A carbanion induced synthesis of highly congested pyrazole and imidazole containing heterocycles

Article abstract of DOI:10.1016/j.tetlet.2014.01.095

An efficient approach to the synthesis of highly congested di, penta and hexacyclic pyrazoles as well as imidazole fragment containing novel heterocyclic molecule has been developed through a carbanion induced transformation of suitably functionalized 2H-

Full text of DOI:10.1016/j.tetlet.2014.01.095

Tetrahedron Letters 55 (2014) 1715–1719
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A carbanion induced synthesis of highly congested pyrazole
and imidazole containing heterocycles
⇑
Hardesh K. Maurya, Atul Gupta
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Picnic spot Road, Lucknow 226015, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach to the synthesis of highly congested di, penta and hexacyclic pyrazoles as well as
imidazole fragment containing novel heterocyclic molecule has been developed through a carbanion
induced transformation of suitably functionalized 2H-pyran-2-ones, benzo[h]chromene and thiochro-
meno[4,3-b]pyrans. Due to the presence of fluorescence, we report their prime application metal sensor
as off/on switching in ferric ions.
Received 7 October 2013
Revised 20 January 2014
Accepted 22 January 2014
Available online 31 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Pyran-2-one
Benzo[h]chromene
Thiochromeno[4,3-b]pyran
Fluorescence
Metal sensor
The interesting conjugation feature of nitrogen in pyrazole and
its structural implications on biological and medicinal systems1–10
has drawn attention of organic chemists towards further explora-
tion of its chemistry. In plants, a small number of biologically ac-
tive natural products1,2 are known in which pyrazole feature is
present as sub-structure. To the best of our knowledge, only four
natural products are reported in the literature. The first member
of this class is nigellicine (i) which was isolated in 1985 from the
seeds of Nigella sativa.1 Later on, two other pyrazole ring containing
alkaloids, nigeglanine (ii) and nigellidine (iii), were isolated from
Nigella glandulifera2 and Nigella sativa,3 respectively. Another pyra-
zole derivative from nature used in ancient natural remedies is
bendacort (AF2071)4 (Fig. 1).
Pyrazoles are commonly present as substructure in diversified
products of therapeutic importance such as antitumor, ACE-inhib-
itor, antifungal, antibacterial, anti-inflammatory, antiviral, anticon-
vulsant and antidepressant agents.5 These are also present as core
moiety in various drugs such as celebrex (non-steroidal anti-
inflammatory drug),6 sildenafil (pulmonary arterial hypertension
and erectile dysfunction drug),7 lonazolac (non-steroidal anti-
inflammatory drug)8 and fipronil (broad spectrum insecticide),9
Figure 2. Pyrazoles are also described as building blocks for the
synthesis of complex derivatives.10 Furthermore, pyrazole frag-
ment containing molecules are also used in dyes and pigments
for their fluorescence characteristic.11 Recently, a poly cyclic
pyrazole derivative was identified as fluorescent probe for
detection of gold(III) ions in living cells.12 Pyrazole derivatives have
O
O
OH
O
N
N
N
N
N
N
nigeglanine (ii)
i
nigellicine ( )
OH
O
COOH
O
O
OH
HO
H
N
N
H
H
O
bendacort (iv)
nigellidine (iii)
Figure 1. Naturally occurring pyrazoles.
N
N
Cl
O
COOH
Cl
CF3
CF3
HN
N
N
O
N
N
N
NC
N
N
)
O
Cl
NH2
H2N
S
O
F3C
O
S
O
O
N
⇑
v
celebrex (
)
vi
vii
lonazolac (
Corresponding author. Tel.: +91 5222718556.
E-mail addresses: hardesh11@yahoo.co.in (H.K. Maurya), atul_gupta04@yahoo.
sildenafil (
)
fipronil (viii)
N
co.in (A. Gupta).
Figure 2. Pyrazole fragment containing drugs.
http://dx.doi.org/10.1016/j.tetlet.2014.01.095
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1716
H. K. Maurya, A. Gupta / Tetrahedron Letters 55 (2014) 1715–1719
been reported to be used as near-infrared cyanine dyes13 and fluo-
rescent sensors in material as well as in biological sciences.14,15
Due to their interesting chemical properties and prevalence as
scaffolds in multifarious applications, we have synthesized active
methylene containing pyrazoles (4) as a novel synthon from the
suitable precursor pyrane-2-ones (3) using efficient chemistry
and explored the synthesis of various novel di, penta and hexacy-
clic pyrazoles as well as imidazole fragment containing heterocy-
cles as future aspects in medicinal and molecular imaging.
