One-pot synthesis of benzofurans via heteroannulation of benzoquinones

Article abstract of DOI:10.1515/hc-2020-0120

Three different reactions were explored leading to the synthesis of various benzofurans. All reactions took place under AcOH catalysis in a one-pot manner. As a result, benzoquinone derivatives underwent heteroannulation with either itself or cyclohexanones to produce furanylidene-benzofuran or benzofuran structures, respectively.

Full text of DOI:10.1515/hc-2020-0120

Heterocycl. Commun. 2021; 27: 24–31
Communication
Open Access
Maryam Pirouz, M. Saeed Abaee*, Pernille Harris, Mohammad M. Mojtahedi
One-pot synthesis of benzofurans via
heteroannulation of benzoquinones
https://doi.org/10.1515/hc-2020-0120
Received December 02, 2020; accepted February 15, 2021.
The broad spectrum of biochemical activities of
various benzofurans has led to many investigations to
prepare specific target structures from natural sources
Abstract: Three different reactions were explored leading or via synthetic methods. Several arylbenzofurans were
to the synthesis of various benzofurans. All reactions extracted from the stem bark [17], root bark [18], and
took place under AcOH catalysis in a one-pot manner. As leaves [19] of various mulberry trees, some of which were
a result, benzoquinone derivatives underwent heteroan- also prepared via multistep syntheses [20,21]. Notable
nulation with either itself or cyclohexanones to produce methods for the synthesis of benzofurans include metal-
furanylidene-benzofuran or benzofuran structures, free cyclization of ortho-hydroxystilbenes mediated by
respectively.
hypervalent iodine reagents [22], Ru-catalyzed isomeri-
zation [23] of appropriate precursors [24], cross-coupling
Keywords: benzofuran, furanylidene-benzofuran, benzo- of alkali-metal salts of silanols with aromatic halides [25],
quinone, heteroannulation, one-pot reaction
Pd-catalyzed addition of potassium aryltrifluoroborates
to aliphatic nitriles [26], Sonogashira coupling of O-iodo-
anisoles with terminal alkynes followed by electrophilic
cyclizations [27], and one-pot Pd-catalyzed coupling of
ortho-bromophenols with enolizable ketones [28].
In the framework of our studies on the synthesis of
various heterocyclic systems [29-31], and in continuation
of our program on the use of cyclohexenone derivatives
Introduction
Heterocyclic compounds possessing the benzofuran core
[
1], of either natural or synthetic origin [2], are very impor-
tant due to their exhibition of various biological activities.
This has led to numerous investigations to design proce-
dures for the synthesis of benzofuran based structures
1
a-c in the synthesis [32-34], we decided to take advantage
of the reactivity of cyclohexenone derivatives for possible
coupling with benzoquinone (BQ), as shown in Scheme 1
for the heteroannulation of 1a with BQ. This work resulted
in the one-pot synthesis of benzofuran and furanylidene-
benzofuran systems 2-4 in PhMe/AcOH (4:1) medium.
[
3,4] and to study their biological behavior [5] as anti-
oxidant [6], anticancer [7], antimicrobial [8], antitumor
9], and immunomodulatory [10] agents. As a result, the
[
extensive physiological properties and the high natural
occurrence of benzofuran derivatives have resulted in
their use as versatile biodynamic and useful therapeutic
agents. Important natural examples include moracins
Results and discussion
[
[
11], cicerfuran [12], and conocarpan [13], while bufuralol
14], amiodarone [15], and ailanthoidol [16] are represen-
Confident in the application of [3+2] heteroannulations
in the preparation of benzofuran structures, we first tar-
geted the synthesis of 2. For this purpose, we reacted 1a
with BQ in a refluxing PhMe/AcOH mixture, in which 81%
of 2 was obtained after 24 h (Scheme 1). It is noteworthy
that the synthesis of 2 was previously reported via a three-
step process taking 6 days and achieving an overall yield
of about 80% [35], whereas we could access 2 through a
single step reaction (Scheme 2). Mechanistically, the reac-
tion is probably going through a formal [3+2] process, and
tative derivatives of biologically active synthetic benzofu-
ran molecules (Fig. 1).
*
Corresponding author: M. Saeed Abaee, Organic Chemistry
Department, Chemistry and Chemical Engineering Research Center
of Iran, P.O. Box 14335-186, Tehran, Iran;
E-mail: abaee@ccerci.ac.ir
Maryam Pirouz and Mohammad M. Mojtahedi, Organic Chemistry
Department, Chemistry and Chemical Engineering Research Center
of Iran, P.O. Box 14335-186, Tehran, Iran
Pernille Harris, Technical University of Denmark, DK-2800,
Copenhagen, Denmark; e-mail: ph@kemi.dtu.dk
+
presumably a cyclic transition state (1a-BQH ) is involved.
Protonation of BQ in acidic conditions and formation of
Open Access. © 2021 Pirouz et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons

M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinonesꢁ
ꢁ25
Figure 1ꢀImportant bioactive benzofuran containing structures
(
entry 7). Changing the solvent (entries 8-12) or the acid
reagent (entries 13-16) did not improve the results. The
use of two other BQ derivatives (2,5-dimethylcyclohexa-
2
,5-diene-1,4-dione, 2,5-DMBQ, entry 17 and 2,6-dimethyl-
cyclohexa-2,5-diene-1,4-dione, 2,6-DMBQ, entry 18) gave
no respective products, as would be expected from their
more electron rich nature.
Scheme 1ꢂOne-pot synthesis of 2
To confirm that a hydrogen donor source such as 1b
+
BQH [36] and its participation in hetrocycloadditions or HQ is needed for the reaction to proceed, we replaced
have precedence [37].
1b with either 1c or 1d and repeated the reactions in the
To gain some understanding of the process, we absence of HQ (Scheme 3). Thus, with 2:1 mixtures of BQ
replaced 1a with 1b. Treatment of BQ with 1b (Table 1) in and 1c (or 1d) no detectable reactions were observed.
refluxing PhMe/AcOH solution for 3 days gave a complex
Based on the results, a pathway was proposed in
+
mixture of products from which m-cresol, hydroquinone which BQ is first protonated to BQH [36]. This hypotheti-
(
HQ), and low yields of product 3 were identified (entry 1). cal intermediate is stabilized via ring opening to a conju-
The presence of a HQ skeleton in the structure of 3 and the gated oxo-bis-enone moiety, which in turn is attacked by
formation of m-cresol as a side product suggested that a water to form the hydroxyethylidene-furanone intermedi-
redox process could be involved. Therefore, similar reac- ate. Further oxidation of this intermediate by BQ and its
tions were performed replacing BQ with HQ. When HQ coupling with the resulting HQ, followed by the final lac-
and 1b were used, no formation of 3 was detected (entry 2), tonization, gives 3 (Scheme 4).
while a repeat of each reaction in the absence of 1b was
The structure of 3 was identified based on its NMR
1
also unsuccessful (entries 3-4). In contrast, a mixture of spectra. In H NMR, the presence of two doublets and one
BQ and HQ produced a 70% yield of 3 after an 18 h reflux doublet of doublets signals at about 6.8-7.2 ppm was in
in PhMe/AcOH (entry 5). It is noteworthy that 3 belongs to accordance with the HQ unit, while two doublet signals at
the group of furanylidene-benzofuran heterocycles which 8.4 and 7.0 ppm were indicative of the unsaturated lactone
contain both benzofuran and additional lactone moieties ring. Similarly, DEPT-135, COSY, HSQC, and APT experi-
and are important for their pigment [38] and biochemical ments supported the formation of the suggested structure.
[
39] properties.
To further understand the process, we repeated ted to X-ray crystallographic experiments. Fig. 2 clearly
the reactions in the presence of CD CO D, in which the supports the assignment.
To confirm, a single crystal of 3 was prepared and subjec-
3
2
same results were obtained (entry 6), proving the lack
Based on these results, we decided to design a pathway
of the participation of acetic acid in the structure of the in which a similar combination of BQ structures would
product. Similarly, use of cyclohexa-1,4-diene (CHD), as occur via an elimination reaction as opposed to a redox
a radical scavenger [40], halted the reaction completely, process. For this purpose, we selected 2,6-dichlorobenzo-
supporting the inclusion of a redox process in the reaction quinone (BQCl ), which is more susceptible to protonation
2

