Studies with enaminones and enaminonitriles: synthesis of 3-aroyl and 3-heteroaroyl-pyrazolo-[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.tet.2009.08.084

The reaction of electron rich aromatics with cyanoacetic acid and acetic anhydride afforded 3-oxoalkanenitriles. Indium trichloride was used as a Lewis acid catalyst when the aromatic ring was not?sufficiently reactive. The synthesized 3-oxoalkanenitriles were subsequently condensed with dimethylformamide dimethylacetal (DMFDMA) to yield enaminones that reacted readily with hydrazine hydrate to yield 4-aroylpyrazole-3-amines. The 4-aroylpyrazole-3-amines were condensed with enaminones to yield 3-aroylpyrazolo[1,5-a]pyrimidines.

Full text of DOI:10.1016/j.tet.2009.08.084

Tetrahedron 65 (2009) 9421–9427
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies with enaminones and enaminonitriles: synthesis of 3-aroyl
and 3-heteroaroyl-pyrazolo-[1,5-a]pyrimidines
*
Khaled D. Khalil, Hamad M. Al-Matar , Doa’a M. Al-Dorri, Mohamed H. Elnagdi
Department of Chemistry, Faculty of Science, University of Kuwait, PO Box 5969, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2009
Received in revised form 10 August 2009
Accepted 28 August 2009
Available online 4 September 2009
The reaction of electron rich aromatics with cyanoacetic acid and acetic anhydride afforded
3-oxoalkanenitriles. Indium trichloride was used as a Lewis acid catalyst when the aromatic ring was
not sufficiently reactive. The synthesized 3-oxoalkanenitriles were subsequently condensed with di-
methylformamide dimethylacetal (DMFDMA) to yield enaminones that reacted readily with hydrazine
hydrate to yield 4-aroylpyrazole-3-amines. The 4-aroylpyrazole-3-amines were condensed with enam-
inones to yield 3-aroylpyrazolo[1,5-a]pyrimidines.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Cyanoacetic acid
Indium trichloride
Lewis acid
Oxoalkanenitriles
Dimethylformamide dimethylacetal
Enamines
1. Introduction
2. Results and discussion
The biological and medicinal activities of pyrazolo[1,5-a]py-
rimidines have stimulated considerable interest in the synthesis of
derivatives of this ring system.1–4 Despite enormous number of
pyrazolo[1,5-a]pyrimidine derivatives that have so far been syn-
thesized,1,2 only a few 3-aroylpyrazolo[1,5-a]pyrimidines have
been prepared. The discovery of the biological activities of
indiplon5 has raised interest in the synthesis of 3-aroylpyr-
azolo[1,5-a]pyrimidines. Recently reported synthesis of 26; R¼2-
thienyl; via reacting 4; R¼2-thienyl; has attracted our attention as
this reaction seemed an interesting entry to 3-aroylpyrazolo[1,5-
a]pyrimidines. However it was recently reported that reacting 2;
R¼Ph; with hydrazine affords also the cyanopyrazoles 3.7 It
seemed to us that the outcome of reacting derivatives of 1 with
hydrazine is very much dependent on the reactivity of the keto-
carbonyl moiety in these molecules, which, in turn, is very much
affected by placing an electron donating moiety at C-1. To check
this assumption, we planned to synthesize a variety of substituted
compounds 1 where R is an electron donating aromatic system
(Scheme 1).
The logical start for the synthesis of 1 would be the reaction of 4
and DMFDMA. Although a variety of derivatives of 4 are already
known8 and several synthetic approaches to such systems are al-
ready available a somewhat easy and efficient route to 4 (R¼3-
indolyl or 2-pyrrolyl) has been reported recently by Slatt et al.,9
Elnagdi et al.,10 and Ibrahim et al.11 This attracted our attention as
an efficient route to derivatives of 4. Thus, N,N-dimethylaniline 5a
reacted readily with a mixture of acetic anhydride and cyanoacetic
acid (thus producing 6 in situ) when heated at 80 ꢀC for 10 min to
yield 7a in 80% yield. However anisole 5b did not react under
similar conditions. Despite this, adding a preheated Ac2O/cyano-
acetic acid mixture to anisole in the presence of 15% by weight
indium trichloride as heterogeneous non-stoichiometric Lewis acid
catalyst, 7b was readily formed. 2-Acetylfuran 8 reacted with mixed
cyanoacetic acid–acetic anhydride to yield either 9 or 10 depending
on the molar ratio. Thus, when a 1:1 molar ratio of 7 and 6 were
used, 9 was produced. Using 1:2 ratio afforded 10 (Scheme 2).
