Reaction of hydrazonoyl halides with bis-enaminones: A convenient route for synthesis of novel polyaza-terheterocycles

Article abstract of DOI:10.1002/jhet.840

New bis(pyrazolylenaminones) were prepared in good yields. Their synthetic utilities as precursors for regioselective synthesis of novel bis(hetarylpyrazoles) were also investigated. The mechanisms and selectivities observed in the studied reactions were

Full text of DOI:10.1002/jhet.840

January 2013
Reaction of Hydrazonoyl Halides with Bis-enaminones: A Convenient
17
Route for Synthesis of Novel Polyaza-Terheterocycles
*
Ahmad S. Shawali and Adel J. M. Haboub
Deapartment of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
*
E-mail: as_shawali@mail.com
Received September 19, 2010
DOI 10.1002/jhet.840
View this article online at wileyonlinelibrary.com.
Het
Het
Me2N-CH=CH-CO
COCH=CH-NMe2
Me
N
N
Me
N
N
Ar
Ar
New bis(pyrazolylenaminones) were prepared in good yields. Their synthetic utilities as precursors for
regioselective synthesis of novel bis(hetarylpyrazoles) were also investigated. The mechanisms and selectivities
observed in the studied reactions were discussed.
J. Heterocyclic Chem., 50, 17 (2013).
INTRODUCTION
3a–c were confirmed by their elemental analyses and spectral
data (Experimental). For example, their IR spectra revealed
Over the past 30 years, we have been interested in the
chemistry of hydrazonoyl halides [RC(X)═NNHAr]. At
present, there are several review articles by Shawali et al.
[1–12] covering their synthesis, physical properties, chemi-
cal reactions, and applications. In addition, the chemistry of
enaminones of the general formula I (Chart 1) has been
extensively investigated by many research groups all over
the world because of their utility as versatile precursors for
synthesis of heterocyclic compounds of various pharmaceu-
tical properties [13–21]. Furthermore, bis-enaminones of the
general formula II (Chart 1) have been shown in some
reports to be useful precursors for synthesis of some bis-
heterocycles [22–27]. In the light of these findings and in
connection with our ongoing studies of the chemistry of
hydrazonoyl halides [1–12], it was thought interesting to
explore the synthesis and reactions of the new bis(enami-
nones), namely 3,4-bis[(N,N0-dimethylamino)-1-oxo-propen-
en-1-yl]-1-aryl-5-methyl-pyrazoles III and study their
reactions with hydrazonoyl halides (Chart 1). Our interest
after such a study is to develop a new one-step synthetic
strategy for 3,4-dihetarylpyrazoles of the general formula
IV (Chart 1). This is because many pyrazole derivatives
and ter-pyrazole derivatives exhibit various medicinal
and pharmaceutical applications [28–30].
C═O absorption bands in the region υ 1675–1696 cmꢀ1
.
1
Their H NMR spectra, in addition to the expected signals
due to the aromatic protons (Experimental), exhibit singlet
signals near d 2.56 (s, 6H) and 3.30 (s, 3H) assignable to
the two acetyl and the 5-methyl groups, respectively. Reac-
tion of each of compounds 3a–c with dimethylformamide–
dimethylacetal (DMF–DMA) under reflux afforded the
respective bis-enaminones 4a–c (Scheme 1). The structures
of the latter bis-enaminones 4 were confirmed by their spec-
tra and elemental analyses. For example, their IR spectra
showed C═O bands in the region υ 1635–1650 cmꢀ1. In
1
addition to the signals of the aromatic protons, their H
NMR spectra revealed a singlet signal due to 5-CH3 in the
region d 3.30–3.41 and two singlet signals at d 2.81–2.83
(6H) and 3.07–3.08 (6H) for the protons of the two –N
(CH3)2 groups. Also, such spectra showed in each case,
two characteristic doublet signals at d 5.25–5.27 (d, 2H)
and 7.30–7.37 (d, 2H) with coupling constant J = 13 Hz
assignable to the two olefinic protons. This coupling constant
value indicates that the bis-enaminones 4 have the indicated
E-configuration (Scheme 1).
The reactions of the bis-enaminones 4 as dipolarophiles,
with nitrilimines I, generated in situ by base-catalyzed
dehydrochlorination of the respective hydrazonoyl chlorides
1A–C, were next examined (Scheme 2). Thus, in our hands,
reaction of each of 4a–d with hydrazonoyl chlorides 1A–C
in refluxing benzene in the presence of triethylamine yielded,
in each case, a single product. The isolated products were
identified, on the basis of their elemental analyses and
RESULTS AND DISCUSSION
The required 1-aryl-3,4-diacetyl-5-methylpyrazoles 3
precursors for synthesis of the new bis-enaminones 3 were
prepared in this study by reaction of 2,4-pentanedione 2
with each of N-aryl 2-oxopropanehydrazonoyl chlorides
1a–d in ethanol in the presence of sodium ethoxide
(Scheme 1). The structures of the latter diacetylpyrazoles
1
spectral (IR, H NMR and MS) data (Experimental), as
the respective 3,5-Bis-(1-phenyl-3-substituted-pyrazol-4-
carbonyl)-5-methyl-1-aryl-pyrazoles 5–7 (Scheme 2).
