Lewis Acid-Mediated Site-Selective Synthesis of Oxygenated Biaryls from Methoxyphenols and Electron-Rich Arenes

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Lewis Acid-Mediated Site-Selective Synthesis of Oxygenated Biaryls

from Methoxyphenols and Electron-Rich Arenes

Shivangi Sharma,^†Santosh Kumar Reddy Parumala,^†and Rama Krishna Peddinti*

Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India

S

* Supporting Information

ABSTRACT: A rapid, eﬃcient, and metal-free Lewis acid-mediated

methodology has been developed for the site-selective synthesis of

unsymmetrical oxygenated biaryls. This simple and eﬃcient

methodology furnished highly oxygenated and functionalized

unsymmetrical biaryls in good to excellent yields by the direct

oxidative coupling of electron-rich arenes to the α-position of

carbonyl functionality of in situ generated masked benzoquinones.

INTRODUCTION

■

The development of simple methods for generating molecular

complexity with deﬁned stereochemistry from easily accessible

starting materials became signiﬁcant and fascinating over the

last few decades. A simple methoxyphenol is found to be the

most appropriate precursor for generating a wide range of

complex cyclic and acyclic architectures. Several chemical¹⁻⁵

and electrochemical methods⁶are known for the umpolung

reactivity of electron-rich nucleophilic 2-methoxyphenols and

4-methoxyphenols by converting them into electrophilic

intermediates through oxidative dearomatization⁷in the

presence of alcoholic solvents. Linearly conjugated cyclo-

hexadienones generated from the oxidative dearomatization of

2-methoxyphenols in the presence of alcoholic solvents by the

aid of hypervalent iodine reagents⁸⁻¹⁴are known as o-

benzoquinone monoketals¹⁵or masked o-benzoquinones

(MOBs, o-benzoquinone protected at one of the carbonyl

functionalities), and cross-conjugated cyclohexadienones¹⁶

generated from 4-methoxyphenols are known as p-benzoqui-

none monoketals or masked p-benzoquinones (MPBs, p-

benzoquinone protected at one of the carbonyl functionalities).

These quinone monoketals undergo numerous transformations

such as (i) cycloaddition reactions, (ii) nucleophilic, electro-

philic, and radical addition reactions, and (iii) photochemical

reactions.¹⁷On account of their unique reactive features, rapid

and easy generation, they grabbed the attention of synthetic

organic chemists.

Figure 1. Some of the biaryls in nature.

prefunctionalization of both coupling partners, which may be

expensive since it needs more than one synthetic step and may

lead to the formation of homocoupling products and often

toxic byproducts. It is also diﬃcult to remove traces of

transition-metal impurities from the ﬁnal products. In line with

traditional cross-coupling methods, cross-dehydrogenative

couplings were developed, which in contrast to traditional

methods involve the direct C−H activation of unactivated

arenes under transition-metal catalysis and avoid the

preactivation of both the coupling partners.³⁶⁻³⁹Over the

past few decades, numerous oxidative cross-coupling strategies

were developed for the synthesis of biaryls using heavy metal

(Pb^IV, Ru^IV, Tl^III, V^V, and Rh^III) oxidizing agents.⁴⁰⁻⁴⁶Because

of the high cost, toxicity to some extent, and moisture

sensitivity of these heavy metal oxidizing reagents, there is a

The synthesis of biaryls^18,19has received much attention in

recent years because of their frequent occurrence in many

natural products²⁰⁻²²and pharmaceutically active com-

pounds²³⁻²⁶(Figure 1) and their wide applications in

asymmetric synthesis, molecular catalysis, and materials

science.²⁷⁻³⁶In the past decades, metal-mediated traditional

cross-coupling reactions have been extensively used for the

construction of these pivotal motifs. Though these protocols

proceed under mild conditions with better selectivities and high

yields, they suﬀer from a few limitations such as the

Received: March 23, 2017

A

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need to develop simple and environmentally friendly protocols

for the synthesis of the title compounds. In this context, the

oxidative cross-coupling of two non-activated arenes by using

oxidants such as TBHP, K₂S₂O₈, and hypervalent iodine

reagents is a convenient and environmentally benign method

for the synthesis of biaryls.⁴⁷⁻⁵²Kozlowski developed homo-

and cross-coupling of phenols by using aerobic chromium

salene catalysts.⁵³

Scheme 1. Possible Products from Conjugate Addition

Kita and co-workers studied the cross-coupling of p-quinone

monoacetals and electron-rich arenes for the synthesis of

oxygenated biaryls using montmorillonite clay in the ﬂuorinated

solvent HFIP,^54,55ﬂuorinated hypervalent iodine reagent.⁵⁶

Fasicinated by the various applications of biaryls in various

areas, we have developed a boron triﬂuoride etherate-promoted

rapid synthesis of biaryls in dichloromethane by the oxidative

cross-coupling of o-benzoquinone monoketals with electron-

rich arenes.⁵⁷Recently, Kita utilized methanesulfonic acid and

hypervalent iodine reagents in HFIP for the cross-couplings of

p-quinone monoacetals and phenols.⁵⁸⁻⁶⁰Kurti et al.⁶¹also

̈

executed the synthesis of biaryls by the cross-coupling of p-

quinone monoacetals and naphthols in the presence of

triﬂuoroacetic acid/toluene and diphenylphosphoric acid/

triﬂuoroethanol. Chittimalla et al.⁶²depicted the regioselective

synthesis of biaryls via the palladium-catalyzed Michael addition

of arylboronic acids to o-quinone monoketals followed by

aromatization. Recently, Quideau and co-workers^17hsynthe-

sized biaryl-based natural products by carrying out the Girgnard

reaction on o-quinol acetates.

RESULTS AND DISCUSSION

■

Inspired by the manifold applications of biaryl systems herein,

we have developed a site-selective Lewis acid-mediated rapid

protocol for the synthesis of oxygenated unsymmetrical biaryls

by the reaction of electron-rich arenes via in situ generated o-

benzoquinone monoketals and p-benzoquinone monoketals.

The possible products A and B through the conjugate addition

of electron-rich arenes to the in situ generated quinone

monoketals at position-3 or position-5, respectively, and C

through the conjugate addition of electron-rich arenes at

position-2 are depicted in Scheme 1.

To facilitate the discussion in this article, the numbering of

compounds is given as follows: 2-methoxyphenols 1−5 and

their oxidized o-benzoquinone monoketals 1a−5a, 4-methox-

yphenols 6−8 and their oxidized p-benzoquinone monoketals

6a−8a, electron-rich benzene derivatives 9a−f, naphthalene

derivatives 10a−c (Figure 2).

Figure 2. Structures of methoxyphenols, benzoquinone monoketals,

and electron-rich arenes.

of the reaction reveals the presence of butyraldehyde, and the

peaks corresponding to the homocoupled product of 9a are

missing. The analysis of another reaction carried out in butanol

in the absence of 9a also supported the formation of

butyraldehyde (see the Supporting Information). In order to

avoid the nucleophilic addition of the solvent MeOH on 1a,

methanol was removed after the dearomatization of phenol 1

by a rotary evaporator in vacuo at room temperature. Then the

residue was diluted in dichloromethane, and 1,3-dimethox-

ybenzene and BF₃·OEt₂(1 equiv) were added sequentially at 0

°C. Surprisingly, the reaction completed within a minute and

furnished biaryl 11 by the attack of electron-rich arene to o-

benzoquinone monoketal 1a in 65% yield (Scheme 2).

Further, the close inspection of proton NMR conﬁrmed the

addition of 1,3-dimethoxybenzene at the C-2 position (α-

position) of the transiently generated reactive cyclohexadie-

none 1a in a vinylogous S_N2′ type addition with subsequent

rearomatization.

At the outset, 4-bromoguaiacol (1) was dearomatized with

diacetoxyiodobenzene (DIB) in MeOH in the presence of 1,3-

dimethoxybenzene (1,3-DMB, 9a) and the reaction was further

stirred for 24 h at room temperature. However, the reaction did

not proceed. When the reaction was carried out in the presence

of 1 equiv of BF₃·OEt₂at 0 °C, it reached completion within a

minute and provided 4-bromo-2,5-dimethoxyphenol in 36%

yield along with 41% 4-bromoguaiacol (1), which was obtained

from the rearomatization of o-quinone monoketal 1a. The

formation of 4-bromo-2,5-dimethoxyphenol resulted from the

attack of methanol on the in situ generated o-quinone

monoketal 1a. The rearomatization of 1a to bromoguaiacol 1

might have taken place with the assistance of either electron-

rich arene 9a or methanol by producing the byproduct diaryl

from the homocoupling of 9a or formaldehyde, respectively. To

provide some insight into this, we carried out the same reaction

by replacing methanol with butanol. The mass spectral analysis

B

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yield of the product, a detailed screening was adopted by the

varying of temperatures, the amount of reagent, and the

addition sequence of the reactant/reagent. Biaryl 11 was

obtained in 82% yield when the reaction was performed in the

presence of 2 equiv of BF₃·OEt₂at −30 °C, though there was

no signiﬁcant diﬀerence in the yield of the biaryl product from

the reaction carried out at −40 °C (entries 7 and 8). The

desired product was abridged by reducing the amount of BF₃·

OEt₂(entry 9). A further increase of BF₃·OEt₂caused the

reaction to aﬀord biaryl 11 in 80% yield (entry 10).

Scheme 2. Preliminary Experiments

After having the optimal conditions in hand (entry 7), we

extended the scope of the reaction. For that matter, we have

performed a reaction between various halo-substituted

guaiacols and 1,3-dimethoxybenzene (9a) under these con-

ditions. Thus, the haloguaiacols were oxidized in the presence

of DIB in MeOH at room temperature. After MeOH was

removed, the o-quinone monoketals were treated with 1,3-

dimethoxybenzene in CH₂Cl₂at −30 °C in the presence of

BF₃·OEt₂to obtain the corresponding biaryls 11, 13, and 15 in

very high yields. Interestingly, in these reactions, along with the

desired biaryls, 10−12% of diaryl ethers 12, 14, and 16 were

also isolated (Scheme 3).

Propelled by the obtained results, we optimized reaction

conditions to improve the yield of biaryl 11 by choosing 4-

bromo-2-methoxyphenol (1) and 1,3-dimethoxybenzene (9a)

as the model reactants and screened out various Brønsted and

Lewis acid activators. After complete oxidation of 4-bromo-2-

methoxyphenol (1) into the corresponding cyclohexadienone

1a in the presence of DIB and methanol, the solvent was

removed under a vacuum and the residue was dissolved in

CH₂Cl₂. Then arene 9a and an activator were added

sequentially at 0 °C. The reaction, when carried out in the

presence of various Brønsted acid activators such as

phosphomolybdic acid and 3,5-dinitrobenzoic acid, did not

proceed (Table 1, entries 1 and 2), whereas the triﬂuoroacetic

Scheme 3. Reactions of Haloguaiacols 1−3 with 1,3-

Dimethoxybenzene (9a)

a

Table 1. Optimization of Reaction Conditions

temp

(°C)

time

(min)

yield

d

b

c

entry

activator

equiv

(%)

e

1

2

phosphomolybdic acid

3,5-dinitrobenzoic acid

TFA

0.2

2

0 to rt

0

24 h

40

nr

e

nr

Then we have tested the scope of the reaction with respect to

1,3-dimethoxybenzene derivatives. For this purpose, we have

performed the reactions of haloguaiacols 1−3 and an electron-

rich guaiacol such as creosol (4) with arenes 9a−d under

optimized reaction conditions. The guaiacol derivatives were

oxidized using DIB in MeOH into the corresponding o-quinone

monoketals 1a−4a followed by the reaction with 1,3-

dimethoxybenzene derivatives in the presence of BF₃·OEt₂.

All the reactions proceeded smoothly to give the corresponding

biaryls 17−29 in good to very high yields under the same set of

conditions. In the case of halo-substituted 1,3-dimethoxyben-

zene derivatives 9b,c, the desired products 17−22 were

obtained in somewhat diminished yields as a result of the

electron-withdrawing nature of the halo group of the

nucleophile, whereas the unsymmetrical oxygenated biaryls

23−25 were obtained from 1,3-dimethoxy-5-methylbenzene

(9d) in high yields (Scheme 4). The same trend was noticed in

the reaction of creosol (4) in providing biaryls 26−29.

3

2

53

58

54

75

82

79

65

80

4

FeCl₃

2

0

20

5

ZrCl₄

2

0

10

6

BF₃·OEt₂

2

0

<1

7

2

−30

−40

−30

<1

8

2

<1

9

1

<1

10

BF₃·OEt₂

4

<1

a

Reaction was carried out with 4-bromoguaiacol (1, 0.5 mmol),

PhI(OAc)₂(0.5 mmol), and 1,3-dimethoxybenzene (9a, 1.0 mmol).

b

c

d

Of activator. Time after addition of activator. Yield of pure and

e

isolated products. nr = no reaction.

acid-mediated reaction aﬀorded product 11 in 53% yield (entry

3). At this juncture, we became interested in improving the

yield of the product further. For this purpose, we continued our

studies by using diﬀerent Lewis acid activators such as FeCl₃,

ZrCl₄, and BF₃·OEt₂, which produced the biaryl product 11

(entries 4−10). When we performed the reaction in the

presence of FeCl₃, biaryl 11 was obtained in 58% yield in 20

min, whereas the ZrCl₄-mediated reaction provided product 11

in 54% yield in 10 min (entries 4 and 5). When the activator

was switched to BF₃·OEt₂, product 11 was obtained in 75%

yield within a minute (entry 6). In order to further improve the

After successfully carrying out the reactions of several

guaiacols 1−4 with 1,3-dimethoxybenzene derivatives, we

further demonstrated the eﬃcacy of the present protocol by

performing the reactions of guaiacols 1−4 with naphthalene

derivatives 10a−d. Initially, we selected β-naphthol (10a) for

our study. The transient reactive cyclohexadienones, generated

from the DIB-mediated oxidation reaction in MeOH, reacted

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Scheme 4. Reactions of Guaiacols 1−4 with 1,3-

Dimethoxybenzene Derivatives 9a−d

Scheme 5. Reactions of Guaiacols 1−4 with 2-Naphthol

Derivatives 10a−d

Scheme 6. Scope of Electron-Rich Arenes

with β-naphthol in the presence of BF₃·OEt₂under standard

conditions to furnish the corresponding unsymmetrical oxy-

genated biaryls 30−33 in excellent yields within a minute

(Scheme 5). Similarly, we also examined the reactivity of the

naphthalene derivatives 10b−d with various guaiacol derivatives

1−4. For this purpose, we have treated the naphthalene

derivatives 10b−d with the o-quinone monoketals 1a−4a

generated by the dearomatization of the guaiacol derivatives 1−

4, in the presence of BF₃·OEt₂under optimized conditions, to

furnish the corresponding unsymmetrical oxygenated biaryls

34−45 in very high yields (Scheme 5).