It is believed that under these conditions the initially formed 9
reacts further with 6 to yield 10. In support of this view, heating 9
with 6 also afforded 10. Under a variety of conditions, the reaction
of 2-bromothiophene 11 with 6 afforded, in contrast to expectation,
the acetyl derivative 12. We thus looked for an alternative approach
for the synthesis of targeted 15. Condensing 12 with DMFDMA gave
the trans enaminone 13 that reacted with hydroxylamine hydro-
chloride to yield oxime 14 that was converted to 15 when heated
* Corresponding author. Tel.: þ965 24987559; fax: þ965 24816482.
E-mail address: h.almatar@ku.edu.kw (H.M. Al-Matar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.084

9422
K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
O
NH2
R
N
O
N
H
O
CN
R
2
CN
DMFDMA
H2N - NH2
R
CN
R
NMe2
4
1
N
N
H
3
Scheme 1.
X
X
O
O
InCl3, 10%wt.
CN
+
Me
O
xylene, 3h
CN
6
O
5a; x = NMe2
5b; x = OCH3
7a; x = NMe2, 80%
7b; x = OCH3, 70%
InCl3, 10%wt.
Me
CN
O
1:1
(8) 1 : (6) 1
O
O
9 (68%)
xylene
6
xylene
3 h
Me
6
+
O
CN
O
O
Me
InCl3, 10%wt.
8
O
O
O
1:2
(8) 1 : (6) 2
10 (70%)
NH2
Scheme 2.
with diethyl oxalate in the presence of sodium hydride following
a recently reported12 procedure for converting oximes to nitriles
(Scheme 3).
3-Acetylindole 16 reacted with 6 to yield 17 as indicated by the
absence of a D2O exchangeable indole NH (Scheme 4).
trichloride as a Lewis acid. Moreover, 2-aroyl-3-dimethylami-
noacrylonitriles with electron rich donating substituent at the
aroyl moiety react with hydrazines to yield aminopyrazoles as
the sole products.
Compounds 7a,b, 9, 15, and 17 were condensed with DMFDMA
to yield enaminones 18a,b–19a,b, and 20. Data suggests one isomer
but presumably it is unknown whether it is cis or trans. These
reacted smoothly with hydrazine hydrate to yield aminopyrazoles
21a,b, 23a,b, and 25, respectively. Although 21a,b, 23a,b, and 25
may exist also as 22a,b, 24a,b, and 25, structures 21a,b, 23a,b, and
25 are established based on the 1H NMR spectrum that revealed the
3. Experimental section
3.1. General procedures
Melting points were recorded on Gallenkamp apparatus. In-
frared spectra (KBr) were determined on a Perkin–Elmer 2000 FT-
IR system. NMR measurements were determined on a Bruker DPX
spectrometer, at 600 MHz for 1H NMR and 125 MHz for 13C NMR, in
DMSO-d6 as solvent and using TMS as internal standard. Mass
spectra were measured on MS 30 and MS 9 (AEI) spectrometers,
with EI 70 eV. Elemental analyses were measured by means of LECO
CHNS-932 Elemental Analyzer. Copies of original data can be pro-
vided upon requisite.
pyrazole CH as a singlet at
d 7.84 ppm (Scheme 5).
Compounds 21a,b were reacted with enaminone 27 to yield the
7-substituted pyrazolo-[1,5-a]pyrimidines 28a,b (Scheme 6).
In conclusion, 3-oxoalkanonitriles can be readily obtained by
reacting cyanoacetic acid–acetic anhydride mixture with
electron rich aromatics. The scope of this approach could be
extended to less electron rich aromatics utilizing indium

K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
9423
O
Br
6
S
Me
DMFDMA
Br
Br
S
xylene, 3 h
S
Reflux, 6 h
O
13
(74%)
12
11
(85%)
NMe2
EtOH
5 h
NH2OH
AcONa
CN
COONa
O
Br
COONa, NaOH
S
Br
S
O
EtOH, reflux 4 h
15
(60%)
NOH
14
(60%)
Scheme 3.
O
O
Me
Me
InCl3, 10%wt.
6
+
N
xylene, 3 h
N
H
CN
O
16
17
(78%)
Scheme 4.
3.2. Synthesis of acetic 2-cyanoacetic anhydride 6
10.0 mmol), (1.08 g, 10.0 mmol) of anisole, and (0.11 g, 10 wt %) of
indium trichloride in 25 mL dry xylene in 25 mL of xylene was
refluxed for 3 h. The crude solid product was poured over ice-water
mixture, then collected by filtration, washed with water, and
recrystallized from ethanol.
A mixture of acetic anhydride (1.02 g, 10.0 mmol) and (0.85 g,
10.0 mmol) of cyanoacetic acid was dissolved in 25 mL dry xylene
and was refluxed for 15 min. The crude product, so formed, was
filtered and the clear filtrate was used after cooling as cyanoace-
tylating agent for aromatic systems in the presence of a catalytic
amount (10 wt %) of InCl3 as Lewis acid.
