One-Pot Three-Component Synthesis of 2-Methyl-3-aminobenzofurans Using Calcium Carbide as a Concise Solid Alkyne Source

Article abstract of DOI:10.1002/cjoc.202100383

A one-pot three-component method for the synthesis of 2-methyl-3-aminobenzofurans using calcium carbide as a concise solid alkyne source, and salicylaldehydes and secondary amines as starting materials is described. This protocol has salient feature of the use of inexpensive, abundant and easy-to-handle alkyne source, avoiding the use of inflammable and explosive acetylene gas as an original alkyne source. In addition, step economy, satisfactory yield, and simple work-up procedure are also advantages of this route.

Full text of DOI:10.1002/cjoc.202100383

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: One-Pot Three-Component Synthesis of 2-Methyl-3-Aminobenzofurans Using
Calcium Carbide as a Concise Solid Alkyne Source
Authors: Xiaolong Ma, Zhiqiang Wang, Zhenrong Liu and Zheng Li*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100383.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202100383.
ISSN 1001-604X • CN 31-1547/O6
mc.manuscriptcentral.com/cjoc
www.cjc.wiley-vch.de

For submission: https://mc.manuscriptcentral.com/cjoc
Report
CJC
For published articles: https://onlinelibrary.wiley.com/journal/16147065
中
国 化 学 - An International Journal
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
One-Pot Three-Component Synthesis of 2-Methyl-3-Aminobenzo-
furans Using Calcium Carbide as a Concise Solid Alkyne Source
Xiaolong Ma, Zhiqiang Wang, Zhenrong Liu and Zheng Li*
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, China
E-mail: lizheng@nwnu.edu.cn
Keywords
Salicylaldehyde | Secondary amine | Calcium carbide | Alkyne source | benzofuran
Main observation and conclusion
The one-pot three-component method for the synthesis of 2-methyl-3-aminobenzofurans using calcium carbide as a concise solid al-
kyne source, and salicylaldehydes and secondary amines as starting materials is described. This protocol has salient feature of the use
of inexpensive, abundant and easy-to-handle alkyne source, avoiding the use of inflammable and explosive acetylene gas as an original
alkyne source. In addition, step economy, satisfactory yield, and simple work-up procedure are also advantages of this route.
Comprehensive Graphic Content
CHO
R1
Na
2CO3
R2
N
R3
H
2O
OH
Ca
+
R1
C C
R2
HN
R3
CuBr
O
DMSO
R1
Me,
OMe, OEt, Cl,
F,
=
H,
Br, NO etc.
,
2
R2 R3
etc.
=
,
alkyl, cycloalkyl,
*E-mail: lizheng@nwnu.edu.cn
View HTML Article
Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX©
2021
SIOC,
CAS,
Shanghai,
&
WILEY-VCH
GmbH
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202100383
This article is protected by copyright. All rights reserved.

First author et al.
Report
Background and Originality Content
Results and Discussion
Benzofuran nucleus is present in a huge number of bioactive
natural and synthetic compounds. Benzofuran derivatives have at-
tracted attention due to their broad range of biological activities,
where some of them possess unique anticancer,[1] antitubercular,[2]
anti-Alzheimer[3] and anti-inflammatory[4] properties. Therefore
they have potent applications in pharmaceuticals, agriculture, and
polymers. Although the synthesis of benzofurans have been widely
documented,[5] 2-methyl-3-aminobenzofurans are rarely reported.
Only few literatures reported the synthesis of 2-substituted 3-ami-
nobenzofurans, which include i) copper-catalyzed annulative ami-
nation of o-alkynylphenols with hydroxylamines;[6] ii) three-compo-
nent coupling reactions of alkynylsilanes, o-hydroxybenzaldehydes,
and secondary amines by Cu(I)/Cu(II) cooperative catalytic sys-
tems;[7] iii) treatment amides bearing an α-phenoxy moiety with tri-
flic anhydride and 2-fluoropyridine (Scheme 1).[8] However, some
methods utilize commercially unavailable substrates as starting ma-
terials, which have to synthesize through many steps. Meanwhile
unstable, expensive and difficult-to-handle alkyne sources have to
be applied, which generally need to synthesize using inflammable
and explosive acetylene gas as an original alkyne source. Therefore
it is necessary to explore concise and convenient routes to synthe-
size these compounds by using cheap and abundant alkyne sources
and easy-to-obtain starting materials.
