Reactions of enaminones 2 with diazotized 5-amino-3-phenylpyrazole provide a convenient route to 3-[(4,5-disubstituted-pyrazol-3-yl)carbonyl]-pyrazolo[5,1-c][1,2,4]triazines. Condensation of the latter with hydrazine hydrate yielded the title compounds. The structures of the compounds prepared were elucidated on the basis of their spectral and elemental analyses.
Trang 1SHORT COMMUNICATION
A new convenient synthesis of
3-hetaryl-pyrazolo[5,1-c][1,2,4]triazines
Ahmad S Shawali
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Received 1 June 2011; revised 29 June 2011; accepted 18 July 2011
Available online 27 August 2011
KEYWORDS
Hydrazonoyl halides;
Heterocycles;
Enaminones;
Pyrazoles
Abstract Reactions of enaminones 2 with diazotized 5-amino-3-phenylpyrazole provide a conve-nient route to 3-[(4,5-disubstituted-pyrazol-3-yl)carbonyl]-pyrazolo[5,1-c][1,2,4]triazines Condensa-tion of the latter with hydrazine hydrate yielded the title compounds The structures of the compounds prepared were elucidated on the basis of their spectral and elemental analyses
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Introduction
A literature survey reveals that there are three synthetic routes
for pyrazolo[5,1-c][1,2,4]triazine derivatives I (Chart 1) These
synthetic strategies include (i) coupling of diazotized
amino-pyrazole with b-keto esters and b-diketones, (ii) reaction of
5-hydrazinopyrazole with 1,2-diones[1,2]and (iii) cyclization of
N-pyrazol-5-yl hydrazonoyl halides [3] In conjunction with
our recent work[4–6]on heteroaryl enaminones II (Chart 1),
it was thought attractive to explore the utility of such
enami-nones as precursors for the synthesis of new
pyrazolo[5,1-c][1,2,4]-triazines that have not been reported hitherto Here
we present a new synthetic strategy for the synthesis of the latter heterocyclic ring system via coupling of such enaminones with diazotized 5-amino-3-phenylpyrazole Also, it was thought interesting to examine the reaction of the resulting cou-pling products with hydrazine hydrate in an attempt to provide
a convenient method for synthesis of the title compounds Experimental
All melting points were determined on an electrothermal Gal-lenkamp apparatus Solvents were generally distilled and dried
by standard literature procedures prior to use The IR spectra were measured on a Pye-Unicam SP300 instrument in potas-sium bromide discs The1H NMR spectra were recorded on
a Varian Mercury VXR-300 MHz spectrometer and the chem-ical shifts d down field from tetramethylsilane (TMS) as an internal standard The mass spectra were recorded on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spec-trometers, the ionizing voltage was 70 eV Elemental analyses were carried out at the Microanalytical Center of Cairo Uni-versity, Giza, Egypt, using automatic CHNS analyzer, Vario
EL III – Elemental fabric_Nr 11042023 Both 3-acetylpyraz-oles 1 and enaminones 2 were prepared as previously described from our laboratory[5,7]
E-mail addresses: as_shawali@yahoo.com , as_shawali@mail.com
2090-1232 ª 2011 Cairo University Production and hosting by
Elsevier B.V All rights reserved.
Peer review under responsibility of Cairo University.
doi: 10.1016/j.jare.2011.07.004
Production and hosting by Elsevier
Journal of Advanced Research (2012) 3, 185–188
Cairo University Journal of Advanced Research
Trang 2Synthesis of
3-[1,4,5-trisubstituted-pyrazol-3-yl)carbonyl]-pyrazolo[5,1-c][1,2,4]triazines (4a,b)
General method: A mixture of the appropriate enaminone 2
(1.76 g, 5 mmol) in pyridine (20 mL) was cooled in an ice bath
at 0–5C while being stirred To the resulting cold solution
was added portion wise a cold solution of the diazonium salt
