Some nucleophilic reactions with isothiocyanatoazobenzene

Article abstract of DOI:10.1080/10426500701513354

The reactivity of Isothiocyanatoazobenzene 2 towards some nucleophiles was investigated. Thus, reaction of isothiocyanate 2 with aromatic amines gave thioureas 3a-d. The reaction of compound 3a with arylidenemalononitriles 4a,b afforded the corresponding

Full text of DOI:10.1080/10426500701513354

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Phosphorus, Sulfur, and Silicon
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Some Nucleophilic Reactions
with Isothiocyanatoazobenzene
Abu-Bakr A. A. M. El-Adasy a
a Department of Chemistry, Faculty of Science , Al-
Azhar University at Assiut , Assiut, Egypt
Published online: 25 Sep 2007.
To cite this article: Abu-Bakr A. A. M. El-Adasy (2007) Some Nucleophilic Reactions
with Isothiocyanatoazobenzene, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:11, 2625-2635, DOI: 10.1080/10426500701513354
To link to this article: http://dx.doi.org/10.1080/10426500701513354
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Phosphorus, Sulfur, and Silicon, 182:2625–2635, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701513354
Some Nucleophilic Reactions with
Isothiocyanatoazobenzene
Abu-Bakr A. A. M. El-Adasy
Department of Chemistry, Faculty of Science, Al-Azhar University at
Assiut, Assiut, Egypt
The reactivity of Isothiocyanatoazobenzene 2 towards some nucleophiles was in-
vestigated. Thus, reaction of isothiocyanate 2 with aromatic amines gave thioureas
3a–d. The reaction of compound 3a with arylidenemalononitriles 4a,b afforded the
corresponding 1,3-pyrimidines 7a,b. Thiosemicarbazide 8 and ethyl thiocarbamate
9 were synthesized by interaction of isothiocyanate 2 with hydrazine hydrate and
ethanol, respectively. Cyclocondensation of isothiocyanate 2 with 2-aminophenol
and anthranilic acid produced the novel benzoxazole 11 and quinazolinone 13
derivatives, respectively. Finally, treatment of isothiocyanatoazobenzene 2 with com-
pounds 14 and 17 afforded the novel thioureas 15 and 18 derivatives, respectively.
The structures of the synthesized compounds were established from their analytical
and spectral data.
Keywords Isothiocyanatoazobenzene; pyrimidine derivatives; thiourea
INTRODUCTION
Aromatic azo compounds have attracted great interest in recent years
due to their carcinogenic potency1−4 and their use in textile5 and
pharmaceutical industries as dyes, coloring agents,6 and analytical
reagents.7 They can also be used as materials for nonlinear optics and
for storage of optical information in laser disks.8 In addition, thiourea
has a variety of biological activities as antibacterial, antifungal, antitu-
bercular, antithroid, and insecticidal agents.9−11 Aryl isothiocyanates12
are useful and widely used for building blocks in the synthesis of hete-
rocyclic compounds containing nitrogen, sulfur and oxygen.13,14
Received February 1, 2007; accepted May 4, 2007.
The author is grateful to Botany and Microbiology Department, Faculty of Science,
Al-Azhar University, Assiut, Egypt for doing the Antibacterial activities tests.
Address correspondence to Abu-Bakr A. A. M. El-Adasy, Department of Chem-
istry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail:
a eladasy@yahoo.com
2625

