Reactivity of functionally substituted azoles towards electrophiles. Novel synthesis of thienylazoles and phenylazoles

Article abstract of DOI:10.1081/SCC-120015571

Phenacyl bromide reacted with imidazole 1a and 1,2,4-triazole 1b to yield the respective azolylacetophenones 1c,d. These reacted with phenyl isothiocyanate and phenacyl bromide yielding thienylazoles 4a,b. Reaction of 1c,d with dimethylformamide dimethyla

Full text of DOI:10.1081/SCC-120015571

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Reactivity of Functionally Substituted Azoles Towards
Electrophiles. Novel Synthesis of Thienylazoles and
Phenylazoles
Mohamed Abdel-Megid a b
a Chemistry Department, Faculty of Education, Ain-Shams University, Roxy, Cairo, Egypt
b Chemistry Department, Faculty of Education, Ain-Shams University, Roxy, Cairo, Egypt
Version of record first published: 20 Aug 2006.
To cite this article: Mohamed Abdel-Megid (2003): Reactivity of Functionally Substituted Azoles Towards Electrophiles. Novel
Synthesis of Thienylazoles and Phenylazoles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:1, 153-160
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 1, pp. 153–160, 2003
Reactivity of Functionally Substituted Azoles
Towards Electrophiles. Novel Synthesis of
Thienylazoles and Phenylazoles
Mohamed Abdel-Megid
Chemistry Department, Faculty of Education,
Ain-Shams University, Roxy, Cairo, Egypt
ABSTRACT
Phenacyl bromide reacted with imidazole 1a and 1,2,4-triazole 1b to
yield the respective azolylacetophenones 1c,d. These reacted with
phenyl isothiocyanate and phenacyl bromide yielding thienylazoles
4a,b. Reaction of 1c,d with dimethylformamide dimethylacetal
followed by treating of the product with thiourea afforded the azo-
lylpyrimidines 10a,b. Azolylpyrans 8a,b were obtained from reaction
of 1c,d with acrylonitrile. The reaction of azoles 1a,b with chloro-
acetylacetone in acetone solution in the presence of base afforded the
phenylazoles 13a,b.
Correspondence: Mohamed Abdel-Megid, Chemistry Department, Faculty of
Education, Ain-Shams University, Roxy, Cairo, Egypt. E-mail: mabdelmegid@
yahoo.com.
153
DOI: 10.1081/SCC-120015571
Copyright & 2003 by Marcel Dekker, Inc.
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Abdel-Megid
INTRODUCTION
Functionally substituted alkylazoles have recently been shown to be
highly reactive towards nitrogen electrophiles.[1] This activity was
recently used for the synthesis of a variety of azolylpyridazines.[2] In
conjunction with our interest in substituted alkylazoles towards electro-
philes,[3] we report the results of an investigation towards phenyl isothio-
cyanate, aryldiazonium chloride and acrylonitrile. In addition, results of
ourtrials to condense a-chloroacetylacetone with azoles 1a,b that results
in a novel route to arylazoles are also reported.
RESULT AND DISCUSSION
Reaction of imidazole 1a and 1,2,4-triazole 1b with phenacyl
bromide yields the respective azolylacetophenones 1c,d.
Azolylacetophenones 1c,d reacted with phenyl isothiocyanate to
afford in situ an adduct that could not be isolated in pure form.
However, when treated with phenacyl bromide in solution, a product
to be formulated as 3a,b orisomeirc 4a,b, both can be formed from
intermediate 2. Structure 3 was readily ruled-out on the basis of IR
1
and H NMR spectra, both of which revealed the presence of an NH,
which is concordant with structure 4.
Compounds 1c,d also coupled with aromatic diazonium salts yield-
ing the corresponding arylhydrazones 5a–c. Boiling of 5a,c in a mixture
of acetic and hydrochloric acid yielded 3-azolylcinnolines 6a,b.
However, trials to utilize these arylhydrazones as synthetic equivalent
to nitrilimines in a way similar to that recently reported by Abdel-
Khalik and Elnagdi[4] for alkylpyrimidinium bromide failed. When com-
pounds 1c,d was allowed to react with acrylonitrile in pyridine–water

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Thienylazoles and Phenylazoles
155
mixture, a product with m/z 240 was obtained which does not show CN
absorption band in its IR spectra. This means that cyanoethylation
took place giving intermediate 7, which on cycloaddition gave 3-azolyl-
pyrans 8a,b.
Taking in consideration our interest in synthesizing some
new bioactive pyrimidines,[5] it was found that reaction of azolyl-
acetophenones 1c,d with dimethylformamide dimethylacetal (DMFDMA)
in xylene solution followed by treatment with thiourea yielded
5-azolylpyrimidinethiones 10a,b. It is believed that DMFDMA con-
denses firstly with azoles 1c,d yielding 9, which reacted further with
thiourea.

