Direct Synthesis of 2-Methylbenzofurans from Calcium Carbide and Salicylaldehyde p -Tosylhydrazones

Article abstract of DOI:10.1021/acs.orglett.8b00676

A new methodology for the construction of methyl-substituted benzofuran rings from the reactions of calcium carbide with salicylaldehyde p-tosylhydrazones/2-hydroxyacetophenone p-tosylhydrazones is described. Various 2-methylbenzofurans and 2,3-dimethylbenzofurans could be obtained in satisfactory yield by using a cuprous chloride catalyst. The advantages of this protocol include the use of a readily available and easy-to-handle acetylene source and simple workup procedure.

Full text of DOI:10.1021/acs.orglett.8b00676

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct Synthesis of 2‑Methylbenzofurans from Calcium Carbide and
Salicylaldehyde p‑Tosylhydrazones
Rugang Fu and Zheng Li*
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, P. R. China
*
S Supporting Information
ABSTRACT: A new methodology for the construction of
methyl-substituted benzofuran rings from the reactions of
calcium carbide with salicylaldehyde p-tosylhydrazones/2-
hydroxyacetophenone p-tosylhydrazones is described. Various
2
-methylbenzofurans and 2,3-dimethylbenzofurans could be
obtained in satisfactory yield by using a cuprous chloride
catalyst. The advantages of this protocol include the use of a
readily available and easy-to-handle acetylene source and simple
workup procedure.
eteroarenes, such as furans, indoles, pyrroles, and their
Scheme 1. Preparation of 2-Methylbenzofurans
H
benzo-fused derivatives, are privileged scaffolds. Among
them, the applications of benzofurans are efficient and
1
important in pharmacology. The core structures of benzofuran
are present in many biologically active compounds, showing a
wide range of drug activities, including anti-HIV, anticancer,
2
and antimicrobial activities. In particular, compounds contain-
ing a 2-methylbenzofuran core have found many applications,
3
4
such as glucokinase activator, thrombin inhibitor, and
5
insecticide, because of their wide range of biological activities
(Figure 1). Therefore, the development of novel synthetic
methods for their direct preparation from readily accessible
materials is very important.
Figure 1. Representative examples bearing 2-methylbenzofuran
structure.
of the corresponding phosphonium bromides intermediate and
a further intramolecular photochemical Wittig reaction onto the
aryloxycarbonyl group.
However, some drawbacks still remain for the existing
synthetic methods, such as using valuable transition metals or
difficult-to-obtain substrates.
For the past few years, calcium carbide as a green material
and inexpensive and easily attainable molecule has become an
important reagent for many organic transformations. The
advantages derived from the use of calcium carbide, instead of
10
Various synthetically viable procedures have been used for
the construction of 2-methylbenzofurans in the literature
(
Scheme 1), which include: (i) Pd-catalyzed oxidative
6
cyclization of 2-allylphenol; (ii) copper-TMEDA complex7-
catalyzed transformation of 1-(2-bromophenyl)propan-2-one;
(iii) Claisen rearrangement and further cyclization of phenyl
8
propargyl ether in the presence of cesium fluoride; (iv) [3,3]-
sigmatropic rearrangement and further cyclization of acetone
O-phenyloxime in the presence of trifluoroacetyl triflate and
9
trimethylamine; and (v) the reaction of 2-(bromomethyl)-
Received: February 28, 2018
phenyl acetate with triphenylphosphine through the formation
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
organic acetylene gas, are mainly embodied in the safety of no
risk of explosion and no requirement for complex equipment.
Until now, there have been a few reports of utilizing calcium
12
(entries 4, 14, and 15). The most effective solvent was DMF,
which could give 2a in 69% yield (entry 4). In addition, 4 equiv
of water based on 1a is an appropriate amount for the reaction
(entry 4). The increase or decrease of the water amount both
can cause the drop of the yield (entries 16 and 17).
11
carbide directly in organic synthesis. In particular, Jiang
reported the reactions of N-tosylhydrazones with calcium
carbide to synthesize various substituted pyrazoles. Our group
recently also made great efforts to research the direct use of
calcium carbide in organic synthesis and reported the synthesis
Using the optimized conditions, synthesis of 2-methylbenzo-
furans was conducted by reactions of varous salicylaldehyde p-
tosylhydrazones with calcium carbide catalyzed by CuCl in the
1
3
14
t
of 1,3,5-triaroylcyclohexanes and symmetric diarylethynes,
presence of BuOK at 90 °C in DMF. The results are shown in
15
and N-propargylation of secondary amines using calcium
carbide as an acetylene source.
Scheme 2. The reactions worked well for a wide range of
a
As an extension of our investigation on the use of calcium
carbide as an acetylene source, in this work, we report a novel
synthetic approach to 2-methylbenzofurans by using calcium
carbide as an acetylene source and salicylaldehyde p-
tosylhydrazones as starting materials through a one-pot
procedure.
Scheme 2. Synthesis of 2-Methylbenzofurans
At the beginning of this transformation, the reaction of
salicylaldehyde p-tosylhydrazone (1a) with calcium carbide was
selected as the model reaction to screen the optimal conditions,
including the use of catalysts, bases, and solvents at a certain
temperature for the appropriate time. The results are
summarized in Table 1. It was found that copper(I) halides,
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
tBuOK
tBuOK
tBuOK
tBuOK
tBuOLi
K CO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
THF
CuI
59
61
69
17
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
3
Cs CO
54
12
a
2
3
Reaction conditions: 1a−w (1 mmol), CaC (3.0 mmol), H O (4
2
2
KOH
t
mmol), CuCl (0.1 mmol), and BuOK (2 mmol) in DMF (4 mL) was
heated at 90 °C for 5 h.
KOAc
trace
10
11
12
13
14
15
16
17
Et N
3
t
BuOK
trace
trace
substrates bearing both electron-donating and electron-with-
drawing groups on their aromatic rings, such as Me, Bu, Bu,
MeO, F, Cl, Br, NO , Me NCH , and Et N, and afforded the
desired products in satisfactory yield (Scheme 2, 2b−i,k−v).
However, the substrates, including biphenyl and naphthyl
groups, gave the corresponding products in lower yield,
possibly because of steric hindrance (Scheme 2, 2j,w).
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
i
t
PhMe
DMSO
MeCN
DMF
DMF
2
2
2
2
15
7
c
57
d
32
a
In addition, 2,3-dimethylbenzofurans could also be synthe-
sized by reactions of 2-hydroxylacetophenone p-tosylhydra-
zones 3a−d with calcium carbide under similar conditions at
Reaction conditions: 1a (1 mmol), CaC (3 mmol), H O (4 mmol),
2
2
CuCl (0.1 mmol), and base (2 mmol) in solvent (4 mL) was heated at
9
b
c
d
0 °C for 5 h. Isolated yield. H O (2 mmol). H O (6 mmol).
2
2
1
00 °C (Scheme 3). The representative 2,3-dimethylbenzofur-
such as CuI, CuBr, and CuCl, could catalyze the reaction to
ans 4a−d could be obtained through this approach in moderate
yield.
give 2-methylbenzofuran (2a) in good yield (entries 2−4), and
t
CuCl exhibited the best catalytic effect (entry 4). BuOLi,
A plausible mechanism is proposed for the synthesis of 2a by
a reaction of 1a with calcium carbide (Scheme 4). Initially, 2-
(diazomethyl)phenol is formed in situ by a reaction 1a with
t
BuOK, K CO , Cs CO , KOH, KOAc, and Et N as bases were
2
3
2
3
3
t
tested (entries 4−10). It was found that BuOK was a more
efficient base than the others (entry 4). In addition, the
selection of the solvents was also important. The reaction did
not take place in EtOH, THF, and PhMe because of the poor
solubility for calcium carbide (entries 11−13). In contrast,
DMF, DMSO, and MeCN were practicable solvents, and the
reaction in these solvents could proceed to a certain extent
t
16
BuOK (Bamford−Stevens reaction). Simultaneously, calcium
carbide reacts with water in the presence of CuCl to give
ethynylcopper as an intermediate, which further reacts with 2-
(diazomethyl)phenol to give copper−carbene species A. The
reductive elimination of A gives intermediate B. Intermediate
B may undergo one of two methods to afford the final product
17
18
17
B
DOI: 10.1021/acs.orglett.8b00676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Synthesis of 2,3-Dimethylbenzofurans
has been developed. Various substituted 2-methylbenzofurans
could be obtained in satisfactory yield. These reactions
represent an efficient and alternative strategy for the synthesis
of 2-methylbenzofurans. The cost-efficient procedure can be
easily employed for the preparation of important 2-methyl-
benzofuran building blocks using standard laboratory equip-
ment. Moreover, these reactions confirm the potential of using
calcium carbide as an acetylene gas replacement in organic
synthesis and provide an opportunity to establish calcium
carbide as a sustainable and cost-effective carbon source in
modern chemical industries.
a
Reaction conditions: 3a−d (1 mmol), CaC (3.0 mmol), H O (4
mmol), CuCl (0.1 mmol), and BuOK (2.5 mmol) in DMF (4 mL)
2
2
t
ASSOCIATED CONTENT
Supporting Information
was heated at 100 °C for 7 h.
■
*
S
Scheme 4. Proposed Mechanism for the Synthesis of 2a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00676.
Additional data on condition optimization, general
experimental information, synthetic procedure, character-
1
13
ization data, and H/ C NMR spectra of all products
PDF)
(
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: lizheng@nwnu.edu.cn.
ORCID
Zheng Li: 0000-0003-1944-8270
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21462038) and Key Laboratory of Eco-Environment-Related
■
(
Polymer Materials of the Ministry of Education of China for
their financial support of this work.
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