2626
A.-B. A. A. M. El-Adasy
TABLE I Antibacterial Activity of Some of the Newly Synthesized
Compounds
Comp. No.
Escherichia coli
Pseudomonas areuginosa
Klebsiella pneumonia
3a
3b
3c
7A
8
—
9
—
10
10
10
10
25
10
20
—
—
—
—
—
—
—
10
9
10
—
—
10
—
—
14
—
10
—
—
9
11
13
15
18
Diameter of inhibition zone in mm; No inhibition: (—).
As an extension of our interest in the synthesis of heterocyclic com-
pounds exhibiting biological activity,15−19 we report herein, the synthe-
sis of new series of thiourea, thiosemicarbazide, benzoxazole, quinazo-
line, and thiophene derivatives containing aryl azo moiety to evaluate
their antimicrobial activity (Table 1).
RESULTS AND DISCUSSION
Isothiocyanatoazobenzene 2 was synthesized by treatment of aminoa-
zobenzene 1 with thiophosgen in chloroform and methylene chloride in
the presence of calcium carbonate at room temperature,20 (Scheme 1).
The reaction of isothiocyanate 2 with some nucleophiles was studied.
Reaction of isothiocyanate 2 with aromatic amines furnished the novel
1, 3-disubstituted thioureas 3a–d in high yields (Table II) The struc-
tures of thioureas 3a–d were established by elemental analysis and
spectral data. The infrared spectra of compounds 3a–d showed the pres-
ence of NH, N=N, and C=S functional groups. Cyclization of thiourea
derivative 3a with arylidenemalononitriles 4a,b in refluxing dimethyl-
formamide in the presence of piperidene afforded pyrimidinethione
derivatives 7a,b. The molecular structures of pyrimidine derivatives
7 were confirmed on the basis of spectral data. The infrared spectra
of the synthesized compounds 7a,b revealed characteristic bands for
NH2, C≡N, C=N and N=N functional groups. Also, the 1H NMR spec-
trum of compound 7a in (DMSO-d6) showed signal characteristic for
pyrimidine-H at δ = 6.10 ppm in addition to the presence of methyl,
amino and aromatic protons. The formation of pyrimidine derivative 7
is assumed to proceed via the nucleophilic addition of thiourea moiety

Recreations with Isothiocyanatoazobenzene
2627
SCHEME 1
to the activated double bond in 4 to form Michael adduct 5 followed
by intramolecular cyclization and tautomerization to give 7 (Scheme 1,
Table II).
The treatment of isothiocyanate 2 with hydrazine hydrate in ethanol
at room temperature yielded the corresponding thiosemicarbazide
derivative 8. The molecular structure of compound 8 was identified by
analytical and spectral data. Infrared spectrum of compound 8 showed
absorption bands for NH, NH2, and N=N functional groups. Ethyl thio-
carbamate derivative 9 was achieved by condensation of isothiocyanate
2 with ethanol as oxygen nucleophiles. (Scheme 2, Table II).
Our investigation was extended to study the reaction of isothio-
cyanate 2 with 2-aminophenol and anthranilic acid. Cyclocondensa-
tion of 2-aminophenol with isothiocyanate 2 in ethanol in the presence
of triethylamine at reflux temperature furnished benzoxazole deriva-
tive 11. The formation of benzoxazole 11 is assumed to procedure

2628

Recreations with Isothiocyanatoazobenzene
2629
SCHEME 2
via thiourea intermediate 10 followed by intramolecular cyclization
through elimination of hydrogen sulfide,21 (Scheme 3). Quinoxaline
derivative 13 was obtained by cyclization of anthranilic acid with isoth-
iocyanate 2, via thiourea intermediate12 followed by elimination of wa-
ter. (Scheme 3, Table II).
SCHEME 3
In continuation of this investigation, interaction of 4-
isothiocyanatoazobenzene 2 with 2-amino-3-ethoxycarbonyl-4, 5, 6,
7-tetrahydrobenzo[b]thiophene22 under reflux in ethanol triethylamine

