Facile synthesis of 2,3-disubstituted benzofurans via DBU-promoted intramolecular annulation of ortho oxyether aroylformates

Article abstract of DOI:10.1080/00397911.2018.1533973

A facile synthesis of 2,3-disubstituted benzofurans from ortho oxyether aroylformates has been developed. Under the mediation of DBU, the intramolecular annulation of ortho oxyether aroylformates proceeds smoothly to provide the corresponding 2,3-disubsti

Full text of DOI:10.1080/00397911.2018.1533973

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Facile synthesis of 2,3-disubstituted benzofurans
via DBU-promoted intramolecular annulation of
ortho oxyether aroylformates
Rongfang Liu, Ling Han, Jialin Liu, Binbin Fan, Ruifeng Li, Yan Qiao & Rong
Zhou
To cite this article: Rongfang Liu, Ling Han, Jialin Liu, Binbin Fan, Ruifeng Li, Yan Qiao & Rong
Zhou (2018) Facile synthesis of 2,3-disubstituted benzofurans via DBU-promoted intramolecular
annulation of ortho oxyether aroylformates, Synthetic Communications, 48:24, 3079-3088, DOI:
10.1080/00397911.2018.1533973
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2018, VOL. 48, NO. 24, 3079–3088
https://doi.org/10.1080/00397911.2018.1533973
Facile synthesis of 2,3-disubstituted benzofurans via
DBU-promoted intramolecular annulation of ortho
oxyether aroylformates
a
a
a
a
a
b
ꢀ
ꢀ
Rongfang Liu , Ling Han , Jialin Liu , Binbin Fan , Ruifeng Li , Yan Qiao , and
Rong Zhoua
aCollege of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan, P. R.
b
China; The State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of
Sciences, Taiyuan, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 16 August 2018
Accepted 5 October 2018
A facile synthesis of 2,3-disubstituted benzofurans from ortho oxy-
ether aroylformates has been developed. Under the mediation of
DBU, the intramolecular annulation of ortho oxyether aroylformates
proceeds smoothly to provide the corresponding 2,3-disubstituted
benzofurans in moderate to good yields under mild conditions.
Furthermore, a one-pot two-step synthesis of 2,3-disubstituted ben-
zofurans has also been demonstrated from readily available ortho
hydroxy aroylformates.
KEYWORDS
Annulation; benzofurans;
DBU; intramolecular; ortho
oxyether aroylformates
GRAPHICAL ABSTRACT
Introduction
The benzofurans are an important class of heterocycles frequently present in a wide
range of naturally occurring molecules and pharmaceutically active compounds.[1–8] For
example, natural products Daphnodorin A and B, which display a wide array of
biological activities, contain the benzofuran nucleus.[2] Amiodarone, a marketed drug
for the treatment of intractable cardiac arrhythmias, is also based on the benzofuran
moiety.[3] The compound SKF-64346 bearing a benzofuran core has been identified as a
potent inhibitor of b-amyloid aggregation and exhibits therapeutic potential toward
CONTACT Ruifeng Li
rfli@tyut.edu.cn; Rong Zhou
zhourong@tyut.edu.cn
College of Chemistry and Chemical
Engineering, Taiyuan University of Technology, Taiyuan 030024, P. R. China.
ꢀ
These authors contributed equally.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

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R. LIU ET AL.
Alzheimer’s disease.[4] Other molecules with a benzofuran moiety have also shown a
variety of biological properties such as antimicrobial,[5] antitumor,[6] antiproliferative,[7]
and MMP-13 inhibitory activities (Figure 1).[8] Furthermore, the benzofurans have also
been demonstrated to be versatile building blocks for construction of complex molecules
with biological interest.[9] The development of efficient synthetic methods to benzofurans
has accordingly attracted extensive efforts from chemists due to their bioactivities and ver-
satility. As a result, a number of synthetic methodologies have been established.[1,10]
Among them, the transition-metal-catalyzed tandem reactions provide powerful
approaches to benzofurans with specific structures.[1,11] However, the use of heavy metals
and the requirement of harsh reaction conditions negatively influence their wide applica-
tion. Efficient synthesis of benzofurans under metal-free and mild conditions is, therefore,
attractive from an aspect of green and environmental benign chemistry, but by far it has
only witnessed limited successes.[12] Additionally, different types of substitution patterns
in benzofurans afford new opportunities for drug discovery and other applications. Thus,
it remains in demand for exploration of new and efficient methodologies for structurally
diverse benzofurans, particularly under metal-free and mild conditions.
Aroylformates are versatile building blocks in organic synthesis due to their function-
ality-enriched structural features. Under the influence of Lewis bases such as phosphines
and amines, the aroylformates can serve as versatile coupling partners in intermolecular
reactions. Our group and others recently have reported in a number of studies that the
aroylformates could readily undergo annulation and insertion reactions with both elec-
trophiles and nucleophiles under the mediation of phoshines through the well-known
Kukhtin–Ramirez adducts.[13] Moreover, the amine-catalyzed annulation reactions
involving aroylformates have also been well documented.[14] Although the aroylformates
involved intermolecular reactions have been extensively explored, the corresponding
intramolecular variants have been seldom touched. Notably, in 2013, a DBU-mediated
intramolecular condensation of the analogous ortho diketo phenoxyethers was reported,
affording 2,3-disubstituted c-benzopyranones selectively (Scheme 1, eq. (a)).[15]
Considering the bioactive prevalence and versatility of benzofurans, we envisioned that
by introducing an oxyether group to the ortho position of the phenyl ring of the aroyl-
formates would lead to a potential intramolecular aldol type condensation in the pres-
ence of a base such as DBU, thus resulting in the formation of 2,3-disubstituted
benzofurans (Scheme 1, eq. (b)). Herein, we report a DBU-mediated intramolecular
annulation of ortho oxyether aroylformates, affording 2,3-disubstituted benzofurans in
Scheme 1. Syntheses of benzopyranones and benzofurans via selective intramolecular cyclization.

