Sequential One-Pot Synthesis of 3-Arylbenzofurans from N-Tosylhydrazones and Bromophenol Derivatives

N ‑Tosylhydrazones and Bromophenol Derivatives

Article

Sequential One-Pot Synthesis of 3‑Arylbenzofurans from

Diana Lamaa, Camille Hauguel, Hsin-Ping Lin, Estelle Messe, Vincent Gandon, Mouad Alami,*

and Abdallah Hamze*

Cite This: https://dx.doi.org/10.1021/acs.joc.0c01835

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ABSTRACT: A divergent and eﬃcient one-pot sequence allowing direct access to 3-arylbenzofuran derivatives has been developed.

cross-coupling,

The process, involving N-tosylhydrazones and bromophenols, proceeds via a palladium-catalyzed Barluenga−Valdes

followed by an aerobic, copper-catalyzed, radical cyclization to form Csp −Csp and O−Csp bonds. 3-Arylated benzofurans bearing

various substituents were obtained with good to excellent yields (up to 90%). Mechanistic investigation strongly supports a radical

process for the cyclization step.

INTRODUCTION

however, bulky derivatives tend to rearrange into the 2-

■

substituted isomer. Copper(II) acetate and 8-hydroxyquino-

line are eﬃcient to promote the formation of 3-phenyl-

benzofurans from 2-hydroxyacetophenones and dimethylace-

The benzofuran skeleton constitutes an essential class of

compounds and is widely present in many pharmaceuticals,

biologically active compounds, and natural products. For

instance, the related drugs amiodarone and dronedarone

showing antiarrhythmic eﬀects, liﬁtegrast, a recently FDA-

approved drug for the treatment of keratoconjunctivitis sicca

dry eye syndrome), methoxsalen, a naturally occurring

furocoumarin compound found in several species of plants

including Psoralea corylifolia, showing activity in case of

psoriasis and vitiligo, vilazodone, a novel active compound

combining high-aﬃnity and selectivity for the 5-hydroxytrypt-

tamide (DMA). 2-Hydroxy-arylstyrenes were also used to

obtain the corresponding benzofurans in moderate to good

yields. Maiti et al. developed a Pd-catalyzed intermolecular

annulation of cinnamic acids and phenols for the selective

(

synthesis of 3-substituted benzofurans (Scheme 1). Anbar-

asan et al. reported a cobalt(III)-catalyzed intramolecular

cross-dehydrogenative C−H/O−H coupling of ortho-alkenyl-

phenols using O as an oxidant. Finally, the C3-selective

direct C−H activation of benzofurans has been rarely achieved

amine (5-HT) transporter and 5-HT(1A) receptors and

indicated for the treatment of the major depressive disorder, all

display a benzofuran core (Figure 1).

because, in addition to obtaining mixtures of C2 and C3

isomers, low to modest yields were observed.

Consequently, there is considerable interest from the

synthetic organic point of view to obtain the 3-arylbenzofuran

motif by eﬃcient methodologies. In the past decade, N-

tosylhydrazones (NTH) have been well recognized as powerful

Over recent years, many eﬀective strategies, including

heteroannulation and transition-metal-catalyzed reactions,

have been described for the synthesis of 2-arylbenzofurans or

polysubstituted benzofurans. However, and contrary to the 2-

arylated benzofuran derivatives, only a few methods for the

synthesis of 3-arylbenzofurans 3 (Scheme 1) are known in the

literature. Some of these synthetic strategies are shown in

Scheme 1.

cross-coupling partners for several transformations, especially

Received: July 30, 2020

A typical method involves the Suzuki cross-coupling starting

from 3-brominated benzofurans or the Larock coupling

between 2-iodophenols and internal alkynes. Zeolite-catalyzed

direct cyclization of α-aryloxyketones is also a notable strategy;

XXXX American Chemical Society

The Journal of Organic Chemistry

J. Org. Chem. XXXX, XXX, XXX−XXX

Article

Figure 1. Approved drugs containing the benzofuran moiety.

Scheme 1. Synthesis of 3-Arylbenzofuran Derivatives

Table 1. Optimization of the Reaction Conditions for Pd-Catalyzed Coupling of NTH and Bromophenol

entry

[Pd]

[L]

solvent

yield (%)

Pd(OAc)₂

Pd dba ·CHCl

Xphos

Sphos

8-HQ

dioxane

DMF

toluene

DMA

dioxane

toluene

dioxane

Pd dba ·CHCl

CuOAc

Reaction conditions: NTH 1a (1.5 mmol), 2-bromophenol 2a (1 mmol), [Pd] source (5 mol %), ligand (10 mol %), base (1.6 mmol), solvent

(

5.0 mL), sealed tube, 100 °C, and 3 h. nd: not detected.

their application as metal carbene precursors in the eﬃcient

construction of carbon−carbon and carbon−heteroatom

bonds. It is still highly desirable to explore NTH as

substrates to enable the concise preparation of complex

molecules, leading to crucial molecular diversity. Herein, we

present a one-pot approach to access a series of 3-

arylbenzofurans from NTHs and bromophenol derivatives.

RESULTS AND DISCUSSION

■

Before optimizing the one-pot sequence of this transformation,

initial studies were devoted to ﬁnding the best conditions for

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Article

each step: the formation of the C−C and then the C−O bond.

Thus, we began our investigations by studying the cross-

coupling between NTH derivative 1a and bromophenol 2a.

The challenge of this coupling was to ﬁnd optimal conditions

that tolerate the presence of free phenol, since NTH could

react with alcohols or phenols, leading to the corresponding

ethers. As a consequence, to avoid the formation of an ether

bond, we ﬁrst prepared the NTH salt and then realized the

coupling with the bromophenol partner (Table 1). Coupling

reaction in dry DMA reduced the yield to 33% (entry 2).

