Lewis Acid-Mediated Site-Selective Synthesis of Oxygenated Biaryls


Sep 1, 2017 - A rapid, efficient, and metal-free Lewis acid-mediated methodology has been developed for the site-selective synthesis of unsymmetrical ...
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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 methods6 are known for the umpolung reactivity of electron-rich nucleophilic 2-methoxyphenols and 4-methoxyphenols by converting them into electrophilic intermediates through oxidative dearomatization7 in the presence of alcoholic solvents. Linearly conjugated cyclohexadienones generated from the oxidative dearomatization of 2-methoxyphenols in the presence of alcoholic solvents by the aid of hypervalent iodine reagents8−14 are known as obenzoquinone monoketals15 or 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-benzoquinone monoketals or masked p-benzoquinones (MPBs, pbenzoquinone protected at one of the carbonyl functionalities). These quinone monoketals undergo numerous transformations such as (i) cycloaddition reactions, (ii) nucleophilic, electrophilic, and radical addition reactions, and (iii) photochemical reactions.17 On account of their unique reactive features, rapid and easy generation, they grabbed the attention of synthetic organic chemists. The synthesis of biaryls18,19 has received much attention in recent years because of their frequent occurrence in many natural products20−22 and pharmaceutically active compounds23−26 (Figure 1) and their wide applications in asymmetric synthesis, molecular catalysis, and materials science.27−36 In 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 © 2017 American Chemical Society

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.36−39 Over the past few decades, numerous oxidative cross-coupling strategies were developed for the synthesis of biaryls using heavy metal (PbIV, RuIV, TlIII, VV, and RhIII) oxidizing agents.40−46 Because of the high cost, toxicity to some extent, and moisture sensitivity of these heavy metal oxidizing reagents, there is a Received: March 23, 2017 Published: September 1, 2017 9367

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

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The Journal of Organic Chemistry 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.47−52 Kozlowski developed homoand cross-coupling of phenols by using aerobic chromium salene catalysts.53 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,54,55 fluorinated 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 electronrich arenes.57 Recently, Kita utilized methanesulfonic acid and hypervalent iodine reagents in HFIP for the cross-couplings of p-quinone monoacetals and phenols.58−60 Kürti et al.61 also executed the synthesis of biaryls by the cross-coupling of pquinone monoacetals and naphthols in the presence of trifluoroacetic acid/toluene and diphenylphosphoric acid/ trifluoroethanol. Chittimalla et al.62 depicted 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-workers17h synthesized biaryl-based natural products by carrying out the Girgnard reaction on o-quinol acetates.

Scheme 1. Possible Products from Conjugate Addition



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 obenzoquinone 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-methoxyphenols 6−8 and their oxidized p-benzoquinone monoketals 6a−8a, electron-rich benzene derivatives 9a−f, naphthalene derivatives 10a−c (Figure 2). At the outset, 4-bromoguaiacol (1) was dearomatized with diacetoxyiodobenzene (DIB) in MeOH in the presence of 1,3dimethoxybenzene (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·OEt2 at 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 electronrich 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

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-dimethoxybenzene 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 obenzoquinone 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 (αposition) of the transiently generated reactive cyclohexadienone 1a in a vinylogous SN2′ type addition with subsequent rearomatization. 9368

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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·OEt2 at −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·OEt2 caused the reaction to afford biaryl 11 in 80% yield (entry 10). 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 conditions. 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 1,3dimethoxybenzene in CH2Cl2 at −30 °C in the presence of BF3·OEt2 to 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).

Scheme 2. Preliminary Experiments

Propelled by the obtained results, we optimized reaction conditions to improve the yield of biaryl 11 by choosing 4bromo-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-2methoxyphenol (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 1,3Dimethoxybenzene (9a)

Table 1. Optimization of Reaction Conditionsa

entry

activator

equivb

temp (°C)

time (min)c

yield (%)d

1 2 3 4 5 6 7 8 9 10

phosphomolybdic acid 3,5-dinitrobenzoic acid TFA FeCl3 ZrCl4 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2

0.2 2 2 2 2 2 2 2 1 4

0 to rt 0 to rt 0 0 0 0 −30 −40 −30 −30

24 h 24 h 40 20 10 <1 <1 <1 <1 <1

nre nre 53 58 54 75 82 79 65 80

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 electronrich 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 1,3dimethoxybenzene 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-dimethoxybenzene 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. 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