The intermediates 2-(5-aryl-1H-pyrazol-3-yl)acetonitrile (4)
were synthesized from 6-aryl-4-methylthio-2H-pyran-2-ones
(3),16 whereas precursors 6-aryl-4-methylthio-2H-pyran-2-ones
(3)17 were prepared from the reaction of methyl 2-cyano-3,3-dim-
ethylthioacrylate (1)16–19 and aryl methyl ketone (2), Scheme 1.
Exploiting the versatility of enamines20,21 for the synthesis of
highly congested heterocycles such as heteroaryl-substituted
Table 1
Yields of 3-(dimethylamino)-2-(5-aryl-1H-pyrazol-3-yl)acrylo-nitrile 6 (Scheme 2)24
S.N.
4/6
R2
R
R3
Mp (°C) of 6
Yields (%) of 6
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
H
H
H
H
OMe
CF3
H
OMe
Br
Cl
Me
F
H
H
H
H
H
H
OMe
H
221–222
213–214
220–221
229–230
215–216
249–250
171–172
155–156
85
79
84
76
80
69
51
61
g
h
OMe
H
formation of 2-(aryl)-7-phenylpyrazolo[1,5-c]pyrimidines (8a–b),
Scheme 3.
Probably, the reaction proceeds with elimination of NMe2 fol-
lowed by intramolecular cyclization, hydrolysis and decarboxyl-
ation, respectively. The structure of pyrazolo[1,5-c]pyrimidines
(8) was identified with the help of mass, IR, 1D and 2D NMR (1H
NMR, 13C NMR, Dept, Cosy, HMQC and HMBC). However, under
similar reaction conditions, the reaction of enamine (6) with 2-
aminopyridine (9) gave 3-(5-aryl-1H-pyrazol-3-yl)-2H-pyr-
ido[1,2-a]pyrimidin-2-ones (10) in 31–33% yield, Scheme 3.
Further, to generalize the reactions of pyrazole (4), reactions of
4 with 12a–d in the presence of KOH/DMF at room temperature
were performed, Scheme 5.
The starting precursor 5,6-dihydro-4-methylthio-2-oxo-2H-
benzo[h]chromene-3-carbonitriles (12a–b)22 were prepared from
the reaction of 1-tetralones (11a–b) with methyl 2-cyano-3,3-dim-
ethylthioacrylate (1) while 5,6-dihydro-4-methylthio-2-oxo-thio-
chromeno[4,3-b]pyran-3-carbonitriles (12c–d)23 were prepared
from the reaction of thiochromen-4-ones (11c–d) with methyl 2-
cyano-3,3-dimethylthioacrylate (1). Compounds 12 (a–d) on
amination with sec.amine in boiling ethanol, afforded 13,
Scheme 4.22,23
As evident from the topography of the lactones 12 and 13 the
positions C2, C4 and C10b are electron deficient and C10b is partic-
ularly prone to nucleophilic attack because of an extended conju-
gation and the presence of an electron-withdrawing CN
substituent at position 3. However, the reaction of an equimolar
mixture of lactones 12 or 13 and pyrazole (4) did not deliver the
expected products 15 and the reaction proceeds from the attack
of nucleophile 4 at C4 position of 12 or 13 which yielded products
14, Scheme 5. Both the lactones 12 and 13 are very useful synthons
for the ring transformation reactions. The basic difference in both
the lactones lies in the nature of substituent present at position
4. In case of lactone 12 the –SCH3 substituent at position 4 is more
labile and highly vulnerable to nucleophilic attack as compared to
sec.amino substituent in 13.
Therefore, various analogues 14a–i have been prepared from
starting the precursor 12 in good yields, Table 3. It is worthy to
note that the reaction of 13a with 4a under similar reaction condi-
tions yielded product 14a only in 14% yield. Attempts were made
to prepare 14a from 12a in improved yield by the use of different
base combinations such as NaH-THF for 2 h at 40 °C and KOH-ionic
liquid (ethyl methyl imidazolium chloride) for 4 h at 40 °C which
yielded compound 14a in 59% and 62% yields, respectively.
As plausible mechanism discussed in Schemes 5 and 6, the ini-
tial step in the synthesis of 14 and 17 is the attack of a carbanion,
generated in situ from pyrazoles (4) at C4 of the lactone (12 or 13),
followed by ring closure involving nitrogen of the pyrazole inter-
mediate and CN function.
a-amino- and a-hydroxy acids, fused pyridinones, pyrimidinones,
pyranones and related system, we have selected enamine inbuilt
heteroarenes such as 2-heteroaryl-3-dimethylamino acrylonitriles
(6) as precursors for the preparation of novel heterocycles (8,10,14
and 17), which are not easily obtainable by other classical routes.
Thus, a reaction of pyrazoles (4) and 1.2 equiv DMFDMA (5) in
dry THF at 80–90 °C for 4–6 h led to the formation of energetically
stable Z-isomer of 3-(dimethylamino)-2-(5-aryl-1H-pyrazol-3-
yl)acrylonitriles (6), Scheme 2. However, the reaction of pyrazole
(4) with DMFDMA (5) under reflux in dry dioxane or DMF for 7–
18 h gave a complex mixture with recovery of major amount of
starting pyrazole (4).