On the other hand, adding a controlled amount of 40 equiv of

H O to the reaction medium promoted a signiﬁcant increase of

the yield to 77% (entry 3). Screening of diﬀerent solvents

revealed that the best yield was obtained in toluene or dioxane

in the presence of 40 equiv of H O (entries 4 and 5).

Then, a variety of reaction conditions were screened to show

the importance of each parameter of this copper catalyst

system (entries 6−10). Surprisingly, the results of the control

experiments showed that the formation of the benzofuran ring

could occur in the absence of ligand and base (entries 6 and 7).

However, no formation of the desired compound 4a was

observed when the reaction was performed without a copper

source (entry 8). It is important to note that dioxygen also

plays an important role in this process, with a dramatic

decrease in the yield when the reaction was carried out under

conditions using Pd(OAc) as a palladium source and XPhos

as a ligand in dioxane led to the desired product 3a in a

moderate 55% yield. The reaction with a catalyst based on the

Sphos ligand exhibited better eﬃciency, the 1,1-diarylethylene

product being obtained in a 67% yield (entry 2). Changing

dioxane for other solvents such as dimethylformamide (DMF),

toluene, or DMA led to a dramatic decrease of the yield

N (entry 9). Finally, we rechecked the role of water in this

(

entries 3−5). Next, we turned our attention to the palladium

transformation, and we observed a signiﬁcant decrease in the

yield when the reaction was carried out in dry toluene (entry

source, and we observed a signiﬁcant improvement of the yield

to 95% using Pd dba ·CHCl instead of Pd(OAc) in dioxane

0).

(

entry 6). In toluene, the product was isolated in a 50% yield

Based on these interesting results (Tables 1 and 2), we

using the same catalytic system (entry 7). Performing the

reaction in the presence of a copper catalyst did not aﬀord the

desired compound 3a.

attempted the one-pot sequential reaction to form the 3-

arylbenzofuran 4a starting from NTH 1a and bromophenol 2a

(

Table 3). Contrary to our expectations, performing the

Next, we turned our attention to the cyclization reaction to

form the benzofuran derivatives. For this purpose, we have ﬁrst

treated the 2-hydroxyarylstyrene 3a under the conditions

reaction sequence under the best-obtained conditions: dioxane

for the ﬁrst step (solvent 1), then H O 40 equiv (solvent 2) for

the second step, aﬀorded a low yield unfortunately (entry 1).

As the cyclization step worked better in toluene, we tried to

add toluene as a cosolvent: dioxane/toluene 1:2 V/V (entry

developed by Dominguez et al.: Cu(OAc) (50 mol %), O ,

and 8-hydroxyquinoline (8-HQ) at 140 °C for 24 h (Table 2,

entry 1).

Under these standard conditions, the desired product 4a was

obtained in a moderate 50% yield, which is incompatible with

the development of a one-pot reaction. Performing the

2), but again a low yield of 4a was obtained. Inversion of the

ratio between dioxane and toluene (dioxane/toluene 2:1)

provided a slight increase in the yield (entry 3). This

observation led us to conduct the ﬁrst step of the coupling

(

C−C bond formation) only in anhydrous dioxane, and we

Table 2. Optimization of the Cyclization Step

added toluene for the second step with a ratio of dioxane/

toluene of 2:1 (entries 4−5).

Without the addition of water for the second step, the

reaction was not totally completed (entry 4), whereas the

addition of 40 equiv of H O resulted in a 90% isolated yield

(

entry 5).

With the optimized conditions in hand, the generality of this

sequential one-pot reaction was examined using a series of

NTHs 1 and diﬀerent 2-hydroxy-bromoaryls 2 (Scheme 2).

Gratifyingly, the reaction works eﬃciently, aﬀording the

coupling products in good to high yields (46−90%). The Pd/

Cu system catalyzes the coupling of 2-hydroxybromophenol 2a

using neutral (4a, 4b), electron-rich (4c−4e), and -deﬁcient

(4f−4g) NTHs. In addition, this transformation tolerates the

coupling of heterocyclic NTHs, aﬀording the corresponding

products in good yields (compounds 4h−i).

Encouraged by these results, we further examined the

substrate scope with respect to the bromophenol. Thus, we

explored modiﬁcations on the electrophilic partner 2. It should

be noted that the reaction proceeded successfully when using

bromophenols bearing electron-donating groups (compounds

entry ligand

base

solvent

DMA

anhyd DMA

DMA

dioxane

toluene

additive

yield (%)

8-HQ

K CO

H O 40 equiv

K CO

j−o). Lastly, we were interested in the application of this

All of the reactions were carried out in a sealed tube using 3a (1

mmol), CuOAc (50 mol %), 8-HQ (50 mol %), K CO (1 mmol),

method to the synthesis of benzofuran 4a in a millimole

quantity. Performing the reaction in a large sealed tube under

the standard conditions aﬀorded compound 4a in a 62% yield

(Scheme 2).

and solvent (5 mL). Isolated yield. 8-Hydroxyquinoline. Reaction

in the presence of 20 and 60 equiv of H O gave 66 and 76% yields,

respectively. A low yield (25%) was obtained when the reaction was

performed in toluene without the addition of water. The reaction was

In addition, bromophenols with diﬀerent R²electron-

withdrawing substituents underwent the reaction to aﬀord

the desired compounds (4p−r) in good yields (52−72%). Our

carried out without CuOAc. The reaction was degassed with N₂

(

without O₂).

