν 1445, 1350 cm−1
(COOCH3), ν 1760 cm−1 (C O), ν 1610, cm−1
(Arc C), 1380, 1180 cm−1 (SO2)
1H NMR of 10: (DMSO-d6): δ 7.86 (s, 2H, 2SO2NH), δ 8.04 (s, 2H,
2CONH), δ 3.87 (s, 6H, 2COOCH3), 2H, ν 4.34 (s,
2H, 2α-CH-alalyl), ν 1.22 (s, 6H, CH3-alalyl) and
other bands supporting the structure of dipeptide
1H NMR of 23: (DMSO-d6): δ 8.01 (s, 2H, 2CONH), δ 3.85 (s, 6H,
2COOCH3), ν4.26 (s, 2H, 2α-CH Valyl), δ 1.79 (s,
2H, 2β CH-Valyl), ν 0.98 [s, 12H, 2(CH3)2] and
other bands supporting the structure of dipeptide
REFERENCES
[1] R. A. El-Sayed, J. Serb. Chem. Soc., 56, 311 (1991).
[2] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and Y. A. Abbas, Pak. J. Sci. Industrial
Research, 34, 369 (1991).
[3] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. F. Badie, J. Chem. Soc. Pak. 14, 49
(1992).
[4] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. H. El-Hakim, Proc. Ind. Nat. Sci.
Acad, 58, 389 (1992).
[5] R. A. El-Sayed, J. Ind. Chem. Soc., 69, 618 (1992).
[6] R. A. El-Sayed, N. S. Khalaf, F. A. Kora, and M. A. El-Gazzar, J. Serb. Chem. Soc.,
59, 727 (1994).
[7] R. A. El-Sayed, Ind. Chem. Soc., 75, 53 (1998).
[8] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 131, 207 (1997).
[9] R. A. El-Sayed, Chemistry of Heterocyclic Compounds, 7, 821 (1998).
[10] R. A. El-Sayed, Chemistry of Heterocyclic Compounds, 1, 95 (2001).
[11] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 179, 237 (2004).
[12] R. A. El-Sayed, Phosphorus, Sulfur, and Silicon, 180, (2006).
[13] K. Mijatake, J. Pharm. Soc. Japan, 72, 1162 (1952); Chem. Abstr., 47, 2733a (1953).

1142
R. A. El-Sayed
[14] O. Meth-Cohn, Thiophene in Comprehensive Organic Chemistry, p. 796, (Pergamon
Press, Oxford, 1979).
[15] R. O. C. Norman, Principles of Organic Synthesis, p. 387, (Methuen, London, 1968).
[16] R. J. Cremlyn, F. J. Swinbourne, and K. Yung, J. Heterocyclic Chem., 18, 997 (1981).
[17] R. J. Cremyln, F. J. Swinbourne, and O. O. Shode, J. Chem. Soc. Pak., 8, 323 (1986).
[18] R. J. Cremlyn, F. J. Swinbourne, and S. Grahan, Phosphorus, Sulfur, and Silicon,
60, 57 (1994).