One-step regioselective synthesis of benzofurans from phenols and α-Haloketones

Article abstract of DOI:10.3390/molecules24112187

Reported here is the direct synthesis of naphthofurans and benzofurans from readily available phenols and α-haloketones promoted by titanium tetrachloride which combines Friedel-Crafts-like alkylation and intramolecular cyclodehydration into one step. This simple protocol allows for the formation of a variety of high value naphthofurans and benzofurans within which a series of cyclic and acyclic groups are readily incorporated. This process demonstrates the advantages of high levels of regioselectivity, broad substrate scope, and moderate to excellent yields.

Full text of DOI:10.3390/molecules24112187

molecules
Article
One-Step Regioselective Synthesis of Benzofurans
from Phenols and α-Haloketones
Bingqiao Wang †, Qiu Zhang †, Juan Luo, Zongjie Gan, Wengao Jiang and Qiang Tang *
College of Pharmacy, Center for Lab Teaching and Management, Chongqing Medical University, No.1
Yixueyuan Road, Chongqing 400016, China; wwangkkang111@163.com (B.W.); zq77668811@163.com (Q.Z.);
102693@cqmu.edu.cn (J.L.); gzj@cqmu.edu.cn (Z.G.); bluesky_gx@sina.com (W.J.)
* Correspondence: tangqiang@cqmu.edu.cn
† These authors contributed equally to this work and should be considered co-first authors.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 16 May 2019; Accepted: 7 June 2019; Published: 11 June 2019
Abstract: Reported here is the direct synthesis of naphthofurans and benzofurans from readily
available phenols and -haloketones promoted by titanium tetrachloride which combines
α
Friedel–Crafts-like alkylation and intramolecular cyclodehydration into one step. This simple
protocol allows for the formation of a variety of high value naphthofurans and benzofurans within
which a series of cyclic and acyclic groups are readily incorporated. This process demonstrates the
advantages of high levels of regioselectivity, broad substrate scope, and moderate to excellent yields.
Keywords: naphthofuran; benzofuran; titanium tetrachloride; α-haloketones; cyclodehydration
1. Introduction
Benzofuran derivatives, especially naphthofurans, constitute a valuable class of heterocyclic
compounds due to their natural occurrence and remarkable biological activities [
more than 30 drugs bearing a benzofuran moiety have been approved by the United States Food
and Drug Administration (USFDA) [ ]. Furthermore, naphthofurans have attracted significant
attention in recent years owing to their powerful paradigm in the development and design of potential
anticancer drugs [ ], dual inhibitors of Alzheimer’s disease [ ], inhibitors of human protein kinase [ ],
and regulators of the nuclear receptor [ ], as well as other bioactivities [10 11]. Several representative
bioactive compounds possessing a naphthofuran or benzofuran skeleton are listed in Figure 1 [12 13].
1,2]. Currently,
3,4
5
6,
7
8
9
,
,
Therefore, the development of novel synthetic methods for their direct preparation from readily
accessible materials is very important.
OH
O
OH
O
OMe
O
OH
O
O
OH
O
O
OMe
Me
O
OH
xylarianaphthol-1
balsaminones A
(anticancer)
(antipruritic activity)
COOMe
OH
rubicordifolin
O
(cytotoxic activity)
I
O
O
O
O
I
O
N
amiodarone
methoxsalen
(antineoplastic agent)
O
(antiarrhythmic medication)
Figure 1. Representative drugs containing benzofuran core.
Molecules 2019, 24, 2187; doi:10.3390/molecules24112187
www.mdpi.com/journal/molecules

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Because of the aforementioned importance, numerous approaches have been reported for the
preparation of these scaffolds through transition-metal catalysis, Lewis or Brønsted acid catalyzed,
or base-promoted cyclizations [14
transition metals, or substrates that are difficult to obtain. The strategy using phenols and
as starting materials to obtain benzofurans is one of the most convenient routes. 3-Substituted
benzo[b]furan can be easily synthesized by a stepwise [16 18] or a one-step method [19 20] which
involves o-alkylation of simple phenols with -haloketone followed by intramolecular cyclization
(Scheme 1a). However, there are seldom reports concerned with the synthesis of 2-substituted
benzo[b]furans using -haloketone and phenols as starting materials [21]. Recently, Arias et al. have
reported that 2-aryl benzo[b]furan can be obtained with excellent regioselectivity under refluxing
temperature using neutral alumina as a promoter and xylene as a solvent [22]. Nevertheless, the scope
of -haloketone is limited to only aryl ketone, without any alkyl ketone being employed (Scheme 1b).
To continue our research [18], we report here that 2-alkyl benzo[b]furan can be regioselectively
formed directly from -haloketones and phenols in the presence of titanium tetrachloride (Scheme 1c).
,
15]. Many of these methods rely on harsh conditions, expensive
α
-haloketones
4
–
,
α
α
5
α
6
α
Scheme 1. Synthesis of benzofurans from α-haloketones and phenols.
2. Results and Discussion
In order to develop a concise approach to naphthofuran, 2-naphthol (1a) and 2-chloroacetone
2a) were selected as model substrates (Table 1). To our delight, the reaction took place smoothly
(
and proceeded to completion in ten hours when titanium tetrachloride was used in the presence of
trifluoroethanol (TFE). The desired product 6a (Table 1) was formed regioselectively, without any other
isomer being detected (entry 8).
As a matter of fact, no conversion to the desired product was observed when commonly used
Brønsted acids or other Lewis acids were tested (Table 1, entries 1–4). When TMSOTf or BF3.Et2O was
used, the reaction produced numerous by-products and finally provided only a few furan products
(Table 1, entries 5 and 6). Using reaction conditions reported in the literature [22], the reaction did take
place but produced an inseparable mixture of 4a and 6a (Table 1, entry 7). Moreover, it was discovered
that increasing or decreasing the amount of titanium tetrachloride led to lower reaction efficiency
(Table 1, entries 9–11). Note that slightly higher reaction temperature is beneficial to both reaction rate
and efficiency. Actually, only a trace amount of 6a was detected by TLC when the reaction mixture was
stirred at room temperature overnight, and the reaction turned out to be complex if prolonging the
reaction time (Table 1, entry 13). The reaction could be carried out in several conventional solvents
(CH2Cl2 and toluene) in addition to TFE, although resulting in significantly diminished conversions
and a longer reaction time (Table 1, entries 14 and 15). Other solvents (CH3CN, Et2O and THF) were
also screened at their refluxing temperatures, but no new product could be detected after stirring
overnight (Table 1, entry 16). The effect of catalyst amount and reaction temperature in this reaction
was then investigated.

