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

Article

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

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

Article

The Journal of Organic Chemistry

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