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moderate to good yields under metal-free and mild conditions. Furthermore, a one-pot
two-step synthesis of 2,3-disubstituted benzofurans has also been demonstrated from
readily available ortho hydroxyl aroylformates.
Results and discussion
We commenced our study with a two-step synthesis of ortho oxyether aroylformates 8,
9, 10, and 11 (Scheme 2). The first step consists of a TiCl4-mediated Friedel–Crafts
acylation of substituted phenol 1 with oxaloyl chloride monoethyl ester 2, which
provided ortho hydroxy aroylformates 3 in generally high yields. Subsequent K2CO3-
promoted nucleophilic substitution of 3 with bromides 4, 5, 6, and 7 afforded the
desired ortho oxyether aroylformates 8, 9, 10, and 11, respectively. We attempted the
proposed annulation with the model substrate 8a. In the presence of DBU (0.04 mmol),
a reaction mixture of 8a (0.2 mmol) in CH2Cl2 was stirred at room temperature for 24
h. To our delight, the expected 2,3-disubstituted benzofuran 12a was exclusively
afforded in 59% yield, without detection of the corresponding benzopyranone byprod-
uct. A brief survey on the model reaction conditions was conducted in order to further
improve the reaction efficiency (Table 1). Solvents screening indicated that CH3CN was
the optimal reaction medium, although other common solvents such as CH2Cl2, THF,
Scheme 2. Synthesis of ortho oxyether aroylformates 8, 9, 10, and 11.

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R. LIU ET AL.
Table 1. Survey on the model reaction conditionsa.
Entry
Base
DBU
DBU
DBU
DBU
DBU
Et3N
DABCO
K2CO3
Cs2CO3
KOH
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CH2Cl2
THF
Toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
24
24
24
22
22
24
24
24
24
24
2
59
52
9
47
65
trace
trace
trace
5
9
10
11
12
13
9
DBU
DBU
DBU
64c
75c,d
50e
1
4
aReaction conditions: substrate 8a (0.2 mmol), base (0.04 mmol), solvent (2 mL), rt.
bIsolated yield.
cDBU (0.2 mmol) was used.
dCH3CN (5.0 mL) was used.
eThe reaction was conducted at 70 ꢁC.
and DMF were accommodated as well (entries 1–4). The influence of base catalysts was
also investigated. Replacement of DBU with other organic or inorganic bases all brought
about inferior results (entries 6–10). Increasing the loading of DBU to stoichiometric
amounts shortened the reaction time significantly while retaining the yield (entry 11).
Using one equivalent of DBU in a diluted reaction mixture further improved the yield
of 12a (entry 12). A decrease in yield was observed when elevating the reaction tem-
ꢁ
perature to 70 C (entry 13).
Employing the optimal reaction conditions listed in Table 1 entry 12, the generality
of the intramolecular annulation was explored (Table 2). Substrates 8 with different sub-
stituents on the phenyl ring were first examined. Both electron-donating and electron-
withdrawing groups on 8 were well tolerated, readily affording their corresponding
products 12 in moderate to good yields. Notably, the steric properties and the location
of the substituents on the phenyl ring of 8 have limited influence on their reactivity.
Substrates 9 and 10, derived from ethyl bromoacetate and diethyl bromomalonate
respectively, were all capable of providing their corresponding benzofuran products 13
under refluxing acetonitrile. It is worth noting that both substrates 9 and 10 afford the
same products under the reaction conditions. The annulation was also applicable to
substrates 11 which were derived from 2-bromoacetophenone. Under the standard con-
ditions, the annulation reactions of 11 uneventfully occurred to afford their correspond-
ing benzofurans 14 in moderate to good yields.
The structures of substrates 8–11, and products 12–14 were all fully characterized by
1H, 13C NMR and HRMS-ESI/MALDI measurements. The annulation reaction pro-
ceeds smoothly by using a common organic base and provides a range of 2,3-disubsti-
tuted benzofurans in generally high yields in one single step under mild conditions,