Initially, the three-component reaction of calcium carbide, sa-
licylaldehyde (1a) and piperidine (2a) was selected as a model reac-
tion to screen the reaction conditions. The reaction was examined
with respect to mediators, bases, solvents, and temperature. It was
found that silver(I) and copper(II) salts (1.0 equivalent based on 2a)
as mediators exhibited quite low effect on the reaction (Table 1, en-
tries 1−5). Copper(I) salts (1.0 equivalent based on 2a), such as CuI,
CuBr, CuCl, CuOTf and CuCN, as mediators had certain effect on the
reaction (Table 1, entries 6−10). Among them, CuBr showed slightly
higher yield for the formation of 2-methyl-3-(piperidin-1-yl)benzo-
furan (3a) (Table 1, entry 7). Owing to the poor solubility of calcium
carbide in most organic solvents, the reaction in DCE and PhMe
could not give product (Table 1, entries 11, 12). In contrast, the re-
action in DMSO, DMF and MeCN could produce a certain amount
of 3a (Table 1, entries 7, 13, 14). DMSO was an applicable solvent
(Table 1, entry 7). Bases played an important role in the reaction.
Some organic bases, such as DMAP, DBU, pyridine and Et3N (Table
1, entries 7, 15−17), and some inorganic bases, such as NaOH,
Na2CO3, K2CO3, Cs2CO3, NaHCO3 and NaOAc (Table 1, entries 18−23)
were tested for the reaction, and the results showed that Na2CO3
could afford higher yield than others (Table 1, entry 19). In the later
research it was found that the increase of the amount of CuBr from
1.0 to 1.2 equivalents could improve the yield of 3a (Table 1, entries
24). In addition, 100 oC was an appropriate temperature for the re-
action, the elevated and lowered temperature could not improve
the yield of 3a (Table 1, entries 25, 26).
Scheme 1 Synthesis of 2-substituted 3-aminobenzofurans
Table 1. The effect of reaction conditions on the yield of 3aa
rev ous wor
P
i
k
R4
R3
N
R2
,
ut
LiOB
u
R3
C
OTf
(
,
4 h
N
)
2
CHO
R1
R2
R1
+
z
B O
Ca
Mediator, base
N
R4
1
2
. .
t
,
(
)
r
+
+
NMP
O
C
C
Solvent,
OH
temperature
N
H
2a
OH
O
R2
R3
N
3a
1a
CHO
OH
R2
HN
R3
-
,
u
u
DMAP
C
,
OTf 2 C Cl
)
(
R1
R1
R4
+
+
e
S
iM
(
)
,
3
e
M
re ux
CN fl
6 h
Yield (%)b
0
R4
O
Entry
1
Mediator (eq) Base (1 eq)
Solvent
DMSO
R4
AgCl (1)
AgOAc (1)
CuCl2 (1)
CuBr2 (1)
Cu(OAc)2 (1)
CuI (1)
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DBU
R4
N
R3
N
-
,
O
O
r
Tf2O 2 FPy
2
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
34
11
12
Trace
38
44
40
41
13
0
R3
R1
Thi
R1
3
( )
R1
R2
. .
,
,
r
t
6 h
CH2Cl2
R2
O
4
s wor
k
R2
R3
5
N
R2
R3
,
,
CHO
u
r
a
N
,
a
B
C
2CO3 H2O
,
C
10 h
C
R1
+
+
6
HN
DMSO 100 o
C
C
O
OH
7
CuBr (1)
CuCl (1)
CuOTf (1)
CuCN (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
8
9
Calcium carbide as a cheap and abundant solid, which is easy to
10
11
12
13
14
15
16
17
18
19
20
21
store and operate, is generally used to prepare acetylene gas in
chemical industry. However, in recent years, calcium carbide was
found that it could be directly used as an alkyne source to synthe-
size important organic compounds.[9] Our group also reported some
reactions direct using calcium carbide as a concise alkyne source to
construct multifunctional alkynes,[10] alkenes,[11] and cyclic com-
pounds.[12] Although calcium carbide shows attractive prospects for
direct use in organic synthesis, it is far from being studied in depth
and breadth.
In this work, we report a one-pot three-component method for
the synthesis of 2-methyl-3-aminobenzofurans direct using calcium
carbide as a concise solid alkyne source, and salicylaldehydes and
secondary amines as starting materials.
