Direct Propargylation of ortho-Quinone Methides with Alkynyl Zinc Reagents: An Application to the One-Pot Synthesis of 2,3-Disubstituted Benzofurans

Article abstract of DOI:10.1055/s-0039-1691739

A transition-metal-free propargylation of ortho-quinone methides (o-QMs) with alkynyl zinc reagents was achieved. A conjugate alkynylation of an o-QM and subsequent cyclization sequence in the presence of KO t-Bu for the synthesis of 2,3-disubstituted benzofurans in one pot was developed. This efficient strategy exhibits good functional-group compatibility and gives moderate to good yields. The present reaction might serve as an attractive method for the synthesis of polysubstituted benzofurans.

Full text of DOI:10.1055/s-0039-1691739

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
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M. Sun et al.
Letter
Synlett
Direct Propargylation of ortho-Quinone Methides with Alkynyl
Zinc Reagents: An Application to the One-Pot Synthesis of
2,3-Disubstituted Benzofurans
Manman Suna
Jinyu Songa
Lei Wangb
R1
R1
R1
BrZn
R3
t-BuOK
Wenguang Yinb
Maozhong Miaob
Hongjun Ren*a
R2
O2STs
OH
R2
R2
R3
R3
O
OH
0
0
0
0-0
0
0
2-
4
5
0
6-1
9
6
1
18 examples
13 examples
12–88% yields
33–84% yields
a Advanced Research Institute and Department of Chemistry,
Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R.
of China
renhj@tzc.edu.cn
b Department of Chemistry, Zhejiang Sci-Tech University, Hang-
zhou 310018, P. R. of China
Received: 18.01.2020
Accepted after revision: 07.02.2020
Published online: 26.02.2020
DOI: 10.1055/s-0039-1691739; Art ID: st-2020-l0040-l
NHCOCH3
HO
H3CO
Abstract A transition-metal-free propargylation of ortho-quinone
methides (o-QMs) with alkynyl zinc reagents was achieved. A conjugate
alkynylation of an o-QM and subsequent cyclization sequence in the
presence of KOt-Bu for the synthesis of 2,3-disubstituted benzofurans
in one pot was developed. This efficient strategy exhibits good func-
tional-group compatibility and gives moderate to good yields. The pres-
ent reaction might serve as an attractive method for the synthesis of
polysubstituted benzofurans.
O
O
O
MeO
MeO
OMe
B, melatonin receptor
ligand
A, Phenolic compound from
Dalbergia cochinchinensis
Key words propargylation, ortho-quinone methides, alkynyl zinc re-
agents, benzofurans
OR
The 1-benzofuran moiety is a common structural motif,
found in natural products, pharmaceuticals, and agrochem-
icals.1 In particular, 2,3-disubstituted 1-benzofurans are
widely distributed in natural products and bioactive struc-
tures.2 For example, phenolic compound A (Figure 1), isolat-
ed from the stems of the tree Dalbergia cochinchinensis, is
an antiandrogenic agents acting against testosterone.3 The
benzofuran compound B is considered to be a human MT1
and MT2 melatonin receptor ligand on the basis of its affin-
ity activity.4 The 2-benzyl-3-biphenyl-4-ylbenzofuran de-
rivatives C exhibit potent protein tyrosine phosphatase in-
hibitory activity and also good oral antihyperglycemic ac-
tivity.5
Among the methods available for C–C bond formation,
one of the most versatile and reliable is the conjugate addi-
tion of organometallics to ,-enones, particularly the con-
jugate addition of terminal alkynes to ,-unsaturated car-
bonyl compounds,6 because of the synthetic utility of the
resulting -alkynyl carbonyls.7 As highly reactive ,-unsat-
urated carbonyl species, ortho-quinone methides (o-QMs)
have been widely used in organic synthesis, materials
chemistry, fine-chemical syntheses, and pharmaceutical
O
C, biphenyl benzofuran
derivatives
Figure 1 Bioactive 2,3-disubstituted 1-benzofurans
production.8 The conjugate addition of nucleophilic re-
agents to o-QMs systems would be very desirable in organic
synthesis and drug discovery.9 Because organic zinc re-
agents are among the most useful organometallic com-
pounds in organic synthesis, we previously reported a tran-
sition-metal-free synthesis of unsymmetrical and highly
functionalized triarylmethanes through arylation of o-QMs,
generated in situ from diarylmethyl p-tolyl sulfones, with
arylzinc reagents (Scheme 1, upper).10 In attempts to install
an alkynyl group on the substrates, we examined the direct
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Sun et al.