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In a trial to condense imidazole 1a and 1,2,4-triazole 1b with a-
chloroacetylacetone 11 in acetone solution and in presence of a base, a
product of such condensation was formed but react directly in situ with
acetone used as solvent yielding the corresponding arylazoles 13a,b. The
formation of arylazoles 13a,b occurred most likely via condensation of
acetone molecule with initially formed 12. To ourknowledge this is first
reported synthesis of azolylphenols via such a route. This reaction is now
being further investigation and the scope of this latter explored.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded as
KBr disks using a FTIR unit Bruker-Vector 22 spectrophotometer. The
1H NMR spectra were recorded on a Bruker Ac-80 spectrometer with
[D6] DMSO as solvent and TMS as internal standard; chemical shifts
are reported in ꢀ units (ppm). Mass spectra were measured on a
MS-5988 HP model. Microanalyses were performed at microanalytical
center, Cairo university.
v-(Imidazol-1-yl)acetophenone (1c)
A mixture of 1a (0.01 mol) in acetone (20 mL) was treated with
phenacyl bromide (0.012 mol) and triethylamine (0.01 mol) and refluxed
for 3 h. The solid product, so formed, was collected by filtration and
crystallized from ethanol to give 1c as a colorless crystals, m.p.
187–188ꢀC; yield (76%). IR (KBr): ꢁ ¼ 3340 (NH), 2980 (aliphatic

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Thienylazoles and Phenylazoles
157
CH), 1690 (CO), cmÀ1.1H NMR ꢀ ¼ 5.5 (s, 2H, COCH2), 6.9–7.6
(m, 8H, Ar-H). MS (EI, 70 eV): m/z ¼ 186 [Mþ]. Analysis for
C11H10N2O (186): Calcd: C 70.96, H 5.37, N 15.05; Found: C 71.00, H
5.50, N 14.90.
v-(1,2,4-Triazol-1-yl)acetophenone (1d)
The titled compound was prepared by the method reported in our
previous work.[3]
1-(2-Benzoyl-3-phenyl-5-phenylaminothien-4-yl)azoles (4a,b)
To a stirred mixture of 1c or 1d (0.025 mol) and potassium hydroxide
(0.025 mol) in dimethyl formamide (20 mL), phenyl isothiocyanate
(0.025 mol) was added and the reaction mixture was stirred at room tem-
perature for 4 h. Phenacyl bromide (0.025 mol) was added to the above
mixture and stirred for 24 h, then poured into cold water and neutralized
with 2 M hydrochloric acid. The solid obtained was filtered off and crystal-
lized from ethanol–water (1:1) to give 4 as yellow crystals.
1-(2-Benzoyl-3-phenyl-5-phenylamino-4-thienyl)imidazole (4a): M.p.
208–209ꢀC; yield (87%). IR (KBr): ꢁ ¼ 3400 (NH), 1680 (CO), cmÀ1
.
1H NMR ꢀ ¼ 10.8 (s, 1H, NH), 6.9–7.7 (m, 18H, Ar-H). MS (EI,
70 eV): m/z ¼ 421 (Mþ), 365 (18.9%), 311 (68%), 105 (100%), 77 (75%).
1-(2-Benzoyl-3-phenyl-5-phenylamino-4-thienyl)-1,2,4-triazole(4b):M.p.
190–192ꢀC; yield (86%). IR (KBr): ꢁ ¼ 3290 (NH), 1681 (CO), cmÀ1
.
1H NMR ꢀ ¼ 11.0 (s, 1H, NH), 6.8–7.6 (m, 15H, Ar-H), 8.8, 8.4 (2s, 2H,
triazolyl H-3 and H-5). MS (EI, 70 eV): m/z ¼ 422 (Mþ, 3.9%), 396
(16.3%), 380 (66.6%), 303 (18.9%), 145 (15.5%), 77 (100%). Analysis
forC 22H18N4SO (422): Calcd: C 71.09, H 4.26, N 13.27; Found: C
71.00, H 4.40, N 13.30.
General Procedure for the Preparation of Arylhydrazones 5a–c
Compound 1c or 1d (0.01 mol) was dissolved in ethanol (30 mL)
and treated with sodium acetate (3.0 g), then gradually treated under
stirring with a solution of aryldiazonium chloride (prepared from the
corresponding aromatic amine (0.01 mol) and the appropriate quantities
of both hydrochloric acid and sodium nitrite). The solid obtained was