To show the applicability of present work, we have

performed the reactions of creosol (4) with various electron-

rich arenes such as resorcinol, p-cresol, and N-methylpyrrole

under optimized conditions. In these reactions, creosol 4 in

MeOH was oxidized in the presence of DIB to generate the o-

quinone monoketal 4a. Then the solvent was evaporated under

a vacuum. To a solution of MOB 4a in CH₂Cl₂were added the

electron-rich arenes in separate reactions followed by BF₃·OEt₂

at −30 °C to obtain the corresponding biaryls 46−48 in good

yields (Scheme 6).

To ﬁnd out the possible electrophilic sites on o-quinone

monoketals bearing no substitution at position 4, we have

examined the reaction of 5-methylguaiacol (5) and 1,3-

dimethoxybenzene (9a) under the same set of conditions. As

anticipated, biaryl 49, derived from the addition of arene at

position 4 of o-quinone monoketal 5a, was isolated (Scheme 7).

To expand the scope further, we studied the reactions of 4-

bromo-5-methylguaiacol and 4-phenylguaiacol to aﬀord the

corresponding biaryls 49a and 49b under similar conditions.

The regiochemistry of the biaryls was conﬁrmed by ¹H NMR

analysis. All compounds obtained from the reaction of 2-

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The structures of all the unsymmetrical oxygenated biaryls

were conﬁrmed on the basis of the data obtained from IR, H

Scheme 7. Reactions of Diﬀerently Substituted Guaiacol

Derivatives

1

and ¹³C NMR, DEPT, and HRMS spectral analysis. For

instance, in compound 20, the aromatic −CH protons resonate

in the region of 7.00−6.47 ppm as a doublet with meta

coupling, whereas the methoxy groups on both the arene

moieties resonate at 3.90, 3.82, and 3.72 ppm as singlets,

respectively. The peak corresponding to the phenolic −OH

proton resonates at 5.62 ppm as a broad singlet. From the

analysis of the HRMS spectrum of compound 20, it was

observed that the peak at m/z 394.9656 is in good agreement

with the calculated value of m/z 394.9656 for [M + Na]⁺. The

structures of 17⁶³and 35⁶³were further conﬁrmed by single-

crystal X-ray analysis (see the Supporting Information).

A mechanistic model proposed for the arylation of guaiacol

derivatives and electron-rich arenes is outlined below. The

coordination of the Lewis acid with a masked o-benzoquinone,

derived from DIB-mediated oxidative acetalization, and the

subsequent loss of the methoxide ion develop a positive charge

on the oxygen atom of the other methoxy group of o-quinone

monoketal (path a). Then the attack of the electron-rich arene

on the electron-deﬁcient carbon 2 (or carbon 4 if it is

unsubstituted) of the MOB in the conjugate addition and the

subsequent rearomatization yield the unsymmetrical oxy-

genated biaryl. The formation of diaryl ethers 12, 14, and 16

may be attributed to the electropositivity on the carbonyl

oxygen due to the presence of a deactivating halogen atom on

position 4 of an electron-deﬁcient species with a positive charge

on the methoxy moiety. The products A and B resulting from

the Michael addition from path b were not observed (Scheme

8).

methoxyphenols showed the coupling constants for the protons

of the guaiacol moiety in the range 1.5−3.0 Hz (meta coupling)

1

in the H NMR spectrum, which indicates that there are no

protons situated ortho to each other in the guaiacol moiety in

the biaryl products (Figure 3). This conﬁrmed that the

electron-rich arene attacks at position 2 of the o-quinone

monoketal leading to the formation of the target biaryl

products 11, 13, 15, and 17−49.

To examine the validity of the protocol for the synthesis of

the biaryl system by the reaction of electron-rich arenes and

linearly conjugated o-quinone monoketals in the presence of

Lewis acid activators, we have extended our methodology to

cross-conjugated p-quinone monoketals. In our preliminary

experiment, p-methoxyphenol (6) was dissolved in methanol

Figure 3. Regiochemistry of biaryls based on coupling constants.

Scheme 8. Plausible Mechanism for the Synthesis of Unsymmetrical Oxygenated Biaryls and Diaryl Ethers

E

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and further subjected to dearomatization with 1 equiv of DIB at

room temperature in 10 min to furnish the corresponding

cross-conjugated cyclohexadienone intermediate 6a. After

complete conversion of p-methoxyphenol (6) into the

corresponding cross-conjugated p-quinone monoketal 6a,

methanol was evaporated under reduced pressure at ambient

temperature. Then the residue was dissolved in CH₂Cl₂, and

the reaction mixture was cooled to 0 °C. To the above mixture

were added 1 equiv of 1,3-dimethoxybenzene (9a) and then 1

equiv of BF₃·OEt₂. The reaction was completed within a

minute just after the addition of BF₃·OEt₂, and two products 50

and 50a were obtained in 31% and 14% yields, respectively

(Table 2, entry 1). These products were analyzed by ¹H NMR,

control experiment where the reaction was carried out with 1

equiv of isolated p-quinone monoketal 6a in CH₂Cl₂at 0 °C,

and then 1 equiv of an electron-rich arene and BF₃·OEt₂were

added. Even in this protocol, the formation of both products 50

and 50a in 30% and 17% yields, respectively, was observed

(entry 6).

Kita and co-workers⁵⁵synthesized 2,6-di(2,4-dimethoxy-

phenyl)-4-methoxyphenol (50a) by the second oxidation of

the primary product 50. However, in our methodology,

surprisingly we obtained 50a along with 50 without any use

of a hypervalent iodine oxidant.

We were delighted by this event and proceeded further with

optimized conditions (entry 4) to explore the scope of the

reaction with respect to electron-rich arenes 9a, 9b, 9e, and 9f

with 4-methoxyphenol. The reaction proceeded smoothly and

aﬀorded the corresponding biaryls within a minute. It is evident

from the results that the electron-rich arenes 9a and 9e having

high electron-donating tendencies aﬀorded two products, viz.,

(i) biaryl products 50 and 52 obtained from the mono attack of

an electron-rich arene and (ii) 50a and 52a obtained by the bis-

attack of an electron-rich arene. The moderate electron-

donating 9c and 9f aﬀorded only biaryl products 51 and 53

(Scheme 9). Further, in order to investigate the eﬀect of the

substitution on phenols in the reaction, we selected 2-bromo-4-

methoxyphenol (7) and 2-methyl-4-methoxyphenol (8)

bearing an electron-withdrawing group (Br) and an electron-

donating group (Me), respectively, as reactants. When p-

quinone monoketals 7a and 8a corresponding to p-methox-

yphenols 7 and 8 were reacted with electron-rich arenes 9a, 9b,

9e, and 9f, all reactions proceeded smoothly and furnished the

products 54−61 in moderate yields of 60−71% (Scheme 9).

It was quite evident that the substitution of the electron-

donating and electron-withdrawing groups on phenols did not

exhibit any signiﬁcant eﬀect on the yields of biaryl products. It

is clear from the reactions of 7 and 8 with 9a and 9d that only

the biaryl product formation is observed because the second

ortho position was already blocked by bromo/methyl groups.

After accomplishing successful results from the reactions

between various 4-methoxyphenol derivatives 6−8 and 1,3-

dimethoxybenzene derivatives 9a, 9b, 9e, and 9f, we further

validated the present protocol by performing the reactions of

6−8 with naphthalene derivatives 10a−d. Initially, we studied

the reactions of 4-methoxyphenol derivatives 6−8 with β-

naphthol (10a). The p-quinone monoketals 6a−8a generated

from the DIB-mediated oxidation of the corresponding phenols

6−8 in methanol and reacted with β-naphthol (10a) in the

presence of BF₃·OEt₂under standard conditions to aﬀord the

corresponding biaryls in high yields of 77−89% (Scheme 10).

Similarly, we studied the reactivity of the naphthol derivatives

10b,c and 2-methoxynaphthalene (10d) with p-quinone

monoketals derivatives, generated by the oxidative dearomati-

zation of 4-methoxyphenol derivatives 6−8, in the presence of

BF₃·OEt₂. The reactions proceeded smoothly within a minute

and aﬀorded oxygenated unsymmetrical biaryls 62−73 in good

to high yields under standard conditions (Scheme 10).

Table 2. Optimization of Reaction Conditions

BF₃·Et₂O

(equiv)

1,3-DMB

(equiv)

temp

(°C) yield 50 (%) yield 50a (%)

c

entry

1

2

3

4

5

1

2

1

2

1

0

−30

−60

0

31

15

38

35

30

14

26

28

27

26

17

0

d

6

0

a

Reaction was carried out with 4-methoxyphenol (6, 0.5 mmol), DIB

(0.5 mmol), and 1,3-dimethoxybenzene (0.5 or 1.0 mmol). All

b

reactions completed in <1 min. Time after addition of BF₃·OEt₂.

c

d

Yield of pure and isolated products. Reaction was carried out with

isolated p-quinone monoketal.

and it was found that product 50 resulted from the attack of the

electron-rich arene at one of the α-positions (C-2) of the

carbonyl carbon of the cross-conjugated p-quinone monoketal

6a, while product 50a was obtained by the attack of the

electron-rich arene on both α- and α′-positions of the carbonyl

carbon of 6a (Table 2). At this juncture, in order to improve

the yield and selectivity of the reaction, we performed the

reaction at −30 and −60 °C; however, the yield of product 50

was decreased to 15%, while the yields of 50a were increased to

26% and 28%, respectively (entries 2 and 3). Further, we

screened out reactions by varying the amount of the electron-

rich arene and BF₃·OEt₂. When a reaction was performed with

2 equiv of the electron-rich arene and 1 equiv of BF₃·OEt₂, the

yield of product 50 was increased to 38%, while 50a was

obtained in 27% yield (entry 4). When the amount of BF₃·OEt₂

was increased to 2 equiv, the products 50 and 50a were

obtained in 35% and 26% yields, respectively (entry 5). In

order to understand the path of the reaction, various factors

such as the role of DIB, participation of the solvent, and

amount of 9a were examined. For that reason, we carried out a

In order to ﬁnd out the priority of the liability of an alkoxy

group, we carried out a reaction between cross-conjugated p-

quinone monoketal 6b having two diﬀerent alkoxy groups,

methoxy and ethoxy, with 1,3-dimethoxybenzene (9a). To a

solution of MPB 6b in CH₂Cl₂were added the electron-rich

arene and BF₃·OEt₂at 0 °C. In this case, the reaction

proceeded smoothly and furnished two products 74 and 74a

F

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The Journal of Organic Chemistry

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Scheme 9. Reactions of 4-Methoxyphenol Derivatives 6−8

with Electron-Rich Arenes 9a,b,e,f

Scheme 10. Reactions of 4-Methoxyphenol Derivatives 6−8

with Electron-Rich Arenes 10a−d

Scheme 11. Reaction of p-Quinone Monoketal 6b with 1,3-

Dimethoxybenzene (9a)

methoxy group remained, and the elimination of the ethoxy

1

group took place in the biaryl system. The analysis of the H

NMR spectrum of 74a inferred that, during the reaction, the

methoxy group eliminated predominantly and the ethoxy group

remained intact.

Further, we have performed a reaction between cross-

conjugated p-quinone monoketal 6b with the naphthalene

derivative 10a in the presence of BF₃·OEt₂. We obtained two

isolable biaryl products: one major product, 75, having an

ethoxy group in 64% yield, while the other having a methoxy

group, 62, in 7% yield as shown in Scheme 12.

through the mono- and bis-addition of 9a to p-quinone

monoketal 6b, respectively (Scheme 11).

By the close inspection of the H NMR spectrum of the

monoaddition product, it was discerned that 74 was not the

sole biaryl product but it was the mixture of biaryls, major 74

and minor 50. In the major product 74, the ethoxy group

remained intact in the product by the elimination of the

methoxy group, while in the minor biaryl product 50, the

1

However, the reactions of p-quinone monoketal 6b or 6c

with 6-bromo-2-naphthol (10b) under optimized conditions

G

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Further, the conﬁrmation for the formation of regioisomer-1

has been carried out by a close inspection of the H NMR

Scheme 12. Reaction of MPB 6b with β-Naphthol (10a)

1

spectrum of compound 56. For instance, in compound 56, the

aromatic H_aand H_bprotons resonate as doublets at δ 7.06 and

6.73 ppm and show meta coupling of 3.2 Hz (Figure 5). The

furnished an inseparable mixture of biaryl products in good

yields. The yields of these products were calculated from their

¹H NMR spectra (Scheme 13).

Scheme 13. Reaction of p-Quinone Monoketals 6b and 6c

with 6-Bromo-2-naphthol (10b)

1

Figure 5. H NMR spectra representing characteristic chemical shifts,

coupling constants, and decoupling experiments of 56.

doublet of the H_aproton at δ 7.06 ppm is simpliﬁed to a singlet

by irradiating (decoupling) the proton at δ 6.73 ppm (Figure

5), which indicates that the H_aand H_bprotons belong to

aromatic ring A. Further regiochemistry of the teraryl and ortho

attack was conﬁrmed by the single-crystal X-ray analysis of

52a⁶³(Figure 6).

The reaction of p-quinone monoketal 6b with 2-methox-

ynaphthalene (10d) under standard conditions provided

predominantly biaryl product 78 in 66% yield (Scheme 14).

Scheme 14. Reaction of MPB 6b with 2-

Methoxynaphthalene (10d)

Figure 6. ORTEP representation of the crystal structure of 52a (50%

probability).

The formation of unsymmetrical oxygenated biaryls (56) by

the attack of electron-rich arenes at the ortho position of p-

quinone monoketal was conﬁrmed by the H NMR spectrum.

A mechanistic model proposed for the arylation of the 4-

methoxyphenol derivatives and electron-rich arenes is outlined

below. The coordination of the Lewis acid with cross-

conjugated quinone monoketal (D), derived from diacetox-

yiodobenzene-mediated oxidative acetalization, undergoes a

subsequent loss of the methoxide ion and develops a positive

charge on the oxygen atom of the other methoxy group of the

cross-conjugated p-quinone monoketal. Then the subsequent

attack of the electron-rich arene on the electron-deﬁcient

carbon-2 of p-quinone monoketal generates intermediate E,

which yields the unsymmetrical oxygenated biaryl 50 (mono

arylated product) with further aromatization. The BF₃-

complexed quinone ketal D undergoes a redox exchange with

biaryl 50 to generate quinone ketal F and methoxyphenol 6.