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Table 3. Optimization of the Sequential One-Pot Reaction: Formation of Csp −Csp and then O−Csp Bonds

entry

solvent 1

dioxane

dioxane/toluene (1:2)

dioxane/toluene (2:1)

anhyd. dioxane

solvent 2

yield

H O 40 equiv

46%

25%

35%

42%

90%

H O 40 equiv

dioxane/toluene = 2:1

dioxane/toluene = 2:1 + H O (40 equiv)

anhyd. dioxane

Reaction conditions: In a sealed tube, NTH 1a (0.6 mmol), NaH (0.64 mmol), and solvent 1 (2.5 mL) were reacted at RT for 1 h; then, 2-

bromophenol 2a (0.4 mmol), Pd dba ·CHCl (5 mol %), and Sphos (10 mol%) were added and heated at 100 °C for 3 h. After completion of the

ﬁrst step, solvent 2, CuOAc (50 mol %), was added under O at 140 °C for 24 h. Isolated yield. In the absence of copper, 4a was not detected.

standard conditions were used to realize the coupling between

NTH derived from 2-phenylacetophenone (Scheme 3). The

ﬁrst coupling led to a mixture of the E/Z isomer with a 60/40

ratio. Only the E-isomer undergoes cyclization, and the

diphenylbenzofuran derivative 4s was obtained in a 30%

yield (Scheme 3).

give radical B. The latter is oxidized by Cu(II) into

carbocation C, which is deprotonated by a hydroxide to

furnish the ﬁnal product 4a.

We believe that our method can be used to obtain other

functionalized 3-arylbenzofurans and will contribute to the

discovery of new biologically active compounds.

Mechanism. While the ﬁrst step of this one-pot sequence

In summary, we have developed a sequential palladium/

copper synthesis of a library of 3-arylbenzofuran derivatives.

14,15

has a well-established mechanism (Scheme 4),

the nature

of the second step was not obvious. As previously

demonstrated in Table 1, there is no need for a ligand or a

base, but O and H O are required to reach a good yield, and

of course, CuOAc (50 mol %) is indispensable in all cases.

The formation of a copper vinylidene under such conditions

is unlikely. The reaction did not work with a methyl group

installed at the oxygen atom or at the terminal alkene carbon of

This one-pot reaction associates a Barluenga−Valdes

cross-

coupling, followed by a radical cyclization, leading to the

formation of Csp −Csp and O−Csp bonds. This method,

based on simple starting materials, tolerates various functional

groups. From the mechanistic point of view, this one-pot

sequence associates a transition-metal-catalyzed reaction with

an aerobic cyclization that is not disrupted by the presence of

the cross-coupling catalytic mixture.

a. Besides, we could not trap the carbene with TMSN , which

is a known vinylidene scavenger (Scheme 4, eq 1).

Interestingly, in the presence of TMSN , the methyl-

substituted substrate 3s transformed into ketone 6s (eq 2).

EXPERIMENTAL SECTION

■

General Methods. Melting points (mp) were uncorrected.

Such aerobic oxidation of terminal oleﬁns using TMSN as a

Solvent peaks were used as reference values with CDCl

at 7.26

reagent and TEMPO as a catalyst has been reported. In this

case, the mechanism involves the formation of free radicals and

ppm for H NMR and 77.16 ppm for C NMR, with DMSO at 2.50

ppm for H NMR and 39.52 ppm for C NMR, with CD CN at 1.94

their reaction with O to give peroxide radical intermediates.

ppm for H NMR, and 1.79, 118.26 ppm for C NMR, with

This led us to consider that perhaps TEMPO could also

catalyze the cyclization of 3a into 4a. In the absence of

(CD ) CO at 2.05 ppm for H NMR, and 29.84 and 206.26 ppm for

C NMR. Chemical shifts δ are given in ppm, and the following

TMSN , and under similar reaction conditions as those

disclosed with copper, 4a was indeed obtained in a 63%

yield (eq 3).

abbreviations are used: singlet (s), doublet (d), doublet of doublet

(dd), triplet (t), quadruplet (q), and multiplet (m). High-resolution

mass spectra were recorded on a Microtof-Q II. Reaction courses and

product mixtures were routinely monitored by TLC on a silica gel,

and compounds were visualized under a UVP Mineralight UVGL-58

lamp (254 nm) and with phosphomolybdic acid/Δ, or vanillin/Δ.

Flash chromatography was performed using silica gel 60 (40−63 mm,

The catalytic cycle postulated for this coupling (Scheme 5,

the top part) starts with the oxidative addition of the

bromophenol 2a to the Pd(0) to give the aryl−Pd complex

I. Then, the reaction of the diazo compound II (generated by

decomposition of NTH 1a in the presence of the base) with I

led to the formation of Pd−carbene complex III. The latter

complex III evolves through the migratory insertion of the

carbene and produces the alkyl−Pd complex IV. At the end of

this ﬁrst cycle, β-hydride elimination provides the oleﬁn 3a.

The results obtained in Scheme 4 strongly support a radical

mechanism, summarized in Scheme 5 (lower part).

30−400 mesh) at medium pressure (200 mbar). Dioxane was

distilled over CaH . Other solvents were used as received. N-

Tosylhydrazones were prepared according to the literature procedure.

Pd (dba) ·CHCl was prepared according to the literature proce-

dure. All products reported showed H and C NMR spectra in

agreement with the assigned structures.