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 Of activator. cTime after addition of activator. dYield of pure and isolated products. enr = 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 9369

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

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The Journal of Organic Chemistry Scheme 4. Reactions of Guaiacols 1−4 with 1,3Dimethoxybenzene 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·OEt2 under standard conditions to furnish the corresponding unsymmetrical oxygenated 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·OEt2 under 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 electronrich 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 oquinone monoketal 4a. Then the solvent was evaporated under a vacuum. To a solution of MOB 4a in CH2Cl2 were 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 1,3dimethoxybenzene (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 4bromo-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 29370

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

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The structures of all the unsymmetrical oxygenated biaryls were confirmed on the basis of the data obtained from IR, 1H 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 1763 and 3563 were further confirmed by singlecrystal 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 oxygenated 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). 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

Scheme 7. Reactions of Differently Substituted Guaiacol Derivatives

methoxyphenols showed the coupling constants for the protons of the guaiacol moiety in the range 1.5−3.0 Hz (meta coupling) in the 1H 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.

Figure 3. Regiochemistry of biaryls based on coupling constants.

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

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control experiment where the reaction was carried out with 1 equiv of isolated p-quinone monoketal 6a in CH2Cl2 at 0 °C, and then 1 equiv of an electron-rich arene and BF3·OEt2 were 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-workers55 synthesized 2,6-di(2,4-dimethoxyphenyl)-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 bisattack of an electron-rich arene. The moderate electrondonating 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-4methoxyphenol (7) and 2-methyl-4-methoxyphenol (8) bearing an electron-withdrawing group (Br) and an electrondonating group (Me), respectively, as reactants. When pquinone monoketals 7a and 8a corresponding to p-methoxyphenols 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 electrondonating 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 1,3dimethoxybenzene 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 βnaphthol (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·OEt2 under 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 dearomatization 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). In order to find out the priority of the liability of an alkoxy group, we carried out a reaction between cross-conjugated pquinone monoketal 6b having two different alkoxy groups, methoxy and ethoxy, with 1,3-dimethoxybenzene (9a). To a solution of MPB 6b in CH2Cl2 were added the electron-rich arene and BF3·OEt2 at 0 °C. In this case, the reaction proceeded smoothly and furnished two products 74 and 74a

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, Table 2. Optimization of Reaction Conditions

entry

BF3·Et2O (equiv)

1,3-DMB (equiv)

temp (°C)

1 2 3 4 5 6d

1 1 1 1 2 1

1 1 1 2 2 1

0 −30 −60 0 0 0

yield 50 (%)c yield 50a (%)c 31 15 15 38 35 30

14 26 28 27 26 17

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 reactions completed in <1 min. bTime after addition of BF3·OEt2. c Yield of pure and isolated products. dReaction 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 electronrich 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 9372

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

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The Journal of Organic Chemistry 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 1,3Dimethoxybenzene (9a)

methoxy group remained, and the elimination of the ethoxy group took place in the biaryl system. The analysis of the 1H 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 crossconjugated 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. However, the reactions of p-quinone monoketal 6b or 6c with 6-bromo-2-naphthol (10b) under optimized conditions

through the mono- and bis-addition of 9a to p-quinone monoketal 6b, respectively (Scheme 11). By the close inspection of the 1H 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 9373

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

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

Further, the confirmation for the formation of regioisomer-1 has been carried out by a close inspection of the 1H NMR spectrum of compound 56. For instance, in compound 56, the aromatic Ha and Hb protons 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 1 H NMR spectra (Scheme 13). Scheme 13. Reaction of p-Quinone Monoketals 6b and 6c with 6-Bromo-2-naphthol (10b)

Figure 5. 1H NMR spectra representing characteristic chemical shifts, coupling constants, and decoupling experiments of 56.

doublet of the Ha proton 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 Ha and Hb protons 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-methoxynaphthalene (10d) under standard conditions provided predominantly biaryl product 78 in 66% yield (Scheme 14). Scheme 14. Reaction of MPB 6b with 2Methoxynaphthalene (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 pquinone monoketal was confirmed by the 1H NMR spectrum. All compounds, obtained by the oxygenative coupling of the pmethoxyphenol derivatives and electron−rich arenes, showed a meta coupling constant in the 1H 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).

