Microwave-assisted synthesis of bis(enaminoketones): Versatile precursors for novel bis(pyrazoles) via regioselective 1,3-dipolar cycloaddition with nitrileimines

Article abstract of DOI:10.1002/jhet.952

Synthesis of bis(enaminones) 6a-c and 7a-c was accomplished by the reaction of bis(acetophenones) 3a-c and 4a-c with dimethylformamide-dimethylacetal, under microwave irradiation. 1,3-Dipolar cycloaddition of bis(enaminones) 6a and 7b,c with nitrileimines

Full text of DOI:10.1002/jhet.952

1120
Microwave-Assisted Synthesis of Bis(enaminoketones): Versatile
Precursors for Novel Bis(pyrazoles) via Regioselective
1,3-Dipolar Cycloaddition with Nitrileimines
Vol 49
Ahmed H. M. Elwahy,a Ahmed F. Darweesh,a and Mohamed R. Shaabana,b
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
bDepartment of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah
Almukkarramah, Saudi Arabia
*
E-mail: rabiemohamed@hotmail.com
Received January 26, 2011
DOI 10.1002/jhet.952
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of bis(enaminones) 6a–c and 7a–c was accomplished by the reaction of bis(acetophenones)
3a–c and 4a–c with dimethylformamide–dimethylacetal, under microwave irradiation. 1,3-Dipolar cyclo-
addition of bis(enaminones) 6a and 7b,c with nitrileimines in refluxing benzene led to the regioselective
synthesis of the novel bis(pyrazoles) 11a–h in 62–89% yield. The bis(pyrazoles) 11b,c underwent
condensation with hydrazine hydrate to give the corresponding bis(pyrazolo[3,4-d]pyridazines) 14a,b in
good yields.
J. Heterocyclic Chem., 49, 1120 (2012).
INTRODUCTION
Keeping the above facts in mind and in continuation
of our interest in the synthesis and chemistry of novel
enaminones [44–52] as well as bis(hetrocycles) [53–60],
we report herein a simple and efficient route for the
synthesis of novel bis(enaminones) under pressurized
microwave irradiation. The synthetic utilities of the new
bis(enaminones) as key intermediates for the synthesis of
novel bis(pyrazoles) were also investigated.
Enaminones are interesting compounds not only for their
therapeutic and pharmacological potentialities but also for
being valuable intermediates for the synthesis of several
heterocyclic systems [1–11]. Moreover, compounds contain-
ing pyrazole moiety exhibit a wide range of biological
activities [12–18]. These include blockbuster drugs such as
Celebrex [19] and Viagra [20]. Recently, the activity of a
series of pyrazole as inhibitors of p38 mitogen-activated
protein kinase has been reported [21]. The large applications
of such heterocycles in pharmaceutical [22] as well as in
agrochemical industry [23] have made them popular
synthetic targets [24].
Furthermore, bis-heterocyclic compounds with a suitable
alkyl spacer constitute an important class of compounds,
and their various types of activities, especially, as antitumor
[25] and as antimicrobial [26], have been studied. These
activities, which result in their pharmacological utility, have
been reported to be enhanced when different functionalities
or substitutions are present on the two heterocyclic moieties
in the bis-compound [27–36].
RESULTS AND DISCUSSION
To synthesize the target bis(enaminones) 6a–c and 7a–c,
our attention was focused on bis(acetophenones) 3 and 4
as precursors, which could be obtained by the reaction
of the potassium salt of 4-hydroxyacetophenones 1a,b
with the appropriate dibromoalkanes 2a–c in boiling
dimethylformamide (DMF) (Scheme 1).
Treatment of 3a–c or 4a–c with dimethylformamide–
dimethylacetal (DMF–DMA) (5) (Scheme 2) under
solvent-free conditions and microwave irradiation using
pressurized conditions (249 psi, 120ꢀC, 20–30 min;
method B) afforded the crystalline products that were identi-
fied as the bis(enaminones) 6a–c or 7a–c in excellent yields.