General Procedure for the Synthesis of Benzofuran from

the One-Pot Reaction (Method A). To a solution in a sealed tube

of N-tosylhydrazone (0.6 mmol) in distilled dioxane (5.0 mL/mmol)

was added NaH (0.96 mmol). This resulting suspension was stirred at

rt for one hour; 2-bromophenol (0.4 mmol), Pd dba CHCl (5 mol

In the presence of O and H O, the copper(I) salt generates

hydroxyl radicals and hydroxides, while being oxidized into

Cu(II). Compound 3a reacts with a hydroxyl radical to give

phenoxyl radical A, which undergoes 5-endo-trig cyclization to

%), and Sphos (10 mol %) were added. The mixture was then heated

at 100 °C for 3 h in an oil bath. The reaction mixture was allowed to

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

Scheme 2. Sequential One-Pot Reaction of NTH 1 and Bromophenol 2: Substrate Scope

Reaction was performed using 2 mmol of 2-bromophenol and NTH. Conditions: step 1: in a sealed tube, NTH 1 (0.6 mmol), bromophenol 2

0.4 mmol), Pd dba ·CHCl (5 mol %), Sphos (10 mol %), and NaH (0.64 mmol) were added in dry dioxane (2.5 mL); step 2: after cooling,

(

CuOAc (50 mol %), toluene 1 mL, and H O (40 equiv) were added under O and the mixture was heated at 140 °C for 24 h.

−

cool to rt. Then, toluene (2.5 mL/mmol), copper(I) acetate (0.2

heptane, 5/95, SiO ); IR (ﬁlm, cm ) 2926, 2854, 1606, 1577, 1491,

mmol), and H O (40 equiv) were added. Oxygen was then bubbled

1451, 1260, 1218, 1153, 1108, 1092, 962, 743; H NMR (300 MHz,

into the reaction mixture, which was later allowed to stir at 140 °C for

CDCl ) δ 7.86 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.66 (d, J = 6.6 Hz,

4 h in an oil bath. The reaction mixture was cooled to room

2H), 7.56 (d, J = 7.1 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.41−7.30 (m,

temperature and ﬁltered through Celite. The solvent was evaporated

under reduced pressure, and the crude product was puriﬁed by ﬂash

chromatography on a silica gel.

3H); C NMR (75 MHz, CDCl ) δ 155.9 (C), 141.4 (CH), 132.2

(C), 129.1 (2CH), 127.7 (2CH), 127.6 (CH), 126.6 (C), 124.7

(CH), 123.1 (CH), 122.4 (C), 120.5 (CH), 111.92 (CH); HRMS

−

-Phenylbenzofuran (4a). 4a was prepared according to method

(ESI) for C H O (M − H) calcd 193.0653, found 193.0656.

A; column chromatography on a silica gel aﬀorded 70 mg of the

Synthesis of 3-Phenylbenzofuran (4a) on a 2 mmol Scale.

desired compound as a colorless oil, yield 90%; R = 0.8 (EtOAc/

To a solution in a sealed tube of N-tosylhydrazone (3 mmol, 865 mg)

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Article

Scheme 3. Coupling of 2-Bromophenol with NTH Derived from 2-Phenylacetophenone: Access to 2,3-Disubstituted

Benzofurans

Scheme 4. Mechanistic Investigation

in distilled dioxane (15.0 mL) was added NaH (4.8 mmol). This

resulting suspension was stirred at rt for one hour; 2-bromophenol (2

mmol, 342 mg), Pd dba CHCl (5 mol %, 103.5 mg), and Sphos (10

mol %, 82 mg) were added. The mixture was then heated at 100 °C

for 3 h in an oil bath. The reaction mixture was allowed to cool to rt.

Then, toluene (7.5 mL), copper(I) acetate (1 mmol, 122 mg), and

3-(p-Tolyl)benzofuran (4c). 4c was prepared according to

method A; column chromatography on a silica gel aﬀorded 50 mg

of the desired compound as a yellow oil, yield 60%; R

= 0.7 (EtOAc/

); IR (ﬁlm, cm ) 2919, 1575, 1541, 1508, 1453,

−

heptane, 5/95, SiO

340, 1109, 1091, 964, 746; H NMR (400 MHz, CDCl ) δ 7.84 (dd,

J =1.2, 7.2 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J = 8.0 Hz, 3H), 7.37−7.28

m, 4H), 2.42 (s, 3H); C{ H} NMR (101 MHz, CDCl ) δ 155.9

C), 141.2 (CH), 137.4 (C), 129.8 (2CH), 129.2 (C), 127.5 (2CH),

26.7 (C), 124.6 (CH), 123.0 (CH), 122.3 (C), 120.6 (CH), 111.9

(

H O (40 equiv) were added. Oxygen was then bubbled into the

(

reaction mixture, which was later allowed to stir at 140 °C for 24 h in

an oil bath. The reaction mixture was cooled to room temperature

and ﬁltered through Celite. The solvent was evaporated under

reduced pressure, and the crude product was puriﬁed by ﬂash

chromatography on a silica gel to aﬀord 240 mg of compound 4a as a

colorless oil, yield 62%.

(

CH), 21.4 (CH ); HRMS (ESI) for C H O (M + H) calcd

15 13

09.0961, found 231.0960.

-(3,5-Dimethoxyphenyl)benzofuran (4d). 4d was prepared

according to method A; column chromatography on a silica gel

aﬀorded 78 mg of the desired compound as a yellow oil, yield 77%; R

-(Naphthalen-2-yl)benzofuran (4b). 4b was prepared accord-

−1

0.4 (EtOAc/heptane, 1/9, SiO ); IR (ﬁlm, cm ) 2838, 1608, 1597,

ing to method A; column chromatography on a silica gel aﬀorded 71

453, 1359, 1267, 1205, 1155, 1110, 1096, 746; H NMR (300 MHz,

CDCl ) δ 7.86 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H), 7.56 (d, J = 8.3 Hz,

