Studies with functionally substituted methylbenzotriazoles: Novel synthesis of functionally substituted pyrazolo[5,1-c]-1,2,4-triazines benzotriazol-1-yl, 1-pyrazol-4-yl benzotriazoles and 1-isoxazol-4-yl benzotriazoles

Article abstract of DOI:10.1002/jccs.200400088

1-Benzotriazolylacetophenone 1 couples with aromatic diazonium salts to yield the corresponding coupling products 2. Reaction of 1 with diazotized aminopyrazole afforded the benzotriazolylpyrazolo[5,1-c][1,2,4]triazine 6. Compound 1 condensed with DMFDMA to yield the enaminone 7 which reacted with hydrazines to yield the pyrazoles 8a,b. Isomeric pyrazoles 10 were synthesized via condensing 1 with phenylhydrazine and subsequent condensation of the formed phenylhydrazone 9 with DMFDMA. Reaction of 7 with hydroxylamine afforded the isoxazole 11 which was converted into the nitrile 13 on reflux in dioxane in the presence of sodium hydride. Compound 13 was also directly obtained from reaction of 1 with 1-cyanobenzotriazole. The reaction of 1 with hippuric acid and arylidenemalononitriles 18a-c afforded the pyranone 17 and pyridine derivatives 23a-c, respectively.

Full text of DOI:10.1002/jccs.200400088

Journal of the Chinese Chemical Society, 2004, 51, 575-579
575
Studies with Functionally Substituted Methylbenzotriazoles: Novel
Synthesis of Functionally Substituted Pyrazolo[5,1-c]-1,2,4-Triazines
Benzotriazol-1-yl, 1-Pyrazol-4-yl Benzotriazoles and 1-Isoxazol-4-yl
Benzotriazoles
Abu Zeid A. Hassanien,a Said A. S. Ghozlanb* and Mohamed H. Elnagdib
aDepartment of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Egypt
1-Benzotriazolylacetophenone 1 couples with aromatic diazonium salts to yield the corresponding cou-
pling products 2. Reaction of 1 with diazotized aminopyrazole afforded the benzotriazolylpyrazolo[5,1-
c][1,2,4]triazine 6. Compound 1 condensed with DMFDMA to yield the enaminone 7 which reacted with
hydrazines to yield the pyrazoles 8a,b. Isomeric pyrazoles 10 were synthesized via condensing 1 with phenyl-
hydrazine and subsequent condensation of the formed phenylhydrazone 9 with DMFDMA. Reaction of 7 with
hydroxylamine afforded the isoxazole 11 which was converted into the nitrile 13 on reflux in dioxane in the
presence of sodium hydride. Compound 13 was also directly obtained from reaction of 1 with 1-cyanobenzo-
triazole. The reaction of 1 with hippuric acid and arylidenemalononitriles 18a-c afforded the pyranone 17 and
pyridine derivatives 23a-c, respectively.
Keywords: Benzotriazol; Enaminone; Arylidinemalononitrile; Pyranone; Hippuric acid; Isoxazole.
INTRODUCTION
N-Functionally substituted methylbenzotriazoles can
bond is believed to be stronger than the oxygen hydrogen
bond. Moreover, recent X-rays of similar systems have estab-
lished preference for the H-N bond over the H-O bond.
afford stabilized carbaniones under relatively mild basic con-
ditions.1-4 This phenomena has recently been extensively uti-
lized by Katritzky et al. in synthetic heterocyclic chemis-
try.5-7 Some time ago Katritzky et al. reported the synthesis of
1a and described some of its reactions with electrophilic re-
agents.8,9 In conjunction with our interest in developing syn-
thesis of polyfunctionally substituted heteroaromatics as po-
tential pharmaceuticals, agrochemicals, or dye intermedi-
ates, we have recently reported on the reactivity of 1b to-
wards aromatic diazonium salts.10-12 In continuation of this
work we report here on the reactivity of 1a towards aromatic
and heteroaromatic diazonium salts as well as reactivity of 1a
towards some carbon electrophiles.
