Studies with functionally substituted heteroaromatics: The chemistry of N-phenylhydrazonylalkylpyridinium salts and of phenylhydrazonylalkylbenzoazoles

Article abstract of DOI:10.1055/s-2000-6326

2-Pyrid-1-yliniumacetonitrile bromide 1a and 2-pyrid-1- ylinium-1-phenylethanone bromide 1b coupled with benzenediazonium chloride to yield the corresponding phenylhydrazones 3a, b. Similarly, compounds 2a-c also coupled with aryldiazonium chloride, yielding the arylhydrazones 10a-b, which were used as precursors for the synthesis of azolypyfidazinones 11a, b. Compounds 3a, b were converted into 1,2,4,5-dihydrotetrazines 4a, b on refluxing in acetonitrile in the presence of ammonium acetate. Refluxing 3a in dimethylformamide resulted in the formation of the 3-cyanoindazole 6. Compound 3a was converted to pyrazole 8 on treatment with the enaminone 7, and to hydrazonyl bromide 9 on heating in dioxane/acetonitrile. Compound 12 was synthesized from the reaction of 10b with ethanolic aqueous sodium hydroxide.

Full text of DOI:10.1055/s-2000-6326

1166
PAPER
Studies with Functionally Substituted Heteroaromatics: The Chemistry of
N-Phenylhydrazonylalkylpyridinium Salts and of
Phenylhydrazonylalkylbenzoazoles
Mervat Mohammed Abdel-Khalik,a Mohammed Hilmy Elnagdi,b,c Samia Michel Agamya
aDepartment of Chemistry, Girls College for Arts, Science and Education, Ain Shams University, Heliopolis, Cairo, A. R. of Egypt
bChemistry Department, Faculty of Science, Cairo University, Giza, A. R. of Egypt
cChemistry Department, Faculty of Science, University of Kuwait, P. O. Box 5969, Safat 13060 Kuwait
Received 30 November 1999; revised 24 February 2000
substituted heteroaromatics utilizing readily obtainable,
Abstract: 2-Pyrid-1-yliniumacetonitrile bromide 1a and 2-pyrid-1-
inexpensive starting materials,7,8 we investigated the reac-
ylinium-1-phenylethanone bromide 1b coupled with benzenediazo-
tivity of 1a, b and 2a-c towards aromatic diazonium salts,
nium chloride to yield the corresponding phenylhydrazones 3a, b.
Similarly, compounds 2a-c also coupled with aryldiazonium chlo-
and achieved new syntheses of 1,2,4,5-tetrazines, 5-ben-
ride, yielding the arylhydrazones 10a-b, which were used as pre- zoyl-3-cyano-1-arylpyrazoles, 3-cyanoindazole, azolyl-
cursors for the synthesis of azolypyridazinones 11a, b. Compounds
3a, b were converted into 1,2,4,5-dihydrotetrazines 4a, b on reflux-
ing in acetonitrile in the presence of ammonium acetate. Refluxing
pyridazinones as well as 2-bromo-2-phenylhydrazonoeth-
anoicnitrile.