This gets support from the control experiment performed

between monoketal 6a and phenol 50 in the presence of BF₃·

OEt₂in dichloromethane where the formation of multiple

products from phenols 6 and 50 and monoketals 6a and F was

observed. The intermediate F, with further complexation with a

1

All compounds, obtained by the oxygenative coupling of the p-

methoxyphenol derivatives and electron−rich arenes, showed a

1

meta coupling constant in the H NMR spectrum. The meta

coupling constants are found to be in the range 1.2−3.4 Hz,

which indicates the formation of regioisomer-1 (Figure 4).

Figure 4. Regiochemistry of biaryls based on coupling constants.

H

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Scheme 15. Plausible Mechanism for the Synthesis of Unsymmetrical Oxygenated Biaryls

middle peak). Coupling constants were expressed in hertz (Hz). The

following abbreviations were used to explain the multiplicities: s =

singlet, d = doublet, t = triplet, dt = doublet of triplet, m = multiplet, br

= broad. High-resolution mass spectra (HRMS) were obtained on a

micrOTOF-Q II mass spectrometer (ESIMS).

Lewis acid, loses the methoxide ion to generate G. The

intermediate G is susceptible to the subsequent attack of an

electron-rich arene at the α-position to carbonyl and undergoes

aromatization to aﬀord bis-arylated methoxyphenol 50a

(Scheme 15).

General Procedure for the Synthesis of Unsymmetrical

Biaryls. To a solution of the guaiacol derivative 1 (0.5 mmol) in dry

MeOH (3 mL) was added solid PhI(OAc)₂(DIB, 0.161 g, 0.5 mmol)

at room temperature, and the mixture was stirred for 5 min. After

complete conversion of the guaiacol derivative into its MOB, MeOH

was removed under reduced pressure. The residue was dissolved in dry

CH₂Cl₂(5 mL), and an electron-rich arene (1 mmol, 2 equiv) and

then BF₃·OEt₂(1 mmol, 2 equiv) were added at −30 °C. The yellow

color of MOB disappeared within a minute after the addition of BF₃·

OEt₂, indicating the completion of the reaction. After the completion

of the reaction, as checked by TLC, the reaction was quenched by

adding saturated NaHCO₃and the aqueous phase was extracted twice

with CH₂Cl₂. The combined extract was dried over anhydrous Na₂SO₄

and then evaporated to dryness, and the residue was puriﬁed by silica

gel column chromatography by using ethyl acetate (10−20%) in

hexanes as an eluent to give the unsymmetrical biaryls in good to

excellent yields.

CONCLUSION

■

We have established a rapid and straightforward method for the

eﬃcient synthesis of unsymmetrical biaryls from the reaction

between simple 2-methoxyphenol or 4-methoxyphenol deriva-

tives and electron-rich arenes in the absence of supplemental

transition metals by using a Lewis acid activator. Mild and

aerobic conditions, enhanced regioselectivities, and the absence

of self-coupling are the other merits of this protocol. The

current methodology illustrates the eﬃcacy of masked o-

benzoquinones or masked p-benzoquinones in combining two

electron-rich arenes to oﬀer highly oxygenated biaryls.

EXPERIMENTAL SECTION

■

Unless otherwise noted, chemicals were purchased from commercial

suppliers at the highest purity grade available and were used without

further puriﬁcation. Solvents were distilled by standard methods. Thin-

layer chromatography was performed on precoated 0.25 mm silica gel

plates (60F-254) using UV light as a visualizing agent and iodine as a

developing agent. Silica gel (100−200 mesh) was used for column

chromatography. Melting points were recorded and were uncorrected.

IR spectra were recorded on an FT-IR spectrometer and expressed as

4-Bromo-6-(2,4-dimethoxyphenyl)-2-methoxyphenol (11): yield

0.139 g (82%) as a brown viscous liquid; IR (KBr) ν_max3441, 2927,

1

2844, 1609, 1507, 1467, 1296, 1210, 1153, 1023, 829, 735 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.20 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.0

Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.60−6.57 (m, 2H), 5.89 (br, s, 1H,

OH), 3.91 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H) ppm; ¹³C NMR (125

MHz, CDCl₃) δ 161.0 (C), 157.2 (C), 148.0 (C), 142.5 (C), 132.1

(CH), 126.8 (C), 126.1 (CH), 117.9 (C), 113.3 (CH), 111.4 (C),

105.1 (CH), 99.0 (CH), 56.3 (CH₃), 55.9 (CH₃), 55.5 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₅H₁₅BrO₄Na [M + Na]⁺361.0046,

found 361.0049.

wave numbers (cm⁻¹). H and ¹³C NMR spectra were recorded on a

1

400 or 500 MHz NMR spectrometer. Spectra were referenced

internally to the residual proton resonance in CDCl₃(δ 7.26 ppm) or

DMSO (δ 2.5 ppm) in the deuterated solvent or with

tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard.

Chemical shifts (δ) were reported as parts per million (ppm) in a δ

scale downﬁeld from TMS. ¹³C NMR spectra were referenced to

CDCl₃(δ 77.0 ppm, the middle peak) and DMSO-d₆(δ 39.5 ppm, the

4-Bromo-1-(2,4-dimethoxyphenoxy)-2-methoxybenzene (12):

yield 0.017 g (10%) as a yellow viscous liquid; IR (KBr) ν_max3080,

1

2943, 2838, 1600, 1502, 1261, 1212, 1118, 1033, 831, 712 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.05 (t, J = 2.5 Hz, 1H), 6.92−6.87 (m,

2H), 6.56 (t, J = 2.5 Hz, 1H), 6.50 (dd, J = 3.0, 8.5 Hz, 1H), 6.41 (td, J

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= 2.5, 5.0 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H) ppm; ¹³

C

(C), 142.2 (C), 135.1 (C), 123.7 (C), 123.4 (CH), 122.6 (C), 117.0

(C), 110.7 (CH), 105.8 (CH), 97.6 (CH), 56.0 (CH₃), 55.9 (CH₃),

55.5 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₄Cl₂O₄Na [M +

Na]⁺351.0161, found 351.0173.

NMR (125 MHz, CDCl₃) δ 157.2 (C), 151.9 (C), 150.2 (C), 147.0

(C), 138.0 (C), 123.3 (CH), 121.2 (CH), 117.2 (CH), 115.5 (CH),

114.4 (CH), 103.9 (CH), 100.5 (CH), 56.2 (CH₃), 55.8 (CH₃), 55.6

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₅BrO₄Na [M + Na]⁺

361.0046, found 361.0054.

6-(2-Chloro-4,6-dimethoxyphenyl)-4-ﬂuoro-2-methoxyphenol

(19): yield 0.106 g (68%) as a colorless solid; mp 124−126 °C; IR

(KBr) ν_max3497, 2923, 1607, 1566, 1421, 1383, 1216, 1118, 1038, 961,

4-Chloro-6-(2,4-dimethoxyphenyl)-2-methoxyphenol (13): yield

1

838, 743 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.66 (dt, J = 3.0, 5.5

0.118 g (80%) as a brown viscous liquid; IR (KBr) ν_max3469, 2930,

1

1604, 1513, 1456, 1256, 1196, 1107, 1017, 934, 830 cm⁻¹; H NMR

Hz, 2H), 6.49 (dd, J = 3.0, 9.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.37

(br, s, 1H, OH), 3.91 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H) ppm; ¹³C

NMR (125 MHz, CDCl₃) δ 160.5 (C), 158.8 (C), 155.8 (d, J = 235.88

Hz, C), 146.9 (d, J = 10.75 Hz, C), 139.6 (d, J = 3.0 Hz, C), 135.2 (C),

121.8 (d, J = 10.0 Hz, C), 117.4 (C), 109.4 (d, J = 22.38 Hz, CH),

105.9 (CH), 98.8 (d, J = 27.38 Hz, CH), 97.8 (CH), 56.1 (CH₃), 55.6

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₄FClO₄Na [M + Na]⁺

335.0457, found 335.0462.

(500 MHz, CDCl₃) δ 7.21 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.5 Hz,

1H), 6.84 (d, J = 2.0 Hz, 1H), 6.61−6.58 (m, 2H), 5.89 (s, 1H, OH),

3.91 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 160.8 (C), 157.1 (C), 147.7 (C), 141.9 (C), 132.0 (CH),

126.2 (C), 124.2 (C), 123.0 (CH), 118.0 (C), 110.4 (CH), 105.0

(CH), 99.0 (CH), 56.2 (CH₃), 55.8 (CH₃), 55.4 (CH₃) ppm; HRMS

(ESI+) m/z calcd for C₁₅H₁₅ClO₄Na [M + Na]⁺317.0551, found

317.0552.

4-Bromo-6-(2-bromo-4,6-dimethoxyphenyl)-2-methoxyphenol

(20): yield 0.152 g (73%) as a brown solid; mp 134−136 °C; IR (KBr)

ν_max3515, 2933, 2845, 1604, 1564, 1403, 1342, 1210, 1115, 1026, 960,

4-Chloro-1-(2,4-dimethoxyphenoxy)-2-methoxybenzene (14):

yield 0.015 g (10%) as a yellow viscous liquid; IR (KBr) ν_max3083,

1

827 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.00 (d, J = 2.0 Hz, 1H),

1

2934, 2839, 1604, 1508, 1260, 1211, 1120, 1033, 829 cm⁻¹; H NMR

6.89 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 2.5 Hz,

1H), 5.66 (br, s, 1H, OH), 3.89 (s, 3H), 3.82 (s, 3H), 3.70 (s, 3H)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.6 (C), 158.7 (C), 147.2

(C), 142.6 (C), 126.3 (CH), 125.1 (C), 125.1 (C), 118.9 (C), 113.4

(CH), 110.6 (C), 108.8 (CH), 98.2 (CH), 56.1 (CH₃), 55.9 (CH₃),

55.5 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₄Br₂O₄Na [M +

Na]⁺438.9151, found 438.9151.

(500 MHz, CDCl₃) δ 6.92 (t, J = 2.5 Hz, 1H), 6.87 (dd, J = 2.5, 7.5

Hz, 1H), 6.76 (td, J = 2.0, 4.5 Hz, 1H), 6.77−6.75 (m, 2H), 6.40 (td, J

= 3.0, 5.5 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H) ppm; ¹³C

NMR (125 MHz, CDCl₃) δ 157.1 (C), 151.8 (C), 150.0 (C), 146.3

(C), 138.2 (C), 127.2 (C), 121.1 (CH), 120.2 (CH), 116.8 (CH),

112.7 (CH), 103.9 (CH), 100.5 (CH), 56.1 (CH₃), 55.8 (CH₃), 55.5

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₅ClO₄Na [M + Na]⁺

317.0551, found 317.0557.

6-(2,4-Dimethoxyphenyl)-4-ﬂuoro-2-methoxyphenol (15): yield

0.110 g (79%) as a brown viscous liquid; IR (KBr) ν_max3518, 2939,

2835, 1613, 1469, 1370, 1297, 1213, 1156, 1034, 961, 834, 791 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.17 (d, J = 8.5 Hz, 1H), 6.58−6.55

(m, 2H), 6.54−6.53 (m, 2H), 5.71 (s, 1H, OH), 3.82 (s, 3H), 3.78 (s,

3H), 3.76 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.8 (C),

157.1 (d, J = 10.12 Hz, C), 155.1 (C), 147.8 (d, J = 10.75 Hz, C),

139.2 (d, J = 2.75 Hz, C), 132.0 (CH), 125.4 (d, J = 9.38 Hz, C), 118.4

(d, J = 1.5 Hz, C), 108.8 (d, J = 22.38 Hz, CH), 105.1 (CH), 99.0

(CH), 98.4 (d, J = 27.25 Hz, CH), 56.1 (CH₃), 55.8 (CH₃), 55.3

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₅FO₄Na [M + Na]⁺

301.0847, found 301.0850.

6-(2-Bromo-4,6-dimethoxyphenyl)-4-chloro-2-methoxyphenol

(21): yield 0.125 g (67%) as a white solid; mp 132−134 °C; IR (KBr)

ν_max3521, 2940, 1598, 1413, 1312, 1213, 1161, 1032, 885, 830, 734

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.87 (d, J = 2.0 Hz, 1H), 6.84

(d, J = 2.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H),

5.57 (s, 1H, OH), 3.91 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H) ppm; ¹³C

NMR (125 MHz, CDCl₃) δ 160.6 (C), 158.7 (C), 146.9 (C), 142.1

(C), 125.1 (C), 124.5 (C), 123.7 (C), 123.4 (CH), 119.0 (C), 110.7

(CH), 108.8 (CH), 98.3 (CH), 56.1 (CH₃), 56.0 (CH₃), 55.5 (CH₃)

ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₄ClBrO₄Na [M + Na]⁺

394.9656, found 394.9685.

6-(2-Bromo-4,6-dimethoxyphenyl)-4-ﬂuoro-2-methoxyphenol

(22): yield 0.125 g (70%) as a white ﬂuﬀy solid; mp 142−144 °C; IR

(KBr) ν_max3532, 2946, 1600, 1563, 1459, 1309, 1218, 1115, 1034, 956,

1-(2,4-Dimethoxyphenoxy)-4-ﬂuoro-2-methoxybenzene (16):

1

828 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.84 (d, J = 2.5 Hz, 1H),

yield 0.017 g (12%) as a brown viscous liquid; IR (KBr) ν_max3091,

1

2946, 2838, 1611, 1515, 1265, 1205, 1127, 1030, 845 cm⁻¹; H NMR

6.67 (dd, J = 2.0, 10.0 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 6.47 (dd, J =

3.0, 9.0 Hz, 1H), 5.37 (s, 1H, OH), 3.91 (s, 3H), 3.83 (s, 3H), 3.72 (s,

3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.6 (C), 158.7 (C),

155.8 (d, J = 236.0 Hz, C), 146.9 (d, J = 10.75 Hz, C), 139.5 (d, J =

3.38 Hz, C), 125.1 (C), 123.7 (d, J = 10.0 Hz, C), 119.4 (C), 109.2 (d,

J = 22.62 Hz, CH), 108.9 (CH), 98.8 (d, J = 27.38 Hz, CH), 98.4

(CH), 56.1 (CH₃), 55.6 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₅H₁₄FBrO₄Na [M + Na]⁺378.9952, found 378.9971.