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Table 2. Synthesis of 2,3-disubstituted benzofuransa.
aReaction conditions: substrate 8 or 9 or 10 or 11 (0.2 mmol), DBU (0.2 mmol), CH3CN (5.0 mL), rt. Isolated yield.
bUnder reflux.
which therefore represents a metal-free and efficient protocol for these biologically
important structural scaffolds.
To make our protocol more synthetically appealing, the feasibility of performing the
reaction in one-pot was examined. As depicted in Scheme 3, in the presence of both
K2CO3 and DBU, a tandem substitution-intramolecular annulation of ortho hydroxy
benzoylformate 3a with 2-bromoacetophenone 7 smoothly proceeded, affording the
benzofuran 14a in 56% yield (for optimization of the reaction conditions, see Table S1
in Supplementary Information).[16] It thus demonstrated a green and step-economic
protocol to 2,3-disubstituted benzofurans.
A proposed mechanism to account for the formation of benzofuran derivatives is
exemplified in Scheme 4 based on the experimental results. The reaction is presumably
initiated with the generation of carbanion intermediate A through deprotonation of
ortho oxyether aroylformate such as 8a by organic base DBU. Intermediate A then trig-
gers an intramolecular aldol type reaction by addition of the carbanion to the carbonyl
group, generating intermediate B, which undergoes protonation to afford intermediate
C. Finally, C brings about the benzofuran product such as 12a after dehydration. As for

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R. LIU ET AL.
Scheme 3. One-pot synthesis of benzofuran 14a.
Scheme 4. A proposed mechanism for the formation of benzofuran.
the annulation of substrates 10, elimination of monoethyl carbonate is envisioned in the
final step to generate the products 13.
Conclusions
In summary, we have developed a facile synthesis of 2,3-disubstituted benzofurans
through DBU-mediated intramolecular annulation of ortho oxyether aroylformates. The
annulation reaction proceeds smoothly under metal-free and mild conditions and
affords a broad range of biologically important 2,3-disubstituted benzofurans in moder-
ate to good yields. It represents a rare intramolecular reaction mode involving aroylfor-
mates. Furthermore, a one-pot two-step synthesis of benzofurans has also been
developed from readily available ortho hydroxy aroylformates, enabling a green and
step-economic synthesis of 2,3-disubstituted benzofurans. Future efforts in our labora-
tory will be directed toward the application of this methodology for the synthesis of bio-
active compounds.
Experimental
Unless otherwise noted, all reactions were carried out under anhydrous conditions. All
1
solvents were purified according to standard procedures. H and 13C NMR spectra
were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard. HRMS
spectra were acquired in the ESI mode with the mass analyzer of TOF used. Column
chromatography was performed on silica gel (200 ꢂ 300 mesh) using a mixture of pet-
roleum ether/ethyl acetate as eluant.

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Figure 1. Representative natural products and bioactive compounds with a benzofuran core.
Typical procedure for synthesis of substrates 8, 9, 10, and 11
The substrates ortho oxylether aroylformates 8, 9, 10, and 11 were synthesized accord-
ing to reported procedures in two steps.[17]
ꢁ
To a solution of phenol (20 mmol) in CH2Cl2 (25 mL) at ꢃ15 C was added TiCl4
(22 mmol). After that ethyl chlorooxoacetate (22 mmol) was added slowly. The resulting
ꢁ
mixture was stirred at ꢃ15 C for 3–5 h for completion. The reaction was then diluted
with CH2Cl2 (30 mL) and poured into previously cooled 1.0 M HCl (75 mL). The aque-
ous layer was separated and extracted with CH2Cl2. The organic layers were combined
and washed with 1.0 M HCl and 20% NaCl aqueous solution, dried over MgSO4, and
filtered, and the filtrate was concentrated and purified by column chromatography on
silica gel to afford compound 3.
To a mixture of compound 3 (10 mmol) and bromides 4 or 5 or 6 or 7 (10.8 mmol)
in DMF (4.0 mL) was added K2CO3 (13 mmol). The reaction mixture was stirred at rt
until compound 3 was completely consumed. Water (50 mL) was added, and the mix-
ture was extracted with ether (3 ꢄ 50 mL). The combined extracts were washed with
brine and dried over MgSO4. After removal of the solvent, the residue was purified by
column chromatography on silica gel to afford compound 8, 9, 10, and 11, respectively.