This compound was obtained as brown solid (70%) (mp 135–
136 ꢀC); IR (KBr):
n
¼2186 (CN), 1710 (C]O) cmꢁ1; 1H NMR (DMSO-
d6):
d
¼3.71 (s, 2H, CH2), 3.89 (s, 3H, CH3), 7.24 (d, 2H, J¼8 Hz), 7.66
(d, 2H, J¼8 Hz); 13C NMR (DMSO-d6):
¼24.8 (CH2), 53.7 (CH3),
d
118.4 (CN), 118.9, 120.6, 127.1, 135.6 (aromatic carbons), 160.8
(C]O); MS, m/z (%), 175.1 (Mþ, 4), 150.1 (35), 135.0 (100), 77.1 (38).
Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.49;
H, 5.14; N, 7.94.
3.3. Reaction of 6 with each of N,N-dimethylaniline and
anisole
3.3.1. Synthesis of 3-(4-(dimethylamino)phenyl)-3-oxopropanenitrile
7a. A mixture of pre-prepared acetic 2-cyanoacetic anhydride 6
(1.27 g, 10.0 mmol), (1.21 g, 10.0 mmol) of N,N-dimethylaniline, and
(0.12 g, 10 wt %) of indium trichloride in 25 mL dry xylene was
refluxed for 3 h. The solid product was collected by filtration,
washed with water, and recrystallized from ethanol.
3.4. Reaction of 6 with 2-acetylfuran
A mixture of pre-prepared acetic 2-cyanoacetic anhydride 6
(1.27 g, 10.0 mmol), (1.10 g, 10.0 mmol) of 2-acetylfuran, and (0.11 g,
10 wt %) of indium trichloride in 25 mL dry xylene was refluxed for
3 h. The crude solid product was collected by filtration, washed
with water, and was then recrystallized from ethanol to yield 9. The
experiment was then repeated with excess amount of 6 (using 1:2
ratio) and the product was triturated by the same above described
way to yield 10.
This compound was obtained as dark brown solid (80%) (mp
164–165 ꢀC); IR (KBr):
n
¼2180 (CN), 1705 (C]O) cmꢁ1
;
1H NMR
(DMSO-d6):
d
¼3.03 (s, 6H, two CH3), 4.54 (s, 2H, CH2), 6.73 (d, 2H,
J¼8 Hz), 7.75 (d, 2H, J¼8 Hz); 13C NMR (DMSO-d6):
¼28.2 (CH2),
d
39.4 (two CH3), 117.1 (CN), 119.7, 123.6, 128.9, 136.2 (aromatic car-
bons), 163.1 (C]O); MS, m/z (%), 188.1 (Mþ, 29), 148.1 (100), 120.1
(27), 77.0 (11). Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88.
Found: C, 70.11; H, 6.39; N, 14.80.
3.4.1. 3-(5-Acetylfuran-2-yl)-3-oxopropanenitrile 9. This compound
was obtained as dark brown solid (68%) (mp 61–62 ꢀC); IR (KBr):
3.3.2. Synthesis of 3-(4-methoxyphenyl)-3-oxopropanenitrile 7b. A
mixture of pre-filtered acetic 2-cyanoacetic anhydride 6 (1.27 g,
n
¼2184 (CN), 1705 and 1708 (two C]O) cmꢁ1; 1H NMR (DMSO-d6):
d
¼2.54 (s, 3H, CH3), 3.51 (s, 2H, CH2), 7.40 (d, 1H, J¼8 Hz), 7.50 (d,

9424
K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
X
DMFDMA
18a,b; a = NMe2, 62%
b = OMe, 60%
7a,b
Reflux, xylene
O
NMe2
CN
NMe2
DMFDMA
9, 15
R
X
CN
Reflux, xylene
O
19a,b; x = O, R = COMe, 70%
x = S, R = Br, 60%
O
Me
DMFDMA
17
N
20 (65%)
Reflux, xylene
O
NMe2
CN
NH2
NH
O
O
NH2
H2N - NH2
18a,b
N
X
N
Reflux, EtOH
X
N
H
22a,b
21a,b; a = NMe2, 60%
b = OMe, 58%
O
O
NH2
X
X
NH2
R
H2N - NH2
R
19a,b
NH
N
Reflux, EtOH
N
N
H
24a,b
23a,b; x = O, R = COMe, 65%
x = S, R = Br, 70%
O
O
Me
Me
N
N
H2N - NH2
20
O
O
Reflux, EtOH
NH
N
N
N
H2N
H2N
H
26
25 (75%)
Scheme 5.