(500 MHz, CDCl₃) δ 6.80 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 3.0, 10.0

Hz, 1H), 6.65 (dd, J = 5.5, 9.0 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 6.51

(dd, J = 3.0, 8.0 Hz, 1H), 6.38 (dd, J = 3.0, 9.0 Hz, 1H), 3.86 (s, 3H),

3.81 (s, 3H), 3.79 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 156.6

(C), 151.5 (C), 139.3 (C), 120.0 (CH), 117.5 (d, J = 9.88 Hz, CH),

114.2 (d, J = 9.5 Hz, C), 106.7 (d, J = 22.75 Hz, C), 106.1 (d, J = 22.75

Hz, CH), 103.7 (CH), 100.5 (d, J = 27.25 Hz, CH), 100.4 (CH), 98.8

(C), 56.1 (CH₃), 55.9 (CH₃), 55.6 (CH₃) ppm; HRMS (ESI+) m/z

calcd for C₁₅H₁₅FO₄Na [M + Na]⁺301.0847, found 301.0846.

4-Bromo-6-(2-chloro-4,6-dimethoxyphenyl)-2-methoxyphenol

(17): yield 0.134 g (72%) as a yellow solid; mp 118−120 °C; IR (KBr)

ν_max3531, 2933, 2845, 1606, 1571, 1406, 1310, 1212, 1117, 1033, 948,

4-Bromo-6-(2,4-dimethoxy-6-methylphenyl)-2-methoxyphenol

(23): yield 0.148 g (84%) as a yellow solid; mp 99−101 °C; IR (KBr)

ν_max3526, 2931, 2843, 1602, 1409, 1329, 1207, 1154, 1017, 857, 721

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.99 (d, J = 2.5 Hz, 1H), 6.88

(d, J = 2.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H),

5.49 (br, s, 1H, OH), 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 2.09

(CH₃) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.2 (C), 158.1 (C),

147.4 (C), 142.5 (C), 139.2 (C), 126.4 (CH), 125.3 (C), 116.9 (C),

113.0 (CH), 111.0 (C), 106.5 (CH), 96.3 (CH), 56.1 (CH₃), 55.8

(CH₃), 55.2 (CH₃), 20.2 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₆H₁₇BrO₄Na [M + Na]⁺375.0202, found 375.0202.

1

821, 717 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.00 (d, J = 2.5 Hz,

1H), 6.92 (d, J = 2.5 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.5

Hz, 1H), 5.62 (br, s, 1H, OH), 3.90 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.5 (C), 158.8 (C), 147.2

(C), 142.8 (C), 135.2 (C), 126.4 (CH), 123.2 (C), 116.9 (C), 113.4

(CH), 110.7 (C), 105.9 (CH), 97.7 (CH), 56.1 (CH₃), 56.0 (CH₃),

55.5 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₄BrClO₄Na [M +

Na]⁺394.9656, found 394.9656.

4-Chloro-6-(2,4-dimethoxy-6-methylphenyl)-2-methoxyphenol

(24): yield 0.133 g (86%) as a yellowish brown viscous liquid; IR

(KBr) ν_max3434, 2945, 1600, 1496, 1457, 1345, 1209, 1155, 1052,

4-Chloro-6-(2-chloro-4,6-dimethoxyphenyl)-2-methoxyphenol

(18): yield 0.114 g (69%) as a colorless solid; mp 116−118 °C; IR

(KBr) ν_max3526, 2940, 1603, 1413, 1314, 1214, 1122, 1041, 943, 827,

1

1015, 829 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.86 (d, J = 2.5 Hz,

1H), 6.74 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.43 (d, J = 2.0

Hz, 1H), 5.50 (s, 1H, OH), 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H),

2.10 (CH₃) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.2 (C), 158.0

(C), 147.1 (C), 141.9 (C), 139.2 (C), 124.6 (C), 123.8 (C), 123.4

(CH), 116.9 (C), 110.2 (CH), 106.4 (CH), 96.2 (CH), 56.0 (CH₃),

1

739 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.88 (d, J = 2.0 Hz, 1H),

6.78 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.47 (d, J = 2.0 Hz,

1H), 5.63 (br, s, 1H, OH), 3.90 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.4 (C), 158.8 (C), 147.0

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55.7 (CH₃), 55.2 (CH₃), 20.2 (CH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₆H₁₇ClO₄Na [M + Na]⁺331.0708, found 331.0714.

1-(5-Chloro-2-hydroxy-4-methoxyphenyl)naphthalen-2-ol (31):

yield 0.143 g (95%) as a brown solid; mp 142−144 °C; IR (KBr)

ν_max3487, 2941, 1618, 1486, 1418, 1348, 1205, 1078, 1002, 954, 851,

815 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H), 7.74 (s, 1H),

7.37 (d, J = 8.5 Hz, 1H), 7.33−7.27 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H),

6.92 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 5.75 (br, s, 1H,

OH), 5.44 (br, s, 1H, OH), 3.84 (s, 3H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 150.8 (C), 147.8 (C), 142.7 (C), 132.8 (C), 130.2 (CH),

129.1 (C), 128.1 (CH), 126.7 (CH), 125.2 (C), 124.4 (CH), 123.9

(CH), 123.5 (CH), 121.0 (C), 117.8 (CH), 115.3 (C), 111.6 (CH),

56.3 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₇H₁₃ClO₃Na [M +

Na]⁺323.0445, found 323.0453.

6-(2,4-Dimethoxy-6-methylphenyl)-4-ﬂuoro-2-methoxyphenol

(25): yield 0.111 g (76%) as a yellowish brown viscous liquid; IR

(KBr) ν_max3503, 2943, 2840, 1601, 1423, 1320, 1239, 1126, 1033, 959,

1

840 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.65 (dd, J = 3.0, 9.5 Hz,

1H), 6.49−6.44 (m, 3H), 5.32 (br, s, 1H, OH), 3.91 (s, 3H), 3.85 (s,

3H), 3.73 (s, 3H), 2.11 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ

160.1 (C), 158.0 (C), 157.5 (C), 156.0 (d, J = 235.88 Hz, C), 147.0

(d, J = 10.75 Hz, C), 139.2 (C), 123.8 (d, J = 9.5 Hz, C), 117.3 (C),

109.1 (d, J = 21.75 Hz, CH), 106.5 (CH), 98.3 (d, J = 27.25 Hz, CH),

96.3 (CH), 56.0 (CH₃), 55.7 (CH₃), 55.2 (CH₃), 20.2 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₆H₁₇FO₄Na [M + Na]⁺315.1003,

found 315.1004.

1-(5-Fluoro-2-hydroxy-4-methoxyphenyl)naphthalen-2-ol (32):

yield 0.133 g (94%) as a brown solid; mp 144−146 °C; IR (KBr)

ν_max3390, 2929, 1624, 1431, 1378, 1339, 1222, 1131, 1021, 956, 813,

6-(2,4-Dimethoxyphenyl)-2-methoxy-4-methylphenol (26): yield

1

749 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.77 (d, J = 8.5 Hz, 2H),

0.119 g (87%) as a brown viscous liquid; IR (KBr) ν_max3503, 2934,

1

2842, 1610, 1502, 1412, 1309, 1211, 1110, 1034, 935, 834 cm⁻¹; H

7.43 (d, J = 8.0 Hz, 1H), 7.36−7.33 (m, 1H), 7.32−7.29 (m, 1H), 7.22

(d, J = 9.0 Hz, 1H), 6.72 (dd, J = 2.5, 9.5 Hz, 1H), 6.63 (dd, J = 3.0,

9.0 Hz, 1H), 5.61 (br, s, 2H, OH), 3.86 (s, 3H) ppm; ¹³C NMR (125

MHz, CDCl₃) δ 156.5 (d, J = 238.62 Hz, C), 150.7 (C), 147.8 (d, J =

10.75 Hz, C), 140.0 (d, J = 2.88 Hz, C), 132.8 (C), 130.2 (CH), 129.1

(C), 128.1 (CH), 126.6 (CH), 124.4 (CH), 123.5 (CH), 120.2 (d, J =

9.25 Hz, C), 117.9 (CH), 115.6 (C), 109.7 (d, J = 22.25 Hz, CH), 99.6

(d, J = 27.5 Hz, CH), 56.2 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₇H₁₃FO₃Na [M + Na]⁺307.0741, found 307.0746.

NMR (500 MHz, CDCl₃) δ 7.23 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 1.5

Hz, 1H), 6.75 (d, J = 1.0 Hz, 1H), 6.61−6.59 (m, 2H), 5.77 (s, 1H,

OH), 3.91 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 2.33 (s, 3H) ppm; ¹³C

NMR (125 MHz, CDCl₃) δ 160.5 (C), 157.3 (C), 147.1 (C), 140.9

(C), 132.1 (CH), 129.0 (C), 123.7 (CH), 119.5 (C), 111.14 (CH),

106.1 (C), 105.0 (CH), 99.0 (CH), 55.9 (CH₃), 55.8 (CH₃), 55.4

(CH₃), 21.1 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₆H₁₈O₄Na

[M + Na]⁺297.1097, found 297.1101.

6-(2-Chloro-4,6-dimethoxyphenyl)-2-methoxy-4-methylphenol

(27): yield 0.111 g (72%) as a yellow solid; mp 104−105 °C; IR (KBr)

ν_max3425, 2935, 1599, 1569, 1408, 1304, 1222, 1169, 1060, 1026, 939,

1-(2-Hydroxy-4-methoxy-5-methylphenyl)naphthalen-2-ol (33):

yield 0.135 g (96%) as a brown solid; mp 142−144 °C; IR (KBr)

ν_max3491, 2925, 1606, 1499, 1460, 1313, 1268, 1199, 1142, 1079, 948,

1

848 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.72 (d, J = 1.5 Hz, 1H),

1

851, 810 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.87 (d, J = 2.0 Hz,

6.66 (d, J = 2.0 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.46

(s, 1H, OH), 3.90 (s, 3H), 3.83 (s, 3H), 3.74 (s, 3H), 2.33 (s, 3H)

ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.2 (C), 159.0 (C), 146.3

(C), 141.2 (C), 135.3 (C), 128.7 (C), 124.0 (CH), 121.4 (C), 118.5

(C), 111.2 (CH), 105.9 (CH), 97.8 (CH), 56.2 (CH₃), 55.8 (CH₃),

55.6 (CH₃), 21.3 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₆H₁₇ClO₄Na [M + Na]⁺331.0708, found 331.0728.

1H), 7.85 (d, J = 3.5 Hz, 1H), 7.57 (d, J = 3.0 Hz, 1H), 7.43 (dt, J =

1.5, 7.0 Hz, 1H), 7.40−7.37 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.87 (d,

J = 1.5 Hz, 1H), 6.79 (s, 1H), 5.78 (br, s, 1H, OH), 5.63 (br, s, 1H,

OH), 3.98 (s, 3H), 2.41 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ

150.7 (C), 147.1 (C), 141.6 (C), 133.1 (C), 130.1 (C), 129.6 (CH),

129.0 (C), 128.0 (CH), 126.3 (CH), 124.7 (CH), 124.3 (CH), 123.2

(CH), 119.3 (C), 117.7 (CH), 116.6 (C), 111.9 (CH), 55.9 (CH₃),

21.0 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₈H₁₆O₃Na [M +

Na]⁺303.0992, found 303.0994.

6-(2-Bromo-4,6-dimethoxyphenyl)-2-methoxy-4-methylphenol

(28): yield 0.129 g (73%) as a yellow solid; mp 160−161 °C; IR (KBr)

ν_max3422, 2930, 1602, 1563, 1461, 1305, 1217, 1156, 1024, 936, 845

6-Bromo-1-(5-bromo-2-hydroxy-4-methoxyphenyl)naphthalen-

2-ol (34): yield 0.182 g (86%) as a brown solid; mp 161−162 °C; IR

(KBr) ν_max3483, 2926, 1609, 1476, 1401, 1306, 1260, 1197, 1073, 948,

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.86 (d, J = 2.0 Hz, 1H), 6.74

(d, J = 2.0 Hz, 1H), 6.56 (d, J = 1.0 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H),

5.48 (s, 1H, OH), 3.91 (s, 3H), 3.84 (s, 3H), 3.73 (s, 3H), 2.35 (s,

3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.2 (C), 158.8 (C),

146.2 (C), 140.9 (C), 128.4 (C), 125.4 (C), 123.8 (CH), 123.2 (C),

120.4 (C), 111.1 (CH), 108.8 (CH), 98.3 (CH), 56.0 (CH₃), 55.7

(CH₃), 55.5 (CH₃), 21.2 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₆H₁₇BrO₄Na [M + Na]⁺375.0202, found 375.0210.

6-(2,4-Dimethoxy-6-methylphenyl)-2-methoxy-4-methylphenol

(29): yield 0.127 g (88%) as a yellow solid; mp 110−111 °C; IR (KBr)

ν_max3418, 2924, 1597, 1457, 1315, 1236, 1157, 1036, 939, 835 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 6.70 (s, 1H), 6.52 (s, 1H), 6.48 (d, J =

2.0 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 5.32 (br, s, 1H, OH), 3.91 (s,

3H), 3.84 (s, 3H), 3.73 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H) ppm; ¹³C

NMR (125 MHz, CDCl₃) δ 159.8 (C), 158.1 (C), 146.4 (C), 140.8

(C), 139.2 (C), 128.4 (C), 123.9 (CH), 123.2 (C), 118.4 (C), 110.6

(CH), 106.4 (CH), 96.3 (CH), 55.7 (CH₃), 55.6 (CH₃), 55.1 (CH₃),

21.0 (CH₃), 20.3 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₇H₂₀O₄Na [M + Na]⁺311.1254, found 311.1253.

1

810, 739 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.86 (d, J = 2.0 Hz,

1H), 7.61 (d, J = 8.5 Hz, 1H), 7.33 (dd, J = 2.0, 9.0 Hz, 1H), 7.20−

7.15 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.50

(br, s, 2H, OH), 3.86 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ

151.1 (C), 148.0 (C), 143.2 (C), 131.4 (C), 130.2 (C), 130.0 (CH),

129.8 (CH), 129.3 (CH), 126.7 (CH), 126.4 (CH), 121.0 (C), 119.0

(CH), 117.2 (C), 115.6 (C), 114.5 (CH), 112.4 (C), 56.4 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₇H₁₂Br₂O₃Na [M + Na]⁺444.9045,

found 444.9045.

6-Bromo-1-(5-chloro-2-hydroxy-4-methoxy-phenyl)naphthalen-

2-ol (35): yield 0.167 g (88%) as a brown solid; mp 141−143 °C; IR

(KBr) ν_max3388, 2939, 1587, 1468, 1413, 1334, 1261, 1199, 1068, 951,

1

816, 756 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 1.5 Hz,

1H), 7.78 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 1.5, 9.0 Hz, 1H), 7.35 (dd,

J = 9.0, 15.0 Hz, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 2.0 Hz,

1H), 5.88 (br, s, 1H, OH), 5.49 (br, s, 1H, OH), 4.02 (s, 3H) ppm;

¹³C NMR (125 MHz, CDCl₃) δ 151.1 (C), 147.8 (C), 142.7 (C),

1-(5-Bromo-2-hydroxy-4-methoxyphenyl)naphthalen-2-ol (30):

yield 0.155 g (90%) as a brown solid; mp 148−150 °C; IR (KBr)

ν_max3482, 2926, 1608, 1487, 1401, 1306, 1260, 1197, 1074, 951, 850,

131.4 (C), 130.2 (C), 130.0 (CH), 129.8 (CH), 129.3 (CH), 126.7

(CH), 125.5 (C), 123.8 (CH), 120.4 (C), 119.0 (CH), 117.2 (C),

115.7 (CH), 111.8 (C), 56.4 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₇H₁₂ClBrO₃Na [M + Na]⁺400.9550, found 400.9554.

1

742 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.79 (dd, J = 4.5, 9.0 Hz,

2H), 7.40 (d, J = 8.5 Hz, 1H), 7.36 (dt, J = 1.0, 6.5 Hz, 1H), 7.32 (dt, J

= 1.5, 8.5 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H),

7.06 (d, J = 2.0 Hz, 1H), 5.79 (br, s, 1H, OH), 5.46 (br, s, 1H, OH),

3.91 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 150.8 (C), 148.0

(C), 143.2 (C), 132.8 (C), 130.3 (CH), 129.1 (C), 128.1 (CH), 126.8

(CH), 126.7 (CH), 124.4 (CH), 123.5 (CH), 121.6 (C), 117.8 (CH),

115.1 (C), 114.3 (CH), 112.3 (C), 56.3 (CH₃) ppm; HRMS (ESI+)

m/z calcd for C₁₇H₁₃BrO₃Na [M + Na]⁺366.9940, found 366.9941.

6-Bromo-1-(5-ﬂuoro-2-hydroxy-4-methoxyphenyl)naphthalen-2-

ol (36): yield 0.156 g (86%) as a brown solid; mp 143−144 °C; IR

(KBr) ν_max3376, 2926, 1591, 1493, 1426, 1373, 1192, 1132, 1074, 955,

1

872, 812 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 1.5 Hz,

1H), 7.67 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 2.0, 9.0 Hz, 1H), 7.29 (d, J

= 9.0 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.74 (dd, J = 3.0, 9.5 Hz, 1H),

6.58 (dd, J = 3.0, 9.0 Hz, 1H), 5.63 (br, s, 1H, OH), 5.47 (br, s, 1H,

OH), 3.90 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 156.6 (d, J =

K

DOI: 10.1021/acs.joc.7b00684

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

239.0 Hz, C), 151.0 (C), 147.8 (d, J = 10.75 Hz, C), 140.0 (d, J = 2.75

Hz, C), 131.4 (C), 130.2 (CH), 129.9 (d, J = 26.5 Hz, CH), 129.2

(CH), 126.4 (CH), 119.5 (C), 119.4 (C), 119.1 (CH), 117.2 (C),

116.0 (C), 109.6 (d, J = 22.5 Hz, CH), 99.8 (d, J = 27.5 Hz, CH), 56.3

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₇H₁₂FBrO₃Na [M + Na]⁺

384.9846, found 384.9847.

1-(5-Bromo-2-hydroxy-4-methoxyphenyl)-2-methoxynaphtha-

lene (42): yield 0.145 g (81%) as a white solid; mp 192−193 °C; IR

(KBr) ν_max3490, 2936, 1615, 1487, 1322, 1256, 1085, 848, 739 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 9.0 Hz, 1H), 7.85−7.83

(m, 1H), 7.47−7.45 (dm, 1H), 7.41−7.36 (m, 3H), 7.09 (d, J = 2.5

Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 5.52 (s, 1H, OH), 3.95 (s, 3H), 3.89

(s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 154.2 (C), 147.6 (C),

142.9 (C), 133.1 (C), 130.1 (CH), 129.0 (C), 128.0 (CH), 126.7

(CH), 126.7 (CH), 124.8 (CH), 124.1 (C), 123.7 (CH), 118.7 (C),

113.6 (CH), 113.5 (CH), 111.2 (C), 56.8 (CH₃), 56.2 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₈H₁₅BrO₃Na [M + Na]⁺381.0097,

found 381.0092.

1-(5-Chloro-2-hydroxy-4-methoxyphenyl)-2-methoxynaphtha-

lene (43): yield 0.122 g (78%) as a brown solid; mp 157−158 °C; IR

(KBr) ν_max3478, 2933, 1609, 1476, 1330, 1226, 1088, 954, 815 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 9.0 Hz, 1H), 7.86−7.85

(m, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.42−7.37 (m, 3H), 6.97 (d, J = 2.5

Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 5.53 (s, 1H, OH), 3.95 (s, 3H), 3.91

(s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 154.2 (C), 147.4 (C),

142.4 (C), 133.1 (C), 130.0 (CH), 129.0 (C), 128.0 (CH), 126.7

(CH), 124.8 (CH), 124.2 (C), 123.8 (CH), 123.7 (CH), 123.5 (C),

118.8 (C), 113.6 (CH), 110.7 (CH), 56.7 (CH₃), 56.1 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₈H₁₅ClO₃Na [M + Na]⁺337.0602,

found 337.0599.

1-(5-Fluoro-2-hydroxy-4-methoxyphenyl)-2-methoxynaphtha-

lene (44): yield 0.122 g (82%) as a brown solid; mp 144−145 °C; IR

(KBr) ν_max3452, 2923, 1610, 1425, 1340, 1140, 1027, 956, 816 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 9.0 Hz, 1H), 7.85−7.84

(m, 1H), 7.48−7.47 (m, 1H), 7.41−7.36 (m, 3H), 6.75 (dd, J = 3.0,

10.0 Hz, 1H), 6.61 (dd, J = 2.5, 9.0 Hz, 1H), 5.34 (br, s, 1H, OH),

3.95 (s, 3H), 3.90 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 156.2

(d, J = 236.25 Hz, C), 154.2 (C), 147.3 (d, J = 11.25 Hz, C), 139.8

(C), 133.1 (C), 130.0 (CH), 129.1 (C), 128.0 (CH), 126.6 (CH),

124.8 (CH), 123.7 (CH), 122.7 (d, J = 2.5 Hz, C), 119.2 (CH), 113.7

(C), 109.6 (d, J = 22.5 Hz, CH), 98.6 (d, J = 27.5 Hz, CH), 56.8

(CH₃), 56.1 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₈H₁₅FO₃Na

[M + Na]⁺321.0897, found 321.0886.

6-Bromo-1-(2-hydroxy-4-methoxy-5-methylphenyl)naphthalen-

2-ol (37): yield 0.158 g (88%) as a brown solid; mp 141−142 °C; IR

(KBr) ν_max3314, 2937, 1590 1493, 1418, 1376, 1286, 1214, 1137,

1

1084, 952, 881, 826 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.97 (s,

1H), 7.70 (d, J = 8.0 Hz, 1H), 7.45−7.36 (m, 2H), 7.30 (d, J = 8.0 Hz,

1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.78 (br, s, 1H, OH), 5.62 (br, s, 1H,

OH), 3.93 (s, 3H), 2.37 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ

151.0 (C), 147.1 (C), 141.6 (C), 131.6 (C), 130.3 (C), 130.1 (C),

129.8 (CH), 129.4 (CH), 128.6 (CH), 126.8 (CH), 124.1 (CH), 118.8

(CH), 118.7 (C), 117.0 (C), 116.9 (C), 112.0 (CH), 55.9 (CH₃), 21.0

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₈H₁₅BrO₃Na [M + Na]⁺

381.0097, found 381.0097.

1-(5-Bromo-2-hydroxy-4-methoxyphenyl)-3-methoxynaphtha-

len-2-ol (38): yield 0.169 g (90%) as a brown viscous liquid; IR (KBr)

ν_max3425, 2927, 1607, 1420, 1343, 1221, 1165, 1020, 832, 748 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.68 (d, J = 8.0 Hz, 1H), 7.35 (d, J =

8.5 Hz, 1H), 7.30−7.27 (m, 1H), 7.25−7.22 (m, 1H), 7.13 (s, 1H),

7.04 (s, 2H), 6.07 (br, s, 1H, OH), 5.61 (br, s, 1H, OH), 3.93 (s, 3H),

3.84 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 147.7 (C), 146.9

(C), 143.0 (C), 142.9 (C), 128.8 (C), 128.3 (C), 126.8 (CH), 126.6

(CH), 124.5 (CH), 124.4 (CH), 124.0 (CH), 123.0 (C), 115.6 (C),

113.8 (CH), 111.4 (C), 106.1 (CH), 56.2 (CH₃), 55.8 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₈H₁₅BrO₄Na [M + Na]⁺397.0046,

found 397.0046.

1-(5-Chloro-2-hydroxy-4-methoxyphenyl)-3-methoxynaphtha-

len-2-ol (39): yield 0.152 g (92%) as a brown semisolid; IR (KBr) ν_max

3438, 2926, 1614, 1472, 1422, 1348, 1258, 1161, 1024, 875, 789 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J = 8.0 Hz, 1H), 7.38 (d, J =

8.0 Hz, 1H), 7.36−7.32 (m, 1H), 7.30−7.26 (m, 1H), 7.21 (s, 1H),

6.97 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.06 (br, s, 1H,

OH), 5.57 (br, s, 1H, OH), 4.06 (s, 3H), 3.96 (s, 3H) ppm; ¹³C NMR

(125 MHz, CDCl₃) δ 147.5 (C), 146.9 (C), 142.9 (C), 142.5 (C),

128.8 (C), 128.3 (C), 126.8 (CH), 124.5 (CH), 124.4 (CH), 124.4

(CH), 124.0 (C), 123.6 (CH), 122.4 (C), 115.7 (C), 111.0 (CH),

106.1 (CH), 56.1 (CH₃), 55.8 (CH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₈H₁₅ClO₄Na [M + Na]⁺353.0551, found 353.0550.

1-(2-Hydroxy-3-methoxy-5-methylphenyl)-2-methoxynaphtha-

lene (45): yield 0.123 g (84%) as a yellow solid; mp 178−179 °C (lit.⁶⁴

180 °C); IR (KBr) ν_max3480, 2930, 1616, 1456, 1323, 1253, 1142,

1068, 948, 845 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 8.5

Hz, 1H), 7.85−7.83 (m, 1H), 7.52−7.50 (m, 1H), 7.41 (d, J = 9.0 Hz,

1H), 7.39−7.35 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.68 (s, 1H), 5.40

(s, 1H, OH), 3.96 (s, 3H), 3.90 (s, 3H), 2.38 (s, 3H) ppm; ¹³C NMR

(125 MHz, CDCl₃) δ 154.2 (C), 146.7 (C), 141.3 (C), 133.5 (C),

129.5 (CH), 129.2 (C), 128.8 (C), 127.9 (CH), 126.4 (CH), 125.2

(CH), 124.3 (CH), 123.6 (CH), 122.1 (C), 120.4 (C), 113.9 (CH),

111.1 (CH), 56.9 (CH₃), 55.9 (CH₃), 21.2 (CH₃) ppm; HRMS (ESI

+) m/z calcd for C₁₉H₁₈O₃Na [M + Na]⁺317.1148, found 317.1144.

3′-Methoxy-5′-methylbiphenyl-2,2′,4-triol (46): yield 0.096 g

(78%) as a brown solid; mp 139−140 °C; IR (KBr) ν_max3501,

1-(5-Fluoro-2-hydroxy-4-methoxyphenyl)-3-methoxynaphtha-

len-2-ol (40): yield 0.143 g (91%) as a brown semisolid; IR (KBr) ν_max

3512, 2928, 2853, 1621, 1468, 1425, 1328, 1261, 1121, 1027, 950, 837,

1

799 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.75 (d, J = 8.5 Hz, 1H),

7.44 (d, J = 8.0 Hz, 1H), 7.36 (dt, J = 1.0, 7.0 Hz, 1H), 7.30 (dt, J =

1.0, 7.0 Hz, 1H), 7.21 (s, 1H), 6.77 (dd, J = 2.5, 9.5 Hz, 1H), 6.68 (dd,

J = 2.5, 9.0 Hz, 1H), 6.13 (br, s, 1H, OH), 5.46 (br, s, 1H, OH), 4.03

(s, 3H), 3.93 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 156.2 (d, J

= 236.75 Hz, C), 147.5 (d, J = 10.75 Hz, C), 146.9 (C), 142.9 (C),

139.8 (d, J = 2.62 Hz, C), 128.9 (C), 128.3 (C), 126.8 (CH), 124.5

(CH), 124.4 (CH), 124.0 (CH), 121.5 (d, J = 9.38 Hz, C), 116.1 (C),

109.5 (d, J = 22.12 Hz, CH), 106.1 (CH), 99.1 (d, J = 27.5 Hz, CH),

56.1 (CH₃), 55.9 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₈H₁₅FO₄Na [M + Na]⁺337.0847, found 337.0847.

1-(2-Hydroxy-4-methoxy-5-methylphenyl)-3-methoxynaphtha-

len-2-ol (41): yield 0.143 g (92%) as a reddish brown solid; mp 134−

136 °C; IR (KBr) ν_max3419, 2925, 1463, 1423, 1317, 1263, 1151,

1081, 1028, 943, 835 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.76 (d, J

= 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (dt, J = 1.5, 7.0 Hz, 1H),

7.31 (dt, J = 1.0, 7.0 Hz, 1H), 7.22 (s, 1H), 6.85 (d, J = 1.5 Hz, 1H),

6.77 (d, J = 1.0 Hz, 1H), 5.59 (br, s, 1H, OH), 5.28 (br, s, 1H, OH),

4.03 (s, 3H), 3.95 (s, 3H), 2.41 (s, 3H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 147.1 (C), 146.8 (C), 142.7 (C), 141.3 (C), 129.2 (C),

128.9 (C), 128.6 (C), 126.7 (CH), 124.7 (CH), 124.1 (CH), 124.0

(CH), 123.8 (CH), 120.7 (C), 117.2 (C), 111.5 (CH), 105.7 (CH),

55.8 (CH₃), 55.7 (CH₃), 21.0 (CH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₉H₁₈O₄Na [M + Na]⁺333.1097, found 333.1097.

1

2940, 2836, 1618, 1507, 1402, 1314, 1201, 1108, 1038, 939 cm⁻¹; H

NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H, OH), 9.03 (s, 1H, OH),

8.02 (s, 1H, OH), 6.93 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.55 (s, 1H),

6.38 (s, 1H), 6.29 (dd, J = 1.0, 8.5 Hz, 1H), 3.79 (s, 3H), 2.23 (s, 3H)

ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ 157.5 (C), 155.1 (C), 147.6

(C), 141.1 (C), 131.9 (CH), 127.3 (C), 126.2 (C), 123.8 (CH), 116.9

(C), 111.0 (CH), 106.6 (CH), 102.9 (CH), 55.8 (CH₃), 20.8 (CH₃)

ppm; HRMS (ESI+) m/z calcd for C₁₄H₁₄O₄Na [M + Na]⁺269.0784,

found: 269.0773.