Thus, compounds 1a, b (generated in situ from reaction of
pyridine with bromoacetonitrile or 2-bromoacetophe-
none) coupled readily with benzenediazonium chloride to
yield the phenylhydrazonylpyridinium bromides 3a, b in
good yields that were found to be stable upon long reflux
in acetonitile. However, compounds 3a, b were readily
converted, almost quantitatively upon reflux in acetoni-
trile in the presence of ammonium acetate, into the 1,4-di-
hydro-1,2,4,5-tetrazines 4a, b (Scheme 1). The reaction
presumably proceeds via the intermolecular nucleophilic
displacement of the pyridinium moiety, by the arylhydra-
zone nitrogen lone pair, or through the intermediacy of the
nitrilimine 5 (Scheme 2), that dimerizes to give the
1,2,4,5-dihydrotetrazines 4a, b. Compound 4b was found
to be identical with the authentic specimen prepared after
the procedure described by Tewari, et al.9
3a in dimethylformamide resulted in the formation of the 3-cy-
anoindazole 6. Compound 3a was converted to pyrazole 8 on treat-
ment with the enaminone 7, and to hydrazonyl bromide 9 on heating
in dioxane/acetonitrile. Compound 12 was synthesized from the re-
action of 10b with ethanolic aqueous sodium hydroxide
Key words: azo compounds, aryl hydrazones, coupling, heterocy-
cles, tetrazines
The reactivity of functionally substituted N-alkylpyridin-
ium halides 1 towards carbon electrophiles has found, in
the past, extensive utility in heterocyclic synthesis.1-3 Re-
cently, Katritzky et al.4-6 investigated the reactivity of
functionally substituted Nilális-alkylbenzotriazoles 2 to-
wards carbon electrophiles. However, to the best of our
knowledge, reactivity of 1 and 2 towards nitrogen electro-
philes has not been investigated. In conjunction to our in-
terest in developing efficient syntheses of functionally
Compound 3a was converted into the cyanoindazole hy-
drobromide 6 when refluxed in dimethylformamide. The
Scheme 1
Synthesis 2000, No. 8, 1166–1169 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Studies with Functionally Substituted Heteroaromatics
1167
Scheme 2
formation of this indazole derivative is believed to pro- ly, in excellent yields. However, these compounds proved
ceed through the intermediary of the nitrilimine 5, which to be stable under conditions that has led to the conversion
undergoes intramolecular cyclization into 6 (Scheme 2).
of 3a into compounds 6 and 8. Compounds 10a, b were
converted into the corresponding pyridazines 11a, b, upon
treatment with ethyl cyanoacetate, in the presence of am-
monium acetate and acetic acid (Scheme 3).
The fusion of 3b with the enaminone 7 afforded the tetra-
zine 4b. In a similar way, treating 3a with 7 resulted in the
formation of the pyrazole 8 (Scheme 2). The nitrilimine 5
is an assumable intermediate. However, possible initial While 10a was recovered unreacted on treatment with eth-
addition of the hydrazone nitrogen to the double bond, fol- anolic aqueous sodium hydroxide, upon long reflux, com-
lowed by intramolecular nucleophilic displacement of the pound 10b afforded the pyruvic acid phenylhydrazone 12.
pyridinium moiety by active methylene in the formed ad-
duct, and subsequent aromatization via dimethylamine
elimination, cannot be overlooked.
Refluxing 3a in a dioxane/acetonitrile mixture resulted in
the formation of the hydrazonyl bromide 9 (Scheme 2),
which is most likely formed via intermolecular displace-
ment of the pyridinium moiety by the bromide ion. Al-
though synthetic approaches to carbohydrazonyl
bromides are well established, none can be readily adopt-
In conclusion, the arylhydrazones 3a, b and 10a, b can be
considered as arylhydrazonyl halide synthetic equivalents
ed to generate 9.10
Coupling 2a, b with p-methoxybenzenediazonium chlo-
ride and with benzenediazonium chloride resulted in the
formation of the arylhydrazones 10a and 10b, respective-
and are thus promising for further utilities especially in di-
polar cycloaddition reactions.
Scheme 3
Synthesis 2000, No. 8, 1166–1169 ISSN 0039-7881 © Thieme Stuttgart · New York

1168
M. M. Abdel-Khalik et al.
PAPER
All mps are uncorrected. IR spectra were recorded in KBr disks us-
ing a Shimadzu IR-740 spectrophotometer. 1H and 13C NMR spec-
tra were recorded on a Bruker Ac-80 spectrometer with DMSO-d6
as solvent and TMS as internal standard; chemical shifts (d) are re-
ported in ppm. Mass spectra were measured on GS/MS INCOS XL
Finnigan MAT. Microanalyses were performed on LECO CHNS-
932. Compounds 2a, c were prepared as described in the litera-
ture.11,12
1-(Benzimidazol-1-yl)-1-phenylhydrazonopropan-2-one (10b)
Yield: 1.75 g (63%), mp: 246-247 ∞C.
IR (KBr): n = 3212 (NH), 1678 (C=O) cm-1.
1H NMR (DMSO): d = 2.59 (s, 3H, CH3), 7.13-7.39 (m, 8H, Ar-H),
7.62-7.79 (m, 1H, Ar-H), 8.20 (s, 1H, benzimidazolyl-H), 10.80 (br
s, 1H, NH).