In order to synthesize novel heterocycles, a model experiment
was performed using 6a and 7 as reactants in different solvent, cat-
alyst/base, temperature and time as summarized in Table 2. As evi-
dent from Table 2, the product 8a has not formed in ethanol, DMF
or BF3Et2O, while in AcOH, TFA or PTSA/AcOH in EtOH the forma-
tion of product 8a was observed in trace. Further exploration of
the reaction with IRA-400 (50 mol %)/TFA or Amberlyst-15
(50 mol %)/TFA yielded the product 8a in 19% and 23% yields,
respectively, while the use of amberlyst-15 (100% mol %)/TFA
improved the yield of product 8a (36%) (Table 2). On the basis of
these results, we explored the reaction of enamines (6) and benz-
amide (7) in TFA using amberlyst-15 as catalyst which led to the
NC
SMe
MeS
NC
SMe
2
( )
ArCOCH3
CN
O
NH2NH2 (1.2eq)
KOH
N
Ar
COOMe
MeOH
Ar
O
N
H
DMSO, rt
reflux, 6-7 h
1
3
4
o
2, 3 4
,
4
4
yield (%) of
Ar
Mp ( C) of
a
b
c
d
e
f
Phenyl
150-151
148-149
180-181
164-165
158-159
188-189
159-160
270-271
212-213
51
53
59
52
50
53
74
51
49
4-Methoxyphenyl
4-Bromophenyl
4-Chlorophenyl
4-Methylphenyl
4-Flurophenyl
g
h
i
3,4,5-Trimethoxyphenyl
3-(Trifluoromethyl)phenyl
4-Nitrophenyl
Scheme 1. Synthesis of pyran-2-one (3)16–19 and 2-(5-aryl-1H-pyrazol-3-yl) ace-
tonitrile (4).16
NC
Me
Me
N
NC
Me
Me
THF, 80-90ºC
4-6 h
N
R2
R
H
N
MeO
OMe
N
H
N
R2
R
N
H
In order to synthesize compound 18, we have also studied the
reaction of 2-cyanomethyl-1H-benzimidazole (16) with 12a under
various reaction conditions such as NaH/THF for 2 h at 40 °C, KOH/
ionic liquid (ethyl methyl imidazolium chloride) for 4 h at 40 °C
and KOH/DMF which yielded compound 17 in 73%, 76% and 84%,
R3
6
5
4
R3
Scheme 2. Synthesis of 3-(dimethylamino)-2-(5-aryl-1H-pyrazol-3-yl)acrylonitrile
(6) (Table 1).

H. K. Maurya, A. Gupta / Tetrahedron Letters 55 (2014) 1715–1719
1717
Table 2
Optimization of reaction conditions of 2-(aryl)-7-phenylpyrazolo [1,5-c]pyrimidine (8a)
S.N.
Catalyst/basea
Solvent
Temp (°C)
Time
Yielda (%) of 8
b
b
b
1
2
3
4
5
6
7
8
KOH
EtOH
EtOH
DMF
AcOH
EtOH
TFA
—
TFA
TFA
TFA
110–120
—
80–90
8 h
KOH/basic alumina in MW (160 watt)
KOH
—
PTSA/AcOH
—
BF3Et2O
IRA-400 (50 mol %)
Amberlyst-15 (50 mol %)
Amberlyst-15 (100 mol %)
Amberlyst-15 (200 mol %)
Amberlyst-15 (300 mol %)
20 min
24 h
08 h
50 h
50 h
5 h
80 h
80 h
50 h
50 h
50 h
130–140
115–120
80–90
100–110
100–110
100–110
100–110
100–110
100–110
Traces
Traces
3
b
19
9
23c
36c
35c
37c
10
11
12
TFA
TFA
a
b
c
Separated yields.
No reaction.
With unseparated mixture from column chromatography.
Me
SCH3
N
O
SCH3
NC
N
H
Me
CN
X
NC
CN
O
X
N
H
CN
X
H3CS
H3CO
KOH
NH
2
O
NH
O
+
O
O
O
C2H5OH
3-4 h
DMSO
5-6 h
7
O
N
N
R1
N
H
R1
1
TFA, Amberlyst-15
N
11
R1
12
13
R
H
°
130-140 C, 50 h
6
11-13 R1
X
Yield of 12(%)
9422a
Yield of 13 (%)
9622a
R
TFA, Amberlyst-15
a
b
c
d
H
OMe
H
CH2
CH2
S
130-140 C, 50 h
- HNMe
8722b
89
°
8223b
7523a
NC
N
NH
2
2
Cl
S
7723b
5723a
9
H
N
OH
N
N
Scheme 4. Synthesis of the substituted 5,6-dihydro-2-oxo-2H-benzo[h]chromene-
3-carbonitriles (12a–b,13a–b) and 2,5-dihydro-2-oxo-thiochromeno[4,3-b]pyran-
3-carbonitriles (12c–d,13c–d).22,23
N
N
N
C
N
H
R
-H
O
2
N
H
in these deuterated solvents because of solubility factor. Therefore,
we prepared the NMR sample in dry NaOH and (CD3)2SO and got a
good quality NMR spectrum. However, it was observed that keep-
ing the sample for longer time (>8 days) in this condition, the prod-
ucts were coagulated and NMR spectrum could not obtained.