PhMe
DMF
0
33
23
Trace
31
35
41
53
43
46
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Pyridine
Et3N
NaOH
Na2CO3
K2CO3
Cs2CO3
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
component reactions of calcium carbide, salicylaldehydes and sec-
ondary amines to synthesize a series of 2-methyl-3-aminobenzofu-
rans were examined by using CuBr as a mediator, Na2CO3 as a base,
and water as a promoter in DMSO at 100 oC. It was found that the
reactions of calcium carbide, salicylaldehyde (1a) with different sec-
ondary amines including cyclic amines, such as piperidine, morpho-
line, 1,2,3,4-tetrahydroisoquinoline and pyrrolidine, and acyclic
amines, such as diethylamine and dibenzylamine, could give the
corresponding products in good yield (Scheme 2, 3a−3e, 3g). How-
ever, diallylamine as a secondary amine only gave the product in 26%
yield (Scheme 2, 3f). The reactions of calcium carbide, piperidine
(2a) with different salicylaldehydes showed that salicylaldehydes
substituted by electron-withdrawing groups (NO2, F, Cl, Br) afforded
higher yield (Scheme 2, 3h−3k) possibly because electron-with-
drawing effect could cause the nucleophilicity increase of salicylal-
dehydes, and favor to subsequent reactions. In contrast, salicylal-
dehydes substituted by electron-donating groups (Me, MeO) af-
forded slightly lower yield (Scheme 2, 3m−3q). In addition, salicylal-
dehydes bearing meta- and para-substituents to OH gave the cor-
responding products in good yield (Scheme 2, 3h−3n). In contrast,
salicylaldehydes bearing ortho-substituents to OH afford products
in moderate yield because of the large steric hindrance (Scheme 2,
3o−3q). In addition, the reactions of calcium carbide, various salic-
ylaldehydes with other secondary amines demonstrated that cyclic
amines (Scheme 2, 3r, 3s, 3w−3y) could give much higher yield than
acyclic amines (Scheme 2, 3t, 3v), except diethylamine (Scheme 2,
3u).
22
23
CuBr (1)
CuBr (1)
NaHCO3
NaOAc
Na2CO3
Na2CO3
Na2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
42
12
70
58
62
24
CuBr (1.2)
CuBr (1.2)
CuBr (1.2)
25c
26d
a Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), CaC2 (3.0 mmol), medi-
ator (appropriate amount), base (1.0 mmol) and H2O (6.0 mmol) in solvent
(3 mL) at 100 oC for 10 h under N2 atmosphere. b The isolated yield. c 80 oC.
d 120 oC
Scheme 2. Synthesis of 2-methyl-3-aminobenzofuransa
R2
R3
N
R2
HN
R3
CHO
CuBr, Na2CO3 H O
,
DMSO, 100 o 10 h
Ca
2
R1
+
+
R1
C
C
C,
OH
O
3a-3y
2
1
O
N
N
N
N
O
O
O
O
3a
70%
,
3d
54%
,
3b
68%
,
3c
65%
,
N
N
N
N
O2N
The synthesis of product 3a through the reaction of salicylal-
dehyde (1a), piperidine (2a) and calcium carbide was also carried
out on a gram scale. The reaction of 1.46 g of 1a, 0.68 g of 2a with
1.53 g of calcium carbide in 40 mL of DMSO under standard condi-
tions gave 1.15 g of 3a in 67% yield. The success of this gram scale
reaction further demonstrated the effectiveness of optimized con-
ditions for the bulk process (Scheme 3).
O
O
O
O
3e
62%
,
3f
26%
3h
81%
,
,
3g
67%
,
N
N
O
N
N
Br
F
O
O
O
Cl
3i
78%
,
3j 75%
,
3k 75%
,
3l 77%
,
Scheme 3. Gram-scale Synthesis of 3aa
N
N
O
N
O
N
O
N
CHO
Na
H
2CO3 2O
,
CuBr,
Ca
+
+
N
H
DMSO, 100 o 10 h
C
C
O
C,
O
OH
1a 1.46
O
3p 44%
3a 1.15
2a
67%
0.68 g
g
1.53 g
g,
3n
59%
,
3o 53%
3m
,
56%
,
,
a Reaction conditions: 1a (12 mmol), 2a (8 mmol), CaC2 (24 mmol),
CuBr (9.6 mmol), Na2CO3 (8 mmol), H2O (48 mmol) in DMSO (24 mL)
was heated at 100 oC for 10 h under N2 atmosphere.