Scheme I
O
Ph
N
N
N
N
N
H
Ar
R
Ar N=N+ Cl -
2
N
N
O
Ph
O
N
N
H
N
1
N
N
Ar
a, R = Ph,
b, R = Me
N
3
a, Ar = C H
6
5
b, Ar = 4-CH -C H
3
6 4
c, Ar = 4-OCH -C H
3
6 4
Compound 1a also coupled with the diazotized amino-
pyrazole 4 to yield the pyrazolo[5,1-c][1,2,4]triazine deriva-
tive 6 which is believed to be formed via intermediates of the
hydrazone 5 which cyclizes spontaneously under coupling
reaction conditions.
RESULTS AND DISCUSSION
It has been found that 1a couples readily with aromatic
diazonium salts to yield the corresponding arylhydrazones.
Although this product can exist as two forms, E form 3 or Z
form 2, only one form has been detected in 1H NMR.
Condensation of 1a with DMFDMA in refluxing
xylene afforded the enaminone 7. This reacted with hydra-
This is most likely form 2 as the hydrogen nitrogen

576 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Hassanien et al.
Compound 7 also reacted with hydroxylamine to yield
an isoxazole derivative which may be formulated as 11 or iso-
meric 12. Again, structure 11 could be established for the re-
action product via its conversion into the nitrile derivative 13
on reflux in dioxane solution in the presence of sodium hy-
dride. Compound 13 could be also obtained via direct cya-
nation of 1a with N-cyanobenzotriazole 1413 (Scheme III).
Compound 7 also reacted with hippuric acid to yield the
pyranone 17 which is an extension of the Kepe-2H-pyranone
synthesis,14 that enables the synthesis of pyranylbenzotri-
azoles. This is believed to be formed via the condensing of 7
with 15 to yield 16 that isomerized into 17 under reaction
conditions. Similar pyranone synthesis has been reported re-
cently by us.15
Scheme II
H
Bt
R
N=N+ Cl -
R
N
N=C
O
1a
+
Ph
NH
NH
Ph
N
Ph
N
4
5
R
N
N
N
N
N
N
Bt =
Ph
N
Bt
Ph
6
a, R = H
b, R = CH
6
3
zine hydrate and phenylhydrazine to yield pyrazole deriva-
tives which may be formulated as 8b or isomeric 10. Struc-
ture 8 could be established for this reaction product based on
its non-identity with a sample of 10 prepared via condensing
1a with phenylhydrazine to form phenylhydrazone 9 and sub-
sequent reaction with DMFDMA.
Scheme IV
Ph
Bt
O
C
O
O
Ph
HN
O
Bt
O
7 +
N
O
N
O
O
Ph
Ph
Scheme III
15
Ph
17
Bt
Ph
Ph
16
DMF/
POCl3
Bt
N
N
NHPh
Compound 1b4 reacted with arylidenemalononitrile
N
9
Ph
18a-c in refluxing ethanol in the presence of a catalytic
amount of triethylamine to yield products that could be for-
mulated as 23. The formation of 23 is assumed to proceed via
initial addition of the active methylene of 1b to a double bond
of 18 yielding the intermediate Michael adduct 19 or 20
which then cyclized into 21 and undergoes Dimorth type re-
arrangement to yield 22 which aromatizes via loss of hydro-
gen molecule to yield the final isolable product 23.17,18
(Scheme V).
10
PhNHNH2
DMFDMA
O
Bt
Bt
Ph
R
Bt
RNHNH2
Ph
1a
N
N
7
Me2N
NH2OH
a, R = H
b, R = Ph
8
Ph
N
Ph
Bt
O
O
12
EXPERIMENTAL SECTION
NHOH
Melting points are uncorrected. IR spectra were recorded
with a FTIR-8201 PC spectrophotometer from Shimadzu. 1H
NMR spectra were obtained on a Varian Gemini 200 MHz
spectrometer in DMSO-d6 as solvent and TMS as an internal
reference. Mass spectra were performed on a Shimadzu
GCMS-QP-1000 EX using the direct inlet system and EI + QI
MSLMRUPLR. Micro-analyses were performed by the
Microanalytical Unit at Cairo University. Thin Layer chro-
matography was carried out on a 5 ´ 20 cm plate coated with
-H O
2
Ph
Bt
Ph
O
Bt
NaH/dioxane
O
CN
N
13
11
N
N
1a
N
CN
14

Functionally Substituted Methylbenzotriazole Studies
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 577
1-(Benzotriazol-1¢-yl)-1-[4-methylphenylhydrazone]aceto-
phenone (3b)
Scheme V
Bt
mp 184°; IR: 3228 (NH), 1696 (CO), 1628 (C=N); 1H
NMR (DMSO-d6): d = 1.35 (s, 3H, CH3), 7.01-8.13 (m, 13H,
H-Ar), 12.1 (s, 1H, NH); MS: m/z = 355 (M+, 18%). Anal.