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R. LIU ET AL.
(E)-Ethyl 4-(2-(2-ethoxy-2-oxoacetyl)phenoxy)but-2-enoate 8a; 58% yield over two
1
steps; a yellow oil; H NMR (400 MHz, CDCl3) d 7.80 (dd, J = 7.8, 1.7 Hz, 1H),
7.54–7.46 (m, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.95 (dt, J = 15.8, 4.4 Hz, 1H), 6.86 (d, J =
8.4 Hz, 1H), 6.07 (dt, J = 15.8, 1.9 Hz, 1H), 4.70 (dd, J = 4.4, 2.0 Hz, 2H), 4.28 (q, J =
7.2 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) d 186.4, 165.6, 164.9, 158.5, 140.7, 136.1, 131.1, 123.3,
122.9, 121.9, 112.8, 67.5, 62.0, 60.7, 14.1, 13.9; HRMS–ESI [M þ H]þ Calcd for
C16H19O6 307.1176, found 307.1187.
Typical procedure for DBU-mediated intramolecular annulation of substrates
8, 9, 10, and 11
To a 25 mL round bottom flask, substrate 8 or 9 or 10 or 11 (0.2 mmol), DBU (0.2 mmol),
and acetonitrile (5 mL) were added. The resulting mixture was stirred at rt (for 8 and 11) or
under reflux (for 9 and 10) until the substrate was completely consumed, as monitored by
TLC. After removing the solvent, the residue was re-dissolved in CH2Cl2 (20 mL), washed
with water and brine, dried with MgSO4. Removal of CH2Cl2 gave the crude product, which
was subjected to column chromatographic isolation on silica gel by gradient elution using
petroleum ether/ethyl acetate (20:1 ꢂ 10:1) to give the annulation product 12 or 13 or 14.
(E)-Ethyl 2-(3-ethoxy-3-oxoprop-1-en-1-yl)benzofuran-3-carboxylate 12a; prepared
according to the typical procedure, 8a (61 mg, 0.2 mmol) is employed to give 12a (43
1
ꢁ
mg, 75%) as a white solid; mp: 100–101 C; H NMR (400 MHz, CDCl3) d 8.31 (d, J =
16.0 Hz, 1H), 8.06 (ddd, J = 7.8, 1.3, 0.6 Hz, 1H), 7.52–7.45 (m, 1H), 7.37 (dtd, J =
15.0, 7.2, 1.2 Hz, 2H), 6.79 (d, J = 16.0 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.30 (q, J =
7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) d 166.0, 163.2, 155.9, 154.4, 130.0, 127.0, 126.2, 124.6, 123.6, 122.9, 113.7, 111.3,
61.0, 60.9, 14.3, 14.2; HRMS–ESI [M þ H]þ Calcd for C16H17O5 289.1071,
found 289.1080.
Typical procedure for one-pot synthesis of benzofuran 14a
K2CO3 (0.26 mmol) and DBU (0.2 mmol) were added to a solution of ortho hydroxyl phe-
nylformate 3a (0.2 mmol) and 2-bromoacetophenone 7 (0.24 mmol) in CH3CN (5.0 mL).
The resulting mixture was stirred at rt for 6 h for completion. The solvent was removed
and the residue was dissolved in CH2Cl2 (10 mL). Water (10 mL) was added, and the aque-
ous phase was extracted with CH2Cl2 (2 ꢄ 10 mL). The organic layers were combined,
washed with brine, dried over MgSO4, filtered, and concentrated, and the crude mixture
was subjected to column chromatographic isolation on silica gel by gradient elution using
petroleum ether/ethyl acetate (20:1 ꢂ 10:1) to give the annulation product 14a.
Funding
Financial support from National Natural Science Foundation of China (Grant No. 21502135) is
gratefully acknowledged.

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[16] A similar one-pot synthesis of benzofurans was reported before, which afforded the analo-
gous benzofuran in low yield (36%) using K2CO3 as the base in DMF at 90 ꢁC. Zhang, C.;
Dumas, J.; Ladouceur, G. H.; Zhao, Q.; Hentemann, M. F.; Verma, S. K.; Zhu, Q.; Lavoie,
R. C.; Fan, J.; Phillips, B. Benzofuran Derivatives Useful for Treating Hyper-Proliferative
Disorders. U.S. Patent 7420066B2, Sep. 2, 2008.
[17] (a) Hu, F.; Guan, X., Shi, M. Tetrahedron. 2012, 68, 4782–4790. (b) Ciganek, E. Synthesis.
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