of 3-phenyl-5-aminopyrazole, prepared as usual by diazotizing
the amine (5 mmol) in hydrochloric acid (6 M, 3 mL) with
so-dium nitrite (0.35 g, 5 mmol) in water (5 mL) After all the
dia-zonium salt solution was added, the mixture was stirred for
further 30 min while cooling in an ice-bath The reaction
mix-ture was then left in a refrigerator for three days The solid that
precipitated was filtered off, washed with water, dried and
fi-nally crystallized from ethanol to give the respective products
4 The compounds 4a,b prepared are listed below together with
their physical constants
3-[(4-Benzoyl-1,5-phenyl-pyrazol-3-yl)carbonyl]-7-phenyl-pyrazolo[5,1-c][1,2,4]-triazine (4a)
Yellow solid, yield 2.18 g, (80%), mp 200C, IR (KBr) mmax/
cm 1 1656 (C‚O) 1H NMR (DMSO-d6) d 7.13–7.35 (m, 20H, ArH), 8.16 (s, 1H, H-8), 9.97 (s, 1H, H-4); 13C NMR (DMSO-d6) d 101.5, 118.0, 119.5, 127.5, 128.1, 128.4, 128.8, 129.0, 129.5, 129.7, 132.1, 134.6, 134.9, 139.5, 140.1, 142.1, 145.5, 151.3, 153.3, 154.5, 181.1, 196.5; MS m/z (%) 547 (M+, 5), 105(26), 92 (10), 76 (100), 65 (12) Anal Calcd for
C34H22N6O2(546.58) C, 74.71; H, 4.06; N, 15.38 Found: C, 74.43; H, 4.15; N, 15.45
3-[(4-Ethoxycarbonyl-1,5-diphenylpyrazol-3-yl)carbonyl]-pyrazolo-[5,1-c][1,2,4]triazine (4b)
Yellow solid, yield 1.80 g, (70%), mp 210–212C, IR (KBr)
mmax/cm 1 1716, 1670 (C‚O), 1028 (C–O–C) 1H NMR (DMSO-d6) d 1.04 (t, J = 7 Hz, 3H, CH3), 4.07 (q,
J= 7 Hz, 2H, CH2), 7.36–7.87 (m, 15H, ArH), 8.20 (s, 1H, H-8), 9.96 (s, 1H, H-4); 13C NMR: (DMSO-d6) d 14.0, 61.1, 101.5, 114.5, 120.0, 127.3, 128.1, 128.4, 129.4, 129.5, 131.9, 134.6, 139.5, 141.4, 149.1, 151.8, 153.3, 154.5, 160.5, 182.4;
MS m/z (%) 517 (M+2, 1.3), 516 (M++1, 3.3), 515 (M+, 23), 442 (71), 299 (14), 223 (24), 217 (13), 180 (46), 142 (31),
128 (22), 101 (10), 77 (100) Anal Calcd for C30H20N6O3 (514.53) C, 70.03; H, 4.31; N, 16.33 Found: C, 70.13; H, 4.38; N, 16.47
O O R
N
Me 2 N
N
N
Ph Ph
O
2
R
Ph
Ph
CH 3
O O R
Ph Ph
O O R
Ph
N N
N N Ph
Ph
N H
2 Cl Ph
O O R
N
O
N
N
Ph Ph
H H
O O R
Ph
N N
N N Ph
Ph
H OH H
2a,b
3
1a,b
DMF-DMA
4a,b
- Me 2 NH
R : a, Ph; b, EtO
X
- H 2 O
HOH
- Me 2 NH
A B
Scheme 1 Synthesis of enaminones 2 and their azo coupling reaction
N
N
N N R'
R
R"
R'"
Het O
NMe 2
Chart 1 Structures of pyrazolo[5,1-c][1,2,4]triazine derivatives
and heteroaryl enaminones
Trang 3Synthesis of
3-(pyrazolo[3,4-d]pyridazin-7-yl)-pyrazolo-[5,1-c] [1,2,4]pyridazines
General method: A mixture of compound 4a (1.09 g, 2 mmol)
or 4b (1.02 g, 2 mmol) and hydrazine hydrate (10 ml) in
abso-lute ethanol (40 ml) was refluxed for 10 h and the reaction
mix-ture was cooled The solid that precipitated was filtered off and
crystallized from ethanol to give compound 5a and 5b,
respec-tively The compounds 5a and 5b together with their physical
constants are given below
3-([2,3,4-Triphenyl-pyrazolo[3,4-d]pyrazin-7-yl)-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine (5a)
Pale green solid, yield 0.71 g (66%), mp 174–176C, IR (KBr)
mmax/cm 11623, 1555 (C‚N).1H NMR (DMSO-d6) d 7.00–
7.46 (m, 20H, ArH), 8.16 (s, 1H, H-8), 9.85 (s, 1H, H-4);13C
NMR (DMSO-d6) d 101.5, 118.2, 125.5, 126.2, 126.8, 127.0,
128.2, 128.4, 129.5, 129.6, 131.2, 131.3, 131.7, 132.2, 135.4,
137.7, 142.3, 146.3, 149.9, 153.3, 156.9, 161.0; MS m/z (%)
544 (M++2, 0.87), 542 (M, 1), 539 (22), 524 (11), 514 (16),
451 (32), 388 (28), 247 (13), 338 (28), 247 (13), 180 (36), 159
(40), 144 (13), 138 (14), 130 (20), 115 (12), 111 (14), 104 (22),
76 (100), 63 (18) Anal Calcd for C34H22N8 (542.59) C,
75.26; H, 4.09; N, 20.65 Found: C, 75.31; H, 4.15; N, 20.86
3-[2,3-Diphenyl-4-oxo-5-H-pyrazolo[3,4-d]pyridazin-7-yl]-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine (5b)