1H, J¼8 Hz); 13C NMR (DMSO-d6):
d
¼26.7 (CH3), 117.6 (CN), 125.1,
84 ꢀC); IR (KBr):
C]O) cmꢁ1 1H NMR (DMSO-d6):
NH2), 5.96 (s, 1H, pyran H), 7.26 (d, 1H, J¼8 Hz), 7.92 (d, 1H, J¼8 Hz);
13C NMR (DMSO-d6):
118.2 (CN), 119.3, 121.6 (furan C-3 and C-4), 147.1, 152.4 (furan C-2
and C-5), 158.2, 160.8 (pyran C-2 and C-6), 183.5, 184.8 (two C]O);
MS, m/z (%), 244.1 (Mþ, 4), 229.1 (28), 201.1 (65), 109.0 (100). Anal.
n
¼3350 (br. NH2), 2188 (CN), 1700 and 1705 (two
125.4, 150.8, 152.3 (furan carbons), 173.6176.7 (C]O); MS, m/z (%),
177.1 (Mþ, 98), 162.1 (24), 137.1 (100), 134.1 (68). Anal. Calcd for
C9H7NO3: C, 61.02; H, 3.98; N, 7.91. Found: C, 60.98; H, 3.97; N, 7.80.
;
d
¼2.09 (s, 3H, CH3), 5.67 (s, 2H,
d¼24.8 (CH3), 89.7, 90.4 (pyran C-3 and C-5),
3.4.2. 2-(5-Acetylfuran-2-yl)-6-amino-4-oxo-4H-pyran-3-carbonitrile
10. This compound was obtained as brown solid (70%) (mp 83–
O
O
O
NH2
N
Reflux, 8 h
+
Ph
NH
N
EtOH
X
N
X
NMe2
N
Ph
27
28a,b; a = NMe2
21a,b; a = NMe2
b = OMe
b = OMe
(28a : 65%, 28b : 60%)
Scheme 6.

K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
9425
Calcd for C12H8N2O4: C, 59.02; H, 3.30; N, 11.47. Found: C, 58.94; H,
3.27; N, 11.43.
product, so formed, was then collected by filtration and recrystal-
lized from ethanol to give 15.
3.5. Reaction of 6 with 2-bromothiophene
3.8.1. 3-(5-Bromothiophen-2-yl)-3-oxopropanenitrile 15. This com-
pound was obtained as pale brown solid (60%) (148–149 ꢀC); IR
A mixture of pre-prepared acetic 2-cyanoacetic anhydride 6
(1.27 g, 10.0 mmol), (2.05 g, 10.0 mmol) of 2-bromothiophene, and
(0.20 g, 10 wt %) of indium trichloride in 25 mL dry xylene was
refluxed for 3 h. The crude solid product was collected by filtration,
washed with water, and was then recrystallized from ethanol to
yield 12.
(KBr):
n
¼2188 (CN), 1708 (C]O) cmꢁ1; 1H NMR (DMSO-d6):
¼3.74
d
(s, 2H, CH2), 7.12 (d, 1H, J¼8 Hz), 7.67 (d, 1H, J¼8 Hz); 13C NMR
(DMSO-d6):
d¼27.8 (CH2), 116.9 (CN), 124.8, 133.2, 135.9, 143.7
(thiophene carbons),183.1 (C]O); MS, m/z (%), 230.1 (Mþ, 11), 190.1
(100), 68.1 (62). Anal. Calcd for C7H4BrNOS: C, 36.54; H, 1.75; Br,
34.73; N, 6.09; S,13.94. Found: C, 36.49; H,1.70; Br, 34.68; N, 5.96; S,
13.89.
3.5.1. 1-(5-Bromothiophen-2-yl)ethanone 12. This compound was
obtained as pale green solid (85%) (mp 91–92 ꢀC); IR (KBr):
n¼1710
3.9. Reaction of 6 with 3-acetylindole 16
(C]O) cmꢁ1
;
1H NMR (DMSO-d6):
d
¼2.61 (s, 3H, CH3), 6.78 (d, 1H,
J¼8 Hz), 7.71(d,1H, J¼8 Hz);13CNMR(DMSO-d6):
d
¼24.7(CH3),119.7,
A mixture ofacetic 2-cyanoacetic anhydride 6 (1.27 g,10.0 mmol),
(1.59 g, 10.0 mmol) of 3-acetylindole, and (0.16 g, 10 wt %) of indium
trichloride in 25 mL dry xylene was refluxed for 3 h. The crude solid
product was collected by filtration, washed with water, and was then
carefully recrystallized from absolute ethanol to yield 17.
123.6, 128.9, 131.2 (thiophene carbons), 184.2 (C]O); MS, m/z (%),
205.9 (Mþ, 76),188.9 (100), 82(38). Anal. Calcd forC6H5BrOS: C, 35.14;
H, 2.46; Br, 38.96; S,15.64. Found: C, 35.09; H, 2.40; Br, 38.91; S,15.59.