ꢁ
M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinones
26ꢁ
Scheme 2ꢂStepwise vs one-pot synthesis of 2
Table 1ꢀOptimization of the synthesis of 3 using 1b
Entry
ꢁb (equiv.)
BQ (equiv.)
HQ (equiv.)
Conditions
Time (h)
Yield (%)a
ꢃ
ꢃ.ꢄ
ꢃ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢄ.ꢄ
ꢅ.ꢆ
ꢄ.ꢄ
ꢃ.ꢄ
ꢄ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄ
ꢅ.ꢄb
ꢅ.ꢄ
ꢅ.ꢄc
ꢄ.ꢄ
ꢅ.ꢆ
ꢄ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
ꢃ.ꢄ
AcOH, PhMe
AcOH, PhMe
AcOH, PhMe
AcOH, PhMe
AcOH, PhMe
CD CO D, PhMe
7ꢅ
7ꢅ
7ꢅ
7ꢅ
ꢃꢉ
ꢃꢉ
7ꢅ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢉ
ꢃꢆ
ꢄ
ꢅ
ꢇ
ꢄ
ꢈ
ꢄ
ꢆ
7ꢄ
7ꢄ
ꢄ
ꢊ
ꢇ
ꢅ
7
CHD, AcOH, PhMe
AcOH, CHClꢇ
ꢉ
ꢄ
ꢄ
ꢆꢆ
ꢆꢇ
ꢇꢇ
ꢄ
9
AcOH, H O
ꢅ
ꢃꢄ
ꢃꢃ
ꢃꢅ
ꢃꢇ
ꢃꢈ
ꢃꢆ
ꢃꢊ
ꢃ7
ꢃꢉ
AcOH, mesitylene
AcOH, xylene
AcOH, benzene
CF CO H, PhMe
ꢇ
ꢅ
HCO H, PhMe
ꢊ7
ꢄ
ꢅ
PTSA, PhMe
HCl, PhMe
ꢄ
AcOH, PhMe
AcOH, PhMe
ꢄ
ꢄ
a
b
c
Isolated yields. BQ was replaced with 2,5-DMBQ. BQ was replaced with 2,6-DMBQ.

M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinonesꢁ
ꢁ27
[
41], and has the potential to produce dibenzofurans, under refluxing acidic conditions, using no coupling
when reacted with ethyl 2-methyl-4-oxocyclohex-2-ene- reagent. The benzofuran formation occurs either through
-carboxylate (Hagmann ester, 1e). This would occur by [3+2] heteroannulation of the starting cyclohexenone
1
taking advantage of a possible facile HCl elimination to moiety with BQ derivatives (in the case of 2 and 4) or the
couple the two reactants and reach a tricyclic dibenzofu- “dimerization” of BQ (in the case of 3), followed by either
ran target structure (Scheme 5). As a result, a facile regio- spontaneous oxidation (aromatization) or elimination
selective coupling was observed, giving 4.
(dehydration) steps. The procedures are clearly effective in
The mechanism of the reaction presumably goes producing the target compounds under inexpensive con-
+
through the formation of BQCl H . This species is formed ditions, in shorter time periods and with fewer reaction
2
upon treatment of the reactants with AcOH, while 1e is steps when compared to the previous reports for known
also enolized to dienol 1eʹ under the acidic conditions. products [35]. Based on these results, we are currently
+
Then, the enol 1eʹ attacks the electron-poor BQCl H to developing the procedures to use a broader spectrum of
2
form 4ʹ. Rearrangement of the double bond to a more reactants, such as phenols and thiophenols.
stable conjugated position promotes the ring closure and
the process is followed by HCl elimination and a final Experimental
dehydration/aromatization step to form 4 (Scheme 6). The
structure of the product was elucidated with NMR spectro- Melting points are uncorrected. FT-IR spectra were recor-
scopy techniques and was confirmed with X-ray crystallo- ded using KBr disks on a Bruker Vector-22 spectrometer.
1
graphic analysis (Fig. 3).
NMR spectra were recorded at 400 MHz for H NMR and
1
3
1
01 MHz for C NMR on a Bruker Ascend 400 MHz spec-
trometer in DMSO-d solutions using TMS as an internal
6
Conclusion
In summary, we successfully conducted the synthesis of
benzofuran and furanylidene-benzofuran systems via the
one-pot coupling of BQ with either itself or cyclohexenone
standard reference. Chemical shift values (δ) are reported
in ppm relative to the residual solvent signal in DMSO,
while coupling constants (J) are given in Hz. Multiplici-
ties are reported as s (singlet), d (doublet), dd (doublet of
doublets), m (multiplet) and etc. Flash column chromato-
graphy was performed using silica gel 60 (0.035-0.070 mm
particle size). Elemental analyses were performed using
a Thermo Finnigan Flash EA 1112 instrument. LCMS ana-
lysis was carried out on a Waters ACQUITY UPLC system
with a PDA and SQD2 electrospray detector and a Thermo
Accucore C18 2.6 µm, 2.1 × 50 mm column. TLC experi-
ments were carried out on pre-coated silica gel plates
using hexanes/EtOAc as the eluent. Chemicals and star-
ting materials were purchased from commercial sources.
Scheme 3ꢂReactions in the presence of 1c-d
Scheme 4ꢀMechanism of the synthesis of 3

