Full text of DOI:10.1002/jhet.5570390115

Studies with 1-Functionally Substituted Alkyl Azoles:
Novel Synthesis of Functionally Substituted Azolylbenzimidazoles
and Functionally Substituted Azolyl-1,2,4-Triazoles
105
Jan-Feb 2002
Mohamed Abdel-Megid* [1], Mohamed H. Elnagdi [2] and Abdalla M. Negm [2]
[1] Chemistry Department, Faculty of Education, Ain-Shams University Roxy, Cairo Egypt
[2] Department of Chemistry, Faculty of Science, Cairo University, Giza-Egypt
Received May 18, 2001
ω-Azolylacetophenones 1 and 2 react with dimethylformamide dimethylacetal to yield enaminones 7,8
that were converted into azolylazoles via reaction with hydrazine and with hydroxylamine. Compounds 1,2
also coupled with aromatic diazonium salts to yield arylhydrazones and reacted with nitrous acid to yield
corresponding oximes.
J. Heterocyclic Chem., 39, 105 (2002).
The ability of the benzotriazole ring to stabilise acyl
Compounds 1 and 2 condensed readily with dimethyl-
formamide dimethylacetal (DMFDMA) to yield the
enaminones 7 and 8. Compound 7 reacted with
hydrazine hydrate and with phenylhydrazine to yield
pyrazole derivatives which may be formulated as 9a,b
or isomeric 10a,b. Structure 9a,b could be established
for these products based on the non-identity of reaction
of 7 with phenylhydrazine with a sample of 10b,
prepared via initial condensation of 1 with phenyl-
hydrazine and subsequent reaction of the formed
phenylhydrazone 11a with DMFDMA. Compound 7
also reacted with hydroxylamine to yield a product that
may be formulated also as 9c or 10c. Attempt to prepare
a sample of 10c from the reaction of oxime 11b with
DMFDMA failed. However, structure 9c could be
established for the reaction product based on its
conversion into the nitrile 12, which was also prepared
via direct cyanation of 1 with N-cyanobenzotriazole 13 :
carbanions directly attached to the ring N-1 by effectively
attracting negative charge has attracted considerable
attention in recent years[1-5]. Recently we have
demonstrated that the pyrazole function in pyrazolylacetone
also stablise adjacent carbanions[6]. Although N-1 function-
ally substituted alkyl benzimidazoles and N-1 functionally
substituted 1,2,4-triazoles are also capable of stabilising
negative charges on carbons adjacent to the ring N, the
carbanionic chemistry of these species has attracted only
very limited interest [7]. As part of biological chemistry
programmes in our laboratory, samples of functionally
substituted benzimidazoles and 1,2,4-triazoles were
required. We have therefore investigated the carbanionic
chemistry of 1 and 2 as an easy route to required compounds.
In the present article we report on the synthesis of 1 and 2
and their utility for the preparation of the desired derivatives.
The work has resulted in the synthesis of a number of
derivatives of 1 and 2, some of which carry latent functional
substituents useful for further chemical transformations.
Thus 1 and 2 were prepared in good yields by reacting
benzimidazole and 1,2,4-triazole 4 with phenacyl bromide
5 in refluxing acetone in the presence of equivalent
amounts of triethyl amine. Although reaction of 4 with 5
may also yield 6, structure 2 was established for the
+
a new synthetic equivalent of CN [8].
1
reaction product based on H NMR spectroscopy which
revealed the two triazolyl ring protons at δ 8.08 and
8.56 ppm,. If the reaction product is 6 the triazolyl protons
should give one nmr signal as the molecule is symmetrical.
Like 7, compound 8 reacted with hydrazines to yield the
pyrazole derivatives 14a,b and with hydroxylamine to
yield isoxazole 14c. The isomeric pyrazole 15b could be

106
Vol. 39
M. Abdel-Megid, M. H. Elnagdi and A. M. Negm
prepared by condensing 2 with phenylhydrazine and
subsequent condensation of the formed phenylhydrazone
with DMFDMA.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were
recorded as KBr discs using a FTIR unit Bruker-Vector 22
1
spectrophotometer. The H NMR spectra were recorded on a
Bruker AC-80 spectrometer with, DMSO-d as solvent and TMS
6
as internal standard. Chemical shifts are reported in δ units
(ppm). Mass spectra were measured on a Shimadzu GCMS-QP
1000 Ex mass spectrometer at 70 eV. Microanalyses were
performed at the microanalytical center, Cairo University.
