Access to a new class of synthetic building blocks via trifluoromethoxylation of pyridines and pyrimidines.

Chemical Science View Article Online Open Access Article. Published on 07 October 2015. Downloaded on 15/05/2018 11:28:23. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. EDGE ARTICLE Cite this: Chem. Sci., 2016, 7, 424 View Journal | View Issue Access to a new class of synthetic building blocks via trifluoromethoxylation of pyridines and pyrimidines† Pengju Feng,‡ab Katarzyna N. Lee,‡ab Johnny W. Lee,ab Chengbo Zhanab and Ming-Yu Ngai*ab Since the first synthesis of trifluoromethyl ethers in 1935, the trifluoromethoxy (OCF3) group has made a remarkable impact in medicinal, agrochemical, and materials science research. However, our inability to facilely incorporate the OCF3 group into molecules, especially heteroaromatics, has limited its potential across a broad spectrum of technological applications. Herein, we report a scalable and operationally simple protocol for regioselective trifluoromethoxylation of a wide range of functionalized pyridines and pyrimidines under mild reaction conditions. The trifluoromethoxylated products are useful scaffolds that can be further elaborated by amidation and palladium-catalysed cross coupling reactions. Received 12th August 2015 Accepted 5th October 2015 Mechanistic studies suggest that a radical O-trifluoromethylation followed by the OCF3-migration reaction pathway is operable. Given the unique properties of the OCF3 group and the ubiquity of pyridine and pyrimidine in biologically active molecules and functional materials, trifluoromethoxylated DOI: 10.1039/c5sc02983j www.rsc.org/chemicalscience pyridines and pyrimidines could serve as valuable building blocks for the discovery and development of new drugs, agrochemicals, and materials. ‡ These authors contributed equally. molecules to improve their efficacy and minimize their side effects (Fig. 1b).1,2,5 Furthermore, incorporation of the OCF3 group into organic molecules can increase their melting point and boiling point difference under ambient pressure, and lower their surface tension, dielectric constant, and pour point.1,11,12 These properties are particularly useful in designing electronic devices and materials; as a result, the OCF3-containing molecules can be found in electro-optical materials used for the development of liquid crystal displays,13 soluble organic semiconductor,14 and melt-processable uoropolymers such as peruoroalkoxy alkanes.12 Given the unique properties of the OCF3 group and the ubiquity of pyridines and pyrimidines in biologically active molecules and functional materials, triuoromethoxylated pyridines and pyrimidines could serve as valuable synthetic building blocks for the discovery and development of new drugs, agrochemicals, and functional materials. However, synthesis of OCF3 containing heteroarenes through either O–CF3 or C–OCF3 bond formation remains a formidable challenge in organic synthesis (Fig. 1c).1–5,15 Unlike its analogous methoxy (OCH3) group, the OCF3 group cannot be formed via triuoromethylation of hard nucleophiles such as phenoxides with CF3I through SN2 type mechanism.11,16,17 This is due to (i) strong electron repulsion between three uorine atoms and an incoming nucleophile; (ii) formation of energetically disfavoured CF3 carbocation transition state structure (TS); and (iii) competing iodination of nucleophiles due to the reversed electron density. In addition, the thermal instability of transition 424 | Chem. Sci., 2016, 7, 424–429 This journal is © The Royal Society of Chemistry 2016 Introduction The triuoromethoxy (OCF3) group has made a signicant impact in medicinal, agrochemical, life- and materials science research1–5 since Booth and Burcheld reported the rst synthesis of triuoromethyl ethers in 1935.6 The increasing importance of the OCF3 group can be attributed to its unique structural and electronic properties. First of all, in aryl triuoromethyl ethers the OCF3 moiety lies in the plane orthogonal to arene ring (Fig. 1a)7 and studies have shown that this unusual orientation may be benecial for providing additional binding affinity in drug–target complexes.8 In addition, the OCF3 group is among the most electronegative groups (c(F) ¼ 4.0, c(OCF3) ¼ 3.7).9 Molecules bearing an electron-withdrawing group have better metabolic stability. Moreover, the OCF3 group has an excellent lipophilicity (px(SCF3) ¼ +1.44, px(SF5) ¼ +1.23, px(OCF3) ¼ +1.04, px(CF3) ¼ +0.88, px(OCH3) ¼ 0.02);10 compounds with higher lipophilicity show enhancement in their in vivo uptake and transport in biological systems. Therefore, the OCF3 group is introduced into biologically active a Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, USA b Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794-3400, USA. E-mail: † Electronic supplementary information (ESI) available: Experimental procedures and analysis data for new compounds. See DOI: 10.1039/c5sc02983j View Article Online Open Access Article. Published on 07 October 2015. Downloaded on 15/05/2018 11:28:23. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Edge Article Chemical Science Fig. 1 Properties, applications, synthetic challenges and methods of synthesis of OCF3-containing compounds. NFSI ¼ N-fluorobenzenesulfonimide, TMSCF3 ¼ trifluoromethyltrimethylsilane. metal–OCF3 complexes (they readily decompose to form uorophosgene and metal uoride)18 and the poor nucleophilicity of the OCF3 anion (a reactive electrophile is needed for the C–OCF3 bond formation)19 have hampered the development of the C– OCF3 bond formation through either transition metal-catalysed C–O bond formation or nucleophilic substitution. Strategies for the synthesis of triuoromethoxylated heteroaromatic compounds are very rare.20–25 Leroux and co-workers reported a detailed examination of several different approaches and concluded that the presence of a chlorine atom at the a-, and/or a0 - position of hydroxy-pyridines is critical (Fig. 1d).20 Without it, little or no desired product was isolated. This requirement greatly limited its application. Recently, Qing and co-workers reported a novel, direct synthesis of pyridyl triuoromethyl ethers from unprotected hydroxypyridines.25 However, excess amounts of reagents and oxidants were required. In addition, only two examples with moderate yield were reported. Due to the lack of a general synthetic method for the synthesis of triuoromethoxylated pyridines and pyrimidines, their full potential has not been fully exploited in pharmaceutical, agrochemical, and materials applications. Herein, we report a scalable and operationally simple protocol for regioselective synthesis of triuoromethoxylated functionalized pyridines and pyrimidines. Several unique features distinguish our strategy from the existing approaches: (i) many substrates with complex skeletons are triuoromethoxylated at or below room temper (...truncated)