Silica sulfuric acid mediated synthesis of naphtho[2,1-b]furan derivatives and development of?one-pot?multicomponent synthesis of substituted pyrazole derivatives

Article abstract of DOI:10.1002/jhet.4280

Silica sulfuric acid (SSA) mediated synthesis of naphtho[2,1-b]furan derivatives starting from β-nitrostyrene derivatives and β-naphthol derivatives under solvent-free conditions have been developed. The scope of SSA as a heterogeneous catalyst is extende

Full text of DOI:10.1002/jhet.4280

Received: 16 February 2021
DOI: 10.1002/jhet.4280
Revised: 20 April 2021
Accepted: 20 April 2021
C O M M U N I C A T I O N S
Silica sulfuric acid mediated synthesis of
naphtho[2,1-b]furan derivatives and development
of one-pot multicomponent synthesis of substituted
pyrazole derivatives
1
2
1
Divya Sree Uppalapati
| Rama Sekhara Reddy Dachuru | Satya Veni Sunkara
1
Department of Chemistry, University
College of Engineering Kakinada,
Jawaharlal Nehru Technological
University Kakinada, Kakinada, India
Abstract
Silica sulfuric acid (SSA) mediated synthesis of naphtho[2,1-b]furan derivatives
starting from β-nitrostyrene derivatives and β-naphthol derivatives under
solvent-free conditions have been developed. The scope of SSA as a heteroge-
neous catalyst is extended to one-pot multicomponent reaction for the synthesis
of functionalized pyrazole derivatives under solvent-free conditions from readily
available β-nitrostyrene derivatives, acetyl acetone, and hydrazine hydrate. The
synthetic methods have significant advantages such as solvent-free conditions,
simple operation, shorter reaction times, ease and clean isolation procedures,
and very good yields of products.
2
Department of Chemistry, Krishna
University, Machilipatnam, India
Correspondence
Rama Sekhara Reddy Dachuru,
Department of Chemistry, Krishna
University, Machilipatnam 521001,
Andhra Pradesh, India.
Email: dachuru@gmail.com
K E Y W O R D S
Multicomponent, naphthofuran, nitrostyrene, Pyrazole, Silica sulfuric acid
1
| INTRODUCTION
always encourage creative spirits by following the basic
quest: three or more compounds are combined to react in a
In recent years, heterogeneous catalysts grabbed much
attention toward synthetic organic chemistry due to
environ-economic factors [1–3]. Among heterogeneous
catalysts silica sulfuric acid (SSA) has demonstrated its
potentiality as an efficient solid catalyst in various organic
transformations under solvent-free conditions [4]. SSA, a
product that is easily synthesized from silica gel and
chlorosulfonic acid [5], was observed to improve the reac-
tivity and selectivity in carbon–carbon bond formation
reactions [6], in cycloaddition reactions [7], in protection–
deprotection reactions of multistep syntheses [8], and in
syntheses of heterocycles [9].
one-pot fashion to form two or more bonds. Therefore,
MCRs are regularly fascinating for industrial applications as
thrilling and stimulating for academia [13].
Furan moieties are common substructures in numerous
natural products [14]. Particularly, naphthofuran derivatives
are known for several types of biological activities like
antifertility, growth inhibitory, antitumor, mutagenic, and
oestrogenic [15]. In recent years, a variety of efficient
methods have been developed for the synthesis of
naphtho[2,1-b]furan derivatives [16]. Recently, Tavakol and
co-workers developed an efficient methodology from nitro-
styrenes and naphthols in ChCl/ZnCl DES as green reaction
2
In the era of gradually increasing relevance of sustain-
ability and environmental concern, the concept of mul-
ticomponent reactions (MCRs) is one of most efficient tools