3.6. Reaction of 12 with DMFDMA
3.9.1. 3-(3-Acetyl-1H-indol-1-yl)-3-oxopropanenitrile 17. This com-
A mixture of 12 (2.06 g, 10 mmol) and (DMFDMA) (15 mmol)
was dissolved in 50 mL dry xylene and the reaction was refluxed
while the reaction was followed by TLC to completion. The reaction
mixture was concentrated under reduced pressure, cooled and the
solid product, so formed, was then filtered and recrystallized from
ethanol.
pound was obtained as dark brown solid (78%) (mp 160–161 ꢀC); IR
(KBr):
n
¼2182 (CN), 1690 and 1695 (two C]O) cmꢁ1
;
1H NMR
(DMSO-d6):
d
¼2.74 (s, 3H, CH3), 3.89 (s, 2H, CH2), 7.25 (m, 4H,
benzene), 7.84 (s, 1H, pyrrole CH); 13C NMR (DMSO-d6):
d¼22.4
(CH2), 31.4 (CH3), 116.7 (CN), 116.5, 119.7, 123.6, 128.9, 133.2, 138.7,
143.1 (aromatic carbons), 193.8 (C]O); MS, m/z (%), 226.1 (Mþ, 20),
159.1 (26), 144.1 (100), 116.1 (15). Anal. Calcd for C13H10N2O2: C,
69.02; H, 4.46; N, 12.38. Found: C, 68.98; H, 4.42; N, 12.32.
3.6.1. 1-(5-Bromothiophen-2-yl)-3-(dimethylamino)prop-2-en-1-
one 13. This compound was obtained as pale green crystals (74%)
(mp 121–123 ꢀC); IR (KBr):
n
¼1696 (C]O) cmꢁ1; 1H NMR (DMSO-
3.10. Reaction of DMFDMA with each of 7a,b, 9, 15 or 17
d6):
d
¼2.91 (s, 3H, CH3), 2.10 (s, 3H, CH3), 5.72 (d, 1H, J¼14 Hz), 7.26
(d, 1H, J¼8 Hz), 7.61 (d, 1H, J¼8 Hz), 7.66 (d, 1H, J¼14 Hz); 13C NMR
A mixture of each 7a,b, 9, 15, and 17 (10 mmol) and DMFDMA
(15 mmol) was dissolved in 50 mL dry xylene and the reaction was
refluxed while the reaction was followed by TLC to completion. The
reaction mixture was concentrated under reduced pressure, cooled
and the solid product, so formed, was then filtered and recrystal-
lized from ethanol.
(DMSO-d6):
d¼42.6 (two CH3, enamine), 96.8 (CH, enamine), 123.1,
125.7, 129.1, 133.6 (thiophene carbons), 148.4 (CH enamine), 174.2
(C]O); MS, m/z (%), 261.1 (Mþ, 58), 244.1 (50), 180.1 (100), 98.0
(86). Anal. Calcd for C9H10BrNOS: C, 41.55; H, 3.87; Br, 30.71; N,
5.38; S, 12.33. Found: C, 41.51; H, 3.83; Br, 30.68; N, 5.32; S, 12.29.
3.7. Reaction of 13 with hydroxylamine hydrochloride
3.10.1. 3-(Dimethylamino)-2-(4-(dimethylamino)benzoyl)acryloni-
trile 18a. This compound was obtained as pale brown powder
A mixture of 13 (2.61 g, 10 mmol), hydroxylamine hydrochloride
(0.69 g, 10 mmol), and sodium acetate anhydrous (3 g) in ethanol
(25 mL) was heated under reflux for 5 h. The reaction mixture was
poured on water while a solid product was formed. The solid
product, so formed, was then collected by filtration and recrystal-
lized from ethanol to give 14.
(62%) (mp 205–206 ꢀC); IR (KBr):
n
¼2180 (CN), 1692 (C]O) cmꢁ1
;
1H NMR (DMSO-d6):
d
¼2.76 (s, 6H, two CH3), 2.92 (s, 6H, two CH3),
7.18 (d,1H, J¼8 Hz), 7.84 (d, 1H, J¼8 Hz), 8.28 (s, 1H, enamine H); 13C
NMR (DMSO-d6):
d
¼38.7 (two CH3, dimethylamino), 39.6 (two CH3,
enamine), 88.6 (C, enamine), 116.2 (2,6-CH, benzene ring), 117.6
(CN), 122.1, 127.1, 135.6 (aromatic carbons), 138.3 (CH, enamine),
172.9 (C]O); MS, m/z (%), 243.1 (Mþ, 14), 148.1 (100), 120.1 (34).
Anal. Calcd for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found: C,
69.06; H, 6.98; N, 17.21.
