Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus

Article abstract of DOI:10.3390/molecules16010307

Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C-and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene]-malononitrile (4a) with reactants having active hydrogen and Et ₃N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H- pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac₂O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR,¹H-NMR/¹³C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi.

Full text of DOI:10.3390/molecules16010307

Molecules 2011, 16, 307-318; doi:10.3390/molecules16010307
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis, Reactions and Biological Evaluation of Some New
Naphtho[2,1-b]furan Derivatives Bearing a Pyrazole Nucleus
Ashraf H. F. Abd El-Wahab 1,*, Zarrag Isa A. Al-Fifi 2, Ahmed H. Bedair 3, Fawzy M. Ali 3,
Ahmed H. A. Halawa 3 and Ahemed M. El-Agrody 3
1
Department of Chemistry, Faculty of Science, Jazan University, Jazan 2097, Saudi Arabia
2
Department of Biology, Faculty of Science, Jazan University, Jazan 2097, Saudi Arabia
3
Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
* Author to whom correspondence should be addressed; E-Mail: ash_abdelwahab@yahoo.com;
Tel.: 00960540963753; Fax: 0096073245212.
Received: 14 November 2010; in revised form: 14 December 2010 / Accepted: 15 December 2010 /
Published: 5 January 2011
Abstract: Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2)
gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was
reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8.
Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-
malononitrile (4a) with reactants having active hydrogen and Et3N gave the corresponding
pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of
three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-
yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl
bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives
14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac2O afford the
corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the
1
synthesized compounds were confirmed by IR, H-NMR/13C-NMR and mass spectral
studies. Compound 14 showed promising effects against the tested Gram positive and
negative bacteria and fungi.
Keywords: Vilsmeier reaction; 2-[3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-
yl)methylene]malononitrile; 1,3,4-thiadiazol-2-ylacetamide; antimicrobial activity

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Molecules 2011, 16
Introduction
Naphthofuran derivatives exhibit very potent antibacterial [1-3], genotoxic [4-6] and anticancer
activity [7-9], but some were shown to be mutagenic in bacteria [10-15]. The present investigation
deals with the synthesis of some new naphtho[2,1-b]furan derivatives bearing pyrazole nuclei attached
to different heterocyclic moieties and their biological activities.
Results and Discussion
Condensation of 2-acetylnaphtho[2,1-b]furan (1) [16] with phenylhydrazine afforded 2-(1-
phenylhydrazonoethyl)naphtho[2,1-b]furan (2). Vilsmeier formylation [17] of the latter afforded 3-
(naphtho-[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (3). Condensation of 3 with a
variety of C-nucleophiles, namely malononitrile, cyanoacetamide, cyanothioacetamide, barbituric acid
and 2-acetylnaphtho[2,1-b]furan (1) give the condensation products 4, 5 and 8, while reactions with N-
nucleophiles, namely hydrazine derivatives or amines, afforded the condensation products 6 and 7
(Scheme 1).
Scheme 1. Synthesis of naphtho[2,1-b]furan pyrazole derivatives.
NHPh
N
i
CH3
O
O
COMe
1
2
Ph
N
N
Ph
ii
N
N
X
R
O
R
CH
iv
CN
1
N
O
Ph
2
3
N
HN
NH
5
4a; X = CN
b; X = CONH2
c; X = CSNH2
R
4
O
CHO
5
3
Ph
N
Ph
N
N
N
vi
R
Ph
R
N
N
CH NNHR'
CH CHCOR
6a; R' = H
R
8
b; R' = Ph
CH NAr
c; R' = COMe
d; R' = CSNH2
e; R' = COCH2CN
7a; Ar = C6H5
b; Ar = C6H4Cl-p
R =
O
Reagents and Conditions: i) PhNHNH2, EtOH, reflux; ii) POCl3, DMF, reflux; iii) XCH2CN,
EtOH, piperidine, reflux; iv) barbaturic acid, EtOH, triethylamine, reflux; v) 2-acetylnaphtho[2,1-
b]furan (1); vi) aniline or p-chloroaniline, EtOH, reflux; vii) hydrazine derivatives, EtOH, reflux.