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filtered off and crystallized from the proper solvent to give 5a–c as yellow
crystals.
v-(Imidazol-1-yl)- v-phenylhydrazonoacetophenone (5a): M.p. 196–
198ꢀC; yield (75%). IR (KBr): ꢁ ¼ 3380 (NH), 2950 (aliphatic CH), 1690
(CO), cmÀ1. 1H NMR ꢀ ¼ 10.6 (s, 1H, NH), 6.9–7.4 (m, 13H, Ar-H). MS
(EI, 70 eV): m/z ¼ 290 (Mþ, 21%), 273 (17%), 213 (26%), 77 (100%).
Analysis forC 17H14N4O (290): Calcd: C 70.34, H 4.80, N 19.31; Found:
C 70.50, H 5.00, N 19.20.
v-(Imidazol-1-yl)-v -tolylhydrazonoacetophenone (5b): M.p. 210–
212ꢀC; yield (72%). IR (KBr): ꢁ ¼ 3390 (NH), 2930 (aliphatic CH),
1695 (CO), cmÀ1
.
1H NMR ꢀ ¼ 10.8 (s, 1H, NH), 6.8–7.6 (m, 12H,
Ar-H), 2.6 (s, 1H, CH3). MS (EI, 70 eV): m/z ¼ 304 (Mþ, 4.9%), 287
(15.3%), 226 (34%), 77 (86%). Analysis forC 18H16N4O (304): Calcd.
C 71.05, H 5.20, N 18.42; Found: C 71.30, H 5.40, N 18.50.
v-(1,2,4-Triazol-1-yl)-v-phenylhydrazonoacetophenone (5c): The
titled compound has been prepared in our previous work.[3]
3-(1-Azolyl)-4-phenylcinnolines 6a,b
Compound 5a or 5c (0.01 mol) was dissolved in a mixture of conc.
hydrochloric and glacial acid (1:1) and refluxed for 3 h, cooled and
poured into cold water. The solid obtained was filtered off and crystal-
lized from the proper solvent to give 5a–c as colorless crystals.
3-(Imidazo-1-yl)-4-phenylcinnoline (6a): M.p. 245–246ꢀC; yield
(66%). IR (KBr): ꢁ ¼ 3030 (CH), 1640 (C¼N), cmÀ1
.
1H NMR
ꢀ ¼ 7–7.8 (m, 12H, Ar-H). MS (EI, 70 eV): m/z ¼ 249 (Mþ, 12.5%), 221
(2.78%), 194 (3.76%), 105 (100%), 77 (8.14%).
4-Phenyl-3-(triazo-1-yl)-cinnoline (6b): M.p. 210–212ꢀC; yield (56%).
1
IR (KBr): ꢁ ¼ 3030 (CH), 1645 (C¼N), cmÀ1. H NMR ꢀ ¼ 6.9–7.6 (m,
9H, Ar-H), 8.1 and 8.4 (2s, 2H, triazolyl H3 and H5). MS (EI, 70 eV):
m/z ¼ 273 (Mþ, 1.2%), 220 (15.6%), 222 (3.69%), 106 (100%), 77 (57%).
Analysis forC 16H11N5 (273): Calcd. C 70.32, H 4.02, N 25.64; Found: C
70.50, H 4.00, N 25.80.
2-Amino-5-(azol-1-yl)-6-phenyl-4H-pyran 8a,b
A mixture of 1c or 1d (0.01 mol) and acrylonitrile (0.015 mol) in
pyridine (10 mL) and water (3 mL) was refluxed for 6 h, cooled and
poured into cold water and neutralize with 2 N hydrochloric acid. The