3.7.1. 1-(5-Bromothiophen-2-yl)-3-(hydroxyamino)prop-2-en-1-one
14. This compound was obtained as pale yellow powder (60%)
(170–171 ꢀC); IR (KBr):
n
¼1690 (C]O) cmꢁ1
;
1H NMR (DMSO-d6):
d
¼2.71 (d, 2H, CH2, J¼6 Hz), 6.52 (d, 1H, thiophene H, J¼8 Hz), 6.86
3.10.2. 3-(Dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile 18b. This
(t, 1H, J¼6 Hz), 7.44 (d, 1H, thiophene H, J¼8 Hz), 9.61 (s, 1H, OH);
compound was obtained as brown powder (60%) (mp 127–128 ꢀC);
13C NMR (DMSO-d6):
d¼92.1 (enamine CH), 119.7, 126.7, 132.6, 138.2
IR (KBr):
n
¼1696 (C]O) cmꢁ1
;
1H NMR (DMSO-d6):
d¼2.53 (s, 6H,
(thiophene carbons), 154.3 (enamine CH) 176.4 (C]O); MS, m/z (%),
248.0 (Mþ, 3),190.0 (100),162.0 (43). Anal. Calcd for C7H6BrNO2S: C,
33.89; H, 2.44; Br, 32.21; N, 5.65; S, 12.92. Found: C, 33.85; H, 2.40;
Br, 32.18; N, 5.61; S, 12.89.
two CH3), 3.88 (s, 3H, CH3), 7.31 (d, 2H, J¼8 Hz), 7.87 (d, 2H, J¼8 Hz);
8.70 (s, 1H, enamine H); 13C NMR (DMSO-d6):
d¼41.1 (two CH3,
enamine), 59.8 (CH3, anisole), 78.6 (C, enamine), 115.8 (2,6-C, ani-
sole),117.7 (CN),128.6,134.5 (anisole carbons),155.6 (CH, enamine),
158.6 (C-1, anisole), 180.3 (C]O); MS, m/z (%), 230.1 (Mþ, 66), 135.1
(100), 107.1 (23). Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N,
12.17. Found: C, 67.76; H, 6.09; N, 12.04.
3.8. Reaction of 14 with diethyl oxalate and NaOH
A mixture of 14 (2.48 g, 10 mmol), diethyl oxalate (2.61 g,
15 mmol), and sodium hydroxide (1 g) in absolute ethanol (25 mL)
was heated under reflux for 4 h. The reaction mixture was poured
on water and neutralized with hydrochloric acid. The crude solid
3.10.3. 2-(5-Acetylfuran-2-carbonyl)-3-(dimethylamino)acrylonitrile
19a. This compound was obtained as brown powder (70%) (mp 98–
91 ꢀC); IR (KBr):
n
¼2184 (CN), 1696 and 1700 (two C]O) cmꢁ1; 1H

9426
K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
NMR (DMSO-d6):
d
¼2.39 (s, 3H, CH3), 2.92 (s, 3H, enamine CH3), 3.09
(mp 93–94 ꢀC); IR (KBr):
cmꢁ1 1H NMR (DMSO-d6):
7.18 (d, 2H, J¼8 Hz), 7.40 (d, 2H, J¼8 Hz), 7.62 (s, 1H, pyrazole CH),
9.87 (s, 1H, pyrazole NH); 13C NMR (DMSO-d6):
(C-4, pyrazole), 123.8, 124.1 (C-3,4, furan), 141.3 (C-3, pyrazole),
145.9 (C-5, pyrazole), 148.7, 148.9 (C-2,5, furan), 167.5 (C]O), 176.8
(C]O, acetyl); MS, m/z (%), 219.1 (Mþ, 6), 176.1 (63), 137.1 (100).
Anal. Calcd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C,
54.72; H, 4.09; N, 18.98.
n
¼3350 (NH2), 1700 and 1686 (two C]O)
¼2.71 (s, 3H, CH3), 5.31 (s, 2H, NH2),
(s, 3H, enamine CH3), 7.12 (d,1H, J¼8 Hz), 7.42 (d,1H, J¼8 Hz), 7.26 (s,
;
d
1H, enamine H); 13C NMR (DMSO-d6):
d¼24.9 (CH3), 43.2 (two CH3,
enamine), 84.8 (C, enamine), 116.7 (CN), 127.1 (C-3,4, furan), 154.1,
155.2 (C-2,5, furan), 155.4 (CH, enamine), 179.8 (C]O); MS, m/z (%),
232.1 (Mþ, 8), 217.1 (62), 189.1 (100). Anal. Calcd for C12H12N2O3: C,
62.06; H, 5.21; N, 12.06. Found: C, 61.97; H, 5.20; N, 11.95.
