1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 A Highly Regioselective and Practical Synthesis of α-Aryl Ketones under a Cooperative Cascade Effect of an Ionic Liquid and Tetrabutylammonium Fluoride Yogesh Thopate + , [a, b] Richa Singh + , [a] Sumit K. Rastogi, [a, b] and Arun K. Sinha* [a, b] Abstract: A metal-free regioselective synthesis of α-aryl ketone from corresponding bromohydrin via cooperative cascade effect of [hmim]Br and tetrabutylammonium fluoride under microwave irradiation is reported. Applica- tions of the protocol are illustrated by synthesis of drug intermediates piperonyl-methyl ketone and 2-tetralone. Interestingly, direct regioselective transformation of epox- ide and 1,2-diol into α-aryl ketone under neat [hmim]Br has also been realized. Advantages of this method are demon- strated through the recyclability of [hmim]Br-tetrabutylam- monium fluoride catalytic system and gram scalability. Wacker process [1] has been a staple reaction for transformation of terminal alkene into aldehyde or ketone depending on the oxidant used along with the palladium catalyst (Scheme 1). However, the transformation of internal alkene viz. phenyl- propene, usually provides isomeric mixture ketones i.e. propio- phenone (i.e. 1-ketone) and α-aryl ketone (i.e. 2-ketone) in varying ratio catalyst (Scheme 1A). [1d–f] Although relentless efforts have been devoted towards efficient regioselective Wacker-type [2] reaction of internal alkene by inserting directing groups in the alkene however the existing methods are limited due to requirement of harsh reaction conditions, low yield etc. On the other hand, 3-phenyloxirane (epoxide) [3] or phenyl- propane-1,2-diol [4] are also widely exploited as a versatile precursor to regioselectively obtain the desired carbonyls (1/2- ketone or aldehyde) in high yield using a variety of catalysts viz. InCl 3 , [3b] BF 3 .Et 2 O [4a] etc. Recently, Coates [5] effectively utilized [Lewis acid] + [Co(CO) 4 ] À catalyst for regioselective isomerization of 3-phenyloxirane into α-aryl ketone as the major product over propiophenone. A different pathway utilizing highly reactive and easily available halohydrin [6] (β-halo alcohol) as an alternative precur- sor for net transformation of alkene into carbonyls including propiophenone [7] or α-aryl ketone [8] has also been explored (Scheme 1A). Literature reveals that β-halohydrin could be readily converted into propiophenone using various catalysts [7] such as Pd(OAC) 2 /P(o-Tol) 3 , [7a–b] CoCl(Ph 3 P) 3 /Et 3 N [7c] and photo- chemical reaction [7d] in benzene in the presence of p-toluene- sulfonic acid. However their conversion into α-aryl ketone is sparsely reported, despite the central importance of α-aryl ketones as key intermediate [9] for various important compounds viz. diarylisoxazoles, [9a] stilbenes [9b] and anthranilodinitrile [9c] etc as well as it’s application in pharmaceuticals and as bioactive molecules. The reported protocol employs catalyst such as highly pyrophoric diethyl zinc [8a] and air-sensitive Grignard reagent. [8c] Recently, Takemoto and co-workers [10] reported rearrangement of tertiary halohydrinsilyl ether into α-aryl ketone derivative using NIS and NISac induced desilylative semipinacol reaction via C À X bond cleavage. Many of the existing strategies still suffer from various limitations such as the use of expensive and toxic transition metal catalysts, formation of regioisomers, lack of catalyst recyclability. Moreover, the requirement of well- tailored tertiary β-halohydrin [8c,e] is a major limitation towards exclusive formation of α-aryl ketone as switching to secondary β-halohydrin results in loss of selectivity. On the other hand, some notable efforts have also been made towards selective formation of α-aryl ketone [11] from internal alkyne, [11a] diazo compounds via rhodium catalyzed selective de-esterification and decarbonylation, [11b] diazonium tetrafluoroborate salts. [11c] As such, a more general and viable greener reaction for regioselective synthesis of α-aryl ketone from versatile secon- dary β–halohydrin is welcomed as a complementary approach to the existing strategies. [a] Dr. Y. Thopate, + Dr. R. Singh, + S. K. Rastogi, Dr. A. K. Sinha Medicinal and Process Chemistry Division CSIR-Central Drug Research Institute Sector 10, Jankipuram Extension Sitapur Road, Lucknow 226031 (India) E-mail: aksinha08@rediffmail.com [b] Dr. Y. Thopate, + S. K. Rastogi, Dr. A. K. Sinha Academy of Scientific and Innovative Research New Delhi (India) [ + ] Yogesh Thopate and Richa Singh contributed equally to this work. Supporting information for this article is available on the WWW under https://doi.org/10.1002/ajoc.201900513 Scheme 1. Concept of ionic liquid-TBAF mediated regioselective conversion of β-bromohydrin into α-aryl ketone. Communication DOI: 10.1002/ajoc.201900513 1 Asian J. Org. Chem. 2019, 8,1–7 © 2019 Wiley-VCH Verlag GmbH & Co. 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