Anal: C16H14N4O (278.30): Calc C, 69.05; H, 5.07; N, 20.13. Found
C, 68.95; H, 5.14; N, 19.86.
Benzimidazo-1-ylacetone (2b)
A
mixture of benzimidazole (1.18 g, 10 mmol), chloroacetone
Tetrazines 4a, b; General Procedure
(0.92 g, 10 mmol) and Et3N (1.01 g, 10 mmol) in toluene (20 mL)
was refluxed for 5 h. The reaction mixture was allowed to cool, and
the organic layer was washed with H2O, dried (MgSO4), and evap-
orated to afford 2b.
A
suspension of each of compounds 3a, b (10 mmol) in MeCN
(30 mL), was treated with ammonium acetate (1 g). The reaction
mixture was refluxed for 1 h, then evaporated under vacuo to half
of its volume. The solid product was collected by filtration and crys-
tallized from EtOH.
Yield: 1.29 g (74%), mp: 115-116 ∞C.
IR (KBr): n = 1720 (C=O) cm-1.
1,4-Diphenyl-1,4-dihydro-1,2,4,5-tetrazine-3,6-dicarbonitrile
(4a)
Yield: 2.40 g (84%), mp: 134-135 ∞C.
IR (KBr): n = 2241 (CN) cm-1.
1H NMR (DMSO-d6): d = 2.21 (s, 3H, CH3), 5.28 (s, 2H, CH2),
7.16-7.27 (m, 2H, Ar-H), 7.42-7.69 (m, 2H, Ar-H), 8.11 (s, 1H, H-
2).
Anal: C10H10N2O (174.20): Calc C, 68.95; H, 5.79; N, 16.08.
FoundC, 69.05; H, 5.79; N, 16.12.
1H NMR (DMSO): d = 7.29-7.42 (m, 10H, Ar-H).
Anal: C16H10N6 (286.29): Calc C, 67.13; H, 3.49; N, 29.37. Found
C, 67.08; H, 3.70; N, 29.13.
Arylhydrazones 3a, b and 10a-b; General Procedure
A solution of aryldiazonium chloride (prepared as described
earlier13) (10 mmol) at 0 ∞C was added to a solution of each of the
N-alkylpyridinium halides 1a, b (10 mmol) or the N-alkylbenzotri-
azoles 2a, b (10 mmol) in EtOH (50 mL) containing sodium acetate
(0.60 g). The reaction mixture was stirred at r.t. for 1 h and the solid
product was collected by filtration and crystallized from EtOH.
3,6-Dibenzoyl-1,4-dihydro-1,4-diphenyl-1,2,4,5-tetrazine (4b)
Yield: 3.37 g (76%), mp: 189-190 ∞C. (Lit. mp: 196 ∞C)
IR (KBr): n = 1660 (C=O) cm-1.
1H NMR (DMSO): d = 7.18-7.34 (m, 10H, Ar-H), 7.57-7.66 (m,
6H, Ar-H), 7.96-8.06 (m, 4H, Ar-H),
Anal: C28H20N4O2 (444.47): Calc C, 75.65; H, 4.54; N, 12.61.
Found C, 75.46; H, 4.73; N, 12.41.
2-Phenylhydrazono-2-pyrid-1-yliniumethanoicnitrile Bromide
(3a)
Yield: 2.06 g (68%), mp: 181-182 ∞C.
IR (KBr): n = 3241 (NH), 2219 (CN) cm-1.
1H NMR (DMSO): d = 7.23-7.67 (m, 5H, Ar-H), 8.32-8.41 (m,
2H, pyridyl-H), 8.64-8.88 (m, 1H, pyridyl-H), 9.47-9.55 (d, 2H,
pyridyl-H), 12.49 (br s, 1H, NH)
3-Cyanoindazole Hydrobromide (6)
A suspension of compound 3a (10 mmol) in DMF (30 mL), was re-
fluxed for 3 h, then evaporated under vacuo to half of its volume.
The solid product was collected by filtration and crystallized from
DMF.
Anal: C13H11N4Br (303.26): Calc C, 51.48; H, 3.63; N, 18.48.
Found C, 51.38; H, 4.01; N, 18.21.
Yield: 1.34 g (60%), mp: 139-140 ∞C.