H), 7.39−−7.29 (m, 2H), 6.81 (d, J = 2.3 Hz, 2H), 6.51 (s, 1H),

3.87 (s, 6H); C{ H} NMR (75 MHz, CDCl ) δ 161.4 (2C), 155.9

C), 141.7 (CH), 134.0 (C), 126.6 (C), 124.7 (CH), 123.1 (CH),

22.5 (C), 120.6 (CH), 111.9 (CH), 105.9 (2CH), 99.7 (CH), 55.6

mg of the desired compound as a colorless oil, yield 73%; R = 0.81

−

(

EtOAc/heptane, 5/95, SiO ); IR (ﬁlm, cm ) 2955, 2867, 1603,

589, 1499, 1443, 1245; H NMR (300 MHz, CDCl ) δ 8.17 (s, 1H),

13 1

.05−7.87 (m, 5H), 7.78 (dd, J = 8.4, 1.7 Hz, 1H), 7.67−7.60 (m,

(

H), 7.60−7.50 (m, 2H), 7.46−7.35 (m, 2H). C NMR (75 MHz,

CDCl ) δ 155.9 (C), 141.7 (CH), 133.8 (C), 132.7 (C), 129.5 (C),

(2OCH ); HRMS (ESI) for C H O (M + H) calcd 255.1021,

16 15

28.6 (CH), 127.9 (CH), 127.8 (CH), 126.6 (C), 126.4 (CH), 126.0

found 255.1027.

(

CH), 125.9 (CH), 125.8 (CH), 124.7 (CH), 123.1 (CH), 122.3

3-(3,4,5-Trimethoxyphenyl)benzofuran (4e). 4e was prepared

according to method A; column chromatography on a silica gel

aﬀorded 75 mg of the desired compound as a yellow oil, yield 66%; R_f

−

C), 120.6 (CH), 111.9 (CH). HRMS (ESI) for C H O (M − H)

calcd 243.0809, found 243.0805.

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Article

Scheme 5. Mechanism Proposal

−

z0.36 (EtOAc/heptane, 2/8, SiO ); IR (ﬁlm, cm ) 2840, 1607,

4-(Benzofuran-3-yl)benzonitrile (4g). 4g was prepared accord-

ing to method A; column chromatography on a silica gel aﬀorded 40

592, 1579, 1506, 1453, 1360, 1272, 1239, 1127, 747; H NMR (300

MHz, CDCl ) δ 7.83−7.80 (m, 1H), 7.77 (s, 1H), 7.56 (dd, J = 7.2,

mg of the desired compound as a colorless oil, yield 46%; R

= 0.66

−

(

EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 3060, 2226, 1610, 1576,

.3 Hz, 1H), 7.39−7.29 (m, 2H), 6.85 (s, 2H), 3.94 (s, 6H), 3.92 (s,

_H₎_;1 C{ H} NMR (75 MHz, CDCl ) δ 155.9 (C), 153.9 (2C),

41.2 (CH), 137.9 (C), 127.72 (C), 126.6 (C), 124.8 (CH), 123.1

1501, 1452, 1345, 1277, 1219, 1114, 1093, 964, 745; H NMR (300

MHz, CDCl ) δ 7.88 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.76 (s, 4H),

.58 (d, J = 7.9 Hz, 1H), 7.38 (m, 2H); C{ H} NMR (75 MHz,

CDCl ) δ 156.1 (C), 142.6 (CH), 137.1 (C), 132.9 (2CH), 127.9

2CH), 125.6 (C), 125.3 (CH), 123.7 (CH), 121.1 (C), 120.1 (CH),

118.9 (C), 112.2 (CH), 111.1 (C). HRMS for C15

10NO (M + H)⁺

calcd 220.0762, found 220.0756.

-(Benzofuran-3-yl)pyridine (4h). 4h was prepared according to

(

CH), 122.5 (C), 120.3 (CH), 112.0 (CH), 105.1 (2CH), 61.1

OCH ), 56.4 (2OCH ); HRMS (ESI) for C H O (M + H) calcd

17 17

(

85.1127, found 285.1131.

-(4-Chlorophenyl)benzofuran (4f). 4f was prepared according

to method A; column chromatography on a silica gel aﬀorded 63 mg

of the desired compound as a colorless oil, yield 69%; R = 0.79

method A; column chromatography on a silica gel aﬀorded 59 mg of

−

(

EtOAc/heptane, 5/95, SiO ); IR (ﬁlm, cm ) 2922, 2866, 1606,

the desired compound as a yellow oil, yield 75%; R = 0.33 (EtOAc/

588, 1495, 1451, 1272, 1220; H NMR (400 MHz, CDCl ) δ 7.81−

−1

cyclohexane, 2/8, SiO ); IR (ﬁlm, cm ) 2967, 2245, 1620, 1567,

510, 1477, 1399; H NMR (300 MHz, CDCl ) δ 8.97 (s, 1H), 8.67

.77 (m, 2H), 7.60−7.55 (m, 3H), 7.48−7.43 (m, 2H), 7.40−7.30

m, 2H). ¹³C{ H} NMR (101 MHz, CDCl ) δ 155.8 (C), 141.4

(s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.83−7.76 (m, 1H),

13 1

CH), 133.3 (C), 130.5 (C), 129.1 (2CH), 128.7 (2CH), 126.2 (C),

7.61−7.55 (m, 1H), 7.47−7.25 (m, 3H). C{ H} NMR (75 MHz,

24.7 (CH), 123.1 (CH), 121.2 (C), 120.1 (CH), 111.8 (CH);

CDCl ) δ 155.8 (C), 148.6 (CH), 148.4 (CH), 141.8 (CH), 134.5

HRMS for C H ClO (M + H) calcd 229.0426, found 229.0421.

(2CH), 125.9 (C), 125.0 (CH), 123.4 (CH), 120.0 (CH), 119.1 (C),

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

12.0 (CH). HRMS for C H ON (M + H) calcd 196.0762, found

(CH), 118.9 (C), 111.6 (CH), 110.8 (C), 21.5 (CH ). HRMS for

96.0759.