Calcd. for C21H17N5O: C, 70.98; H, 4.78; N, 19.70. Found C,
71.10; H, 4.60; N, 20.10.
CH3
CN
Ar
CH3
N
N
O
+
O
N
Ar
CN
18a-c
NC
CN
1
19
1-(Benzotriazol-1¢-yl)-1-[4-methoxyphenylhydrazone]-
acetophenone (3c)
mp 179°; IR: 3220 (NH), 1685 (CO); 1H NMR
(DMSO-d6): d = 3.51 (s, 3H, CH3), 7.03-8.21 (m, 13H, H-Ar),
11.1 (s, 1H, NH). Anal. Calcd. for C21H17N5O2: C, 67.92; H,
4.58; N, 18.86. Found C, 67.90; H, 4.50; N, 19.0.
Bt
Bt
Ar
CH3
Ar
CH3
O
OH
NC
NC
CN
NH
21
20
Bt
Pyrazolo[5,1-c][1,2,4]triazine derivatives (6a,b)
Bt
Ar
CH3
A solution of diazotized heterocyclic amines [prepared
from (0.01 mol) of heterocyclic amine and the appropriate
quantities of concentrated hydrochloric acid and sodium ni-
trite as has been previously described16 was added with stir-
ring to a cold solution of 1a (0.01 mol) in ethanol (150 mL)
and sodium acetate (5 g). The solid products so formed were
collected by filtration and recrystallized from ethanol.
Ar
CH3
-H
2
NH
NH
NC
NC
O
23
O
22
a, Ar = C H
18,23,
6
5
4
4
b, Ar = C H -OCH (p);
6
3
c, Ar = C H -CH (p)
6
3
silica gel GF 254 type 60, mesh size 50-250. (Benzotriazol-
1-yl)acetophenone 1a was prepared according to the lit.,9 and
1-cyanobenzotriazole (14) was prepared according to the
lit.13
2-(Benzotriazol-1¢-yl)-1,6-diphenylpyrazolo[5,1-c][1,2,4]-
triazine (6a)
1
mp 216o; IR: 3050 (CH-Ar), 1615 (C=N); H NMR
(DMSO-d6): d = 6.5 (s, 1H, 4H pyrazole), 7.03 (m, 14H, H-
Ar); MS: m/z = 389 (M+, 23%). Anal. Calcd. for C23H15N7: C,
70.95; H, 3.85; N, 25.19. Found C, 70.70; H, 4.00; N, 25.50.
1-(Benzotriazol-1¢-yl)-1-[arylhydrazono]acetophenone
(3a-c)
General Procedure
2-(Benzotriazol-1¢-yl)-5-methyl-1,6-diphenylpyrazolo[5,1-
c][1,2,4]triazine (6b)
A solution of the appropriate aryldiazonium chloride
(0.005 mol) was added portionwise to a cold solution of 1 in
ethanol (50 mL) in the presence of sodium acetate trihydrate
(6 g) with stirring. After the addition was complete, the mix-
ture was stirred at 0-5 °C for a further 4 h. The solid product
that formed was collected, washed with water, dried, and
recrystallized from ethanol.
1
mp 226o; IR: 3047 (CH-Ar), 1606 (C=N); H NMR
(DMSO-d6): d = 2.68 (s, 3H, CH3), 7.36-8.14 (m, 14H, H-Ar);
MS: m/z = 403 (M+, 27%), 375 (M+ - N2, 10.4%). Anal. Calcd.
for C24H17N7: C, 71.34; H, 4.24; N, 24.42. Found C, 71.30; H,
4.30; N, 24.30.
2-(Benzotriazolo-1¢-yl)-1-phenyl-3-dimethylaminoprop-2-
en-1-one (7)
1-(Benzotriazol-1¢-yl)-1-[phenylhydrazone]acetophenone
(3a)
Equimolar amounts (0.01 mol) of 1 and N,N-dimethyl-
formamide-dimethylacetal in dry toluene (30 mL) was heated
under reflux for 5 h. The solvent was removed in vacuo and
the formed solid product was collected by filtration and
recrystallized from methanol to give a colorless product. mp
139-141°; IR: 2983 (CH-aliphatic), 1641 (CO); MS: m/z =
mp 208°; IR: 3222 (NH), 1706 (CO), 1625 (C=N); 1H
NMR (DMSO-d6): d = 7.1-8.22 (m, 14H, H-Ar); 11.9 (br, 1H,
NH); MS: m/z = 341 (M+, 2.9%), 313 (M+ - N2, 16.4%). Anal.
Calcd. for C20H15N5O: C, 70.38; H, 4.39; N, 20.52%. Found
C, 70.40; H, 4.40; N, 20.60.

578 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Hassanien et al.
292 (M+, 35%). Anal. Calcd. for C17H16N4O: C, 69.75; H,
5.51; N, 19.17. Found C, 69.80; H, 5.30; N, 19.80.
hydroxylamine hydrochloride. The reaction mixture was
refluxed for 10 h and left to cool at room temperature; the
solid product so formed was collected by filtration and re-
crystallized from ethanol as colorless crystals in 71% yield;
1-(Substituted pyrazol-4¢-yl)benzotriazole 8a,b
1
A mixture of enamine 7 (0.01 mol) and hydrazine hy-
drate or phenylhydrazine (0.01 mol) in (30 mL) ethanol was
refluxed for 4 h, then left to cool. The solid product so formed
was collected by filtration and recrystallized from ethanol.
mp 186-8 °C; IR: 3050 (CH-Ar), 1625 (C=N); H NMR
(DMSO-d6): d = 7.20-7.89 (m, 9H, H-Ar), 8.43 (s, 1H, H-3
isoxazine); MS: m/z = 262 (M+, 18%), 234 (M+ - N2, 30%).
Anal. Calcd. for C15H10N4O: C, 68.63; H, 3.84; N, 21.42.
Found C, 68.50; H, 3.90; N, 22.20.
1-(3¢-Phenylpyrazole-4¢-yl)benzotriazole (8a)
mp 169-70 °C; IR: 3280 (NH), 3035 (CH-Ar); 1H NMR
(DMSO-d6): d = 7.23-8.20 (m, 10H, H-Ar + H-3 pyrazole),
9.95 (s, 1H, NH). Anal. Calcd. for C15H11N5: C, 68.96; H,
4.21; N, 26.81. Found C, 68.90; H, 4.20; N, 26.90.
1-(Benzotriazole-1¢-yl)cyanoacetophenone (13)
Method A
A mixture of 11 (0.01 mol) and sodium hydride (0.01
mol) in dioxane was heated under reflux for 8 h; the reaction
mixture was left to cool, then poured onto ice water and neu-
tralized by HCl; the solid product so formed was collected by
filtration and recrystallization from EtOH to yield a colorless
crystals in (48% yield).
1-(2¢,3¢-Diphenylpyrazole-4¢-yl)benzotriazole (8b)
mp 180-2 °C; IR: 3055 (CH-Ar); 1H NMR (DMSO-d6):
d = 7.36-8.20 (m, 15H, H-Ar + H-3 pyrazole). MS: m/z = 337
(M+, 3.5%), 304 (M+ - N2, 46.4%). Anal. Calcd. for C21H15N5:
C, 74.70; H, 4.47; N, 20.82. Found C, 74.80; H, 4.50; N,
21.10.
Method B
Compound 13 was obtained from reaction of 14 (0.01
mol) with 1a (0.01 mol) according to Hughes et al.13 The ob-
tained product (60% yield) was confirmed by mp, mixed mp
and spectral data in comparison with an authentic sample
from method A. mp 158-160 °C; IR: 2218 (CN), 1678 (C=O);
Anal. Calcd. for C15H10N4O: C, 68.70; H, 3.81; N, 21.37.
Found C, 68.90; H, 3.91; N, 21.40.
2-(Benzotriazole-1¢-yl)-1-phenyl-1-(phenylhydrazone)eth-
ane (9)
A mixture of compound 1 (0.01 mol) and phenylhy-
drazine (0.01 mol) in (30 mL) ethanol and acetic acid (1 mL)
was refluxed for 4 h, then left to cool and poured into cold wa-
ter. The solid so formed was collected by filtration and
recrystallized from ethanol to yield pale yellow crystals in
80% yield, mp. 139 °C; IR: 3301 (NH), 3050 (CH-Ar). MS:
m/z = 327 (M+, 23%). Anal. Calcd. for C20H17N5: C, 73.39; H,
5.19; N, 21.40. Found C, 73.40; H, 5.20; N, 21.60.
5-(Benzotriazole-1-yl)-3-benzoylamino-6-phenyl-2H-
pyran-2-one (17)
A solution of 7 (0.01 mol) and hippuric acid (0.01 mol)
in acetic anhydride was heated under reflux for 2 h. The reac-
tion mixture was concentrated under reduced pressure. The
formed solid product was filtered off and crystallized from
EtOH to yield colorless crystals, mp 212-3 °C; IR: 3300
(NH), 1710 (C=O); 1H NMR (DMSO-d6): d = 7.31-7.89 (m,
14H, H-Ar), 8.41 (s, 1H, H4-pyrane), 9.98 (s, 1H, NH); MS:
m/z = 408 (M+, 18%); Anal. Calcd. for C24H16N4O3: C, 70.54;
H, 3.94; N, 13.76. Found C, 70.40; H, 3.90; N, 14.00.
1-(1,3-Diphenylpyrazole-4-yl)benzotriazole (10)
To a suspension of compound 9 (0.01 mol) in dry
xylene (20 mL), dimethylformamidedimethylacetal (0.011
mol) was added. The reaction mixture was heated under re-
flux for 6 hr; the solvent was removed under reduced pres-
sure. The resulting solid was filtered off and recrystallized
from ethanol to give 10 as orange crystals, mp 123 °C; IR:
3035 (CH-Ar), 1625 (C=N); 1H NMR (DMSO-d6): d = 7.24-
8.31 (m, 15H, 14H, H-Ar + H-5 pyrazole); MS: m/z = 337
(M+, 13%), 309 (M+-N2, 38%). Anal. Calcd. for C21H15N5: C,
74.77; H, 4.45; N, 20.77. Found C, 74.90; H, 4.60; N, 20.70.
3-(Benzotriazole-1-yl)-1H-6-oxo-2-methyl-4-arylpyridine-
5-carbonitrile (23a-c)
General Procedure
A mixture of 1b (0.01 mol) and arylidenemalononitriles
18a-c in absolute ethanol (30 mL) containing triethylemine
(5 drops) was boiled under reflux for 4 h. The reaction mix-
ture was left to cool, poured onto cold water and neutralized
by dilute hydrochloric acid. The formed solid product was fil-
tered off and recrystallized from EtOH:DMF mixture.
1-(5-Phenylisoxazole-4-yl)benzotriazole (11)
To a solution of 1a (0.01 mol) in ethanol in the presence
of sodium acetate (0.015 mol) was added (0.01 mol) of

Functionally Substituted Methylbenzotriazole Studies
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 579
2. Katritzky, A. R.; Lan, X.; Yang, J. Z.; Densiko, O. V. Chem.
Rev. 1998, 98, 409.
3-(Benzotriazole-1-yl)-1H-2-methyl-6-oxo-4-phenylpyri-
dine-5-carbonitrile (23a)
3. Elnagdi, M. H.; Abdel-Khalik, M. M.; Agamy, S. M. Synthe-
sis, 2000, 1166.
4. Al-Naggar, A. A.; Abdel-Khalik, M. M.; Elnagdi, M. H. J.
Chem. Research (S), 1999, 648; (M) 2801.
5. Katritzky, A. R.; Drewiak, M. J. Chem. Soc. Perkin Trans 1
1998, 1, 2339.
mp 304-306 °C; IR: 3259 (NH), 2222 (CN), 1739 (C=O);
1H NMR (DMSO-d6): d = 1.98 (s, 3H, CH3), 7.12-8.31 (m,
9H, H-Ar), 11.3 (s, 1H, NH); MS: m/z = 389 (M+, 9.5%).
Anal. Calcd. for C19H13N5O: C, 69.72; H, 3.97; N, 21.40.
Found C, 70.00; H, 3.90; N, 21.60.
6. Katritzky, A. R. Handbook of Heterocyclic Chemistry;
Pergamon Press, 1985, 101.
7. Katritzky, A. R.; Qiu, G.; Yang, B.; He, H. J. Org. Chem.
1999, 64, 7618.
8. Al-Zaydi, K. M.; Hafez, E. A.; Elnagdi, M. H. J. Chem. Re-
search (S), 2000, 154; (M) 510.
9. Katritzky, A. R.; Shcherbakova, I. V. J. Heterocyclic Chem.
1996, 33, 2031.
10. Al-Omran, F.; Al-Awadi, N.; Abdel-Khalik, M. M.; Kaul, K.;
El-Khmir, A. A.; Elnagdi, M. H. J. Chem. Res. Synop. 1997,
84.
11. Mohamed, M. H.; Abdel-Khalik, M. M.; Elnagdi, M. H. J.
Heterocyclic Chem. 2001, 38, 685.
3-(Benzotriazole-1-yl)-1H-2-methyl-4-(p-methoxyphenyl)-
6-oxo-pyridine-5-carbonitrile (23b)
mp 290 °C; IR: 3213 (NH), 2221 (CN), 1739 (C=O); 1H
NMR (DMSO-d6): d = 1.93 (s, 3H, CH3), 3.51 (s, 3H, OCH3),
7.13-8.19 (m, 8H, H-Ar), 13.98 (s, 1H, NH); MS: m/z = 357
(M+, 6.6%), 391 (M+-N2, 44.9%). Anal. Calcd. for C20H15N5O2:
C, 67.22; H, 4.20; N, 19.60. Found C, 67.10; H, 4.20; N,
19.80.
3-(Benzotriazole-1-yl)-1H-2-methyl-6-oxo-4-(p-tolyl)pyri-
dine-5-carbonitrile (23c)
mp 320-2 °C; IR: 3260 (NH), 2219 (CN), 1725 (C=O);
1H NMR (DMSO-d6): d = 1.23 (s, 3H, CH3), 1.90 (s, 3H,
CH3), 7.01-8.12 (m, 8H, H-Ar), 13.01 (s, 1H, NH). Anal.
Calcd. for C20H15N5O: C, 70.38; H, 4.39; N, 20.52. Found C,
70.10; H, 4.40; N, 20.30.
12. Al-Awadi, N.; Elnagdi, M. H.; Ibrahim, Y.; Kaul, K.; Kumar,
A. Tetrahedron 2001, 57, 1609.
13. Hughes, T. S.; Hammoud, S. D.; Cava, M. P. J. Org. Chem.
1998, 63, 401.
14. Kepe, V.; Kocevar, M.; Polanc, S. J. Heterocyclic Chem.
1996, 33, 1707.
15. Alsaleh, R.; Abdel-Khalek, M. M.; Elnagdi, M. H.
Heteroatom Chem. 2002, 13, 141.
16. Elnagdi, M. H.; Elmoghayer, M. R. H.; Kandeel, E. M.;
Ibraheim, M. K. A. J. Heterocyclic Chem. 1977, 14, 227 and
references their in.
Received August 14, 2003.
REFERENCES
17. Katritzky, A. R.; Wa, J. Synthesis 1994, 597.
18. Al-Omran, F.; Abdel-Hay, O. Y.; Al-Khair, A. A. J.
Heterocyclic Chem. 2000, 37, 1617.
1. Katritzky, A. R.; Henderson, R. S. A.; Yang, B. J. Hetero-
cyclic Chem. 1998, 35, 1123.