N
N
N
O
O2N
O2N
N
O2N
O
O
O
O
3q 41%
3s 75%
3t 17%
,
,
,
3r 77%
,
The obtained product could also be found applications in
the organic synthesis. For example, product 3y could be easily
reacted with phenol to synthesize 2-methyl-3-(morpholin-4-
N
O
N
N
N
O
yl)-5-phenoxybenzofuran (
4
) in good yield (Scheme 4).
O2N
O2N
O
O
Scheme 4. Application of 3y
3v
38%
3w 47%
3x
, 41%
3u 75%
,
,
,
O
O
OH
N
N
O
O
Br
CsOH
+
N
DMSO, 150 o 12
h
C,
Br
O
O
4
,
3y
65%
O
,
aReaction conditions: 3y (1 mmol), phenol (1.2 mmol), CsOH (2.5
3y 74%
mmol) in DMSO (1 mL) under air was heated at 150 oC for 12 h.
a
Reaction conditions: 1 (1.5 mmol), 2 (1.0 mmol), CaC2 (3.0 mmol), CuBr (1.2
mmol), Na2CO3 (1.0 mmol) and H2O (6.0 mmol) in DMSO (3 mL) at 100 oC for 10 h
A plausible mechanism for the synthesis of 3a was proposed
(Scheme 5). Salicylaldehyde (1a) first reacts with piperidine (2a)
through nucleophilic addition to give adduct A, which loses hydroxyl
under N2 atmosphere.
Based on the above findings, the scope of the one-pot three-
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
to form B. B easily tautomerizes into quaternary ammonium hy-
droxide C.[13,14] Meanwhile calcium carbide is hydrolyzed to yield
acetylene calcium hydroxide (D),[9f, 9g] which can be further trans-
formed into cuprous acetylide E in the presence of cuprous bromide.
C is attacked by E to give intermediate F. F is further hydrolyzed to
afford intermediate G.[15] The hydroxyl in G attacks intramolecular
triple bond to produce intermediate H,[16, 17] followed by isomeriz-
ing into the more stable 3a as a final product.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Acknowledgement
The authors 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.
Scheme 5. Proposed Mechanism for the Synthesis of 3a
N
H
2a
References
O
N
N
N
OH-
OH-
Coskun, D.; Erkisa, M.; Ulukaya, E.; Coskun, M. F.; Ari, F. Novel 1-(7-
Ethoxy-1-Benzofuran-2-yl) Substituted Chalcone Derivatives: Synthe-
sis, Characterization and Anticancer Activity. Eur. J. Med. Chem. 2017,
136, 212−222.
OH
OH
OH
OH
C
OH
1a
B
A
(a) Xu, Z.; Zhao, S.; Lv, Z.; Feng, L.; Wang, Y.; Zhang, F.; Bai, L.; Deng, J.
Benzofuran Derivatives and Their Anti-Tubercular, Anti-Bacterial Activ-
ities. Eur. J. Med. Chem. 2019, 162, 266−276; (b) Telvekar, V. N.; Be-
lubbi, A.; Bairwa, V. K.; Satardekar, K. Novel N′-Benzylidene Benzofu-
ran-3-Carbohydrazide Derivatives as Antitubercular and Antifungal
Agents. Bioorg. Med. Chem. Lett. 2012, 22, 2343−2346; (c) Yempala, T.;
Sridevi, J. P.; Yogeeswari, P.; Sriram, D.; Kantevari, S. Design, Synthesis
and Antitubercular Evaluation of Novel 2-Substituted-3H-Benzofuro
Benzofurans via Palladium-Copper Catalysed Sonagashira Coupling Re-
action. Bioorg. Med. Chem. Lett. 2013, 23, 5393−5396.
(a) Goyal, D.; Kaur, A.; Goyal, B. Benzofuran and Indole: Promising Scaf-
folds for Drug Development in Alzheimer's Disease. ChemMedChem
2018, 13, 1275−1299; (b) Ha, H. J.; Kang, D. W.; Kim, H. M.; Kang, J. M.;
Ann, J.; Hyun, H. J.; Lee, J. H.; Kim, S. H.; Kim, H.; Choi, K.; Hong, H. S.;
Kim, Y. H.; Jo, D. G.; Lee, J.; Lee, J. Discovery of an Orally Bioavailable
Benzofuran Analogue That Serves as a β-Amyloid Aggregation Inhibitor
for the Potential Treatment of Alzheimer’s Disease. J. Med. Chem.