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Table 1. Model reaction optimization a.
Yield of 6a b
Entry
Acid
Solvent
T (◦C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
HCl
TsOH
ZnCl2
TFE
TFE
TFE
TFE
TFE
TFE
xylene
TFE
TFE
TFE
TFE
TFE
TFE
CH2Cl2
Toluene
Solvent c
70
70
70
70
70
70
150
70
70
70
70
50
25
40
110
reflux
NA
NA
NA
NA
14
AlCl3
TMSOTf
BF3.Et2O
Al2O3
TiCl4 (1.0 eq)
TiCl4 (0.2 eq)
TiCl4 (0.5 eq)
TiCl4 (1.5 eq)
TiCl4
26
d
–
76%
16%
38%
71%
45%
<10%
34%
38%
NA
TiCl4
TiCl4
TiCl4
TiCl4
a
b
c
The mole ratio between 1a and 2a is 1:1.2. Isolated yields. Solvents: ACN, Et2O, THF. d An inseparable mixture
of 4a and 6a was obtained.
With an optimal set of catalysis conditions selected, we were then poised to test the one-pot
process and evaluate the substrate scope of this reaction. When the reaction was conducted in refluxing
TFE in the presence of titanium tetrachloride, we were delighted to find that both 1- and 2-naphthols
functioned efficiently in the reaction with 2-chloroacetone, with nearly single isomer being isolated
(Table 2, 6a–6d, 99:1 rr). The yields and reaction rates for 1-naphthol, in general, were a little better
than those of 2-naphthol. Bromo-substituted naphthols were also highly effective regardless of the
position of the bromo group on the phenyl ring (Table 2, 6c and 6d, 89% and 66% yields, respectively).
Additionally, simple 3-chloro-2-butanone was also highly effective in the current protocol (Table 2,
6e and 6f, 74% and 76% yields, respectively).
Regioisomers were obtained in the reactions of other acyclic
α-haloketones (Table 2, 6g–6l).
The phenomenon of isomerization was particularly obvious for the reaction of 2-chloro-3-pentanone
stirred at room temperature (Table 2, 6g, 2:1 rr). However, the problem caused by isomerization was
readily overcome by slightly raising the reaction temperature and dropping α-haloketones into the
reaction mixture. By employing the above-mentioned procedures, the desired products were afforded
with high regioselectivity and good yields (Table 2, 6g, 9:1 rr; 6h, 10:1 rr).
Table 2. Reaction of naphthols with different acyclic α-haloketones a, b, c
.

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Table 2. Cont.
a
b
c
The molar ratio between naphthol 1, haloketone 2 and TiCl4 is 1:1.2:1. Isolated yield. The ratio of regioisomers
was determined by crude 1H NMR (see Supplementary Materials). The products were inseparable when purified
by chromatography on silica gel. Using 1-napthol as starting material.
d
e
We next examined the scope of cyclic α-chloroketone which finally produced furans with four
cycles (Table 3). It was gratifying to find that these reactions were completed in 3–10 h to afford the
corresponding tetracyclic products with moderate to excellent yields. Importantly, the transformation
is not limited to six-membered cyclic
-chloroketones are competent substrates. Interestingly, both reaction rate and yield for six-membered
cyclic -chloroketone (Table 3, 7b 7e 7i, and 7 ) were better than those of other cyclic -chloroketones.
Intriguingly, all the reactions of 1-naphthol with cyclic -chloroketones proceeded to completion in 3 h,
α-chloroketone, as five-, seven-, and eight-membered cyclic
α
α
,
,
m
α
α
offering products with excellent yields (Table 3, 7e–7g). However, the reactions of bromo-substituted
naphthols, such as 6-bromo or 7-bromo-2-naphthol, required longer reaction times (10–24 h) and
offered only moderate yields of naphthofurans 7h, 7j–7l, and 7n–7o (Table 3).

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Table 3. Reaction of naphthols with different cyclic α-haloketones a, b
.
O
O
86% yield
O
O
7a,
72% yield
7b,
7c,
78% yield
O
O
[c]
[c]
7f,
84% yield
7e,
92% yield
7d,
71% yield
O
O
O
Br
Br
Br
[c]
7h,
61% yield
7g,
7i,
77% yield
87% yield
O
O
O
Br
Br
Br
7j,
7k,
7l,
62% yield
65% yield
68% yield
O
O
O
Br
Br
7o,
70% yield
7m,
7n,
68% yield
81% yield
a The molar ratio between naphthol is 1:1.2. b Isolated yield. c Using 1-napthol as starting material.
1 and haloketone 2
To further extend the reaction scope, we carried out the reaction with phenols. First, we used
2-chlorocyclohexanone to examine the reactivity of various substituted phenols. Gratifyingly, all alkyl-
or alkoxy-substituted phenols reacted successfully with 2-chlorocyclohexanone to produce the desired
benzofurans 9a–9h (Table 4) with excellent yields. Additionally, it was found that the substituent
patterns (ortho-, meta- and para-) on the benzene ring showed no observed effects on the reaction

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outcomes (Table 4, 9b
–9d). Note that the reaction exhibits sensitivity to steric constraints on the phenol
substrate, that is, the Friedel–Crafts-like alkylation occurs preferentially at the less hindered position,
which can be demonstrated by the formation of a single isomer (Table 4, 9c). Unfortunately, phenols
incorporating an electron-withdrawing group did not react under these conditions. For example, no
new spot was detected by TLC when 4-nitrophenol was employed to react with 2-chlorocyclohexane
for 24 h. Moreover, phenols bearing a strong electron-donating substituent, such as methoxyl, failed to
give better yields (Table 4, 9e and 9f, 72% and 73% yields, respectively), although the reaction rates
were faster than that of non-substituted phenol. On the other hand, the reactions of phenols with
acyclic α-haloketones were also examined, which proceeded smoothly (Table 4, 9i–9k, 77–81% yields).
Table 4. Reaction of phenols with different α-haloketones a, b
.
a
b
The molar ratio between phenol 8 and haloketone 2 is 1:1.2. Isolated yield.
To gain insight into the reaction mechanism, we carried out the reaction with unsymmetrically
substituted haloketone 2m (Scheme 2), under the optimized conditions. Pleasingly, both the desired
furan 6m and isomer 6f (Scheme 2) were isolated in nearly equal amounts. However, reactions for
α
-halo aromatic ketones, such as 2-bromoacetophenone and 2-bromo-1-phenylpentanone, failed to
occur. These facts suggested that oxy-allyl cation may be one of the key intermediates for the reaction
between α-halo alkyl ketones and phenols.
Scheme 2. Mechanism research.