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Molecules 2011, 16
Compounds 4a and 6d were used as key intermediates in the synthesis of novel pyran, pyrazole and
thiazole derivatives via their interaction with different reagents. Thus, the reaction of 4a with 3-
methyl-1-phenyl-2-pyrazolin-5-one in the presence of triethylamine did not give the expected
pyrazolopyran 9 and instead, only one compound was isolated, identified as 4-[3-(naphtho[2,1-b]furan-
2-yl)-1-phenyl-1H-pyrazol-4-yl]methylene-3-methyl-1-phenyl-2-pyrazoline-5-one (10), while with
hydrazine hydrate in refluxing ethanol it furnished 6a (as verified by m.p. and mixed m.p.) instead of
the pyrazole derivative 11. The formation of 6a and 10 were assumed to proceed via elimination of
malononitrile [18] and their structures were further confirmed by independent synthesis via direct
condensation of 3 with hydrazine hydrate (Scheme 1) or with 3-methyl-1-phenyl-2-pyrazolin-5-one
(Scheme 2), respectively The reaction of 4a with ethyl acetoacetate in dry methylene chloride
containing triethylamine gave the pyrazolopyran derivative 12, while with 4-hydroxycoumarin under
Michael reaction conditions it afforded the 4H-pyran derivative 13 (Scheme 2). The structure of 13
was further verified by m.p. and mixed m.p after independent synthesis via direct condensation of 3
with 4-hydroxycoumarin in the presence of malononitrile and a few drops of piperidine as a base
(a one pot reaction).
Scheme 2. Synthesis of pyran, pyrazole and thiazole derivatives.
Ph
N
N
3
R
Ph
NH2
N
N
ii
Ph
N
N
N
R
H2N
N
11
Me
CN
6a
R
EtO2C
iii
CN
N
O
NH2
N
Ph
ii
4a
O
NH2
Me
9
i
12
2
N
1
Ph
N
3
5
R
4
Me
iv
N
O
NH2
CN
O
N
Ph
O
i
iv, viii
3
3
10
O
R'
13
S
S
vi
v
N
6d
vii
N
N
N
H
15
CH3
N
N
H
O
R'
R'
14
R'
COCH3
N
S
N
NHCOCH3
,
R' =
R =
O
O
16
N
N
Ph
Reagents and Conditions: i) 3-methyl-1-phenyl-2-pyrazolin-5-one, EtOH, triethylamine, reflux; ii)
NH2NH2·H2O, EtOH, reflux; iii) AcCH2CO2Et, CH2Cl2, triethylamine, reflux; iv) 4-hydroxy-
coumarin, EtOH, piperidine, reflux; v) BrCH2CO2Et, CH3CO2Na, EtOH, reflux; vi) ClCH2COCH3,
CH3CO2Na, EtOH, reflux; vii) Ac2O, reflux, viii) CH2(CN)2.

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Molecules 2011, 16
When thiosemicarbazone derivative 6d was allowed to react with ethyl bromoacetate or
chloroacetone in the presence of fused sodium acetate, it gave the corresponding thiazolidinone and
thiazoline derivatives 14 and 15, respectively, while with refluxing acetic anhydride it afforded the
thiadiazole derivative 16 (Scheme 2). These reactions were assumed to proceed via S-alkylation
followed by intramolecular cyclization with concomitant loss of an alcohol molecule and/or
dehydration.
Structures 2, 3, 4, 5, 6, 7 and 8 were established by spectral and physical data (Tables I-II). The
mass spectra of 3, 4b,c, 5, 6a-d, 7a,b and 8 showed the corresponding molecular ion peaks at m/z 338
(M+, 100%), m/z 420 (M+, 35 %), m/z 404 (M+, 100 %), m/z 448 (M+, 100%), m/z 352 (M+, 100 %),
m/z 404 (M+, 100 %), m/z 394 (M+, 100%), m/z 411 (M+, 2 %), m/z 413 (M+, 100 %), m/z 447(M+,
100%) and m/z 530 (M+, 65 %), respectively. The fragmentation patterns of compounds 3, 4b,c, 5, 6a-
d, 7a,b and 8 are illustrated in Scheme 3.
Table I. Physical and analytical data of new synthesized compounds 1-16.
Analysis (%)
Comp.
No.
M.P.
