Phosphine-Catalyzed Chemoselective Reduction/Elimination/Wittig Sequence for Synthesis of Functionalized 3-Alkenyl Benzofurans

Article abstract of DOI:10.1021/acs.orglett.1c00737

An efficient protocol for the construction of functionalized 3-alkenyl benzofurans is demonstrated under metal-free conditions using catalytic amount of phosphine proceeding an intramolecular Wittig reaction. This one-pot reaction initiated by the phospha

Full text of DOI:10.1021/acs.orglett.1c00737

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Letter
Phosphine-Catalyzed Chemoselective Reduction/Elimination/Wittig
Sequence for Synthesis of Functionalized 3‑Alkenyl Benzofurans
Yan-Cheng Liou, Heng-Wei Wang, Athukuri Edukondalu, and Wenwei Lin*
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ABSTRACT: An efficient protocol for the construction of
functionalized 3-alkenyl benzofurans is demonstrated under
metal-free conditions using catalytic amount of phosphine
proceeding an intramolecular Wittig reaction. This one-pot
reaction initiated by the phospha-Michael addition of phosphine
to O-acylated nitrostyrene, in which phosphine was in-situ-
generated from the chemoselective reduction of phosphine oxide
with PhSiH3, would provide the phosphorus ylide to result in the
aforementioned multifunctionalized benzofuran via O-acylation/nitrous acid elimination/Wittig reaction.
Scheme 1. Our Approach for the Functionalized 3-Alkenyl
Benzofurans
hosphine-catalyzed reactions of electron-deficient alkenes
have emerged as a powerful tool in organic synthesis,
P
because of their potential to construct a variety of natural
products and biologically active molecules.1 Consequently, the
conversion of the phosphine-mediated reactions to their
catalytic process was achieved by in situ reduction of
phosphine oxide using hydrosilane.2,3 The challenges to be
overcome for achieving the chemoselective reduction of
phosphine oxide are not affecting the accompanying substrates,
reagents, and formed products in a multistep reaction.2
Remarkably, the development of new methods for the
synthesis of multifarious functionalized heteroarenes/hetero-
cycles under phosphine catalysis is of foremost interest.
Benzofuran heterocycles are important synthetic targets,
because of their prevalence in bioactive natural products and
medicinally valuable compounds.4 The importance of bio-
logical activities of the benzofurans highly relies on their
substitution pattern, because their activity is variable, according
to the nature of the substituents.5 Hence, numerous synthetic
methods were developed for their production of benzofurans
bearing various functional groups.6 However, a few methods
have been reported regarding the synthesis of 3-alkenyl
substituted benzofurans, and most of the reactions are o-
hydroxy-substituted alkynes activated by transition-metal
catalysts (Scheme 1a).7 Therefore, the development of new
methods to access functionalized benzofurans has attracted
great interest. Besides, starting from more available substrates
and the use of metal-free conditions are highly desirable in
modern organic chemistry.
stituted nitrostyrene derivatives could be useful synthons to
install the extra alkenyl functionality at the heteroaryl ring by in
situ removal of nitrous acid.10 The appropriate design of
substrate bearing a nitro group plays a dual role, such as
initiation of the phospha-Michael addition, and in situ
elimination of nitrous acid to incorporate the additional
alkenyl functionality at the desired products. However, the
most challenging part is to avoid the polymerization of
nitrostyrene under our catalytic Wittig reaction conditions.11
In this context, we have developed a novel method for the
construction of functionalized 3-alkenyl benzofurans from the
readily available nitrostyrene derivatives via chemoselective
Received: March 3, 2021
Published: April 6, 2021
Earlier, a novel method for the synthesis of benzofurans
from α,β-unsaturated carbonyl compounds via intramolecular
Wittig reaction has been demonstrated under catalytic
phosphine conditions in this laboratory.8 To continue our
efforts to develop novel methods in the area of organo-
phosphane chemistry,9 we conceived that o-hydroxy sub-
https://doi.org/10.1021/acs.orglett.1c00737
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3064−3069
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reduction/nitrous acid elimination/Wittig reaction sequence
under metal-free conditions. Note that the formation of two
CC conjugated double bonds are achieved by employing the
nitrostyrene, acyl chloride in the presence of a limited amount
of base under phosphine-catalyzed reaction conditions.
Initially, we have performed the reaction of nitrostyrene
derivative 1a with PhCOCl (2a) using a catalytic amount of
phosphine oxide 4a in the presence of Et3N and PhSiH3 in
toluene at 100 °C (Table 1, entry 1). To our delight, the 3-
chemoselective reduction/nitrous acid elimination/Wittig
reaction sequence to access the 3-alkenyl benzofuran 3aa.
