Internationale Ausgabe: DOI: 10.1002/anie.201611360 Arenes Deutsche Ausgabe: DOI: 10.1002/ange.201611360 Template-Assisted meta-C À H Alkylation and Alkenylation of Arenes Sukdev Bag, Ramasamy Jayarajan, Rahul Mondal, and Debabrata Maiti* Abstract: To expand the scope of meta-functionalization, a pyrimidine-based template effective for the formation of b- aryl aldehydes and ketones, using allyl alcohols, by meta-C À H activation of benzylsulfonyl esters is described. In addition, a,b-unsaturated aldehydes were generated by in situ olefination and deprotection of allyl benzyl ethers. These new function- alizations at the meta-position of an arene have also been successfully implemented in benzylphosphonate, phenethyl carbonyl, and phenethylsulfonyl ester scaffolds. Key to these successful new functionalizations is the creation of an electro- positive palladium center by accepting the electron cloud from the metal to the energetically low-lying p-orbitals of pyrimidine ring, and it favors coordination of allyl alcohol to the metal center. Selective C À H functionalization has long been considered a tremendous challenge in organic synthesis owing to the subtle difference in intrinsic reactivity of C ÀH bonds present at different sites of an organic molecule. The last three decades have witnessed significant progress in selective ortho- C À H functionalization of arenes with the aid of stable five to seven membered metallacycles. [1] The activation of a distal C À H bond, which lies farther away from a functional group, has remained a great challenge because of the requirement of forming an unstable macrocyclic pre-transition state. [2] Recently, the meta-C ÀH bond activation has been achieved by the meticulous design of an end-on nitrile coordinating template. [3] Although the weak coordinating nitrile template is capable of olefination with activated olefins, acetoxylation, and arylation, the introduction of other functionalities, which are comparably difficult using a weak coordinating group, has remained unexplored to date. Herein, we report the forma- tion of b-aryl aldehydes and ketones by pyrimidine-based template-assisted meta-C À H functionalization with alkenyl alcohols. Additionally, the formation of a,b-unsaturated aldehydes have been discovered with an unconventional approach of in situ deprotection of the benzyl group affixed with allyl alcohols. Since the 1970s, the b-aryl aldehyde and ketone products from allyl alcohol and alkenyl alcohols have been gradually evolved by traditional Heck reactions. [4] In 2012, Sigman and co-workers reported the breakthrough discovery of the generation of a remote quaternary stereocenter using a redox relay strategy of alkenyl alcohols with aryl diazonium salts. [5] In 2013, elegant ortho-C À H activation studies by the groups of Jiang and Glorius demonstrated the formation of b- aryl aldehydes and ketones with allyl alcohols using a rhodium catalyst. [6] In this work, we intended to incorporate allyl alcohol and allyl benzyl ether at the meta-position of arene through a palladium-catalyzed approach (Figure 1). A nitrile- group-directed meta-C À H activation strategy was unsuccess- ful for incorporating an allyl alcohol. [7] Subsequently, we planned to explore a heterocycle-con- taining directing group (DG) wherein the metal can strongly coordinate with a heteroatom and deliver the desired functionalization at the remote meta-position of an arene. Notably, the pyridine-based DG has recently been utilized for meta-olefination with activated olefins and for iodination reaction. [8] In this report, we have synthesized heteroatom- containing biphenyl scaffolds and presumed that it would be flexible for selective meta-C ÀH activation as well as effective for installation of functional groups. Our initial attempts were focused on the benzylsulfonyl ester of a pyridine-based biphenyl template (Figure 2). Interestingly, the reaction of 1 with allyl alcohol provided the b-aryl aldehyde product in 23 % yield with a 7:1 meta selectivity. We have subsequently synthesized substituted pyridine and quinoline scaffolds. The use of a 2-fluoro- Figure 1. DG-assisted meta-C ÀH functionalization. Figure 2. a) Initial reaction conditions with allyl alcohol. b) Template modification for improved yield and selectivity. [7] [*] S. Bag, Dr. R. Jayarajan, R. Mondal, Prof. Dr. D. Maiti Department of Chemistry Indian Institute of Technology Bombay Powai, Mumbai-400 076 (India) E-mail: dmaiti@chem.iitb.ac.in Dr. R. Jayarajan Department of Biosciences and Bioengineering Indian Institute of Technology Bombay (India) Supporting information for this article can be found under: http://dx.doi.org/10.1002/anie.201611360. A ngewandte Chemi e Zuschriften 1 Angew. Chem. 2017, 129,1–6  2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Ü Ü