-(Benzofuran-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine (4i). 4i was

prepared according to method A; column chromatography on a silica

gel aﬀorded 61 mg of the desired compound as a colorless oil, yield

1%; R = 0.7 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 2842,

C H ON (M + H) calcd 234.0919, found 234.0924.

4-(5-Methoxybenzofuran-3-yl)benzonitrile (4o). 4o was prepared

according to method A; column chromatography on a silica gel

aﬀorded 73 mg of the desired compound as a colorless oil, yield 73%;

−

(

R = 0.66 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 3121, 2950,

608, 1598, 1452, 1377; H NMR (300 MHz, CDCl ) δ 7.86−7.79

2340, 1620, 1587, 1505, 1467, 1399; H NMR (300 MHz, CDCl ) δ

m, 1H), 7.73 (s, 1H), 7.57−7.51 (m, 1H), 7.39−7.27 (m, 2H),

7.84 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.47

13 1

.21−7.10 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.32 (s, 4H). C{ H}

(

d, J = 9.0 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.00 (dd, J = 9.0, 2.6 Hz,

NMR (75 MHz, CDCl ) δ 155.7 (C), 143.9 (C), 143.1 (C), 140.9

H), 3.88 (s, 3H). C NMR (75 MHz, CDCl ) δ 156.8 (C), 153.4

(

CH), 126.5 (C), 125.4 (C), 124.5 (CH), 122.9 (CH), 121.7 (C),

(

C), 143.4 (CH), 140.5 (CH), 133.0 (2CH), 128.6 (C), 127.9

20.7 (CH), 120.4 (CH), 117.8 (CH), 116.3 (CH), 111.7 (CH),

2CH), 124.8 (C), 121.2 (C), 113.9 (CH), 112.7 (CH), 103.3 (CH),

4.5 (2CH ). HRMS for C H O (M + H) calcd 253.0865, found

16 13

02.8 (C), 56.2 (OCH ). HRMS (ESI) for C H O N (M + H) :

16 12

53.0861.

calcd 250.0868, found: 250.0873.

-(5-Fluorobenzofuran-3-yl)benzonitrile (4p). 4p was prepared

-Methyl-3-(p-tolyl)benzofuran (4j). 4j was prepared according to

method A; column chromatography on a silica gel aﬀorded 67 mg of

the desired compound as a colorless oil, yield 81%; R = 0.78 (EtOAc/

pentane, 5/95, SiO ); IR (ﬁlm, cm ) 3022, 2895, 1610, 1588, 1502,

463; H NMR (300 MHz, CDCl ) δ 7.76 (s, 1H), 7.66 (s, 1H), 7.58

d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H),

.20 (d, J = 6.8 Hz, 1H), 2.52 (s, 3H), 2.46 (s, 3H). C{ H} NMR

75 MHz, CDCl ) δ 154.2 (C), 141.2 (CH), 137.2 (C), 132.4 (C),

29.7 (2CH), 129.3 (C), 127.4 (2CH), 126.7 (C), 125.7 (CH), 121.9

C), 120.2 (CH), 111.2 (CH), 21.50 (CH ), 21.29 (CH ). HRMS for

C H O (M + H) calcd 223.1123, found 223.1119.

-Methoxy-3-phenylbenzofuran (4k). 4k was prepared accord-

ing to method A; column chromatography on a silica gel aﬀorded 64

according to method A; column chromatography on a silica gel

−

aﬀorded 44 mg of the desired compound as a yellow oil, yield 52%; R

−1

= 0.8 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 2954, 2888, 1602,

(

566, 1521, 1445, 1398; H NMR (300 MHz, CDCl ) δ 7.91 (s, 1H),

7.77 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.51 (dd, J = 9.0,

.9 Hz, 1H), 7.45 (dd, J = 8.7, 2.6 Hz, 1H), 7.11 (m, 1H). C{ H}

NMR (75 MHz, CDCl

) δ 161.3 (C-F, JC‑F = 239.6 Hz), 158.1 (C-F,

JC‑F = 239.6 Hz), 152.1 (C), 144.1 (CH), 136.4 (C), 132.9 (2CH),

127.6 (2CH), 118.7 (2C), 113.2 (C-F, J = 26.5 Hz), 112.9 (C-F,

C‑F

J_C_‑_F= 26.5 Hz), 112.9 (C-F, J = 9.8 Hz), 112.8 (C-F, J = 9.8

C‑F C‑F

Hz) 111.2 (C), 106.0 (C-F, J = 25.8 Hz), 105.6 (C-F, J = 25.8

C‑F

mg of the desired compound as a yellow oil, yield 71%; R = 0.67

Hz). F NMR (188 MHz, CDCl ) δ −121.3 HRMS (ESI) for

−

(

EtOAc/pentane, 5/95, SiO ); IR (ﬁlm, cm ) 3075, 2967, 2854,

C H ONF (M + H) : calcd 238.0668, found: 238.0672.

(

604, 1584, 1499, 1452; H NMR (300 MHz, acetone-d ) δ 7.37 (s,

-(3,5-Dimethoxyphenyl)-5-ﬂuorobenzofuran (4q). 4q was pre-

H), 7.34 (s, 1H), 7.14−7.05 (m, 1H), 6.97 (dd, J = 7.5, 1.8 Hz, 1H),

pared according to method A; column chromatography on a silica gel

.91−6.83 (m, 3H), 6.72−6.59 (m, 2H), 3.37 (s, 3H); C{ H} NMR

aﬀorded 67 mg of the desired compound as a colorless oil, yield 62%;

75 MHz, acetone-d ) δ 159.6 (C), 149.2 (CH), 148.8 (C), 141.5

−1

R = 0.69 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 3101, 2930,

2C), 136.8 (CH), 125.8 (C), 122.0 (CH), 120.4 (CH), 115.9

2CH), 114.9 (2CH), 55.8 (OCH ). HRMS (ESI) for C H O Na

M + Na) : calcd 247.0730, found: 247.0732.