2018, 61, 396−402.
Ca
H2O
CuBr
C
Cu
C
CH
(HO)Ca
(HO)Ca
C
C
E
D
H2O
N
N
N
CuOH
CuOH
Ca(OH)
O
OH
OH
CuOH
Cu2O
Ca(OH)2
G
F
H
N
O
3a
(a) Yadav, P.; Singh, P.; Tewari, A. K. Design, Synthesis, Docking and
Anti-Inflammatory Evaluation of Novel Series of Benzofuran Based
Prodrugs. Bioorg. Med. Chem. Lett. 2014, 24, 2251−2255; (b) Hassan,
G. S.; Abou-Seri, S. M.; Kamel, G.; Ali, M. M. Celecoxib Analogs Bearing
Benzofuran Moiety as Cyclooxygenase-2 Inhibitors: Design, Synthesis
and Evaluation as Potential Anti-Inflammatory Agents. Eur. J. Med.
Chem. 2014, 76, 482−493.
(a) Duc, D. X. Recent Achievement in the Synthesis of Benzo[b]furans.
Curr. Org. Synth. 2020, 17, 498−517; (b) Agasti, S.; Dey, A.; Maiti, D.
Palladium-Catalyzed Benzofuran and Indole Synthesis by Multiple C-H
Functionalizations. Chem. Commun. 2017, 53, 6544−6556; (c) Blanc, A.;
Beneteau, V.; Weibel, J. M.; Pale, P. Silver & Gold-Catalyzed Routes to
Furans and Benzofurans. Org. Biomol. Chem. 2016, 14, 9184−9205.
(a) Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed Annulative Ami-
nation of ortho-Alkynylphenols with Hydroxylamines: Synthesis of 3-
Aminobenzofurans by Umpolung Amination Strategy. Org. Lett. 2011,
13, 2395−2397; (b) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. An
Annulative Electrophilic Amination Approach to 3-Aminobenzoheter-
oles. J. Org. Chem. 2012, 77, 617−625.
(a) Sakai, N.; Uchida, N.; Konakahara, T. Facile and Efficient Synthesis
of Polyfunctionalized Benzofurans: Three-Component Coupling Reac-
tions from an Alkynylsilane, an O-Hydroxybenzaldehyde Derivative,
and a Secondary Amine by a Cu(I)-Cu(II) Cooperative Catalytic System.
Tetrahedron Lett. 2008, 49, 3437−3440; (b) Sharghi, H.; Shiri, P.; Aberi,
M. A Solvent-Free and One-Pot Strategy for Ecocompatible Synthesis
of Substituted-Benzofurans from Various Salicylaldehydes, Secondary
Amines, and Nonactivated Alkynes Catalyzed by Copper(I) Oxide Na-
noparticles. Synthesis 2014, 46, 2489−2498; (c) Li, H.; Liu, J.; Yan, B.; Li,
Y. New Domino Approach for the Synthesis of 2,3-Disubstituted
Conclusions
In conclusion, a concise method for the synthesis of 2-methyl-
3-aminobenzofurans through one-pot three-component reactions
of calcium carbide, salicylaldehydes and secondary amines has de-
veloped. The salient features of this protocol are the use of inex-
pensive and easy-to-handle alkyne source, broad substrate scope,
satisfactory yield, and simple work-up procedure. This method may
be good alternative to the synthesis of biologically active sub-
stances bearing benzofuran moiety through further structural mod-
ification.
Experimental
General procedure for the synthesis of 2-methyl-3-aminoben-
zofurans: Salicylaldehyde (1.5 mmol), calcium carbide (3 mmol, 98 %
purity), secondary amine (1.0 mmol), cuprous bromide (1.2 mmol),
sodium carbonate (1.0 mmol) and water (6 mmol) in DMSO (dry) (3
mL) were stirred at 100 oC for 10 h. The reaction was monitored by
TLC. After the reaction was complete, the resulting mixture was fil-
tered to remove the solid, and the liquor was extracted with ethyl
acetate (3×10 mL), and washed with saturated brine (3×10 mL).
The resulting organic phase was dried with anhydrous sodium sul-
fate, and concentrated under reduced pressure. The residue was
isolated by aluminum oxide column chromatography by using pe-
troleum ether and ethyl acetate as eluent to give the pure products.