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It is reported that azepinium ions can be generated by the ether cleavage reaction of
2-methoxy-2H-azepine derivatives with titanium tetrachloride as a Lewis acid [23 24]. Furthermore,
,
titanium tetrachloride is also a powerful dehydrating agent and demonstrates a prominent effect in
the condensation reaction of triketones to yield furans [25]. Apart from the reaction paths reported
in the literature (Scheme 1a,b) [22], another reaction route for the one-pot synthesis of benzofuran
was proposed in Scheme 3 [26,27]. First, oxy-allyl cation I, evolved from 2m with the aid of titanium
tetrachloride, reacts with 1b to produce Friedel–Crafts type intermediate II or III (Scheme 3). Then,
due to the powerful dehydration ability of titanium tetrachloride, intramolecular cyclodehydration of
the intermediate II or III easily takes place to obtain benzofuran 6m or 6f (Scheme 3).
Scheme 3. Proposed mechanism.
3. Experimental Section
3.1. General Information
Nuclear magnetic resonance spectra (1H and 13C) were recorded on 400 and 600 MHz spectrometers
(Bruker, Karlsruhe, Germany) with tetramethylsilane (TMS) as an internal standard.The splitting
patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets),
m (multiplets), etc. All first-order splitting patterns were assigned on the basis of the appearance
of the multiplet. Splitting patterns that could not be easily interpreted were designated as
multiplet (m) or broad (br). High resolution mass spectral analysis (HRMS) was performed on
an ESI-QTOP mass spectrometer (Bruker Solari XFT-ICR-MS system). Purification was done by
column chromatography and preparative TLC using silica gel. TLC analyses were performed on
commercial glass plates (Qingdao Haiyang Chemical Co., Ltd, Qingdao, China) bearing a 0.25-mmlayer
of silica gel GF254.Visualization was performed using a UV lampor chemical stains like KMnO4 and I2.
Commercially available materials were used as received.
All reactions were carried out under nitrogen atmosphere. Dehydrated solvents were purchased
from commercial suppliers (Alfa Aesar, Ward Hill, MA, USA; Adamas, Shanghai, China) and stored
under nitrogen atmosphere. Unless otherwise noted, materials were obtained from commercial
suppliers and used without further purification. Some of the
prepared using literature methods [28,29].
α-chloroketones and bromoketones were
3.2. General Procedure for the Reaction between Phenol and α-Haloketone
To a 25 mL two-necked flask equipped with a reflux condenser, fresh distilled 2,2,2-trifluoroethanol
(1.0 mL), phenol (1.0 mmol), and titanium tetrachloride (1.0 mmol) were added under nitrogen
atmosphere. Then, a mixture of α-haloketone (1.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was dropped
into the reaction mixture under refluxing temperature. After completion of the reaction (monitored by
TLC), the mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL). After filtration of
the mixture, the water layer was extracted by dichloromethane (3
sodium sulphate. The organic mixture was concentrated under reduced pressure, and separated by
×
10 mL) and dried with anhydrous
silica-gel column chromatography using ethyl acetate
the desired furan compound.
−
hexane as eluent in increasing polarity to yield

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3.2.1. Characterizations of Naphthofuran 6 (Table 2)
2-Methylnaphtho[2,1-b]furan (6a) [30]. The title compound was obtained as white solid (76%),
1
mp: 39–40 ◦C, and the analytical data are consistent with those in the literature. H NMR (600 MHz,
CDCl3)
δ 8.07 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.9 Hz,
1H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 6.87 (s, 1H), 2.56 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 154.7, 151.9, 130.3, 128.7, 127.4, 125.9, 124.2, 124.2, 123.8, 123.4, 112.1, 101.7, 14.3; GC-MS (m/z):
182.1 [M]+.
2-Methylnaphtho[1–b]furan (6b) [31]. The title compound was obtained as colorless oil (80%), and the
analytical data are consistent with those in the literature. 1H NMR (600 MHz, CDCl3)
δ 8.27
(d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.74–7.51 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 2.58
(s, 3H); 13C NMR (150 MHz, CDCl3)
119.3, 103.7, 14.2.
δ 154.6, 149.9, 130.8, 128.3, 126.1, 124.6, 124.4, 123.0, 121.2, 119.7,
7-Bromo-2-methylnaphtho[2,1-b]furan (6c) [32]. The title compound was obtained as white solid (89%),
1
mp: 91–92 ◦C, and the analytical data are consistent with those in the literature. H NMR (600 MHz,
CDCl3) δ 8.06 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 8.8, 1.8 Hz, 2H), 7.53 (d, J = 8.9 Hz,
1H), 6.81 (s, 1H), 2.55 (s, 3H); 13C NMR (150 MHz, CDCl3)
124.3, 122.7, 117.8, 113.1, 101.6, 14.2.
δ 155.3, 151.9, 131.4, 130.6, 129.0, 125.8, 125.2,
8-Bromo-2-methylnaphtho[2,1-b]furan (6d). The title compound was obtained as white solid (66%), mp:
93–94 ◦C. 1H NMR (600 MHz, CDCl3)
8.20 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.59 (s, 2H), 7.52
(dd, J = 8.7, 2.0 Hz, 1H), 6.80 (s, 1H), 2.55 (d, J = 0.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
155.2, 152.3,
δ
δ
130.3, 128.6, 128.5, 127.5, 125.9, 123.6, 123.5, 120.0, 112.5, 101.6, 14.2; HRMS (ESI) calcd for C13H10BrO
(M + H)+: 260.9910. Found: 260.9909.
1,2-Dimethylnaphtho[2,1-b]furan (6e) [33]. The title compound was obtained as yellowish oil (74%),
1
and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ 8.40 (d,
J = 8.3 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.63–7.53 (m, 2H), 7.53–7.38 (m, 1H),
2.57 (s, 3H), 2.49 (s, 3H); 13C NMR (150 MHz, CDCl3)
123.8, 123.2, 123.0, 112.1, 111.7, 11.8, 11.4.
δ 151.3, 149.9, 130.7, 128.9, 128.7, 125.8, 124.0,
2,3-Dimethylnaphtho[1,2-b]furan (6f) [30]. The title compound was obtained as yellowish solid (71%),
1
mp: 201–202 ◦C, and the analytical data are consistent with those in the literature. H NMR (400 MHz,
CDCl3)
δ 8.26 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.61–7.51 (m, 2H),
7.51–7.36 (m, 1H), 2.50 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3)
126.0, 125.7, 124.3, 122.5, 121.1, 119.7, 117.9, 110.9, 12.00, 8.1.
δ
149.8, 148.9, 130.9, 128.3,
1
2-Ethyl-3-methylnaphtho[1,2-b]furan (6g). The title compound was obtained as yellowish oil (88%). H
NMR (600 MHz, CDCl3)
δ 8.27 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54
(t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 2.86 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H);
13C NMR (150 MHz, CDCl3)
δ 154.9, 148.9, 130.9, 128.3, 126.0, 125.7, 124.3, 122.5, 121.2, 119.8, 118.0,
109.9, 19.9, 13.1, 8.0; HRMS (ESI) calcd for C15H15O (M + H)+: 211.1117. Found: 211.1118.
2-Ethyl-1-methylnaphtho[2,1-b]furan (6h) [26]. The title compound was obtained as yellowish oil (80%),
1
and the analytical data are consistent with those in the literature. H NMR (400 MHz, CDCl3)
δ 8.41 (d,
J = 8.3 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.74–7.53 (m, 3H), 7.53–7.41 (m, 1H), 2.87 (q, J = 7.6 Hz, 2H),
2.59 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 155.0, 151.3, 130.7, 129.0, 128.9, 125.8,
124.0, 123.7, 123.3, 123.1, 112.2, 110.8, 19.6, 13.2, 11.3.

