Synthesis of new azolyl azoles and azinyl azoles

Article abstract of DOI:10.1002/jhet.5570420402

Synthesis of new azolyl azoles and azinyl azoles from the reaction of compounds 1, 4 and 7 with phenyl isothiocyanate is reported. Compound 10 reacts with benzene diazonium chloride to yield either phenylhydrazones 11 and 12 or the triazoloquinoline 13.

Full text of DOI:10.1002/jhet.5570420402

May-Jun 2005
483
Synthesis of New Azolyl Azoles and Azinyl Azoles
Balkis Al-Saleh†*, Morsy Ahmed El-Apasery†, Mohamed Hilmy Elnagdi‡*
†
Department of Chemistry, Faculty of Science,
University of Kuwait, P. 0. Box 5969, 13060 Safat, KUWAIT.
Department of Chemistry, Faculty of Science, Cairo University, Giza, EGYPT.
‡
Received May 24, 2004
Synthesis of new azolyl azoles and azinyl azoles from the reaction of compounds 1, 4 and 7 with phenyl
isothiocyanate is reported. Compound 10 reacts with benzene diazonium chloride to yield either phenylhy-
drazones 11 and 12 or the triazoloquinoline 13.
J. Heterocyclic Chem., 42, 483 (2005).
Scheme 2
It is known that a methylene group attached to nitrogen
atoms of azoles is activated toward electrophilic reagents
and this feature has stimulated recent interest in the utility
of azolylmethyl ketones as building block in heterocyclic
chemistry [1-7]. In conjunction with previous work [7-9],
we now report the synthesis of the title compounds 1, 4, 7
and 10. As part of our ongoing program, we decided to
synthesize new N-heteroarylazoles in order to explore the
biological properties and the pyrolysis in the gas phase.
Scheme 1
Like in previous reports [6] compounds 1c and 10c react
with benzene diazonium chloride to yield the arylhydra-
zones 11 and 1 2. However, these compounds did not con-
dense with active methylene reagents, such as malononi-
trile derivatives, to yield pyridazinones as it was reported
for benzotriazolyl derivatives [3]. Reaction of compound
4b with benzenediazonium chloride did not afford the
expected arylhydrazones, instead compound 13 was
formed. This compound could be formed via further
cyclization under these reaction conditions (see Scheme 3).
Compounds la and 1b react with phenyl isothiocyanate
in dimethylformamide (DMF) in the presence of potas-
sium hydroxide and after acidification of the reaction mix-
ture compounds 2a and 2b are obtained. Analysis of 13C-
nmr data of compounds 2a and 2b shows a signal at ca.
190 ppm which is assigned to the presence of conjugated
carbonyl carbon (CO) and the signal corresponding to the
methylene group was not observed. NOE experiments
show that the Z isomer of compound 2 was preferred over
the E isomer indicating that the Ph and the R groups are
close to each other (Figure 1). Similarly, compounds 4a
and 7 react with phenyl isothiocyanate to yield compounds
5 and 8 but these compounds could not be isolated.
However, when compounds 2b, 5a and 8 were treated with
chloroacetone or phenacyl bromide in the presence of
potassium hydroxide thiophene derivatives 3, 6, and 9
were formed and isolated in good yields (see Schemes 1
and 2). Compounds 4b, 10a and 10b failed to react with
phenyl isothiocyanate under a variety of experimental con-
ditions; diphenylthiourea was the only product isolated
from these reactions.
Scheme 3
Treatment of la with bromine in acetic acid followed by
reaction with potassium thiocyanate led to the thiocyanate

484
B. Al-Saleh, M. A. El-Apasery, M. H. Elnagdi
Vol. 42
and potassium hydroxide (0.06 g) was stirred overnight. The sol-
vent was evaporated and the residue was ground with water and
then neutralized with concentrated hydrochloric acid. The solid
product so formed was collected and crystallized from ethanol.
derivative 14. Compound la reacted with sodium nitrite in
the presence of hydrochloric acid to yield oxime 15 which
gave the phenylhydrzone 16 when reacted with phenylhy-
drazine. In a previous report [8] we assumed that oxime 15
underwent Beckman rearrangement. In fact, we verified
that the Beckman rearrangement of oxime 15 did not take
place under different experimental conditions (Scheme 4).