For example, the 1H NMR spectra of the products isolated
© 2013 HeteroCorporation

18
A. S. Shawali and A. J. M. Haboub
Vol 50
O
1, to the activated double bonds in the bis-enaminone 4 to
afford the non-isolable cycloadducts II as intermediates that
undergo in situ elimination of dimethylamine to give 5–7 as
end products. This suggested pathway is consistent with
literature reports that indicate the reaction of hydrazonoyl
halides with various enaminones is regioselective and lead
to the formation of 5 unsubstituted pyrazole derivatives
[10,17,18].
R
(Me2N-CH=CH-CO)2R
II
NMe2
Me2N-CH=CH-CO
I
Het
Het
COCH=CH-NMe2
Me
N
N
Me
N
N
The products 5–7 were obtained in overall good yields
75–84% (Experimental). The data show that an electron-
withdrawing group such as Cl group in the hydrazonoyl
chloride 1 increases the yield of the products 6 and 7. How-
ever, such a group was found to decrease the yield of the
product 5 whether it is present in the bis-enaminone 4 or
the hydrazonoyl chloride 1.
Next, the reaction of 5–7 with hydrazine hydrate was
examined to shed some light on its site selectivity as such
hydrazinolysis can lead to the pyrazolopyridazines 8 and/or
9 (Scheme 3). In our hands, when a mixture of 5a and hydra-
zine hydrate was refluxed, it yielded only one product as
evidenced by TLC of the crude product. The IR spectrum
of the isolated product showed the absence of carbonyl ab-
sorption bands. On the basis of this finding and other
spectral data (Experimental), the isolated product was
assigned structure 8a (Scheme 3). This finding indicates that
the studied reaction of hydrazine hydrate with 5a is site-
selective. To provide further evidence for this site-selectivity,
Ar
Ar
IV
III
Chart 1
Scheme 1
EtONa / EtOH
CH3COC(Cl)=NNHAr + (CH3CO)2CH2
1
2
O
O
CH3CO
COCH3
NMe2
DMFDMA
Me2N
N
CH3
N
N
CH3
N
Ar
4
Ar
3
X: a, H; b, Me; c, Cl; d, MeO
Ar = 4-XC6H4
Scheme 2
RCOC(Cl)=NNHAr'
1A-C
O
O
Et3N /
- HCl
+
COR
COR
H
H
Scheme 3
-
4
+
N
N
N
O
O
COR
COR
RCO-C=N-N-Ar'
I
N
N
N
Ar'
CH
3NMe2
N
N
N
Ar'
NMe2
N
Ar
N
N
CH3
Ph
Ph
II
Ph
O
O
COR
COR
5a,6a,7a
NH2NH2.H2O
N
N
N
N
Ar'
R = CH3
N
R = EtO or PhNH
H2NNH
- Me2NH
N
CH3
Ar'
NHNH2
O
NHNH2
Ar
O
O
O
H2NNH
O
CH3
H3C
5-7
O
Ar / Ar' : XPh / YPh
N
N
N
N
N
N
N
N
N
N
CH3
N
Ph
Ph
X / Y
X / Y
R
N
CH3
Ph
Ph
Ph
B
Ph
Me
A
1A (5)
1B (6)
a
b
4-MeO / H
H / H
d
e
H
N
H
N
N
N
O
O
N
EtO
CH3
H3C
N
H / 4-Me
H / 4-Cl
N
4-Me / H
4-Cl / H
N
N
1C (7)
PhNH
c
f
N
N
N
N
N
N
N
N
Ph
N
N
N
CH3
CH3
Ph
Ph
Ph
Ph
Ph
showed in each case two singlet signals (1H each) in the
region d 7.73–7.93 and 8.58–9.22, which correspond to
the two distinct H-5 protons of the two pyrazole ring
residues in such products. To account for the formation
of such products, it is suggested, as depicted in Scheme 2,
that the reaction of 4 with each of 1A–C proceeds via
initial 1,3-dipolar cycloaddition of nitrilimine, derived from
8a
8b
COR
N
N
COR
N
N
N
N
N
N
CH3
Ph
Ph
Ph
9
R : 5a, Me; 6a, EtO; 7a, PhNH
9a, Me; b, EtO; c, PhNH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Reaction of Hydrazonoyl Halides with Bis-enaminones: A Convenient Route for
19
Synthesis of Novel Polyaza-Terheterocycles
EXPERIMENTAL
the reactions of hydrazine hydrate with both 6a and 7a were
carried out. The studied reactions afforded, in both cases, one
and the same product, whose spectra (IR, 1H NMR, and MS)
and elemental analysis data proved it to have structure 8b
(Scheme 3). To account for the observed site selectivity, it
is suggested that hydrazine hydrate attacks first the pendant
carbonyl groups (CH3CO, EtOCO, and PhNHCO) because
they are least hindered to form the corresponding intermedi-
ates of type A and B, which in turn undergo dehydrative
cyclization to form the respective product 8. This automat-
ically nullifies the possibility of formation of the other
isomers of type 9 (Scheme 3).