ω-(Benzimidazol-1-yl)acetophenone (1).
A mixture of 3 (0.01 mol) and 5 (0.011 mol) in acetone (20 ml)
was treated with triethylamine (0.01 mol) and refluxed for
2 hours. The solid product, so formed, was collected by filtration
and crystallized from DMF to give 1 as colourless crystals; mp
1
240-1 °C; yield (92 %); H NMR (200 MHz, DMSO-d ): δ 5.6
6
(s, 2H, COCH ), 6.8-7.6 (m, 10H, Ar-H); IR (KBr): ν 2970
2
-1
(aliphatic CH) and 1690 (CO )cm ; MS (EI, 70 eV): m/z (%),
236 [M (7)], 213(7), 199(7), 185(7).
+
Anal. Calcd. for C
H N O: C 76.27; H, 5.08; N 11.86%.
15 12 2
Found: C 76.50; H 5.0; N 11.80%.
ω-(1,2,4-Triazol-1-yl)acetophenone (2).
A mixture of 4 (0.01 mol) and 5 (0.011 mol) in acetone (20 ml)
was treated with triethylamine (0.01 mol) and refluxed for
8 hours. The solid obtained upon heating was collected by
filtration and crystallized from ethanol to give 2 as colourless
1
crystals; mp 195-6 °C; yield 86%. H NMR (200 MHz,
DMSO-d ): δ 5.6 (s, 2H, COCH ), 6.9-7.6 (m, 5H, Ar-H), 8.08
6
2
Likewise, the isoxazole 14c was converted into the
oxoalkanenitrile 16 on refluxing in dioxane in the presence
of NaH. Alternatively 16 was directly prepared from
reaction of 2 with 13.
and, 8.50 (2s, 2H, H-3 and H-5); IR (KBr): ν 2920 (aliphatic CH)
-1
+
and 1680 (CO) cm ; MS (EI, 70 eV): m/z (%), 187 [M , (5)],
167(26), 150(12), 149(100), 129(12).
Anal. Calcd. for C H N O: C 64.17; H 4.81; N 22.45%.
10
9 3
Compound 1 and 2 coupled with aromatic diazonium
salts to yield the corresponding arylhydrazones 17a,b and
18a,b (or possible steric isomers), respectively.
Found: C 64.40; H, 5.00 ; N 22.50%.
Formation of Enaminones 7 and 8.
A mixture of 1 or 2 (0.01 mol) and DMFDMA (0.012 mol) in
xylene (30 ml) was refluxed for 12 hours. The reaction mixture
was evaporated in vacuo to give enaminone 7 or 8 as a yellow oil.
Reaction of Enaminones 7 with Hydrazines: Formation of
Pyrazoles (9a,b).
A mixture of 7 (0.01 mol) and hydrazine hydrate or phenyl-
hydrazine (0.012 mol) was heated under reflux in absolute
ethanol for 4 hours, then allowed to cool to room temperature and
poured into cold water. The solid product, so formed, was
collected by filtration and crystallized from the appropriate
solvent to give 9a,b.
Compounds 1 and 2 also reacted with sodium nitrite in
acetic acid solution to yield oximes 19 and 20.
2-(Benzimidazol-1-yl)-5-phenyl-1H-pyrazole (9a).
Compound 9a was obtained as yellow crystals from
ethanol/water(1:1), mp 168-170 °C; yield 68%. H NMR
1
(200 MHz, DMSO-d ): δ 6.8-7.6 (m, 11H, Ar-H and pyrazolyl H-
6
-1
4), 11.0 (s, 1H, NH); IR (KBr): ν 3400 (NH), 1630 (C=N) cm ;
MS (EI, 70 eV): m/z (%) = 260 [M , (6)], 257(7), 255(5),
+
250(50), 237(15).
Anal. Calcd. for C
H N : C 73.84; H 4.61; N 21.53%.
16 12 4
Found: C 74.00; H 4.50; N 21.50%.

Studies with 1-Functionally Substituted Alkyl Azoles
107
Jan-Feb 2002
4-(Benzimidazol-1-yl)-1,5-diphenyl pyrazole (9b).
mixture was poured into cold water. The solid obtained was
isolated by filtration and crystallized from acetic acid to give 12,
mp 210 °C; yield 62%.
Compound 9b was obtained as yellow crystals from acetic
1
acid, mp 185-6 °C; yield 72%. H NMR (200 MHz, DMSO-d ):
6
δ 6.8-7.4 (m, 16H, Ar-H and pyrazolyl H-3); IR (KBr): ν 3050
(CH), 640 (C=N) cm .
Method B.
-1
A mixture of 1 (0.01 mol) and 13 (0.01 mol) in dioxane (20 ml)
containing sodium hydride was refluxed for 6 hours. The solid so
formed was collected by filtration and crystallized from acetic
Anal. Calcd. for C
Found: C 78.80; H 4.60; N 16.50%.
H N : C 78.57; H 4.76; N 16.66%.
22 16 4
1
acid to give 12, mp 210-12 °C; yield 82%. H NMR (200 MHz,
4-(Benzimidazol-1-yl)-5-phenylisoxazole (9c).
DMSO-d ): δ 6.8-7.7 (m, 10H, Ar-H), 11.5 (s, 1H, OH); IR
6
A mixture of 7 (0.01 mol) and hydroxyl amine (0.012 mol) in
absolute ethanol (20 ml) containing fused sodium acetate (1.0 g)
was refluxed for 5 hours, then allowed to cool at room tempera-
ture and poured into cold water. The solid product obtained was
collected by filtration and crystallized from dioxane to give 9c as
-1
(KBr): ν 3320 (OH), 2922 (CH), 2171(CN), 1670 (CO) cm ; MS
+
(EI, 70 eV): m/z (%) = 261 [M , (1)], 236(2), 235(11), 194(3),
178(6).
Anal. Calcd. for C
H N O: C 73.56; H 4.21; N 16.09%.
16 11 3
Found: C 73.70; H 4.50; N 16.00%.
1
yellow crystals, mp 176-8 °C; yield 72%. H NMR (200 MHz,
DMSO-d ): δ 6.8-7.6 (m, 11H, Ar-H and isoxazolyl H-3); MS
1-Cyanobenzotrizole (13).
6
+
(EI, 70 eV): m/z (%)= 261 [M , (5)], 257(6), 233(4), 222(88).
The titled compound was prepared according to the reported
method [8].
-1
%); IR (KBr): ν 3058 (CH), 1645 (C=N) cm .
Anal. Calcd. for C
H N O: C 73.56; H 4.21; N 16.09%.
16 11 3
Found: C 73.80; H 4.40; N 16.00%.
4-(1,2,4-Triazol-1-yl)-5-phenyl-1H-pyrazole (14a).
ω-(Benzimidazol-1-yl)acetophenonephenylhydrazone (11a).
Compound 14a, was obtained by the same manner used for
preparation of 9a using 2 instead of 1. The solid so formed was
A mixture of 1 (0.01 mol) and phenyl hydrazine (0.012 mol) in
absolute ethanol (30 ml) containing a few drops of acetic acid
was refluxed for 6 hours, after which the reaction mixture was
cooled and poured into cold water. The solid product obtained
was collected by filtration and crystallized from ethanol/water
crystallized from ethanol to give 14a, as pale yellow crystals, mp
1
182-4 °C; yield 87%. H NMR (200 MHz, DMSO-d ): δ 6.7-7.6
6
(m, 6H, Ar-H and pyrazole H-3), 8.1, 8.49 (2s, 2H, triazole H-3
and H-5), 10.6 (s, 1H, NH); IR (KBr): ν 3420 (NH), 1630(C=N)
-1
+
cm ; MS (EI, 70 eV): m/z (%) = 211 [M , (10)], 185(10),
167(14), 149(5).