Further evaluation of other factors, such as utilizing excess
amounts of base, different reaction temperatures, and catalyst
loading, did not improve the yield of the desired product
(Table 1, entries 9−12). When employing the phosphine oxide
(4b) in the reaction, the desired product was obtained in
similar yield within 3 h (Table 1, entry 13). Furthermore, the
amount of reducing agent, and the addition of additives, were
also tested, but no significant improvement of the yields of the
products was observed (Table 1, entries 14−17). Finally, the
suitable conditions for synthesis of 3-alkenyl benzofurans are
shown in entry 4 in Table 1.
Table 1. Optimization of the Catalytic Intramolecular
a
Wittig Reaction for 3aa
With the optimal conditions in hand, the scope of the
substrates was investigated (Scheme 2). At first, substrate 1,
bearing different R1 and R2 substituents, were tested with
PhCOCl (2a). The substrates with electron-donating groups
(R1) worked more efficiently than those with the electron-
withdrawing groups, furnishing the desired products 3ba−3ga
in moderate to good yields, regardless of the position of the
substituent. The substrates with various R2 substituents
afforded the corresponding 3-alkenyl benzofurans 3ha−3ka
in good yields, irrespective of the electronic and steric nature
of the substituent. Delightfully, the substrate containing the
heteroaryl (2-furyl) group was also well-tolerated to provide
the desired product 3la in 58% yield. Notably, the substrates
with aliphatic methyl and hydrogen as R2 substituents also
participated in the reaction, albeit providing the corresponding
products 3ma and 3na in lower yields. Interestingly, when the
vinyl group bearing substrate 1o was subjected to 2a, the
doubly conjugated benzofuran 3oa was obtained in 65% yield
without any difficulties. We have noticed that the substrates
bearing the aryl or vinyl group as the R2 substituent were well-
participated to furnish the desired 3-alkenyl benzofuran
derivatives in good yields, when compared with substrates
with less-reactive aliphatic R2 substituents (1m and 1n).
Furthermore, various acyl chlorides were tested under
standard reaction conditions with 1a to prepare a series of 3-
alkenyl benzofuran derivatives 3. The acyl chlorides with
electron-donating groups and electron-withdrawing groups at
the para-position provided the desired products 3ab−3ae in
yields up to 69%. The meta- and ortho-chloro-substituted aroyl
chlorides also reacted with 1a smoothly to afford the
corresponding products 3af and 3ag in 65% and 57% yields,
respectively. Delightfully, 1-naphthoyl and heteroaroyl (2-furyl
and 2-thienyl) chlorides furnished the desired products 3ah−
3aj in yields of 60%−68% within 4 h. Interestingly, aliphatic
acyl chlorides 2k and 2l were also well-tolerated to provide the
corresponding benzofuran derivatives 3ak and 3al in yields up
to 67%. In addition, to test the preparative utility of our
catalytic protocol, we have performed a gram-scale reaction of
1a with 2a under the standard conditions. The 3-alkenyl
benzofuran 3aa was obtained in 69% yield with substantial
quantities within 3 h.
b
entry
solvent
base
Et3N
Et3N
Et3N
Et3N
t (h)
3aa/5aa (%)
1
2
3
4
5
6
7
8
toluene
xylenes
1
5
3
3
3
3
3
3
1
5
1
24
3
1
5
5
3
65/−
67/−
67/−
o-xylene
m-xylene
p-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
c
70(69) /−
Et3N
51/−
70/−
49/14
54/−
65/−
54/24
61/−
69/−
69/−
70/−
43/36
54/18
60/−
DIPEA
DABCO
DMAP
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
d
9
e
10
f
11
g
12
h
13
i
14
j
15
k
16
Et3N
Et3N
l
17
a
The reactions were performed with nitrostyrene 1a (0.2 mmol), O
PR3 4a (20 mol %), PhCOCl 2a (1.1 equiv), base (1.2 equiv), and
PhSiH3 (2.0 equiv) sequentially in solvent (1.0 mL) under argon
b
atmosphere at 100 °C. The yield of 3aa and 5aa was determined by
1H NMR analysis of the crude mixture using Ph3CH as an internal
c
d
e
standard. Isolated yield of 3aa. Reaction at 120 °C. Reaction at 80
f
g
h
°C. 30 mol % of 4a was used. 10 mol % of 4a was used. 4b was
i
j
used. 3.0 equiv of PhSiH3 was used. 1.0 equiv of PhSiH3 was used.
k
l
2.0 equiv of Ph2SiH2 was used. TESCl was used as an additive.
alkenyl benzofuran derivative 3aa was obtained in 65% yield
within 1 h. At an instance, we assumed that the in situ
elimination of nitrous acid, along with the Wittig reaction,
could be responsible for the generation of the alkenyl
functionality on the heteroaryl ring of the benzofuran. These
intriguing results of the synthesis of alkenyl-functionalized
benzofurans under metal-free conditions encourage us to
investigate the reaction conditions (Table 1).
