Regiocontrolled Benzannulation of Diaryl(<i>gem</i>-dichlorocyclopropyl)methanols for the Synthesis of Unsymmetrically Substituted α-Arylnaphthalenes:  Application to Total Synthesis of Natural Lignan Lactones

Dedicated to Professor E. J. Thomas on the occasion of his 60th BirthdayWhereas the application of atom-transfer radical cyclization reactions [1] (ATRC reactions) to the synthesis of g-butyrolactams and g-butyrolactones is now reasonably well established, [2] the same cannot be said of this approach to the synthesis of medium-sized rings.[3] Previously [4d] we had shown that the trichloroacetate 1 (Scheme 1) undergoes sequential 5-exo, 6-exo ATRC reactions to provide rapid access to the 2-oxabicyclo[4.3.0]nonane ring system. Alternate modes of cyclization (by 9-exo or 10-endo pathways [5] ) were not observed. As a continuation of our interest [4] in this area we investigated the cyclization of trichloroacetate 3 (Scheme 1) under ATRC conditions. The synthesis of benzoxocins by radical cyclization reactions has received scant attention, [6,7] and at the outset we wished to determine if ATRC of 3 would occur by a 7-exo or 8-endo pathway [8] and whether structural features could be incorporated into the substrate to modify the regiochemical outcome of the reaction.[9] Furthermore, we also believed that this potentially problematic cyclization [10] reaction would also serve as a suitable test case for the development and evaluation of more efficient catalysts for ATRC reactions. [11] Cyclization (CuCl, 5 mol %; 2, [12,13] 5 mol %; toluene; reflux) of the readily available ester 3 proved to be rather sluggish (95 % completion after 48 h) and afforded the labile [13] lactone 4 through an 8-endo-trig reaction. [7] This cyclization was also accompanied by the formation of a minor, wholly aromatic, by-product whose generation lagged behind the formation of lactone 4. Repeating the ATRC reaction of 3 for 120 h in refluxing toluene resulted in the total consumption of both ester 3 and the lactone 4, and the formation of 1-chloronaphthalene (6), which was isolated [14] in 23 % yield after column chromatography. Moreover we were delighted to observe that irradiation [15][16][17] of a solution of the ester 3 in 1,2-dichloroethane containing our standard catalyst system in a microwave reactor [18] afforded 6 in 84 % yield after a much reduced reaction time of two hours (Scheme 1).Wishing to establish the synthetic generality of this reaction, we subjected a variety of readily available aryl trichloroacetates (8, 10, 12 a-12 f; Scheme 2) to the same experimental protocol and found that, in each case, benzannulation proceeded smoothly over two hours at 200 8C to produce their respective naphthalene derivatives. The requisite ortho-allyl phenols used in this study are themselves readily available from an ortho-Claisen rearrangement [19] of their respective allyl aryl ethers, a process which in many cases can also be efficiently accomplished in a microwave reactor. [20] Of note is the observation that the benzannulation reaction proceeds with complete regiochemical control to afford an aryl chloride as a single regioisomer in each case. For example, subjecting the isomeric naphthyl esters 8 and 10 separately to our standard react...

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“…The application of this methodology to the synthesis of novel aromatic scaffolds [31] and target-oriented synthesis is now underway.…”

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confidence: 99%

A Remarkably Simple and Efficient Benzannulation Reaction

2007

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“…An application to the total syntheses of unsymmetrically substituted natural lignan lactones, justicidin B, 13 retrojusticidin B, 14 and dehydrodesoxypodophyllotoxin 15 was achieved. 11 In addition, unique chirality-exchange benzannulations from central…”

Section: Scheme 5 Plausible Mechanism For the Benzannulationmentioning

confidence: 99%

Gram-Scale Robust Synthesis of 1-Chloro-2,3-dimethyl-4-phenylnaphthalene: A Promising Scaffold with Three Contiguous Reaction Positions

Moriguchi

Kono²,

Seko³

et al. 2020

Synthesis

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A three-step reaction sequence for the gram-scale synthesis of 1-chloro-2,3-dimethyl-4-phenylnaphthalene was developed. (i) Stereoselective dichlorocarbene addition to methyl angelate afforded methyl (1S*,3S*)-2,2-dichloro-1,3-dimethylcyclopropane-1-carboxylate (78% yield, >98% purity, distillation). (ii) Addition reaction of two molar amounts of PhLi afforded (1S*,3S*)-2,2-dichloro-1,3-dimethylcyclopropyldiphenylmethanol (81% yield, >98% purity, recrystallization). (iii) Key SnCl4-mediated benzannulation produced the desired product (83% yield, >98% purity, recrystallization) with three contiguous reaction sites. Five derivatization examples including benzylic reactions and cross-couplings at the pendant Cl-position are demonstrated. Some relevant distinctive benzannulations are also discussed.

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“…97 The Lewis acid catalyzed benzannulation protocol was used for the synthesis of lignan type lactones such as justicidin B and retrojusticidin. 97 The Lewis acid catalyzed benzannulation protocol was used for the synthesis of lignan type lactones such as justicidin B and retrojusticidin.…”

Section: Bezannulationmentioning

confidence: 99%

Recent advances in the syntheses, transformations and applications of 1,1-dihalocyclopropanes

et al. 2015

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gem-Dihalocyclopropanes have wide-spread applications in organic synthesis due to their versatile chemistry. They can serve as substrates for a large range of useful materials such as natural products, alkaloids, cyclopropanes, heterocycles, aromatic ring systems etc. Normally the dihalocyclopropanes are prepared by the addition of dihalocarbene to alkene, but due to the great synthetic efficacy of gem-dihalocyclopropanes a number of methods have been developed for their synthesis. Generally gem-dihalocyclopropanes exist as strained cyclic systems with astonishing kinetic stability. They are capable of undergoing transformations leading to a variety of products which have potential applications in various synthetic organic chemistry fields.

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Regiocontrolled Benzannulation of Diaryl(gem-dichlorocyclopropyl)methanols for the Synthesis of Unsymmetrically Substituted α-Arylnaphthalenes: Application to Total Synthesis of Natural Lignan Lactones

Cited by 58 publications

References 58 publications

A Remarkably Simple and Efficient Benzannulation Reaction

A Remarkably Simple and Efficient Benzannulation Reaction

Gram-Scale Robust Synthesis of 1-Chloro-2,3-dimethyl-4-phenylnaphthalene: A Promising Scaffold with Three Contiguous Reaction Positions

Recent advances in the syntheses, transformations and applications of 1,1-dihalocyclopropanes

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