Pale green solid, yield 0.72 g (78%), mp 240C, IR (KBr) mmax/
cm 13234 (NH), 1671 (C‚O).1H NMR (DMSO-d6) d 7.37–
7.79 (m, 15H, ArH), 8.04 (s, 1H, H-8), 9.83 (s, 1H, H-4), 12.40
(s, 1H, NH); 13C NMR (DMSO-d6) d 101.5, 111.4, 117.7,
122.5, 127.1, 128.1, 128.4, 129.2, 129.5, 130.3, 131.0, 135.4,
137.8, 145.4, 148.4, 153.3, 158.7, 161.0; MS m/z (%) 482
(M+, 7), 189 (15), 167 (11), 158 (10), 151 (15), 134 (40), 128
(18), 114 (53), 106 (42), 91 (43), 76 (81), 70 (30), 60 (45), 45
(100) Anal Calcd for C28H18N8O (482.49) C, 69.70; H,
3.76; N, 23.22 Found: C, 69.82; H, 3.55; N, 23.30
Results and discussion
The starting enaminones 2a,b were prepared by condensation
of the respective 3-acetylpyrazole derivatives 1a-b each with
dimethylformamide dimethyl acetal (DMF–DMA) as
previ-ously described from our laboratory (Scheme 1)[5,7] Coupling
of 2a with diazotized 3-phenyl-5-aminopyrazole in pyridine at 0–5C gave the coupling product that was identified as 3-[(4- benzoyl-1,5-diphenylpyrazol-3-yl)carbonyl]-7-phenyl-pyrazol-o[5,1-c][1,2,4]triazine 4a (Scheme 2) Similar reaction of 2b with the same diazonium salt yielded 3-[(4-ethoxycarbonyl-1,5-diph-enylpyrazol-3-yl) carbonyl]-7-phenyl-pyrazolo[5,1-c][1,2,4]tri-azine 4b (Scheme 2) The structures of the products 4a,b were elucidated on the basis of their spectra (IR, 1H NMR and MS) and elemental analyses For example, the IR spectrum
of 4b showed two characteristic C‚O bands at v 1716 and
1670 cm 1 In addition,1H NMR spectra of both compounds 4a and 4b revealed, in each case, two characteristic singlet sig-nals near d 8.20 and 9.96 assignable to the H-8 and H-4 of the pyrazolo[5,1-c][1,2,4]-triazine ring residue, respectively To ac-count for the formation of such products, it is suggested as de-picted inScheme 1, that the initially formed coupling product 3 undergoes in situ cyclization via either route A or B (Scheme 1)
In the former route A, intramolecular elimination of dimethyl-amine gives 4 directly as end product In route B, the interme-diate 3 is hydrolyzed first to give the respective arylhydrazone derivative X, by analogy to azo coupling of enaminones with aromatic diazonium salts[8,9] The latter intermediate X under-goes in turn cyclization via dehydration to give 4 as end prod-uct However, all attempts to isolate intermediate of type X failed
Next, the condensation of the products 4a,b with hydrazine hydrate was examined In our hands, such a reaction yielded products that were identified, on the basis of their spectral and elemental analyses, as the respective 3-[2,3,4-triphenyl-pyrazolo[3,4-d]pyridazin-7-yl]-7-phenyl-pyrazolo[5,1-c][1,2,4] triazine 5a and 3-(2,3-diphenyl-4-oxo-5H-pyrazolo[3,4-d]-pyri-dazin-3-yl)-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine 5b, respec-tively (Scheme 2) For example, the IR spectrum of compound 5a showed the absence of carbonyl absorption bands present in the IR spectrum of its precursor 4a Also, the spectrum of 5b reveals two bands due to cyclic amide moi-ety at v 3234 (NH) and 1671 (C‚O) cm 1 Furthermore, its1H NMR spectrum showed a characteristic NH signal at d 12.4
In conclusion, the studied azo coupling reaction of the enaminones 2 and the hydrazinolysis of the resulting products
4 provide a convenient route for the title compounds References
[1] Partridge MW, Stevens MFG Pyrazolo-as-triazines Part I J Chem Soc C Organ 1966:1127–31.
O O R
Ph
N N
N N Ph
Ph
N N
N N
Ph Ph
N N
N N
Ph Ph
H
NH 2 NH 2 .H 2 O
NH 2 NH 2 .H 2 O 4
5a
5b
R = Ph
R = EtO
Scheme 2 Synthesis of pyrazolo[3,4-d]pyridazin-7-yl]-pyrazolo[5,1-c][1,2,4]triazines
A new convenient synthesis of 3-hetaryl-pyrazolo[5,1-c][1,2,4]triazines 187
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