ꢁ
M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinones
28ꢁ
Product 2 [35] was known and identified by NMR spectra.
Products 3 and 4 were new and were characterized by
1
13
analysis of their H NMR, C NMR, IR, mass spectra, and
X-ray crystallography.
Synthesis of 8-hydroxy-3,4-dihydrodibenzo[b,d]furan-
1(2H)-one (2)
To a solution of PhMe (4.0 mL) and glacial AcOH (1.0 mL)
was added 1a (100 µL, 1.0 mmol) and benzoquinone
(
216 mg, 2.0 mmol) and the mixture was refluxed for
Figure 2ꢀORTEP representation of 3, thermal ellipsoids set at the
0% probability level
4
24 hours. Saturated aqueous NaHCO (excess) was added
3
Scheme 5ꢀSynthesis of 4
Scheme 6ꢀMechanism of the synthesis of 4

M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinonesꢁ
ꢁ29
-1
Dc = 1.626 g/cm-3, μ(Mo-Kα) = 0.129 mm , crystal dimen-
sion of 0.1 × 0.1 × 0.1 mm. The X-ray data collection for 3
was performed on an Agilent Supernova Diffractometer.
Data processing was done using CrysAlisPro (Agilent Tech-
nologies). The structure was solved by using SHELXS, and
structure refinement was carried out with SHELXL [42].
The non-hydrogen atoms were refined anisotropically by
full matrix least-squares on F2 values to final R1 = 0.0822,
wR2 = 0.2630, and S = 1.009 with 309 parameters using
4
647 independent reflection (θ range = 3.19–29.65°).
Figure 3ꢀORTEP representation of 4, thermal ellipsoids set at the
0% probability level
4
Hydrogen atoms were included on ideal positions using
riding coordinates. Crystallographic data for 3 have been
to the mixture and the organic layer was diluted with deposited with the Cambridge Crystallographic Data
EtOAc (10.0 mL). The organic layer was dried over Na SO4 Centre. Copies of the data can be obtained, free of charge,
2
and after evaporation of the volatiles, the residue was on application to The Director, CCDC-2046512, Union
purified with flash chromatography over silica gel using Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033 or
EtOAc/hexanes (1:5) to obtain 2.
e-mail: deposit@ccdc.cam.ac.uk.
1
White crystals (81%); H NMR (400 MHz, DMSO-d )
6
δ 9.40 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H),
Synthesis of ethyl 6-chloro-8-hydroxy-1-
methyldibenzo[b,d]furan-2-carboxylate (4)
6
.75 (dd, J = 2.5, 9.0 Hz, 1H), 3.03-3.00 (m, 2H), 2.49-2.48
13
(
m, 2H), 2.19-2.12 (m, 2H); C NMR (101 MHz, DMSO-d )
6
δ 194.8, 172.5, 155.1, 148.3, 124.6, 115.9, 113.6, 112.2, 106.1,
To a solution of PhMe (4.0 mL) and glacial AcOH (1.0 mL)
+
33.8, 23.7, 22.4; MS: m/z 202 (M ).
was added 1e (160 µL, 1.0 mmol) and BQCl (264 mg,
2
1
.5 mmol) and the mixture was refluxed for 3 hours. Satu-
Synthesis of (E)-5-hydroxy-3-(5-oxofuran-2(5H)-ylidene)
benzofuran-2(3H)-one (3)
rated aqueous NaHCO (excess) was added to the mixture
3
and the organic layer was diluted with EtOAc (10.0 mL).
The organic layer was dried over Na SO and after evapo-
2
4
To a solution of PhMe (4.0 mL) and glacial AcOH (1.0 mL) ration of the volatiles, the residue was purified with flash