A mechanistic model proposed for the arylation of the 4methoxyphenol derivatives and electron-rich arenes is outlined below. The coordination of the Lewis acid with crossconjugated quinone monoketal (D), derived from diacetoxyiodobenzene-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 BF3complexed 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· OEt2 in 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

Figure 4. Regiochemistry of biaryls based on coupling constants. 9374

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Article

The Journal of Organic Chemistry 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). 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 NaHCO3 and 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. 4-Bromo-6-(2,4-dimethoxyphenyl)-2-methoxyphenol (11): yield 0.139 g (82%) as a brown viscous liquid; IR (KBr) νmax 3441, 2927, 2844, 1609, 1507, 1467, 1296, 1210, 1153, 1023, 829, 735 cm−1; 1H 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. 4-Bromo-1-(2,4-dimethoxyphenoxy)-2-methoxybenzene (12): yield 0.017 g (10%) as a yellow viscous liquid; IR (KBr) νmax 3080, 2943, 2838, 1600, 1502, 1261, 1212, 1118, 1033, 831, 712 cm−1; 1H 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

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).



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 derivatives 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 obenzoquinones 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. Thinlayer 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 wave numbers (cm−1). 1H and 13C NMR spectra were recorded on a 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 9375

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry = 2.5, 5.0 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H) ppm; 13C 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. 4-Chloro-6-(2,4-dimethoxyphenyl)-2-methoxyphenol (13): yield 0.118 g (80%) as a brown viscous liquid; IR (KBr) νmax 3469, 2930, 1604, 1513, 1456, 1256, 1196, 1107, 1017, 934, 830 cm−1; 1H NMR (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-Chloro-1-(2,4-dimethoxyphenoxy)-2-methoxybenzene (14): yield 0.015 g (10%) as a yellow viscous liquid; IR (KBr) νmax 3083, 2934, 2839, 1604, 1508, 1260, 1211, 1120, 1033, 829 cm−1; 1H NMR (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) νmax 3518, 2939, 2835, 1613, 1469, 1370, 1297, 1213, 1156, 1034, 961, 834, 791 cm−1; 1 H 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. 1-(2,4-Dimethoxyphenoxy)-4-fluoro-2-methoxybenzene (16): yield 0.017 g (12%) as a brown viscous liquid; IR (KBr) νmax 3091, 2946, 2838, 1611, 1515, 1265, 1205, 1127, 1030, 845 cm−1; 1H NMR (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) νmax 3531, 2933, 2845, 1606, 1571, 1406, 1310, 1212, 1117, 1033, 948, 821, 717 cm−1; 1H 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-chloro-4,6-dimethoxyphenyl)-2-methoxyphenol (18): yield 0.114 g (69%) as a colorless solid; mp 116−118 °C; IR (KBr) νmax 3526, 2940, 1603, 1413, 1314, 1214, 1122, 1041, 943, 827, 739 cm−1; 1H 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

(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. 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) νmax 3497, 2923, 1607, 1566, 1421, 1383, 1216, 1118, 1038, 961, 838, 743 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.66 (dt, J = 3.0, 5.5 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. 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) νmax 3515, 2933, 2845, 1604, 1564, 1403, 1342, 1210, 1115, 1026, 960, 827 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 2.0 Hz, 1H), 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. 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) νmax 3521, 2940, 1598, 1413, 1312, 1213, 1161, 1032, 885, 830, 734 cm−1; 1H 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) νmax 3532, 2946, 1600, 1563, 1459, 1309, 1218, 1115, 1034, 956, 828 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.84 (d, J = 2.5 Hz, 1H), 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. 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) νmax 3526, 2931, 2843, 1602, 1409, 1329, 1207, 1154, 1017, 857, 721 cm−1; 1H 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. 4-Chloro-6-(2,4-dimethoxy-6-methylphenyl)-2-methoxyphenol (24): yield 0.133 g (86%) as a yellowish brown viscous liquid; IR (KBr) νmax 3434, 2945, 1600, 1496, 1457, 1345, 1209, 1155, 1052, 1015, 829 cm−1; 1H 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), 9376

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry

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) νmax 3487, 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. 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) νmax 3390, 2929, 1624, 1431, 1378, 1339, 1222, 1131, 1021, 956, 813, 749 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.5 Hz, 2H), 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. 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) νmax 3491, 2925, 1606, 1499, 1460, 1313, 1268, 1199, 1142, 1079, 948, 851, 810 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 2.0 Hz, 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-Bromo-1-(5-bromo-2-hydroxy-4-methoxyphenyl)naphthalen2-ol (34): yield 0.182 g (86%) as a brown solid; mp 161−162 °C; IR (KBr) νmax 3483, 2926, 1609, 1476, 1401, 1306, 1260, 1197, 1073, 948, 810, 739 cm−1; 1H 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)naphthalen2-ol (35): yield 0.167 g (88%) as a brown solid; mp 141−143 °C; IR (KBr) νmax 3388, 2939, 1587, 1468, 1413, 1334, 1261, 1199, 1068, 951, 816, 756 cm−1; 1H 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; 13 C NMR (125 MHz, CDCl3) δ 151.1 (C), 147.8 (C), 142.7 (C), 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. 6-Bromo-1-(5-fluoro-2-hydroxy-4-methoxyphenyl)naphthalen-2ol (36): yield 0.156 g (86%) as a brown solid; mp 143−144 °C; IR (KBr) νmax 3376, 2926, 1591, 1493, 1426, 1373, 1192, 1132, 1074, 955, 872, 812 cm−1; 1H 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 =

55.7 (CH3), 55.2 (CH3), 20.2 (CH3) ppm; HRMS (ESI+) m/z calcd for C16H17ClO4Na [M + Na]+ 331.0708, found 331.0714. 6-(2,4-Dimethoxy-6-methylphenyl)-4-fluoro-2-methoxyphenol (25): yield 0.111 g (76%) as a yellowish brown viscous liquid; IR (KBr) νmax 3503, 2943, 2840, 1601, 1423, 1320, 1239, 1126, 1033, 959, 840 cm−1; 1H 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. 6-(2,4-Dimethoxyphenyl)-2-methoxy-4-methylphenol (26): yield 0.119 g (87%) as a brown viscous liquid; IR (KBr) νmax 3503, 2934, 2842, 1610, 1502, 1412, 1309, 1211, 1110, 1034, 935, 834 cm−1; 1H 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) νmax 3425, 2935, 1599, 1569, 1408, 1304, 1222, 1169, 1060, 1026, 939, 848 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.72 (d, J = 1.5 Hz, 1H), 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. 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) νmax 3422, 2930, 1602, 1563, 1461, 1305, 1217, 1156, 1024, 936, 845 cm−1; 1H 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) νmax 3418, 2924, 1597, 1457, 1315, 1236, 1157, 1036, 939, 835 cm−1; 1 H 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-(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) νmax 3482, 2926, 1608, 1487, 1401, 1306, 1260, 1197, 1074, 951, 850, 742 cm−1; 1H 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. 9377

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry

1-(5-Bromo-2-hydroxy-4-methoxyphenyl)-2-methoxynaphthalene (42): yield 0.145 g (81%) as a white solid; mp 192−193 °C; IR (KBr) νmax 3490, 2936, 1615, 1487, 1322, 1256, 1085, 848, 739 cm−1; 1 H 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-methoxynaphthalene (43): yield 0.122 g (78%) as a brown solid; mp 157−158 °C; IR (KBr) νmax 3478, 2933, 1609, 1476, 1330, 1226, 1088, 954, 815 cm−1; 1 H 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-methoxynaphthalene (44): yield 0.122 g (82%) as a brown solid; mp 144−145 °C; IR (KBr) νmax 3452, 2923, 1610, 1425, 1340, 1140, 1027, 956, 816 cm−1; 1 H 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. 1-(2-Hydroxy-3-methoxy-5-methylphenyl)-2-methoxynaphthalene (45): yield 0.123 g (84%) as a yellow solid; mp 178−179 °C (lit.64 180 °C); IR (KBr) νmax 3480, 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) νmax 3501, 2940, 2836, 1618, 1507, 1402, 1314, 1201, 1108, 1038, 939 cm−1; 1H 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) νmax 3328, 2920, 2858, 1604, 1491, 1368, 1268, 1148, 1095, 913 cm−1; 1H 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.