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2-Benzyl-1-phenylnaphtho[2,1-b]furan (6i) [34]. The title compound was obtained as yellow oil (70%),
1
and the analytical data are consistent with those in the literature. H NMR (400 MHz, CDCl3)
δ
7.90
(d, J = 8.2 Hz, 1H), 7.71 (dd, J = 12.8, 8.7 Hz, 2H), 7.63 (d, J = 8.9 Hz, 1H), 7.58–7.44 (m, 5H), 7.38 (t,
J = 7.5 Hz, 1H), 7.35–7.20 (m, 6H), 4.08 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ
152.7, 151.7, 138.2, 133.9,
130.7, 130.6, 128.8, 128.7, 128.6, 128.6, 127.8, 126.5, 125.8, 125.0, 124.1, 123.2, 122.2, 120.0, 112.3, 32.6.
2-Benzyl-3-phenylnaphtho[1,2-b]furan (6j) [35]. The title compound was obtained as yellow oil (74%),
1
and the analytical data are consistent with those in the literature. H NMR (400 MHz, CDCl3)
δ 8.29 (d,
J = 8.2 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.67 (s, 2H), 7.56 (ddd, J = 8.1, 5.1, 2.1 Hz, 3H), 7.53–7.45 (m,
3H), 7.45–7.19 (m, 6H), 4.32 (s, 2H); LCMS (ESI) calcd for C25H19O (M + H)+: 335.1. Found: 335.0.
2-Butyl-1-propylnaphtho[2,1-b]furan (6k). The title compound was obtained as yellowish oil (83%).
1H NMR (400 MHz, CDCl3)
δ 8.24 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H),
7.62–7.50 (m, 2H), 7.44 (dd, J = 11.1, 4.0 Hz, 1H), 3.03–2.87 (m, 2H), 2.88–2.69 (m, 2H), 1.87–1.67 (m,
4H), 1.42 (dd, J = 15.0, 7.5 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.4, 151.6, 130.7, 129.1, 128.4, 125.9, 124.1, 123.7, 123.2, 122.5, 116.2, 112.3, 30.9, 27.3, 26.0,
23.4, 22.5, 14.1, 14.0; HRMS (ESI) calcd for C19H23O (M + H)+: 267.1743. Found: 267.1741.
2-Butyl-3-propylnaphtho[1,2-b]furan (6l). The title compound was obtained as yellowish oil (84%).
1H NMR (400 MHz, CDCl3)
δ 8.26 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.57 (ddd, J = 17.6, 16.0,
8.2 Hz, 3H), 7.50–7.36 (m, 1H), 2.82 (dt, J = 9.9, 7.5 Hz, 2H), 2.68 (dd, J = 15.8, 7.9 Hz, 2H), 1.91–1.72 (m,
2H), 1.67 (dd, J = 15.7, 7.6 Hz, 2H), 1.51–1.33 (m, 2H), 0.98 (ddt, J = 16.3, 8.9, 7.4 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 154.1, 149.1, 130.8, 128.3, 125.9, 125.0, 124.3, 122.3, 121.2, 119.8, 118.3, 115.8, 23.5, 23.4,
22.6, 22.5, 22.1, 14.1, 13.9; HRMS (ESI) calcd for C19H23O (M + H)+: 267.1743. Found: 267.1744.
1
2-Ethylnaphtho[1,2-b]furan (6m) [36].The title compound was obtained as yellowish oil (40%). H NMR
(600 MHz, CDCl3) δ 8.27 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.65–7.51 (m, 3H), 7.50–7.38 (m,
1H), 6.51 (d, J = 0.9 Hz, 1H), 2.92 (qd, J = 7.5, 0.9 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 160.3, 149.8, 130.9, 128.3, 126.1, 124.4, 124.4, 122.9, 121.2, 119.7, 119.4, 102.1, 21.9, 12.2.
3.2.2. Characterizations of Naphthofuran7 (Table 3)
9,10-Dihydro-8H-cyclopenta[b]naphtho[1,2-d]furan (7a). The title compound was obtained as white solid
(72%), mp: 125–126 ◦C. 1H NMR (400 MHz, CDCl3)
δ
8.05 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H),
7.59 (s, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 3.16–2.99 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H),
2.73–2.52 (m, 2H); 13C NMR (100 MHz„ CDCl3)
δ 162.0, 157.3, 130.4, 128.5, 127.5, 125.8, 124.2, 124.1,
123.1, 122.2, 121.7, 113.0, 27.9, 25.0, 23.9; HRMS (ESI) calcd for C15H13O (M + H)+: 209.0961. Found:
209.0960.
8,9,10,11-Tetrahydronaphtho[2,1-b]benzofuran (7b) [37]. The title compound was obtained as yellowish
1
oil (86%), and the analytical data are consistent with those in the literature. H NMR (400 MHz, CDCl3)
δ
8.25 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.75–7.60 (m, 2H), 7.60–7.50 (m, 1H), 7.50–7.37 (m,
1H), 3.21–3.03 (m, 2H), 2.85 (t, J = 4.8 Hz, 2H), 2.14–1.86 (m, 4H); 13C NMR (150 MHz, CDCl3)
δ 153.3,
151.5, 130.6, 129.5, 128.7, 125.7, 123.8, 123.7, 123.5, 122.5, 114.3, 112.3, 23.8, 23.2, 23.1, 22.6.
9,10,11,12-Tetrahydro-8H-cyclohepta[b]naphtho[1,2-d]furan (7c). The title compound was obtained as
1
yellowish oil (78%). H NMR (400 MHz, CDCl3)
δ 8.46 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.63
(d, J = 8.8 Hz, 1H), 7.61–7.52 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H), 3.37–3.17 (m, 2H), 3.03 (d, J = 5.9 Hz, 2H),
2.13–1.77 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 155.8, 150.7, 130.8, 129.1, 128.8, 125.6, 124.1, 123.7,
123.1, 123.0, 118.3, 112.2, 29.6, 28.5, 28.0, 26.1, 25.8;HRMS (ESI) calcd for C17H17O (M + H)+: 237.1274.
Found: 237.1276.