-(3,5-Dimethoxyphenyl)-5-methylbenzofuran (4l). 4l was pre-

pared according to method A; column chromatography on a silica gel

aﬀorded 69 mg of the desired compound as a colorless oil, yield 64%;

R = 0.62 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm) 3082, 2936, 1604,

588, 150, 1452, 1345, 1277, 1219, 1114, 1093, 964, 745 cm ; H

NMR (300 MHz, CDCl ) δ 7.77 (s, 1H), 7.64 (s, 1H), 7.44 (d, J =

.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2.3 Hz, 2H), 6.51

t, J = 2.3 Hz, 1H), 3.88 (s, 6H), 2.49 (s, 3H). C{ H} NMR (75

226, 1620, 1589, 1520, 1466, 1345; H NMR (400 MHz, CDCl ) δ

15 12

7.82 (s, 1H), 7.47 (td, J = 8.8, 3.4 Hz, 2H), 7.07 (td, J = 9.0, 2.6 Hz,

H), 6.74 (d, J = 2.3 Hz, 2H), 6.50 (t, J = 2.3 Hz, 1H), 3.86 (s, 6H).

C{ H} NMR (101 MHz, CDCl ) δ 161.4 (2C), 160.8 (C-F, J

C‑F

38.5 Hz), 158.4 (C-F, J = 238.5 Hz), 152.1 (C), 143.3 (CH),

C‑F

33.4 (C), 127.4 (C-F, J = 10.3 Hz), 127.3 (C-F, J = 10.3 Hz),

C‑F

−

1 1

122.7 (C-F, 4JC-F = 3.9 Hz), 122.7 (C-F, 4JC-F = 3.9 Hz), 112.6 (C-

F, JC‑F = 6.9 Hz), 112.6 (C-F, JC‑F = 6.9 Hz), 112.5 (C-F, JC‑F = 9.8

(

Hz), 112.4 (C-F, JC‑F = 9.8 Hz), 106.3 (C-F, JC‑F = 25.4 Hz), 106.1

(C-F, J = 25.4 Hz), 105.7 (2CH), 99.7 (CH), 55.6 (2OCH3). F

C‑F

MHz, CDCl ) δ 160.1 (2C), 153.1 (C), 140.6 (CH), 133.0 (C),

NMR (188 MHz, CDCl ) δ −120.4. HRMS (ESI) for C H O F (M

16 14

31.5 (C), 125.4 (C), 124.8 (CH), 121.0 (C), 119.1 (CH), 110.2

+ H) : calcd 273.0927, found: 273.0926.

(

CH), 104.7 (2CH), 98.2 (CH), 54.4 (2OCH ), 20.4 (CH ). HRMS

3-(4-Cyanophenyl)benzofuran-5-carbonitrile (4r). 4r was pre-

pared according to method A; column chromatography on a silica gel

aﬀorded 70 mg of the desired compound as a colorless oil, yield 72%;

for C H O (M + H) calcd 269.1178, found 269.1176.

-(3,5-Dimethoxyphenyl)-5-methoxybenzofuran (4m). 4m was

prepared according to method A; column chromatography on a silica

−1

R = 0.24 (EtOAc/cyclohexane, 3/7, SiO ); IR (ﬁlm, cm ) 2993,

gel aﬀorded 64 mg of the desired compound as a white solid, yield

901, 2225, 1625, 1588, 1510, 1487, 1452; H NMR (300 MHz,

−

3%; R = 0.56 (EtOAc/pentane, 5/95, SiO ); IR (ﬁlm, cm ) 3088,

DMSO-d ) δ 8.78 (s, 1H), 8.55 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.95

954, 2886, 1611, 1576, 1520, 1491, 1432; H NMR (300 MHz,

(

d, J = 8.5 Hz, 2H), 7.93−7.83 (m, 2H). C{ H} NMR (75 MHz,

DMSO) δ 156.9 (C), 146.6 (CH), 135.0 (C), 132.9 (2CH), 128.8

CH), 127.7 (2CH), 125.9 (CH), 125.4 (C), 119.8 (C), 119.0 (C),

18.6 (C), 113.4 (CH), 110.2 (C), 106.7 (C). HRMS (ESI) for

CDCl ) δ 7.68 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 3.7 Hz,

H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.69 (d, J = 2.3 Hz, 2H), 6.42 (t, J

(

2.3 Hz, 1H), 3.79 (s, 9H). C{ H} NMR (75 MHz, CDCl ) δ

61.2 (2C), 156.2 (C), 150.7 (C), 142.4 (CH), 134.0 (C), 129.8 (C),

26.9 (C), 113.3 (CH), 112.2 (CH), 105.7 (2CH), 102.9 (CH), 99.4

C H ON (M + H) : calcd 245.0715, found: 245.0712.

-Methoxy-2,3-diphenylbenzofuran (4s). 4s was prepared

(

CH), 56.0 (OCH ), 55.4 (2OCH ). HRMS (ESI) for C H O Na

3 3 17 16 4

according to method A; column chromatography on a silica gel

M + Na) : calcd 307.0946, found: 307.0948.

