Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 1 Review Article 2 3 Recent advances on radical phosphorylation (2016-up till now) 4 5 Jie Liu1#, Han-Zhi Xiao1#, Qiang Fu2*, Da-Gang Yu1,3* 6 7 1Key Laboratory of Green Chemistry & Technology of Ministry of Education, College 8 of Chemistry, Sichuan University, Chengdu 610064, Sichuan, China. 9 2Department of medicinal chemistry, School of Pharmacy, Southwest Medical 10 University, Luzhou 646000, Sichuan, China. 11 3Beijing National Laboratory for Molecular Sciences, Beijing 100190, China. 12 #Authors contributed equally. 13 14 Correspondence to: Dr. Qiang Fu, Department of medicinal chemistry, School of 15 Pharmacy, Southwest Medical University, No.319 Section 3, Zhongshan Road, Luzhou 16 646000, Sichuan, China. E-mail: [email protected], ORCID: 17 0000-0001-9993-8776; Dr. Da-Gang Yu, Key Laboratory of Green Chemistry & 18 Technology of Ministry of Education, College of Chemistry, Sichuan University, No.24 19 South Section 1, Yihuan Road, Chengdu 610064, Sichuan, China. E-mail: 20 [email protected]; ORCID: 0000-0001-5888-1494 21 22 How to cite this article: Liu J, Xiao HZ, Fu Q, Yu DG. Recent advances on radical 23 phosphorylation (2016-up till now). Chem Synth 2021;1:[Accept]. 24 http://dx.doi.org/10.20517/cs.2021.07 25 26 Received: 9 Jul 2021 Revised: 10 Aug 2021 Accepted: 26 Aug 2021 First 27 online: 26 Aug 2021 28 29 30 Abstract 31 Organophosphorus compounds are of great significance in organic chemistry. Therefore, 32 the construction of phosphorus-containing compounds has attracted much attention of 33 organic chemists. Radical phosphorylation has become a powerful strategy to build 1 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 34 organophosphorus compounds, and great achievements has been obtained in the past 35 several years. In this review, we summarize the development on the generation and 36 application of phosphorus radical in organic chemistry since 2016. Special emphasis is 37 put on various new transformations involving the generation of P-centered radicals via 38 transition metal-catalysis, photochemical, and electrochemical means. Recent advances 39 on the development of metal-free catalytic phosphorylatations involving P-centered 40 radicals are also reviewed. 41 42 Keywords: Organophosphorus compounds, phosphorus radical, transition-metal 43 catalysis, visible light photoredox catalysis, unsaturated compounds 44 45 46 INTRODUCTION 47 Organophosphorus compounds are highly important and privileged, which have been 48 widely applied in the field of materials science, medicinal chemistry, and organic 49 synthesis[1-3]. The introduction of phosphorus functionalities into molecules could 50 effectively modify the medicinal properties and biological responses. Traditional 51 strategies for the formation of C-P bond heavily rely on the nucleophilic substitution, 52 such as Arbuzov reaction, Friedel-Crafts type reaction of PCl3 with aromatic 53 compounds as well as the reactions of organometallic reagents with electrophilic [4] 54 phosphorus species, including Ph2P(O)Cl . Although the transition-metal-catalyzed 55 cross-coupling reactions of C-X bonds in organo- (pseudo)halides with P(O)-H 56 compounds have demonstrated to be a powerful method for C-P bonds formation[5], the 57 development of other efficient methods from inexpensive and readily available starting 58 materials for the construction of new organophosphorus compounds is highly important 59 and thus has gained great attention of the organic community. 60 61 In the past decades, along with the rapid development of radical chemistry, the 62 construction of X-P (X = C, N, O or S etc.) bonds with P-centered radicals, which could 63 be easily generated through single electron transfer (SET) or hydrogen atom transfer 64 (HAT) by using metal salts, peroxides, photocatalysts and others, has created a new 65 avenue for the construction of organophosphorus compounds. As a consequence, these 66 past several years have witnessed a renewed awareness that the P-centered radicals 2 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 67 could be utilized to construct vitally important organophosphorus compounds[6-11]. The 68 main characteristic of the non-planar P-centered radicals with variable degree of 69 s-character (especially those containing P=O bonds) is their high reactivity to undergo 70 radical addition to unsaturated compounds (Figure 1)[12]. Particularly, P-centered 71 radical-based phosphorylation of organic compounds mediated by transition metal or 72 excessive oxidants has made great achievements. In addition, visible light photoredox 73 catalysis has emerged as a powerful means to achieve new reactions in organic 74 chemistry under mild conditions (Figure 2). Since Rueping’s group[13] reported the first 75 example of visible light photoredox-catalyzed C-P bonds formation under mild reaction 76 conditions in 2011, much progress was achieved in this rapid-growing research filed. 