Further, when we placed the solution of different pyrazole
R
NC
N
N
N
HN
N
N
N
derivatives (500 lM in DMF or 3:1 CHCl3/MeOH) under UV rays
N
R
of long wave length (365 nm), compounds 8 and 10 displayed a
white fluorescence whereas compounds 14 and 17 displayed fluo-
rescent green colour (kmax = 540–560 nm) in visual as well as long
wave ultraviolet lamp (365 nm). In this context, on the basis of pre-
viously reported fluorescence sensing activities of pyrazoles ana-
logues,12 we focused our attention towards exploring the metal
sensing activity of the pyrazoles analogue 14 which contain three
nitrogen and one carbonyl oxygen for coordination with a metal
hydrolysis
H
-CO
2
R
hydrolysis
N
N
N
O
N
N
R
N
b
N
H
°
8a) R=OMe (37%, mp 104-105 C)
8b) R=H (31%, mp 113-114 °C)
a
ion. To pursue this goal, we prepared a 500 lM solution of pyrazole
a
R
°
10a) R=H (31%, mp 308-309 C)
a
14b in DMF and 16 mM solution of FeCl3 in DMF. Titration of
0.5 mL solution of 14b with 16 mM solution of FeCl3 showed that
green colour fluorescence completely disappeared on the addition
of 2 mL of FeCl3 solution with formation of a non fluorescent yel-
low solution.
10b )
R=CH (33%, mp 172-173 °C)
3
Scheme 3. Synthesis of 2-(aryl)-7-phenylpyrazolo[1,5-c]pyrimidine (8) and 3-(5-
aryl-1H-pyrazol-3-yl)-2H-pyrido[1,2-a]pyrimidin-2-one (10),24 aAmberlyst-15
(100 mol %), bAmberlyst-15 (300 mol %).
Further, our attention was to explore off/on switching sensing
activity for 14b. For this purpose, we titrated further the above
non fluorescent yellow solution with 16 mM solution of EDTA in
water. We observed that on addition of 2.5 mL EDTA solution,
the green fluorescent colour of the compound appeared again,
Figure 3. Thus, the pyrazole derivative can be explored as off/on
switching sensor for metal detection.
respectively instead of the product 18. Thus, the use of KOH/DMF
at 40 °C for this reaction was found to be appropriate. After opti-
mizing reaction conditions, we have explored various reactions of
lactone 12 and imidazole 16 in KOH/DMF as shown in Table 4
(Scheme 6). Under these conditions (in KOH/DMF), reaction of
13a with 16 yielded product 17a in 16% yield.
The synthesized compounds 14 and 17 have shown partial sol-
This observation was further generalized by the use of different
metal salts such as ZnCl2, CdCl2, CsCl, CaCl2, LiCl BF3ÁEt2O, HgCl2,
CuCl and AgNO3 with compound 14b. Among these ZnCl2, CdCl2,
CsCl, CaCl2, LiCl and BF3ÁEt2O could not stop green fluorescence,
ubility (>500 lM/mL) in various deuterated solvents such as chlo-
roform/methanol, DMSO, TFA and D2O. It was difficult to get 1H
NMR as well as 13C NMR spectra of compounds (10, 14 and 17)

1718
H. K. Maurya, A. Gupta / Tetrahedron Letters 55 (2014) 1715–1719
R2
R
Y
N
4
CN
R3
NC
Y
X
N
KOH/DMF
rt, 5-8 h
N
Y
+
H
CN
N
4
CN
10b O
O
CN
NC
N
H
X
X
KOH/DMF
rt, 5-8 h
R2
NH
+
12: Y=SMe
NC
O
O
H
10b
O
N
O
13: Y=piperidin-1-y
R1
16
Y
N
CN
R
X
H
X
12: Y=SMe
R1
R1
R3
4
13: Y=piperidin-1-yl
-YH
H
O
O
O
H
X
O
HN
N
R1
-YH
CN
Y
NC
N
R2
N
R
H
H
CN
H
O
R2
R3
X
N
H
R1
-CO2
H-shift
X
N
O
N
CN
R
O
O
Y
N
R3
NC
CN
R1
N
O
R1
Y
H
NC
H-shift
X
N
N
X
N
CN
O
N
N
-CO2
H-shift
H
NC
H-shift
R1
X
R1
R2
R2
R
X
NH
Y
N
NC
HN
-YH
R3
R
O
O
NC
CN
R1
R3
R1
X
N
H
N
X
N
O
NC
N
H-shift12
13
N
CN
H
11
10
NH
X
-YH
R1
X
O
14
NC
9
NC
N 8
R2
NC
15
16
X
7 NH2
R1
N
N
X
6
N
R
H-shift
1
2
O
5
O
R2
10
R
N
R3
4
CN
H
3
CN
18
R3
R1
17
R1
R1
11
9
NC
12
NH
NC
13
R2
Scheme 6. Synthesis of 7-amino-6-oxo-6,8,15-trihydro-15H-benzo[h]chromeno
[4,3-d]pyrido[1,2-a]benzimidazole-14-carbonitrile (17a–b)/7-amino-6-oxo-6,8,15-
trihydro-15H-thiochromeno[4,3-b]pyrao[4,3-d]pyrido[1,2-a]benzimidazole-14-
carbonitrile (17c–d) (Table 4).
N
O
8
7
N
14 X
NH
N
X
R
6
1
2
O
5
R3
CN
15
4
3
R1
14
R1
Table 4
9-Amino-5-chloro-8-oxo-8,9a-dihydro-1H-benzo[d]imidazolo[2,1-g]thiochro-
meno[4,3-c]isochromene-15-carbonitriles (17) synthesized from lactone 12 with
yields and mp (Scheme 6)24
Scheme 5. Synthesis of 7-imino-6-oxo-10-aryl-6,7,9,14-tetrahydro-13H-benzo[h]
chromeno[4,3-d]pyrazolo[1,5-a]pyridine-12-carbonitrile (14a–d)/7-imino-6-oxo-10-
aryl-6,7,9-trihydro-13H-thiochromeno[4,3-b]pyrao[4,3-d]pyrazolo[1,5-a]pyridine-
12-carbonitrile (14e–i).
Entry
R1
X
mp (°C)
Yield (%)
17a
17b
17c
17d
H
OMe
H
CH2
CH2
S
>315
>315
309a
312a
76
98
84
76
Table 3
Yields and mp of 7-imino-6-oxo-10-aryl-6,7,9,14-tetrahydro-13H-benzo[h]chromeno
[4,3-d]pyrazolo[1,5-a]pyridine-12-carbonitrile (14a-d)/7-imino-6-oxo-10-aryl-6,7,9-
trihydro-13H-thiochromeno[4,3-b]pyrao[4,3-d]pyrazolo[1,5-a]pyridine-12-carbonitrile
(14e–i) synthesized from lactone 12, (Scheme 5)24
Cl
S
a
Start to decompose.
Entry
R
R2
R3
R1
X
Mp (°C)
Yield (%)
added FeCl3
solution
14a
14b
14c
14d
14e
14f
14g
14h
14i
H
OMe
H
NO2
H
OMe
F
H
H
H
H
H
H
H
CF3
OMe
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
CH2
CH2
CH2
CH2
S
S
S
S
S
303–304
280–281
305–306
350a
67
60
79
90
66
61
63
76
65
added EDTA
solution
290a
280a
(i)
(ii)
(iii)
310a
Figure 3. Change of fluorescence colour as observed in long wave ultraviolet lamp
(365 nm): (i) 500 M solution of compound 14b in DMF, (ii) 500 M solution of
compound 14b and 16 mM solution of ferric chloride in DMF (1:4), (iii) 500
H
OMe
309–310
275a
l
l
OMe
l
M
a
Start to decompose.
solution of compound 14b, 16 mM solution of ferric chloride in DMF and16 mM
solution of EDTA in water (1:4:5).
whereas HgCl2, CuCl and AgNO3 could diminished green fluores-
cence of compound 14b and converted the solution into non
fluorescence transparent solution. Thus, we report preliminary
results of molecular sensing activity of pyrazole derivative 14b.
In conclusion, we have developed an efficient method for the
synthesis of enamines (6) and highly congested di (8), penta (14)
and hexacyclic (17) pyrazoles as well as imidazole fragment
containing novel heterocyclic molecules. In addition, this report

H. K. Maurya, A. Gupta / Tetrahedron Letters 55 (2014) 1715–1719
1719
Found: C, 66.98; H, 5.94; N, 20.76; General procedure for the synthesis of 2-
(aryl)-7-phenylpyrazolo[1,5-c]pyrimidine (8) and 3-(5-aryl-1H-pyrazol-3-yl)-2H-
pyrido[1,2-a]pyrimidin-2-one (10): 3-(dimethylamino)-2-(5-aryl-1H-pyrazol-3-
yl)acrylonitrile (6, 3.73 mmol) and benzamide (7, 5.60 mmol) or 2-
aminopyridine (9, 4.40 mmol) were refluxed in TFA (10 mL) for 50 h in the
presence of 100 mol % amberlyst-15. The reaction mixture was poured in water
and filtered. The sticky residue thus obtained was dried in oven and residue
was dissolve in DCM. Amberlyst-15 was filtered and filtrate was concentrated
and purified by silica gel column chromatography using chloroform (50–99%)
in hexane; 2-(4-methoxyphenyl)-7-phenylpyrazolo[1,5-c]pyrimidine (8a): Light
greenish white solid, white fluorescence in long range UV; Rf 0.82 (5% MeOH/
DCM); 1H NMR (300 MHz, DMSO-d6): d 3.85 (s, 3H, OMe), 6.79 (s, 1H, pyrazole
ring), 6.97 (d, 2H, J = 8.4 Hz, Ar-H), 7.34 (d, 1H, J = 6.0 Hz, Ar-H), 7.58 (br s, 3H,
Ar-H), 7.90 (d, J = 6.0 Hz, 1H Ar-H), 7.94 (d, J = 8.7 Hz, 2H, Ar-H), 8.62 (br s, 2H,
pyrazine ring); 13C NMR (75 MHz, DMSO-d6): d 55.74 (OMe), 94.13 (CH),
111.27 (CH), 114.59 (2 Â CH), 125.56 (C), 128.46 (2 Â CH), 128.69 (2 Â CH),
130.80 (2 Â CH), 131.45 (CH), 133.06 (C), 137.94 (CH), 144.21(C), 149.52 (C),
155.57 (C), 160.93 (C); MS: 302.2 (M+H)+; Anal. Calcd (C19H15N3O): C, 75.73; H,
5.02; N, 13.94. Found: C, 75.63; H, 4.99; N, 13.89; 3-(5-phenyl-1H-pyrazol-3-yl)-
2H-pyrido[1,2-a]pyrimidin-2-one (10a): Light yellowish solid, white
fluorescence in long range UV; Rf 0.26 (EtOAc); IR (KBr): 1669 (C@O), 3334
demonstrates the utility of the pyrazole derivative 14b for preli-
minary metal sensing activity.
Acknowledgement
This work was supported by DST, New Delhi, India for financial
support as DST fast track young scientist fellowship [No SR/FT/CS-
20/2011] to H.K.M.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
095. These data include experimental data of all new synthesized
compounds, scan copy of spectra, MOL files and InChiKeys of the
most important compounds described in this article.
(NH) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 3.64 (br s, 1H, NH), 7.14 (m, 1H,
;
Ar-H), 7.22 (s, 1H, pyrazole ring), 7.26 (m, 3H, Ar-H), 7.62–7.77 (m, 4H, Ar-H),
8.04 (m, 1H, Ar-H), 9.08 (m, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): d 101.91,
112.72, 113.70, 116.87 (2C), 124.91, 125.78, 126.87, 127.64, 128.93 (2C),
134.94, 138.46, 144.63, 148.86, 149.15, 155.49; MS: 289.3 (M+H)+; Anal. Calcd
(C17H12N4O): C, 70.82; H, 4.20; N, 19.43. Found: C, 70.71; H, 4.18; N, 19.36;
General procedure for the synthesis of 7-imino-6-oxo-10-aryl-6,7,9,14-tetrahydro-
13H-benzo[h]chromeno[4,3-d]pyrazolo[1,5-a] pyridine-12-carbonitrile (14a–d)/
7-imino-6-oxo-10-aryl-6,7,9-trihydro-13H-thiochromeno[4,3-b]pyrao[4,3-d]
References and notes
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pyrazolo[1,5-a]pyridine-12-carbonitrile (14e–i):
A mixture of lactone 12
(1.0 mmol) and 2-(5-aryl-1H-pyrazol-3-yl)acetonitrile (4, 1.0 mmol) in DMF
(9 mL) in the presence of powdered KOH (1.2 mmol) was stirred at room
temperature for 5–8 h. The reaction was monitored using silica gel TLC. After
consumption of 12, the crude residue was poured onto crushed ice with
vigorous stirring. The aqueous suspension was neutralized with dil. HCl (if
required) and the precipitate obtained was filtered, washed with water and
dried. Residue was purified by silica gel column chromatography using
chloroform/methanol (0–30%); 7-imino-6-oxo-10-phenyl-6,7,9,14-tetrahydro-
9. Buntain, I. G.; Hatton, L. R.; Hawkins, D. W.; Pearson, C. J.; Roberts, D. A. EP
352944 A1, 1990.
10. www.alfa.com/en/docs/Pyrazoles.pdf.