2630
A.-B. A. A. M. El-Adasy
afforded the novel thiourea derivative 15 and tetrahydrobenzo
[b]thieno[2,3-d]pyrimidin-4-one derivative 16 was discarded on the
basis of analytical and spectral data. The 1H NMR spectrum of
compound 15 showed signals at δ: 1.23 (t, 3H, CH3), 4.23 (q, 2H, CH2),
7.21–7.98 ppm (m, 9H, H-Ar), and 11.29, 12.01 ppm (2s, 2H, 2NH).
Condensation of compound 2 with 2-aminothiophene derivative 17 in
ethanol and triethylamine yielded the corresponding disubstituted
thiourea 18. The IR spectrum of compound 18 revealed the presence of
a strong absorption band characteristic for C≡N function at 2203 cm−1
in addition to NH and C=O functional groups (Scheme 4, Table II).
,
SCHEME 4
ANTIBACTERIAL ACTIVITY
Ten compounds were screened in vitro for their antibacterial against
three strains of bacteria: Escherichia coli, Pseudomonas areuginosa and
Klebsiella pneumonia by the agar diffusion technique.23 A 1 mg/mL so-
lution in dimethylformamide was used. The bacteria were maintained
on nutrient agar media. Dimethylformamide showed no inhibition
zones. The agar media was incubated with different microorganisms
culture tested, after 24 h of incubation at 30◦C for bacteria, the di-
ameter of inhibition zone (mm) was measured (Table I). Compounds 9

Recreations with Isothiocyanatoazobenzene
2631
and 13 exhibited antimicrobial activity against all the microorganisms
used. Compounds 3b and 3c showed weak activities against Escherichia
coli and Pseudomonas areuginosa. The rest of the compounds exhibited
from weak to nil activities against all strains of bacteria used.
CONCLUSION
Isothiocyanatoazobenzene (2) was used as starting material for the
synthesis of some novel thiourea, aminopyrimidine, thiosemicarbazide,
thiocarbamate, benzoxazole, and quinazoline derivatives depend on re-
action conditions (temperature and time).
EXPERIMENTAL
All melting points are uncorrected (Stuart Scientific Co., UK). The IR
spectra were measured as KBr pellets on Shimadzu IR 200 spectropho-
tometer. 1H NMR spectra were recorded in DMSO-d6 at 200 MHz on a
Varian Gemini NMR spectrometer (Varian, UK), using tetramethylsi-
lane as internal reference. Elemental analyses were carried out at the
Microanalytical Center of Cairo University. The characteristic data for
the synthesized compounds are given in Table II.
N-{4-[Phenyldiazenyl]phenyl}-N-pyridin-3-ylthiourea (3a)
A mixture of 2 (2.39 g, 0.01 mol), 3-aminopyridine (0.94 g, 0.01 mol) in
toluene (30 mL) containing few drops of triethylamine was refluxed for
3 h. The precipitate formed after cooling was collected by filtration and
recrystallized from ethanol to give 3a in good yielded (Table II). 3a: IR
(KBr) ν 3219, 3108 (NH), 3045 (CH-arom.), 1594 (N=N) cm−1. 1H NMR
(DMSO-d6) δ 6.67, 6.70, 7.38, 8.10 (s,4H, pyridine), 7.40–7.90 (m, 15H,
Ar-H and NH), 10.67 ppm (s, 1H, 1NH).
N-Substituted-N-(4-phenylazophenyl)thiourea
(3b–d)—General Procedure
To a suspension of isothiocyanate 2 (2.39 g, 0.01 mol) and aryl amines
3b–d (1.50, 2.67 and 1.41 g, respectively 0.01 mol) in dioxane (30 mL),
triethylamine (0.5 mL) was refluxed until the clear solution was ob-
tained. The solid residue was collected by filtration, washed with cold
water and recrystallized from the proper solvent to give compounds
3a–b (Table II).