Letter
Synlett
conjugate alkynylation of o-QMs and a subsequent cycliza-
tion for the synthesis of 2,3-disubstituted benzofurans in
the presence of KOt-Bu in one pot (Scheme 1, lower).
butyllithium, and zinc bromide, and our key results are
summarized in Table 1. We first carried out the reaction by
using CuCl (5 mol%) as catalyst in tetrahydrofuran (THF) at
60 °C for 12 hours, and we obtained the desired propargyla-
tion product 2a in 53% isolated yield (Table 1, entry 1).
Through control experiments, we found that both CuBr and
CuI effectively promoted the reaction at 60 °C, giving the
desired product 2a in yields of 73 and 74%, respectively (en-
tries 2 and 3). Gratifyingly, when the reaction was carried
out at room temperature for 12 h in the presence of CuI (5
mol%), the yield improved to 80% (entry 4). When CoCl2 was
used as a catalyst, the yield decreased to 31% at room tem-
perature (entry 5). When FeCl3 or Fe(acac)3 was used as cat-
alyst, the desired product 2a was obtained after 12 hours in
yields of 86 and 73%, respectively (entries 6 and 7). When
the reaction was carried out without any catalyst at 60 °C
for 12 hours, the desired product 2a was obtained in 55%
yield (entry 9) but, to our delight, when the reaction was
carried out without any catalyst at room temperature for 24
hours, the yield increased to 82% (entry 8).
(1) Reported work
R1
R1
R1
NuH
O2STs
OH
R2
R2
Nu
OH
R2
O
(2) This work
R1
R1
R1
BrZn
R3
t-BuOK
O2STs
OH
R2
R2
R2
R3
R3
O
OH
Scheme 1 The conjugate addition of nucleophilic reagents to o-QMs
systems
Having established the optimal reaction conditions, we
next evaluated the generality of our propargylation reac-
tion (Scheme 2). A series of substituted 2-(tosylmeth-
yl)phenols were first investigated. The reaction proved to
be broadly applicable; both the ortho- and para-substituted
phenols were reactive with good conversions, giving 2b–d
Experimentally, we began our investigation by examin-
ing the reaction of 2-[(4-methoxyphenyl)(tosyl)meth-
yl]phenol (1a), synthesized by a modified version of the re-
ported method, with three equivalents of bromo(phenyl-
ethynyl)zinc, prepared in situ from ethynylbenzene,
R2
R2
BrZn
R3
Ts
room temperature
R1
R1
R3
OH
OH
1
2
OMe
OMe
OMe
OMe
R
R
OH
OMe
OH
OH
OH
OH
OMe
2b, R = F, 84%
2c, R = Cl, 63%
2d, R = OMe, 63%
2e, 39%
2f, 57%
2g, 81%
2h, 72%,R = F,
2i, 82%,R = Cl,
OMe
OMe
OMe
OMe
S
OH
OH
OH
OH
2q, 43%
OH
OH
2p, 72%
R
2j, R = OMe, 88%
2k, R = Cl, 62%
2l, R = F , 65%
2n, 88%
2o, 83%
2r,12%
2m, R = CH3, 77%
Scheme 2 Scope of the propargylation. Reagents and conditions: 1 (0.5 mmol), bromo(alkynyl)zinc (3.0 mmol; generated from the corresponding
alkyne, BuLi, and ZnBr2) under N2, rt, 12–24 h.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
M. Sun et al.
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Synlett
Table 1 Optimization of the Reaction Conditionsa
R2
R2
OMe
One-Pot
BrZn
OMe
R3
1)
Ts
R1
2) t-BuOK
+
Ph
ZnBr
R1
OH
Ts
R3
O
1
3
(3.0 equiv)
Ph
OH
OH
2a
F
OMe
Cl
1a
Entry
Cat.