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. 6-Bromo-1-(2-hydroxy-4-methoxy-5-methylphenyl)naphthalen2-ol (37): yield 0.158 g (88%) as a brown solid; mp 141−142 °C; IR (KBr) νmax 3314, 2937, 1590 1493, 1418, 1376, 1286, 1214, 1137, 1084, 952, 881, 826 cm−1; 1H 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-methoxynaphthalen-2-ol (38): yield 0.169 g (90%) as a brown viscous liquid; IR (KBr) νmax 3425, 2927, 1607, 1420, 1343, 1221, 1165, 1020, 832, 748 cm−1; 1 H 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-methoxynaphthalen-2-ol (39): yield 0.152 g (92%) as a brown semisolid; IR (KBr) νmax 3438, 2926, 1614, 1472, 1422, 1348, 1258, 1161, 1024, 875, 789 cm−1; 1 H 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-(5-Fluoro-2-hydroxy-4-methoxyphenyl)-3-methoxynaphthalen-2-ol (40): yield 0.143 g (91%) as a brown semisolid; IR (KBr) νmax 3512, 2928, 2853, 1621, 1468, 1425, 1328, 1261, 1121, 1027, 950, 837, 799 cm−1; 1H 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-methoxynaphthalen-2-ol (41): yield 0.143 g (92%) as a reddish brown solid; mp 134− 136 °C; IR (KBr) νmax 3419, 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. 9378

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry

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.55 188−189 °C); IR (KBr) νmax 3445, 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. 2-(2-Chloro-4,6-dimethoxyphenyl)-4-methoxyphenol (51): yield 0.091 g (62%) as a white solid; mp 108−110 °C; IR (KBr) νmax 3459, 2996, 2940, 2837, 1603, 1569, 1480, 1273, 1210, 1147, 1037, 941, 809 cm−1; 1H 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. 2-(2,4,6-Trimethoxyphenyl)-4-methoxyphenol (52): yield 0.066 g (45%) as a colorless solid; mp 140−142 °C (lit.53 141−143 °C); IR (KBr) νmax 3432, 2951, 2899, 2833, 1609, 1485, 1418, 1336, 1269, 1209, 1155, 1126, 1035, 807 cm−1; 1H 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) νmax 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-Dihydoxyphenyl)-4-methoxyphenol (53): yield 0.082 g (71%) as a viscous liquid; IR (KBr) νmax 3373, 2940, 2834, 1620, 1495, 1419, 1276, 1209, 1205, 1167, 1035, 973, 814 cm−1; 1H NMR (400 MHz, CDCl3 with 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, CDCl3 with 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) νmax 3431, 3004, 2937, 2837, 1587, 1467, 1410, 1328, 1200, 1125, 1033, 940, 815 cm−1; 1H 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) νmax 3485, 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-Methoxy-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)phenol (48): yield 0.066 g (61%) as a colorless liquid; IR (KBr) νmax 3499, 2925, 2854, 1600, 1507, 1458, 1364, 1271, 1130, 1038, 806, 702 cm−1; 1H 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) νmax 3495, 2934, 2862, 1603, 1522, 1410, 1223, 1110, 1030, 939, 838 cm−1; 1 H 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. 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) νmax 3410, 2976, 2838, 1608, 1512, 1472, 1437, 1262, 1115, 934, 825 cm−1; 1H 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-Dimethoxyphenyl)-6-methoxy-4-phenylphenol (49b): yield 0.100 g (60%) as a viscous yellow liquid; IR (KBr) νmax 3430, 2959, 2925, 2852, 1608, 1511, 1460, 1304, 1260, 1102, 923, 803 cm−1; 1H 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 NaHCO3 solution and the aqueous phase was extracted twice with CH2Cl2/ethyl acetate (2 × 10 mL). The combined extract was dried over anhydrous Na2SO4 and 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-Dimethoxyphenyl)-4-methoxyphenol (50): yield 0.049 g (38%) as a white solid; mp 117−118 °C (lit.55 117−118 °C); IR (KBr) νmax 3421, 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, 9379

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry

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 NaHCO3 solution and the aqueous phase was extracted twice with CH2Cl2/ethyl acetate (2 × 10 mL). The combined extract was dried over anhydrous Na2SO4 and 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. 1-(2-Hydroxy-5-methoxyphenyl)naphthalen-2-ol (62): 60 yield 0.118 g (89%) as a brownish viscous liquid; IR (KBr) νmax 3413, 3057, 3001, 2938, 2837, 1619, 1499, 1424, 1339, 1271, 1208, 1033, 953, 816, 752 cm−1; 1H 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. 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) νmax 3494, 3057, 3028, 2948, 2907, 2831, 1612, 1569, 1469, 1426, 1388, 1205, 1179, 1037, 811 cm−1; 1H 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; 13 C 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-(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) νmax 3489, 3459, 3057, 2996, 2939, 2825, 1624, 1597, 1471, 1385, 1189, 1143, 1053, 813, 752 cm−1; 1H 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. 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) νmax 3286, 3001, 2940, 1533, 1491, 1335, 1267, 1205, 1163, 1037, 942, 877, 762 cm−1; 1H 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)naphthalen2-ol (66): yield 0.159 g (75%) as a white solid; mp 181−183 °C; IR (KBr) νmax 3496, 3420, 3066, 2978, 2933, 2837, 1590, 1468, 1418, 1383, 1334, 1196, 1129, 1038, 852, 816 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.32 (dd,

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) νmax 3432, 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. 2-(2,4-Dihydoxyphenyl)-6-bromo-4-methoxyphenol (57): yield 0.104 g (67%) as a white solid; mp 166−168 °C; IR (KBr) νmax 3360, 2936, 2825, 1601, 1465, 1398, 1348, 1255, 1205, 1173, 971, 776 cm−1; 1H NMR (400 MHz, CDCl3 with 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, CDCl3 with 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 (OCH 3 ) ppm; HRMS (ESI+) m/z calcd for C13H11O4BrNa [M + Na]+ 332.9732, found 332.9725. 2-(2,4-Dimethoxyphenyl)-6-methyl-4-methoxyphenol (58): yield 0.085 g (62%) as an orange viscous liquid; IR (KBr) νmax 3429, 3007, 2942, 2836, 1610, 1471, 1301, 1205, 1159, 1038, 836, 771 cm−1; 1H 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) νmax 3463, 3010, 2943, 2837, 1603, 1469, 1304, 1213, 1149, 1043, 941, 821 cm−1; 1H 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. 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) νmax 3463, 3013, 2944, 2836, 1608, 1470, 1331, 1225, 1153, 942, 804 cm−1; 1H 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) νmax 3413, 3307, 3169, 2990, 2919, 2834, 1612, 1480, 1203, 1162, 1055, 974, 847 cm−1; 1H NMR (400 MHz, CDCl3 with 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, CDCl3 with 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. 9380

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry

(KBr) νmax 3489, 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-methoxynaphthalene (73): yield 0.101 g (69%) as a white solid; mp 136−138 °C; IR (KBr) νmax 3532, 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. 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 1,3dimethoxybenzene/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 NaHCO3 solution and the aqueous phase was extracted twice with CH2Cl2/ethyl acetate (2 × 10 mL). The combined extract was dried over anhydrous Na2SO4 and 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. 2-(2,4-Dimethoxyphenyl)-4-ethoxyphenol (74): yield calcd by 1H NMR spectrum 0.036 g (26%) [R = Et], 0.007 g (5%) [R = Me] as a brownish viscous liquid; IR (KBr) νmax 3422, 2972, 2931, 2834, 1612, 1498, 1302, 1261, 1205, 1160, 1044, 822 cm−1; 1H 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) νmax 3434, 3001, 2933, 2838, 1610, 1508, 1401, 1304, 1206, 1157, 1034, 951, 837, 788 cm−1; 1H 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-(5-Ethoxy-2-hydroxyphenyl)naphthalen-2-ol (75): yield 0.090 g (64%) as a brownish viscous liquid; IR (KBr) νmax 3420, 3059, 2976, 1621, 1500, 1425, 1340, 1203, 1038, 815, 750 cm−1; 1H 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),