77 Besides, organic electrochemistry has also been established as an increasingly powerful 78 technique for molecular construction, which could replace sacrificial oxidizing or 79 reducing reagents[14]. As a result, electrochemical method has also been exploited for 80 the building of various organophosphorus compounds[15]. In recent years, some reviews 81 on phosphorylation have been reported. For example, Zhao’s group[6,8] reported a 82 review on phosphorus radical-based difunctionlization of unsaturated compounds in 83 2017 and 2018; Cai et al.[9] published a review on visible light-mediated C-P bond 84 formation reactions in 2019; Chen’s group[10] summarized the recent advances in the 85 construction of phosphorus-substituted heterocycles in 2020; In 2021, Li’s group[11] 86 reported a review on photo-mediated C-H phosphorylation reactions. As the reviews 87 available concentrate on a relatively narrow research area, there is no comprehensive 88 review on P-centered radical-based phosphorylation in organic chemistry integrating 89 transition metal catalysis, photocatalysis and electrocatalysis. Moreover, a lot of new 90 works have been reported in the past several years. In this review, we summarized 91 recent advances on transition-metal-catalyzed, photocatalytic and electrocatalytic C-P, 92 N-P, S-P and O-P bonds formation, which are based on P-centered radicals. This review 93 mainly deals with the reaction which appeared in the past 5 years and some earlier 94 pioneering works are also mentioned. 3 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 95 96 Figure 1. The geometry of P-centered radicals and general ways to generate P-centered 97 radicals. 98 99 100 Figure 2. The structures of photocatalysts used in phosphorylation reactions. 101 102 PHOSPHORYLATION OF ALKENES 103 Alkenes, such as styrenes, enamides and enolsilanes, are valuable and readily available 4 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 104 feedstocks. The functionalization of alkenes, especially the difunctionalization of 105 alkenes, has developed into a highly fascinating methodology for the building of highly 106 functionalized skeletons in organic chemistry. Specifically, P-radical-based 107 functionalization of alkenes could be divided into the following categories (Figure 3). 108 The intermolecular phosphorylation process is initiated by radical addition to the 109 carbon-carbon double bond with generation of carbon-centered radical intermediate, 110 which can combine with an extrinsic radical donor, metal complexes or further be 111 oxidized to carbocation or reduced to carboanion. Additionally, the carbocation can also 112 undergo β-H elimination to regenerate the alkenyl functionality. With regard to 113 intramolecular functionalization, alkenes tethered with radical acceptors, nucleophilic 114 or electrophilic groups dominate in this reaction. Generally, after the addition of 115 P-centered radical to the alkenes, the subsequent carbon-centered radical, carbocation 116 or carboanion may be trapped intramolecularly by a radical acceptor, nucleophilic or 117 electrophilic groups, leading to the intramolecular cyclizing products. 118 119 5 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx 120 Figure 3. Radical functionalization of alkenes based on P-centered radical. 121 122 Hydrophosphonylation of alkenes 123 The hydrofunctionalization of alkenes provides a facile access to a wide range of 124 functionalized alkanes. In the last decade, Lewis acid-catalyzed or transition 125 metal-catalyzed hydrophosphorylation of alkenes, especially the activated alkenes, has 126 been well developed. However, the method for hydrophosphorylation of unactivated 127 alkenes through radical pathway were still limited[16]. In 2013, Kobayashi and 128 co-workers[17] described visible light photoredox-catalyzed hydrophosphinylation of 129 unactivated alkenes with secondary phosphine oxides (SPOs) under mild reaction 130 conditions using a commercially available and inexpensive organic dye as a 131 photocatalyst, and isopropanol as a green solvent (Figure 4). The mild protocol is 132 compatible with a variety of unactivated alkenes and functional groups, including 133 alcohol, alkenyl ether and so on. However, diaryl phosphine oxide containing a slightly 134 more electron-rich substituent could only provide the