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Benzo[b]furans via Copper-Catalyzed Multi-Component Coupling Re-
Cycloaddition of in Situ Generated Nitrile Imines and Acetylene for As-
sembling of 1,3-Disubstituted Pyrazoles with Quantitative Deuterium
Labeling. J. Org. Chem. 2018, 83, 3819−3828; (t) Beek, W. E. V.; Gadde,
K.; Tehrani, K. A. The Use of Calcium Carbide as Acetylene Source in a
Three-Component Coupling with ω-Chlorinated Ketones and Primary
Amines. Chem. Eur. J. 2018, 24, 16645−16651; (u) Ledovskaya, M. S.;
Rodygin, K. S.; Ananikov, V. P. Calcium-Mediated One-Pot Preparation
of Isoxazoles with Deuterium Incorporation. Org. Chem. Front. 2018, 5,
226−231; (v) Rodygin, K. S.; Vikenteva, Y. A.; Ananikov, V. P. Calcium-
Based Sustainable Chemical Technologies for Total Carbon Recycling.
ChemSusChem 2019, 12, 1483−1516; (w) Hosseini, A.; Schreiner, P. R.
Synthesis of Exclusively 4-Substituted β-Lactams through the Kinugasa
Reaction Utilizing Calcium Carbide. Org. Lett. 2019, 21, 3746−3749.
(a) Gao, L.; Li, Z. Direct Synthesis of 1-Arylprop-1-ynes with Calcium
Carbide as an Acetylene Source. Synlett 2019, 30, 1580−1584; (b) Fu,
R.; Li, Z. Direct Synthesis of Symmetric Diarylethynes from Calcium Car-
bide and Arylboronic Acids/Esters. Eur. J. Org. Chem. 2017, 6648−6651;
(c) Ma, X.; Li, Z. Synthesis of Diarylethynes from Aryldiazonium Salts by
Using Calcium Carbide as an Alkyne Source in a Deep Eutectic Solvent.
Synlett 2021, 32, 631−635; (d) Liu, Z.; Li, Z. Synthesis of 1,3-Diynes Us-
ing Calcium Carbide as an Alkyne Source. Eur. J. Org. Chem. 2021,
302−308.
(a) Gao, L.; Liu, Z.; Ma, X.; Li, Z. Direct Synthesis of Propen-2-yl Sulfones
through Cascade Reactions Using Calcium Carbide as an Alkyne Source.
Org. Lett. 2020, 22, 5246−5250; (b) Gao,L.; Li, Z. Synthesis of Aromatic
Terminal Allenes and Aliphatic Terminal Alkynes from Hydrazones Us-
ing Calcium Carbide as an Acetylene Source. Org. Chem. Front. 2020,
7, 702−708; (c) Song, G.; Li, Z. One-Pot Multi-Component Synthesis of
Triarylacrylonitriles Directly by Using CaC2 as a Concise Acetylene
Source and K4[Fe(CN)6] as an Eco-Friendly Cyanide Source. Eur. J. Org.
Chem. 2018, 1326−1332; (d) Lu, H.; Li, Z. Palladium-Catalyzed One-Pot
Four-Component Synthesis of β-Cyano-α,β-Unsaturated Ketones Us-
ing Calcium Carbide as an Acetylene Source and Potassium Hexacy-
anoferrate(II) as an Eco-Friendly Cyanide Source. Adv. Synth. Catal.
2019, 361, 4474−4482.
(a) Fu, R.; Li, Z. Direct Synthesis of 2-Methylbenzofurans from Calcium
Carbide and Salicylaldehyde p-Tosylhydrazones. Org. Lett. 2018, 20,
2342−2345; (b) Li, Z.; He, L.; Fu, R.; Song, G.; Song, W.; Xie, D.; Yang, J.
One-Step Construction of Saturated Six-Membered Rings Directly Us-
ing Calcium Carbide as an Acetylene Source: Synthesis of 1,3,5-Tri-
aroylcyclohexanes. Tetrahedron 2016, 72, 4321−4328.
Gall, E. L.; Sengmany, S.; Hauréna, C.; Léonel, E.; Martens, T. Mannich-
Like Three-Component Synthesis of α-Branched Amines Involving Or-
ganozinc Compounds: ReactIR Monitoring and Mechanistic Aspects. J.
Organomet. Chem. 2013, 736, 27−35.