(T/oC)a
Molecular
Found/calculated
H
Formula (MW)
C
N
1
108-110a
172-174a
180-182a
185-187a
292-294b
265-267a
350-352a
280-282c
190-192d
220-222d
228-230b
345-347e
174-176d
170-172d
260-262b
218-220c
208-210a
260-262b
271-273c
220-222c
255-257c
C14H10O2 (210.23)
C20H16N2O (300.35)
C22H14N2O2 (338.36)
C25H14N4O (386.40)
C25H16N4O2 (404.42)
C25H16N4OS (420.49)
C26H16N4O4 (448.43)
C22H16N4O (352.39)
C29H24N4O (444.53)
C25H22N4O2 (410.47)
C23H17N5OS (411.48)
C25H17N5O2 (419.43)
C29H23N3O (429.51)
C29H22ClN3O (463.96)
C36H22N2O3 (530.57)
C32H22N4O2 (494.54)
C31H24N4O4 (516.55)
C34H20N44O4 (548.55)
C25H17N5O2S (451.50)
C26H19N5OS (449.53)
C27H21N5O3S (495.55)
79.95 (79.98)
79.96 (79.98)
78.00 (78.09)
77.65 (77.71)
74.20 (74.25)
71.35 (71.41)
69.60 (69.64)
74.90 (74.98)
78.29 (78.36)
73.10 (73.15)
67.09 (67.13)
71.50 (71.59)
81.00 (81.09)
75.00 (75.07)
81.40 (81. 49)
77.70 (77.72)
72.00 (72.08)
74.40 (74.44)
66.45 (66.50)
69.42 (69.47)
65.38 (65.44)
4.78 (4.79)
5.35 (5.37)
4.12 (4.17)
3.60 (3.65)
3.95 (3.99)
3.80 (3.84)
3.55 (3.60)
4.50 (4.58)
5.35 (5.44)
5.32 (5.40)
4.12 (4.16)
4.05 (4.09)
5.32 (5.40)
4.70 (4.78)
4.12 (4.18)
4.35 (4.48)
4.60 (4.68)
3.60 (3.67)
3.72 (3.80)
4.23 (4.26)
4.23 (4.27)
-
2
9.30 (9.33)
8.20 (8.28)
14.47 (14.50)
13.78 (13.85)
13.25 (13.32)
12.35 (12.49)
15.85 (15.90)
12.55 (12.60)
13.60 (13.65)
16.95 (17.02)
16.67 (16.70)
9.70 (9.78)
9.00 (9.06)
5.25 (5.28)
11.30 (11.33)
10.80 (10.85)
10.18 (10.21)
15.45 (15.51)
15.54 (15.85)
14.00 (14.13)
3
4a
4b
4c
5
6a
6b
6c
6d
6e
7a
7b
8
10
12
13
14
15
16
a From EtOH; b from dioxane; c from acetic acid; d from benzene; e from DMF

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Molecules 2011, 16
Table II. Significant peaks in the EI (70 ev) spectra of compounds 1, 3, 4b,c, 5, 6a-d,7b,
8, 10, 12, 13, 16.
Comp.
No.
m/z (intensity/%)
193 139
139(100)
M+
210 (32)
336
310
232
77
Other peaks
168(3), 113(11), 89(15),
63(38).
1
3
4b
4c
5
338 (100)
404 (100)
420 (35)
310 (20)
310 (1)
139 (15) 77 (62) 234 (1), 208 (1), 167 (1)
139 (12) 77 (67) 360 (25), 283 (4), 257 (3),
139 (15) 77 (58) 386(100), 281(2)
232 (1) 193 (3)
193 (8)
448 (100)
139 (7)
77 (34) 338 (14), 290 (11), 22
4(5), 181 (3)
6a
6b
6c
352 (100)
428 (100)
394 (100)
336 (66)
336 (60)
336 (29)
139 (30) 77 (44) 168 (20)
139 (13) 77 (64) 351 (1), 284 (15), 176 (11)
139 (5)
77 (20) 352 (10), 309 (2), 232 (3),
180 (1)
6d
411 (1)
336 (100)
77 (32) 308 (2), 233 (2), 20 (1),
181 (1)
7b
8
530 (65)
447 (100)
336 (100)
336 (7)
232 (5)
139 (41) 77 (28) 258 (4), 195 (16)
310 (2)
310 (2)
233 (3), 207 (5), 141 (15),
76 (64)
10
12
494 (100)
516 (2)
193 (5)
139 (8)
139 (5)
77 (31) 466 (2), 386 (25), 233 (4)
193 (13)
77 (16) 386 (100), 323 (12), 254
(4),
13
16
548 (2)
310 (5)
139 (11)
482 (15), 414 (9), 268
(12), 215 (25), 162 (23),
71 (60)
495 (45)
336(100)
232 (3)
193(4)
77 (40) 453 (18), 394 (29), 306 (4)
Structures 10, 11, 12, 13, and 16 were established by spectral data (Tables I-II). The mass spectra of
10, 12, 13 and 15 showed molecular ion peaks at m/z; 494 (M+, 100), m/z; 516 (M+, 2), m/z; 548 (M+,
2), and m/z; 495 (M+, 45), respectively. The fragmentation pattern of compounds 10, 12, 13 and 15 are
illustrated in Scheme 3.
Scheme 3. Proposed fragmentation pathways for the EI spectra of the substituted
naphtho[2,1-b]furans 3-16.
O
H
O
CH3
O
CH2 = C = O
(42)
m/z: 139 (100)
CO, H (29)
(1)
m/z: 210 (M+, 32)
m/z: 168 (3)
H
H
N
N
Ph
N
N
N
N
H
(3)
O
O
C6H4 (76)
C2H2 (26)
CO (28)
m/e: 139 (15)
O
CO (28)
O
CHN2 (41)
m/e: 167 (1)
m/e: 234 (1)
m/e: 208 (1)
m/e: 310 (20)
Ph
N
N
Ph
Ph
C
N
N
N
N
O
O
(4b)
+
H
CN
HC
H
O
O
NH
NH2 (16)
+
O
Ph
(Z)
CO (28)
CO (28)
CN (26)
m/e: 360 (25)
O
m/e: 376 (2)
NH2
N
O
N
m/e: 193 (3)
(167)
m/e: 139 (12)
H
m/e: 139 (7)
NC
NC
m/e: 309 (0)
CN
m/e; 448 (100)
Ph
N
N
N
NH
CN
H
(4c)
O
O
O
(161a)
m/e: 386 (M+, 100)
CO (28)
CN (26)
CN
C6H4 (76)
H2S (34)
m/e: 310 (1)
m/e: 193 (22)
m/e: 139 (8)
CN
CN
H2C
CN
CN
NC
NC
(117)

312
Molecules 2011, 16
Scheme 3. Cont.
Ph
N
N
C6H5
m/e: 77 (44)
Ph
CN
N
CN (26)
N
N
N2 (28)
(6a)
m/e: 168 (20)
O
NH2 (16)
HC
m/e: 336 (66)
H
m/e: 168 (20)
O
CO, H
(28)
m/e: 139 (30)
Ph
N
N
N
(6b)
H
Ph
O
N
C6H5, NH
(77) (15)
N
HC2N (39)
CO (28)
m/e: 336 (60)
HC
m/e: 139 (13)
(6d)
O
HCN (27)
CN (26)
C6H5 (77)
NH2CSNH2 (76)
m/e: 335 (100)
CN
NH2 (16)
Ph
Ph
N
Ph
N
N
N
N
N
(7b)
(6C)
O
O
O
C6H4Cl (11)
m/e: 310 (2)
HC
NH2
CN (26)
H
CH2=CO
(42)
N
Ph
m/e: 336 (7)
N
N
N
m/e: 152 (10)
O
(8)
m/e: 335 (100)
CH
HC
Ph
Ph
N
N
N
N
(7a)
H
O
O
C6H5 (77)
CO
m/e: 336 (8)
CN (26)
CO (28)
CN (26)
C6H5 (77)
H2C2N (40)
HC
m/e: 310 (3)
N
m/e: 139 (12)
O
2CO (28)
H
m/e: 195 (16)
C6H5 (77)
C4H3 (51)
CO (28)
N2C (40)
m/e: 139 (41)
(15)
+
.
CH2CO (42)
Ph
Ph
+
+
N
N
N
N
(10)
H
O
O
+
Ph
CO (28)
MeCN (41)
HC2N (39)
CO (28)
C6H5 (77)
CN (26)
H2C2N(40
)
N
C6H4 (78)
m/e: 310 (2)
m/e: 139 (8)
N
N
m/e: 386 (25)
Ph
O
m/e: 453 (18)
+
COCH3
Ph
S
N
N
N
(12)
+
+
O
H
H
H2N
CN
NH
CH2CO (42)
NH3 (17)
2CH2CO (42)
H2O (18)
C2H4 (28)
HC=C(CN)2 (77)
CN (26)
HC2N (39)
C6H5 (77)
CO (28)
m/e: 139 (5)
m/e: 386 (100)
m/e: 139 (11)
CO (28)
C6H5 (77)
CN (26)
H2C2N(40
)
Ph
N
N
O
+
Ph
m/e: 394 (29)
N
Ph
N
S
N
N
N
Ph
N
N
N
N
(13)
O
N
S
O
CH2(CN)2
O
O
COPh
(59)
O
m/e: 310 (5)
m/e: 414 (9)
O
+
m/e: 482 (15)
O
+
Ph
.
CO (28)
C6H4 (76)
N
(86)
CN
O
O
O
C6H5 (77)
HC3N2 (65)
m/e: 193 (4)
NC
m/e: 335 (100)
Biological activities
Compound 14 which contains the thiazolidin-4-one nucleus showed highest antibacterial activity
(+++ ve inhibition zone was between 12–15 mm) against Bacillus subtilis, Staphylococcus aureus,
Escherichia coli, Pseudomonas aeuroginosa, Candida albicans and Aspergillus niger. Compound 2

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Molecules 2011, 16
showed moderate inhibition (++ ve inhibition zone up to 8 mm) against Bacillus subtilis,
Staphylococcus aureus, Escherichia coli and Pseudomonas aeuroginosa , the remaining tested
compounds 4a-c, 5, 6, 7a,b, 8a-c, 10, 12, 13 showed no activities against any of the test microorganisms.
Experimental
General
Melting points were measured on a Stuart Scientific Co (UK) melting point apparatus and are
uncorrected. The IR spectra were recorded on a Shimadzu IR 440, spectrophotometer (Shimadzu,
1
Japan) in KBr. The H-NMR/13C-NMR spectra were measured on a Varian Mercury (300 MHz)
spectrometer (Varian, UK), using TMS as an internal standard and DMSO-d6 as solvent. Mass spectra
were run on a Shimadzu GC-Ms QP 1000 EX mass spectrometer. Microanalytical data were obtained
from the Microanalytical Unit Center, Faculty of Science, Cairo University (Egypt). Spectral and
microanalytical data are given in Tables I-III. The paper discs were manufactured by Bristol-Myers
Squibb, Giza, Egypt.
Table III. Antibacterial and antifugal activities of select synthesized compounds.
Inhibition zone diameter (mm per 200 mcg sample)
Comp.
No.
(BS)
(SA)
NCTC
7447
++ ve
+++ ve
+++ ve
(EC)
(PA)
(CA)
(AN)
ATCC
6275
- ve
+++ ve
+++ ve
ACTC
10400
++ ve
+++ ve
+++ ve
NCTC ATCC IMRU
10410
++ ve
+++ ve +++ ve +++ ve
+++ ve +++ ve +++ ve
10415
++ ve
3669
- ve
2
14
Neomycin
(30 µg mL–1)
a c = 1 mg mL–1 of new compounds in DMF; - ve (no inhibition zone); + ve (inhibition zone up to
8 mm); ++ ve (inhibition between 8-12 mm); +++ ve (inhibition between 12-15 mm)
Synthesis of 2-acetylnaphtho[2,1-b]furan (1): A mixture of 2-hydroxy-1-naphthaldehyde (0.01 mol),
chloroacetone (0.01 mol) and anhydrous potassium carbonate (0.02 mol) in anhydrous acetone (50
mL) was refluxed for 8 hours. The mixture was allowed to cool and poured onto crushed ice (50 gm)
and water (100 mL) then acidified with conc. HCl and the solid product was formed was filtered off,
1
washed with water and recrystallized from ethanol to give 1 (90% yield); IR: 1,666 (CO): H-NMR:
8.59–7.70 (m, 6H, Ar-H), 7.89 (s, 1H, H-3), 2.62 (s, 3H, Me): 13C-NMR: 187.19 (CO), 153.36 (C-9a),
151.90 (C-2), 130.11 (C-3a), 129.90 (C-8), 128.98 (C-7), 127.85 (C-7a), 127.52 (C-6), 125.60 (C-5),
123.64 (C-4), 122.61 (C-3b), 113.69 (C-3), 112.74 (C-9), 26.33 (Me).
Synthesis of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2): A mixture of 1 (1.72 g, 0.01 mol) and
phenylhydrazine (1.08 g, 0.01 mol) in ethanol (50 mL) was refluxed for 2 h, the solid that separated on
heating was filtered off and recrystallized from EtOH to give 2 (80% yield); IR : 3,459, 3,346
(NH),1,601 (C=N); 1H-NMR: 8.17–6.92 (m, 12H, Ar-H+NH), 7.70 (s, 1H, H-3), 2.35 (s, 3H, Me); 13C-
NMR: 154.81 (C-9a), 151.72 (C=N), 145.45 (C-2), 132.94 (C-1`), 130.01 (C-3a), 128.94 (C-8), 128.66

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(C-3`,5`), 127.06 (C-7a), 126.44 (C-7), 125.28 (C-6), 124.75 (C-5), 123.97 (C-3b), 123.65 (C-4), 119.39
(C-4`), 113.04 (C-3), 112.22 (C-9), 102.89 (C-2`,6`), 12.80 (Me).
Synthesis of 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3): To ice cold
dimethylformamide (0.01 mol) was added dropwise with stirring phosphorus oxychloride (0.01 mol)
over a period of 30 min. stirring was continued for further 45 min keeping the reaction mixture at 0 °C.
The hydrazone 2 (3 g, 0.01 mol) was then added and the reaction mixture was allowed to attain room
temperature. The mixture was heated at 90 °C for 2 h, allowed to cool and poured onto crushed ice (50
gm) and water (100 mL), the solid product that was formed was filtered off and washed with water and
1
recrystallized from EtOH to give 3 (70% yield); IR: 1,670 (CO): H-NMR: 10.33 (s, 1H, CHO), 9.37
(s, 1H, H-5), 8.43–7.47 (m, 11H, Ar-H), 7.92 (s, 1H, H-3`).
Synthesis of 2-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene) malononitrile (4a),
2-cyano-3-(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) acrylamide (4b) and 2-cyano-3-
(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) prop-2-enethioamide (4c): A mixture of
aldehyde 3 (3.38 g, 0.01 mol) and malononitrile, cyanoacetamide or cyanothioacetamide (0.01 mol) in
ethanol (30 mL) and few drops of piperidine was refluxed for 3 h, The resulting solid after cooling was
collected and recrystallized from the proper solvent to give 4a-c (70–80% yield);. 4a: IR: 2,208, 2,200
1
(2 CN): H-NMR: 10.15 (s, 1H, CH=C), 8.65 (s, 1H, H-5), 8.55–7.52 (m, 12H, Ar-H). 4b: IR: 3,464,
3,368 (NH2), 2,210 (CN), 1,698 (CO): 1H-NMR: 9.19 (s, 1H, CH=C), 8.60 (s, 1H, H-5), 8.55–7.52 (m,
1
14H, Ar-H +NH2). 4c: IR: 3,344, 3,286 (NH2), 2,212 (CN), 1,340 (C=S): H-NMR: 10.12 (br, 2H,
NH2), 9.67 (s, 1H, CH=C), 9.19 (s, 1H, H-5), 8.59–7.48 (m, 12H, Ar-H).
Synthesis of 5-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene) pyrimidine-
2,4,6(1H,3H,5H)trione (5): A mixture of aldehyde 3 (3.38 g, 0.01 mol) and barbituric acid (0.01 mol)
in ethanol (30 mL) containing triethylamine (0.01 mL) was heated under reflux for 1h. The solid
separated on heating was filtered off and recrystallized from ethanol to give 5 (80% yield). IR: 3,200
(NH), 1,700 (CO), 1,670 (CO): 1H-NMR: 11.38, 11.30 (2s, 2H, 2NH), 9.67 (s, 1H, CH=C), 8.77 (s,
1H, H-5), 8.27–7.36 (m, 12H, Ar-H).
Synthesis of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene) hydrazone (6a), 1-
((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b), N'-((3-
(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)
acetohydrazone
(6c),
1-((3-
(naphtha[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene) thiosemicarbazone (6d) and 2-
cyano-N'-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)acetohydrazone (6e): A
mixture of aldehyde 3 (3.38 g, 0.01 mol) and hydrazine hydrate, phenyl hydrazine, acetylhydrazine,
thiosemicarbazide or cyanoacetic acid hydrazide (0.01 mol) in ethanol (30 mL) was refluxed for 3 h,
the solid separated on heating was filtered off and recrystallized from a suitable solvent to give 6a-e
(75–80 %). 6a: IR: 3,400, 3,364 (NH2), 1,598 (C=N),1H-NMR: 8.78 (s, 1H, CH=N), 8.41 (s, 1H, H-5),
1
8.37–7.33 (m, 12H, Ar-H), 6.86 (brs, 2H, NH2). 6b: IR: 3,320 (NH), 1,602 (C=N); H-NMR: 10.39
(brs, 1H, NH), 9.01 (s, 1H, CH=N), 8.40 (s, 1H, H-5), 8.36-7.17 (m, 12H,Ar-H). 6c: IR: 3,156 (NH),
1
1,686 (CO); H-NMR: 11.60 (brs, 1H, NH), 11.26 (s, 1H, CH=N), 9.17 (s, 1H, H-5), 9.06-7.34 (m,
1
12H, Ar-H), 2.26 (s, 3H, Me). 6d: IR: 3,420, 3,374, 3,262, 3,178 (NH, NH2), 1,334 (C=S); H-NMR:

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11.40 (s, 1H, NH), 9.27 (s, 1H, CH=N), 8.72 (s, 1H, H-5), 8.32 (brs, 2H, NH2), 8.41–7.41 (m, 12H,
1
Ar-H). 6e: IR: 3,310, 3,210, (NH), 2,256 (CN), 1,666 (CO); H-NMR: 12.02 (brs, 1H, NH), 9.10 (s,
1H, CH=N), 8.9 (s, 1H, CH-pyrazole), 8.93-7.41 (m, 12H, Ar-H), 4.28 (s, 2H, CH2).
Synthesis of N-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene) aniline/4-chloro-
aniline (7a,b): A mixture of aldehyde 3 (3.38 g, 0.01 mol) and the appropriate aromatic amine, namely
aniline or p-chloroaniline (0.01 mol) in ethanol (40 mL) was refluxed for 1 h. The obtained product
was collected and recrystallized from the proper solvent to give 7a,b. (80–85% yield)) 7a: IR: 1,614
1
(C=N); H-NMR: 9.40 (s, 1H, CH=N), 8.96 (s, 1H, H-5), 8.33–7.36 (m, 17H, Ar-H). 7b: IR: 1,620
(C=N); 1H-NMR: 9.25 (s, 1H, CH=N), 8.95 (s, 1H, H-5), 8.36–7.35 (m, 16H, Ar-H).
Synthesis of 1-(naphtho[2,1-b]furan-2-yl)-3-(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-
yl)prop-2-en-1-one (8): A mixture of 2-acetyl naphtho[2,1-b]furan (1, 0.01 mol) with aldehyde 3 (0.01
mol) in ethanol (30 mL) and few drops of piperidine was heated under reflux for 1 h. The solid
separated on heating was filtered off and recrystallized from dioxane to give 8 (80 % yield): IR: 1,662
(CO), 1H-NMR: 8.96 (s, 1H, H-5), 8.30–7.20 (m, 19H, Ar-H), 5.93–5.69(dd, 2H, CH=CH, J = 11.4 Hz).
Synthesis of 4-[3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl]methylene-3-methyl-1-phenyl-
2-pyrazoline-5-one (10): To a mixture of 4a (0.01mol) and 3-methyl-1-phenyl-2-pyrazolin-5-one
(0.01 mol) in ethanol (30 mL), triethylamine (0.01 mL) was added. The resulting mixture was heated
under reflux for 30 min and left to cool. The precipitated product was collected and recrystallized from
acetic acid to give 10 (85 %). IR: 1,678 (CO), 1,610 (C=N); 1H-NMR: 10.09 (s, 1H, CH=C), 8.41 (s,
1H, H-5), 8.14–7.18 (m, 17H, Ar-H), 2.3 (s, 3H, CH3).
Synthesis of ethyl 6-amino-5-cyano-2-methyl-4-(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-
yl)-4H-pyran-3-carboxylate (12): To a solution of 4a (0.01 mol) and ethyl acetoacetate (0.01 mol) in
methylene chloride (50 mL), triethylamine (0.01 mL) was added. The mixture was heated under reflux
for 4 h, concentrated and allowed to cool. The precipitated product was collected and recrystallized
1
from ethanol to give 12 (70 % yield). IR: 3,402, 3,328, 3,206 (NH2), 2,194 (CN), 1,690 (CO); H-
NMR: 8.58 (s, 1H, H-5), 8.43–7.34 (m, 12H, Ar-H), 6.94 (brs, 2H, NH2, exchangeable by D2O), 5.05
(s, 1H, 4H-pyran), 3.89 (q, 2H, CH2; J = 7.0 Hz), 2.27 (s, 3H, Me), 0.84 (t, 3H CH3; J = 7.0 Hz).
Synthesis of 3-amino-1,5-dihydro-1-(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-
pyrano[2,3-c]chromene-2-carbonitrile (13): To a solution of 4a (0.01 mol) and 4-hydroxycoumarin
(0.01mol) in ethanol (50 mL) a few drops of piperidine (0.01 mL) were added. The mixture was heated
under reflux for 4h and allowed to cool. The precipitated product was collected and recrystallized from
1
dioxane to give 13 (70% yield). IR: 3,406, 3,324, 3,294 (NH2), 2,196 (CN), 1,708 (CO); H-NMR:
8.74 (s, 1H, H-5), 8.38–7.41 (m, 18H, Ar-H + NH2), 5.06 (s, 1H, 4H-pyran).
Synthesis
of
2-[(3-naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl]methylene-hydrazono-
thiazolidin-4-one (14) and 2-[(3-Naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl]methylene-
hydrazono-4-methylthizole (15). A mixture of 6d (0.01 mol), ethyl bromoacetate (0.01 mol) or
chloroacetone (0.01 mol) and fused sodium acetate (0.02 mol) in ethanol (40 mL) was refluxed for 2 h.

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The product obtained was collected by filtration, washed with water and recrystallized from acetic acid
1
to give 14, 15. Compound 14: 80% yield; IR: 3,400, 3,300 (NH), 1,706 (CO); H-NMR: 11.51 (brs,
1H, NH), 9.28 (s, 1H, CH=N), 8.78(s, 1H, H-5), 8.71–7.42 (m, 12H, Ar-H), 4.00 (s, 2H, CH2).
Compound 15, 80% yield; IR: 3,152 (NH), 1,614 (C=N); 1H-NMR: 11.81 (brs, 1H, NH; exchanged by
D2O), 9.00 (s, 1H, CH=N), 8.51 (s, 1H, H-5), 8.41–7.39 (m, 12H, Ar-H), 6.40 (s, 1H, CH-thiazoline),
2.19 (s, 3H, Me).
Synthesis of N-(4-acetyl-4,5-dihydro-5-(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)-
1,3,4-thiadiazol-2-yl)acetamide (16): A solution of 6d (0.01 mol), and acetic anhydride (5 mL) was
heated under refluxed for 3 h. After the reaction mixture had attained room temperature, excess acetic
anhydride was decomposed by water (10 mL) and the mixture was stirred for 30 min. The separated
product was filtered and recrystallized from acetic acid to give 16 (60 % yield); IR: 3,248 (NH), 1,664,
1
1,634 (2CO); H-NMR: 11.78 (brs, 1H, NH), 8.47 (s, 1H, H-5), 8.30–7.35 (m, 12H, Ar-H), 6.44 (s,
1H, CH-thiapyrazole) 2.31 (s, 3H, Me), 2.01 (s, 3H, Me).
Antibacterial activity
The newly synthesized compounds were screened for their antimicrobial activities in vitro against
two species of Gram-positive bacteria Bacillus subtilis (NCTC- 10400)(BS), Staphylococcus aureus
(NCTC 7447)(SA), and three Gram-negative bacteria, Escherichia coli (NCTC 10410)(EC),
Pseudomonas aeruginosa (ATCC 10415)(PA), Candida albicans (IMRU 3669)(CA), and one fungus,
Aspergillus niger (ATCC 6275)(AN). The activities of these compounds were tested using the disc
diffusion method [19,20]. The area of zone of inhibition was measured using neomycin
(30 µg mL-1) as standard antibiotic (Table III). The tested compounds were dissolved in N,N-
dimethylformamide (DMF) to give a solution of 1 mg mL−1. The inhibition zones were measured in
millimeters at the end of an incubation period of 48 h at 28 °C. N,N-dimethylformamide (DMF)
showed no inhibition zone.
Conclusions
A series of novel naphtho[2,1-b]furan pyrazole derivatives were prepared. The antimicrobial
activity of these compounds was evaluated against various Gram-positive, Gram-negative bacteria and
fungi. 2-[(3-Naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl]methylenehydrazonothiazolidin-4-
one (14) showed the highest antibacterial activity, while compound 2 showed moderate activity, and
the remaining tested compounds 4a-c, 5, 6, 7a,b, 8a-c, 10, 12, 13 showed no activities against any of
the test microorganisms.
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Sample Availability: Samples are available from the authors.
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