When the condensation of 3a–c or 4a,b with DMF–DMA
was carried out under conventional heating conditions
(method A), the corresponding bis(enaminones) 6a–c or
7a–c were obtained in 5–80% yield and the reaction time
exceeded 10 h (Table 1). It is noteworthy to mention that
Moreover, the use of microwave irradiation in chemical
reaction enhancement has attracted much attention in the
last decades [37–43]. The use of microwave heating has
been shown to dramatically reduce reaction times, increase
product yields, and enhance product purities by reducing
unwanted side reactions compared with conventional
heating methods.
© 2012 HeteroCorporation

September 2012
Microwave-Assisted Synthesis of Bis(enaminoketones): Versatile Precursors
1121
for Novel Bis(pyrazoles) via Regioselective 1,3-Dipolar Cycloaddition with Nitrileimines
Table 1
Scheme 1
Comparative study for the synthesis of bis(enaminones) 6a–c and 7a–c
under microwave irradiation and conventional heating.
Yield % (time)
Method Aa
Yield %
6a‐c (o‐isomer)
X
Method Bb
a
b
c
(CH2)2
(CH2)3
(CH2)4
5 (20h)
34 (10h)
80 (10h)
96
84
89
enaminones 7b,c were recently obtained in 62 and 57%
yields, respectively, by heating 4b,c with DMF–DMA
(Scheme 2) under reflux conditions for 10 h [61].
7 a‐c (p‐isomer)
a
b
c
(CH2)2
(CH2)3
(CH2)4
27 (10h)
91
90
93
43 (62)61 (10h)
33 (57)61 (10h)
The structure of the bis(enaminones) 6 and 7 was estab-
lished on the basis of their elemental analysis and spectral
data. The 1H-NMR spectrum of 6a as a representative
example, displayed a singlet at d 2.94 due to N,N-dimethyl
protons, a singlet at d 4.38 due to methylene group, two
doublets at d 5.75 and 7.44 (J = 11.7 Hz) due to olefinic
protons, besides the aromatic multiplet at d 6.95–7.50. The
value of the coupling constant (J = 11.7 Hz) for the ethylenic
protons indicates that the bis(enaminone) 6 or 7 exists
exclusively in the E-configuration.
The now available, bis(enaminones) prompted us to
study their synthetic utilities as building blocks for novel
bis(pyrazoles) via 1,3-dipolar cycloaddition with nitrilimines.
Thus, the reaction of the bis(enaminones) 6a and 7b,c
with the nitrilimines 9 (generated in situ by the action of
triethylamine on the hydrazonoyl chloride 8) in dry benzene
at room temperature afforded a single product (as examined
by thin layer chromatography (TLC) and 1H-NMR spectros-
copy) for which the two regioisomeric cycloadducts 11 and
13 seemed possible (Scheme 3). However, the regioisomers
11 were assigned for the reaction products on the basis of their
1H-NMR spectra. For example, the 1H-NMR spectrum of 11a
revealed two singlets at d 2.43 and d 3.74 due to acetyl-CH3
and OCH2 protons, respectively, a characteristic singlet at d
8.69 due to pyrazole-5-CH protons in addition to the multiplet
signals of the aromatic protons at d 6.70–7.71. The presence of
a singlet at d 8.69 as well as the absence of any signals around
d 5–6 ppm due to a =CHÀC protons of pyrazole ring confirms
the existence of regioisomers 11 and rules out the other alter-
native structure 13.
aMethod A: Δ, neat.
bMethod B: MW, 300W, 20–30 min
As further confirmation of the regiochemistry of 11 comes
from its reaction with hydrazine hydrate to afford a high
yield of a yellow-colored product, which was identified as
the bis(pyrazolo[3,4-d]pyridazinea) 14a,b (Scheme 4). The
IR spectra of compounds 11b or 11c showed two carbonyl
absorption bands in the region of 1689–1642 cmÀ1, which
disappeared in the IR spectrum of the bis(pyrazolo[3,4-d]
pyridazine) products 14a,b.
In conclusion, we developed an efficient synthetic route
for a series of novel bis(enaminones) under microwave irra-
diation and solvent-free conditions. The synthetic utility of
these compounds as building blocks for novel bis(pyrazoles)
has been achieved via regioselective 1,3-dipolar cycloaddi-
tion with nitrilimines. The structure of the new compounds
was confirmed by spectral data as well as by chemical
reactions. The novel starting bis(enaminones) would open a
new access to a variety of heterocyclic systems with possible
pharmaceutical properties. The new synthesized bis (fused
heterocycles) offer an advantage of their easy synthesis
from inexpensive starting materials, and we believe that
they should be useful compounds with potentially high
pharmacological and biological activities.