All melting points are uncorrected. IR spectra were recorded in
KBr using Pye Unicam SP-1000 spectrophotometer (Pye Unicam
1
Ltd., Cambridge, UK). H NMR spectra were recorded in DCCl3
and DMSO-d6 using a Varian Em-200MHz spectrometer (Varian,
Santa Clara, CA) and TMS as internal reference. Mass spectra were
recorded on AEI MS 30 mass spectrometer operating at 70 eV
(Shimadzu Scientific Intruments, Tokyo, Japan). Elemental analyses
were carried out at the Microanalytical Centre of Cairo University.
The hydrazonoyl halides 1A–C were prepared following literature
procedures [31–34].
Preparation of 3,4-Diacetyl-5-methyl-1-aryl-1H-pyrazoles
(3a–d). General method: To sodium ethoxide solution, prepared
from sodium metal (0.46 g, 0.02 g atom) and absolute ethanol
(15 mL), was added 2,4-pentanedione 2 (2 g, 0.02 mol). The
mixture was stirred for 10 min. To the resulting solution was added
the appropriate hydrazonoyl chloride 1 (0.02 mol), and the reaction
mixture was left overnight at room temperature while being stirred.
The solid, which precipitated, was filtered off, washed with water,
dried, and finally crystallized from appropriate solvent to give the
respective 3. The compounds 3a–d prepared together with their
physical constants are listed in the succeeding text.
An unambiguous evidence for the observed site selectivity
in the foregoing reaction of hydrazine hydrate with each of
5,6, and 7 was provided by comparison of the product 8a
with a sample of 9a prepared by independent synthesis as
depicted in Scheme 4. Thus, reaction of pyrazole derivative
3a with hydrazine hydrate yielded the respective pyrazolo
[3,4-d]pyridazine derivative 10. Heating the latter with
DMF–DMA afforded the bis-enamine 11. The structures of
1
both 10 and 11 were compatible with their spectra (IR, H
3,4-Diacetyl-5-methyl-1-phenyl-1H-pyrazole (3a). White
NMR, and Ms) and elemental analyses (Experimental).
Reaction of the latter bis-enamine 11 with hydrazonoyl
chloride 1a in benzene in the presence of triethylamine
yielded 9a as end product. The latter was found to have
crystals, (0.18 g, 77% yield), mp 132ꢁC (EtOH) (Lit. mp 130ꢁC
1
[35]); IR (KBr) nmax/cmꢀ1 1684 (C═O); H NMR (DMSO-d6):
d 2.57 (s, 6H, 2COCH3), 3.31 (s, 3H, CH3), 7.55–7.59 (m, 5H,
Ar–H); MS m/z (%): 242 (M+, 8), 227 (100), 185 (16), 156
(15), 141 (7), 128 (8), 117 (24), 77 (39). Anal. Calcd for
C14H14N2O2 (242.28): C, 69.41; H, 5.82; N, 11.56. Found: C,
69.11; H, 6.10; N, 11.46%.
1
different physical properties (mp, IR, H NMR, and Ms)
and elemental analysis from that of 8a (Experimental).
3,4-Diacetyl-5-methyl-1(4-methylphenyl)-1H-pyrazole (3b).
White crystals, (0.17 g, 70% yield), mp 96–98ꢁC (EtOH) (Lit.
mp 90ꢁC [36]); IR (KBr) nmax/cmꢀ1 1686 (C═O); 1H NMR
(DMSO-d6): d 2.48 (s, 3H, CH3), 2.57 (s, 6H, 2COCH3), 3.30
(s, 3H, CH3), 7.37 (d, J = 8 Hz, 2H, Ar–H), 7.44 (d, J = 8 Hz,
2H, Ar–H); MS m/z (%): 256 (M+, 46), 241 (100), 198 (20),
170 (16), 155 (12), 131 (25), 122 (11), 90 (41), 76 (8). Anal.
Calcd for C15H16N2O2 (256.31): C, 70.29; H, 6.29; N, 10.93.
Found: C, 70.31; H, 6.44; N, 10.88%.
CONCLUSION
In summary, the studied reactions of hydrazonoyl halides
with each of the bis-enaminones 4a–d and bis-enamine 11
proved useful for synthesis of novel terheterocycles. The
mechanism and selectivity of the studied reactions were
discussed.
3,4-Diacetyl-5-methyl-1(4-chlorophenyl)-1H-pyrazole (3c).
White crystals, (0.19 g, 70% yield), mp 152ꢁC (EtOH); IR
(KBr) nmax/cmꢀ1 1696, 1675 (C═O); H NMR (DMSO, d6): d
1
Scheme 4
2.57 (s, 6H, 2COCH3), 3.28 (s, 3H, CH3), 7.66–7.67 (m, 4H,
Ar–H); MS m/z (%): 278 (M+ + 2, 19), 276 (M+, 46), 261
(100), 219(12), 152(28), 122 (18), 110 (39), 77 (20). Anal
Calcd for C14H13ClN2O2 (276.72): C, 60.77; H, 4.74; N,
10.12. Found: C, 60.70; H, 4.80; N, 10.14%.
O
O
N
N
CH3
CH3
NH2NH2.H2O
CH3
H3C
H3C
N
N
N
CH3
10
N
Ph
3,4-Diacetyl-5-methyl-1(4-methoxyylphenyl)-1H-pyrazole (3d).