13H-benzo[h]chrom-eno[4,3-d]pyrazolo[1,5-a]pyridine-12-carbonitrile
Yellow solid; Rf 0.38 (CHCl3); IR (KBr): 1577, 1611, 1692 (C@O), 2203 (CN),
3259 and 3370 (NH) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 2.94 (t, 2H,
(14a):
;
11. Kanetkar, V. R.; Shankarling, G.; Malanker, J. Colourage 1998, 45, 40–42.
12. Yang, Y.; Yin, C.; Huo, F.; Chao, J. RSC Adv. 2013, 3, 9637.
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2013, 89, 326.
J = 7.2 Hz, CH2), 3.21 (t, 2H, J = 7.8 Hz, CH2), 6.61 (s, 1H, CH), 7.28–7.48 (m, 7H,
Ar-H & NH), 7.64 (m, 1H, Ar-H), 8.02 (d, 3H, J = 7.5 Hz, Ar-H); MS: 403.1
(MÀH)+; Anal. Calcd (C25H16N4O2): C, 74.25; H, 3.99; N, 13.85. Found: C, 74.12;
H, 3.96; N, 13.78; 7-imino-6-oxo-10-phenyl-6,7,9-trihydro-13H-thiochro-
meno[4,3-b]pyrao[4,3-d]pyrazolo[1,5-a]pyridine-12-carbonitrile (14e): Yellow
solid; Rf 0.46 (CHCl3); IR (KBr): 1586, 1690 (C@O), 2208 (CN), 3305 and 3436
14. Ziessel, R.; Starck, M.; Sutter A. WO 2013041811 A1 2013.
15. Wandelt, B.; Sadowska, M.; Hachulka, K. Chemik 2008, 61, 65.
16. (a) Mishra, P.; Kumar, S.; Maurya, H. K.; Gautam, S. K.; Kumar, B.; Tandon, V. K.;
Ram, V. J. Heterocycles 2012, 82, 189; (b) Ram, V. J.; Verma, M.; Hussaini, F. A.;
Shoeb, A. Chem. Res.(S) 1991, 98; (c) Maurya, H. K.; Verma, R.; Saba, A.; Pandey,
S.; Pathak, V.; Sharma, S.; Srivastava, K. K.; Negi, A. S.; Gupta, A. Bioorg. Chem.
Lett. 2013, 23, 5844; (d) Kumar, A.; Husain, M.; Prasad, A.; Singh, I.; Vats, A.;
Sharma, N. K.; Sharma, S. K.; Gupta, R. K.; Olsen, C. E.; Bracke, M. E. Ind. J. Chem.-
B 2003, 42B, 1950; (e) Ram, V. J.; Haque, N.; Singh, S. K.; Hussaini, F. A.; Shoeb,
A. Ind. J. Chem.-B 1993, 32B, 924.
17. (a) Ram, V. J.; Nath, M.; Srivastava, P.; Sarkhel, S.; Maulik, P. R. J. Chem. Soc.,
Perkin Trans. 1 2000, 3719; (b) Maurya, H. K.; Vasudev, P. G.; Gupta, A. RSC Adv.
2013, 3, 12955.
18. (a) Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Heterocycl. Chem. 1987, 24,
1557; (b) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. Liebigs Ann. Chem.
1991, 1229.
19. Nath, M.; Srivastava, P.; Goel, A.; Ram, V. J. Eur. J. Org. Chem. 1998, 10, 2083.
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21. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
22. (a) Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 1715; (b) Goel, A.; Taneja, G.;
Raghuvanshi, A.; Kant, R.; Maulik, P. R. Org. Biomol. Chem. 2013, 11, 5239.
23. (a) Maurya, H. K.; Tandon, V. K.; Kumar, B.; Kumar, A.; Huch, V.; Ram, V. J. Org.
Biomol. Chem. 2012, 10, 605; (b) Maurya, H. K.; Gautam, S. K.; Pratap, R.;
Tandon, V. K.; Kumar, A.; Bajpai, V.; Kumar, B.; Ram, V. J. Org. Biomol. Chem.
2012, 10, 4977.
(NH) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 4.43 (s, 2H, SCH2), 6.65 (s, 1H, CH),
;
7.30–7.45 (m, 7H, Ar-H & NH), 7.74 (d, 1H, J = 7.5 Hz, Ar-H), 8.02 (d, 3H,
J = 7.5 Hz, Ar-H); 13C NMR (75 MHz, DMSO-d6): d 25.05, 68.76, 88.12, 95.59,
106.96, 121.48, 126.08, 127.02, 127.28 (2C), 127.87, 128.55, 129.35, 129.43
(2C), 131.17, 133.32, 134.88, 140.56, 143.05, 150.56, 153.38, 153.75, 161.72;
MS: 421.1 (MÀH)+; Anal. Calcd (C24H14N4O2S): C, 68.23; H, 3.34; N, 13.26.