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8,9,10,11,12,13-Hexahydrocycloocta[b]naphtho[1,2-d]furan (7d). The title compound was obtained as white
solid (71%).1H NMR (400 MHz, CDCl3)
8.37 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.62 (q,
δ
J = 8.8 Hz, 2H), 7.58–7.52 (m, 1H), 7.50–7.42 (m, 1H), 3.30–3.12 (m, 2H), 3.12–2.88 (m, 2H), 1.96 (dt,
J = 12.6, 6.3 Hz, 2H), 1.89–1.73 (m, 2H), 1.68–1.53 (m, 2H), 1.46 (dd, J = 11.2, 5.5 Hz, 2H);13C NMR
(100 MHz, CDCl3) δ 155.0, 151.3, 130.6, 129.0, 128.6, 125.8, 123.8, 123.8, 123.0, 122.6, 115.6, 112.4, 29.6,
28.1, 26.7, 26.0, 25.8, 23.3;HRMS (ESI) calcd for C18H19O (M + H)+: 251.1430. Found: 251.1435.
7,8,9,10-Tetrahydronaphtho[1,2-b]benzofuran (7e) [36].The title compound was obtained as yellowish oil
1
(92%), and the analytical data are consistent with those in the literature. H NMR (400 MHz, CDCl3)
δ
8.29 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.61–7.50 (m, 2H), 7.51–7.37 (m,
1H), 2.99–2.81 (m, 2H), 2.81–2.61 (m, 2H), 2.14–1.96 (m, 2H), 1.96–1.80 (m, 2H); LCMS (ESI) calcd for
C16H15O (M + H)+: 223.1. Found: 223.3.
8,9,10,11-Tetrahydro-7H-cyclohepta[b]naphtho[2,1-d]furan (7f) [38]. The title compound was obtained as
white solid (84%), mp: 38–39 ◦C, and the analytical data are consistent with those in the literature.
1H NMR (400 MHz, CDCl3)
δ 8.25 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H),
7.54 (ddd, J = 8.5, 5.5, 2.0 Hz, 2H), 7.43 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 3.14–2.97 (m, 2H), 2.89–2.71 (m,
2H), 2.00–1.75 (m, 6H); 13C NMR (100 MHz, CDCl3)
121.22, 119.8, 117.7, 117.2, 30.8, 29.4, 28.4, 26.5, 23.5.
δ 155.8, 148.2, 130.8, 128.3, 126.0, 125.7, 124.2, 122.5,
7,8,9,10,11,12-Hexahydrocycloocta[b]naphtho[2,1-d]furan (7g) [38]. The title compound was obtained
as colorless oil (87%), and the analytical data are consistent with those in the literature. 1H NMR
(400 MHz, CDCl3)
J = 8.1 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 3.18–2.99 (m, 2H), 2.99–2.82 (m, 2H), 2.03–1.72 (m, 4H), 1.68–1.44
(m, 4H); 13C NMR (100 MHz, CDCl3)
154.3, 148.8, 130.8, 128.4, 126.0, 125.2, 124.3, 122.5, 121.3, 119.8,
δ 8.29 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.57 (t,
δ
117.7, 115.0, 28.3, 27.6, 26.5, 26.1, 25.6, 21.6.
3-Bromo-9,10-dihydro-8H-cyclopenta[b]naphtho[1,2-d]furan (7h). The title compound was obtained as
white solid (61%), mp: 36–37 ◦C. 1H NMR (600 MHz, CDCl3)
δ
8.06 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.60
(dd, J = 18.5, 8.8 Hz, 2H), 7.51 (d, J = 8.9 Hz, 1H), 3.06 (t, J = 6.8 Hz, 2H), 3.00–2.89 (m, 2H), 2.77–2.56
(m, 2H); 13C NMR (150 MHz, CDCl3)
δ 162.7, 157.3, 131.5, 130.4, 128.9, 125.9, 125.8, 122.1, 122.0, 121.8,
117.9, 114.0, 27.9, 25.0, 23.8; HRMS (ESI) calcd for C15H12BrO (M + H)+: 287.0066. Found: 287.0068.
3-Bromo-8,9,10,11-tetrahydronaphtho[2,1-b]benzofuran (7i). The title compound was obtained as white
1
solid (77%). H NMR (400 MHz, CDCl3)
δ 8.04 (dd, J = 9.2, 5.4 Hz, 2H), 7.68–7.53 (m, 2H), 7.49 (d,
J = 8.9 Hz, 1H), 3.00 (t, J = 4.8 Hz, 2H), 2.83 (t, J = 5.0 Hz, 2H), 2.04–1.84 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 153.9, 151.5, 131.8, 130.7, 128.8, 126.8, 125.2, 122.7, 122.6, 117.5, 114.1, 113.3, 23.7, 23.0, 23.0,
22.5; HRMS (ESI) calcd for C16H14BrO (M + H)+: 301.0223. Found: 301.0220.
3-Bromo-9,10,11,12-tetrahydro-8H-cyclohepta[b]naphtho[1,2-d]furan (7j). The title compound was obtained
1
as yellowish oil (65%). H NMR (400 MHz, CDCl3)
δ
8.29 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H),
7.56 (ddd, J = 25.1, 13.7, 5.5 Hz, 3H), 3.34–3.09 (m, 2H), 3.01 (d, J = 6.1 Hz, 2H), 2.06–1.76 (m, 6H); 13
NMR (100 MHz, CDCl3) 156.4, 150.7, 132.1, 131.0, 128.7, 127.2, 124.8, 123.2, 123.0, 118.1, 117.2, 113.2,
29.5, 28.5, 27.9, 26.0, 25.7; HRMS (ESI) calcd for C17H16BrO (M + H)+: 315.0379. Found: 315.0381.
C
δ
3-Bromo-8,9,10,11,12,13-hexahydrocycloocta[b]naphtho[1,2-d]furan (7k). The title compound was obtained
as white solid (68%), mp: 36–37 ◦C. 1H NMR (600 MHz, CDCl3)
8.20 (s, 1H), 8.07 (s, 1H), 7.60 (s,
2H), 7.52 (s, 1H), 3.13 (s, 2H), 2.98 (s, 2H), 1.93 (s, 2H), 1.78 (s, 2H), 1.58 (s, 2H), 1.45 (s, 2H); 13C NMR
(150 MHz, CDCl3) 155.5, 151.4, 132.0, 130.9, 128.9, 127.0, 124.7, 122.8, 122.7, 117.4, 115.5, 113.4, 29.5,
28.0, 26.6, 26.0, 25.7, 23.3; HRMS (ESI) calcd for C18H18BrO (M + H)+: 329.0536. Found: 329.0534.
δ
δ