d¼25.2 (CH3), 91.3
3.10.4. 2-(5-Bromothiophene-2-carbonyl)-3-(dimethylamino)acrylo-
nitrile 19b. This compound was obtained as pale brown powder
(60%) (mp 144–146 ꢀC); IR (KBr):
n
¼2185 (CN), 1700 (C]O) cmꢁ1
;
3.11.4. (5-Amino-1H-pyrazol-4-yl)(5-bromothiophen-2-yl)metha-
none 23b. This compound was obtained as pale brown powder
1H NMR (DMSO-d6):
d
¼2.91 (s, 3H, CH3), 3.14 (s, 3H, CH3), 7.06 (d,
1H, J¼8 Hz), 7.79 (d, 1H, J¼8 Hz); 8.42 (s, 1H, enamine H); 13C NMR
(70%) (mp 182–183 ꢀC); IR (KBr):
n
¼3330 (NH2), 1688 (C]O)
¼5.70 (s, 2H, NH2), 6.66 (d, 2H,
J¼8 Hz), 7.60 (d, 2H, J¼8 Hz), 7.74 (s, 1H, pyrazole CH), 9.21 (s, 1H,
pyrazole NH); 13C NMR (DMSO-d6):
(DMSO-d6):
d
¼42.7 (two CH3, enamine), 81.4 (C, enamine), 117.6
cmꢁ1 1H NMR (DMSO-d6):
; d
(CN), 122.3, 125.0, 128.1, 131.2 (thiophene carbons), 156.7 (CH, en-
amine), 181.6 (C]O); MS, m/z (%), 286.0 (Mþ, 24), 190.0 (100), 123.0
(51). Anal. Calcd for C10H9BrN2OS: C, 42.12; H, 3.18; Br, 28.02; N,
9.82; S, 11.24. Found: C, 41.51; H, 3.12; Br, 27.92; N, 9.78; S, 11.21.
d
¼87.7 (C-4, pyrazole), 120.4
(C, C–Br), 132.9, 136.7, 144.2 (thiophene carbons), 137.8 (C-3, pyr-
azole), 148.3 (C-5, pyrazole), 173.8 (C]O); MS, m/z (%), 272.1 (Mþ,
100), 190.1 (77), 110 (35). Anal. Calcd for C8H6BrN3OS: C, 35.31; H,
2.22; Br, 29.36; N, 15.44; S, 11.78. Found: C, 35.27; H, 2.17; Br,
29.29; N, 15.36; S, 11.71.
3.10.5. 2-(3-Acetyl-1H-indole-1-carbonyl)-3-(dimethylamino)acrylo-
nitrile 20. This compound was obtained as pale yellow powder
(65%) (mp 133–135 ꢀC); IR (KBr):
n
¼2182 (CN), 1700 and 1693
(two C]O) cmꢁ1
;
1H NMR (DMSO-d6):
d
¼2.69 (s, 3H, CH3), 3.41
3.11.5. 1-(2-(5-Amino-1H-pyrazole-4-carbonyl)-1H-indol-3-yl)etha-
none 25. This compound was obtained as pale brown powder
(s, 3H, CH3), 3.50 (s, 3H, CH3), 7.12 (m, 4H, benzene), 7.87 (s, 1H,
pyrrole H H); 8.76 (s, 1H, enamine H); 13C NMR (DMSO-d6):
(75%) (mp 174–176 ꢀC); IR (KBr):
n
¼3340 (NH2), 1694 and 1688
1H NMR (DMSO-d6):
¼2.39 (s, 3H, CH3), 4.85
(s, 2H, NH2), 7.31 (m, 4H, benzene), 7.89 (s, 1H, pyrazole CH),
11.87 (s, 1H, pyrazole NH); 13C NMR (DMSO-d6):
d
¼26.2 (CH3), 40.8 (two CH3, enamine), 92.1 (C, enamine), 113.6
(two C]O) cmꢁ1
;
d
(CH, benzene), 116.7 (CN), 118.9, 120.6, 124.1, 126.5, 128.3 (aro-
matic carbons), 162.7 (CH, enamine), 183.7 (N–C]O), 191.8 (C]O,
acetyl); MS, m/z (%), 281.1 (Mþ, 16), 238.1 (35), 186.1 (100). Anal.
Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.27;
H, 5.31; N, 14.72.
d
¼26.4 (CH3),
88.6 (C-4, pyrazole), 113.1, 116.9, 120.6, 122.6, 127.1, 128.5, 135.6,
144.8, 151.6 (aromatic carbons), 177.3 (C]O), 187.4 (C]O, acetyl);
MS, m/z (%), 268.1 (Mþ, 8), 186.1 (100), 110.1 (39). Anal. Calcd for
C14H12N4O2: C, 62.68; H, 4.51; N, 20.88. Found: C, 62.61; H, 4.47;
N, 20.81.
3.11. Reaction of 18a,b, 19a,b, and 20 with hydrazine hydrate
A mixture of enamine 18a,b, 19a,b, and 20 (10 mmol) and hy-
drazine hydrate (10 mmol) was dissolved in 50 mL absolute ethanol
and then refluxed for 6 h. The reaction mixture was cooled and the
solid product, so formed, was then collected by filtration and
recrystallized from ethanol.