EXPERIMENTAL
Melting points were measured on a Gallenkamp melting point
apparatus. IR spectra were recorded on a Shimadzu FT-IR 8101
PC infrared spectrophotometer. The 1H-NMR and 13C-NMR
spectra were determined in dimethyl sulfoxide (DMSO-d6) on a
Varian Mercury VX 300 NMR spectrometer (1H at 300 MHz
and 13C at 75 MHz) using tetramethylsilane (TMS) as an internal
standard. Mass spectra were recorded on a Shimadzu GCMS-QP
The formation of the 5-unsubstituted bis (pyrazoles) 11 is
assumed to take place via a regioselective 1,3-cycloaddition
of the nitrilimine intermediate 9 to the activated double
bond of the bis(enaminone) 6 or 7 to form the nonisolable
intermediate 10, followed by elimination of dimethylamine
under the reaction conditions.
Scheme 2
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A. H. M. Elwahy, A. F. Darweesh, and M. R. Shaaban
Vol 49
Scheme 3
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Microwave-Assisted Synthesis of Bis(enaminoketones): Versatile Precursors
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for Novel Bis(pyrazoles) via Regioselective 1,3-Dipolar Cycloaddition with Nitrileimines
1000 EX mass spectrometer at 70 eV. Elemental analyses were
carried out at the Microanalytical Center of Cairo University,
Giza, Egypt. Microwave experiments were carried out using
CEM MARS synthator™ microwave apparatus. The hydrazonoyl
halides 8a–g [62] were prepared according to literature
procedures.
5.76 (d, 2H, J = 12.3 Hz), 6.99 (d, 4H, J = 8 Hz), 7.62 (d, 2H,
J = 12 Hz), 7.86 (d, 4H, J = 8 Hz); ms: m/z (%) 408 (5.3, M+).
Anal. calcd. for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found:
C, 70.61; H, 6.88; N, 6.88.
7b: mp. 168–170ꢀC [Lit mp. 170–172ꢀC]61; IR: (potassium
bromide) 1642 (C=O) cmÀ1 1H-NMR: d 2.18–2.22 (m, 2H),
;
2.89 (br, 6H), 3.08 (br, 6H), 4.17–4.23 (m, 4H), 5.78 (d, 2H,
J = 12 Hz), 6.96 (d, 4H, J = 8 Hz), 7.65 (d, 2H, J = 12 Hz),
7.85 (d, 4H, J = 8 Hz); ms: m/z (%) 422 (8.3, M+). Anal. calcd.
for C25H30N2O4: C, 71.07; H, 7.16; N, 6.63. Found: C, 71.01;
H, 7.14; N, 6.59.
Synthesis of 1,v-bis(2-acetylphenoxy)alkanes 3a–c and 1,v-
bis(4-acetylphenoxy)alkanes 4a,b. 2-Hydroxyacetophenone 1a or
4-hydroxyacetophenone 1b (10 mmol) was dissolved in a hot
ethanolic KOH solution (prepared by dissolving 0.56 g (10 mmol)
of KOH in 10 mL of absolute ethanol), and the solvent was then
removed in vacuo. The remaining material was dissolved in DMF
(10 mL) and the appropriate dibromides (5 mmol) were added. The
reaction mixture was refluxed for 10 min during which KBr was
separated. The solvent was then removed in vacuo, and the
remaining materials were poured onto crushed ice. The crude
precipitate of bis(acetylphenoxy)alkanes 3a–c and 4a,b were
recrystallized from ethanol [54,63].
7c: mp. 204–206ꢀC [Lit mp. 200–202ꢀC]61; IR: (potassium
bromide) 1641 (C=O) cmÀ1 1H-NMR: d 2.02–2.23 (m, 4H),
;
2.91 (s, 6H), 3.08 (s, 6H), 4.19–4.23 (m, 4H), 5.78 (d, 2H,
J = 12 Hz), 6.96 (d, 4H, J = 9 Hz), 7.65 (d, 2H, J = 12 Hz),
7.87–7 (d, 4H, J = 9 Hz); ms: m/z (%) 436 (21.2, M+). Anal.
calcd. for C26H32N2O4: C, 71.53; H, 7.39; N, 6.42. Found: C,
71.50; H, 7.43; N, 6.44.