Found: C, 68.14; H, 3.31; N, 13.20; General procedure for the synthesis of 7-
amino-6-oxo-6,8,15-trihydro-15H-benzo[h]chromeno[4,3-d]pyrido[1,2-a]benzimid-
azole-14-carbonitrile (17a–b)/7-amino-6-oxo-6,8,15-trihydro-15H-thiochromeno
[4,3-b]pyrao[4,3-d]pyrido[1,2-a]benzimidazole-14-carbonitrile (17c–d): A mixture
of lactone 12 (1.0 mmol),2-cyanomethyl-1H-benzimidazole (16, 1.0 mmol) and
powdered KOH (1.2 mmol) in DMF (9 mL) was stirred at room temperature for
5–8 h. The reaction was monitored using silica gel TLC. After consumption of
12, the residue was poured onto crushed ice with vigorous stirring. The
aqueous suspension was neutralized with dil. HCl (if required) and the
precipitate obtained was filtered, washed with water and dried. The crude
residue was purified by silica gel column chromatography using chloroform/
methanol (0–30%); 7-amino-6-oxo-6,8,15-trihydro-15H-benzo[h]chromeno[4,3-
d]pyrido[1,2-a]benzimidazole-14-carbonitrile (17a): Orange solid; Rf 0.42
(CHCl3:MeOH, 10:1); IR (KBr): 1563, 1612, 1692 (C@O), 2208 (CN), 3173 and
3440 (NH) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 2.93 (br s, 2H, CH2), 3.22 (br
;
s, 2H, CH2), 7.11 (m, 1H, Ar-H), 7.32 (m, 4H, Ar-H), 7.49 (m, 1H, Ar-H), 7.64 (m,
1H, Ar-H), 7.89 & 9.93 (br s, 2H, NH2), 8.79 (m, 1H, Ar-H); MS: 377.1 (MÀH)+;
Anal. Calcd (C23H14N4O2): C, 73.01; H, 3.73; N, 14.81. Found: C, 72.92; H, 3.70;
N, 14.73; 7-amino-6-oxo-6,8,15-trihydro-15H-thiochromeno[4,3-b]pyrao[4,3-
d]pyrido[1,2-a]benzimidazole-14-carbonitrile (17c): Orange solid; Rf 0.64
(CHCl3:MeOH, 10:1); IR (KBr): 1556, 1603, 1691 (C@O), 2208 (CN), 3177 and
24. General procedures and spectral data: General procedure for the synthesis of 3-
(dimethylamino)-2-(5-aryl-1H-pyrazol-3-yl)acrylonitrile
(6):
2-(5-Aryl-1H-
pyrazol-3-yl)acetonitrile (4, 0.02 mol) and DMFDMA (5, 0.03 mol) were
refluxed in dry THF (50 mL) for 4–6 h. The excess THF was evaporated at
reduced pressure. The crude product poured into methanol and the precipitate
obtained was filtered. The obtained crude was recrystallized with methanol.
(Z)-3-(dimethylamino)-2-(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)acrylonitrile
(6b): White crystalline solid; Rf 0.63 (EtOAc); IR (KBr): 3312 (NH), 2187 (CN)
3426 (NH) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 4.48 (s, 2H, SCH2), 7.14 (t,
;
2H, J = 7.5 Hz, Ar-H), 7.25–7.41 (m, 5H, Ar-H & NH2), 7.55 (d, 1H, J = 7.8 Hz, Ar-
H), 7.74 (dd, 1H, J = 1.5 & 7.5 Hz, Ar-H), 8.80 (d, 1H, J = 8.1 Hz, Ar-H); 13C NMR
(75 MHz, DMSO-d6): d 25.24, 69.31, 88.97, 107.11, 115.55, 117.50, 117.64,
121.08, 124.37, 126.29, 127.02, 127.90, 128.56, 131.32, 132.86, 135.22, 144.50,
145.41, 151.28, 151.59, 154.97, 161.31; MS: 395.1 (M+-1); Anal. Calcd
(C22H12N4O2S): C, 66.66; H, 3.05; N, 14.13. Found: C, 66.51; H, 3.01; N, 14.03.
cmÀ1 1H NMR (300 MHz, DMSO-d6): d 3.38 (s, 6H, NMe2), 3.83 (s, 3H, OCH3),
;
6.36 (s, 1H, @CH), 6.93 (d, 2H, J = 3.6 Hz, Ar-H), 7.36 (s, 1H, CH), 7.53 (d, 2H,
J = 3.6 Hz, Ar-H), 12.12 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 40.21
(2C), 54.64, 96.70, 113.47 (3C), 120.24 (CN), 126.06 (4C), 147.01, 148.68,
158.68; MS: 269.2 (M+H)+; Anal. Calcd (C15H16N4O): C, 67.15; H, 6.01; N, 20.88.