Temp
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
CuI
60 °C
60 °C
60 °C
rt
12
12
12
24
24
24
24
24
12
53
73
74
80
31
86
73
82
55
O
O
O
3a, 63 %
OMe
3b, 84%
OMe
3c, 47%
OMe
CuI
CoCl2
FeCl3
rt
rt
Fe(acac)3
rt
MeO
F
Cl
c
–
rt
c
O
–
60 °C
O
O
a Reaction conditions: 1a (0.5 mmol), bromo(phenylethynyl)zinc (3.0
mmol; generated from ethynylbenzene, BuLi, and ZnBr2), catalyst (5
3d, 57%
3e,43%
3f, 82%
mol%), THF, under N2.
b Isolated yield.
OMe
OMe
OMe
c No catalyst.
and 2g in isolated yields of up to 84%. Substitution at the
meta-position led to decreased reactivity and a poor yield of
2e. In the case of a 2-hydroxynaphth-1-yl substrate, the
conjugated propargylation product 2f was obtained in 57%
yield. Substitution of the phenyl ring increased the reactivi-
ty, leading to high yields of 2h and 2i from the correspond-
ing fluoro- and chloro-substituted substrates. As expected,
substitution of the terminal phenyl group of the alkyne act-
ing as a nucleophile toward their corresponding zinc re-
agent did not affect the conversion rate to products 2j–m.
However, decreased yields of 2q and 2r were obtained
when the aromatic ring was replaced by an alkyl group,
possibly because the resulting o-QM intermediate is less re-
active. Deprotonation of the arylmethyl p-tolyl sulfone to
the respective styrene is very likely to be a major side-reac-
tion pathway.
O
O
S
O
MeO
OMe
3h,67%
3g, 33%
3i, 64%
OMe
OMe
O
S
O
3j,47%
3k,71%
Scheme 3 Scope of the synthesis of 2,3-disubstituted benzofurans by
a one-pot process. Reagents and conditions: 1 (0.5 mmol), bro-
mo(alkynyl)zinc (3.0 mmol; generated from the corresponding alkyne,
BuLi, and ZnBr2), under N2, rt, 12–24 h.
On the basis of reports in the literature regarding the
synthesis of substituted benzofurans from (hydroxyphe-
nyl)propargylic alcohols,11 we surmised that 2,3-disubsti-
tuted benzofurans might be accessible from our reaction
products in a one-pot operation. After consumption of the
starting material 1a in THF (TLC monitoring), KOt-Bu was
added, and the desired 2-benzyl-3-(4-methoxyphenyl)ben-
zofuran (3a) was obtained in 44% yield at room tempera-
ture, through exo-dig cycloisomerization.12 When the exo-
dig cycloisomerization was carried out in 1,4-dioxane at
room temperature, the yield of product 3a increased to 63%
(Scheme 3). With success in the formation of 2-benzyl-3-
(4-methoxyphenyl)benzofuran (3a) by a one-pot protocol,
we examined the scope and generality of the method, and
our results are summarized in Scheme 3.13 When the prop-
argylphenol had an electron-donating substituent (p-OMe)
or a weakly electron-withdraw substituent (p-Cl) on the
aryl group, the reaction proceeded cleanly to afford 3a and
3b, respectively, in yields of 63 and 84%. However, when an
electron-withdrawing p-fluoro substituent was present, the
yield of 3c dropped to 47%. The presence of an electron-do-
nating substituent on the phenol ring increased the yields
of 3d–f and 3h to as much as 82%. However, in the case of
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
M. Sun et al.
Letter
Synlett
the m-methoxy-substituted phenol, the yield of 3g de-
creased to 33%, which matched the yield of 2e. Heterocy-
cles, as exemplified by thiophene, were also compatible
with this reaction, giving 3i and 3k in yields of 64 and 71%,
respectively. Furthermore, cyclopropylethyne could also be
used in this reaction to give the cyclopropane-containing
2,3-disubstituted benzofuran 3j in 47% yield.