3-Methoxy-5,5′-dimethylbiphenyl-2,2′-diol (47): yield 0.088 g

(72%) as a brown solid; mp 130−131 °C; IR (KBr) ν_max3328,

1

2920, 2858, 1604, 1491, 1368, 1268, 1148, 1095, 913 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 7.12−7.10 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H),

6.77 (s, 1H), 6.74 (s, 1H), 6.32 (s, 2H, OH), 3.92 (s, 3H), 2.36 (s,

3H), 2.34 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 151.1, 146.2,

139.2, 131.2, 130.4, 130.2, 129.8, 125.2, 123.9, 123.7, 117.6, 110.8,

56.0, 21.1, 20.5 ppm; HRMS (ESI+) m/z calcd for C₁₅H₁₆O₃Na [M +

Na]⁺267.0992, found 267.0984.

L

DOI: 10.1021/acs.joc.7b00684

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2-Methoxy-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)phenol (48):

yield 0.066 g (61%) as a colorless liquid; IR (KBr) ν_max3499, 2925,

3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.9 (C), 156.4 (C),

153.6 (C), 147.6 (C), 132.7 (CH), 126.7 (C), 119.5 (C), 117.9 (CH),

116.2 (CH), 114.2 (CH), 106.2 (CH), 99.1 (CH), 56.1 (OCH₃), 55.7

(OCH₃), 55.4 (OCH₃) ppm.

2,6-Di(2,4-dimethoxyphenyl)-4-methoxyphenol (50a): yield 0.027

g (27%) as a white solid; mp 186−188 °C (lit.⁵⁵188−189 °C); IR

(KBr) ν_max3445, 3001, 2937, 2831, 1609, 1508, 1461, 1305, 1205,

1155, 1035, 918, 838, 779 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.32

(s, 1H), 7.30 (s, 1H), 6.83 (s, 2H), 6.63 (dd, J = 2.0, 8.0 Hz, 2H), 6.60

(d, J = 2.5 Hz, 2H), 5.94 (s, 1H, OH), 3.86 (s, 6H), 3.83 (s, 6H), 3.81

(s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.6 (C), 157.2 (C),

152.9 (C), 145.3 (C), 132.4 (CH), 127.5 (C), 120.4 (C), 116.0 (CH),

105.2 (CH), 99.0 (CH), 55.9 (OCH₃), 55.7 (OCH₃), 55.4 (OCH₃)

ppm.

1

2854, 1600, 1507, 1458, 1364, 1271, 1130, 1038, 806, 702 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 6.77−6.76 (m, 1H), 6.73 (s, 1H), 6.71 (s,

1H), 6.25 (t, J = 3.0 Hz, 1H), 6.21−6.20 (m, 1H), 5.72 (s, 1H, OH),

3.93 (s, 3H), 3.58 (s, 3H), 2.34 (s, 3H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 146.4, 141.2, 128.7, 127.4, 123.8, 122.8, 119.3, 111.3, 108.8,

107.6, 55.9, 34.5, 21.0 ppm; HRMS (ESI+) m/z calcd for

C₁₃H₁₅NO₂Na [M + Na]⁺240.0995, found 240.0990.

4-(2,4-Dimethoxyphenyl)-2-methoxy-5-methylphenol (49): yield

0.089 g (65%) as a colorless solid; mp 122−123 °C; IR (KBr) ν_max

3495, 2934, 2862, 1603, 1522, 1410, 1223, 1110, 1030, 939, 838 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 7.08 (d, J = 9.0 Hz, 1H), 6.83 (s, 1H),

6.70 (s, 1H), 6.58−6.55 (m, 2H), 5.58 (s, 1H, OH), 3.87 (s, 3H), 3.85

(s, 3H), 3.77 (s, 3H), 2.05 (s, 3H) ppm; ¹³C NMR (125 MHz,

CDCl₃) δ 160.1 (C), 157.7 (C), 144.4 (C), 144.1 (C), 131.5 (CH),

130.0 (C), 129.6 (C), 123.4 (C), 115.7 (CH), 113.0 (CH), 104.0

(CH), 98.5 (CH), 56.0 (CH₃), 55.4 (CH₃), 55.3 (CH₃), 19.2 (CH₃)

ppm; HRMS (ESI+) m/z calcd for C₁₆H₁₈O₄Na [M + Na]⁺297.1097,

found 297.1074.

2-(2-Chloro-4,6-dimethoxyphenyl)-4-methoxyphenol (51): yield

0.091 g (62%) as a white solid; mp 108−110 °C; IR (KBr) ν_max3459,

2996, 2940, 2837, 1603, 1569, 1480, 1273, 1210, 1147, 1037, 941, 809

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.93 (d, J = 8.5 Hz, 1H), 6.86

(dd, J = 3.0, 9.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 3.5 Hz,

1H), 6.49 (d, J = 2.0 Hz, 1H), 4.61 (s, 1H, OH), 3.85 (s, 3H), 3.77 (s,

3H), 3.75 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 160.8 (C),

158.9 (C), 153.2 (C), 147.4 (C), 136.0 (C), 122.6 (C), 116.9 (CH),

116.8 (CH), 116.5 (CH), 115.0 (CH), 106.6 (CH), 97.9 (CH), 56.2

(OCH₃), 55.7 (OCH₃), 55.7 (OCH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₅H₁₅O₄ClNa [M + Na]⁺317.0551, found 317.0551.

4-Bromo-2-(2,4-Dimethoxyphenyl)-3-methyl-6-methoxyphenol

(49a): yield 0.086 g (55%) as a pale yellow solid; mp 155−157 °C; IR

(KBr) ν_max3410, 2976, 2838, 1608, 1512, 1472, 1437, 1262, 1115, 934,

1

825 cm−¹; H NMR (400 MHz, CDCl₃) δ 7.06 (s,1H), 7.02 (d, J =

8.8 Hz, 1H), 6.62−6.54 (m, 2H), 5.38 (s, 1H, OH), 3.89 (s, 3H), 3.86

(s, 3H), 3.74 (s, 3H), 2.04 (s, 3H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ 160.8 (C), 157.9 (C), 145.0 (C) 142.6 (C), 131.7 (CH),

129.9 (C), 125.7 (CH), 117.2 (C), 114.0 (CH), 113.9 (CH), 104.6

(CH), 99.0 (CH), 56.2 (OCH₃), 55.6 (OCH₃), 55.3 (OCH₃), 19.9

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₆H₁₇BrO₄Na [M + Na]⁺

375.0202, found 375.0207.

2-(2,4,6-Trimethoxyphenyl)-4-methoxyphenol (52): yield 0.066 g

(45%) as a colorless solid; mp 140−142 °C (lit.⁵³141−143 °C); IR

(KBr) ν_max3432, 2951, 2899, 2833, 1609, 1485, 1418, 1336, 1269,

1

1209, 1155, 1126, 1035, 807 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

6.95 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 3.4, 8.8 Hz, 1H), 6.76 (d, J = 2.8

Hz, 1H), 6.27 (s, 2H), 5.04 (s, 1H, OH), 3.87 (s, 3H), 3.77 (s, 3H),

3.76 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 161.3 (C), 158.5

(C), 152.7 (C), 147.7 (C), 121.6 (C), 117.4 (CH), 116.5 (CH), 114.0

(CH), 106.3 (C), 91.1 (CH), 55.8 (OCH₃), 55.4 (OCH₃), 55.2

(OCH₃) ppm.

2,6-Di(2,4,6-trimethoxyphenyl)-4-methoxyphenol (52a): yield

0.037 g (32%) as a brownish solid; mp 201−203 °C; IR (KBr) ν_max

3428, 2998, 2931, 2842, 1607, 1509, 1416, 1330, 1227, 1154, 1122

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.77 (s, 2H), 6.25 (s, 4H), 5.15

(s, 1H), 3.86 (s, 6H), 3.76 (s, 3H), 3.75 (s, 12H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 160.9 (C), 158.6 (C), 152.0 (C), 145.9 (C), 122.1

(C), 116.9 (CH), 108.3 (C), 91.2 (CH), 56.0 (OCH₃), 56.0 (OCH₃),

55.3 (OCH₃) ppm; HRMS (ESI+) m/z calcd for C₂₅H₂₈O₈Na [M +

Na]⁺479.1676, found 479.1676.

2-(2,4-Dimethoxyphenyl)-6-methoxy-4-phenylphenol (49b): yield

0.100 g (60%) as a viscous yellow liquid; IR (KBr) ν_max3430, 2959,

1

2925, 2852, 1608, 1511, 1460, 1304, 1260, 1102, 923, 803 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 7.60 (s,1H), 7.58 (s, 1H), 7.42 (t, J = 7.6

Hz, 2H), 7.33−7.28 (m, 2H), 7.12 (d, J = 5.2 Hz, 2H), 6.63 (d, J = 6.4

Hz, 2H), 5.97 (s, 1H, OH), 4.00 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H)

ppm; ¹³C NMR (100 MHz, CDCl₃) δ 160.7 (C), 157.3 (C), 147.5

(C), 142.8 (C), 141.3 (C), 133.0 (C), 132.4 (CH), 132.1 (CH), 128.6

(CH), 126.9 (C), 125.5 (C), 122.5 (CH), 122.3 (CH), 119.2 (C),

109.1 (CH), 108.9 (CH), 105.1 (CH), 99.0 (CH), 56.1 (OCH₃), 55.9

(OCH₃), 55.4 (OCH₃) ppm; HRMS (ESI+) m/z calcd for

C₂₁H₂₀O₄Na [M + Na]⁺359.1253, found 359.1275.

General Procedure for the Synthesis of Unsymmetrical

Biaryl Derivatives 50−61. To a solution of 4-methoxy derivatives

(6−8, 0.5 mmol) in dry methanol (3 mL) was added solid PhI(OAc)₂

(DIB, 0.161 g, 0.5 mmol) at room temperature, and the mixture was

stirred for 10 min. After complete conversion of the 4-methoxy

derivatives into p-quinone monoketals (6a−8a), methanol was

removed under reduced pressure. The residue was dissolved in dry

CH₂Cl₂(5 mL) (for 9a−c,e) or a 4:1 mixture of dry CH₂Cl₂/

acetonitrile (5 mL) (for 9f), and the 1,3-dimethoxybenzene derivative/

dihydroxybenzene (2 equiv, 1 mmol) was added followed by BF₃·OEt₂

(0.5 mmol, 1 equiv) at 0 °C. The yellow color of the p-quinone

monoketals disappeared by the addition of BF₃·OEt₂, indicating the

completion of the reaction. After completion of the reaction, as

checked by TLC, the reaction was quenched by adding a saturated

NaHCO₃solution and the aqueous phase was extracted twice with

CH₂Cl₂/ethyl acetate (2 × 10 mL). The combined extract was dried

over anhydrous Na₂SO₄and evaporated to dryness. The residue was

puriﬁed by silica gel column chromatography by using ethyl acetate

(10−30%) in hexanes as an eluent to give the unsymmetrical biaryls

50−61.

2-(2,4-Dihydoxyphenyl)-4-methoxyphenol (53): yield 0.082 g

(71%) as a viscous liquid; IR (KBr) ν_max3373, 2940, 2834, 1620,

1

1495, 1419, 1276, 1209, 1205, 1167, 1035, 973, 814 cm⁻¹; H NMR

(400 MHz, CDCl₃with 1 drop of DMSO) δ 7.12 (d, J = 8.0 Hz, 1H),

6.94 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 3.2, 8.8 Hz, 1H), 6.77 (d, J = 3.2

Hz, 1H), 6.54−6.48 (m, 2H), 6.07 (br s, 1H, OH), 5.51 (br s, 1H,

OH), 5.45 (br s, 1H, OH), 3.78 (s, 3H) ppm; ¹³C NMR (100 MHz,

CDCl₃with 1 drop of DMSO) δ 157.6 (C), 153.6 (C), 152.7 (C),

146.4 (C), 131.3 (CH), 131.2 (CH), 126.8 (C), 116.8 (CH), 115.4

(CH), 112.8 (C), 107.8 (CH), 103.2 (CH), 54.9 (OCH₃) ppm.

2-(2,4-Dimethoxyphenyl)-6-bromo-4-methoxyphenol (54): yield

0.111 g (66%) as a brown solid; mp 93−94 °C; IR (KBr) ν_max3431,

3004, 2937, 2837, 1587, 1467, 1410, 1328, 1200, 1125, 1033, 940, 815

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.21 (d, J = 8.0 Hz, 1H), 7.09

(d, J = 2.0 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H),

6.60 (s, 1H), 6.09 (s, 1H, OH), 3.86 (s, 3H), 3.86 (s, 3H), 3.77 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 161.1 (C), 156.6 (C),

153.3 (C), 144.5 (C), 132.5 (CH), 127.6 (C), 118.9 (CH), 117.0

(CH), 116.6 (CH), 113.4 (C), 105.8 (CH), 99.0 (CH), 56.0 (OCH₃),

55.9 (OCH₃), 55.5 (OCH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₅H₁₅O₄BrNa [M + Na]⁺361.0045, found 361.0061.

2-(2-Chloro-4,6-dimethoxyphenyl)-6-bromo-4-methoxyphenol

(55): yield 0.122 g (66%) as a white solid; mp 123−125 °C; IR (KBr)

ν_max3485, 3010, 2975, 2928, 2825, 1605, 1562, 1468, 1409, 1296,

1215, 1116, 1033, 936, 819, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.08 (d, J = 3.2 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.67 (d, J = 2.4 Hz,

2-(2,4-Dimethoxyphenyl)-4-methoxyphenol (50): yield 0.049 g

(38%) as a white solid; mp 117−118 °C (lit.⁵⁵117−118 °C); IR

(KBr) ν_max3421, 2984, 2938, 2831, 1609, 1393, 1346, 1299, 1205,

1154, 1043, 1014, 849, 761, 632 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ

7.27 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.85 (dd, J = 3.0, 9.0

Hz, 1H), 6.80−6.78 (m, 1H), 6.66 (dd, J = 2.0, 8.0 Hz, 1H), 6.62 (d, J

= 2.0 Hz, 1H), 5.90 (s, 1H, OH), 3.88 (s, 3H), 3.86 (s, 3H), 3.80 (s,

M

DOI: 10.1021/acs.joc.7b00684

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1H), 6.47 (d, J = 2.0 Hz, 1H), 5.10 (s, 1H, OH), 3.84 (s, 3H), 3.76 (s,

3H), 3.73 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 160.7 (C),

158.7 (C), 153.0 (C), 144.4 (C), 135.4 (C), 123.7 (C), 117.4 (CH),

117.3 (CH), 117.1 (CH), 110.1(C), 106.1 (CH), 97.7 (CH), 56.1

(OCH₃), 55.8 (OCH₃), 55.6 (OCH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₅H₁₄O₄BrClNa [M + Na]⁺394.9656, found 394.9656.