-(5-Methylbenzofuran-3-yl)benzonitrile (4n). 4n was prepared

aﬀorded 36 mg of the desired compound as a colorless oil, yield 30%,

R = 0.76 (EtOAc/cyclohexane, 1/9, SiO ); H NMR (300 MHz,

according to method A; column chromatography on a silica gel

CDCl ) δ 7.69−7.62 (m, 2H), 7.55−7.43 (m, 6H), 7.35−7.29 (m,

aﬀorded 51 mg of the desired compound as a colorless oil, yield 55%;

−

3H), 6.97-6.94 (m, 2H), 3.82 (s, 3H). C{ H} NMR (75 MHz,

R = 0.66 (EtOAc/pentane, 1/9, SiO ); IR (ﬁlm, cm ) 3042, 2933,

CDCl ) δ 156.3 (C), 151.4 (C), 149.0 (C), 133.0 (C), 130.8 (2C),

228, 1624, 1577, 1512, 1487, 1452, 1277; H NMR (300 MHz,

CDCl ) δ 7.83 (s, 1H), 7.73 (s, 4H), 7.59 (s, 1H), 7.45 (d, J = 8.4 Hz,

129.8 (2CH), 129.0 (2C), 128.4 (2C), 128.3 (CH), 127.6 (CH),

H), 7.21 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H). C{ H} NMR (75 MHz,

126.9 (2CH), 117.7 (C), 113.6 (CH), 111.6 (CH), 102.3 (CH), 56.0

CDCl ) δ 154.4 (C), 142.7 (CH), 137.2 (C), 133.1 (C), 132.7

(OCH

found: 301.1224

). HRMS (ESI) for C21

(M + H) : calcd 301.1229,

(

2CH), 127.7 (2CH), 126.4 (CH), 125.5 (C), 120.6 (C), 119.8

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Aggregation Inhibitor for the Potential Treatment of Alzheimer ’s

Article

Disease. J. Med. Chem. 2018, 61, 396−402.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c01835.

■

(3) (a) La Clair, J. J.; Rheingold, A. L.; Burkart, M. D. Ganodone, a

Bioactive Benzofuran from the Fruiting Bodies of Ganoderma tsugae.

J. Nat. Prod. 2011, 74, 2045−2051. (b) Simonetti, S. O.; Larghi, E. L.;

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Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye

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Bui, M.; Shen, W.; Burnier, J.; Barr, K. J.; Hanan, E. J.; Oslob, J. D.;

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an Ophthalmic Solution for Treating Dry Eye. ACS Med. Chem. Lett.

Experimental procedures; compound characterizations;

and H and C NMR spectra (PDF )

AUTHOR INFORMATION

Corresponding Authors

■

Mouad Alami − Universite

Paris-Saclay, CNRS, BioCIS, 92290

Chatenay-Malabry, France; Email: mouad.alami@universite-

paris-saclay.fr

Abdallah Hamze − Universite

Paris-Saclay, CNRS, BioCIS,

2290 Cha tenay-Malabry, France; orcid.org/0000-0001-

425-1971; Email: abdallah.hamze@universite-paris-

saclay.fr

Authors

Diana Lamaa − Universite

Chatenay-Malabry, France

Camille Hauguel − Universite

2290 Chatenay-Malabry, France

Hsin-Ping Lin − Universite

Chatenay-Malabry, France

Estelle Messe − Universite

Chatenay-Malabry, France

Paris-Saclay, CNRS, BioCIS, 92290

(

012, 3, 203−206.

5) Hughes, Z. A.; Starr, K. R.; Langmead, C. J.; Hill, M.; Bartoszyk,

Paris-Saclay, CNRS, BioCIS,

G. D.; Hagan, J. J.; Middlemiss, D. N.; Dawson, L. A. Neurochemical

evaluation of the novel 5-HT1A receptor partial agonist/serotonin

reuptake inhibitor, vilazodone. Eur. J. Pharmacol. 2005, 510, 49−57.

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Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. CuI-

Catalyzed Suzuki −Miyaura and Sonogashira Cross-Coupling Reac-

tions Using DABCO as Ligand. J. Org. Chem. 2007 , 72 , 2053 −2057.

Paris-Saclay, CNRS, BioCIS, 92290

Vincent Gandon − Institut de Chimie Moleculaire et des

Materiaux d’Orsay (ICMMO), CNRS UMR 8182, Universite

Paris-Saclay, 91405 Orsay, France; Laboratoire de Chimie

Moleculaire (LCM), CNRS UMR 9168, Ecole Polytechnique,

Institut Polytechnique de Paris, 91128 Palaiseau, France;

c) Protti, S.; Fagnoni, M.; Albini, A. A Photochemical Route to 2-

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orcid.org/0000-0003-1108-9410

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c01835

cyclization of phenols and alkynes. Chem. Commun. 2013, 49, 6611 −

6613. (e) Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K. Direct

Access to Benzo[b]furans through Palladium-Catalyzed Oxidative

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Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors gratefully acknowledge the support of this project

by CNRS, Univ. Paris-Sud, and by La Ligue Nationale Contre

le Cancer through an Equipe Labellisee 2014 grant. The

BioCIS UMR 8076 laboratory is a member of the Laboratory

of Excellence LERMIT supported by a grant from Agence

Nationale de la Recherche (ANR-10-LABX-33). D.L. thanks

the Ministere de l’Enseignement Superieur, de la Recherche et

de l’Innovation (MESRI), for her Ph.D. grant.

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Heterocycles via Palladium-Catalyzed Oxidative Addition. Chem. Rev.

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Transition-Metal-Catalyzed Addition of Heteroatom −Hydrogen

Bonds to Alkynes. Chem. Rev. 2004, 104, 3079−3160. (c) For

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Iron and Copper Salts in the Synthesis of Benzo[b]furans. Adv. Synth.

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Catalyzed Tandem Oxidative Coupling and Annulation: An Efficient

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Isocyanide Assisted Reductive Cyclization of 1-(2-Hydroxyphenyl)-

propargyl Alcohols for 2-Alkyl/Benzyl Benzofurans and Their Useful

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