3a
White crystals, (0.16g, 60% yield), mp 126ꢁC (EtOH); IR (KBr)
Ph
n
max/cmꢀ1 1682 (C═O), 1255 (C–O–C); 1H NMR (DMSO-d6): d
DMF-DMA
2.56 (s, 6H, 2COCH3), 3.26 (s, 3H, CH3), 3.89 (s, 3H,OCH3), 7.12
(d, J= 8 Hz, 2H, Ar–H), 7.45 (d, J= 8 Hz, 2H, Ar–H); MS m/z
(%): 272 (M+, 59), 257 (100), 213 (25), 199 (11), 172 (17), 158
(16), 147 (31), 127 (12), 108 (16), 94 (21), 76 (20). Anal. Calcd
for C15H16N2O3 (272.31): C, 66.16; H, 5.92; N, 10.29. Found: C,
65.89; H, 6.25; N, 10.13%.
Synthesis of 3,4-Bis[3-(N,N-dimethylamino)acryloyl]-1-aryl-
5-methyl-1H-pyrazoles (4a–d). General method: A mixture of
appropriate pyrazole derivative 3 (10 mmol) and DMF–DMA
(2.5g, 20mmol) was refluxed for 20–30 h then left to cool.
O
O
CH3
CH3
N
N
N
N
N
N
N
NMe2
Me2N
Ph
N
Ph
i
N
N
CH3
11
CH3
N
N
Ph
Ph
9a
i = CH3COC(Cl)=NNHPh / PhH / Et3N
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

20
A. S. Shawali and A. J. M. Haboub
Vol 50
Methanol was added to the cold mixture. The resulting solid was
collected by filtration, washed with methanol, dried, and finally
crystallized from ethanol to afford the respective bis-enaminone 4.
The compounds 4a–d together with their physical constants are
listed in the succeeding text.
3,4-Bis[3-(N,N-dimethylamino)acryloyl]-1-phenyl-5-methyl-1H-
pyrazole (4a). Pale brown solid, (0.31 g, 88% yield), mp 148–
150ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1642 (C═O); 1H NMR
(DMSO-d6): d 2.83 (s, 6H, N(CH3)2), 3.08 (s, 6H, N(CH3)2), 3.40
(s, 3H, CH3), 5.30 (d, J = 13Hz, 2H, ═CH), 5.60 (d, J = 13Hz,
2H, ═CH), 7.32–7.57 (m, 5H, Ar–H); MS m/z (%): 353 (M+ + 1,
5), 352 (M+, 22), 334 (13), 317 (15) 308 (41) , 290 (12), 282 (31),
280 (14), 264 (20), 118 (18), 98 (100), 82 (18), 77 (33). Anal.
Calcd for C20H24N4O2 (352.44): C, 68.16; H, 6.86; N, 15.90.
Found: C, 67.94; H, 6.89; N, 15.76%.
3,4-Bis[3-(N,N-dimethylamino)acryloyl]-1-(p-tolyl)-5-methyl-
1H-pyrazole (4b). Pale yellow solid, (0.31 g, 84% yield), mp
134ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1643 (C═O); 1H NMR
(DMSO-d6): d 2.39 (s, 3H, CH3), 2.83 (s, 6H, N(CH3)2), 3.07 (s,
6H, N(CH3)2), 3.39 (s, 3H, CH3), 5.29 (d, J = 13 Hz, 2H, ═CH),
5.60 (d, J = 13 Hz, 2H, ═CH), 7.37–7.59 (m, 4H, ArH); MS m/z
(%): 368 (M+ + 2, 0.4), 367 (M+ + 1, 2), 366 (M+, 8), 322 (15)
296 (14), 132 (16), 98 (100), 91 (18), 82 (17), 71 (15). Anal.
Calcd for C21H26N4O2 (366.47): C, 68.83; H, 7.15; N, 15.29.
Found: C, 68.90; H, 7.40; N, 15.28%.
3,4-Bis[3-(N,N-dimethylamino)acryloyl]-1-(p-chlorophenyl)-
5-methyl-1H-pyrazole (4c). Brown solid, (0.32 g, 83% yield), mp
160ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1648, 1635 (C═O); 1H NMR
(DMSO-d6): d 2.81(s, 6H, N(CH3)2), 3.08 (s, 6H, N(CH3)2), 3.30
(s, 3H, CH3), 5.25 (d, 2H, J = 13 Hz, ═CH), 7.31 (d, J = 13 Hz,
2H, ═CH), 7.54–7.61(2d, J = 8 Hz, 4H, Ar–H); MS m/z (%):
388 (M+ + 2, 3), 386 (M+ + , 7), 369 (14), 351 (12), 342 (22),
316 (17), 298(15), 258 (7), 151(18), 110 (15), 98 (100), 81 (17),
77 (3). Anal. Calcd for C20H23ClN4O2 (386.88): C, 62.09; H,
5.99; N, 14.48. Found: C, 62.11; H, 6.02; N, 14.50%.
7.35–7.59 (m, 15,Ar–H), 7.85 (s, 1H, pyrazole-H-5), 9.33 (s, 1H,
pyrazole-H-5); MS m/z (%): 583 (M+ + 1, 1), 424 (14), 384 (10),
371 (22), 355 (39), 340 (10), 254 (28), 213 (47), 184 (17), 142
(13), 129 (12) , 117 (54), 98 (30), 91(30), 85 (95), 77(57), 45
(100). Anal. Calcd for C34H26N6O4 (582.62): C, 70.09; H, 4.50; N,
14.42, Found: C, 70.39; H, 4.75; N, 14.51%.