1
(1:1) to give 11a as yellow crystals, mp 142-3 °C; yield 68%. H
NMR (200 MHz, DMSO-d ): δ 5.6 (s, 2H, -NCH C=N-), 6.8-7.4
6
2
Anal. Calcd. for C H N : C 62.55; H 4.26; N 33.17%. Found:
11
9 5
(m, 15H, Ar-H), 10.2 (s, 1H, NH); IR (KBr): ν 3210 (NH), 1640
C 62.80; H 4.40; N 33.50%.
-1
(C=N) cm .
4-(1,2,4-Triazol-1-yl)-1,5-diphenylpyrazole (14b).
Compound 14b, was formed on applying the same method used
for the preparation of 9b using 2 instead of 1. The solid so formed
Anal. Calcd. for C
H N : C 77.30; H 5.52; N 17.17%.
21 18 4
Found: C 77.50; H 5.50; N 17.40%.
was crystallized from dioxane to give 14b, as yellow crystals, mp
ω-(Benzimidazol-1-yl)acetophenoneoxime (11b).
1
211-12 °C; yield 78%. H NMR (200 MHz, DMSO-d ): δ 6.6-7.4
6
A mixture of 1 (0.01 mol) and hydroxylamine (0.012 mol) in
pyridine (20 ml) was refluxed for 6 hours. The solid obtained on
evaporating excess solvent was collected by filtration and
crystallized from ethanol to give 11b as colourless crystals, mp
(m, 11H, Ar-H and pyrazole H-3), 8.08, 8.50 (2s, 2H, triazole H-3
-1
and H-5); IR (KBr): ν 3030 (CH), 1645 (C=N) cm .
Anal. Calcd. for C
H N : C 71.08; H 4.52; N 24.39%.
17 13 5
Found: C 71.00; H 4.50; N 24.50%.
-1
192-4 °C; yield 55%. IR (KBr): ν 3450 (OH), 1645 (C=N) cm ;
1
H NMR (200 MHz, DMSO-d ): δ 5.8 (s, 2H, NCH C=N),
4-(1,2,4-Triazol-1-yl)-5-phenylisoxazole (14c).
6
2
6.8-7.6 (m, 10H, Ar-H), 11.0 (s, 1H, OH).
Compound 14c, was prepared by the same method as used for
9c using 2 instead of 1. The solid so formed was crystallized from
ethanol to give 14c as colourless crystals, mp 185-6 °C; yield
Anal. Calcd. for C
H N O: C 71.71; H 5.17; N 16.73%.
15 13 3
Found: C 72.0; H 5.40; N 16.50%.
1
72%. H NMR (200 MHz, DMSO-d ): δ 6.8-7.2 (m, H, Ar-H and
4-(Benzimidazol-1-yl)-1,3-diphenylpyrazole (10b).
6
pyrazole H-3), 8.0, 8.50 (2s, 2H, triazole H-3 and H-5); IR (KBr):
ν 3025 (CH), 1640 (C=N) cm .
A mixture of 11a (0.01 mol) and DMFDMA (0.012 mol) in
xylene (20 ml) was refluxed for 18 hours. The solid obtained on
evaporating excess solvent was collected by filtration and
-1
Anal. Calcd. for C H N O: C 62.26; H 3.77; N 26.41%.
11
8 4
Found: C 62.50; H 4.00; N 26.50%.
crystallized from ethanol to give 10b, mp 200-2 °C; yield
1
62%. H NMR (200 MHz, DMSO-d ): δ 6.7-7.2 (m, 16H, Ar-H
4-(1,2,4-Triazol-1-yl)-1,3-diphenyl pyrazole (15b).
6
-1
and pyrazolyl H-5); IR (KBr): ν 3045 (CH),1645 (C=N) cm .
Compound 15b, was obtained by the same manner used for the
preparation of 10b using phenylhydrazone produced from the
reaction of 2 with phenylhydrazine. The solid so formed was
Anal. Calcd. for C
H N : C 78.57; H 4.76; N 16.66%.
22 16 4
Found: C 78.50 ; H 4.90; N 16.90%.
ω-(Benzimidazol-1-yl)ω-acetophenone (12).
Method A.
crystallized from acetic acid to give 15b, mp 178-80 °C; yield
1
87%. H NMR (200 MHz, DMSO-d ): δ 6.8-7.6 (m, 11H, Ar-H
6
and pyrazole H-5), 8.08, 8.49 (2s, 2H, triazole H-3 and H-5); IR
-1
(KBr): ν 3045 (CH), 1635 (C=N) cm .
A mixture of 9c (0.01 mol) and sodium hydride (0.012 mol) in
dioxane (20 ml) was refluxed for 8 hours. The solid so formed
during heating was collected by filtration and the reaction
Anal. Calcd. for C
H N : C 71.08; H 4.52; N 24.39%.
17 13 5
Found: C 71.20; H 4.50; N 24.50%.

108
Vol. 39
M. Abdel-Megid, M. H. Elnagdi and A. M. Negm
ω-(1,2,4-Triazol-1-yl)ω-cyanoacetophenone (16).
ω-(1,2,4-Triazol-1-yl)ω-tolylhydrazonoacetophenone (18b).
Compound 18b was obtained as yellow crystals, mp 165-7 °C;
This compound was obtained from the two method (a and b)
used for the preparation of 12 using 14c instead of 9c in Method
A and 2 instead of 1 in Method B. Compound 15b, was
1
yield (78%). H NMR (200 MHz, DMSO-d ): δ 1.5 (s, 3H, CH ),
6
3
7.0-7.6 (m, 9H, Ar-H), 8.1, 8.50 (2s, 2H triazolyl H-2 and H-5),
1
11.0 (s, 1H, NH); IR (KBr): ν 3390 (NH), 2920 (CH), 1675 (CO)
crystallized from ethanol, mp 240-2 °C; yield 86%. H NMR
-1
+
cm ; MS (EI, 70 eV): m/z (%) = 305 [M , (3)], 269(13).
Anal. Calcd. for C N O: C 66.88; H 4.91; N 22.95%.
(200 MHz, DMSO-d ): δ 6.8-7.5 (m, 5H, Ar-H), 8.08, 8.50
6
H
(2s, 2H, triazole H-3 and H-5), 11.2 (s, 1H, OH); IR (KBr):
17 15
5
-1
Found: C 67.00; H 5.00; N 22.60%.
ν 3340 (OH), 2210 (CN), 1665 (CO) cm .
Anal. Calcd. for C H N O: C 62.26; H 3.77; N 26.41%.
Found: C 62.50; H 3.60; N 26.60%.
11
8 4
Action of Nitrous Acid on 1 and 2; Formation of Oximes 19 and 20.
To an ice-cold solution of 1 or 2 (0.01 mol) in acetic acid (30 ml),
sodium nitrite (0.015 mol) was added dropwise with stirring, then
the reaction mixture left overnight. The solid obtained was isolated
by filtration and crystallized from ethanol to give 19 or 20.
General Procedure for the Preparation of Arylhydrazones 17a,b
and 18a,b.
Compound 1 or 2 (0.01 mol) was dissolved in ethanol
(50 ml) and treated with sodium acetate (5.0 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 product, so formed, was
collected by filtration and crystallized from the proper solvent
to give 17a,b or 18a,b.
1-(Benzimidazol-1-yl)-2-phenyl-1-glyoxalmonooxime (19).
Compound 19 was obtained as yellow crystals, mp 126-8 °C;
1
yield (76%). H NMR (200 MHz, DMSO-d ): δ 6.8-7.2 (m, 10H,
6
Ar-H), 10.6 (s, 1H, OH); IR (KBr): ν 3450 (OH), 2920 (CH),
-1
+
1670 (CO) cm ; MS (EI, 70 eV): m/z (%) 265 [M , (3)], 239(3),
236(3), 228(2).