in synthetic organic chemistry since they have all features
that contribute to ideal synthesis [10–12]. In synthetic meth-
odology, MCRs never become old-fashioned because they
media [16d]. Hajra and co-workers used In(OTf) as a cata-
3
lyst for the reaction of nitroalkenes with naphthols that
yielded naphthofuran derivatives in good yield [17]. Zheng
and co-workers reported the synthesis of naphtho[2,1-b]furan
derivatives under microwave irradiation [18]. Zhang et al.
reported the synthesis of benzoindoles and naphthofuran
J Heterocyclic Chem. 2021;1–5.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
UPPALAPATI ET AL.
derivatives using carbonaceous materials [19]. However,
most of the methods suffer from using metals as a catalyst,
higher temperatures, and longer reaction times.
Due to the broad spectrum of applications of pyrazole
moiety the synthesis of diversified pyrazole derivatives
has been a continuously challenging task to synthetic
organic chemist [30–33]. Shang and co-workers
employed SSA as a heterogeneous catalyst for the syn-
thesis of series of substituted pyrazole derivatives from
the reaction of hydrazines with 1,3-dicarbonyl com-
pounds [34]. Herein, we wish to report synthetic meth-
odology for the construction of naphtho[2-1,b]furan
derivatives and also functionalized pyrazole derivatives
by one-pot multicomponent procedure using SSA as a
catalyst.
Heterocyclic compounds containing pyrazole
nucleus is a recurring structural motif in a large num-
ber of drug molecules and pharmaceutically important
naturally occurring molecules [20]. Importantly, bioactive
natural products and synthetic analogs of pyrazole deriva-
tives have demonstrated various biological profiles such as
antibacterial, antihyperglycemic, antiviral, anti-inflamma-
tory, pesticidal, and antitumor agents [20–28]. In general,
the synthesis of pyrazoles can be achieved by reacting
(
1
substituted) hydrazines with β-functional (either
,3-dicarbonyl compounds or α,β-unsaturated com-
From the literature survey, it was revealed that many
synthetic procedures are reported for the preparation of
benzofuran derivatives. However, the reports corresponding
to the preparation of naphthofuran derivatives are scanty.
We became interested to develop a facile and efficient meth-
odology for the naphthofuran derivatives.
pounds) compounds, 1,3-dipolar cycloaddition with
diazo compounds, degradation of fused pyrazole, and
rearrangement of other monocyclic heterocycles under
chemical, thermal, and photochemical conditions [29].
TABLE 1 Optimization of reaction
conditions for the synthesis of
naphthofuran derivative 3a
OH
NO2
catalyst
O
1
a
2a
3a
a
Catalyst
loading
Time
(h)
Yield
(%)
Entry
Catalyst
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Solvent
Neat
1
2
3
4
5
6
7
8
9
500 mg
600 mg
400 mg
500 mg
500 mg
500 mg
500 mg
500 mg
20 mol%
500 mg
400 mg
400 mg
400 mg
400 mg
400 mg
400 mg
2
60
61
52
Neat
2
Neat
2
b
Neat
2
59
H
2
O
4
17
29
Acetic acid
CH Cl
6
c
2
2
8
Trace
Trace
24
c
CHCl
Neat
Neat
Neat
3
8
H
2
SO
4
3
10
11
12
13
14
15
16
SSA
SSA
SSA
SSA
SSA
SSA
SSA
0.5
0.5
4
94
96
H
2
O
74
CH
2
Cl
2
8
11
c
CHCl
Neat
3
8
Trace
b
0.5
6
92
Acetic acid
25
Note: All reactions were carried out with 1 equiv. of β-naphthol and 1 equiv. of β-nitrostyrene at room
temperature unless otherwise mentioned. In case of water as solvent 5 ml and others 3 ml has been used. Bold
value indicates that the reaction was stirred for 30 minutes underaerobic conditions using 400 mg of SSA.
a
Yields of isolated products.
b
ꢀ
Reaction carried out at 50 C.
c
Isolated using preparative TLC.

UPPALAPATI ET AL.
3
In our initial experiments, 1 mmol of β-naphthol 1a is
treated with 1 mmol of β-nitrostyrene 2a in the presence
of 500 mg of silica gel (100–200 mesh) at room tempera-
ture for 2 h. To our delight, we have obtained the product
solvents shows a negative effect on the yield of the prod-
uct 3a (Table 1, entries 12, 13, 14, and 16).
With a consistent set of conditions in hand, we have
extended this synthetic procedure for the reactions of dif-
ferent β-nitrostyrenes 2a-e with substituted β-naphthols
1a-d (Table 2). The reactions proceeded smoothly at
room temperature to furnish the naphtho[2,1-b]furan
derivatives 3a-3i in good to very good yield. When the
reactions were performed with halogen-substituted
β-naphthols the yield of naphthofuran derivatives 3b, 3d,
3f and 3h was dropped (Table 2, entries 2, 4, 6, and 8).
This is perhaps due to the withdrawing nature of the
halogen which reduces the nucleophilicity of β-naphthols.
Accordingly, we carried out another reaction of β-naphthol
bearing cyano group as a substituent (1d) with
β-nitrostyrene under optimized conditions (Table 2,
entry 10). No formation of the product 3j even after 8 h
shown by thin-layer chromatography (TLC) analysis
and the reactants were recovered. The reactivity of
β-nitrostyrene was not much affected by the electronic
effects.
3
a in 60% yield (Table 1 entry 1). To gauge the effect of
catalyst loading, solvent and temperature we have per-
formed series of reactions under different conditions and
results of which are summarized in Table 1. Increasing the
catalyst loading does not improve the yield of the
product 3a (Table 1, entry 2). However, decreasing the cata-
lyst loading drops the yield of the product 3a (Table 1, entry
3
). No progress was observed when the reaction was carried
ꢀ
out at 50 C (Table 1, entry 4) for 2 h and the product 3a
was isolated in 59% yield. Furthermore, the reaction was
screened using different solvents (Table 1, entries 5, 6,
7, and 8) but yields of the product 3a were not improved.
We shifted our attention to SSA and carried out the
reaction under solvent-free conditions. Intriguingly, the
yield of the product 3a was increased from 60% to 94%
(
Table 1, entry 10). Encouraged by these results we esti-
mated the effect of solvents, temperature, and catalyst
loading parameters. The yield of the product 3a was
slightly increased by decreasing catalyst loading from
Apparently, the reaction involves Michael's addition
of β-naphthol to β-nitrostyrene provides Michael adduct
which simultaneously undergoes cyclization followed
by loss of nitro group under the reaction produce
naphtho[2,1-b]furan derivative (Scheme 1).
5
00 to 400 mg (Table 1, entry 11). It was found that tem-
perature was not showing any improvement of the yield
of the product 3a (Table 1, entry 15) and use of the
After successfully developing the synthesis of
naphtho[2,1-b]furan derivatives by Michael addition of
β-naphthols with β-nitrostyrenes followed by cyclization,
it occurred to us that 1,3-diketones act as good nucleo-
philes via enol formation in the presence of acidic
medium and then react with β-nitrostyrenes, transform
into Michael adducts. The presence of functional group
proximate in Michael adduct can be synthetically
transformed into heterocyclic compounds with suitable
TABLE 2 Scope of the substrates
R2
OH
NO
2
SSA
O
R1
R2
RT, 30 min
R1
1a-d
2a-e
3a-j
substrates. Accordingly, we designed
a
one-pot
Yield
(%)
1
2
a
Entry
R
R
Product
1
2
3
4
5
6
7
8
9
H
H
3a
3b
3c
3d
3e
3f
96
79
93
78
90
75
97
75
78
HO
O
O
N
Br
H
H
OH
N
O
CH
CH
3
3
OH
Br
H
OCH
OCH
Br
3
3
Br
H
3g
3h
3i
HO
N OH2
Cl
Br
CN
Cl
Br
H
O
b
O
1
0
H
3j
ND
-
-
H O
2
NOH
Note: All reactions were carried out with 1 equiv. of β-naphthol and 1 equiv.
of β-nitrostyrene unless otherwise mentioned.
Yields of isolated products.
a
SCHEME 1 Plausible mechanism for the formation of
b
Not detected.
naphthofuran derivatives

4
UPPALAPATI ET AL.
N
NH
multicomponent procedure starting from readily available
β-nitrostyrenes, acetylacetone, and hydrazine in the presence
of SSA. The products are isolated in excellent yield. Neverthe-
less, the presented method provides a simple and short route
for naphtho[2,1-b]furan and pyrazole derivatives.
NO2
O
O
NH -NH H O
2
2
2
R
NO2
SSA, RT
- 10 min
R
5
4
2
5
N
NH
N
NH
N NH
NO
2
NO2
O
NO2
2 | EXPERIMENTAL SECTION
O
2.1 | General procedure for the synthesis
5f, 95%
5g, 97%
of (3a)
5a, 98%
N
NH
N
NH
To a mixture of β-naphthol (1) (1.0 mmol) and
N
NH
β-nitrostyrene 2 (1.0 mmol) was added 400 mg of SSA
and allowed to stir for 30 min at room temperature. The
progress of the reaction was monitored by TLC, after
completion of the reaction as shown by TLC. The product
was extracted with ether and purified using silica gel col-
umn chromatography using 1:5 ethyl acetate and hexanes
as eluent.
NO
2
NO
2
NO
2
OMe
h, 98%
MeO
OMe
5i, 97%
MeO
5
5
c, 93%
SCHEME 2 Synthesis of pyrazole derivatives. All reactions
were carried out with 1 equiv. of β-nitrostyrene, 1 equiv. of
acetylacetone, and 1 equiv. of hydrazine hydrate unless otherwise
2.2 | General procedure for the synthesis
of (5a)
mentioned. Yields of isolated products
To a mixture of β-nitrostyrene 2 (1.0 mmol), acetylacetone
(1.0 mmol), and hydrazine hydrate (1.0 mmol) was added
multicomponent synthetic strategy for the synthesis of
pyrazole derivatives by employing β-nitrostyrenes,
acetylacetone, and hydrazine hydrate in the presence of
SSA. In our preliminary investigations, we allowed
β-nitrostyrene, acetylacetone, and hydrazine hydrate to
react in the presence of SSA at room temperature under
solvent-free conditions. Surprisingly, the reaction was
completed after 10 min and the corresponding pyrazole
derivative 5a was isolated in 98% yield (Scheme 2).
400 mg of SSA and allowed to stir for 5–10 min. The
progress of the reaction was monitored by TLC, after com-
pletion of the reaction as shown by TLC. The product was
extracted with ethyl acetate and purified using silica gel
column chromatography using 1:5 ethyl acetate and
hexanes as eluent.
2.3 | 1-Phenylnaphtho[2,1-b]furan (3a)
Encouraged by these results we proceeded further to
extend this procedure to substituted β-nitrostyrenes. The
reaction of masked β-nitrostyrene (2g) with acetylacetone
and hydrazine hydrate provided the pyrazole derivative
1
H NMR (500 MHz, CDCl ): δ 8.05 (d, J = 8.5 Hz, 1H),
3
7.98 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.73
(d, J = 12.5 Hz, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.57–7.51
(m, 3H), 7.47 (t, J = 7.5 Hz, 1H), 7.41–7.37 (m, 1H) ppm.
5
g in very good yield without cleavage of acetal func-
13
tional group. This observation reveals that the reaction
conditions are very mild. The reactions of other
β-nitrostyrenes with acetyl acetone and hydrazine
hydrate went smoothly and furnished the corresponding
pyrazole derivatives in excellent yield.
C NMR (125 MHz, CDCl ): δ 153.2, 141.7, 133.1, 130.8,
3
129.9, 128.9, 128.6, 128.3, 127.9, 126.0, 126.0, 124.5, 124.4,
123.4, 120.7, 112.6 ppm.
In summary, we have developed an efficient methodol-
ogy for the synthesis of naphtho[2,1-b]furan derivatives from
β-nitrostyrenes with β-naphthols in the presence of SSA at
room temperature under solvent-free conditions. The method
is operationally simple and high yielding at room tempera-
ture and circumvents purification problems. A variety of
pyrazole derivatives was prepared from one-pot
2.4 | 3,5-dimethyl-4-(2-nitro-
1-phenylethyl)-1H-pyrazole (5a)
1
H NMR (500 MHz, CDCl ): 7.35–7.29 (m, 2H), 7.28–
3
7.22 (m, 1H), 7.18–7.13 (m, 2H), 5.09–4.99 (m, 1H),
1
3
4.93–4.83 (m, 2H), 2.18 (s, 6H). C NMR (100 MHz,
CDCl ): 11.61, 38.82, 78.11, 112.70, 127.09, 127.27,
3

UPPALAPATI ET AL.
5
1
28.86, 138.67, 142.56. See Appendix S1 for full
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[
1
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
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2021, 1. https://doi.org/10.1002/jhet.4280
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