3.12. Reaction of 21a,b with enaminone
A mixture of 21a,b (10 mmol) and enaminone 23 (10 mmol)
was dissolved in 50 mL absolute ethanol and then refluxed for
8 h. The reaction mixture was cooled and the solid product, so
formed, was then collected by filtration and recrystallized from
ethanol.
3.11.1. (5-Amino-1H-pyrazol-4-yl)(4-(dimethylamino)phenyl)metha-
none 21a. This compound was obtained as dark brown powder (60%)
(mp 241–242 ꢀC); IR (KBr):
n
¼3340 (NH2), 1688 (C]O) cmꢁ1
;
1H
3.12.1. (4-(Dimethylamino)phenyl)(7-phenylpyrazolo[1,5-a]pyrimidin-
3-yl)methanone 28a. This compound was obtained as dark brown
NMR (DMSO-d6):
d
¼2.89 (s, 6H, two CH3), 3.50 (s, 2H, NH2), 7.16 (d,
2H, J¼8 Hz), 7.78 (d, 2H, J¼8 Hz), 7.84 (s,1H, pyrazole CH), 9.39 (s,1H,
powder (65%) (mp 216–217 ꢀC); IR (KBr):
n
¼1698 (C]O) cmꢁ1
;
1H
pyrazole NH); 13C NMR (DMSO-d6):
d¼43.1 (two CH3), 97.5 (C-4,
NMR (DMSO-d6):
d
¼2.69 (s, 6H, two CH3), 7.16 (m, 12H, aromatic);
pyrazole), 114.4 (C-2,6, benzene), 123.9, 131.6, 156.3 (benzene car-
bons), 146.7 (C-3, pyrazole), 155.6 (C-5, pyrazole), 187.2 (C]O); MS,
m/z (%), 230.1 (Mþ, 11), 148.1 (100), 110.1 (63). Anal. Calcd for
C12H14N4O: C, 62.59; H, 6.13; N, 24.33. Found: C, 62.53; H, 6.09; N,
24.29.
13C NMR (DMSO-d6):
d
¼41.7 (two CH3), 109.8, 113.9, 118.9, 120.6,
127.1, 128.3, 135.6, 142.7, 153.4 (aromatic carbons), 187.1 (C]O); MS,
m/z (%), 344.0 (Mþ, 3), 224.1 (73), 77.1 (100). Anal. Calcd for
C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.62; H, 5.22; N,
16.28.
3.11.2. (5-Amino-1H-pyrazol-4-yl)(4-methoxyphenyl)methanone
3.12.2. (4-Methoxyphenyl)(7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)-
21b. This compound was obtained as dark brown powder (58%)
methanone 28b. This compound was obtained as dark brown
(mp 172–173 ꢀC); IR (KBr):
n
¼3350 (NH2), 1690 (C]O) cmꢁ1
;
1H
powder (60%) (mp 164–165 ꢀC); IR (KBr):
n
¼1695 (C]O) cmꢁ1; 1H
NMR (DMSO-d6):
d
¼3.74 (s, 3H, CH3), 5.63 (s, 2H, NH2), 7.21 (d,
NMR (DMSO-d6):
NMR (DMSO-d6):
135.6, 146.8 (aromatic carbons), 184.2 (C]O); MS, m/z (%), 329.1
(Mþ,18), 222.1 (78),135.1 (100), 77 (80). Anal. Calcd for C20H15N3O2:
C, 72.94; H, 4.59; N, 12.76. Found: C, 72.89; H, 4.55; N, 12.68.
d
¼3.67 (s, 3H, CH3), 7.21 (m, 12H, aromatic); 13C
2H, J¼8 Hz), 7.69 (d, 2H, J¼8 Hz), 7.86 (s, 1H, pyrazole CH), 11.83
d¼58.6 (CH3), 111.6, 114.7, 116.9, 118.9, 122.1, 125.1,
(s, 1H, pyrazole NH); 13C NMR (DMSO-d6):
d
¼52.4 (CH3, anisole),
89.6 (C-4, pyrazole), 115.7, 124.6, 128.4 (anisole carbons), 148.3
(C-3, pyrazole), 152.8 (C-5, pyrazole), 159.8 (C-1, anisole), 186.1
(C]O); MS, m/z (%), 135.1 (Mþ, 100), 110.1 (48). Anal. Calcd for
C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C, 60.79; H, 5.09;
N, 19.26.
Acknowledgements
The support of this work was received from University of Kuwait
by research grant (SC01/08) and the facilities of Analab/SAF by re-
search grant (GC01/01), (GC01/03), and (GS03/01) are gratefully
3.11.3. 1-(5-(5-Amino-1H-pyrazole-4-carbonyl)furan-2-yl)ethanone
23a. This compound was obtained as dark brown powder (65%)

K.D. Khalil et al. / Tetrahedron 65 (2009) 9421–9427
9427
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acknowledged. Partial financial support by college of graduate
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appreciated.
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Supplementary data
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Supplementary data associated with this article can be found in
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