2632
A.-B. A. A. M. El-Adasy
N-(1,3-Benzothiazol-2-yl)-N-{4-[phenyldiazenyl]phenyl}
thiourea (3b)
IR(KBr) ν 3316, 3159 (NH), 3035 (CH-arom.), 1592 (N=N) cm−1
.
1HNMR (DMSO-d6)δ 7.53–8.10(m, 14H, Ar-H and NH), 10.39 ppm(s,
1H, NH).
N-(4,5-Dimethyl-1,3-oxazol-2-yl)-4-{[({4-[phenyldiazenyl]
phenyl}amino)carbono-thioyl]amino}benzenesulfonamide (3c)
IR (KBr) ν 3334, 3280, 3100 (NH), 3040 (CH-arom.), 2940 (CH-aliph.),
1595 (N=N) cm−1. 1HNMR (DMSO-d6) δ 1.92 (s, 3H, CH3), 2.02 (s, 3H,
CH3), 7.29–7.86 (m, 15H, Ar-H and 2NH), 9.45 ppm (b, 1H, NH).
4-{[({4-[phenyldiazenyl] phenyl} amino) carbonothioyl] amino}
benzenesulfonic acid (3d)
IR (KBr) ν 3413 (OH), 3307, 3195 (NH), 3037 (CH-arom.), 1592
(N=N) cm−1
.
6-Amino-3-(4-phenylazo-phenyl)-1-pyridin-2-yl-2-thioxo-4–(4-
substituted-aryl)-1, 2, 3, 4-tetrahydro-pyrimidine-5-
carbonitrile (7a, b)—General Procedure
A mixture of thiourea 3a (3.33 g, 0.01 mol), arylidinemalononitril
4a,b (1.68 and 1.89 g, respectively 0.01 mol) and piperidine (0.5 mL)
in dimethylformamide (30 mL) was heated under reflux for 6 h. The
reaction mixture was then cooled, poured into crushed ice, neutralized
with diluted HCl, and the obtained product was collected, washed with
cold water and recrystallized from proper solvent to give compound 7
(Table II).
6-Amino-3-(4-phenylazo-phenyl)-1-pyridin-2-yl-2-thioxo-4-p-
tolyl-1,2,3,4-tetra-hydro-pyrimidine-5-carbonitrile (7a)
IR (KBr) ν 3320, 3246 (NH2), 3050 (CH-arom.), 2932 (CH-aliph.),
2196 (C≡N), 1592 (N=N) cm−1. 1H NMR (DMSO-d6)δ 2.07 (s, 3H, CH3),
3.88 (s, 2H, NH2), 6.10 (s, 1H, 4H-pyrimidine), 6.65, 6.76, 7.45, 8.20
(4H-pyridine), 7.51–7.86 ppm (m, 13H, Ar-H).
6-Amino-4-(4-chloro-phenyl)-3-(4-phenylazo-phenyl)-1-
pyridin-2-yl-2-thioxo-1, 2, 3,
4-tetrahydro-pyrimidine-5-carbonitrile (7b)
IR (KBr) ν 3335, 3285 (NH2), 3044 (CH-arom.), 2935 (CH-aliph.),
2210 (C≡N), 1595 (N=N) cm−1. 1H NMR (DMSO-d6)δ 3.91 (s, 2H, NH2),
5.18 (s, 1H, 4H-pyrimidine), 6.61, 6.70, 7.43, 8.11 (4H-pyridine), 7.48–
7.93 ppm (m, 13H, Ar-H).

Recreations with Isothiocyanatoazobenzene
2633
N-{4-[Phenyldiazenyl]phenyl}hydrazinecarbothioamide (8)
A suspension of 4-isothiocynatoazobenzene 2 (2.39 g, 0.01 mol), hy-
drazine hydrate (0.5 mL, 0.01 mol) and ethanol (30 mL) was stirred
at room temperature for 1 h. The solid that separated out was filtered
off and recrystallized from proper solvent to give compound 8 (Table II).
IR (KBr) ν 3290, 3248, 3187 (NH, NH2), 3040 (CH-arom.), 1546 (N=N)
cm−1. 1H NMR (DMSO-d6) δ 3.85 (s, 2H, NH2), 7.64–7.95 (m, 9H, Ar-H),
9.25 (s, 1H, NH), 11.23 ppm (s, 1H, NH).
N-ethoxy-N-{4-[phenyldiazenyl]phenyl}thiourea (9)
A solution of compound 2 (2.39 g, 0.01 mol) in ethanol (30 mL) was
heated under reflux for 3 h and then left to cool; the crystalline prod-
uct thus formed was filtered, washed with diethyl ether, and recrystal-
lized from dioxan to give compound 9 (Table II). IR (KBr) ν 3227 (NH),
3041(CH-ar.), 2980 (CH-aliph.), 1546 (N=N) cm−1. 1H NMR (DMSO-d6)
δ 1.33 (t, 3H, CH3), 4.56 (q, 2H, OCH2), 7.55–7.91 (m, 9H, Ar-H), 11.37
ppm (s, 1H, NH).
N-{4-[Phenyldiazenyl]phenyl}-1,3-benzoxazol-2-amine (11)
A mixture of 2 (2.39 g, 0.01 mol) and 2-aminophenol (1.09 g, 0.01 mol)
in dimethyl-formamide containing few drops of triethylamine was re-
fluxed until evolution of H2S had stopped (lead acetate paper). After
cooling, the reaction mixture was poured into cold water and the solid
product that obtained was collected by filtration, washed with water
and recrystallized from proper solvent to give compound 11 (Table II).
IR (KBr) ν 3352 (NH), 3030 (CH-aromatic), 1596 (N=N) cm−1. 1H NMR
(DMSO-d6) δ 7.25–7.95 (m, 13H, Ar-H), 11.26 ppm (s, 1H, NH).
3-{4-[phenyldiazenyl]phenyl}-2-thioxo-2,3-dihydroquinazolin-
4(1H)-one (13)
A suspension of 4-isothiocyanatoazobenzene 2 (2.39 g, 0.01 mol) and
anthranilic acid (1.37 g, 0.01 mol) in toluene (30 mL) containing tri-
ethylamine (0.5 ml). The reaction mixture was heated under reflux for
30 min. The solid product, which produced on heating, was collected
and recrystallized from dioxan to give compound13 (Table II). IR (KBr)
ν 3231 (NH), 3030 (CH-arom.), 1658 (C=O), 1596 (N=N) cm−1. 1H NMR
(DMSO-d6) δ 7.33–7.98 (m, 13H, Ar-H), 13.10 ppm (b, 1H, NH).

2634
A.-B. A. A. M. El-Adasy
Preparation of Compounds 15 and 18—General Procedure
A mixture of isothiocyanate 2 (2.39 g, 0.01 mol) and 2-amino-3-
ethoxycarbonyl-7,5,6,7-tetrahydrobenzo[b]thiophene 16 or 2-amino-3-
cyano-5-methyl-N-(4-methyl-phenyl)thiophene-4-carboxamide 17 (2.27
and 2.71 g, respectively 0.01 mol) in ethanol (30 mL) containing triethy-
lamine (0.5 mL) was heated under reflux for 3. The solid obtained was
crystallized from proper solvent to give 15 and 18 (Table II).
Ethyl-2-{[(4-[phenyldiazenyl]phenylamino)carbonothioyl]
amino}-4,5,6,7 tetrahydro-1-benzothiophene-3-carboxylate
(15)
IR (KBr) ν 3240, 3160 (NH), 3042 (CH-arom.), 2933 (CH-aliph.), 1656
(C=O), 1595 (N=N) cm−1. 1H NMR (DMSO-d6)δ 1.23 (t, 3H, CH3), 1.72,
2.49 (8H, m, tetrahydraobenzo), 4.23 (q, 2H, OCH2), 7.21–7.98 (m, 9H,
Ar-H), 11.29 (s. 1H, NH), 12.01 ppm (S, 1H, NH).
3-Cyano-5-methyl-2-{[(4-[methyldiazenyl]phenyl}amino)
carbonothioyl]amino-N-(4-methylphenyl)thio-phene-4-
carboxamide (18)
IR (KBr) ν 3380, 3310, 3203 (NH), 3035 (CH-arom.), 2920 (CH-aliph.),
2203 (C≡N), 1660 (C=O), 1540 (N=N) cm−1. 1H NMR (DMSO-d6)δ 2.08
(s, 3H, CH3), 2.35 (s, 3H, CH3), 7.08–7.87 (m, 14H, Ar-H and NH), 9.56,
11.39 ppm (2s, 2H, 2NH).
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