Correa, W. H.; Edwards, J. K.; McCluskey, A.; McKinnonc, I.; Scott, J. L.
A Thermodynamic Investigation of Solvent-Free Reactions. Green
Chem. 2003, 5, 30−33.
Ramu, E.; Varala, R.; Sreelatha, N.; Adapa, S. R. Zn(OAc)2·2H2O: A Ver-
satile Catalyst for the One-Pot Synthesis of Propargylamines. Tetrahe-
dron Lett. 2007, 48, 7184−7190.
actions Followed by Cyclization. Tetrahedron Lett. 2009, 50,
2353−2357; (d) Dang-Bao, T.; Pradel, C.; Favier, I.; Gomez, M. Making
Copper(0) Nanoparticles in Glycerol: A Straightforward Synthesis for a
Multipurpose Catalyst. Adv. Synth. Catal. 2017, 359, 2832−2846; (e)
Zhang, X.; Li, D.; Jia, X.; Wang, J.; Fan, X. Catal. Commun. 2011, 12, 839–
843.
Dagoneau, D.; Kolleth, A.; Quinodoz, P.; Tanriver, G.; Catak, S.; Lum-
broso, A.; Sulzer-Mossé, S.; Mesmaeker, A. D. Keteniminium Salts as
Key Intermediates for the Efficient Synthesis of 3-Amino-Indoles and -
Benzofurans. Helv. Chim. Acta 2020, 103, e1900217.
(a) Zhang, W.; Wu, H.; Liu, Z.; Zhong, P.; Zhang, L.; Huang, X.; Cheng, J.
The Use of Calcium Carbide in One-Pot Synthesis of Symmetric Diaryl
Ethynes. Chem. Commun. 2006, 4826−4828; (b) Jiang, Y.; Kuang, C.;
Yang, Q. The Use of Calcium Carbide in the Synthesis of 1-Monosubsti-
tuted Aryl 1,2,3-Triazole via Click Chemistry. Synlett 2009, 19,
3163−3166; (c) Chuentragool, P.; Vongnam, K.; Rashatasakhon, P.;
Sukwattanasinitt, M.; Wacharasindhu, S. Calcium Carbide as a Cost-Ef-
fective Starting Material for Symmetrical Diarylethynes via Pd-Cata-
lyzed Coupling Reaction. Tetrahedron 2011, 67, 8177−8182; (d) Yang,
Q.; Jiang, Y.; Kuang, C. Facile One-Pot Synthesis of Monosubstituted 1-
Aryl-1H-1,2,3-triazoles from Arylboronic Acids and Prop-2-ynoic Acid
(=Propiolic Acid) or Calcium Acetylide (=Calcium Carbide) as Acetylene
Source. Helv. Chim. Acta 2012, 95, 448−454; (e) Lin, Z.; Yu, D.; Sum, Y.
N.; Zhang, Y. Synthesis of Functional Acetylene Derivatives from Cal-
cium Carbide. ChemSusChem 2012, 5, 625−628; (f) Yu, D.; Sum, Y. N.;
2
Ean, A. C. C.; Chin, M. P.; Zhang, Y. Acetylide Ion (C2 −) as a Synthon To
Link Electrophiles and Nucleophiles: A Simple Method for Enaminone
Synthesis. Angew. Chem. Int. Ed. 2013, 52, 5125−5128; (g) Sum, Y. N.;
Yu, D.; Zhang, Y. Synthesis of Acetylenic Alcohols with Calcium Carbide
as the Acetylene Source. Green Chem. 2013, 15, 2718−2721; (h) Thav-
ornsin, N.; Sukwattanasinitt, M.; Wacharasindhu, S. Direct Synthesis of
Poly(p-Phenyleneethynylene)s from Calcium Carbide. Polym. Chem.
2014, 5, 48−52; (i) Hosseini, A.; Seidel, D.; Miska, A.; Schreiner, P. R.
Fluoride-Assisted Activation of Calcium Carbide: A Simple Method for
the Ethynylation of Aldehydes and Ketones. Org. Lett. 2015, 17,
2808−2811; (j) Kaewchangwat, N.; Sukato, R.; Vchirawongkwin, V.; Vi-
laivan, T.; Sukwattanasinitt, M.; Wacharasindhu, S. Direct Synthesis of
Aryl Substituted Pyrroles from Calcium Carbide: an Underestimated
Chemical Feedstock. Green Chem. 2015, 17, 460−465; (k) Rodygin, K.