3,4-Bis-(1-phenyl-3-acetyl-pyrazol-4-carbonyl)-5-methyl-1-
p-tolyl-pyrazole (5b). Pale red solid, ( 0.48 g, 80% yield), mp 98ꢁC
(EtOH); IR (KBr) nmax/cmꢀ1 1693, 1642 (C═O); 1H NMR
(DMSO-d6): d 2.33 (s, 6H, ArCH3), 2.68 (s, 6H, 2COCH3), 2.80
(s, 3H, CH3), 7.13–7.35 (m, 13H, ArH), 7.83 (s, 1H, pyrazole-H-5),
8.60 (s, 1H, pyrazole-H-5); MS m/z (%): 598 (M+ +2, 4), 597(M+, 14),
553(47), 531(14), 514 (16), 481 (19), 464 (17), 448 (13), 438 (30), 398
(22), 390 (15), 384 (17), 370 (30), 268 (54), 254 (78), 249 (19), 213
(100), 185 (13), 170 (20), 138 ( 19), 132 (28), 118 (32), 104 (23), 98
(82), 90 (44). Anal. Calcd for C35H28N6O4 (596.65): C, 70.46; H, 4.73;
N, 14.09. Found: C, 70.70; H, 4.80; N, 14.30%.
3,4-Bis-(1-phenyl-3-acetyl-pyrazol-4-carbonyl)-5-methyl-1
(4-chloro-phenyl)-pyrazole (5c). Deep brown solid, (0.48 g, 77%
yield), mp 122–124ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1689, 1642
1
(C═O); H NMR (DMSO-d6): d 2.67 (s, 6H, 2COCH3), 2.78 (s,
3H, CH3), 7.01–7.89 (m, 14H, ArH), 7.84 (s, 1H, pyrazole-H-5),
8.58 (s, 1H, pyrazole-H-5); MS m/z (%): 619 (M+ + 2, 2), 617
(M+, 3), 574 (15), 502 (17), 458 (42), 389(28), 296 (12), 288 (60),
270 (19), 213 (100), 170 (23), 151 (37), 117 (26), 103 (27), 97
(67), 77(32). Anal. Calcd for C34H25ClN6O4 (617.07): C, 66.18;
H, 4.08; N, 13.62. Found: C, 66.45; H, 4.20; N, 13.85%.
3,4-Bis-(1-phenyl-3-acetyl-pyrazol-4-carbonyl)-5-methyl-1-
(p-methoxyphenyl)-pyrazole (5d). Brown solid, ( 0.48g, 78%
yield), mp 92ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1693, 1643 (C═O);
1H NMR (DMSO-d6): d 2.68 (s, 6H, 2COCH3), 2.82 (s, 3H,
CH3), 3.77 (s, 3H, OCH3), 7.07–7.96 (m, 14H, Ar–H), 7.80
(s, 1H, pyrazole-H-5), 8.60 (s, 1H, pyrazole-H-5); MS m/z (%):
612 (M+, 3), 284 (11), 213 (26), 148 (16), 142 (10), 103 (10), 98
(48), 92 (17), 77 (100). Anal. Calcd for C35H28N6O5 (612.65): C,
68.62; H, 4.61; N, 13.72. Found: C, 68.82; H, 4.79; N, 13.95%.
3,4-Bis-(1-(p-tolyl)-3-acetyl-pyrazol-4-carbonyl)-5-methyl-1-
phenyl-pyrazole (5e). Orange solid, ( 0.48 g, 79% yield), mp
3,4-Bis[3-(N,N-dimethylamino)acryloyl]-1-(p-methoxyphenyl)-
5-methyl-1H-pyrazole (4d). Brown solid, (0.32 g, 84% yield), mp
144ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1643 (C═O); 1H NMR
(DMSO-d6): d 2.82 (s, 6 H, N(CH3)2), 3.07 (s, 6H, N(CH3)2),
3.41 (s, 3H, CH3), 3.82 (s, 3H, OCH3) 5.26 (d, J = 13Hz ,2H,
═CH), 5.59 (d, J = 13 Hz, 2H, ═CH), 7.15 (d, J = 7 Hz, 2H, ArH),
7.6 (d, J = 7 Hz, 2H, ArH); MS m/z (%): 383 (M+ + 1, 2), 382
(M+, 4), 338 (12), 294 (11) 148 (16), 98 (100), 82 (14), 77 (16).
Anal. Calcd for C21H26N4O3 (382.47): C, 65.95; H, 6.85; N,
14.65. Found: C, 65.57; H, 7.21; N, 14.54%.
1
136–138ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1676, 1644 (C═O); H
NMR (DMSO-d6): d 2.26 (s, 6H, 2Ar-CH3), 2.49 (s, 6H, COCH3),
2.90 (s, 3H, CH3), 7.13–7.35 (m, 13H, ArH), 7.87 (s, 1H, pyrazole-
H-5), 8.61 (s, 1H, pyrazole-H-5); MS m/z (%): 611 (M+ +1, 2), 368
(18), 254 (26), 227 (27), 209 (23), 185 (11), 154 (12.73), 131 (30),
125 (12), 122 (17), 117 (34), 105 (71), 97 (61), 90 (28), 82 (52), 77
(38), 70(100). Anal. Calcd for C36H30N6O4 (610.23): C, 70.81; H,
4.95; N, 13.76. Found: C, 70.86; H, 4.96; N, 13.79%.
Reaction of bis-enaminones with hydrazonoyl chlorides.
General procedure: To a stirred solution of the appropriate bis-
enaminone 4 (1mmol ) and the hydrazonoyl chloride 1 (2mmol) in
dry benzene (30 mL), triethylamine (0.5 mL) was added and the
mixture was refluxed for 15–20h. The precipitated triethylamine
hydrochloride was filtered off, and the filtrate was evaporated
under reduced pressure. The residue was triturated with methanol.
The solid product, so formed in each case, was filtered off,
washed with water, dried, and crystallized from ethanol to afford
the corresponding pyrazole derivative. The compounds 5–7
prepared are listed in the succeeding text together with their
physical constants.
3,4-Bis-(1-(p-chlorophenyl)-3-acetyl-pyrazol-4-carbonyl)-5-
methyl-1-phenyl-pyrazole (5f). Brown solid, (0.50 g, 77%
yield), mp 160ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1683, 1640
(C═O); 1H NMR (DMSO-d6): d 2.48 (s, 6H, 2 COCH3), 3.10 (s,
3H, CH3), 7.38 (d, J = 8 Hz ,4H), 7.44 (d, J = 8.4 Hz, 4H), 7.2–7.7
(m, 5H, ArH), 7.84 (s, 1H, Pyrazole-H-5), 8.55 (s, 1H, Pyrazole-
H-5); MS m/z (%): 652 (M+ + 1, 6), 609 (22), 390 (10), 387 (10),
254 (15), 247 (32), 232 (25), 230 (35), 154 (20), 152 (54), 139
(20), 125 (100), 118 (20), 110 (30) , 98 (70), 90 (32), 82(29), 77
(23). Anal. Calcd for C34H24Cl2N6O4 (651.50): C, 62.68; H, 3.71;
N, 12.9. Found: C, 62.70; H, 3.75; N, 13.03%.
3,4-Bis-(1-phenyl-3-ethoxycarbonyl-pyrazol-4-carbonyl)-5-
methyl-1-phenyl-pyrazole (6a). Orange solid, (0.3 g, 47%
yield), mp 80ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1700, 1640
3,4-Bis-(1-phenyl-3-acetyl-pyrazol-4-carbonyl)-5-methyl-1-
phenyl-pyrazole (5a). Red solid, (0.49 g, 84% yield), mp 110–
112ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1689, 1642 (C═O); 1H
NMR (DMSO-d6): d 2.57 (s, 6H, 2COCH3), 2.79 (s, 3H, CH3),
1
(C═O); H NMR (DMSO-d6): d 1.29 (t, J = 7 Hz, 6H, 2CH3),
3.33 (s, 3H, CH3), 4.28 (q, J = 7 Hz, 4H, 2CH2), 7.14–7.70 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Reaction of Hydrazonoyl Halides with Bis-enaminones: A Convenient Route for
21
Synthesis of Novel Polyaza-Terheterocycles
1 mmol) and hydrazine hydrate (10 mL) in absolute ethanol was
refluxed for 10 h, and the reaction mixture was cooled. The
solid that precipitated was filtered off and crystallized from
ethanol to give compound 8a.
When the earlier procedure was repeated using either 6a or 7a,
in place of 5a, it yielded in both cases only one and the same
product namely the respective pyrazolo[4,3-d]pyridazine 8b.
The compounds 8a,b prepared are listed in the succeeding text
together with their physical constants.
3,4-Bis-(3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyridazin-6-yl)-
5-methyl-1-phenylpyrazole (8a). Pale yellow crystal, (0.35 g, 60%
yield), mp 240–242ꢁC (EtOH/Dioxane); IR (KBr) nmax/cmꢀ1 1633
(C═N); 1H NMR (CDCl3): d 2.49 (s, 6H, 2CH3), 3.30 (s, 3H,
CH3), 7.53–7.83 (m, 15H, Ar–H), 7.95 (s, 1H, Pyrazole-H-5), 9.37
(s, 1H, Pyrazole-H-5); MS m/z (%): 575 (M+ + 1, 0.6), 433 (14),
432 (32), 406 (19), 405 (58), 149( 12), 142(13), 128 (15) , 125
(11), 123 (12), 119 (112), 118 (30), 119 (11), 118 (30), 77 (100),
109 (11), 108 (20), 104(30), 95(21), 92 (80), 91 (12), 77 (100).
Anal. Calcd for C34H26N10 (574.65): C,71.06; H, 4.56; N, 24.37.
Found: C, 71.22; H, 4.65; N, 24.39%.
15H, Ar–H), 7.95 (s, 1H, pyrazole-H-5), 9.22 (s, 1H, pyrazole-H-5);
MS m/z (%): 644.85 (M+ + 2, 0.64), 643.10 (M+ + 1, 4), 570 (15),
498 (12), 480 (15), 424 (11), 407 (13), 355 (30), 340 (17), 325 (12),
264 (13), 255 (20), 244 (27), 237 (14), 224 (17), 215 (33), 210 (20),
184 (17), 171 (20), 154 (15), 128 (18), 118 (84), 104 (55), 98 (57),
92 (80), 81 (12), 77 (100). Anal. Calcd for C36H30N6O6 (642.68): C,
67.28; H, 4.71; N, 13.08. Found: C, 67.58; H, 4.80; N, 13.12%.
3,4-Bis-(1-(p-tolyl)-3-ethoxycarbonyl-pyrazol-4-carbonyl)-5-
methyl-1-phenyl-pyrazole (6e). Yellow crystal, (0.50 g, 75%
yield), mp 100ꢁC (EtOH); IR (KBr) nmax/cmꢀ1 1708, 1640
1
(C═O); H NMR (DMSO-d6): d 1.31 (t, J = 7 Hz, 6H, 2CH3),
2.24 ( s, 6H, CH3), 3.32 (s, 3H, CH3), 4.29 (q, J = 7 Hz, 4H,
2CH2), 7.11–7.26 (m, 13H, Ar–H) , 7.84 (s, 1H, pyrazole-H-5),
8.60 (s, 1H, pyrazole-H-5); MS m/z (%): 671 (M+ + 1, 59), 242
(11), 241 (25), 166 (17), 132 (10), 118 (12), 104 (100), 90
(15), 77 (34). Anal. Calcd for C38H34N6O6 (670.73): C, 68.05;
H, 5.11; N, 12.53. Found: C, 68.10; H, 5.18; N, 12.60%.
3,4-Bis-(1-(p-4-chlorophenyl)-3-ethoxycarbonyl-pyrazol-4-
carbonyl)-5-methyl-1-phenyl-pyrazole (6f). Yellow crystal,
( 0.55 g, 77% yield), mp 146–148ꢁC (EtOH); IR (KBr) nmax/cmꢀ1
1710, 1640 (C═O); 1H NMR (DMSO-d6): d 1.31 (t, J = 7 Hz,
6H, 2CH3), 3.30 (s, 3H, CH3), 4.30 (q, J = 7 Hz, 4H, 2CH2),
7.36–7.56 (m,13H, Ar–H), 7.90 (s, 1H, Pyrazole-H-5), 8.58 (s,
1H, Pyrazole-H-5); MS m/z (%): 711.85 (M+, .11), 262 (18), 260
(24), 254 (26), 188 (16), 186 (28), 138 (11), 125 (100), 118 (21),
110 (17), 98 (73), 80 (29), 77(19). Anal. Calcd for
C36H28Cl2N6O6 (711.57): C, 60.77; H, 3.97; N, 11.81. Found: C,
60.80; H, 4.00; N, 11.85%.
3,4-Bis-(1-phenyl)-3-phenylaminocarbonyl-pyrazol-4-carbonyl)-
5-methyl-1-phenyl-pyrazole (7a). Brown solid, (0.58 g, 79% yield),
mp 160ꢁC (EtOH/Dioxane); IR (KBr) nmax/cmꢀ1 3390 (NH), 1682,
1643 (C═O); 1H NMR (DMSO-d6): d 3.31 (s, 3H, CH3), 7.05–7.66
(m, 25H, Ar–H), 7.89 (s, 1H, pyrazole-H-5), 9.20 (s, 1H, pyrazole-H-
5), 9.95 (s, 2H, 2NH); MS m/z (%): 738.05 (M+ + 2, 12), 355 (20),
237 (10), 144 (12), 133 (11) , 118 (76), 104 (26), 92 (100), 76 (72).
Anal. Calcd for C44H32N8O4 (736.80): C, 71.73; H, 4.38; N, 15.21.
Found: C,71.82; H,4.42; N,15.23%.
3,4-Bis-(3-oxo-1-phenyl-1H,3H-pyrazolo[3,4-d]pyridazin-6-yl)-
5-methyl-1-phenylpyrazole (8b). Pale yellow crystal, (0.37 g, 64%
yield), mp 286–288ꢁC (EtOH/Dioxane); IR (KBr) nmax/cmꢀ1
1
3434 (NH), 1677 (C═O), 1638 (C═N); H NMR (CDCl3): 3.29
(s, 3H, CH3), 7.10–7.31 (m, 15H, Ar–H), 7.90 (s, 1H, pyrazole-
H-5), 9.40 (s, 1H, pyrazole-H-5), 12.46 (s, 2H, 2NH); MS m/z
(%): 580 (M+ + 2, 0.15), 394 (20), 143 (21), 118 (39), 104 (27),
93 (100), 77 (70). Anal. Calcd for C32H22N10 O2 (578.60): C,
66.43; H, 3.83; N, 24.21. Found: C, 66.70; H, 3.90; N, 24.50%.
Synthesis of 1,4,5-trimethyl-6-phenyl-6H-pyrazolo[3,4-d]-
pyridazine (10). A mixture of the pyrazole derivative 3a (0.25 g,
1 mmol) and hydrazine hydrate (10 mL) in absolute ethanol was
refluxed for 10 h, and the reaction mixture was cooled. The solid
that precipitated was filtered off and crystallized from ethanol
to give compound 10 as white solid, 0.15 g, 63% yield, mp
254–256ꢁC (EtOH) (Lit. mp 239–40ꢁC [37]). IR (KBr) nmax/cmꢀ1
1634 (C═N); 1H NMR (CDCl3): d 2.75 (s, 3H, CH3), 2.89 (s, 6H,
2CH3), 7.49–7.63 (m, 5H, Ar–H); MS m/z (%): 238 (M+, 100), 117
(13), 141 (12), 77 (45). Anal. Calcd for C14H14N4 (238.29): C,
70.75; H, 5.92; N, 23.51. Found: C, 70.79; H, 6.02; N, 23.55%.
Synthesis of bis-enamine 11. A mixture of compound 10
(1.5 g, 6.3 mmol) and DMF–DMA (4 g) was refluxed for 20 h
then left to cool. Methanol was added to cold mixture. The
resulting solid was collected by filtration, washed with
methanol, dried, and finally crystallized from ethanol to afford
the enaminone 11 as pale orange solid, (1.7 g, 78% yield),
mp 242–244ꢁC; 1H NMR (CDCl3) d 2.77 (s, 3H, CH3), 2.87
(s, 6H, N(CH3)2), 2.93 (s, 6H, N(CH3)2), 5.86 (d, J = 13 Hz,
2H, ═CH), 7.50–7.59 (m, 5H, ArH), 7.61 (d, J = 13 Hz, 2H,
═CH); MS m/z (%): 348 (M+, 0.74), 238 (32), 149 (22), 141
(11.26), 118 (28.31), 104 (32.7), 98 (20), 77 (45), 46 (100).
Anal. Calcd for C20H24N6 (348.45): C, 68.94; H, 6.94; N,
24.12. Found: C, 69.05; H, 7.10; N, 24.25%.
3,4-Bis-(1-p-tolyl)-3-phenylaminocarbonyl-pyrazol-4-carbonyl)-
5-methyl-1-phenyl-pyrazole (7e). Deep orange solid, (0.60 g, 78%
yield), mp 166–168ꢁC (EtOH/Dioxane); IR (KBr) nmax/cmꢀ1 3382
1
(NH), 1683, 1644 (C═O); H NMR (DMSO-d6): d 2.25 (s, 6H,
ArCH3), 3.31 (s, 3H, CH3), 7.09–7.72 (m, 23H, Ar–H), 7.89(s,
1H, Pyrazole-5-H), 8.60 (s, 1H, Pyrazole-5-H), 9.84 (s, 2H, 2NH);
MS m/z (%): 766 (M+ + 2, .29), 765 (M+ + 1, 0.34), 618 (12), 526
(19), 304 (20), 412 (12), 255 (62), 238 (26), 185 (24), 370 (56),
155 (14), 152 (11), 149 (11), 140 (28), 130 (25), 118 (81), 109
(12), 105 (71), 98 (100), 93 (44), 77 (75). Anal. Calcd for
C46H36N8O4 (764.85): C, 72.24; H, 4.74; N, 14.65. Found: C,
72.26; H, 4.74; N, 14.75%.
3,4-Bis-(1-(p-chlorophenyl)-3-phenylaminocarbonyl-pyrazol-
4-carbonyl)-5-methyl-1-phenyl-pyrazole (7f). Pale red solid,
( 0.68 g, 81% yield), mp 180ꢁC (EtOH); IR (KBr) nmax/cmꢀ1
3387(NH), 1680, 1640 (C═O); 1H NMR (CDCl3): d 3.17 (s, 3H,
CH3), 7.12–7.53 (m, 23H, Ar–H), 7.73 (s, 1H, Pyrazole-H-5),
8.58 (s, 1H, Pyrazole-H-5), 10.05 (s, 2H, 2 NH); MS m/z (%):
806 (M+ + 2, 0.4), 254 (37), 390 (15), 238 (18), 152 (10), 138
(12), 126 (15), 118 (48), 104 (15) , 98 (61), 92 (60), 77 (52), 70
(42), 45 (100). Anal. Calcd for C44H30Cl2N8O4 (805.69): C,
65.60; H, 3.75; N, 13.91. Found: C, 65.90; H, 4.00; N, 14.25%.
Hydrazinolysis of compounds 5a, 6a, and 7a. General
procedure: A mixture of the pyrazole derivative 5a (0.58 g,
Synthesis of 3,6-bis-(3-acetyl-1-phenyl-1H-pyrazol-4-yl)-5-
methyl-1-phenyl-1H-pyrazolo[3,4-d]pyridazine (9a). To
a
stirred solution of bis-enamine 11 (0.39 g, 1 mmol) and the
hydrazonoyl chloride 1a (0.392 g, 2 mmol) in dry benzene
(20 mL), triethylamine (0.2 mL) was added, and the mixture was
refluxed for 20 h. The precipitated triethylamine hydrochloride
was filtered off, and the filtrate was evaporated under reduced
pressure. The residue was triturated with methanol. The solid
product, so formed in each case, was collected by filtration,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

22
A. S. Shawali and A. J. M. Haboub
Vol 50
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washed with water, dried, and crystallized from ethanol to give
compound 9a as orange solid, (0.52 g, 90% yield), mp 162–
1
164ꢁC; IR (KBr) nmax/cmꢀ1 1680 (C═O); H NMR (CDCl3) d
2.57 (s, 6H, 2COCH3), 2.83 (s, 3H, CH3), 7.45–7.59 (m, 15H,
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77 (100). Anal. Calcd for C34H26N8O2 (578.64): C, 70.58; H,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet