Synthesis and Biological Evaluation of Furo[3,2-c]pyrazole-5-carbimidates

Article abstract of DOI:10.14233/ajchem.2019.21971

In the present work, novel pyrazole fused dihydrofurans synthesized via a chronological addition of N-chloro succinimide and base piperidine to pyrano[3,2-c]pyrazole carbonitrile derivatives in methanol medium. Oxidative difunctionalization was done with

Full text of DOI:10.14233/ajchem.2019.21971

Asian Journal of Chemistry; Vol. 31, No. 10 (2019), 2389-2393
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21971
Synthesis and Biological Evaluation of Furo[3,2-c]pyrazole-5-carbimidates
1,2,*,
1
3
SRAVANTHI SILIVERI
, HARINADHA BABU VAMARAJU and SHIVARAJ
1Department of Pharmaceutical Chemistry, G. Pulla Reddy College of Pharmacy, Mehidipatnam, Hyderabad-500028, India
2Department of Pharmacy, Osmania University College of Technology (OUCT), Osmania University, Hyderabad-500007, India
3Department of Chemistry, Osmania University, Hyderabad-500007, India
*Corresponding author: E-mail: sravanthisiliveri@gmail.com
Received: 1 February 2019;
Accepted: 16 July 2019;
Published online: 30 August 2019;
AJC-19557
In the present work, novel pyrazole fused dihydrofurans synthesized via a chronological addition of N-chloro succinimide and base
piperidine to pyrano[3,2-c]pyrazole carbonitrile derivatives in methanol medium. Oxidative difunctionalization was done with the reagent
N-chloro succinimide by the addition of both chlorine and alkoxy groups crosswise the chromene double bond. The addition of base
results in the construction of dihydrofuran derivatives by ring contraction. The structures of newly synthesized compounds were characterized
on the basis of physical and spectral data. Synthesized compounds were evaluated for antibacterial and anti-inflammatory activities. All
the compounds exhibited significant antibacterial activity against all the four strains of bacteria and their MICs ranged between 1.56 and
12.55 µg/mL. In anti-inflammatory screening, among all the tested compounds, compounds 7, 8, 9, 11, 12, 13, 14, 16, 17 and 18 exhibited
significant protection against the edema formation at a concentration of 100 mg/kg.
Keywords: N-Chloro succinimide, Piperidine, Pyrano[3,2-c]pyrazole carbonitriles,Antibacterial activity,Anti-inflammatory activity.
agonist, COX-2 inhibitor [8], β-blockers [9], muscarinic receptor
agonist, α-adrenergic blockers, calcium channel blockers [10]
etc. Furan drugs have broadened scope in remedying various
dispositions in clinical medicines [11-15].Apart from pyrazole
and furan, annulated furo pyrazoles are important structural
motifs in the domain of medicinal chemistry due to their myriad
biological activities. Bi heterocyclic compounds in which pyra-
zole moiety is coupled with furan nucleus exhibit antimicrobial
and anti-inflammatory activities. However there are no reports
in literature concerning coupling of pyrazole ring with another
biologically active furan nucleus either directly or through
carbon bridge. In view of the above facts and in continuation
of our research program [16] directed towards the development
of a new, simple and less toxic biologically active molecules.
The present work encompasses with dihydrofuro fused system
of pyrazole ring to study the changes in biological activity. The
current work presents, direct efficient and operationally conve-
nient approach to the synthesis of some novel dihydrofuro
fused pyrazole derivatives.
INTRODUCTION
Pyrazoles have wide applications in the fields of agricul-
ture as herbicides and insecticides as well as in pharmaceutical
industry. Pyrazole derivatives have been reported to show a
wide-ranging of biological activity together with antibacterial
[1,2], antifungal [3], analgesic [4], anti-inflammatory, anti-
diabetic, neuroprotective, estrogen receptor binding, anti-
neoplastic [5] activities. Due to their broad spectrum of biolo-
gical activities, pyrazoles received a substantial interest in the
area of drug discovery and therefore pyrazole ring constitutes
an important synthetic target in pharmaceutical industry. On
the other hand, furan, a five membered heterocycle containing
oxygen as a hetero atom is a well known heterocyclic comp-
ound have an important attribute of a range of medicinal agents.
The high therapeutic properties of the furan related drugs have
encouraged the researchers to synthesize a large number of
novel pharmacological agents which can act on various recep-
tors in the body as MAO inhibitors [6], kappa opioid receptor
agonist [7], sigma receptor agonist, γ-amino butyric acid receptor
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2390 Siliveri et al.
Asian J. Chem.
Ar-H), 7.42 (t, 2H,Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d, J = 8.89
Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 6.65 (brs, 2H,
NH2), 4.54 (s, 1H, 4-H), 4.01 (s, 3H, OCH3), 1.82 (s, 3H, CH3);
Mass (ESI-MS): 413 (M+H)+.Anal. calcd. for C21H18N4O2ClF
% calcd. (found): C, 61.09 (60.85); H, 4.39 (4.50); N, 13.57
(13.27); O, 7.75 (8.18); F, 4.60 (4.81); Cl, 8.59 (8.39).
5-Amino-6-chloro-5-methoxy-7-(4-bromophenyl)-3-
methyl-1-phenyl-1,5,6,7-tetrahydro pyrano[3,2-c]pyrazole-
6-carbonitrile (4): Yield: 85 %; m.p.: 183-185 °C; IR (KBr,
EXPERIMENTAL
All the chemicals used were of synthetic grade obtained
from Sd fine, Spectrochem andAldrich Chemicals. Completion
of the reactions was monitored by analytical thin layer chroma-
tography (TLC) using E-Merck 0.25 mm silica gel plates.
Visualization melting points were determined on ANALAB
melting point apparatus and were uncorrected.All the 1H NMR
spectra were recorded in CDCl3 and DMSO-d6 solvents unless
otherwise mentioned. Chemical shifts are reported onAVANCE
300 MHz and INNOVA 500 MHz spectrometers relative to
TMS internal standard on the δ-scale. The IR spectra were
recorded on Shimadzu FT-IR Spectrophotometer by using 1 %
potassium bromide discs. The mass spectra were recorded on
Quadruple mass spectrometry.
General procedures for the synthesis and spectral data
of compounds (1-9): To a suspension of pyrano[3,2-c]pyrazole
analogs (1 mmol) in 5 mL of methanol NCS (1.1 mmol) was
added while stirring at room temperature open to air. The resul-
ting clear is stirred at room temperature till the product precipi-
tates out from it. The reaction mixture was filtered and washed
with corresponding alcohol to separate the desired product.
The structures of the products were assigned on the basis of
the spectral data.
General procedures for the synthesis and spectral data
of compounds (10-18): To a suspension of pyrano[3,2-c]pyrazole
analogs (5 mmol) in alcohol (10 mL), N-chloro succinimide
(5.5 mmol) was added at room temperature.After 3 h of stirring,
piperidine (6 mmol) was added and stirred at same temperature
for 5-6 h, till the product is completely precipitated out. The
reaction mixture was filtered and washed with ethanol to sepa-
rate the desired product (or) recrystallized from ethanol to
afford the pure product.
ν
max, cm–1): 762, 1095, 3370.63 (N-H str.) 2200.98 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.42 (d, J = 7.90 Hz, 2H,
Ar-H), 7.18-6.7 (m, 5H, Ar-H) 6.50 (d, J = 8.89 Hz, 2H, Ar-
H), 6.30 (brs, 2H, NH2), 4.58 (s, 1H, 4-H), 3.42 (s, 3H, OCH3),
1.82 (s, 3H, CH3); Mass (ESI-MS): 474 (M+H)+. Anal. calcd.
for C21H18N4O2BrCl % calcd. (found): C, 53.24 (53.46); H,
3.83 (4.02); N, 11.83 (12.39); O, 6.75 (6.85); Br, 16.87 (16.30);
Cl, 7.48 (6.98).
5-Amino-6-chloro-5-methoxy-7-(4-nitrophenyl)-3-
methyl-1-phenyl-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-
6-carbonitrile (5): Yield: 80 %; m.p.: 165-167 °C; IR (KBr,
ν
max, cm–1): 762, 1095, 3391.43 (N-H str.) 2202.39 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 8.20 (d, J = 8.30 Hz, 2H,
Ar-H), 7.80 (d, J = 8.12 Hz, 2H,Ar-H), 7.55-7.38 (m, 4H,Ar-H),
7.25 (t, 1H, Ar-H), 6.97 (s, 2H, NH2), 4.78 (s, 1H, 4H), 3.6 (s,
3H, OCH3) 1.84 (s, 3H, CH3); Mass (ESI-MS): 440 (M+H)+.
Anal. calcd. for C21H18N5O4Cl % calcd. (found): C, 57.34 (56.98);
H, 4.12 (4.32); N, 15.92 (15.50); O, 14.55 (15.03); Cl, 8.06
(8.17).
5-Amino-6-chloro-5-methoxy-7-(4-methylphenyl)-3-
methyl-1-phenyl-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-
6-carbonitrile (6): Yield: 86 %; m.p.: 152-154 °C; IR (KBr,
ν
max, cm–1): 772, 1090, 3390.63 (N-H str.) 2190.98 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.79 (d, J = 7.90 Hz, 2H,
Ar-H), 7.42 (t, 2H,Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d, J = 8.89
Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 6.65 (brs, 2H,
NH2), 4.54 (s, 1H, 4-H), 3.41 (S, 3H, OCH3), 2.03 (s, 3H, CH3),
1.82 (s, 3H, CH3); Mass (ESI-MS): 409 (M+H)+. Anal. calcd.
for C22H21N4O2Cl % calcd. (found): C, 64.62 (64.73); H, 5.18
(5.30); N, 13.70 (13.01); O, 7.83 (8.02); Cl, 8.67 (8.94).
5-Amino-6-chloro-5-methoxy-3-methyl-7-(3-phenoxy-
phenyl)-1-phenyl-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-
6-carbonitrile (7): Yield: 75 %; m.p.: 182-184 ºC; IR (KBr,
5-Amino-6-chloro-5-methoxy-3-methyl-1,7-diphenyl-
1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-carbonitrile
(1): Yellow solid; yield: 86 %; m.p.: 150-152 °C; IR (KBr,
ν
max, cm–1): 762, 1090, 3321.85 (N-H str.), 2195.70 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.78 (d, J = 7.74 Hz, 2H,
Ar-H), 7.32 (t, 2H, Ar-H), 7.36-7.17 (m, 6H, Ar-H), 6.48 (brs,
2H, NH2), 4.58 (s, 1H, 4-H), 3.50 (s, 3H, OCH3), 1.83 (s, 3H, CH3);
Mass (ESI-MS): 395 (M+H)+. Anal. calcd. for C21H19N4O2Cl
% calcd. (found): C, 63.88 (63.51); H, 4.85 (5.25); N, 14.19
(15.02); O, 8.10 (7.93); Cl, 8.98 (8.29).
ν
max, cm–1): 762, 1095, 3288.19 (N-H str.) 2193.58 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.77 (d, J = 8.30 Hz, 2H,
Ar-H), 7.41 (t, 2H, Ar-H), 7.35-7.19 (m, 4H, Ar-H), 7.11-6.81
(m, 6H,Ar-H), 6.46 (brs, 2H, NH2), 4.58 (s, 1H, 4-H), 3.61 (s,
3H, OCH3) 1.90 (s, 3H, CH3); Mass (ESI-MS): 487 (M+H)+.
Anal. calcd. for C27H23N4O3Cl % calcd. (found): C, 66.60
(66.26); H, 4.76 (5.22); N, 11.51 (12.17); O, 9.86 (9.23); Cl,
7.28 (7.012).
5-Amino-6-chloro-5-methoxy-7-(4-methoxyphenyl)-3-
methyl-1-phenyl-1,5,6,7-tetrahydro pyrano[3,2-c]pyrazole-
6-carbonitrile (2): Yield: 90 %; m.p.: 163-165 °C; IR (KBr,
ν
max, cm–1): 772, 1090, 3390.63 (N-H str.) 2190.98 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.79 (d, J = 7.90 Hz, 2H,
Ar-H), 7.42 (t, 2H,Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d, J = 8.89
Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 6.65 (brs, 2H,
NH2), 4.54 (s, 1H, 4-H), 4.01 (s, 3H, OCH3), 3.41 (S, 3H,
OCH3) 1.82 (s, 3H, CH3); Mass (ESI-MS): 426 (M+2H)+.Anal.
calcd. for C21H21N4O3Cl: C, 62.19 (62.32); H, 4.98 (4.55); N,
13.19 (12.98); O, 11.30 (12.13); Cl, 8.34 (8.02).
5-Amino-6-chloro-5-methoxy-3-methyl-1-phenyl-7-
(thiophen-2-yl)-1,5,6,7-tetrahydro pyrano[3,2-c]pyrazole-
6-carbonitrile (8): Yield: 82 %; m.p.: 210-212 ºC; IR (KBr,
ν
max, cm–1): 762, 1085, 3356.87 (N-H str.) 2189.52 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.42 (d, J = 7.90 Hz, 2H,
Ar-H), 7.18-6.7 (m, 4H, Ar-H) 6.50 (d, J = 8.89 Hz, 2H, Ar-
H), 6.30 (brs, 2H, NH2), 4.58 (s, 1H, 4-H), 3.42 (s, 3H, OCH3),
1.82 (s, 3H, CH3); Mass (ESI-MS): 401 (M+H)+. Anal. calcd.
for C19H17N4O2SCl % calcd. (found): C, 56.93 (56.64); H, 4.27
5-Amino-6-chloro-5-methoxy-7-(4-flourophenyl)-3-
methyl-1-phenyl-1,5,6,7-tetrahydro pyrano[3,2-c]pyrazole-
6-carbonitrile (3): Yield: 85 %; m.p.: 172-174 °C; IR (KBr,
ν
max, cm–1): 762, 1095, 3390.63 (N-H str.) 2180.98 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 7.79 (d, J = 7.90 Hz, 2H,

Vol. 31, No. 10 (2019)
Synthesis and Biological Evaluation of Furo[3,2-c]pyrazole-5-carbimidates 2391
(4.35); Cl, 8.84 (8.75); N, 13.98 (13.70), O, 7.98 (8.35), S,
8.00 (8.21).
5-Amino-6-chloro-5-methoxy-3-methyl-1-phenyl-7-
(pyridin-3-yl)-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-
carbonitrile (9): Yield: 75 %; m.p.: 195-197 °C; IR (KBr,
CH3); Mass (ESI-MS): 438 (M+H)+, 13C NMR (75 MHz, CDCl3
+ DMSO) δ ppm: 175.0, 151.2, 145.2, 140.2, 141.3, 128.2,
123.2, 122.3, 120.3, 117.6, 116.0, 115.1, 112.5, 75.1, 58.2,
48.2, 9.1; Anal. calcd. for C21H17N4O2Br % calcd. (found): C,
57.68 (57.66); H, 3.92 (3.94); Br, 18.27 (18.25); N, 12.81 (12.82);
O, 7.32 (7.33).
ν
max, cm–1): 782, 1085, 3364.66 (N-H str.), 2190.81 (C≡N str.);
1H NMR (300 MHz, CDCl3), δ ppm: 8.50 (d, J = 4.34 Hz, 2H,
Ar-H), 7.79 (d, J = 7.74 Hz, 2H, Ar-H), 7.67 (d, J = 7.74 Hz,
1H, Ar-H) 7.51 (t, 2H, Ar-H), 7.44-7.23 (m, 4H, 2H-NH2, 2H-
Ar-H), 4.79 (s, 1H, 4-H), 3.5 (s, 3H, OCH3), 1.79 (s, 3H, CH3);
Mass (ESI-MS): 396 (M+H)+. Anal. calcd. for C20H18N5O2Cl
% calcd. (found): C, 60.68 (60.34); H, 4.58 (4.84); N, 17.69
(18.02); O, 8.08 (8.15); Cl, 8.96 (8.65).
Methyl-5-cyano-6-(4-nitrophenyl)-3-methyl-1-phenyl-
5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate (14):
Yield: 81 %; m.p.: 188-190 °C; IR (KBr, νmax, cm–1): 1683,
1095, 3391.43 (N-H str.) 2202.39 (C≡N str.); 1H NMR (300
MHz, CDCl3), δ ppm: 8.51 (s, 1H, NH), 8.20 (d, J = 8.30 Hz,
2H, Ar-H), 7.80 (d, J = 8.12 Hz, 2H,Ar-H), 7.55-7.38 (m, 4H,
Ar-H), 7.25 (t, 1H, Ar-H), 4.78 (s, 1H, 4-H), 3.6 (s, 3H, OCH3)
13
Methyl-5-cyano-3-methyl-1,6-diphenyl-5,6-dihydro-
1H-furo[3,2-c]pyrazole-5-carbimidate (10): Yield: 80 %;
m.p.: 170-172 °C; IR (KBr, νmax, cm–1): 1090, 1672, 3321.85
(N-H str.), 2195.70 (C≡N str.); 1H NMR (300 MHz, CDCl3), δ
ppm: 8.41 (s, 1H, NH), 7.78 (d, J = 7.74 Hz, 2H, Ar-H), 7.32
(t, 2H, Ar-H), 7.36-7.17 (m, 6H, Ar-H), 4.58 (s, 1H, 4-H), 3.50
(s, 3H, OCH3), 1.83 (s, 3H, CH3); Mass (ESI-MS): 359 (M+H)+;
13C NMR (75 MHz, CDCl3 + DMSO), δ ppm: 174.1, 155.1,
150.0, 140.0, 135.1, 127.5, 128.1, 125.1, 124.3, 120.2, 119.4,
115.2, 112.2, 76.2, 58.2, 48.8, 8.1;Anal. calcd. for C21H18N4O2
% calcd. (found): C, 70.38 (70.36); H, 5.06 (5.08); N, 15.63
(15.61); O, 8.93 (8.95).
1.84 (s, 3H, CH3); Mass (ESI-MS): 404 (M+H)+, C NMR
(75 MHz, CDCl3 + DMSO) δ ppm: 175.0, 156.1, 151.2, 145.2,
140.2, 141.3, 128.2, 123.2, 122.3, 117.6, 116.0, 115.1, 112.5,
75.1, 58.2, 48.2, 9.1;Anal. calcd. for C21H17N5O4 % calcd. (found):
C, 62.53 (62.55); H, 4.25 (4.23); N, 17.36 (17.38); O, 15.86 (15.84).
Methyl-5-cyano-6-(4-methylphenyl)-3-methyl-1-
phenyl-5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate
(15): Yield: 80 %; m.p.: 182-184 °C; IR (KBr, νmax, cm–1): 1680,
1090, 3390.63 (N-H str.) 2190.98 (C≡N str.); 1H NMR (300
MHz, CDCl3), δ ppm: 8.4 (s, 1H, NH), 7.79 (d, J = 7.90 Hz,
2H, Ar-H), 7.42 (t, 2H, Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d, J =
8.89 Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 4.54 (s,
1H, 4-H), 3.41 (S, 3H, OCH3), 2.03 (s, 3H, CH3), 1.82 (s, 3H,
CH3); Mass (ESI-MS): 409 (M+H)+, 13C NMR (75 MHz, CDCl3
+ DMSO) δ ppm: 174.5, 156.1, 153.0, 147.5, 140.0, 135.8,
131.1, 126.1, 125.3, 118.2, 117.5, 110.2, 108.2, 76.2, 58.2,
48.5, 25.2, 9.2; Anal. calcd. for C22H20N4O2 % calcd. (found):
C, 70.95 (70.93); H, 5.41 (5.43); N, 15.04 (15.06); O, 8.59 (8.57).
Methyl-5-cyano-3-methyl-6-(3-phenoxyphenyl)-1-
phenyl-5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate
(16): Yield: 75 %; m.p.: 210-212 °C; IR (KBr, νmax, cm–1):
1682, 1095, 3288.19 (N-H str.) 2193.58 (C≡N str.); 1H NMR
(300 MHz, CDCl3), δ ppm: 8.41 (s, 1H, NH), 7.77 (d, J = 8.30
Hz, 2H, Ar-H), 7.41 (t, 2H, Ar-H), 7.35-7.19 (m, 4H, Ar-H),
7.11-6.81 (m, 6H,Ar-H), 4.58 (s, 1H, 4-H), 3.61 (s, 3H, OCH3),
Methyl-5-cyano-6-(4-methoxyphenyl)-3-methyl-1-
phenyl-5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate
(11): Yield: 80 %; m.p.: 185-187 °C; IR (KBr, νmax, cm–1):
1090, 1670, 3390.63 (N-H str.) 2190.98 (C≡N str.); 1H NMR
(300 MHz, CDCl3), δ ppm: 8.5 (s, 1H, NH), 7.79 (d, J = 7.90
Hz, 2H, Ar-H), 7.42 (t, 2H, Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d,
J = 8.89 Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 4.54
(s, 1H, 4-H), 4.01 (s, 3H, OCH3), 3.60 (S, 3H, OCH3) 1.82 (s,
3H, CH3); Mass (ESI-MS): 389 (M+H)+, 13C NMR (75 MHz,
CDCl3 + DMSO) δppm: 174.5, 156.1, 153.0, 147.5, 140.0, 141.2,
131.1, 126.1, 125.3, 118.2, 117.5, 110.2, 108.2, 76.2, 58.2,
53.1, 48.5, 9.2; Anal. calcd. for C22H20N4O3 % calcd. (found): C,
68.03 (68.05); H, 5.19 (5.17); N, 14.42 (14.44); O, 12.36 (12.34).
Methyl-5-cyano-6-(4-flourophenyl)-3-methyl-1-
phenyl-5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate
(12): Yield: 85 %; m.p.: 192-194 °C; IR (KBr, νmax, cm–1):
1095, 1684, 3390.63 (N-H str.) 2180.98 (C≡N str.); 1H NMR
(300 MHz, CDCl3), δ ppm: 8.6 (s, 1H, NH), 7.79 (d, J = 7.90
Hz, 2H, Ar-H), 7.42 (t, 2H, Ar-H), 7.23 (t, 1H, Ar-H), 7.14 (d,
J = 8.89 Hz, 2H, Ar-H), 6.83 (d, J = 8.89 Hz, 2H, Ar-H), 4.54
(s, 1H, 4-H), 4.01 (s, 3H, OCH3), 1.82 (s, 3H, CH3); Mass
(ESI-MS): 377 (M+H)+, 13C NMR (75 MHz, CDCl3 + DMSO)
ppm: 175.0, 160.1, 151.2, 145.2, 140.2, 141.3, 128.2, 123.2,
122.3, 117.6, 116.0, 115.1, 112.5, 75.1, 58.2, 48.2, 9.1; Anal.
calcd. for C21H17N4O2F % calcd. (found): C, 67.01 (67.03); H,
4.55 (4.53); N, 14.89 (14.90); O, 8.50 (8.50); F, 5.05 (5.04).
Methyl-5-cyano-6-(4-bromophenyl)-3-methyl-1-
phenyl-5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate
(13): Yield: 82 %; m.p.: 202-204 °C; IR (KBr, νmax, cm–1):
1670, 1095, 3370.63 (N-H str.) 2200.98 (C≡N str.); 1H NMR
(300 MHz, CDCl3), δ ppm: 8.4 (s, 1H, NH), 7.42 (d, J = 7.90
Hz, 2H, Ar-H), 7.18-6.7 (m, 5H, Ar-H) 6.50 (d, J = 8.89 Hz,
2H, Ar-H), 4.58 (s, 1H, 4-H), 3.42 (s, 3H, OCH3), 1.82 (s, 3H,
13
1.90 (s, 3H, CH3); Mass (ESI-MS): 451 (M+H)+, C NMR
(75 MHz, CDCl3 + DMSO) δ ppm: 175.4, 159.1, 158.5, 155.3,
144.2, 143.3, 144.1, 129.1, 128.3, 127.5, 124.3, 121.2, 120.2,
119.4, 118.5, 117.2, 115.5, 112.2, 110.1, 73.2, 52.3, 37.5, 12.1;
Anal. calcd. for C27H22N4O3 % calcd. (found): C, 71.99 (71.97);
H, 4.92 (4.94); N, 12.44 (12.45); O, 10.65 (10.64).
Methyl-5-cyano-3-methyl-1-phenyl-6-(thiophen-2-yl)-
5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate (17):
Yield: 78 %; m.p.: 230-232 °C; IR (KBr, νmax, cm–1): 1685,
1085, 3356.87 (N-H str.) 2189.52 (C≡N str.); 1H NMR (300
MHz, CDCl3), δ ppm: 8.2 (s, 1H, NH), 7.42 (d, J = 7.90 Hz,
2H, Ar-H), 7.18-6.7 (m, 4H, Ar-H) 6.50 (d, J = 8.89 Hz, 2H,
Ar-H), 4.58 (s, 1H, 4-H), 3.42 (s, 3H, OCH3), 1.82 (s, 3H, CH3);
13
Mass (ESI-MS): 365 (M+H)+, C NMR (75 MHz, CDCl3 +
DMSO) δ ppm: 174.5, 153.0, 147.5, 140.0, 141.2, 131.1, 126.1,
125.3, 118.2, 117.5, 110.2, 108.2, 76.2, 58.2, 53.1, 48.5, 9.2;
Anal. calcd. for C19H16N4O2S % calcd. (found): C, 62.62 (62.60);
H, 4.43 (4.44); N, 15.37 (15.38); O, 8.78 (8.79); S, 8.80 (8.79).
Methyl-5-cyano-3-methyl-1-phenyl-6-(pyridin-3-yl)-
5,6-dihydro-1H-furo[3,2-c]pyrazole-5-carbimidate (18):

2392 Siliveri et al.
Asian J. Chem.
Yield: 75 %; m.p.: 195-197 °C; IR (KBr, νmax, cm–1): 1680,
1085, 3364.66 (N-H str.), 2190.81 (C≡N str.); 1H NMR (300
MHz, CDCl3), δ ppm: 8.55 (s, 1H, NH), 7.79 (d, J = 7.74 Hz,
2H, Ar-H), 7.67 (d, J = 7.74 Hz, 1H, Ar-H) 7.51 (t, 2H,Ar-H),
7.44-7.23 (m, 4H,Ar-H), 4.79 (s, 1H, 4-H), 3.42 (s, 3H, OCH3),
in methanol medium. In this reaction with NCS addition of
both chlorine and alkoxy groups takes place crosswise the
chromene double bond and resulted the products (1-9).Annexes
to this, compounds (10-18) were synthesized via dehydro-
halogenation on compounds (1-9) with piperidine as a base in
solvent methanol at room temperature. The reaction mixture
turned to a clear brown coloured solution, followed by the
precipitation of product after 6 h. The structures of newly
synthesized compounds were characterized on the basis of
physical and spectral data. The possible mechanism for the
synthesis of compounds (10-18) is shown in Scheme-II.
13
1.79 (s, 3H, CH3); Mass (ESI-MS): 360 (M+H)+, C NMR
(75 MHz, CDCl3 + DMSO) δ ppm: 175.0, 156.1, 149.4, 146.9,
142.7, 140.7, 138.5, 133.5, 133.0, 130.0, 127.2, 125.9, 124.3,
120.0, 76.3, 55.7, 40.2, 9.5; Anal. calcd. for C20H17N5O2 %
calcd. (found): C, 66.84 (66.86); H, 4.77 (4.75); N, 19.49
(19.48); O, 8.90 (8.91).
Biological evaluation
RESULTS AND DISCUSSION
Antibacterial activity: All the synthesized compounds
were screened for antibacterial activity against four strains of
bacteria, Bacillus subtilis and Staphylococcus aureus (Gram-
The synthetic route of title compounds [(1-9) and (10-
18)] is shown in Scheme-I. Oxidative difunctionalization of
pyrano[3,2-c]pyrazole carbonitriles was done with NCS reagent
H3C
N
O
R
NH2
CN
O
(I)
N
N
CN
CN
rt
Ph
CN
CN
N
HC
R
+
RCHO
3-5 min
(II)
H2O/EtOH (1:1)
reflux 3-5 h
O
MeOH
3h
R = C6H5-, 4-OCH3-C6H4-, 4-NO2-C6H4-,4-Br-C6H4
4F- C6H4, 4-CH3-C6H4-, 3-Phenoxy phenyl
2-Thienyl, 3-pyridinyl
N
Cl
O
H3C
NH
H3C
NH2
O
O
N
OCH3
CN
Cl
OCH3
N
Piperidine
rt, 6h
N
N
CN
R
R
(10-18)
(1-9)
Scheme-I: Synthetic route for the compounds (1-18)
O
N
1
NH2
Cl
ROH
O
NH
CN
O
O
NH2
CN
O
2
OR
Aryl
Aryl
Aryl
NH
CN
Cl
3
Cl
O
R1
R1
Base
R1
NH
O
Base
H
H
N
O
O
OR
Aryl
Aryl
OR
CN
CN
Cl
Base.HCl
R1
R1
Scheme-II: Mechanism for the synthesis of compounds (10-18)

Vol. 31, No. 10 (2019)
Synthesis and Biological Evaluation of Furo[3,2-c]pyrazole-5-carbimidates 2393
TABLE-1
ANTIBACTERIAL ACTIVITY OF DIFFERENT COMPOUNDS BY BROTH MICRO DILUTION MIC METHOD
Antibacterial activity against standard strains–compounds
µg/mL
Compound 7
Compound 8
Compound 9
Compound 11
Compound 12
Compound 17
Compound 18
1
+
+
+
–
–
–
–
–
–
2
+
+
+
–
–
–
–
–
–
3
+
+
–
–
–
–
–
–
–
4
+
+
–
–
–
–
–
–
–
1
+
+
+
+
–
–
–
–
–
2
+
+
+
+
–
–
–
–
–
3
+
+
+
+
–
–
–
–
–
4
+
+
+
+
–
–
–
–
–
1
+
+
+
–
–
–
–
–
–
2
+
+
+
–
–
–
–
–
–
3
+
+
+
–
–
–
–
–
–
4
+
+
+
+
–
–
–
–
–
1
+
+
+
–
+
–
–
–
–
2
+
+
+
–
–
–
–
–
–
3
+
+
–
–
–
–
–
–
–
4
+
+
+
+
–
–
–
–
–
1
+
+
–
+
–
–
–
–
–
2
+
+
+
+
–
–
–
–
–
3
+
+
–
+
+
–
–
–
–
4
+
+
+
+
–
–
–
–
–
1
+
+
–
+
–
–
–
–
–
2
+
+
–
+
–
–
–
–
–
3
+
+
+
+
–
–
–
–
–
4
+
+
+
+
–
–
–
–
–
1
+
+
+
+
–
–
–
–
–
2
+
+
+
+
–
–
–
–
–
3
+
+
+
+
–
–
–
–
–
4
+
+
+
+
–
–
–
–
–
0.3
0.7
1.5
3.1
6.2
12.5
25
50
100
1 = Bacillus subtilis; 2 = Staphylococcus aureus; 3 = Escherichia coli; 4 = Pseudomonas aeruginosa; + Resistant; – Susceptible.
Ciprofloxacin is taken as a standard drug and its MIC is 1.56 µg/mL against all the four strain.
positive), Escherichia coli and Pseudomonas aeruginosa
(Gram-negative) using ciprofloxacin as a standard drug as per
the reported methods [17-19] and MICs were determined at
different concentrations 0.39, 0.78, 1.56, 3.125, 6.25, 12.5,
25, 50, 100 µg/mL by using Broth Micro dilution MIC method
[20]. Among all, compounds 7, 8, 9, 11, 12, 17 and 18 showed
antibacterial activity against all the four strains of bacteria and
their MICs ranged between 1.56 and 12.55 µg/mL. The results
are tabulated in Table-1.
Anti-inflammatory activity: Ten compounds were tested
for anti-inflammatory activity by Plethysmography. From the
data obtained, the mean paw edema volume and percentage
reduction in edema was calculated. All the compounds were
found to possess good anti-inflammatory activity and repre-
sented in Table-2.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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22.4
30.4
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22.5
12.7
11.7
39.8
50.5
34.3
44.2
35.1
27.7
30.5
51.8
66.1
46.9
63.3
55.7
43.4
43.8
65.5
72.0
67.6
71.9
68.8
52.7
56.9
50.6
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Conclusion
The present work intended at synthesizing the structurally
different dihydrofuran derivatives via an one pot reaction of
pyrano[2,3-c]pyrazole carbonitriles with N-chloro succinimide
and base piperidine. The purity and structures of the synthe-
sized compounds were confirmed by physical and spectral data
(IR, NMR and Mass).All the compounds were tested for anti-
bacterial and anti-inflammatory activities.Among all the tested
compounds, 7, 8, 9, 11, 12, 17 and 18 showed anti bacterial
activity against both Gram-positive and Gram-negative standard
strains and their MICs ranged between 1.56 and 12.55 µg/mL.
In anti-inflammatory studies all the compounds exhibited good
percentage protection against edema formation.
https://doi.org/10.4103/0250-474X.49090.
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