IR (KBr): n = 3241 (NH), 2221 (CN) cm-1.
1H NMR (DMSO): d = 7.04-7.37 (m, 4H, Ar-H), 11.20 (br s, 1H,
NH)
1-Phenyl-2-pyrid-1-ylinium-2-phenylhydrazono-1-ethanone
Bromide (3b)
Yield: 2.63 g (69%), mp: 172-173 ∞C.
IR (KBr): n = 3256 (NH), 1668 (C=O) cm-1.
1H NMR (DMSO): d = 7.14-7.70 (m, 10H, Ar-H), 8.46-8.90 (m,
3H, pyridyl-H), 9.69-9.78 (d, 2H, pyridyl-H), 12.60 (br s, 1H, NH)
MS: m/z = 144 (M+).
Anal: C8H6N3Br (224.14): Calc C, 42.84; H, 2.67; N, 18.75. Found
C, 42.51; H, 2.48; N, 18.98.
4-Benzoyl-1-phenylpyrazole-3-carbonitrile (8)
Anal: C19H16N3OBr (382.20): Calc. C, 59.68; H, 4.18; N, 10.99.
Found C, 59.45; H, 4.21; N, 10.92.
A mixture of 3a (3.03 g, 10 mmol) and the enaminone 7 (1.75 g, 10
mmol) was heated at 250∞C for 10 min. The reaction mixture was
left to cool, then triturated with MeOH and precipitated by adding a
few drops of H2O. The solid product, so formed, was collected by
filtration and crystallized from the EtOH.
1-(Benzotriazol-1-yl)-1-p-methoxyphenylhydrazonopropan-2-
one (10a)
Yield: 2.37 g (77%), mp: 141-142 ∞C.
IR (KBr): n = 3210 (NH), 1663 (C=O) cm-1.
1H NMR (DMSO): d = 2.72 (s, 3H, CH3), 3.79 (s, 3H, OCH3),
6.83-6.94 (m, 2H, Ar-H), 7.25-7.37 (m, 5H, Ar-H), 7.69-7.87 (m,
1H, Ar-H), 10.13 (br s, 1H, NH).
Yield: 1.85 g (68%), mp: 136-137 ∞C.
IR (KBr): n = 2215 (CN), 1644 (C=O) cm-1.
1H NMR (DMSO): d = 7.02-8.10 (m, 11 H).
Anal: C17H11N3O (273.28): Calc C, 74.71; H, 4.06; N, 15.38. Found
C, 74.83; H, 4.19; N, 15.01.
Anal: C16H15N5O2 (309.32): Calc C, 62.12; H, 4.89; N, 22.64.
Found C, 62.10; H, 5.06; N, 22.60.
Synthesis 2000, No. 8, 1166–1169 ISSN 0039-7881 © Thieme Stuttgart · New York

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Studies with Functionally Substituted Heteroaromatics
1169
2-Bromo-2-phenylhydrazonoethanoicnitrile (9)
Pyruvic Acid Phenylhydrazide (12)
A suspension of compound 3a (10 mmol) in a mixture of dioxane/
MeCN (30 mL, 3:1) was refluxed for 3 h, then evaporated under
vacuo to half of its volume. The solid product was collected by fil-
tration and crystallized from MeCN.
A suspension of compound 4b (10 mmol) in ethanolic aq NaOH 5%
(20 mL, 2:1) was refluxed for 3 h. Neutralization with HCl (2.0 M)
gave the desired product, that was collected by filtration and crys-
tallized from EtOH.
Yield: 1.47 g (66%), mp: 125-126 ∞C.
IR (KBr): n = 3235 (NH), 2220 (CN) cm-1.
Yield: 0.99 g (74%), mp: 259-260 ∞C.
IR (KBr): n = 1678 (C=O) cm-1.
1H NMR (DMSO): d = 7.26-7.78 (m, 5H, Ar-H), 12.67 (br s, 1H,
NH)
1H NMR (DMSO): d = 2.34 (s 3H, CH3), 7.85-8.05 (m, 5H, Ar-H),
10.26 (s, 1H, NH), 11.95 (s, 1H, NH).
MS: m/z = 223 (M+-1).
Anal: C9H10N2O2 (178.19): Calc C, 60.66; H, 5.66; N, 15.72. Found
C, 60.99; H, 5.83; N, 15.45.
Anal: C8H6N3Br (224.05): Calc C, 42.84; H, 2.67; N, 18.75. Found
C, 43.01; H, 2.93; N, 18.66.
References
Pyridazinones 11a, b; General Procedure
(1) Kolb, M. Synthesis 1990, 171.
(2) Al-Omran, F.; El-Khair, A. A.; Elnagdi, M. H. OPPI 1998, 30,
211.
(3) Matsuda, Y.; Ide, S.; Furuno, K.; Itou, T.; Motokawa, C.;
Chiyomaru, Y. Tetrahedron 1993, 49, 9947.
(4) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Densiko, O. V. Chem.
Rev. 1998, 98, 409.
A mixture of ethyl cyanoacetate (1.13 g, 10 mmol), ammonium ac-
etate (4 g) and HOAc (0.6 mL) was treated with either of the aryl
hydrazones 10a, b (10 mmol). The reaction mixture was heated at
220∞C for 15 min, left to cool, then triturated with EtOH. The solid
product, so formed, was collected by filtration and crystallized from
EtOH.
(5) Katritzky, A. R.; Henderson, S. A.; Yang, B. J. Heterocycl.
Chem. 1998, 35, 1123.
(6) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H. J. Org. Chem.
1999, 64, 7618.
(7) Al-Omran, F.; Al-Awadi, N.; Abdel-Khalik, M. M.; Kaul, K.;
El-Khair, A. A.; Elnagdi, M. H. J. Chem. Res., Synop. 1997,
84.
3-(Benzotriazol-1-yl)-1,6-dihydro-4-methyl-6-oxo-1-p-methox-
yphenylpyridazine-5-carbonitrile (11a)
Yield: 2.32 g (65%), mp: 174-175 ∞C.
IR (KBr): n = 2205 (CN), 1667 (C=O) cm-1.
1H NMR (DMSO): d = 2.66 (s, 3H, CH3), 3.84 (s, 3H, OCH3),
6.91-7.03 (m, 2H, Ar-H), 7.54-7.67 (m, 5H, Ar-H), 8.08-8.20 (m,
1H, Ar-H).
Al-Omran, F.; Al-Awadi, N.; Abdel-Khalik, M. M.; Kaul, K.;
El-Khair, A. A.; Elnagdi, M. H. J. Chem. Res., Miniprint
1997, 601.
Anal: C19H14N6O2 (358.39): Calc C, 63.68; H, 3.94; N, 23.45.
Found C, 63.86; H, 4.00; N, 23.45.
(8) Al-Omran, F.; Abdel-Khalik, M. M.; El-Khair, A. A.; Elnagdi,
M. H. Synthesis 1997, 91.
(9) Tewari, R. S.; Awasthi, A. K.; Parihar, P.; Synthesis 1983,
334.
(10) Shawali, A. S. Chem. Rev. 1993, 93, 2731.
(11) Katritzky, A. R.; Wu, J. Synthesis 1994, 596.
(12) Katritzky, A. R.; Sherbakova, I. J. Heterocycl. Chem. 1996,
33, 2031.
(13) Fahmy, S. M.; Abed, N. M.; Mohareb, R. M.; Elnagdi M. H.
Synthesis 1982, 490.
3-(Benzimidazol-1-yl)-1,6-dihydro-4-methyl-6-oxo-1-phenylpy-
ridazine-6-carbonitrile (11b)
Yield: 1.99 g (61%), mp: 173 ∞C.
IR (KBr): n = 2233 (CN), 1678 (C=O) cm-1.
1H NMR (DMSO): d = 2.48 (s, 3H, CH3), 7.28-8.02 (m, 8H, 7H,
Ar-H, and 1H, benzimidazolyl-H), 8.18-8.35 (m, 2H, Ar-H).
Anal: C19H13N5O (327.33): Calc C, 69.71; H, 4.00; N, 21.40. Found
C, 69.82; H, 4.21; N, 21.37.
Article Identifier:
1437-210X,E;2000,0,08,1166,1169,ftx,en;P06699SS.pdf
Synthesis 2000, No. 8, 1166–1169 ISSN 0039-7881 © Thieme Stuttgart · New York