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2-Bromo-9,10-dihydro-8H-cyclopenta[b]naphtho[1,2-d]furan (7l). The title compound was obtained as
white solid (62%), mp: 35–36 ◦C 1H NMR (600 MHz, CDCl3)
8.18 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 8.7 Hz
δ
,
1H), 7.59 (dd, J = 22.5, 8.9 Hz, 2H), 7.52 (dd, J = 8.7, 2.0 Hz, 1H), 3.15–3.02 (m, 2H), 3.02–2.84 (m, 2H),
2.68 (dd, J = 14.2, 7.4 Hz, 2H); HRMS (ESI) calcd for C15H12BrO (M + H)+: 287.0066. Found: 287.0069.
2-Bromo-8,9,10,11-tetrahydronaphtho[2,1-b]benzofuran (7m). The title compound was obtained as white
1
solid (81%). H NMR (400 MHz, CDCl3)
δ 8.31 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.64–7.53 (m,
2H), 7.50 (dd, J = 8.7, 1.9 Hz, 1H), 3.04 (t, J = 4.7 Hz, 2H), 2.83 (t, J = 4.9 Hz, 2H), 1.96 (dd, J = 6.7, 3.9 Hz,
4H); 13C NMR (100 MHz, CDCl3)
δ 153.8, 151.9, 130.3, 129.5, 128.9, 127.1, 125.8, 123.4, 121.8, 119.8, 114.1,
112.7, 23.7, 22.97, 22.92, 22.5; HRMS (ESI) calcd for C16H14BrO (M + H)+: 301.0223. Found: 301.0220.
2-Bromo-9,10,11,12-tetrahydro-8H-cyclohepta[b]naphtho[1,2-d]furan (7n). The title compound was obtained
1
as yellowish oil (68%). H NMR (400 MHz, CDCl3)
δ
8.54 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H),
7.66–7.45 (m, 3H), 3.31–3.10 (m, 2H), 3.01 (d, J = 6.2 Hz, 2H), 2.10–1.73 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 156.3, 151.1, 130.6, 129.8, 129.2, 126.9, 125.5, 123.8, 122.4, 119.9, 118.1, 112.6, 29.5, 28.5, 27.9,
25.97, 25.58; HRMS (ESI) calcd for C17H16BrO (M + H)+: 315.0379. Found: 315.0377.
2-Bromo-8,9,10,11,12,13-hexahydrocycloocta[b]naphtho[1,2-d]furan (7o). The title compound was obtained
1
as colorless oil (70%). H NMR (600 MHz, CDCl3)
δ
8.45 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H),
7.58 (d, J = 1.9 Hz, 2H), 7.51 (dd, J = 8.7, 1.9 Hz, 1H), 3.22–3.09 (m, 2H), 3.09–2.86 (m, 2H), 2.07–1.90 (m,
2H), 1.88–1.73 (m, 2H), 1.58 (d, J = 6.3 Hz, 2H), 1.52–1.40 (m, 2H);13C NMR (150 MHz, CDCl3)
δ
155.3,
151.7, 130.5, 129.7, 129.1, 127.1, 125.4, 123.6, 121.9, 120.0, 115.5, 112.8, 29.4, 27.9, 26.7, 26.0, 25.6, 23.2;
HRMS (ESI) calcd for C18H18BrO (M + H)+: 329.0536. Found: 329.0538.
3.2.3. Characterizations of Benzofuran 9 (Table 4)
1,2,3,4-Tetrahydrodibenzo[b,d]furan (9a) [39]. The title compound was obtained as colorless oil (68%),
1
and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ
7.42
(ddd, J = 5.7, 3.3, 1.1 Hz, 2H), 7.21 (pd, J = 7.2, 3.8 Hz, 2H), 2.76 (tt, J = 6.3, 1.8 Hz, 2H), 2.64 (tt, J = 6.0,
1.9 Hz, 2H), 2.04–1.92 (m, 2H), 1.92–1.79 (m, 2H); 13C NMR (150 MHz, CDCl3)
123.0, 122.1, 118.4, 112.9, 110.8, 23.46, 23.0, 22.7, 20.5.
δ 154.3, 154.0, 128.9,
6-Methyl-1,2,3,4-tetrahydrodibenzo[b,d]furan (9b). The title compound was obtained as colorless oil (76%).
1H NMR (600 MHz, CDCl3)
7.25 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H),
2.76 (ddd, J = 8.1, 4.1, 1.9 Hz, 2H), 2.62 (tt, J = 5.9, 1.8 Hz, 2H), 2.51 (s, 3H), 2.02–1.91 (m, 2H), 1.91–1.78
δ
(m, 2H); 13C NMR (150 MHz, CDCl3)
δ 152.6, 152.2, 127.3, 123.0, 121.1, 119.9, 114.8, 112.0, 22.5, 22.0,
21.7, 19.5, 14.0; HRMS (ESI) calcd for C13H15O (M + H)+: 187.1117. Found: 187.1121.
7-Methyl-1,2,3,4-tetrahydrodibenzo[b,d]furan (9c) [40]. The title compound was obtained as yellowish oil
1
(82%), and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ
7.28 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 0.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 2.81–2.68 (m, 2H), 2.61 (tt,
J = 5.9, 1.8 Hz, 2H), 2.46 (s, 3H), 2.01–1.90 (m, 2H), 1.90–1.77 (m, 2H); 13C NMR (150 MHz, CDCl3)
δ
153.7, 152.3, 131.9, 125.3, 122.3, 116.8, 111.6, 110.1, 22.4, 21.9, 21.7, 20.6, 19.5.
8-Methyl-1,2,3,4-tetrahydrodibenzo[b,d]furan (9d) [40]. The title compound was obtained as colorless oil
1
(72%), and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ
7.30 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 2.75 (ddd, J = 8.0, 4.1, 1.8 Hz, 2H), 2.62
(tt, J = 5.9, 1.8 Hz, 2H), 2.46 (s, 3H), 2.03–1.92 (m, 2H), 1.91–1.79 (m, 2H);13C NMR (150 MHz, CDCl3)
δ
154.1, 152.7, 131.5, 129.0, 124.0, 118.4, 112.6, 110.2, 23.5, 23.0, 22.8, 21.4, 20.5.

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6-Methoxy-1,2,3,4-tetrahydrodibenzo[b,d]furan (9e). The title compound was obtained as yellow oil (70%).
1H NMR (600 MHz, CDCl3)
7.11 (t, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.7, 0.9 Hz, 1H), 6.74 (dd, J = 7.9,
0.5 Hz, 1H), 4.00 (s, 3H), 2.84–2.69 (m, 2H), 2.69–2.52 (m, 2H), 1.99–1.89 (m, 2H), 1.89–1.78 (m, 3H);
δ
13C NMR (150 MHz, CDCl3)
δ 154.2, 145.0, 143.2, 130.5, 122.8, 113.2, 111.0, 105.5, 56.0, 23.4, 22.9, 22.7,
20.6; HRMS (ESI) calcd for C13H15O2 (M + H)+: 203.1067. Found: 203.1066.
8-Methoxy-1,2,3,4-tetrahydrodibenzo[b,d]furan (9f) [41]. The title compound was obtained as colorless oil
1
(71%), and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ
7.27 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.8, 2.6 Hz, 1H), 3.84 (s, 3H), 2.71 (ddd,
J = 6.2, 4.8, 1.7 Hz, 2H), 2.59 (tt, J = 5.8, 1.7 Hz, 2H), 2.00–1.89 (m, 2H), 1.89–1.77 (m, 2H); 13C NMR
(150 MHz, CDCl3) δ 154.6, 154.0, 148.2, 128.4, 112.0, 110.0, 109.9, 100.5, 54.9, 22.5, 21.9, 21.6, 19.5.
8-(tert-Butyl)-1,2,3,4-tetrahydrodibenzo[b,d]furan (9g). The title compound was obtained as colorless oil
1
(80%), and the analytical data are consistent with those in the literature. H NMR (600 MHz, CDCl3)
δ
7.39 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.27–7.24 (m, 1H), 2.75–2.69 (m, 2H), 2.63 (ddd, J = 7.7,
4.0, 1.8 Hz, 2H), 1.98–1.90 (m, 2H), 1.89–1.78 (m, 2H), 1.37 (s, 9H); 13C NMR (150 MHz, CDCl3)
151.4, 144.2, 127.4, 119.7, 113.5, 111.8, 109.0, 33.7, 30.9, 22.5, 22.0, 21.7, 19.5.
δ 153.1,
6-Benzyl-1,2,3,4-tetrahydrodibenzo[b,d]furan (9h). The title compound was obtained as yellowish oil
1
(85%). H NMR (600 MHz, CDCl3)
δ 7.35–7.27 (m, 5H), 7.24–7.19 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.98
(d, J = 7.3 Hz, 1H), 4.26 (s, 2H), 2.88–2.72 (m, 2H), 2.64 (tt, J = 5.8, 1.7 Hz, 2H), 2.06–1.92 (m, 2H), 1.87
(dtd, J = 9.0, 6.0, 2.8 Hz, 2H); 13C NMR (150 MHz, CDCl3)
δ
153.9, 152.8, 140.5, 129.0, 128.7, 128.39,
126.0, 124.2, 123.6, 122.4, 116.4, 113.1, 77.3, 77.1, 76.9, 35.5, 23.6, 23.0, 22.7, 20.6; HRMS (ESI) calcd for
C19H19O (M + H)+: 263.1430. Found: 263.1433.
2,3-Dimethylbenzofuran (9i) [30]. The title compound was obtained as yellow oil (73%), and the analytical
data are consistent with those in the literature. 1H NMR (600 MHz, CDCl3)
δ 7.48–7.39 (m, 1H),
7.39–7.32 (m, 1H), 7.23–7.15 (m, 2H), 2.38 (d, J = 0.6 Hz, 3H), 2.16 (d, J = 0.7 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 152.8, 149.4, 129.4, 122.0, 120.9, 117.5, 109.4, 108.7, 10.8, 6.9.
2,3,5-Trimethylbenzofuran (9j) [30]. The title compound was obtained as colorless oil (81%), and the
analytical data are consistent with those in the literature. 1H NMR (600 MHz, CDCl3)
δ 7.23 (d,
J = 8.3 Hz, 1H), 7.18 (s, 1H), 7.00 (dd, J = 8.2, 1.3 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 2.12 (s, 3H); 13
NMR (150 MHz, CDCl3) δ 152.2, 150.6, 131.3, 130.5, 124.1, 118.5, 109.9, 109.4, 21.7, 11.8, 7.9.
C
1
5-Methoxy-2,3-dimethylbenzofuran (9k). The title compound was obtained as yellow oil (77%). H NMR
(600 MHz, CDCl3)
δ 7.25 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.8, 2.6 Hz, 1H), 3.85
(s, 3H), 2.36 (s, 3H), 2.12 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 154.5, 150.4, 147.7, 130.0, 110.0, 109.7,
108.8, 100.6, 54.9, 10.9, 7.0; HRMS (ESI) calcd for C11H13O2 (M + H)+: 177.0910. Found: 177.0909.
4. Conclusions
In conclusion, we have found that titanium tetrachloride can act as an efficient Lewis acid
catalyst and a strong dehydrating agent to promote the regioselective Friedel–Crafts-like alkylation
and subsequent intramolecular cyclodehydration. This process provides a general method for the
preparation of a wide range of naphthofurans and benzofurans from readily available phenols and
α-haloketones.
Supplementary Materials: The following are available online. The NMR spectra for all the synthesized
compounds.
Author Contributions: Data Curation, B.W., Q.Z., and Q.T.; Writing—Original Draft Preparation, Q.T.;
Writing—Review and Editing, J.L. and Q.T.; Project Administration, Q.T., Z.G., and W.J.