was added benzoquinone (216 mg, 2.0 mmol) and hydro- chromatography over silica gel using EtOAc/hexanes (1:5)
quinone (110 mg, 1.0 mmol) and the mixture was refluxed to obtain 4.
1
for 18 hours. Saturated aqueous NaHCO (excess) was
White crystals (83%); mp = 183-184 °C; H NMR (400
3
added to the mixture and the organic layer was diluted MHz, DMSO-d ) δ 9.99 (s, 1H), 7.91 (d, J = 9.0, 1H), 7.58 (d,
6
with EtOAc (10.0 mL). The organic layer was dried over J = 9.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H),
Na SO and after evaporation of the volatiles, the residue 4.32 (q, J = 7.0 Hz, 2H), 2.88 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H);
2
4
1
3
was purified with flash chromatography over silica gel
using EtOAc/hexanes (1:5) to obtain 3.
CNMR (101 MHz, DMSO-d ) δ 167.3, 157.6, 154.7, 145.6,
6
136.8, 130.6, 126.2, 125.9, 123.9, 115.9, 116.0, 109.8, 107.9, 61.2,
1
-1
Red crystals (70%); 210 °C (decomposes); H NMR 17.3, 14.6 ; IR (KBr) ν 3344, 2853, 1681, 1258, 1073, 779 cm ;
+
(
400 MHz, DMSO-d ) δ 9.65 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), MS: m/z = 304 [M] . Anal. Calcd for C H ClO : C, 63.07; H,
6
16 13
4
7
.18(d, J=2.5Hz, 1H), 7.10(d, J=8.5Hz, 1H), 7.01(d, J=5.5Hz, 4.30. Found: C, 63.25; H, 4.52.
13
1
H), 6.85 (dd, J = 2.5, 8.5 Hz, 1H); C NMR (101 MHz, DMSO-
d6) δ 168.0, 166.9, 155.4, 154.5, 146.9, 141.2, 125.2, 122.0,
X-ray data for 4
1
19.2, 120.4, 111.1, 106.0; IR (KBr) ν 1064, 1466, 1766, 2922,
-1
+
3
467 cm ; MS: m/z 230 (M ). Anal. Calcd for C H O : C,
12 6 5
C H ClO , M = 304.71 g/mol, monoclinic system, space
1
6
13
4
6
2.62; H, 2.63. Found: C, 62.50; H, 2.75.
group P2 /c, a = 12.0554(3), b = 7.2442(1), c = 15.3414(3) Å,
1
3
β = 95.954(2), V = 1332.56(5) Å , Z = 4, Dc = 1.519 g/cm-3,
-1
X-ray data for 3
μ(Cu-Kα) = 2.672 mm , crystal dimension of 0.25 × 0.20 ×
0
.18 mm. The structure was solved using SHELXS and
C H O , M = 230.17 g/mol, triclinic system, space group P-1, refined with SHELXL [40]. The non-hydrogen atoms were
12
6
5
a = 7.0075(7), b = 9.9741(7), c = 14.5706(12) Å, α=81.108(6), refined anisotropically by full matrix least-squares on F2
3
β = 79.856(8), γ=70.532(8), V = 940.10(15) Å , Z = 4, values to final R1 = 0.0470, wR2 = 0.1360, and S = 1.025

ꢁ
M. Pirouz et al.: One-pot synthesis of benzofurans via heteroannulation of benzoquinones
30ꢁ
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Research funding:ꢀThe Research Council at CCERCI is
acknowledged for financial support of this work.
Conflict of interest:ꢀAuthors state no conflicts of interest.
Data availability statement:ꢀCrystallographic data for
[
4
have been deposited with the Cambridge Crystallogra-
2
-[1-hydroxy-2-(tert-butylamino)ethyl]benzofurans, the
phic Data Centre. Copies of the data can be obtained, free
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or e-mail: deposit@ccdc.cam.ac.uk. All other data gene-
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