3-Benzotriazol-1-yl-4-mercapto-4-phenylamino-but-3-en-2-one
(2a).
This compound was obtained in 55 % yield, mp 172-173 °C,
-1
IR (KBr): ν 3010 (NH), 1654 (CO) cm ; H nmr; (dimethylsul-
1
foxide-d ): δ = 15.47 (s, 1H, SH), 8.21 (s, 1H, NH), 7.66-7.25 (m,
13
6
9H, Ar-H), 1.69 (s, 3H, CH ); C nmr; (dimethylsulfoxide-d ): δ
Scheme 4
3
= 196.1 (CO), 146.2, 132.9, 130.2, 129.5, 128.5, 124.2, 118.9,
6
115.1, 113.5, 25.3 (CH ).
3
Anal. Calcd. for C H N OS (310.37): C, 61.91; H, 4.54; N,
16 14
18.05; S, 10.33. Found: C, 61.90; H, 4.61; N, 18.07; S, 10.34.
4
2-Benzotriazol-1-yl-3-mercapto-1-phenyl-3-phenylamino-
propenone (2 b) .
This compound was obtained in 61 % yield, mp 174-176 °C,
-1
IR (KBr): ν 3163 (NH), 1607 (CO) cm ; H nmr; (dimethylsul-
1
foxide-d ): δ = 15.84 (s, 1H, SH), 8.38 (s, 1H, NH), 7.91-7.01 (m,
13
6
14H Ar-H); C nmr; (dimethylsulfoxide-d ): δ = 195.1 (CO),
6
190.3, 146.3, 139.9, 136.1, 134.3, 123.0, 129.5, 128.9, 128.5,
The presented results when combined with previous
reports [3-9] clearly demonstrate that 2-azolyl-1-substi-
tuted ethanones are valuable precursor for N-heteroaryl
substituted azoles that are of interest for potential biologi-
cal activity evaluation.
127.67, 125.4, 124.2, 123.9, 120.3, 113.2, 72.8.
Anal. Calcd. for C H N OS (372.44): C, 67.72; H, 4.32; N,
21 16
4
15.04; S, 8.6. Found: C, 67.70; H, 4.52; N, 15.16; S, 8.41.
Preparation of Compounds 3, 6 and 9.
General Procedure.
EXPERIMENTAL
To a stirred suspension of compound 1b (or 4a or 7) (10
mmol), phenyl isothiocyanate (1.35 g, 10 mmol) and potassium
hydroxide (0.06 g) in DMF (20 ml) the α-haloketone (10 mmol)
was added. The reaction mixture was stirred for 16 hours. Then,
the reaction mixture was heated under reflux for an additional 4
hours. The solvent was evaporated under vacuum and the residue
was ground with water and neutralized with concentrated
hydrochloric acid. The solid product so formed was collected and
crystallized from dioxane.
All melting points are uncorrected. IR spectra were recorded in
1
KBr with a Pye Unicam SP 1100 spectrophotometer. H Nmr and
13
C nmr were run in deuteriochloroform or dimethylsulfoxide-d
at 400 MHz with a Varian EM-390 spectrometer. Chemical shifts
are reported in ppm values, using TMS as internal standard. Mass
spectra were obtained under electron impact on MS 30 and MS 9
(AEI) at 70 eV. Microanalyses were performed on LECO CHNS-
932. Compounds 1-3 were prepared following on published
procedure [9].
6
(4-Benzotriazol-1-yl-3-phenyl-5-phenylamino-thiophen-2-yl)-
phenyl-methanone (3).
l-Benzimidazol-l-yl-propan-2-one (1c).
This compound was obtained in 56 % yield, mp 282-283 °C,
To a solution of benzimidazole (1.18 g, 10 mmol) and triethy-
lamine (1 ml) in acetone (20 ml) was added chloroacetone (0.91
g, 10 mmol) and the reaction mixture was refluxed for 4 hrs.
After removal of the triethylamine hydrochloride by filtration,
the filtrate was evaporated under vacuum and the resulting solid
was collected and crystallized from toluene to give 1c in 77 %
-1
IR (KBr): ν 3049 (NH), 1622 (CO) cm ; H nmr; (dimethylsul-
1
foxide-d ): δ = 9.88 (s, 1H, NH), 9.36 (s, 1H imidazol H-2), 8.05-
6
7.17 (m, 17H, 3phenyl and imidazole H-4, H-5), 5.98 (s, 2H
CH ), 1.80 (s, 3H, CH ).
Anal. Calcd. for C H N OS (472.56): C, 62.36; H, 4.33; N,
2
3
29 20
4
7.52; S, 5.74. Found: C, 62.57; H, 4.53; N, 7.94; S, 5.64.
-1
1
yield, mp 136-137 °C, IR (KBr): ν 1720 (CO) cm ; H nmr;
(dimethylsulfoxide-d ): δ = 8.11 (s, 1H benzimidazole H-2),
1-(5-Acetyl-4-phenyl-2-phenylamino-thiophen-3-yl)-pyridinium
Bromide (6).
6
7.79-7.19 (m, 4H benzimidazolyl H), 5.32 (s, 2H, CH ), 2.24 (s,
13
2
3H, CH ); C nmr; (dimethylsulfoxide-d ): δ = 203.32 (CO),
3
145.6, 144.1, 142.9, 122.8, 122.5, 120.3, 116.3, 111.5, 54.3
6
This compound was obtained in 71 % yield, mp 218-219 °C,
-1
IR (KBr): ν 3057 (NH), 1608 (CO) cm ; H nmr; (dimethylsul-
1
(COCH ), 27.9 (CH ).
2
Anal. Calcd. for C
3
foxide-d ): δ = 9.42 (s, 1H, NH), 8.01-6.74 (m, 19H Ar-H).
6
Anal. Calcd. for C
H N O (174.20): C, 68.94; H, 5.78; N,
10 10 2
H BrN OS (451.38): C, 73.70; H, 4.26;
23 19 2
N, 11.85; S, 6.78. Found: C, 73.74; H, 4.28; N, 11.96; S, 6.82.
16.08. Found: C, 68.97; H, 5.76; N, 16.08.
Preparation of Compounds 2a and 2b.
General Procedure.
3-(5-Acetyl-4-phenyl-2-phenylamino-thiophen-3-yl)-1-(2-oxo-
2-phenyl-ethyl)-3H-imidazol-1-ium Bromide (9).
To a stirred suspension of la (or 1b) (10 mmol) and phenyl
isothiocyanate (1.35 g, 10 mmol) in dimethylformamide (20 ml)
This compound was obtained in 27 % yield, mp. 198-200 °C,
-1
IR (KBr): ν 3041 (NH), 1622 (CO) cm ; H nmr; (dimethylsul-
1

May-Jun 2005
Synthesis of New Azolyl Azoles and Azinyl Azoles
485
11.95. Found: C, 78.68; H, 5.04; N, 11.19.
foxide-d ): δ = 10.05 (s, 1H, NH), 9.3 (1H pyridyl H-6; J = 4 Hz),
8.82 (1H pyridyl H-4), 8.3 (m, 2H, pyridyl H-3, H-5), 7.72-7.01
6
1-Benzotriazol-1-yl-3-thiocyanato-propan-2-one (14).
(m, 10H Ar-H), 1.95 (s, 3H, CH ).
Anal. Calcd. for C
3
H BrN O S (558.49): C, 61.20; H, 4.24;
A mixture of compound 1a (1.75 g, 10 mmol) and bromine
(0.8 g, 10 mmol) in acetic acid was stirred for 2 hours. After stir-
ring, potassium thiocyanate (0.97 g) was added and the reaction
mixture was stirred for additional 4 hours. The reaction mixture
was poured onto water and neutralized with a dilute hydrochloric
acid solution (0.1 N) resulting in a solid precipitate. The solid
residue was collected by filtration and crystallized from
dimethylformamide to give 14 in 53 % yield, mp 178-180 °C, IR
29 24 3 2
N, 6.20; S, 7.10. Found: C, 61.22; H, 4.64; N, 6.14; S, 6.67.
l,3-Bis-(2-oxo-2-phenylethyl)-3H-imidazol-1-ium Bromide (7).