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Thienylazoles and Phenylazoles
159
solid, so formed, was collected and crystallized from DMF-water to give
8a,b as yellow crystals.
2-Amino-5-(imidazol-1-yl)-6-phenyl-4H-pyran (8a): M.p. 286–287ꢀC;
yield (89%). IR (KBr): ꢁ ¼ 3420–3330 (NH), 2920 (CH), 1645 (C¼N),
1100 (C-O-C) cmÀ1. 1H NMR ꢀ ¼ 5.5 (brs, 2H, NH 2), 6.5 (m, 2H, C4-H-
pyran), 6.9–7.6 (m, 9H, Ar-H). MS (EI, 70 eV): m/z ¼ 239 (Mþ, 12.0%),
235 (27.1%), 186 (18.6%), 123 (7.6%).
2-Amino-6-phenyl-5-(triazol-1-yl)-4H-pyran (8b): M.p.>300ꢀC; yield
(65%). IR (KBr): ꢁ ¼ 3420, 3330 (NH2), 2950 (CH), 1640 (C¼N), 1150
(C-O-C) cmÀ1. 1H NMR ꢀ ¼ 5.6 (br, 2H, NH2), 6.5 (m, 2H, C4-H-pyran),
6.9–7.6 (m, 5H, Ar-H), 8.1 and 8.45 (2s, 2H, triazolyl H3 and H5). MS
(EI, 70 eV): m/z ¼ 240 (Mþ, 16%), 236 (33.6%), 185 (21.4%), 152
(28.38%). Analysis forC 13H12N4O (240): Calcd: C 65.00, H 5.00, N
23.33; Found: C 65.40, H 5.20, N 23.50.
5-(Azol-1-yl)-4-phenyl 2(1H)-pyrimidinethiones 10a,b
A mixture of 1c or 1b (0.01 mol) and DMFDMA (0.03 mol) in xylene
(20 mL) was refluxed for 12 h, then evaporated the excess solvent. To the
above reaction mixture thiourea (0.012 mol) was added and refluxed for
1 h, then treated with ethanol and poured into cold water. The solid
obtained was filtered off and crystallized from the proper solvent to
give 10a,b as yellow crystals.
5-(Imidazol-1-yl)-4-phenyl 2(1H)-pyrimidinethione (10a): M.p. 196–
198ꢀC; yield (72%). IR (KBr): ꢁ ¼ 3330 (NH), 1660 (C¼N) cmÀ1
.
1H NMR ꢀ ¼ 9.6 (s, 1H, NH), 6.8–7.6 (m, 9H, Ar-H). MS (EI, 70 eV):
m/z ¼ 254 (Mþ, 6.1%), 187 (21.2%), 77 (100%). Analysis forC 13H10N4S
(254): Calcd: C 63.73, H 3.93, N 22.04; Found: C 63.80, H 4.00, N 22.00.
4-Phenyl-5-(1 ,2,4-triazol-1-yl)-2(1H)-pyrimidinethione (10b): M.p.
150–152ꢀC; yield (78%). IR (KBr): ꢁ ¼ 3340 (NH), 1680 (C¼N) cmÀ1
.
1H NMR ꢀ ¼ 9.8 (s, 1H, NH), 6.9–7.6 (m, 6H, Ar-H), 8.08 and 8.49 (2s,
2H, triazolyl H3 and H5). MS (EI, 70 eV): m/z ¼ 255 (Mþ, 26%), 198
(12%), 123 (68%), 77 (17%). Analysis forC 13H10N4S (254): Calcd: C
56.47, H 3.52, N 27.45; Found: C 56.40, H 3.50, N 27.60.
1-(3,5-Dimethylphenol-2-yl)azoles 12a,b
A mixture of 1a or 1c (0.01 mol) and a-chloroacetylacetone
(0.012 mol) in acetone (30 mL) was refluxed for 3 h. The solid obtained

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Abdel-Megid
during heating was filtered off and washed with ice-cold ethanol to give
12a,b as colorless crystals.
1-(3,5-Dimethylphenol-2-yl)imidazole (12a): M.p. 235–237ꢀC; yield
(86%). IR (KBr): ꢁ ¼ 3450 (OH), 1690 (C¼O), 1665 (C¼N) cmÀ1
.
1H NMR ꢀ ¼ 9.32 (s, 1H, OH), 6.8–7.4 (m, 5H, Ar-H), 2.8 (s, 3H, C3-
CH3), 2.6 (s, 3H, C5-CH3). MS (EI, 70 eV): m/z ¼ 188 (Mþ, 1.6%), 149
(3.6%), 123 (12%), 84 (100%).
1-(3,5-Dimethylphenol-2-yl)1,2,4-triazole (12b): M.p. 245–247ꢀC;
yield (78%). IR (KBr): ꢁ ¼ 3440 (OH), 1690 (C¼O), 1660 (C¼N) cmÀ1
.
1H NMR ꢀ ¼ 9.3 (s, 1H, OH), 6.6–7.2 (m, 4H, Ar-H), 8.1 and 8.39 (2s,
2H, triazolyl H-3 and H-5), 3.0 (s, 3H, C3-CH3), 2.5 (s, 3H, C5-CH3). MS
(EI, 70 eV): m/z ¼ 189 (Mþ, 2.0%), 167 (15.3%), 129 (22.8%), 84 (100%).
Analysis forC 10H11N3O (189): Calcd: C 63.49, H 5.82, N 22.22; Found:
C 64.00, H 5.60, N 22.30.
REFERENCES
1. Al-Naggar, A.; Abdel-Khalik, M.M.; Elnagdi, M.H. J. Chem. Res.
(S) 1999, 654–655.
2. Al-Omran, F.; Al-Awadi, N.; Yousef, O.; Elnagdi, M.H.;
J. Heterocyclic Chem. 2000, 37, 167.
3. Abdel-Megid, M.; Elnagdi, M.H.; Negm, A.M. J. Heterocyclic
Chem. in press.
4. Abdel-Khalik, M.M.; Elnagdi, M.H.; Agamy, S.M. Synthesis 2000,
1166–1169.
5. Abdel-Megid, M. Pharmazie 2000, 55, 263–266.
Received in the UK June 15, 2001