2-(2,4,6-Trimethoxyphenyl)-6-bromo-4-methoxyphenol (56):

yield 0.126 (68%) as a brown solid; mp 175−177 °C; IR (KBr)

ν_max3432, 2951, 2899, 2833, 1609, 1485, 1418, 1336, 1269, 1209,

1155, 1126, 1035, 807 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.06 (d, J

= 3.2 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 6.25 (s, 2H), 5.35 (s, 1H,

OH), 3.86 (s, 3H), 3.75 (s, 3H), 3.75 (s, 6H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 161.6 (C), 158.5 (C), 152.8 (C), 144.7 (C), 122.7

(C), 117.9 (CH), 116.8 (CH), 110.1 (C), 106.1 (C), 91.0 (CH), 55.9

(OCH₃), 55.7 (OCH₃), 55.3 (OCH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₆H₁₇O₅BrNa [M + Na]⁺391.0151, found 391.0151.

General Procedure for the Synthesis of Unsymmetrical

Biaryl Derivatives 62−73. To a solution of 4-methoxy derivatives

(6−8, 0.5 mmol) in dry methanol (3 mL) was added solid PhI(OAc)₂

(DIB, 0.5 mmol, 0.161 g) at room temperature, and the mixture was

stirred for 10 min. After complete conversion of the 4-methoxyphenols

6−8 into p-quinone monoketals 6a−8a, methanol was removed under

reduced pressure. The residue was dissolved in a 4:1 mixture of dry

CH₂Cl₂/CH₃CN (5 mL) (for 10a−c) or dry CH₂Cl₂(5 mL) (for

10d), and the 1,3-naphthalene derivative (2 equiv, 1 mmol) was added

followed by BF₃·OEt₂(1 equiv, 0.5 mmol) at 0 °C. The yellow color of

the p-quinone monoketals disappeared by the addition of BF₃·OEt₂,

indicating the completion of the reaction. After completion of the

reaction, as checked by TLC, the reaction was quenched by adding a

saturated NaHCO₃solution and the aqueous phase was extracted

twice with CH₂Cl₂/ethyl acetate (2 × 10 mL). The combined extract

was dried over anhydrous Na₂SO₄and evaporated to dryness. The

residue was puriﬁed by silica gel column chromatography by using

ethyl acetate (10−30%) in hexanes as an eluent to give the

unsymmetrical biaryls 62−73.

2-(2,4-Dihydoxyphenyl)-6-bromo-4-methoxyphenol (57): yield

0.104 g (67%) as a white solid; mp 166−168 °C; IR (KBr) ν_max

3360, 2936, 2825, 1601, 1465, 1398, 1348, 1255, 1205, 1173, 971, 776

1-(2-Hydroxy-5-methoxyphenyl)naphthalen-2-ol (62):⁶⁰yield

0.118 g (89%) as a brownish viscous liquid; IR (KBr) ν_max3413,

3057, 3001, 2938, 2837, 1619, 1499, 1424, 1339, 1271, 1208, 1033,

1

cm⁻¹; H NMR (400 MHz, CDCl₃with 1 drop of DMSO) δ 9.49 (s,

1H, OH), 8.64 (s, 1H, OH), 7.53 (s, 1H, OH), 7.06−7.00 (m, 2H),

6.75−6.72 (m, 1H), 6.55−6.52 (m, 1H), 6.49−6.43 (m, 1H), 3.71 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃with 1 drop of DMSO) δ

158.3 (C), 153.5 (C), 153.2 (C), 144.3 (C), 132.2 (CH), 129.0 (C),

116.5 (CH), 116.5 (CH), 115.9 (CH), 112.2 (C), 108.6 (CH), 103.1

(CH), 55.7 (OCH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₃H₁₁O₄BrNa [M + Na]⁺332.9732, found 332.9725.

1

953, 816, 752 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.87−7.81 (m,

2H), 7.42−7.33 (m, 3H), 7.28 (dd, J = 1.2, 8.8 Hz, 1H), 7.06 (dd, J =

1.6, 8.8 Hz, 1H), 6.98 (dt, J = 2.8, 8.8 Hz, 1H), 6.79 (d, J = 3.2 Hz,

1H), 5.46 (s, 1H, OH), 4.68 (s, 1H, OH), 3.77 (s, 3H) ppm; ¹³C

NMR (100 MHz, CDCl₃) δ 153.7 (C), 151.4 (C), 148.0 (C), 132.9

(C), 130.5 (CH), 129.0 (C), 128.1 (CH), 127.0 (CH), 124.1 (CH),

123.7 (CH), 120.0 (C), 117.7 (CH), 117.6 (CH), 117.2 (CH), 116.3

(CH), 114.6 (C), 55.6 (OCH₃) ppm.

2-(2,4-Dimethoxyphenyl)-6-methyl-4-methoxyphenol (58): yield

0.085 g (62%) as an orange viscous liquid; IR (KBr) ν_max3429, 3007,

1

2942, 2836, 1610, 1471, 1301, 1205, 1159, 1038, 836, 771 cm⁻¹; H

1-(3-Bromo-2-hydroxy-4-methoxyphenyl)naphthalen-2-ol (63):

yield 0.136 g (79%) as a white solid; mp 163−165 °C; IR (KBr)

ν_max3494, 3057, 3028, 2948, 2907, 2831, 1612, 1569, 1469, 1426,

NMR (500 MHz, CDCl₃) δ 7.16 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H),

6.56−6.50 (m, 3H), 5.72 (s, OH, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.68

(s, 3H), 2.22 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 160.7 (C),

156.4 (C), 152.9 (C), 145.7 (C), 132.7 (CH), 126.8 (C), 126.0 (C),

119.6 (C), 115.8 (CH), 113.4 (CH), 105.9 (CH), 98.9 (CH), 55.9

(OCH₃), 55.5 (OCH₃), 55.3 (OCH₃), 16.7 (CH₃) ppm; HRMS (ESI

+) m/z calcd for C₁₆H₁₈O₄Na [M + Na]⁺297.1097, found 297.1068.

2-(2-Chloro-4,6-dimethoxyphenyl)-6-methyl-4-methoxyphenol

(59): yield 0.092 g (60%) as a white solid; mp 134−135 °C; IR (KBr)

ν_max3463, 3010, 2943, 2837, 1603, 1469, 1304, 1213, 1149, 1043, 941,

1

1388, 1205, 1179, 1037, 811 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

7.88−7.81 (m, 2H), 7.42−7.35 (m, 3H), 7.30−7.23 (m, 2H), 6.84−

6.81 (m, 1H), 5.26 (s, 1H, OH), 5.19 (s, 1H, OH), 3.78 (s, 3H) ppm;

¹³C NMR (100 MHz, CDCl₃) δ 153.9 (C), 151.0 (C), 145.0 (C),

132.7 (C), 130.7 (CH), 129.1 (C), 128.2 (CH), 127.1 (CH), 124.1

(CH), 123.8 (CH), 121.3 (C), 118.9 (CH), 117.8 (CH), 117.1 (CH),

115.1 (C), 111.3 (C), 56.0 (OCH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₇H₁₃O₃BrNa [M + Na]⁺366.9940, found 366.9947.

1

821 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 6.76−6.75 (m, 1H), 6.70

(d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H),

4.52 (s, 1H, OH), 3.85 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 2.30 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 160.7 (C), 159.0 (C),

152.5 (C), 145.6 (C), 136.1 (C), 125.6 (C), 121.9 (C), 117.0 (C),

116.6 (CH), 113.8 (CH), 106.5 (CH), 97.9 (CH), 56.1 (OCH₃), 55.6

(OCH₃), 55.6 (OCH₃), 16.6 (CH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₆H₁₇O₄ClNa [M + Na]⁺331.0707, found 331.0704.

1-(3-Methyl-2-hydroxy-4-methoxyphenyl)naphthalen-2-ol (64):

yield 0.108 g (77%) as a brown solid; mp 120−122 °C; IR (KBr)

ν_max3489, 3459, 3057, 2996, 2939, 2825, 1624, 1597, 1471, 1385,

1

1189, 1143, 1053, 813, 752 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

7.87−7.81 (m, 2H), 7.42−7.33 (m, 3H), 7.29 (d, J = 9.2 Hz, 1H), 6.89

(dd, J = 0.8, 3.2 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 5.42 (s, 1H, OH),

4.60 (s, 1H, OH), 3.75 (s, 3H), 2.35 (s, 3H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 153.4 (C), 151.6 (C), 146.5 (C), 132.9 (C), 130.7

(CH), 129.0 (C), 128.2 (CH), 127.2 (CH), 127.0 (C), 124.2 (CH),

123.8 (CH), 118.6 (C), 118.2 (C), 117.6 (CH), 114.3 (C), 112.9

(CH), 55.6 (OCH₃), 16.6 (CH₃) ppm; HRMS (ESI+) m/z calcd for

C₁₈H₁₆O₃Na [M + Na]⁺303.0991, found 303.0975.

2-(2,4,6-Trimethoxyphenyl)-6-methyl-4-methoxyphenol (60):

yield 0.103 g (68%) as a brown solid; mp 137−139 °C; IR (KBr)

ν_max3463, 3013, 2944, 2836, 1608, 1470, 1331, 1225, 1153, 942, 804

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 6.72 (d, J = 4.0 Hz, 1H), 6.58

(d, J = 3.6 Hz, 1H), 6.26 (s, 2H), 4.97 (s, 1H, OH), 3.87 (s, 3H), 3.76

(s, 6H), 3.75 (s, 3H), 2.29 (s, 3H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ 161.4 (C), 158.7 (C), 152.3 (C), 146.0 (C), 125.7 (C),

120.7 (C), 116.0 (CH), 114.6 (CH), 106.5 (C), 91.1 (CH), 56.0

(OCH₃), 55.5 (OCH₃), 55.4 (OCH₃), 16.7 (CH₃) ppm; HRMS (ESI

+) m/z calcd for C₁₇H₂₀O₅Na [M + Na]⁺327.1202, found 327.1203.

2-(2,4-Dihydoxyphenyl)-4-methoxy-6-methylphenol (61): yield

0.080 (65%) as a white solid; mp 129−131 °C; IR (KBr) ν_max3413,

3307, 3169, 2990, 2919, 2834, 1612, 1480, 1203, 1162, 1055, 974, 847

cm⁻¹; ¹H NMR (400 MHz, CDCl₃with 1 drop of DMSO) δ 7.10 (d, J

= 8.8 Hz, 1H), 6.76 (dd, J = 0.8, 0.4 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H),

6.51 (sextet, J = 2.4 Hz, 2H), 5.81 (br s, 1H, OH), 5.44 (br s, 1H,

OH), 5.14 (br s, 1H, OH), 3.76 (s, 3H), 2.30 (s, 3H) ppm; ¹³C NMR

(100 MHz, CDCl₃with 1 drop of DMSO) δ 157.7 (C), 153.7 (C),

153.2 (C), 145.5 (C), 132.4 (CH), 127.4 (C), 126.3 (C), 117.2 (C),

115.9 (CH), 113.2 (CH), 108.8 (CH), 103.3 (CH), 55.6 (OCH₃), 16.9

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₄H₁₄O₄Na [M + Na]⁺

269.0784, found 269.0773.

6-Bromo-1-(2-hydroxy-5-methoxyphenyl)naphthalen-2-ol (65):

yield 0.141 g (82%) as a brown solid; mp 157−159 °C; IR (KBr)

ν_max3286, 3001, 2940, 1533, 1491, 1335, 1267, 1205, 1163, 1037, 942,

1

877, 762 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 2.0 Hz,

1H), 7.77 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 2.0, 8.8 Hz, 1H), 7.33−

7.27 (m, 2H), 7.08 (d, J = 9.2 Hz, 1H), 7.01 (dd, J = 2.8, 8.8 Hz, 1H),

6.77 (d, J = 3.2 Hz, 1H), 5.37 (s, 1H, OH), 4.52 (s, 1H, OH), 3.79 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 154.1 (C), 151.8 (C),

148.0 (C), 131.5 (C), 130.4 (CH), 130.2 (C), 130.2 (CH), 129.8

(CH), 126.1 (CH), 119.0 (CH), 118.8 (C), 117.6 (CH), 116.9 (CH),

116.0 (CH), 114.5 (C), 55.8 (OCH₃) ppm; HRMS (ESI+) m/z calcd

for C₁₇H₁₃O₃BrNa [M + Na]⁺366.9940, found 366.9940.

6-Bromo-1-(3-bromo-2-hydroxy-5-methoxyphenyl)naphthalen-

2-ol (66): yield 0.159 g (75%) as a white solid; mp 181−183 °C; IR

(KBr) ν_max3496, 3420, 3066, 2978, 2933, 2837, 1590, 1468, 1418,

1

1383, 1334, 1196, 1129, 1038, 852, 816 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 7.85 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.32 (dd,

N

DOI: 10.1021/acs.joc.7b00684

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

J = 2.4, 9.2 Hz, 1H), 7.17−7.09 (m, 3H), 6.67 (d, J = 3.2 Hz, 1H), 5.17

(s, 1H, OH), 5.08 (s, 1H, OH), 3.65 (s, 3H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 154.0 (C), 151.2 (C), 144.9 (C), 131.4 (C), 130.2

(CH), 130.1 (CH), 129.6 (CH), 126.1 (CH), 120.9 (C), 118.9 (CH),

118.8 (CH), 117.5 (CH), 117.2 (C), 111.5 (C), 56.0 (OCH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₇H₁₂O₃Br₂Na [M + Na]⁺444.9045,

found 444.9045.