To a solution of imidazole (0.68 g, 10 mmol) and triethy-
lamine (1 ml) in acetone (20 ml) phenacylbromide (1.99 g, 10
mmol) was added. The reaction mixture was refluxed for 2 hrs.
The solvent was evaporated under vacuum and the solid prod-
uct was collected and crystallized from ethanol to give 7 in 74
% yield, mp 264-266 °C, IR (KBr): ν 3310 (OH), 1690 (CO
-1
1
(KBr): ν 2156 (CN), 1743 (CO) cm ; H nmr; (dimethylsulfox-
ide-d ): δ = 8.09-7.41 (m, 4H, benzotriazole H), 6.00 (2H,
13
6
CH SCN), 4.56 (CH ); C nmr; (dimethylsulfoxide-d ): δ =
-1
1
(CO) cm ; H nmr; (dimethylsulfoxide-d ): δ = 9.16 (s, 1H
imidazole H-2), 8.40-7.66 (m, 12H Ar-H and imidazole H-4 and
2
2
6
6
202.2 (CO), 146.0, 134.7, 128.3, 124.9, 120.1, 118.8 (CN), 57.5,
28.2.
Anal. Calcd. for C H N OS (232.26): C, 51.71; H, 3.47; N,
H-5), 6.24, 6.22 (4H, 2CH ).
Anal. Calcd. for C
2
H BrN O (385.25): C, 59.27; H, 4.44;
19 17 2 2
10
8 4
N, 7.2. Found: C, 59.27; H4.42; N, 7.50.
Preparation of Compounds 11, 12 and 13.
General Procedure.
24.12; S, 13.80. Found: C, 51.75; H, 3.50; N, 24.24; S, 13.96.
1-Benzotriazol-1-yl-propan-1,2-dione-1-oxime (15).
A suspension of compound la (1.75 g, 10 mmol) and hydrochlo-
ric acid (20 ml) in the presence of sodium nitrite (0.69 g) was
stirred overnight at room temperature and then poured onto ice
water. The solid was collected and crystallized from ethanol to give
15 in 79 % yield, mp 152-154 °C, IR (KBr): ν 3310 (OH), 1705
A solution of compound 1c (or 4b or 10c) (10 mmol) in
ethanol (10 ml) was treated with sodium acetate (2 g) and a solu-
tion of aryldiazonium chloride (prepared from the corresponding
aromatic amine (10 mmol) and the appropriate quantities of both
hydrochloric acid and sodium nitrite) was added dropwise under
stirring at room temperature for 1 hour. The solid product was
collected by filtration and crystallized from dioxane.
-1
1
(CO) cm ; H nmr; (dimethylsulfoxide-d ): δ = 13.88 (s, 1H, N-
13
6
OH), 8.17-7.46 (m, 4H, benzotriazole H), 2.65 (s, 3H, CH ).;
C
nmr; (dimethylsulfoxide-d ): δ = 191.8 (CO), 145.0, 142.9, 133.8,
3
6
129.6, 127.6, 125.6, 118.9, 112.5, 25.8 (CH ).
3
Anal. Calcd. for C H N O (204.19): C, 52.94; H, 3.94; N,
1-Imidazol-1-yl-1-(phenyl-hydrazono)-propan-2-one (11).
9
27.43. Found: C, 52.92; H, 3.41; N, 27.49.
8 4 2
This compound was obtained in 61 % yield, mp 248-250 °C,
-1
1
IR (KBr): ν 3165 (NH), 1678 (CO) cm ; H nmr; (dimethylsul-
l-Benzotriazol-l-yl-2-(phenylhydrazono)-propan-1-one Oxime
(16).
foxide-d ): δ = 10.61 (s, 1H, NH), 7.68 (s, 1H imidazol H-2),
7.40 (d, 1H, J = 8Hz imidazol H-5), 7.36-7.00 (m, 6H, Ar-H and
6
A mixture of compound 15 (2.04 g, 10 mmol) and phenylhy-
drazine (1.08 g, 10 mmol) in ethanol (10 ml) was refluxed for 1 h.