Synthesis of bis(pyrazoles) 11a–h.
Synthesis of bis(enaminones).
General procedure. To a mixture of bis(enaminones) 6a or
7b,c (0.02 mol) and the appropriate hydrazonyl halide 8 (0.02 mol),
in benzene (25 mL), an equivalent amount of triethylamine was
added. The reaction mixture was heated under reflux for 4 h, and
the solvent was distilled off under reduced pressure. The residual
brown viscous liquid was taken in methanol, and the resulting solid
was collected by filtration, washed thoroughly with methanol,
dried and finally recrystallized from ethanol/DMF to afford the
corresponding bis(pyrazole) derivatives 11a–h in 62–89% yield.
General procedure.
Method A. A mixture of the appropriate bis(acetylphenoxy)
alkanes 3a–c or 4a–c (0.01 mol) and DMF–DMA (10 equiv) was
heated under reflux for 8–18 h. The excess DMF–DMA was
distilled off under reduced pressure. The residual viscous
liquid was taken in petroleum ether (bp 60–80ꢀC; 20 mL), and
the resulting crystals were collected by filtration, washed
thoroughly with ether, dried, and finally recrystallized from dry
benzene or dioxane to afford the corresponding bis(enaminone)
6a–c and 7a–c.
11a: (74% yield), mp. 226–228ꢀC; IR: (potassium bromide)
1696, 1648 (2 C=O) cmÀ1; 1H-NMR: d 2.43 (s, 6H), 3.74 (s, 4H),
6.70 (d, 2H, J = 8 Hz), 6.86 (t, 2H, J = 7 Hz), 7.25 (d, 2H, J = 7
Hz), 7.29 (t, 2H, J = 7 Hz), 7.42 (t, 2H, J = 8 Hz), 7.50 (d, 2H,
J = 8 Hz), 7.63 (d, 2H, J = 7 Hz), 7.71 (s, 2H), 8.69 (s, 2H); ms:
m/z (%) 707 (5.3, M+). Anal. calcd. for C38H28Cl2N4O6: C, 64.50;
H, 3.99; N, 7.92. Found: C, 64.42; H, 4.05; N, 7.87.
Method B. The appropriate bis(acetylphenoxy)alkanes 3a–c
or 4a–c (10 mmol) and DMF–DMA (20 mmol) were mixed in a
process vial. The vial was capped properly and irradiated by
microwaves using pressurized conditions (249 psi, 120 ꢀC) for
20–30 min. The vial contents were taken in ether, collected by
filtration, washed with ether, dried, and finally recrystallized from
dioxane to afford the corresponding bis(enaminones) 6a–c and
7a–c in excellent yield (cf. 1). The physical and spectral data of
the synthesized compounds 6a–c and 7a–c are listed below.
11b: (89% yield), mp. 192–194ꢀC; IR: (potassium bromide)
1
1689, 1643 (2 C=O) cmÀ1; H-NMR: d 1.90–1.93 (m, 4H), 2.41
(s, 6H), 2.56 (s, 6H), 4.14–4.21 (m, 4H), 7.01 (d, 4H, J = 9 Hz),
7.24 (d, 2H, J = 8 Hz), 7.42 (t, 2H, J = 8 Hz), 7.75–7.82 (m, 8H),
8.90 (s, 2H); 13C-NMR: d 20.9, 25.1, 27.0, 67.5, 114.2, 116.5,
119.8, 122.9, 128.5, 129.4, 130.1, 130.7, 131.5, 138.5, 139.4,
149.6, 162.7, 187.8, 192.5; ms: m/z (%) 694 (16.7, M+). Anal. calcd.
for C42H38N4O6: C, 72.61; H, 5.51; N, 8.06. Found: C, 72.55; H,
5.43; N, 8.11.