6-Bromo-1-(3-methyl-2-hydroxy-4-methoxyphenyl)naphthalen-

2-ol (67): yield 0.130 g (73%) as a brown solid; mp 123−125 °C; IR

(KBr) ν_max3260, 2996, 2960, 2828, 1589, 1495, 1468, 1335, 1197,

1060, 958, 860, 818 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J =

2.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 2.0, 8.0 Hz, 1H),

7.32−7.26 (m, 2H), 6.89 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H),

5.41 (s, 1H, OH), 4.48 (s, 1H, OH), 3.76 (s, 3H), 2.34 (s, 3H) ppm;

¹³C NMR (100 MHz, CDCl₃) δ 153.4 (C), 151.8 (C), 146.3 (C),

(KBr) ν_max3489, 3051, 3004, 2934, 2828, 1617, 1468, 1419, 1263,

1144, 1043, 806 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 9.2

Hz, 1H), 7.87−7.83 (m, 1H), 7.50−7.35 (m, 4H), 7.19 (d, J = 3.2 Hz,

1H), 6.79 (d, J = 3.2 Hz, 1H), 5.14 (s, 1H, OH), 3.91 (s, 3H), 3.78 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 154.2 (C), 153.2 (C),

144.8 (C), 133.2 (C), 130.5 (CH), 129.1 (C), 128.0 (CH), 127.0

(CH), 124.7 (CH), 124.4 (C), 123.9 (CH), 118.8 (C), 117.4 (CH),

113.3 (CH), 110.4 (CH), 56.7 (OCH₃), 55.8 (OCH₃) ppm; HRMS

(ESI+) m/z calcd for C₁₈H₁₅O₃BrNa [M + Na]⁺397.0045, found

397.0039.

1-(3-Methyl-2-hydroxy-4-methoxyphenyl)-3-methoxynaphtha-

lene (73): yield 0.101 g (69%) as a white solid; mp 136−138 °C; IR

(KBr) ν_max3532, 3521, 3056, 2929, 2839, 1618, 1593, 1470, 1378,

1263, 1167, 1048, 862, 738 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.95

(d, J = 9.2 Hz, 1H), 7.87−7.82 (m, 1H), 7.56−751 (m, 1H), 7.42−

7.36 (m, 3H), 6.84 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 4.67

(s, 1H, OH), 3.91 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H) ppm; ¹³C NMR

(100 MHz, CDCl₃) δ 154.3 (C), 152.6 (C), 146.0 (C), 133.6 (C),

130.4 (CH), 129.3 (C), 128.0 (CH), 127.0 (CH), 125.9 (C), 125.1

(CH), 124.0 (C), 122.3 (C), 118.8 (C), 116.6 (CH), 113.8 (CH),

113.3 (CH), 56.7 (OCH₃), 55.6 (OCH₃), 16.7 (CH₃) ppm; HRMS

(ESI+) m/z calcd for C₁₉H₁₈O₃Na [M + Na]⁺317.1148, found

317.1149.

131.5 (C), 130.3 (CH), 130.1 (C), 130.1 (CH), 129.6 (CH), 127.1

(C), 126.1 (CH), 118.7 (CH), 118.3 (CH), 118.2 (C), 117.5 (C),

114.8 (C), 112.9 (CH), 56.6 (OCH₃), 16.6 (CH₃) ppm; HRMS (ESI

+) m/z calcd for C₁₈H₁₅O₃BrNa [M + Na]⁺381.0096, found

381.0096.

1-(2-Hydroxy-5-methoxyphenyl)-3-methoxynaphthalen-2-ol

(68): yield 0.131 g (89%) as a brownish viscous liquid; IR (KBr) ν_max

3429, 3066, 3005, 2930, 2834, 1616, 1508, 1499, 1466, 1423, 1341,

1261, 1206, 1027, 905, 810 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.75

(d, J = 8.8 Hz, 1H), 7.50−7.46 (m, 2H), 7.40−7.35 (m, 1H), 7.33−

7.27 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 3.2, 8.8 Hz, 1H),

6.83 (d, J = 3.2 Hz, 1H), 6.20 (s, 1H, OH), 4.79 (s, 1H, OH), 4.06 (s,

3H), 3.77 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 153.3 (C),

147.7 (C), 146.9 (C), 143.1 (C), 129.1 (C), 128.3 (C), 126.8 (C),

124.7 (CH), 124.4 (CH), 124.2 (CH), 121.8 (C), 117.0 (CH), 116.4

(CH), 115.7 (CH), 115.4 (C), 106.3 (CH), 55.8 (OCH₃), 55.5

(OCH₃) ppm; HRMS (ESI+) m/z calcd for C₁₈H₁₆O₄Na [M + Na]⁺

319.0940, found 319.0939.

1-(3-Bromo-2-hydroxy-4-methoxyphenyl)-3-methoxynaphtha-

len-2-ol (69): yield 0.144 g (77%) as a brownish viscous liquid; IR

(KBr) ν_max3423, 1724, 1615, 1571, 1470, 1424, 1259, 1210, 1032, 832,

753 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76−7.72 (m, 1H), 7.42−

7.27 (m, 3H), 7.23 (s 1H), 7.19 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 3.2

Hz, 1H), 6.14 (s, 1H, OH), 5.17 (s, 1H, OH), 4.06 (s, 3H), 3.77 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 153.4 (C), 146.8 (C),

144.7 (C), 143.0 (C), 129.0 (C), 128.3 (C), 126.9 (CH), 124.9 (CH),

124.3 (CH), 123.2 (C), 117.9 (C), 117.2 (C), 115.9 (C), 110.7 (C),

106.4 (C), 56.0 (OCH₃), 55.9 (OCH₃) ppm; HRMS (ESI+) m/z

calcd for C₁₈H₁₅O₃BrNa [M + Na]⁺381.0096, found 381.0081.

1-(3-Methyl-2-hydroxy-4-methoxyphenyl)-2-methoxynaphtha-

len-2-ol (70): yield 0.116 g (75%) as a brown solid; mp 160−162 °C;

IR (KBr) ν_max3487, 3439, 3078, 3004, 2922, 2831, 1600, 1470, 1426,

157, 1198, 1058, 903, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76

(d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.40−7.27 (m, 2H), 7.23

(s, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 6.17 (s,

1H), 4.72 (s, 1H, OH), 4.05 (s, 3H), 3.76 (s, 3H), 2.36 (s, 3H) ppm;

¹³C NMR (100 MHz, CDCl₃) δ 152.9 (C), 147.0 (C), 146.0 (C),

General Procedure for the Synthesis of Unsymmetrical

Biaryls 74−78. To a stirred solution of a p-quinone monoketal (7b or

7c, 0.5 mmol) in a 4:1 mixture of dry CH₂Cl₂/CH₃CN (5 mL)(for

10a,c) or dry CH₂Cl₂(5 mL) (for 9a and 10d) was added 1,3-

dimethoxybenzene/naphthalene derivatives (2 equiv, 1 mmol)

followed by BF₃·OEt₂(1 equiv, 0.5 mmol) at 0 °C. The yellow

color of p-quinone monoketals disappeared by the addition of BF₃·

OEt₂, indicating the completion of the reaction. After completion of

the reaction, as checked by TLC, the reaction was quenched by adding

a saturated NaHCO₃solution and the aqueous phase was extracted

twice with CH₂Cl₂/ethyl acetate (2 × 10 mL). The combined extract

was dried over anhydrous Na₂SO₄and evaporated to dryness. The

residue was puriﬁed by silica gel column chromatography by using

ethyl acetate (10−30%) in hexanes as an eluent to give the

unsymmetrical biaryls 74−78.

1

2-(2,4-Dimethoxyphenyl)-4-ethoxyphenol (74): yield calcd by H

NMR spectrum 0.036 g (26%) [R = Et], 0.007 g (5%) [R = Me] as a

brownish viscous liquid; IR (KBr) ν_max3422, 2972, 2931, 2834, 1612,

1

1498, 1302, 1261, 1205, 1160, 1044, 822 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 7.29−7.25 (m, 1H), 6.97−6.92 (m, 1H), 6.86−6.81 (m,

1H), 6.78 (d, J = 3.2 Hz, 1H), 6.67−6.62 (m, 1H), 6.62−6.60 (m,

1H), 5.89 (s, 1H), 4.00 (q, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H),

3.79 (s, 0.58H), 1.40 (t, J = 7.2 Hz, 2.66H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 160.8 (C), 156.3 (C), 153.0 (C), 147.5 (C), 132.7

(CH), 126.7 (C), 119.5 (CH), 117.9 (C), 116.9 (CH), 114.9 (CH),

106.1 (CH), 99.0 (CH), 63.9 (CH₂), 56.1 (OCH₃), 55.5 (OCH₃), 14.9

(CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₆H₁₈O₄Na [M + Na]⁺

297.1097, found 297.1097.

2,6-Di(2,4-dimethoxyphenyl)-4-ethoxyphenol (74a): yield 0.030 g

(29%) as a white solid; mp 143−145 °C; IR (KBr) ν_max3434, 3001,

2933, 2838, 1610, 1508, 1401, 1304, 1206, 1157, 1034, 951, 837, 788

143.2 (C), 129.2 (C), 128.5 (C), 126.9 (CH), 126.4 (C), 124.9 (CH),

124.6 (CH), 124.4 (CH), 120.8 (C), 117.3 (CH), 115.7 (C), 113.3

(CH), 106.4 (CH), 56.0 (OCH₃), 55.6 (OCH₃), 16.7 (CH₃) ppm;

HRMS (ESI+) m/z calcd for C₁₉H₁₈O₄Na [M + Na]⁺333.1097, found

333.1115.

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.30 (d, J = 8.4 Hz, 2H), 6.81

(s, 2H), 6.63 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.58 (d, J =

4.0 Hz, 2H), 5.96 (s, 1H), 4.02 (q, J = 6.8 Hz, 2H) 3.85 (s, 6H), 3.82

(s, 6H), 1.40 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ

160.5 (C), 157.1 (C), 152.2 (C), 145.1 (C), 132.4 (CH), 127.4 (C),

120.4 (C), 116.6 (CH), 105.0 (CH), 98.8 (CH), 63.8 (CH₂), 55.9

(OCH₃), 55.4 (OCH₃), 15.0 (CH₃) ppm; HRMS (ESI+) m/z calcd

for C₂₄H₂₆O₆Na [M + Na]⁺433.1621, found 433.1633.

1-(2-Hydroxy-5-methoxyphenyl)-3-methoxynaphthalene (71):⁵⁴

yield 0.106 g (76%) as a brownish viscous liquid; IR (KBr) ν_max

3420, 3054, 2993, 2936, 2835, 1617, 1500, 1463, 1332, 1267, 1206,

1153, 1062, 1032, 915, 811, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.95 (d, J = 8.8 Hz, 1H), 7.87−7.82 (m, 1H), 7.57−7.52 (m, 1H),

7.43−7.35 (m, 3H), 7.04 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 2.8, 8.8 Hz,

1H), 6.78 (d, J = 3.2 Hz, 1H), 4.72 (s, 1H, OH), 3.91 (s, 3H), 3.78 (s,

3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 154.3 (C), 153.3 (C),

147.8 (C), 133.5 (C), 130.5 (CH), 129.4 (C), 128.0 (CH), 127.1

(CH), 125.0 (CH), 124.1 (CH), 123.1 (C), 118.6 (C), 116.8 (CH),

115.0 (CH), 113.4 (CH), 56.8 (OCH₃), 55.7 (OCH₃) ppm.

1-(3-Bromo-2-hydroxy-4-methoxyphenyl)-2-methoxynaphtha-

lene (72): yield 0.125 g (70%) as a white solid; mp 171−173 °C; IR

1-(5-Ethoxy-2-hydroxyphenyl)naphthalen-2-ol (75): yield 0.090 g

(64%) as a brownish viscous liquid; IR (KBr) ν_max3420, 3059, 2976,

1

1621, 1500, 1425, 1340, 1203, 1038, 815, 750 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 7.83−7.78 (m, 2H), 7.40−7.31 (m, 3H), 7.25 (d, J =

8.8 Hz, 1H), 7.03 (dd, J = 1.2, 8.8 Hz, 1H), 6.95−6.92 (m, 1H), 6.76

(d, J = 3.2 Hz, 1H), 5.53 (br s, OH, 1H), 4.75 (br s, OH, 1H), 3.94 (q,

J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ 153.3 (C), 151.5 (C), 148.0 (C), 132.9 (C), 130.6 (CH),

O

DOI: 10.1021/acs.joc.7b00684

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

129.0 (C), 128.2 (CH), 127.2 (CH), 124.1 (CH), 123.8 (CH), 119.6

(C), 117.7 (CH), 117.3 (CH), 117.3 (CH), 116.8 (C), 114.3 (C), 64.0

(CH₂), 14.8 (CH₃) ppm; HRMS (ESI+) m/z calcd for C₁₈H₁₆O₃Na

[M + Na]⁺303.0991, found 303.1007.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

6-Bromo-1-(2-hydroxy-5-ethoxyphenyl)naphthalen-2-ol (76):

1

This work was supported by DST [Research Grant no. SR/S1/

OC-38/2011], New Delhi. We thank DST for providing the

HRMS facility in the FIST program. S.S. thanks UGC and

S.K.R.P. thanks CSIR for their research fellowships.

yield calcd by H NMR spectrum 0.114 g (64%) [R = Et], 0.005 g

(3%) [R = Me] as a brown solid; mp 85−86 °C; IR (KBr) ν_max3428,

3054, 2975, 2924, 2875, 1587, 1499, 1340, 1271, 1194, 1037, 919, 879,

1

731 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 2.0 Hz, 1H),

7.73 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 2.0, 9.2 Hz, 1H), 7.26 (dd, J =

3.2, 9.2 Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 2.8, 8.8 Hz,

1H), 6.74 (d, J = 3.2 Hz, 1H), 5.56 (s, 1H, OH), 4.71 (s, 1H, OH),

3.97 (q, J = 6.8 Hz, 2.11H), 3.75 (s, 0.14H), 1.38 (t, = 6.8 Hz, 3.06H)

ppm; ¹³C NMR (100 MHz, CDCl₃) δ 153.4 (C), 151.8 (C), 147.9

(C), 131.5 (C), 130.4 (CH), 130.2 (C), 130.1 (CH), 129.7 (CH),

126.1 (CH), 119.1 (CH), 118.9 (CH), 117.6 (CH), 117.6 (CH), 117.5

(CH), 116.8 (CH), 114.7 (C), 64.1 (CH₂), 14.8 (OCH₃) ppm; HRMS

(ESI+) m/z calcd for C₁₈H₁₅O₃BrNa [M + Na]⁺381.0096, found

381.0091.

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116.8 (CH), 115.8 (CH), 113.4 (CH), 63.9 (CH₂), 56.7 (OCH₃), 14.9

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ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.7b00684.

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Copies of ¹H and ¹³C NMR spectra for all new products,

mass spectral analysis, ORTEP diagrams and X-ray data

for products 17, 35, and 52a (PDF)

Crystallographic data for 17 (CIF)

Crystallographic data for 35 (CIF)

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AUTHOR INFORMATION

Corresponding Author

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Lewis Acid-Mediated Site-Selective Synthesis of Oxygenated Biaryls from Methoxyphenols and Electron-Rich Arenes

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