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)naphthalen2-ol (67): yield 0.130 g (73%) as a brown solid; mp 123−125 °C; IR (KBr) νmax 3260, 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; 13 C NMR (100 MHz, CDCl3) δ 153.4 (C), 151.8 (C), 146.3 (C), 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) νmax 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-methoxynaphthalen-2-ol (69): yield 0.144 g (77%) as a brownish viscous liquid; IR (KBr) νmax 3423, 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-methoxynaphthalen-2-ol (70): yield 0.116 g (75%) as a brown solid; mp 160−162 °C; IR (KBr) νmax 3487, 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; 13 C NMR (100 MHz, CDCl3) δ 152.9 (C), 147.0 (C), 146.0 (C), 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-(2-Hydroxy-5-methoxyphenyl)-3-methoxynaphthalene (71): 54 yield 0.106 g (76%) as a brownish viscous liquid; IR (KBr) νmax 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-methoxynaphthalene (72): yield 0.125 g (70%) as a white solid; mp 171−173 °C; IR 9381

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

The Journal of Organic Chemistry Notes

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. 6-Bromo-1-(2-hydroxy-5-ethoxyphenyl)naphthalen-2-ol (76): yield calcd by 1H NMR spectrum 0.114 g (64%) [R = Et], 0.005 g (3%) [R = Me] as a brown solid; mp 85−86 °C; IR (KBr) νmax 3428, 3054, 2975, 2924, 2875, 1587, 1499, 1340, 1271, 1194, 1037, 919, 879, 731 cm−1; 1H 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. 6-Bromo-1-(2-hydroxy-5-isopropoxyphenyl)naphthalen-2-ol (77): yield calcd by 1H NMR spectrum 0.126 g (67%) [R = i-Pr], 0.003 g (2%) [R = Me] as a brown solid; mp 93−94 °C; IR (KBr) νmax 3428, 3054, 2975, 2924, 2875, 1587, 1499, 1340, 1271, 1194, 1037, 919, 879, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 2.0, 8.8 Hz, 1H), 7.29−723 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 2.8, 9.2 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 5.53 (s, 1H, OH), 5.08 (s, 1H, OH), 4.41 (sept, J = 6.0 Hz, 1.07H), 3.81 (s, 0.08H, OMe), 1.31 (d, J = 2.8 Hz, 3H), 1.30 (d, J = 2.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 152.2 (C), 151.7 (C), 148.0 (C), 131.5 (C), 130.3 (CH), 130.2 (C), 130.1 (CH), 129.6 (CH), 126.1 (CH), 119.3 (CH), 119.2 (C), 119.0 (CH), 118.9 (CH), 117.5 (CH), 114.9 (C), 71.1 (OCH3), 22.0 (CH3), 22.0 (CH3) ppm; HRMS (ESI+) m/z calcd for C19H17O3BrNa [M + Na]+ 395.0253, found 395.0253. 1-(2-Hydroxy-5-ethoxyphenyl)-3-methoxynaphthalene (78): yield 0.097 g (66%) as a brownish viscous liquid; IR (KBr) νmax 3429, 2971, 2924, 2854, 2929, 1636, 1590, 1497, 1334, 1265, 1108, 937, 814 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 10.0 Hz, 1H), 7.57 (d, J = 10.4 Hz, 1H), 7.41−7.37 (m, 3H), 7.03 (d, J = 9.2 Hz, 1H), 6.94 (dd, J = 3.6, 9.6 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 4.74 (s, 1H, OH), 4.00 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 154.2 (C), 152.6 (C), 147.7 (C), 133.5 (C), 130.4 (CH), 129.3 (C), 128.0 (CH), 127.0 (CH), 125.0 (CH), 124.0 (C), 123.0 (CH), 118.7 (C), 117.5 (CH), 116.8 (CH), 115.8 (CH), 113.4 (CH), 63.9 (CH2), 56.7 (OCH3), 14.9 (CH3) ppm; HRMS (ESI+) m/z calcd for C19H18O3Na [M + Na]+ 317.1148, found 317.1157.



The authors declare no competing financial interest.



ACKNOWLEDGMENTS 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.



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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00684. 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) Crystallographic data for 52a (CIF)



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Rama Krishna Peddinti: 0000-0001-7340-1516 Author Contributions †

These authors contributed equally. 9382

DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383

Article

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DOI: 10.1021/acs.joc.7b00684 J. Org. Chem. 2017, 82, 9367−9383