Anal. Calcd. for C H N O : C 67.92; H 4.15; N 15.85%.
15 11
3 2
Found: C 67.70; H 4.40; N 15.90%.
ω-(Benzimidazol-1-yl)ω-phenylhydrazonoacetophenone (17a).
1-(1,2,4-Triazol-1-yl)-2-phenyl-1-glyoxalmonooxime (20).
Compound 20 was obtained as yellow crystals, mp 68-70 °C;
Compound 17a was obtained as yellow crystals, mp 178-9 °C;
1
yield 78%. H NMR (200 MHz, DMSO-d ): δ 6.9-7.5 (m, 15H,
6
1
+
yield (65%). H NMR (200 MHz, DMSO-d ): δ 6.8-7.6 (m, 5H,
Ar-H), 10.6 (s, 1H, NH); MS (EI, 70 eV): m/z (%) 340 [M ,
6
Ar-H), 8.08, 8.49 (2s, 2H triazolyl H-3 and H-5), 11.0 (s, 1H,
OH); IR (KBr): ν 3390 (OH), 1695 (CO) cm .
(32)], 237(2), 207(10), 193(55); IR (KBr): ν 3390 (NH), 2920
(CH), 1695 (CO) cm .
-1
-1
Anal. Calcd. for C H N O : C 55.5; H 3.70; N 25.92%.
Anal. Calcd. for C
H N O: C 74.11; H 4.70; N 16.47%.
10
8 4 2
21 16 4
Found: C 55.50 ; H 3.60; N 26.00%.
Found: C 74.40 ; H 4.50; N 16.50%.
ω-(Benzimidazol-1-yl)ω-tolylhydrazonoacetophenone (17b).
REFERENCES AND NOTES
Compound 17b was obtained as yellow crystals, mp 186-8 °C;
yield (82%).- IR (KBr): ν 3390 (NH), 2922 (CH), 1700 (CO)
cm ; MS (EI, 70 eV): m/z (%) 354 [M , (46)], 264(13), 259(49),
242(53).
[1] A .A. Al-Naggar, M. M. A. Khalik and M. H. Elnagdi,
J. Chem Res.(S),648 (1999), ibid, M., 2801 (1999).
[2] M. M. A. Khalik, M. H. Elnagdi, and S. M. Agamy, Synthesis,
1166 (2000).
[3] F. Al-omran , N. Al- awadi, O. Yousef and M. H. Elnagdi,
J. Heterocyclic Chem., 37, 167 (2000).
-1
+
Anal. Calcd. for C
H N O: C 74.57; H 5.08; N 15.81%.
22 18 4
Found: C 74.50; H 5.00; N 15.80%.
[4] S. Al-Moussawi, M. M. A. Khalik S. El-Sherbiny, E. John and
M. H. Elnagdi, J. Heterocyclic Chem., 38 (2001) in press.
[5] F. Al-Omran, J. Heterocyclic Chem., 37,1219 (2000).
[6] M. H. Mohamed, M. M. A. Khalik and M. H. Elnagdi,
J. Heterocyclic Chem., 38, 685 (2001).
ω-(1,2,4-Triazol-1-yl)ω-phenylhydrazonoacetophenone (18a).
Compound 18a was obtained as yellow crystals, mp 110-2 °C;
yield (62%). IR (KBr): ν 3390 (NH), 2924 (CH), 1670 (CO)
-1
+
cm ; MS (EI, 70 eV): m/z (%) 291 [M , (41)], 255(25), 249(13),
232(5).
[7] A. R. Katritzky, M. Darabantu, D. C. Aslan and D. C. Oniciu
J. Org. Chem., 63, 4323 (1998).
Anal. Calcd. for C
Found: C 66.10; H 4.50; N 24.20%.
H N O: C 65.97; H 4.46; N 24.05%.
[8] T. V. Hughes, S. D. Hammond and M. P. Cava, J. Org. Chem.,
63, 401 (1998).
16 13 5