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Funding: This research was funded by the Fundamental and Advanced Research Projects of Chongqing City,
China (No. cstc2018jcyjA0150).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
Dawood, K.M. Benzofuran derivatives: A patent review. Expert Opin. Ther. Pat. 2013, 23, 1133–1156.
[CrossRef] [PubMed]
Boto, A.; Alvarez, L. Furan and its derivatives.
In Heterocycles in Natural Product Synthesis;
Wiley-VCHVerlagGmbH&Co.KGaA: Weinheim, Germany, 2011; pp. 97–152.
Smith, D.T.; Vitaku, E.; Njardarson, J.T. Dearomatization approach to 2-trifluoromethylated benzofuran and
dihydrobenzofuran products. Org. Lett. 2017, 19, 3508–3511. [CrossRef] [PubMed]
Radadiya, A.; Shah, A. Bioactive benzofuran derivatives: An insight on lead developments, radioligands
and advances of the last decade. Eur. J. Med. Chem. 2015, 97, 356–376. [CrossRef] [PubMed]
Srivastava, V.; Negi, A.S.; Kumar, J.K.; Faridi, U.; Sisodia, B.S.; Darokar, M.P.; Luqman, S.; Khanuja, S.P.S.
Synthesis of 1-(30,40,50-trimethoxy) phenyl naphtho[2,1b]furan as a novel anticancer agent. Bioorg. Med.
Chem. Lett. 2006, 16, 911–914. [CrossRef] [PubMed]
6.
7.
Mathiyazhagan, K.; Kumaran, A.; Arjun, P. Isolation of natural naphthoquinones from juglans regia and
in vitro antioxidant and cytotoxic studies of naphthoquinones and the synthetic naphthofuran derivatives.
Russ. J. Bioorg Chem 2018, 44, 346–353. [CrossRef]
Kumar, A.; Srivastava, G.; Srivastava, S.; Verma, S.; Negi, A.S.; Sharma, N. Investigation of naphthofuran
moiety as potential dual inhibitor against BACE-1 and GSK-3β: Molecular dynamics simulations,
binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer’s disease.
J. Mol. Model. 2017, 16, 911–914. [CrossRef]
8.
9.
Cozza, G.; Sarno, S.; Ruzzene, M.; Girardi, C.; Orzeszko, A.; Kazimierczuk, Z.; Zagotto, G.; Bonaiuto, E.;
Di Paolo, M.L.; Pinna, L.A. Exploiting the repertoire of CK2 inhibitors to target DYRK and PIM kinases.
Biochim. Et Biophys. Acta Proteins Proteom. 2013, 1834, 1402–1409. [CrossRef]
Le Guével, R.; Oger, F.; Lecorgne, A.; Dudasova, Z.; Chevance, S.; Bondon, A.; Barath, P.; Simonneaux, G.;
Salbert, G. Identification of small molecule regulators of the nuclear receptor HNF4α based on naphthofuran
scaffolds. Biorg. Med. Chem. 2009, 17, 7021–7030. [CrossRef]
10. Phan, P.-T.T.; Nguyen, T.-T.T.; Nguyen, H.-N.T.; Le, B.-K.N.; Vu, T.T.; Tran, D.C.; Pham, T.-A.N. Synthesis
and bioactivity evaluation of novel 2-salicyloylbenzofurans as antibacterial agents. Molecules 2017, 22, 687.
[CrossRef]
11. Ma, Y.; Zheng, X.; Gao, H.; Wan, C.; Rao, G.; Mao, Z. Design, synthesis, and biological evaluation of novel
benzofuran derivatives bearing N-aryl piperazine moiety. Molecules 2016, 21, 1684. [CrossRef]
12. Kotoku, N.; Higashimoto, K.; Kurioka, M.; Arai, M.; Fukuda, A.; Sumii, Y.; Sowa, Y.; Sakai, T.; Kobayashi, M.
Xylarianaphthol-1, a novel dinaphthofuran derivative, activates p21 promoter in a p53-independent manner.
Bioorg. Med. Chem. Lett. 2014, 24, 3389–3391. [CrossRef] [PubMed]
13. Lumb, J.-P.; Trauner, D. Biomimetic synthesis and structure elucidation of rubicordifolin, a cytotoxic natural
product from rubia cordifolia. J. Am. Chem. Soc. 2005, 127, 2870–2871. [CrossRef] [PubMed]
14. Moldoveanu, C.; Mangalagiu, I.; Isac, D.L.; Airinei, A.; Zbancioc, G. A new pathway for the synthesis of a
new class of blue fluorescent benzofuran derivatives. Molecules 2018, 23, 1968. [CrossRef] [PubMed]
15. Chen, Q.; Jiang, P.; Guo, M.; Yang, J. Synthesis of new 2-arylbenzo[b]furan derivatives via palladium-catalyzed
Suzuki cross-coupling reactions in aqueous media. Molecules 2018, 23, 2450. [CrossRef] [PubMed]
16. Bai, W.-J.; Xie, J.-H.; Li, Y.-L.; Liu, S.; Zhou, Q.-L. Enantioselective synthesis of chiral β-aryloxy alcohols by
ruthenium-catalyzed ketone hydrogenation via dynamic kinetic resolution (DKR). Adv. Synth. Catal. 2010
,
352, 81–84. [CrossRef]
17. Ando, K.; Kawamura, Y.; Akai, Y.; Kunitomo, J.-I.; Yokomizo, T.; Yamashita, M.; Ohta, S.; Ohishi, T.; Ohishi, Y.
Preparation of 2-, 3-, 4- and 7-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans and their BLT1 and/or BLT2
inhibitory activities. Org. Biomol. Chem. 2008, 6, 296–307. [CrossRef] [PubMed]
18. Zhang, Q.; Luo, J.; Wang, B.; Xiao, X.; Gan, Z.; Tang, Q. Titanium tetrachloride promoted cyclodehydration of
aryloxyketones: Facile synthesis of benzofurans and naphthofurans with high regioselectivity. Tetrahedron
Lett. 2019, 60, 1337–1340. [CrossRef]