The solvent was evaporated under vacuum, and the solid residue
was collected and crystallized from ethanol to five 16 in 54 %
13
imidazole H-4), 2.51 (s, 3H, CH ); C nmr; (dimethylsulfoxide-
3
d ): δ = 191.8 (CO), 144.0, 138.6, 136.1, 130.6, 129.9, 129.7,
6
121.2, 115.9, 25.8 (CH ).
3
Anal. Calcd. for C
24.54. Found: C, 63.15; H, 5.42; N, 24.59.
H N O (228.25): C, 63.14; H, 5.29; N,
12 12 4
-1
yield, mp 198-200 °C, IR (KBr): ν 3294 (OH), 3012(NH) cm ;
1
H nmr; (dimethylsulfoxide-d ): δ = 12.55 (s, 1H, N-OH), 9.72
(s, 1H, NH), 8.21-6.52 (m, 9H, benzotriazole H, Ar-H), 2.36 (s,
3H, CH ).
6
1-Benzoimidazol-1-yl-1-(phenyl-hydrazono)-propan-2-one (12).
This compound was obtained in 72 % yield, mp 263-264 °C,
-1 1
IR (KBr): ν 3165 (NH), 1678 (CO) cm ; H nmr; (dimethylsul-
3
Anal. Calcd. for C
28.55. Found: C, 61.40; H, 4.83; N, 28.26.
H N O (294.31): C, 61.16; H, 4.79; N,
15 14 6
foxide-d ): δ = 10.82 (s, 1H, NH), 8.22 (s, 1H benzimidazol
13
6
H-2), 7.77-7.03 (m, 9H, Ar-H), 2.59 (s, 3H, CH ); C nmr;
3
(dimethylsulfoxide-d ): δ = 192.0 (CO), 145.3, 144.1, 143.9,
Acknowledgement.
6
134.1, 130.3, 128.9, 124.3, 123.9, 121.5, 120.8, 115.9, 110.0,
107.5, 25.8 (CH ).
The authors are grateful to University of Kuwait, Research
Administration for financial support through project SC 103.
Analytical facilities provided by SAF are highly appreciated.
3
Anal. Calcd. for C
20.13. Found: C, 69.00; H, 5.08; N, 20.08.
H N O (278.31): C, 69.05; H, 5.07; N,
16 14 4
Phenyl-(3-phenyl-3,3a-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1-
yl)-methanone (13).
REFERENCES AND NOTES
[1] A. R. Katritky, X. Lan and W. Fan Synthesis, 445 (1993).
[2] R. Katritzky, X. Lan, J. Z. Yang and O. V. Denisko Chem.
Rev., 98, 409 (1998).
[3] A-Al-Naggar, M. M. Abdel-Khalik and M. H. Elnagdi, J.
Chem. Res.(S), 654 (1999).
This compound was obtained in 51 % yield, mp 106-108 °C,
-1 1
IR (KBr): ν 1641 (CO) cm ; H NMR (dimethylsulfoxide-d ): δ
6
= 8.02 (d, 1H, J = 8Hz, H5), 7.95 (d, 1H, J = 8Hz, H6), 7.2-7.92
(m, 13H, Ar-H), 7.01 (d, 1H, J = 6Hz, H3a), 4.4 (d, 1H, J = 6Hz,
13
H4); C NMR (dimethylsulfoxide-d ): δ = 192.00 (CO), 156.2,
[4] M. M. Abdel-Khalik, S. M Agamy and M. H. Elnagdi,
Synthesis, 8, 1166 (2000).
6
144.6, 143.2, 142.7, 135.3, 130.1, 129.5, 128.9m 128.5, 127.5,
127.1, 122.5, 120.5, 118.9, 113.3, 112.5, 111.2, 68.9.
Anal. Calcd. for C
[5] M. A. Megid, M. H. Elnagdi and A. M. Negm, J. Heterocyclic
Chem., 39, 105 (2002).
H N O (351.40): C, 78.61; H, 4.87; N,
23 17 3

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B. Al-Saleh, M. A. El-Apasery, M. H. Elnagdi
Vol. 42
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