First, various solvents have been screened to find the optimal
conditions (Table 1, entries 1−5). After solvent screening, m-
xylene was found to be the best solvent for the catalytic Wittig
reaction (see the Supporting Information (SI) for the detailed
optimization). Furthermore, different bases were tested (Table
1, entries 6−8), and Et3N was found to be a suitable base for
synthesis of the 3-alkenyl benzofuran 3aa. The O-acylated
nitrostyrene derivative 5aa was obtained in 14% yield when the
reaction was performed using 1,4-diazabicyclo[2.2.2]octane
(DABCO) as a base. It could be an intermediate for the
Furthermore, a reaction of 1a and PhCOCl in the presence
of Et3N was examined by employing the stoichiometric
amount of PBu3 in toluene at 30 °C. The desired 3-alkenyl
benzofuran derivative 3aa was obtained in only 50% yield in 3
h. To investigate the mechanism, the O-acylated nitrostyrene
derivative 5aa was also prepared (quantitative yields, 30 °C, 15
min.) from the substrate 1a, PhCOCl, and Et3N in CH2Cl2.
The intermediate 5aa was tested in the reaction with 4a (20
mol %) and PhSiH3 in the absence of Et3N in toluene at 100
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Letter
a b
,
Scheme 2. Substrate Scope of 3-Alkenyl Benzofurans
a
The reactions were performed with nitrostyrene 1a (0.3 mmol), OPR3 4a (20 mol %), PhCOCl 2a (1.1 equiv), Et3N (1.2 equiv), and PhSiH3
b
c
(2.0 equiv) sequentially in m-xylene (1.5 mL) under argon atmosphere at 100 °C. Isolated yield of 3. Performed a gram-scale reaction (1a: 4
mmol, 1.0 g).
°C. The 3-alkenyl benzofuran derivative 3aa was obtained in
64% yield in 3 h. Similar results were also found by employing
stoichiometric amount of PBu3 and 5aa in toluene at 30 °C
(Scheme 3). It clearly indicates that the Wittig reaction
demonstrated in our protocol is a base-free Wittig reaction,
and only 1.2 equiv of base was required for the initial O-
acylation of 1a to generate O-acylated derivative 5aa.
Scheme 3. Control Experiments for the Base-Free Wittig
Reaction
Based on the results and the control experiments, a plausible
mechanism is depicted in Scheme 4. Initially, the O-acylation
occurred to generate the intermediate 5 from substrate 1 and
acyl chloride 2 in the presence of Et3N. The phospha-Michael
addition reaction of phosphine to 5, in which phosphine was
in-situ-generated from the chemoselective reduction of 4a with
PhSiH3, would provide the phosphonium species Ia. The
subsequent H-shift of Ia would generate the phosphorus yilde
Ib. The crucial conjugated ylide III was generated either from
the cleavage of C−NO2 bond of ylide Ib, and further
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Scheme 4. Plausible Mechanism for the Synthesis of 3-
Alkenyl Benzofuran 3
AUTHOR INFORMATION
Corresponding Author
■
Wenwei Lin − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan, Republic of
China; orcid.org/0000-0002-1121-072X;
Email: wenweilin@ntnu.edu.tw
Authors
Yan-Cheng Liou − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan, Republic
of China; orcid.org/0000-0002-1013-0808
Heng-Wei Wang − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan, Republic
of China
Athukuri Edukondalu − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan, Republic
of China; orcid.org/0000-0003-4593-3843
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00737
Notes
The authors declare no competing financial interest.
elimination of nitrous acid from the phosphonium salt II (Path
a), or the direct eviction of HNO2 from the ylide Ib (Path b).
Note that the phosphonium salt II was found in ESI-HRMS
analysis when the reaction was performed with substrate 1n
and acyl chloride 2a in the presence of 4a (50 mol %) under
the standard conditions.12 Finally, the intramolecular Wittig
reaction of ylide III proceeded to result in the desired 3-alkenyl
benzofurans 3.
In summary, we have demonstrated a novel catalytic Wittig
protocol for synthesis of 3-alkenyl benzofurans in moderate to
good yields under metal-free conditions. The highly function-
alized 3-alkenyl benzofurans were provided by in situ
elimination of HNO2 along with the Wittig reaction under
our reaction conditions. The highly chemoselective reduction
of phosphine oxide has been achieved by using PhSiH3 without
affecting of electron-deficient olefins and acyl chlorides in our
protocol. This methodology could be scaled-up for the
preparation of substantial quantitative of 3-alkenyl benzofuran
derivatives. Further exploration of this protocol for synthesis of
other multifunctional heteroarenes is underway in our
laboratory.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the Republic of China (No. MOST 107-2628-M-003-001-
MY3) for financial support.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00737.
Optimization data, control experiments, experimental
procedures, characterization data and spectra of all
compounds (PDF)
Accession Codes
CCDC 2054215 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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(12) The reaction of substrate 1n and acyl chloride 2a has been
examined in the presence of 4a (50 mol %) under the standard
conditions. After 1 h, the reaction mixture was monitored by the ESI-
HRMS analysis. The phosphonium salt II was found in ESI-HRMS
analysis (see the Supporting Information for the experimental details).
It indicated that path a is more likely to happen than path b for
formation of III.
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