6a: mp. 156–158ꢀC; IR: (potassium bromide) 1631 (C=O) cmÀ1
;
1H-NMR: d 2.94 (s, 12H), 4.38 (s, 4H), 5.75 (d, 2H, J = 11.7 Hz),
6.95 (t, 2H, J = 7 Hz), 7.08 (d, 2H, J = 8 Hz), 7.34 (t, 2H, J = 7
Hz), 7.44 (d, 2H, J = 11.7 Hz), 7.50 (d, 2H, J = 8 Hz); 13C-NMR:
d 44.2, 67.3, 96.9, 112.8, 120.4, 129.6, 130.7, 131.0, 153.3, 156.2,
186.3; ms: m/z (%) 408 (3.3, M+). Anal. calcd. for C24H28N2O4: C,
70.57; H, 6.91; N, 6.86. Found: C, 70.54; H, 6.96; N, 6.89.
11c: (81% yield), mp. 240–242ꢀC; IR: (potassium bromide)
1
6b: Orange oil; IR: (potassium bromide) 1641 (C=O) cmÀ1
;
1689, 1642 (2 C=O) cmÀ1; H-NMR: d 1.90–1.94 (m, 4H), 2.57
1H-NMR: d 2.22–2.24 (m, 2H), 2.85 (s, 12H), 4.19 (s, 4H), 5.54
(d, 2H, J = 11 Hz), 6.89 (t, 2H, J = 7 Hz), 6.98 (d, 2H, J = 8 Hz),
7.26 (d, 2H, J = 7 Hz), 7.32 (d, 2H, J = 11 Hz), 7.43 (d, 2H, J = 8
Hz); ms: m/z (%) 422 (7.9, M+). Anal. calcd. for C25H30N2O4: C,
71.07; H, 7.16; N, 6.63. Found: C, 71.14; H, 7.11; N, 6.66.
(s, 6H), 4.14–4.24 (m, 4H), 7.01 (d, 4H, J = 9 Hz), 7.51 (d, 2H,
J = 7 Hz), 7.58 (t, 2H, J = 7 Hz), 7.77 (d, 4H, J = 9 Hz), 7.95
(d, 2H, J = 7 Hz), 8.09 (s, 2H), 9.00 (s, 2H); ms: m/z (%) 735
(11.4, M+). Anal. calcd. for C40H32Cl2N4O6: C, 65.31; H, 4.38;
N, 7.62. Found: C, 65.35; H, 4.41; N, 7.61.
6c: mp. 110–112ꢀC; IR: (potassium bromide) 1661 (C=O) cmÀ1
;
11d: (79% yield), mp. 276–278ꢀC; IR: (potassium bromide)
1H-NMR: d 1.78–1.90 (m, 4H), 2.75 (br, 6H), 3.02 (br, 6H),
4.05–4.12 (m, 4H), 5.50 (d, 2H, J = 12.6 Hz), 6.93 (d, 2H, J = 7
Hz), 7.02 (d, 2H, J = 8 Hz), 7.31 (t, 2H, J = 7 Hz), 7.34 (d, 2H,
J = 12.3 Hz), 7.43 (d, 2H, J = 8 Hz); 13C-NMR: d 25.8, 44.2,
67.6, 97.0, 112.6, 120.0, 129.0, 130.5, 131.3, 153.3, 155.9, 186.2;
ms: m/z (%) 436 (4.2, M+). Anal. calcd. for C26H32N2O4: C,
71.53; H, 7.39; N, 6.42. Found: C, 71.48; H, 7.41; N, 6.39.
1693, 1643 (2 C=O) cmÀ1 1H-NMR: d 1.89–1.91 (m, 4H),
;
2.59 (s, 6H), 4.01–4.16 (m, 4H), 6.92 (d, 4H, J = 9 Hz), 7.79
(d, 4H, J = 9 Hz), 7.85 (t, 2H, J = 8 Hz), 8.25 (d, 2H, J = 8
Hz), 8.42 (d, 2H, J = 8 Hz), 8.77 (s, 2H), 9.12 (s, 2H); ms: m/z
(%) 756 (22.2, M+). Anal. calcd. for C40H32N6O10: C, 63.49; H,
4.26; N, 11.11. Found: C, 63.44; H, 4.32; N, 11.18.