Molecules 2019, 24, 2187
14 of 15
19. Wang, Z.; Gu, J.; Jing, H.; Liang, Y. Novel one-pot synthesis of 3-phenylnaphtho[2,3-b]furan and
3-phenylbenzofurans under microwave irradiation and solvent-free conditions. Synth. Commun. 2009, 39,
4079–4087. [CrossRef]
20. Wang, H.-S.; Chan, C.-K.; Chang, M.-Y. Ga(OTf)3-mediated synthesis of substituted benzofurans. Tetrahedron
2016, 72, 5132–5141. [CrossRef]
21. Erian, A.; Sherif, S.; Gaber, H. The chemistry of
Molecules 2003, 8, 793. [CrossRef]
22. Arias, L.; Vara, Y.; Cossío, F.P. Regioselective preparation of benzo[b]furans from phenols and α
J. Org. Chem. 2012, 77, 266–275. [CrossRef] [PubMed]
23. Kubota, Y.; Satake, K.; Okamoto, H.; Kimura, M. Electrophilic behavior of the
α
-haloketones and their utility in heterocyclic synthesis.
-bromoketones.
delocalized azepinium
π
ion: Friedel–Crafts reactions with benzenes and five-membered aromatic heterocycles. Org. Lett. 2005, 7,
5215–5218. [CrossRef] [PubMed]
24. Satake, K.; Kubota, Y.; Cordonier, C.E.J.; Okamoto, H.; Kimura, M. Synthesis of a delocalized azepinium ion
and investigation of its electrophilic character. Angew Chem. Int. Ed. 2004, 43, 736–738. [CrossRef] [PubMed]
25. Luo, J.; Lu, D.; Peng, Y.; Tang, Q. Paal-Knorr furan synthesis using titanium tetrachloride as dehydrating
agent: A concise furan synthesis from α-haloketones and β-dicarbonyl compounds. Asian J. Org. Chem.
2017, 6, 1546–1550. [CrossRef]
26. Luo, J.; Zhou, H.; Hu, J.; Wang, R.; Tang, Q. Efficient catalytic-free method to produce alpha-aryl
cycloalkanones through highly chemoselective coupling of aryl compounds with oxyallyl cations. RSC Adv.
2014, 4, 17370–17377. [CrossRef]
27. Tang, Q.; Chen, X.; Tiwari, B.; Chi, Y.R. Addition of indoles to oxyallyl cations for facile access to α-indole
carbonyl compounds. Org. Lett. 2012, 14, 1922–1925. [CrossRef] [PubMed]
28. Laskovics, F.M.; Schulman, E.M. Mechanism of the reaction of hexachloroacetone with enamines. A new,
convenient synthesis of .alpha.-chloro ketones, .beta.-chloro enamines, and allylic chloro enamines. J. Am.
Chem Soc. 1977, 99, 6672–6677. [CrossRef]
29. Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. A mild and efficient procedure for
alpha-bromination of ketones using N-bromosuccinimide catalysed by ammonium acetate. Chem. Commun.
2004, 470–471. [CrossRef] [PubMed]
30. Fu, R.; Li, Z. Direct synthesis of 2-methylbenzofurans from calcium carbide and salicylaldehyde
p-tosylhydrazones. Org. Lett. 2018, 20, 2342–2345. [CrossRef]
31. Yamamoto, Y.; Matsui, K.; Shibuya, M. A combined experimental and computational study on the
cycloisomerization of 2-ethynylbiaryls catalyzed by dicationic arene ruthenium complexes. Chem. A
Eur. J. 2015, 21, 7245–7255. [CrossRef]
32. Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D. Palladium-catalyzed synthesis of benzofurans and
coumarins from phenols and olefins. Angew Chem. Int. Ed. 2013, 52, 12669–12673. [CrossRef] [PubMed]
33. Mishra, A.K.; Biswas, S. Brønsted acid catalyzed functionalization of aromatic alcohols through Nnucleophilic
substitution of hydroxyl group. J. Org. Chem. 2016, 81, 2355–2363. [CrossRef] [PubMed]
34. Li, W.-T.; Nan, W.-H.; Luo, Q.-L. Metal-free sequential reaction via a propargylation, annulation and
isomerization sequence for the one-pot synthesis of 2,3-disubstituted benzofurans. Rsc Adv. 2014, 4,
34774–34779. [CrossRef]
35. Liu, Z.; Liu, L.; Shafiq, Z.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. InCl3-catalyzed propargylation of indoles and
phenols with propargylic acetates: Application to the syntheses of benzofurans and naphthofurans. Synthesis
2007, 2007, 1961–1969. [CrossRef]
36. Lee, D.-H.; Kwon, K.-H.; Yi, C.S. Dehydrative C–H alkylation and alkenylation of phenols with alcohols:
Expedient synthesis for substituted phenols and benzofurans. J. Am. Chem. Soc. 2012, 134, 7325–7328.
[CrossRef] [PubMed]
37. Ghosh, M.; Santra, S.; Mondal, P.; Kundu, D.; Hajra, A. Diversified synthesis of furans by coupling between
enols/1,3-dicarbonyl compounds and nitroolefins: Direct access to dioxa[5]helicenes. Chem. Asian J. 2015, 10,
2525–2536. [CrossRef]
38. Orovecz, O.; Kovács, P.; Kolonits, P.; Kaleta, Z.; Párkányi, L.; Szabó, É.; Novák, L. Rearrangement of allyl aryl
ethers; VI: Reaction of naphthols with cycloalkadienes. Synthesis 2003, 2003, 1043–1048.
39. Gao, H.; Xu, Q.-L.; Keene, C.; Kürti, L. Scalable, Transition-metal-free direct oxime O-arylation: Rapid access
to O-arylhydroxylamines and substituted benzo[b]furans. Chem. A Eur. J. 2014, 20, 8883–8887. [CrossRef]

Molecules 2019, 24, 2187
15 of 15
40. Alemagna, A.; Baldoli, C.; Del Buttero, P.; Licandro, E.; Maiorana, S. Nucleophilic aromatic substitution on
tricarbonylchromium-complexed haloarenes: Synthesis of O-aryloximes and their cyclization to benzofurans.
Synthesis 1987, 1987, 192–196. [CrossRef]
41. Yagoubi, M.; Cruz, A.C.F.; Nichols, P.L.; Elliott, R.L.; Willis, M.C. Cascade palladium-catalyzed direct
intramolecular arylation/alkene isomerization sequences: Synthesis of indoles and benzofurans. Angew Chem.
Int. Ed. 2010, 49, 7958–7962. [CrossRef]
Sample Availability: All data generated and/or compound samples analyzed during this study are included in
this article and are available from the corresponding author on reasonable request.
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