China's flourishing synthetic organofluorine chemistry: innovations in the new millennium

National Science Review 4: 303–325, 2017 doi: 10.1093/nsr/nwx058 REVIEW CHEMISTRY Special Topic: Organic Chemistry Booming in China China’s flourishing synthetic organofluorine chemistry: innovations in the new millennium Qinghe Liu† , Chuanfa Ni† and Jinbo Hu∗ ABSTRACT The new millennium has witnessed the rapid development of synthetic organofluorine chemistry all over the world, and chemists in China have made significant contributions in this field. This review aims to provide a brief introduction to China’s primary innovations from 2000 to early 2017, covering fluorination, fluoroalkylation, fluoromethylthiolation, fluoroolefination and polyfluoroarylation, as well as synthesis with fluorinated building blocks. Recent advances in the chemistry of difluorocarbene and the chemistry of carbon–fluorine bond activation are also discussed. As a conclusion, the review ends with some personal perspectives on the future development of China’s synthetic organofluorine chemistry. Keywords: fluorine, organic chemistry, synthetic methods, fluorination, trifluoromethylation, trifluoromethylthiolation, difluoromethylation, difluoroalkylation, fluoromethylation, fluoroolefination INTRODUCTION Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China ∗ Corresponding author. E-mail: † Equally contributed to this work. Received 4 February 2017; Revised 22 March 2017; Accepted 23 March 2017 In the field of organic chemistry, fluorine is a supersubstituent due to its high electronegativity (4.0 on the Pauling scale), small atomic radius (rv = 1.47 Å) and the great strength of the carbon–fluorine (C−F) bond (averages about 116 kcal/mol) [1]. The incorporation of fluorine atoms or fluorinated moieties into organic molecules can often lead to profound changes in the latter’s physical, chemical and biological properties, and a variety of fluorine-containing materials, pharmaceuticals and agrochemicals have been developed [2]. However, although fluorine is an abundant halogen element and ranks number 13 among all elements in the Earth’s crust, naturally occurring organofluorine compounds (organic compounds bearing a C−F bond) are rare [3]. Therefore, the development of efficient ways to introduce fluorine into organic compounds has become one of the hottest areas of organic synthesis research in recent years. Many efficient methodologies for the synthesis of organofluorine compounds have been developed by chemists all over the world [3–14]. China is rich in fluorspar deposits and most of the fluorine-containing basic chemicals, such as sim- ple fluorocarbons, are readily available from the Chinese chemical industry. Chinese chemists have engaged in organofluorine chemistry since the 1950s and have made significant contributions. In the past decade, many young Chinese scientists have joined this intriguing research field. Several books and book chapters have already described the development of China’s organofluorine chemistry efforts prior to 2000 [15–17]. This Review focuses on providing a brief summary of China’s primary innovations in the field of synthetic organofluorine chemistry from 2000 to early 2017, covering fluorination, fluoroalkylation, fluoromethylthiolation, fluoroolefination and polyfluoroarylation, as well as synthesis with fluorinated building blocks. Special topics on the chemistry of difluorocarbene and the chemistry of the C–F bond activation are also discussed. FLUORINATION C−F bond formation is one of the core contents in the field of organofluorine chemistry. In recent years, increasing attention has been paid to the development of selective fluorination reagents and exploration of conceptually new methods for the formation of C−F bonds [6,13,18].  C The Author(s) 2017. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. All rights reserved. For permissions, please e-mail: 304 REVIEW Natl Sci Rev, 2017, Vol. 4, No. 3 Scheme 1. Representative nucleophilic fluorination reactions. est reports of the use of boron trifluoride for nucleophilic ring-opening fluorination reactions [12]. In more recent organofluorine chemistry, more attention has been paid to controlling selectivity and exploiting new reactivity [21]. Hu et al. at SIOC recently developed a novel deoxyfluorination strategy based on cyclopropenium cation activation via the use of 3,3-difluoro-1,2-diarylcyclopropenes (CpFluors) (Scheme 1, Eq 1) [21] to tackle the problem of deoxyfluorination of alcohols not usually being sensitive toward the electronic nature of the substrates. The key to the success of this approach is the fine-tuning of the electronic nature of the CpFluor reagents to improve the nucleophilic fluorination. Moreover, the challenge of taming direct nucleophilic fluorination of arynes with fluoride ions has been achieved by the same group by using a diphenyliodonium salt as the catalyst (Scheme 1, Eq 2) [22]. In addition, transition metals have also been utilized to promote reactions that are otherwise difficult to achieve. Liu et al. at SIOC [23,24], Weng et al. at Fuzhou University (FZU) [25] and Jiang et al. at the South China University of Technology [26] (Scheme 1, Eqs 3–6) have published representative works on copper-catalyzed/mediated or silver-mediated nucleophilic fluorination. Electrophilic fluorination Scheme 2. Representative electrophilic fluorination reactions. Nucleophilic fluorination Nucleophilic fluorination is a fundamental methodology for the synthesis of organofluorine compounds. Huang and Guo’s pioneering work at the Shanghai Institute of Organic Chemistry (SIOC) in 1981 described the deoxyfluorination of sterols with phenyl sulfur trifluorides [19]; however, the low efficiency of this method limited its adoption for widespread use. Hou et al. at SIOC, in 2004 developed an efficient and highly regioselective method for the fluorination of aziridines using BF3 ·Et2 O as the fluoride source [20], which is one of the earli Electrophilic fluorination reactions are mainly performed with ‘N-F’ reagents, Selectfluor and N-fluorobenzenesulfonimide (NFSI) [27–35]. Ma et al. at Zhejiang University (ZJU) demonstrated the fluorohydroxylation of simple allenes with high regioselectivity, using Selectfluor as the electrophilic fluorination reagent in 2008 (Scheme 2) [27]. The regioselectivity was proposed to be determined by the electronic effect, while the reactivity was controlled by the stabilization effect of the aryl group in the allylic cationic intermediates. Recently, the combination of metal catalysis with electrophilic fluorination has led to the development of new methods for the synthesis of organofluorine compounds (Scheme 2) [28–35]. Liu et al. at SIOC reported a palladium(II)-catalyzed intermolecular fluoroamination of styrenes with NFSI in 2010, which was the first report of the application of NFSI as a source of both nitrogen a (...truncated)