To further demonstrate the potential utility of this alky-
nylation of o-QMs and the subsequent cyclization reaction,
an additional gram-scale experiment was performed. Un-
der the optimal reaction conditions, the desired 2-benzyl-
3-biphenyl-4-yl-1-benzofuran derivative 3l was synthe-
sized straightforwardly in 80% yield (Scheme 4). Interest-
ingly, terminal alkynes made by a Corey–Fuchs protocol can
be used directly in our reaction. Thus, after treatment of the
1,1-dibromoolefin 5 with BuLi at a low temperature, the
corresponding terminal alkynyllithium salt was formed
through a Fritsch–Buttenberg–Wiechell rearrangement.
Subsequent reaction with 1a and treatment with KOt-Bu
provided the corresponding 2,3-disubstituted benzofuran
3m, an isomer of 3l, in 53% yield.
OMe
Ts
1)
ZnBr
OH
2) t-BuOK
OMe
O
3l, 80%
Ts
3)
Br
OH
1) n-BuLi
Br
O
2) ZnBr2
4) t-BuOK
MeO
5
OMe
3m, 53%
Scheme 4 Practical syntheses of biphenylylbenzofuran derivatives
In summary, we have developed a new method for the
effective synthesis of 2,3-disubstituted benzofurans in one-
pot through transition-metal-free conjugate alkynylation of
o-QMs and a subsequent cyclization sequence in the pres-
ence of KOt-Bu. This efficient strategy exhibits good func-
tional-group compatibility with moderate to good yields.
The present reaction might serve as an attractive method
for the synthesis of polysubstituted benzofurans.
References and Notes
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Funding Information
We gratefully acknowledge assistance from the Natural Science Foun-
dation of Zhejiang Province and Taizhou University.
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n
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691739.
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(13) 4-Fluoro-2-[1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-
yl]phenol (2b); Typical Procedure
A 2.5 M solution of BuLi in hexanes (1.5 mmol) was added drop-
wise to a solution of ethynylbenzene (1.5 mmol) in anhyd THF
(2 mL) at –20 °C under N2, and the mixture was stirred for 30
min at –20 °C. A 1.0 M solution of ZnBr2 in THF (1.5 mL) was
added, and the resulting mixture was stirred for about 15 min at
0 °C. 4-fluoro-2-((4-methoxyphenyl)(tosyl)methyl)phenol 1b
(193 mg, 0.5 mmol) was then added, and the mixture was
stirred at rt for 15 h until the reaction was complete. The reac-
tion was then quenched by adding sat. aq NH4Cl (5 mL) and the
mixture was extracted with EtOAc (3 × 10 mL). The combined
organic phase was washed with H2O (3 × 10 mL), dried (Na2SO4),
concentrated in vacuo, and purified by flash chromatography
(silica gel, petroleum ether/EtOAc = 5:1) to give a yellow solid;
yield: 140 mg (84%); mp 89–90 °C (PE–EtOAc); Rf = 0.66 (PE–
EtOAc, 3:1). IR (neat): 3380, 2221, 1605, 1512, 1234, 1182, 1024
cm–1. 1H NMR (400 MHz, CDCl3):  = 7.48–7.46 (m, 2 H), 7.37 (d,
J = 8.8 Hz, 2 H), 7.32–7.30 (m, 3 H), 7.14–7.11 (m, 1 H), 6.89–
6.82 (m, 3 H), 6.76–6.73 (m, 1 H), 5.37 (s, 1 H), 5.29 (s, 1 H), 3.79
(s, 3 H). 13C NMR (100 MHz, CDCl3):  = 158.6 (d, JC–F = 40 Hz),
156.0, 149.1, 131.7, 131.6, 129.4, 129.3, 128.8, 128.3, 128.2,
122.7, 117.4 (d, JC–F = 7.9 Hz), 115.7 (d, JC–F = 24 Hz), 114.7 (d, JC-F
= 22.8 Hz), 114.2, 88.5, 85.4, 55.3, 37.7. HRMS (ES+-TOF): m/z [M
+ H]+ calcd for C22H18FO2: 333.1291; found: 333.1288.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E