11e: (62% yield), mp. 234–236ꢀC; IR: (potassium bromide)
7a: mp. 231–233ꢀC; IR: (potassium bromide) 1643 (C=O)
1728, 1643 (2 C=O) cmÀ1 1H-NMR: d 1.08 (t, 6H, J = 6.9
;
cmÀ1
;
1H-NMR: d 3.01 (br, 6H), 3.17 (br, 6H), 4.39 (s, 4H),
Hz), 1.89–1.92 (m, 4H), 4.09–4.19 (m, 8H), 6.93 (d, 4H, J = 9
Journal of Heterocyclic Chemistry
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A. H. M. Elwahy, A. F. Darweesh, and M. R. Shaaban
Vol 49
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Hz), 8.75 (s, 2H), 9.23 (s, 2H); ms: m/z (%) 816 (2.5, M+). Anal.
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11f: (68% yield), mp. 158–160ꢀC; IR: (potassium bromide)
1681, 1630 (2 C=O) cmÀ1 1H-NMR: d 2.13–2.23 (m, 2H),
;
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2.41 (s, 6H), 2.56 (s, 6H), 4.22–4.24 (m, 4H), 7.04 (d, 4H,
J = 9 Hz), 7.24 (d, 2H, J = 7.5 Hz), 7.42 (t, 2H, J = 7.5 Hz),
7.74–7.81 (m, 8H), 8.90 (s, 2H); ms: m/z (%) 680 (4.6, M+). Anal.
calcd. for C41H36N4O6: C, 72.34; H, 5.33; N, 8.23. Found: C,
72.36; H, 5.26; N, 8.28.
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Vulpetti, A.; Roletto, F.; Alzani, R.; Ciomei, M.; Albanese, C.; Pastori,
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11g: (72% yield), mp. 214–216ꢀC; IR: (potassium bromide)
1
1681, 1646 (2 C=O) cmÀ1; H-NMR: d 2.12–2.25 (m, 2H), 2.57
(s, 6H), 4.23–4.27 (m, 4H), 7.04 (d, 4H, J = 9 Hz), 7.49 (d, 2H,
J = 8 Hz), 7.58 (t, 2H, J = 8 Hz), 7.78 (d, 4H, J = 9 Hz), 7.96
(d, 2H, J = 8 Hz), 8.10 (s, 2H), 9.00 (s, 2H); 13C-NMR: d 27.0,
28.2, 64.6, 114.3, 117.9, 119.1, 123.0, 127.6, 130.1, 131.2, 131.3,
131.6, 134.1, 139.7, 149.9, 162.5, 187.6, 192.5; ms: m/z (%) 721
(11, M+). Anal. calcd. for C39H30Cl2N4O6: C, 64.92; H, 4.19; N,
7.76. Found: C, 64.88; H, 4.23; N, 7.71.
11h: (63% yield), mp. 228–230ꢀC; IR: (potassium bromide)
1674, 1645 (2 C=O) cmÀ1 1H-NMR: d 2.23–2.25 (m, 2H),
;
2.59 (s, 6H), 4.23–4.27 (m, 4H), 7.06 (d, 4H, J = 9 Hz), 7.81
(d, 4H, J = 8 Hz), 7.87 (t, 2H, J = 8 Hz), 8.26 (d, 2H, J = 8
Hz), 8.43 (d, 2H, J = 8 Hz), 8.78 (s, 2H), 9.16 (s, 2H); ms: m/z
(%) 742 (11.9, M+). Anal. calcd. for C39H30N6O10: C, 63.07; H,
4.07; N, 11.32. Found: C, 63.05; H, 4.11; N, 11.36.
Reaction of 11 with hydrazine. A mixture of the appropriate
bis(pyrazole) 11b,c (1 mmol) and hydrazine hydrate (98%; 2 mL,
10 mmol) was heated under reflux for 1 h, and then the mixture
was left to cool at room temperature. The formed precipitates
were collected by filtration, washed with ethanol, and dried.
Recrystallization from DMF afforded yellow crystals of the
corresponding bis(pyrazolo[3,4-d]pyridazine) derivatives 14a,b.
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14a: (90% yield), mp. 234–236ꢀC; IR: (potassium bromide) 1604
(C=N) cmÀ1; 1H-NMR: d 1.83–1.96 (m, 4H), 2.42 (s, 6H, CH3), 2.82
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