S.; Ananikov, V. P. An Efficient Metal-Free Pathway to Vinyl Thioesters
with Calcium Carbide as the Acetylene Source. Green Chem. 2016, 18,
482−486; (l) Teong, S. P.; Yu, D.; Sum, Y. N.; Zhang, Y. Copper Catalysed
Alkynylation of Tertiary Amines with CaC2 via sp3 C-H Activation. Green
Chem. 2016, 18, 3499−3502; (m) Rattanangkool, E.; Vilaivan, T.; Suk-
wattanasinitt, M.; Wacharasindhu, S. High Catalytic Performance of
MIL-101-Immobilized NiRu Alloy Nanoparticles towards the Hydrolytic
Dehydrogenation of Ammonia Borane. Eur. J. Org. Chem. 2016,
4347−4353; (n) Samzadeh-Kermani, A. Ethynylation of Isoquinoline
and Quinoline Derivatives with Calcium Carbide. Synlett 2017, 28,
2126−2130; (o) Hosseini, A.; Pilevar, A.; Hogan, E.; Mogwitz, B.; Schulze,
A. S.; Schreiner, P. R. Calcium Carbide Catalytically Activated with
Tetra-n-Butyl Ammonium Fluoride for Sonogashira Cross Coupling Re-
actions. Org. Biomol. Chem. 2017, 15, 6800−6807; (p) Werner, G.;
Rodygin, K. S.; Kostin, A. A.; Gordeev, E. G.; Kashin, A. S.; Ananikov, V.
P. A Solid Acetylene Reagent with Enhanced Reactivity: Fluoride-Me-
diated Functionalization of Alcohols and Phenols. Green Chem. 2017,
19, 3032−3041; (q) Rodygin, K. S.; Gyrdymova, Y. V.; Zarubaev, V. V.
Synthesis of Vinyl Thioethers and Bis-Thioethenes from Calcium Car-
bide and Disulfides. Mendeleev Commun. 2017, 27, 476−478; (r)
Turberg, M.; Ardila-Fierro, K. J.; Bolm, C.; Hernandez, J. G. Altering Cop-
per-Catalyzed A3 Couplings by Mechanochemistry: One-Pot Synthesis
of 1,4-Diamino-2-butynes from Aldehydes, Amines, and Calcium Car-
bide. Angew. Chem. Int. Ed. 2018, 57, 10718−10722; (s) Voronin, V. V.;
Ledovskaya, M. S.; Gordeev, E. G.; Rodygin, K. S.; Ananikov, V. P. [3+2]-
Nguyen, R. V.; Li, C. J. Efficient Synthesis of Dihydrobenzofurans via a
Multicomponent Coupling of Salicylaldehydes, Amines, and Alkynes.
Synlett 2008, 1897−1901.
Wongsa, N.; Sommart, U.; Ritthiwigrom, T.; Yazici, A.; Kanokmedhakul,
S. Kanokmedhakul, K.; Willis, A. C.; Pyne, S. G. Concise Synthesis of α-
Substituted 2-Benzofuranmethamines and Other 2-Subsituted Benzo-
furans via α-Substituted 2-Benzofuranmethyl Carbocation Intermedi-
ates. J. Org. Chem. 2013, 78, 1138−1148.
Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Entry for the Table of Contents
One-Pot Three-Component Synthesis of 2-Methyl-3-Aminobenzofurans Using Calcium Carbide as a Concise Solid Alkyne Source
Xiaolong Ma, Zhiqiang Wang, Zhenrong Liu and Zheng Li*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
In this protocol, calcium carbide was
R2
R3
N
used as a concise solid alkyne source to
react with salicylaldehydes and second-
ary amines through one-pot three-com-
ponent procedure, and a series of 2-
methyl-3-aminobenzofurans were syn-
thesized in satisfactory yield.
R2
CHO
OH
Na
H
2CO3 2O
,
CuBr,
Ca
C C
R1
R1
+
+
HN
DMSO, 100 o 10
R3
h
C,
O
and
of substrates
source
easy-to-handle alkyne
Inexpensive
range
R1
Me,
=
OMe, OEt, Cl,
F,
H,
Wide
Br, NO2 etc.
,
One-pot three-component
procedure
R2 R3
=
examples
etc.
,
alkyl, cycloalkyl,
Twenty-five
to
81%
Up
yield
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim