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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.

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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

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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

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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 corresponding product with 135 moderate yields. The mechanism is proposed as following. The SET oxidation of 136 phosphinous acid is promoted by the photoexcited Rhodamine B (PC*) to generate the 137 corresponding radical cation. The deprotonation of such radical cation generates 138 phosphinoyl radical, which undergoes radical addition to alkene to form an alkyl 139 radical intermediate. Regeneration of phosphinoyl radical and yielding of the desired 140 hydrophosphinylation product could be realized by chain propagation from the HAT of 141 SPO or its trivalent tautomer with the alkyl radical intermediate. As to the reduced 142 photocatalyst PC•−, it may be quenched by tiny amounts of oxygen gas in the solvent to 143 regenerate the Rhodamine B (PC). 144

145 146 147 Figure 4. Hydrophosphinylation of unactivated alkenes with secondary phosphine 148 oxides under visible-light photoredox catalysis. 6 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

149 150 Recently, based on previous works, Liu and coworkers[18] have reported a nice 151 P-centered radical-mediated anti-Markovnikov hydrophosphorylation of unactivated 152 alkenes and remote alcohol oxidation through an intramolecular 1,5(6)-HAT procedure 153 (Figure 5). Notably, diverse sulfonyl- and malonate-substituted ketones or aldehydes 154 could also be obtained from the alkenols. This mild and versatile method provides a 155 general method to access diverse hydrofunctionalized products in moderate to good 156 yields from a wide range of alkenols. 157

158 159 Figure 5. Anti-Markovnikov hydrofunctionalization of unactivated alkenes via 160 1,5(6)-HAT procedure. 161 162 In addition, the visible light-driven hydrophosphinylation of unactivated alkenes was 163 also explored by Li’s group[19] by using a simple and cheap compound, salicylaldehyde, 164 as photocatalyst (Figure 6). The air and water insensitive reaction was conducted in a 165 basic aqueous solution which enabled the deprotonated salicylaldehyde to absorb 166 visible light. As shown in Figure 6, under visible light irradiation, the phenoxide could 167 reach its excited state, which interacts with the ground state phenoxide to generate the 168 benzoyl radical and the hydroxybenzyl radical. Next, a HAT process between the 169 benzoyl radical with SPO could generate phosphonyl radical and the phenoxide. An 170 anti-Markovnikov addition of phosphorus radical with alkene could result in the alkyl 171 radical, which then undergo HAT with the hydroxybenzyl radical to offer the product 172 and regenerate phenoxide. The base might be not only used for the deprotonation of

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173 catalyst but also the HAT process. 174

175 176 177 Figure 6. Visible light-induced salicylaldehyde-catalyzed hydrophosphinylation of 178 unactivated alkenes. 179 180 Carbophosphorylation 181 The carbophosphorylation means construction of new C-P bond with the simultaneous 182 forging C-C bond, including C(sp3)-C(sp), C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. In 183 this section, we divide the content of carbophosphorylation into two categories of 184 intramolecular and intermolecular carbophosphorylation to enhance the 185 understandability. 186 187 Intramolecular carbophosphorylation 188 Aromatic organophosphorus compounds are ubiquitous and can be found in a wide 189 range of pharmaceuticals, nucleotides, and phosphine-containing ligands. Thus, the 190 development of a concise and efficient method for the C-P bond formation is hugely 191 desirable. In 2012, Yang’s group[20] reported a silver-catalyzed carbon-phosphorus 192 difunctionalization of alkenes through a carbophosphorylation and C-H 193 functionalization cascade process, leading to a diverse of phosphorylated oxindoles 194 through intramolecular direct annulation (Figure 7). To understand the catalytic cycle 195 of the carbon phosphorylation reactions, high resolution mass spectrometry (HRMS) 196 was used to monitor the key intermediates. Mechanistic studies indicated that a 197 silver-promoted generation of the phosphoryl radical might be involved in this radical 198 cascade reaction. In 2014, a metal-free oxidative arylphosphination of activated 199 N-substituted-N-arylacrylamide derivatives by phosphorylation cascade has been 8 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

200 developed by Li’s group[21] to afford a variety of phosphorus-containing oxindole 201 moieties. 202

203 204 205 Figure 7. Silver-catalyzed carbon-phosphorus functionalization of alkenes. 206 207 The chroman-4-one framework is a privileged structural motif widely existing in 208 numerous natural products and pharmaceuticals. Due to the importance of the 209 chroman-4-one scaffold and organophosphorus compound, the synthesis of 210 phosphorylated chroman-4-one has attracted great attention of chemists. Although 211 much progress has been achieved in this fields, the development of transition metal-free 212 approach for the synthesis of chroma-4-ones bearing with a phosphine oxide 213 functionality is still highly desirable. In 2016, Li’s group[22] reported a novel and direct 214 approach to construct a phosphonate functionalized chroman-4-ones by using silver salt

215 as the catalyst and K2S2O8 as an oxidant under mild conditions (Figure 8). The authors 216 propose that the cascade reaction proceeds through an intramolecular addition of the in 217 situ generated acyl radical onto alkenes, followed by a selective nucleophilic 218 radical-electrophilic radical coupling (path A). Alternatively, the formation of the final 219 product could possibly be due to the addition of a phosphorus radical to the alkene 220 (path B). Based on the control experiments and the structure of the byproduct, the 221 authors prefer the formation of the product via Path A. In 2020, Xie’s group[23] reported 222 a transition metal-free synthesis of a variety of chroman-4-ones bearing phosphine 223 oxide motifs from 2-(allyloxy)benzaldehydes and diphenylphosphine oxides via a

224 radical phosphinoylation-cyclization cascade mediated by K2S2O8. 225

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226 227 228 Figure 8. Radical cascade cyclization-coupling of 2-(allyoxy)arylaldehydes for the 229 straightforward synthesis of functionalized chroman-4-ones. 230 231 Indoles, including oxindoles and indolines, fall into a ubiquitous structural motif that 232 constitutes a variety of natural alkaloids and clinically used drugs. The combination of 233 indole motif with phosphorus group could result in a wide range of compounds 234 exhibiting promising bioactivity, such as anti-tumor, anti-HIV and antimycobacterial. 235 Although a pioneering radical amino-phosphorylation of unactivated alkenes of 236 2-allylanilines toward 2-phosphonomethyl-N-sulfonyl indolines has been established by 237 Yang’s group[24], the development of an economical manner from readily available 238 material remains highly desirable. In 2018, Liang’s group developed a silver-catalyzed 239 radical arylphosphorylation of unactivated alkenes via a cascade 240 phosphorylation-arylation sequence (Figure 9). The protocol displays broad substrate 241 scope, high exo/endo selectivity, simple operation and a diverse array of 242 3-phosphonoalkyl indolines could be obtained in satisfactory yields. As depicted in 243 Figure 9, a plausible mechanism is proposed. Firstly, the oxidation of H-phosphonate

244 or phosphine oxides by AgNO3 furnishes the phosphoryl radical. The addition of 245 phosphoryl radical to the N-tethered double bond leads to carbon radical intermediate, 246 which was intramolecularly trapped by the phenyl ring, affording ring closure 247 intermediate. Then, a subsequent SET with Ag(I) produces the indoline product and 248 Ag(0) and a proton. At last, Ag(0) is oxidized to Ag(I) by benzoyl peroxide (BPO) to 249 finish the catalytic cycle. 250

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251 252 Figure 9. Silver-catalyzed radical arylphosphorylation of unactivated alkenes for the 253 synthesis of 3-phosphonoalkyl indolines. 254 255 Dihydroisoquinolones have also been widely found in complex natural products, 256 biomolecules and pharmaceuticals, displaying extraordinary biological activities. By 257 elegantly design the substrates, in 2019, Yu’s group[25] reported a silver-mediated 258 phosphorylation/cyclization of N-allylbenzamides with phosphine oxides for the 259 synthesis of phosphoryl-substituted dihydroisoquinolones (Figure 10). The method 260 displays broad substrate scope, good scalability and high efficiency under mild reaction 261 conditions. As shown in Figure 10, apart from the application of stoichiometric silver 262 salts as the oxidants, the reaction mechanism is similar to the above silver-catalyzed 263 radical arylphosphorylation of unactivated alkenes. 264

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265 266 267 Figure 10. Silver-mediated radical phosphorylation/cyclization of N-allylbenzamides 268 to access phosphoryl-substituted dihydroisoquinolones. 269 270 Despite the above achievements, transition-metal reagents and/or high temperature are 271 still required in those approaches. Thus, it is highly desirable to develop more 272 environmentally friendly and practical procedures to construct dihydroisoquinolone 273 derivatives under room temperature. In 2019, Yu and co-workers[26] reported a 274 visible-light-promoted transition-metal-free approach toward phosphoryl-substituted 275 dihydroisoquinolones via cascade phosphoarylation/cyclization of N-Allybenzamides 276 (Figure 11). The visible-light-promoted transition metal-free approach features mild 277 reaction conditions, convenient operation, broad substrate scope. A series of 278 Stern-Volmer fluorescence quenching experiments implied that the excited 279 photocatalyst was effectively quenched by diphenylphosphine oxide. Besides, the 280 quantum yield of the reaction was determined to be 0.26, precluding the radical chain 281 processes in this photochemical reaction.

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282 283 Figure 11. Visible-light-promoted transition-metal-free approach toward 284 phosphoryl-substituted dihydroisoquinolones via cascade phosphorylation/cyclization 285 of N-allylbenzamides. 286 287 Polyheterocycles are ubiquitous structural motifs widely found in natural products and 288 pharmaceuticals, which have attracted tremendous attention from chemists. In 2016, 289 Yue and Liu’s group[27] reported a silver-catalyzed carbon-phosphorus functionalization 290 for the synthesis of various phosphorylated polyheterocycles in moderate to good yields 291 with high diastereoselectivity. Notably, the existing of P-centered radicals in the 292 reaction was confirmed by EPR experiments. As depicted in Figure 12, the selective 293 addition of phosphorus radical to the α-position of α, β-unsaturated carbonyl compound 294 is crucial for the success of the reaction. 295

296 297

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298 Figure 12. Silver-catalyzed carbon-phosphorus functionalization for polyheterocycle 299 formation. 300 301 Afterwards, a similar strategy was reported by Akondi group[28], who employed eosin Y 302 as photocatalyst to promote the metal-free phosphorus radical mediated construction of 303 phosphinoylpyrroloindoles (Figure 13). The protocol features air as a green oxidant, 304 high functional group tolerance, excellent chemo- and diastereoselectivity as well as 305 mild reaction conditions. Importantly, the transformation proceeded through a cascade 306 C-P and C-C (5-endo-trig cyclization) bond formation with excellent diastereo- and 307 chemo-selectivity. The mechanism of the reaction is illustrated in Figure 13. Firstly, 308 photoexcited eosin Y (EY*) oxidizes diphenylphosphine oxide via SET to generate 309 radical cation. Then, upon deprotonation of radical cation, the generated the 310 phosphinoyl radical adds to the highly electron dense α-position of the carbonyl group 311 followed by 5-endo-trig cyclization, giving rise to the radical intermediates. 312 Subsequently, intermediate was oxidized to deliver the carbocation, which produces the 313 final product upon protonation. Eventually, the photocatalytic cycle will be closed after •− 314 oxidation of the reduced photocatalyst (EY ) by O2. 315

316 317 318 Figure 13. Visible-light-driven metal-free aerobic synthesis of highly diastereoselective 319 phosphinoylpyrroloindoles. 320 321 Phenanthridine derivatives represents an important category of scaffolds in biologically 322 active molecules. The synthesis of functionalized phenanthridines starting from 323 biphenylvinyl azides via a radical tandem cyclization strategy has achieved much 324 progress. Inspired by the works of alkylation and trifluoromethylation of vinyl azides,

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325 in 2017, Yang’s group[29] described a visible-light-induced tandem phosphorylation 326 cyclization of vinyl azides for the synthesis of phosphorylated phenanthridines (Figure 327 14). As drawn in Figure 14, the addition of phosphoryl radicals to vinyl azide 328 compounds in the reactions generate iminyl radicals, which undergo intramolecular 329 homolytic aromatic substitution, delivering the final phenanthridines. 330

331 332 Figure 14. Visible-light-induced tandem phosphorylation cyclization of vinyl azides. 333 334 Benzimidazo-isoquinoline-6(5H)-ones as a class of important N-containing polycyclic 335 scaffolds have attracted much attention of chemists. In 2019, Yu’s group[30] described 336 an efficient protocol for the synthesis various of phosphoryl-substituted 337 benzimidazo[2,1-a]isoquinoline-6(5H)-ones from 2-arylbenzoimidazoles and 338 phosphine oxides, including various diphenylphosphine oxides, ethyl

339 phenylphosphinate, as well as dialkyl H-phosphonates, by using AgNO3/K2S2O8 340 catalytic system. The reaction features wide substrate scope, mild reaction conditions 341 and easy scaling up, providing a straightforward method for the synthesis of valuable 342 phosphoryl-substituted benzimidazo[2,1-a]isoquinoline-6(5H)-ones (Figure 15). A 343 manganese(Ⅲ)-promoted tandem phosphinoyl/cyclization of 344 2-arylindoles/2-arylbenzimidazoles with disubstituted phosphine oxides were also 345 developed by Li and Song’s group[31]. As illustrated in Figure 15, the reaction 346 mechanism for the reaction is similar to the above-discussed phosphorus 347 radical-initiated radical cascade reactions. 348

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349 350 351 Figure 15. Silver-catalyzed synthesis of phosphoryl-substituted 352 benzimidazo[2,1-a]isoquinoline-6(5H)-ones. 353 354 Most of the radical cyclization reactions involving phosphorus radicals focused on 355 oxidative process. In constrast, redox-neutral phosphorylation/cyclization pathway 356 remains less explored. Based on our previous work[32] of visible light-induced 357 phosphonocarboxylation of alkenes, in 2021, we disclosed the visible-light-driven 358 phosphonoalkylation of alkenes tethered with alkyl sulfonates to construct 359 phosphorylated three-membered carbocyclic scaffolds with H-P(O) compounds 360 (Figure 16)[33]. The transition-metal-free protocol exhibits good functional group 361 tolerance, broad substrate scope, high yields under mild reaction conditions. As 362 illustrated in Figure 16, the intramolecular nucleophilic substitution reaction is the key 363 step to furnish the final cyclized product. 364

365 366 367 Figure 16. Visible-light-driven phosphonalkylation of alkenes.

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368 369 Phosphinylation with concomitant 1,n-migration of a functional group represents a 370 powerful strategy to build structurally uneasily accessible scaffolds. In 2014, Ji and 371 Xu’s group[34] reported a silver-catalyzed radical phosphinylation of α, α-diaryl allylic 372 alcohols with diarylphosphine oxides for the convenient synthesis of 373 α-aryl-β-phosphinylated carbonyl ketones in moderate to good yields through 374 chemoselective 1,2-aryl migration, involving the formation of C(Ar)-C(sp3) and 375 C(sp3)-P bonds in one step (Figure 17). At the same year, a similar work with 376 H-phosphonates as the radical precursors was proposed by Wu’s group[35]. 377

378 379 380 Figure 17. Silver-catalyzed carbophosphonation of α, α-diaryl allylic alcohols for the 381 synthesis of β-aryl-γ-ketophosphonates. 382 383 Although approaches for the construction of β-aryl-γ-ketophosphine oxides via a 384 radical carbophosphinylation of allylic alcohols have been described, the methods 385 available still suffer from the requirement of expensive transition metal salts and high 386 reaction temperatures. Inspired by these precedents, Zhang and co-workers[36] 387 developed a visible-light-promoted phosphinylation of allylic alcohols via concomitant 388 1,2-aryl migration by using an inexpensive organic dye, eosin Y, as the photocatalyst, 389 promoting the reaction process efficiently under metal-free and mild conditions (Figure 390 18). Notably, unsymmetric phosphine oxides, dialkylphosphine oxides and ethyl 391 phenylphosphinate were transformed into the desired products in good to moderate 392 yields.

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393 394 Figure 18. Eosin Y-catalyzed, visible-light-promoted carbophosphinylation of allylic 395 alcohols via a radical neophyl rearrangement. 396 397 As the generation of phosphorus radical is frequently accompanied by stoichiometric 398 amounts of radical initiators or external oxidants, the design and synthesis of new 399 phosphorus radical precursors remain to be investigated. In 2018, Yang’s group[37] 400 reported a novel type of phosphine radical precursor, oxime phosphonate, which was 401 synthesized and applied in the visible light-catalyzed phosphonation-annulation of 402 unsaturated sulfonamides and carboxylic acids, affording a variety of 403 β-phosphonopyrrolidines and β-phosphonolactones. Notably, additional oxidants and 404 bases were not needed in the reaction. Recently, the novel radical precursor was applied 405 in the semi-pinacol rearrangement reaction for the synthesis of γ-oxo-phosphonates by 406 the same group[38] (Figure 19). Importantly, the reaction avoids using external oxidants. 407 As displayed in Figure 19, the proposed mechanism for semi-pinacol rearrangement 408 reaction commences with a photo-induced SET between oxime phosphonate and 409 excited-state *Ir(Ⅲ), leading to the formation of phosphorus radical. Then, the addition 410 of the P-centered radical to alkene of the substrate rapidly gives alkyl radical, which 411 immediately generates benzyl radical via semipinacol rearrangement process. Finally, 412 the resulting benzyl radical was oxidized by the Ir(IV) complex to form benzyl cation, 413 which converts to the ultimate product after deprotonation. 414

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415 416 417 Figure 19. Photo-induced phosphorus radical involved semipinacol rearrangement 418 reaction: highly synthesis of γ-oxo-phosphonates. 419 420 Although difunctionalization of unactivated alkenes with radical 1,2-aryl migration 421 provides an efficient way to access highly functionalized products, the radical 422 1,2-alkynyl-migration has rarely been studied. Recently, on the basis of sequential 423 oxidation mechanism, Chen and coworkers[39] reported a silver-promoted 424 phosphonation/alkynylation of alkene proceeding with radical 1,2-alkynyl migration, 425 affording a range of α-alkynyl γ-ketophosphine oxides in moderate to good yields 426 (Figure 20). It is noteworthy that the addition of the P-centered radical to the alkenes 427 initiated 1,2-alkynyl migration via 3-exo-dig cyclization. 428

429 430 431 Figure 20. Silver-promoted phosphonation/alkynlation of alkenes proceeding with 432 radical 1,2-alkynyl migration. 433 434 Intermolecular carbophosphorylation

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435 Although intermolecular reactions are more challenging than the intramolecular 436 reactions, intermolecular reactions remain as an efficient pathway for 437 difunctionalization of alkenes. Cyano is a versatile group which could be converted to a 438 diverse array of functionalities, such as amides, acids, aldehydes and heterocycles for 439 the building of structurally intriguing bioactive compound. In 2017, Zhang and Zou’s [40] 440 group reported a cyanophosphinoyl of alkenes using Mn(OAc)3 as an oxidant to 441 generate P-centered radical and CuCN as a catalyst to facilitate the cyanation process 442 (Figure 21). The reaction is performed under mild conditions, tolerating both aromatic 443 and aliphatic alkenes to afford vicinal cyanophosphinoylation products with high 444 regioselectivity. The cyano group in the product could be easily transformed to other 445 valuable compounds with synthetic and biological interests. 446

447 448 Figure 21. Cyanophosphinoyl of alkenes. 449 450 Although a series of phosphonylation-based difunctionalization of alkenes have been 451 developed, phosphorus radical-initiated asymmetric reactions have seldom been 452 reported owing to the involvement of the highly reactive carbon-centered radical 453 intermediates. In 2019, Liu’s and Zou’s group[41] collaboratively reported a 454 copper-catalyzed enantioselective phosphinoylcyanation of styrenes via a tandem 455 radical relay, allowing for the synthesis of various β-cyanodiaryphosphine oxides 456 directly and efficiently (Figure 22). Preliminary mechanistic studies demonstrate that

457 t-BuOOSiMe3 generated in situ from t-BuOOH serves as a radical initiator to trigger 458 t-butoxy radical production upon oxidization of (L5)CuICN species via 459 proton-coupled-electron transfer (PCET) pathway, leading to the generation of 460 phosphinoyl radical and benzyl radical by sequence. A series of chiral 461 γ-aminophosphine ligands could be easily obtained from the β-cyanodiarylphosphine 20 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

462 oxides. 463

464 465 466 Figure 22. Proton-coupled electron transfer enables tandem radical relay for 467 asymmetric copper-catalyzed phosphinoylcyanation of styrenes. 468 469 β-Pyridylphosphine motifs consisting of a pyridine with hard σ-donor feature and a 470 phosphine with soft π-acceptor are widely employed as versatile ligands for designing 471 transition-metal catalysts. However, the simultaneous incorporation of both phosphine 472 and pyridyl moieties into unsaturated C-C bonds remained an unresolved challenge to 473 date. In 2018, Hong and Baik’s group[42] developed a one-pot difunctionalization of 474 unactivated alkenes with P(O)-H compounds and N-methoxypyridinium salts for the 475 preparation of a variety of synthetically and biologically important β-pyridyl 476 alkylphosphonates (Figure 23). The authors propose that the addition of a phosphonyl 477 radical to the alkene to form alkyl radical intermediate, which adds to the 478 N-methoxypyridinium salt, is involved in the reaction. DFT calculations were 479 implemented to illustrate solvation effect and the detailed mechanism of the reaction. 480 Notably, other pathways lead to the byproducts are discussed in the reaction. 481

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482 483 484 Figure 23. Difunctionalization of unactivated alkenes for the synthesis of β-pyridyl 485 alkylphosphonates. 486 487 In contrast to the above work using silver salts and stoichiometric metal oxidants, a 488 photocatalytic polarity-reversing radical cascade strategy for difunctionalization of 489 alkene using has been developed by Nagib’s group[43] (Figure 24). The phosphorus 490 group and a heteroarene, such as pyridine, are concurrently added onto an olefin, which 491 is enabled by visible light-induced generation of electrophilic P-centered radicals. The 492 methods presented would serve as an inspiration for exploiting more multicomponent 493 couplings based on radical polarity reversal. Notably, the same group[44] has expanded

494 the polarity-reversed radical cascades to a variety of radical precursors, including N3,

495 P(O)R2 and CF3, by employing hypervalent iodine reagents. 496

497 498 499 Figure 24. Heteroarene phosphinylalkylation via a catalytic, polarity-reversing radical 500 cascade. 22 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

501 502 While pyridylation/phosphinoylation as a new 1,2-difunctionlization of alkenes at the 503 C-2 position of pyridines has been realized, the alkylation of pyridines at the C-4 504 position remains unresolved. In 2021, Shen and coworkers[45] described an 505 intermolecular pyridylation/phosphinoylation of alkenes at the C-4 position of 506 pyridines using 4-cyanopyridines and diphenylphosphine oxides under photoredox 507 conditions (Figure 25). Mechanistic studies indicate that triethylamine serves as both 508 HAT and SET reagents via visible-light photoredox catalysis. The condition screening 509 shows that photocatalyst is essential for this reaction. Aromatic and aliphatic olefins 510 could be converted to corresponding products with moderate to good yields. A possible ox 511 mechanism has been proposed in Figure 25. Et3N (E 1/2 = + 0.83 V vs. SCE) can be ox •− 512 oxidized by PC*(E 1/2 PC*/PC = + 1.35 V vs. SCE) generated from the ground state

513 photocatalyst under visible light irradiation, then a SET between Et3N and excited state •+ •− 514 PC* could produce Et3N and PC . Then, the HAT between diarylphosphine oxide and •+ + 515 Et3N provides Et3NH and phosphinoyl radical. Subsequently, the phosphinoyl radical 516 undergoes facile radical addition to the alkenes, leading to carbon radical. At the same •− red •− 517 time, the reduced PC (E 1/2 PC/PC = -0.75 V vs. SCE in TFE) reduces the red 518 4-cyanopyridine (E 1/2 = -0.62 V vs. SCE in TFE) via a SET affording a persistent 519 radical anion along with the regeneration of the PC. Finally, the fusion of C-C bond via 520 intermolecular radical-radical coupling gives rise to the anion intermediate, which 521 undergoes rapid rearomatization to afford the desired product along with the 522 elimination of a cyanide anion. 523

524 525 526 Figure 25. Metal-free visible-light-induced photoredox catalyzed intermolecular 527 pyridylation/ phosphinoylation of alkenes. 23 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

528 529 Both phosphonyl and carboxyl groups are valuable groups, the simultaneous 530 incorporation of them into organic molecules could serve as an efficient method to 531 access pharmaceutically important β-phosphono carboxylic acids. In 2020, Yu’s 532 group[32] provides an method for the phosphonocarboxylation of alkenes with carbon 533 dioxide via visible light photoredox catalysis (Figure 26). The protocol features low 534 catalyst loading, high regio- and chemo-selectivities, amd good functional group 535 tolerance. The sustainable, general and practical strategy generates important 536 β-phosphono carboxylic acids, containing structurally complex unnatural α-amino acids. 537 A wide range of alkenes, including enamides, styrenes, enolsilanes and acrylates, could 538 be transformed to desired products efficiently under mild reaction conditions. As 539 presented in Figure 26, SET between H-P(O) compounds and a photoexcited 540 photocatalyst with the assistance of a base generates the phosphonyl radicals, which 541 was captured by C=C double bonds of enamides to selectively form the α-amido radical 542 stabilized by phenyl and amide groups. Then, a subsequent SET reduction by the

543 reduced photocatalyst affords the α-amido carbanions, which then could react with CO2 544 to deliver the desired β-phosphono α-amino acids. Notably, the reaction outcompetes 545 several side reactions, such as C-H bond carboxylation, hydrocarboxylation, 546 hydrophosphinylation reactions as well as nucleophilic addition reactions between 547 enamides, which could tautomerize to imines, and H-P(O) compounds. 548

549 550 Figure 26. Transition metal-free phosphonocarboxylation of alkenes with carbon 551 dioxide via visible-light photoredox catalysis. 552 553 Oxyphosphorylation of Alkenes 554 β-Ketophosphine oxides are valuable phosphorous-containing compounds, which

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555 exhibit a diverse range of applications in various synthetically useful transformations, 556 especially as synthetic precursors to access olefins through the well-known 557 Horner-Wittig reaction[46]. In 2011, the first catalytic and direct oxyphosphorylation of 558 alkenes leading to β-ketophosphonates was reported by Ji’s group[47] by using 559 copper(Ⅱ)/iron(Ⅲ) as catalysts, avoiding the use of stoichiometric organometallic 560 reagents (Figure 27). Preliminary mechanic investigation suggests that the carbonyl 561 oxygen originates from dioxygen and this method involves a radical process. Since then, 562 a variety of methods have been explored for oxyphosphorylation of alkene. For 563 example, Song’s group[48] disclosed a domino Knoevenagel-decarboxylation-alkene 564 difunctionlization sequence for construction β-ketophosphonates in moderate to good 565 yields via oxyphosphorylation of in situ generated cinnamic acids from easily available 566 benzaldehydes and H-Phosphonates by a cooperative Cu/Fe catalytic system in 2015 567 (Figure 28). 568

569 570 Figure 27. Cu/Fe-cocatalyzed oxyphosphorylation of alkenes. 571

572 573 574 Figure 28. Cu/Fe-cocatalyzed formation of β-ketophosphonates by a domino 575 Knoevenagel-decarboxylation-oxyphosphorylation sequence. 576 577 In 2017, Chen’s group[49] described an efficient one-pot synthesis of 25 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

578 β-ketophosphonates from cinnamic acids or alkenes with H-phosphonates and dioxygen 579 via Cu-catalysis (Figure 29). The reaction is suitable for alkenyl carboxylic acids and 580 alkenes as well as a series of organophosphorus reagents, including diphenylphosphine 581 oxide, dialkyl H-phosphonates and ethyl phenylphosphinate. The authors proposed that Ⅱ 582 active oxygen complex[(MeCN)nCu -O-O] was involved in the reaction. 583

584 585 Figure 29. Oxyphosphorylation of alkenyl acids or alkenes. 586 587 Owing to their continuing interest on the efficient synthesis of β-ketophosphine oxides, 588 Wei and Ji’s group[50] have developed efficient methods for the synthesis of 589 β-ketophosphine oxides from ketones in 2017 (Figure 30). Such a copper-catalyzed 590 aerobic oxidative coupling of ketones with P(O)-H compounds leads to a series of 591 β-ketophosphine oxides with good functional group tolerance assisted by TBSOTf 592 (tbutyldimethylsilyl triflate). Isotope-labelling experiments indicate that the carbonyl 593 oxygen atom of the products originates from dioxygen. Firstly, the reaction is initiated

594 by SET between Ph2P(O)H and Cu(Ⅱ) species to form diphenyl phosphine oxide cation

595 radical species and Cu(Ⅰ) species. With the help of Et3N, the deprotonation happened to 596 generate the P-radical, which attacked enolsilane to give β-phosphoryl alkyl radical.  ‒ + 597 Afterwards, the unstable radical reacted with superoxide radical O2 and Et3NH to 598 deliver hydroperoxide intermediate. Subsequently, the intramolecular elimination of

599 R3SiOH in the presence of Et3N gave hydroperoxide species, which was further 600 reduced by diphenylphosphine oxide to give the enolate, which was eventually 601 transformed into product via a quick tautomerization. 602 603 At the same year, the same group[51] reported copper-catalyzed one-pot synthesis of 604 β-ketophosphine oxides from ketones and H-phosphine oxides, in which 605 vinylhydrazinedicarboxylate was the key intermediates (Figure 31a). Soon after, Wei’s 606 group[52] demonstrated a copper-catalyzed oxyphosphorylation of enamides with 607 P(O)-H compounds and dioxygen, which allows for the synthesis of a series of valuable 608 β-ketophosphine oxides/β-ketophosphonates in moderate to good yields (Figure 31b).

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609 Afterwards, Yue and Nan’s group[53] presented an additive-free way for 610 β-ketophosphine oxides using CuCN as catalyst and dioxygen as external oxidant, 611 providing a convenient and cost-effective approach to diverse β-ketophosphine oxides 612 from alkenes in moderate to good yields (47%-72%) (Figure 31c). In addition, Yi’s 613 group[54] reported hydrochloric acid-promoted copper/iron-cocatalyzed deesterificative 614 oxyphosphorylation of 2-substituted acrylates with H-phosphine oxides. Notably, quite 615 similar reaction mechanisms were proposed for the above continuously published 616 works. In contrast to previous works, in 2019, She’s group[55] described a 617 copper-catalyzed oxidative radical coupling/fragmentation reaction, giving rise to 618 diverse β-ketophosphine oxides from simple allylic alcohols and H-phosphine oxides 619 (Figure 31d). Remarkably, an unprecedented three component oxidative radical 620 coupling/fragmentation processes on the basis of a series of control experiments was 621 proposed. 622

623 624 625 Figure 30. Copper-catalyzed phosphorylation of ketones assisted by silylating reagent. 626

627 628 629 Figure 31. Oxyphosphorylation of enolsilane, enamide, cinnamic acid and allylic 630 alcohol derivatives.

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631 632 Concurrently, Cai group[56] reported a temperature-controlled chemoselective 633 dehydrogenative phosphorylation or oxyphosphorylation of alkenes with H-phosphine 634 oxides via copper/iron catalysis. Not only vinylphosphonates but also 635 β-ketophosphonates could be obtained in moderate to good yields depending on the 636 reaction temperature (Figure 32). Mechanistic studies indicate that when the reaction 637 temperature is 90 °C, the formed β-phosphoryl alkyl radical interacts with the hydroxyl

638 radical, which is generated from Cu(I) with DTBP and H2O, to form β-hydroxyl 639 phosphonate, which would undergo oxidation to give the desired β-ketophosphonates. 640 When the reaction temperature is 110 °C, the formed β-phosphoryl alkyl radical is 641 believed to undergo direct oxidation and following deprotonation to deliver the 642 vinylphosphonate product. 643

644 645 646 Figure 32. Copper/Iron-catalyzed C-P cross-coupling of styrenes with H-phosphine 647 oxides. 648 649 Apart from homogeneous catalysis, heterogeneous catalysis also contributed greatly to 650 the oxyphosphorylation of alkene. In 2020, Moghaddam’s group[57] disclosed a typical

651 copper ferrite nanoparticles CuFe2O4-catalyzed formation β-ketophosphonates in good 652 to excellent yields via oxyphosphorylation of styrenes with H-phosphonates (Figure 653 33). Notably, the catalyst could be reused for 6 times without significant decreasing of 654 the yields, and the FE SEM images revealed that the morphology of the catalyst 655 remained constant. The reaction mechanism proposed by the authors is similar to the 656 above-mentioned oxyphosphorylation of alkenes.

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657 658 659 Figure 33. Copper ferrite nanoparticles catalyzed formation of β-ketophosphonates. 660 661 Despite great progress in the synthesis of β-ketophosphine oxides, the development 662 more environmentally mild, green and efficient methods for the synthesis of 663 β-ketophosphine oxides remains highly desirable. In 2018, Zhu and co-workers[58] 664 developed the visible light-induced oxyphosphorylation of simple alkenes with 665 H-phosphine oxides under ambient air (Figure 34). In this reaction, cheap organic dye 666 was used as the photocatalyst, providing an array of β-ketophosphine oxides with good 667 yields under mild conditions. 668

669 670 Figure 34. Visible light-promoted metal-free aerobic oxyphosphorylation of olefins: A 671 facile approach to β-ketophosphine oxides. 672 673 Attribute to the stability and accessibility of cinnamic acids, they have been employed 674 as viable precursors to construct a various of valuable compounds through extrusion of 675 carbon dioxide. As a result, Zou and co-workers[59] reported the visible light

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676 photoredox-catalyzed decarboxylative oxyphosphorylation of cinnamic acids with 677 diarylphosphine oxides to afford the corresponding β-ketophosphine oxides under mild 678 conditions (Figure 35). Nevertheless, α or β-methyl substituted alkenes could not be 679 tolerated in such a reaction. Initially, the oxidation of excited state (RB*) by oxygen 680 from air generates the superoxide anion radical and RB radical cation (RB•+), which 681 further interacts with diarylphosphine oxide to provide radical cation and ground state 682 RB to complete the photoredox cycle. Cinnamic acid could not be oxidized by RB* ox 683 owing to the high oxidation potential (E1/2 = +2.01 V vs. SCE in MeCN). 684

685 686 Figure 35. Visible light photoredox-catalyzed transition metal-free cross-coupling 687 reaction of alkenyl carboxylic acids with diarylphosphine oxides. 688 689 After that, Kim and co-workers[60] introduced a visible light photoredox-catalyzed 690 phosphorylation of vinyl azides to prepare β-ketophosphine oxides under mild reaction 691 conditions, which provides a convenient way by utilizing cheap and commercially 692 available Eosin Y as a photocatalyst and avoiding additive, oxidant and metals (Figure 693 36). Among various organic solvents, dichloromethane (DCM) was found as the

694 friendly support for the reaction and H2O could also promote the process smoothly as a 695 benign and green solvent. As to the aromatic moiety of the vinyl azides, a variety of 696 electron-deficient and electron-rich substrates could easily take part in the reaction 697 under optimized reaction conditions and generate the desired β-ketophosphine oxides in 698 good to excellent yields. To further certificate the reaction mechanism, addition of 699 excess 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) to the reaction under the 700 standard reaction conditions resulted in a trace amount of the corresponding 701 β-ketophosphine oxide, supporting a radical pathway in the present reaction. The 702 mechanistic course for this reaction is displayed in Figure 36. Photocatalyst eosin Y 703 reaches its excited state eosin Y* under visible light irradiation. Initially, phosphinous 30 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

704 acid is oxidized by Eosin Y* via SET process to generate radical cation. Then, 705 phosphinoyl radical is formed upon deprotonation and undergoes following radical 706 addition with vinyl azides to afford iminyl radical intermediate, which is reduced by 707 Eosin Y•− to furnish the corresponding anion. Eventually, protonation and hydrolysis 708 lead to generate the β-ketophosphine oxides. 709

710 711 712 Figure 36. Visible light-mediated photocatalytic phosphorylation of vinyl azides: A 713 mild synthesis of β-ketophosphine oxides. 714 715 On the basis of previous reports of hydroxyphosphorylation of alkenes[61-62], Wei’s 716 group[63] furnished the copper-catalyzed direct hydroxyphosphorylation of 717 electron-deficient alkene with H-phosphine oxides and dioxygen, delivering various of 718 β-hydroxyphosphine oxides bearing with a quaternary carbon center in moderate to 719 good yields (Figure 37). The authors proposed that the reduction of the resulting

720 hydroperoxide by HP(O)Ph2 was the key step for the reaction. 721

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722 723 Figure 37. Hydroxyphosphorylation and oxyphosphorylation of electron-defficient 724 alkenes. 725 726 Peroxide-containing compounds have attracted considerable attention in pharmacy and 727 biochemistry as well as in food chemistry. Due to the low dissociation energy of O-O 728 bond of the peroxy group, the synthesis of organic peroxides is particularly challenging. 729 After disclosing the iron-catalyzed three-component carbonylation-peroxidation 730 reaction of styrenes, aldehydes and hydroperoxides, Li and coworkers[64] provide a 731 direct approach to access multi-substituted β-phosphoryl peroxides by the reaction of 732 alkenes, H-P(O) compounds and tert-butyl hydroperoxide (TBHP) (Figure 38). It is 733 worth noting that the reaction efficiency is opposite to the stability of P-center radical 734 generated in situ by the SET oxidation of the organophosphorus precursors following

735 the order: (EtO)2P(O)-H > (EtO)PhP(O)-H Ph2P(O)-H. Unfortunately, the

736 diarylphosphine oxides were not tolerated in th≫e reaction. Moreover, the obtained 737 β-phosphoryl peroxides could be easily transformed into β-phosphoryl epoxides with 738 moderate diastereoselectivity by using lithium bis(trimethylsilylsilyl)amide (LHMDS) 739 as the base. 740

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741 742 743 Figure 38. Copper-catalyzed three-component phosphorylation-peroxidation of 744 alkenes. 745 746 In 2019, Yang and his colleagues[65] established a system to achieve 747 P(O)-radical-mediated difunctionalization of alkenes with diarylphosphine oxide and 748 peroxides employing the low-cost cobalt (Ⅱ) catalyst, affording a wide variety of 749 phosphonation-peroxidation products in a one-pot manner (Figure 39). The authors 750 proposed that tert-butyloxy and tert-butylperoxy radicals were generated from excess 751 tert-butyl hydroperoxide via Co(Ⅲ)/Co(Ⅱ) catalytic cycle. Then, the tert-butyloxy 752 radical abstracted the hydrogen atom of diarylphosphine oxide to produce phosphorus 753 radical, which was different from the generation of P-centered radical through SET 754 oxidation. After the radical addition of phosphorus radical to the alkenes, the carbon 755 radical undergoes a radical-radical cross-coupling with a tert-butylperoxy radical to 756 afford the final product. 757

758 759 Figure 39. Cobalt (Ⅱ)-catalyzed difunctionalization of alkenes with diarylphosphine 760 oxide and peroxide. 761 762 Varied from above-mentioned radical coupling mechanism, stoichiometric

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763 metal-mediated sequential oxidation of carbon radical to carbocation ended with 764 nucleophilic attack has also become a powerful tool for the oxyphosphorylation of 765 alkenes. For example, in 2015, Zou’s group[66] developed a Mn(Ⅲ)-mediated radical 766 acetoxyphosphorylation of styrenes with phosphine oxides (Figure 40), and Vincent’s 767 groups[67] reported a Mn(Ⅲ)-mediated diastereoselective synthesis of 3,3-spirocyclic 768 2-phosphonoindolines via a dearomative addition of phosphonyl radicals to indoles 769 followed by the intramolecular trapping of the resulting carbocation before 770 rearomatization (Figure 41). Being different with previous works, Wang’s group[68] 771 reported a cerium(Ⅳ)-promoted phosphinoylation-nitratation of alkenes under mild 772 conditions, delivering various of β-nitrooxyphosphonates in high yields in a one-pot

773 manner (Figure 42). Notably, ceric ammonium nitrate (Ce(NH4)2(NO3)6, CAN) acts as 774 an oxidant as well as a nitrate-source in the reaction. Although significant progresses 775 have been achieved in these reactions, the development of catalytic approaches remains 776 hugely desirable.

777 778 Figure 40. Mn(Ⅲ)-mediated acetoxyphosphorylation of styrenes.

779 780 Figure 41. Mn(Ⅲ)-mediated synthesis of 3,3-spirocyclic 2-phosphonoindolines via a 34 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

781 dearomative addition of phosphonyl radicals to indoles. 782

783 784 Figure 42. Cerium(Ⅳ)-promoted phosphinoylation-nitration of alkenes. 785 786 Difunctionalization with other heteroatom-containing groups (N, S, or F) 787 The unique properties of fluoride as well as the significant application of 18F-labled 788 organic compounds as contrast agents for positron emission tomography (PET) has 789 attracted much attention of chemists for the development of new method for the 790 construction of C-F bond under mild reaction conditions. Moreover, fluorinated 791 phosphonates have also found wide applications, especially in biomedical studies. 792 However, methods for the synthesis of the important class of β-fluorinated 793 phosphonates are extremely limited. In 2013, Li’s group[69] reported a mild and

794 catalytic method for the phosphonofluorination of unactivated alkenes with AgNO3 as 795 catalyst (Figure 43). The protocol features good stereoselectivity, broad substrate scope 796 and wide functional compatibility. The author proposed that silver-catalyzed oxidative 797 generation of phosphonyl radical and silver-assisted fluoride atom transfer were 798 involved in the reaction. 799

800 801 Figure 43. Silver-catalyzed radical phosphonofluorination of unactivated alkenes. 802 803 Nitrogen heterocyclic components have found abundant applications as privileged

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804 structural motifs in biologically active compounds. Difunctionalization of 2-allylaniline 805 derivatives represents a direct and atom-economical approaches for the preparation of 806 indolines with different substituent. However, the synthesis of phosphorylated indoline 807 by aminophosphophination via radical cascade cyclization has never been realized. In 808 2015, Yang’s group[70] described a copper-catalyzed radical cascade cyclization for the 809 synthesis of phosphorylated indolines (Figure 44). The reaction features mild reaction 810 conditions with cheap copper salts as catalyst. Notably, the authors proposed that an 811 intramolecular Ullmann-type reaction, followed by reductive elimination to release the 812 product, was involved in the reaction.

813 814 Figure 44. Copper-catalyzed radical cascade cyclization for the synthesis of 815 phosphorylated indolines. 816 817 Bifunctional α,β-aminophosphinoyl compounds possess special biological activities, 818 however, synthetic methods for α,β-aminophosphinoyl compounds remains limited. 819 Contrast with Yang’s work, in 2017, Zou and Zhang’s group[71] reported a phosphinoyl 820 radical-initiated intermolecular α,β-aminophosphinoylation of alkenes (Figure 45). The 821 one-pot, three component reaction is performed under mild reaction conditions to 822 afford α,β-aminophosphinoylation products. In addition to diarylphosphine oxides, 823 dialkylphosphites are also tolerant in the reaction. As illustrated in Figure 44, the 824 carbon radical coordinating with Cu(Ⅱ)-aniline complex delivers the key 825 Cu(Ⅲ)-complex, which undergoes a reductive elimination step to give the final product.

826 A similar work by using FeCl3 as the catalyst and TBHP as the oxidant was described 827 by Fang and Wang’s group[72] in 2018. 828

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829 830 Figure 45. Phosphinoyl radical-initiated α,β-aminophosphinoylation of alkenes. 831 832 Compounds containing nitrogen and phosphorus atoms have been widely applied in 833 many research areas, and phosphinoylazidation of alkenes serves as a direct method to 834 construct nitrogen- and phosphorus-containing compounds. Although 835 phosphinoylazidation have been realized by Zhao’s group[73] in 2015 by using

836 stoichiometric amount of the oxidative radical initiator Mn(OAc)3  H2O, catalytic 837 phosphinoylazidation of alkenes remains unresolved. Recently, Bao’s group[74] 838 developed an iron phthalocyanine-catalyzed radical phosphinoylazidation of alkenes 839 for the facile synthesis of β-azido-phosphine oxide under relatively mild reaction 840 conditions (Figure 46). Mechanistic studies reveal the unusually low activation energy 841 4.8 kcal/mol of the azido transfer process from the azidyl iron(Ⅲ) phthalocyanine Ⅲ 842 species (PcFe N3) to a benzylic radical. 843

844 845 Figure 46. PcFe-catalyzed phosphinoylazidation of alkenes. 846 847 Both phosphinoyl and thiocyano are valuable functional groups commonly found in 848 pharmaceutically active molecules. Thiocyanodiphenylphosphinoylated compounds 849 could be applied in the development of new bioactive compounds and 37 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

850 phosphine-containing ligands. In 2018, Zhang and Zou’s group[75] established 851 phosphinoyl radical-initiated 1,2-bifunctional thiocyanodiphenylphosphinoylation of

852 alkenes using CuBr2 as catalyst and Mn(OAc)3 as oxidant, affording a range of 853 thiocyanodiphenylphosphinoylated compounds in reasonable yields (Figure 47). 854 Mechanistic studies reveal that copper-catalyzed thiocyanation is involved in the 855 reaction. 856

857 858 Figure 47. Phosphinoyl radical-initiated 1,2-bifunctional 859 thiocyanodiphenylphosphinoylation of alkenes. 860 861 PHOSPHORYLATION OF ALKYNES 862 Hydrophosphorylation of alkynes 863 Alkenylphosphoryl compounds are highly useful organophosphorus compounds in 864 organic chemistry. Comparing with transition metal-catalyzed hydrophosphorylation of 865 alkynes, radical addition to alkynes has directly become an alternative approach to 866 assemble functionalized alkenes. In 2018, Han and coworkers[76] reported radical 867 hydrophosphorylation of alkynes with P(O)-H compounds, obtaining anti-Markovnikov 868 alkenylphosphine oxides in moderate yields (Figure 48). Particularly, propargyl 869 alcohols, which are not compatible to the palladium-catalyzed hydrophosphorylation, 870 can also deliver the desired products in good yields. This green approach avoids the use 871 of a metal catalyst, which can serve as a complementary reaction to the metal-mediated 872 hydrophosphorylation. 873

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874

875 Figure 48. Radical hydrophosphorylation of alkynes with R2P(O)H generating 876 alkenylphosphine oxides. 877 878 Radical addition to alkynes offers a straightforward, atom-economical, and 879 environmentally benign method for the synthesis of functionalized alkenes. However, 880 the control of the stereoselectivity and regioselectivity remains highly challenging, 881 especially for the synthesis of Z-alkenes. In 2018, the addition of diaryl phosphine 882 oxides to alkynes with excellent and challenging Z-stereoselectivity and regioselectivity 883 via photoredox catalysis was revealed by Lei and co-workers[77] (Figure 49). Various 884 terminal and internal alkynes could be transformed to higher-energy Z-alkenes. A series

885 of mechanistic studies advocate the following conclusion: K2CO3 as aqueous base plays 886 a decisive role for the transformation; π-π stacking interaction with the phosphorus 887 substituents greatly promotes Z-selectivity; and the reaction conducts through 888 free-radical addition. A tentative mechanism for this Z-selective protocol is proposed, 889 which is shown in Figure 49. First, a phosphinoyl radical is generated via proton 890 coupled electron transfer (PCET) oxidation in the presence of photoexcited catalysts. 891 Then, a phosphinoyl radical combines with phenylacetylene, affording the α-alkenyl 892 carbon radical. Afterwards, the SET between PC•− and the linear radical delivers 893 Z-alkenyl anion. In this process, Z-selectivity could be greatly improved by a proposed 894 π-π stacking interaction between the phenyl ring of the phenylacetylene and one of the 895 aromatic rings diphenylphosphine oxide. Notably, an X-ray single-crystal structure 896 shows one of the aromatic rings of diphenylphosphine oxide and the pyridine are on the 897 same side, suggesting the existence of the π-π stacking interaction between aromatic 898 rings. Finally, Z-alkenyl anion undergoes protonation to afford Z-alkenylphosphine 899 oxides. 39 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

900

901 902 Figure 49. Z-Selective addition of diaryl phosphine oxides to alkynes via photoredox 903 catalysis. 904 905 In contrast to the high Z-selectivity of the work of Lei’s group, Wu and coworkers[78] 906 discovered earth-abundant cobaloxime could convert H-phosphine oxide to its reactive 907 radical species under visible light irradiation, then the P-centered radicals reacts with 908 alkynes to generate E-alkenylphosphine oxides with excellent chemo- and 909 stereoselectivity (Figure 50). Linear E-alkenylphosphine oxide could be obtained from 910 the reaction with terminal alkynes, while addition with internal alkynes leads to cyclic 911 benzophosphine oxides and hydrogen. Notably, the mechanistic investigation shows the 912 dual roles of cobaloxime, both as the visible light absorber to activate the P(O)-H bond 913 as well as a HAT reagent. Following is the proposed mechanism, the P(O)-H bond was 914 activated by cobaloxime under photoexcitation to generate the phosphinoyl-centered 915 radical. Next, the addition of phosphinoyl radical intermediate to an alkyne gives 916 alkenyl carbon radical, which is captured by the CoⅡ intermediate to form intermediate 917 vinyl CoⅢ intermediate. Final protonation would form hydrophosphorylation product 918 and regenerate the initial CoⅢ complex, which closes the catalytic cycle. In terms of 919 internal alkynes, the alkenyl carbon radical would attack the arenes to give a cyclic 920 radical intermediate, which would react with CoⅡ complex to give CoⅢ-H complex via 921 HAT. In the absence of external oxidant, the combination of cobaloxime (CoⅢ-H) and 922 electron result in the release of the captured proton and electron as hydrogen (detected 923 by GC). 924

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925 926 Figure 50. Cobaloxime catalysis: selective synthesis of alkenylphosphine oxides under 927 visible light. 928 929 Being different from transition-metal or photoredox-mediated generation of P-centered 930 radical through oxidative process via SET, recently, Zhu and coworkers[79] have 931 introduced a stereo- and regioselective cis-hydrophosphorylation reaction of the 932 internal alkyne of 1,3-enynes via reactive nickel(Ⅱ)-phosphorus species migratory 933 insertion into the internal alkyne, giving rise to a variety of 1,3-dienes with good yields 934 (Figure 51). Notably, the phosphorus radical derives from the hydrogen atom 935 abstraction of H-P(O) compound. In the reaction, reactive nickel(Ⅱ)-phosphorus

936 species is generated from visible light irradiation of the NiCl2(PPh3)2, and the function 937 of ligand should not be neglected. A possible mechanism for this double-component 938 transformation involving visible-light-induced nickel phosphine species generation via

939 an Ni(Ⅱ)/Ni(Ⅰ)/Ni(Ⅱ) cycle was proposed. The coordination of the Ni(PPh3)2Cl2 with 940 1,3-enyne would form the NiⅡ intermediate, which would generate the Ni(Ⅰ) species and 941 the chlorine atom radical Cl via the LMCT process under the visible light irradiation. 942 The phosphorus atom radical, in situ generated through hydrogen atom abstraction by

943 Cl, could re-bond with Ni(Ⅰ) species resulting in the formation of Cl-Ni(Ⅱ)-P(O)Ph2

944 species. Then, the insertion of Cl-Ni(Ⅱ)-P(O)Ph2 species into the C≡C bond of the 945 1,3-enyne would generate the intermediate alkenyl NiⅡ intermediate. Finally, after the 946 rapid protonation of the intermediate by MeOH would produce the desired 947 cis-hydrophosphorylation product. 948

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949 950 Figure 51. Stereo- and regioselective cis-hydrophosphorylation of 1,3-enynes enable

951 by the visible-light irradiation of NiCl2(PPh3)2. 952 953 Difunctionalized phosphorylation of alkynes 954 A series of transition-metal-catalyzed aerobic phosphorylation of alkynes or 955 alkynylcarboxylic acids have been reported by Zhang et al.[80], Chen et al.[81], Yi et 956 al.[82]and Zhou et al.[83-84], delivering synthetically and biologically valuable 957 β-ketophosphonates. In 2018, Zeng’s group reported a simple and efficient method for 958 the oxyphosphorylation of alkynes using LiOH without the assistance of any transition 959 metal, delivering a wide range of β-ketophosphonates. Mechanistic studies indicate that

960 inorganic base promoting the oxyphosphorylation and H2O plays a synergistic role in 961 the formation of the products (Figure 52). 962

963 964 Figure 52. Base-promoted direct oxyphosphorylation of alkynes with H-phosphine 965 oxides in the presence of water. 966 967 Recently, Zou and Zhang’s group[85] described a copper-catalyzed difunctional cyano-, 968 thiocyano-, and chlorophosphorylation reaction of alkynes with P(O)-H compounds 969 and various coupling partners (TBACN, TMSNCS and TMSCl) (Figure 53). A diverse

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970 array of tri- and tetra-substituted alkenyl phosphine oxides/phosphonates were 971 constructed regio- and stereoselectively. Mechanistic studies indicate that the reaction 972 is initiated by the addition of P-centered radical to the alkyne to form an alkenyl radical, 973 which could combine with Cu(Ⅱ) specie to form a Cu(Ⅲ) complex. Then, a reductive 974 elimination step leads to the formation of final cyano-, thiocyano- or chlorophosphoryl 975 alkenes, which would be valuable building blocks with potential medicinal, 976 agrochemical, and functional material applications. 977

978 979 Figure 53. Difunctional cyano-, thiocyano-, and chlorophosphorylation reaction of 980 alkynes with P(O)-H compounds. 981 982 Radical cascade cyclization phosphorylation of alkynes 983 π-Conjugated phosphole molecules has become vitally important in the blooming arena 984 of organic light-emitting diodes (OLEDs) and photovoltaic cells. Transition 985 metal-mediated synthesis of benzo[b]phosphole oxides have been reported, for instance, 986 Tang’s group described a copper-catalyzed cycloaddition between secondary phosphine 987 oxides and alkyne to give benzophosphole oxides. However, it is still highly appealing 988 to develop an approach for the construction of benzo[b]phosphole oxides without 989 requirement of expensive transition metal catalysts or toxic reagents[86]. In 2016, 990 Lakhdar and co-workers[87] described a metal-free, visible light photoredox-catalyzed 991 synthesis of benzo[b]phosphole oxides using N-ethoxy-2-methylpyridinium 992 tetrafluoroborate as the oxidant and eosin Y as the catalyst under mild conditions 993 (Figure 54). Alkynes bearing alkyl, ester, alcohol groups could be transformed to 994 desired products. However, the aryl migration of the diphenylphosphine oxides

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995 including electron donor or electron acceptor groups at the aromatic rings resulting in 996 the formation of regioisomers of benzophospholes. Mechanistic investigations show 997 that the formation of a ground state electron donor-acceptor complex (EDA) between 998 the pyridinium salt and eosin Y. A plausible mechanism for the generation of the 999 product is given in Figure 53. The formation of the EDA complex between the eosin Y 1000 and the onium salt initiates the reaction. Upon absorption of a green photon and a SET 1001 event, the EDA complex generates the unstable ethoxy radical, which abstracts a 1002 hydrogen from the secondary phosphine oxide to quickly deliver the corresponding 1003 phosphinoyl radical. Next, this radical adds to the alkyne to give the alkenyl radical. 1004 Subsequently, such radical was trapped by the phenyl ring of the phosphine oxide to 1005 produce the cyclohexadienyl radical, which (with a redox potential of about -0.1 V) is 1006 readily oxidized by EY•+ (E0(EY•+/EY) = 0.70 V/SCE) to release the photocatalyst and 1007 provide the Wheland intermediate. At last, the Wheland intermediate is immediately 1008 rearomatized to yield the desired benzophosphole oxide upon deprotonation with

1009 NaHCO3.

1010 1011 Figure 54. Metal-free, visible light-photocatalyzed synthesis of benzo[b]phosphole 1012 oxides: synthetic and mechanistic investigations. 1013 1014 Heterocyclic skeletons, which are ubiquitous in natural products and exhibit a wide 1015 range of pharmacological properties, have attracted much attention of chemists for the 1016 synthesis of pharmaceutically relevant molecules. Besides, the intermolecular radical 1017 addition/cyclization cascade reaction represents an efficient and powerful strategy to 1018 forge highly functionalized organic heterocycles. Although significant progresses have 1019 been achieved, the elaboration of the phosphorylation products of alkynes remains 1020 highly desirable. In 2017, Jiang and Tu’s group[88] reported a silver-mediated radical

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1021 5-exo-dig cyclization of 2-alkynylbenzonitrile with disubstituted phosphine oxides and

1022 H2O for the synthesis of phosphinylated 1-indenones (Figure 55). Multiple bonds, 1023 including C-P, C-C and C-O bonds, were successively constructed under atmospheric 1024 conditions. The reaction displays flexible structural modification, a broad substrate 1025 scope and high functional group tolerance. Besides, P-centered radical addition, 1026 5-exo-dig cyclization and hydrolysis processes were proposed as the key steps in the 1027 reaction by the authors.

1028 1029 1030 Figure 55. Silver-mediated radical 5-exo-dig cyclization of 2-alkynylbenzonitrile with 1031 H-P(O) compounds. 1032 1033 In 2020, Zhu and coworkers[89] described an intermolecular hydro-phosphorylative 1034 cyclizations of enynes and dienes to access heterocycles under visible-light irradiation 1035 (Figure 56). The phosphinoyl radical were formed via direct HAT between the 1036 phosphine oxides and photoexcited catalyst. The desired heterocycles were obtained in 1037 good yields via the radical addition/cyclization/HAT reaction sequences of 1,6-enynes 1038 and 1,6-dienes.

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1039 1040 Figure 56. Visible-light mediated hydrophosphorylative cyclizations of enynes and 1041 dienes. 1042 1043 Phosphorylated 2-oxazolidinone have found numerous applications in pharmaceutical 1044 chemistry, homogeneous catalysis, and organic materials. In 2020, He’s group[90] 1045 described an efficient and selective protocol for straightforward synthesis of various of 1046 5-[(diarylphosphoryl)methyl]oxazolidin-2-ones via the copper-catalyzed

1047 difunctionalization of the propargylic amines with CO2 and phosphine oxides (Figure 1048 57). The approach exhibits wide substrate scope, excellent functional group 1049 compatibility and exclusive selectivity. Mechanistic studies reveal that a one-pot 1050 tandem cyclization/radical addition sequence, along with the 1051 phosphorylation/cyclization scheme, is involved in the reaction. 1052

1053 1054 Figure 57. Copper-catalyzed phosphonocarboxylative cyclization reaction of 1055 propargylic amines. 46 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1056 1057 Thioflavones are valuable functional motifs that being found in numerous natural 1058 products, drugs and moterials. The incorporation phosphorus functional groups into the 1059 skeleton of thioflavones has attracted extensive attention of chemists. In 2019, a 1060 visible-light-induced metal-free phosphorylation of methylthiolated alkynones to 1061 synthesis of 2-phosphorylated thioflavones has been developed by Yu and Chen’s 1062 group[91] (Figure 58). Interestingly, the non-toxic, low cost, and easily available water 1063 acts as the reaction medium to promote this reaction, and this is the first example of 1064 4CzIPN as a photocatalyst to construct C-P bonds in water. To demonstrate the 1065 applicability of the approach, they carried out a gram-scale synthesis and obtained the 1066 product in good yield (67%). A plausible reaction mechanism for this reaction is shown 1067 in Figure 57. Initially, the photocatalyst 4CzIPN is activated to its excited-state 1068 4CzIPN* under the irradiation of visible-light. Diphenylphosphine oxide is in level 1069 between tri-coordinated and tetra-coordinated forms. Then, a SET between the 1070 tri-coordinated form of diphenylphosphine oxide and 4CzIPN* will lead to the 1071 phosphoryl radical and radical anion 4CzIPN  ‒. Subsequently, addition of the 1072 phosphoryl radical to the triple bond and the following intramolecular cyclization will 1073 furnish the final product and release methyl radical. Moreover, the photoredox cycle is 1074 completed after the oxidation of the radical anion 4CzIPN•− by dilauroyl peroxide 1075 (LPO). 1076

1077 1078 Figure 58. Visible-light-induced metal-free synthesis of 2-phosphorylated thioflavones 1079 in water. 1080 1081 PHOSPHORYLATION OF ISOCYANIDES 47 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1082 Arylphenylisonitriles which contains the C≡N π-bond are good radical acceptors as the 1083 C≡C π-bond, and can be employed to construct diverse 6-substituted phenanthridines. 1084 In spite of the development of silver-promoted radical phosphorylation of isonitriles, it 1085 is still highly desirable to exploit a more effective and environmentally friendly 1086 protocol. In 2016, an efficient visible light photoredox-catalyzed tandem 1087 phosphorylation/cyclization reaction of three kinds of radical acceptors, including 1088 2-arylphenylisonitrile, vinyl isocyanides and N-arylacrylamides, with 1089 diphenylphosphine oxide was unmasked by Lu’s group[92] (Figure 59). This reaction 1090 generates phosphorus-containing phenanthridines, isoquinolines, and indolin-2-ones by

1091 construction of both C-P and C-C bonds with [Ir(ppy)2(dtbpy)]PF6 as the catalyst,

1092 K2S2O8 as the oxidant and CsF or Cs2CO3 as the base. Phosphine oxides, such as 1093 tertbutyl(phenyl)phosphine oxides and ethyl pheylphosphinates, and a series of vinyl 1094 isocyanides could also tolerate in this transformation. It is remarkable that the strategy 1095 can be utilized to the synthesis of bioactive oxindoles using N-arylacrylamide as radical 1096 receptors. On the basis of the mechanistic studies and literature, a tentative mechanism 1097 is proposed in Figure 58. Firstly, the ground state photocatalyst Ir-(Ⅲ) is converted 1098 into the excited-state species Ir-1(Ⅲ)* under visible-light irradiation, which then 1099 reduces persulfate anion to generate Ir-(Ⅳ), sulfate dianion, and sulfate radical anion. 1100 Next, after a HAT process between the active sulfate radical anion and 1101 diphenylphosphine oxide, the crucial intermediate P-centered radical would be 1102 produced. Then, the intermolecular radical addition of P-centered radicals to radical 1103 acceptors will result in imine radical intermediate. It then undergoes the intramolecular 1104 cyclization to generate cyclohexadiene-type free radical, which can be oxidized by 1105 Ir-(Ⅳ) to regenerate Ir-(Ⅲ) and give the cationic intermediate. Finally, in the presence 1106 of a base, the cationic intermediate undergoes deprotonation to give the desired 1107 product. 1108

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1109 1110 Figure 59. Visible light-induced cascade reaction of isocyanides and N-arylacrylamides 1111 with diphenylphosphine oxide via radical C-P and C-C Bond formation. 1112 1113 Benzothiazole and its derivatives, which are vital building blocks in synthetic 1114 intermediates, usually have unexpected biological and pharmacological properties. 1115 Previously, Yang and Feng’s group[93] disclosed a novel way to synthesize 1116 2-phosphorylated thioethers. Nevertheless, the cascade reaction heavily relies on the 1117 use of stoichiometric metal salts and high reaction temperature. Later on, the same 1118 group discovered metal-free photo-induced radical cascade reactions of isocyanides 1119 with phosphine oxides for the formation of 2-phosphoryl benzothiazoles (Figure 60). 1120 The cascade reactions involving concomitant C(sp3)-S bond cleavage and imidoyl C-S 1121 formation. The environmentally friendly approach was decorated with organic dye 1122 Rose Bengal as the photocatalyst, without additional transition-metal or peroxide 1123 oxidants and a variety of 2-phosphoryl benzothiazoles were produced in moderate to 1124 good yields. 1125

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1126 1127 Figure 60. Metal-free photo-induced radical C-P and C-S bond formation for the 1128 synthesis of 2-phosphoryl benzothiazoles. 1129 1130 Despite that significant progress has been achieved in the photoredox-mediated tandem 1131 cyclization of isocyanides with organic metal-based photocatalyst, such as Ir and Ru, 1132 the dye-catalyzed P-radical initiated cascade cyclization of isocyanides the remains 1133 highly intriguing. In 2020, 1134 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)-isophthalonitrile (4CzIPN-tBu) was 1135 utilized to realize the radical cascade cyclization reaction for the synthesis 1136 phosphorylated N-heteroaromatics using various isocyanide-containing substrates, such 1137 as 2-arylphenylisonitrile, 2-isocyanoaryl thioethers and vinyl isocyanides, via 1138 visible-light-induced PCET strategy (Figure 61)[94]. A broad range of phosphorylated 1139 aromatics including phenanthridines, quinolines, and benzothiazoles were efficiently 1140 constructed. The transition metal-free strategy should be of great interest for the future 1141 development of phosphorus radical-based reactions.

1142

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1143 Figure 61. 4CzIPN-tBu-catalyzed proton-coupled electron transfer for photosynthesis 1144 of phosphorylated N-heteroaromatics. 1145 1146 CROSS-COUPLING PHOSPHORYLATION REACTIONS 1147 Transition metal/photoredox dual catalyzed phosphorylation reactions of 1148 (pseudo)halides 1149 The carbonyl-containing compounds and phenols, ubiquitous in diverse organic 1150 compounds, are readily available in nature and industry. In addition, the easily 1151 generated alkenyl and aryl C-O electrophiles are attractive in photoredox and transition 1152 metal dual catalysis. In 2017, Yu’s group[95] reported a phosphorylation of alkenyl and 1153 aryl C-O bonds at room temperature via photoredox/nickel dual catalysis (Figure 62). 1154 A diverse of structurally important alkenyl phosphonates and aryl phosphine oxides are 1155 generated in moderate to excellent yields. On the basis of their exploration and 1156 previous studies, they proposed the reaction mechanism for the reaction. Firstly, the 1157 P-centered radical is generated through SET between phosphine oxides with excited 1158 photocatalyst following based-promoted deprotonation. Meanwhile, the oxidative 1159 addition between the tosylate and a Ni0 species gives the NiⅡ intermediate, which 1160 rapidly captures the P-centered radical to afford the NiⅢ complex. Finally, the desired 1161 product was formed through facile reductive elimination. Notably, both the 1162 photocatalyst and the nickel catalyst are regenerated to complete the dual catalytic Ⅰ 1163 cycle via the reduction of complex LnNi -OTs by the reduced form of Ru-photocatalyst.

1164 1165 1166 Figure 62. Photoredox/Nickel dual catalyzed phosphorylation of alkenyl and aryl C-O 1167 bonds. 1168 1169 The strong base and/or high energy ultraviolet irradiation required for metal-free

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1170 photoredox-mediated cross-coupling phosphorylation reaction of aryl halide restricts its 1171 functionality compatibility. Therefore, the development of an efficient and mild 1172 phosphorylation reaction is highly demanding. In2021, Li and coworkers discovered 1173 visible light-induced thioxanthen-9-one/nickel dual catalysis promoted C(sp2)-P 1174 coupling reaction between (hetero)aryl halides and H-phosphine oxides or 1175 H-phosphites (Figure 63). The efficient method could afford arylphosphineoxides and 1176 arylphosphonates in moderate to excellent yields and a series of functional groups were 1177 tolerant in the transformation[96]. The proposed mechanism is shown below. First, the 1178 phosphorus radical is easily generated via SET or HAT process with the excited state Ⅱ 1179 photocatalyst TXO. Then, the phosphorus radical is captured by LnNi (Ar)X 0 1180 intermediates which derives from the oxidative addition of the low-valent form LnNi 1181 with ArX to produce a high-valent Ni(Ⅲ) intermediate. Subsequently, the reductive Ⅰ 1182 elimination delivers the desired product along with the generation of LnNi X species, 1183 which undergoes reduction by the reduced form of TXO to concurrently complete the 1184 catalytic cycle.

1185 1186 Figure 63. Visible-light-induced nickel-catalyzed C(sp2)-P(O) coupling using 1187 thioxanthen-9-one as a photoredox catalyst. 1188 1189 Recently, visible-light-driven ligand to metal charge transfer (LMCT)-enabled 1190 phosphorylation of aryl halides was discovered by Zhu and co-workers[97] (Figure 64). 1191 Various tertiary phosphine oxides were obtained under photocatalyst-free conditions. 1192 Interestingly, amino acid-derived aryl iodides could also undergo this transformation to 1193 furnish the corresponding products. A Ni(Ⅱ)/Ni(Ⅰ)/Ni(Ⅲ)/Ni(Ⅳ)/Ni(Ⅱ) cycle is proposed for 1194 the nickel-catalyzed C-P bond construction under visible-light irradiation. The Ni(Ⅱ)

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(Ⅰ) 1195 intermediate was formed by ligand exchange of Ni(PPh3)2Cl2 with ligand. Then, Ni 1196 species and the chlorine atom radical Cl would generate via the LMCT process under 1197 visible light irradiation. Afterwards, the hydrogen atom abstraction between phosphine 1198 oxides and Cl would afford the phosphorus radical. Meanwhile, the oxidative addition 1199 between aryl halides with Ni(Ⅰ) species would afford a Ni(Ⅲ) species, which will capture 1200 the phosphorus radical to give the Ni(Ⅳ) intermediate. Eventually, this intermediate 1201 would undergo the reductive elimination step to give the final desired products. 1202 1203

1204 1205 Figure 64. Visible-light-induced ligand to metal charge transfer excitation enabled 1206 phosphorylation of aryl halides. 1207 1208 Decarboxylative or denitro phosphorylation 1209 Transition metals-catalyzed decarboxylative coupling towards C-C bond construction 1210 have been extensively studied. However, comparatively little attention has been 1211 focused on C-P bond formation, especially by using easily available alkenyl acids as 1212 the starting materials. In 2017, Wang and Tang’s group[98] reported an efficient protocol 1213 for highly chemo- and stereoselective synthesis of (E)-alkenyl-phosphonates from 1214 easily accessible alkenyl acids and H-P(O) compounds by using the cheap

1215 Cu(OAc)2/K2S2O8 catalytic system s (Figure 65). Mechanistic studies indicate that 1216 acetonitrile is a good solvent and ligand, which could be readily recycled after the 1217 reaction. Notably, cross-coupling of styrenes with H-phosphonates, as well as 1218 denitration of β-nitrostyrene with H-phosphonates, is also achieved to give the final 1219 products. 1220

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1221 1222 Figure 65. Solvent-controlled copper-catalyzed radical decarboxylative coupling. 1223 1224 β-Nitrostyrenes are useful starting materials in organic synthesis for many classes of 1225 compounds. Although Mn(Ⅲ)-catalyzed reaction of 2-nitrostyrenes with dialkyl 1226 phosphites have been developed by Zou’s group[99], the development of new 1227 methodologies with more mild reaction conditions remains highly desirable. In 2016, a 1228 silver-catalyzed synthesis of 2-arylvinylphosphonates by cross-coupling of 1229 β-nitrostyrenes with H-phosphites was developed by Qu and Yuan’s group[100] (Figure 1230 66). The reaction proceeds smoothly and could provide the desired products in 1231 moderate to good yields with the simultaneous losing the nitro group. 1232

1233 1234 Figure 66. Silver-catalyzed cross-coupling of β-nitrostyrenes with H-phosphites. 1235 1236 Dehydrogenative C-H phosphorylation 1237 Compared to the use of prefunctionalized aromatics, such as aryl halides, boronic acids, 1238 as coupling partners, the direct C-H functionalization has emerged as an 1239 atom-economical and environmentally benign synthetic tool as it avoids the necessity 1240 for the prefunctionalization of the coupling partner. Transition-metal-catalyzed C-H 1241 bond activation has emerged as an efficient method for the construction of C-P bonds. 1242 However, here we mainly discuss P-radical-based C-H dehydrogenative C-H 1243 phosphorylation. In the past decades, the development of efficient methods for the 1244 introduction of phosphonyl group into those pharmaceutically important molecules 1245 have received special attention of chemists, and chromenes and coumarins are 1246 privileged structure in natural products, biological molecules and materials chemistry. [101] 1247 In 2012, Zhang and Zou’s group reported a Mn(OAc)3-mediated radical 1248 phosphorylation at the 3-postion of flavones and coumarins. In 2015, Yuan’s group[102] 1249 developed a silver-catalyzed direct C(sp2)-H radical phosphorylation of coumarins with 1250 H-phosphites, affording selective coumarin-3-yl phosphonate in moderate to good

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1251 yields. In 2016, a silver-mediated C-H phosphonylation reaction of ferrocenyl anilides 1252 with dialkyl phosphites was developed (Figure 67)[103]. The method is free of 1253 palladium and copper catalyst and tolerates a variety of functional groups. Mechanistic 1254 studies indicate that a radical pathway is involved in these reactions.

1255 1256 Figure 67. Silver-mediated C-H phosphonylation reaction of ferrocenyl anilides with 1257 dialkyl phosphites. 1258 1259 Wu and co-workers[104] reported the first direct C-H phosphorylation of thiazole 1260 derivatives with diarylphosphine oxides without an external oxidant via eosin 1261 B-catalysis (Figure 68). The photoredox approach tolerates diverse functional groups 1262 and produces a variety of thiazole derivatives bearing electron-donating groups, such as 1263 methoxy, methyl, and phenyl, in medium to excellent yields. 1264

1265 1266 Figure 68. Cross-coupling hydrogen evolution by visible light photocatalysis toward 1267 C(sp2)-P formation. 1268 1269 The C-H phosphonation of the quinoline ring is a highly efficient method to access 1270 phosphorylated quinoline ring. The C5-H phosphonation of 8-aminoquinoline amides 55 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1271 been realized by Wu’s group[105] using silver salts, however, the method suffers from 1272 stoichiometric metal salts, high reaction temperature and limited substrate scope 1273 (Figure 69). Besides, the C4-H phosphonation of 8-aminoquinoline amide remains 1274 elusive. Therefore, developing a mild and simple reaction procedure is indispensable to 1275 construct site-selective C4-H or C5-H phosphonation of 8-aminoquinoline amides. In 1276 2017, the same group described the site-selective C4-H or C5-H phosphonation of 1277 8-aminoquinoline amides via merging photoredox catalysis with transition metal 1278 catalysis. In addition, the substrates bearing Me and MeO groups on the quinoline ring 1279 could also provide the desired products with good yields. Notably, the strength of 1280 coordination bonds of the bidentate chelated complexes between 8-aminoquinoline and 1281 the metal salt determines the regioselectivity at the C4-H or C5-H of 8-aminoquinoline

1282 amides. The bidentate chelated complexes with strong Npyr→M bond gives

1283 C4-phophonation product, while those weak Npyr→M bond gives C5-phophonation 1284 product. According to previous reports, a plausible mechanism is illustrated in Figure 2+ 1285 69. Firstly, the excited state LnRu * or PC* was formed under the irradiation of 1286 household light, which undergoes a reductive quenching process with diarylphosphine + 1287 oxide to provide the LnRu or PC radical anion and an intermediate radical. To + 1288 complete the photocatalytic cycle, the oxidation of LnRu or PC radical anion by 2+ 1289 K2S2O8 regenerates the ground state LnRu or PC. Meanwhile, the addition of 1290 phosphorus radical to the complex of 8-aminoquinoline amide with transition metal at 1291 the C5 position would lead to a radical intermediate. After the oxidation by a sulfate 1292 radical anion and deprotonation, the product was obtained along with completion of the 1293 catalytic cycle of C5 phosphonation. On the other hand, the coordination of 1294 8-aminoquinoline amide with Ag(I) affords a chelated intermediate. The addition of 1295 phosphorus radical to the chelated intermediate at the C4 position would produce an 1296 intermediate radical. Subsequently, oxidation of such an intermediate and following 1297 decomposition would deliver the desired C4-phophonation product. 1298

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1299 1300 Figure 69. Merging photoredox catalysis with transition metal catalysis: site-selective 1301 C4 or C5-H phosphonation of 8-aminoquinoline amides. 1302 1303 Great progresses have been achieved in the mono-phosphorylation of quinolines, 1304 nevertheless, dephosphorylation of quinolines remains to be addressed due to the 1305 importance of organic phosphorus compound. In 2020, Wu and co-workers[106] reported 1306 a diphosphonation of quinoline compounds under visible light irritation (Figure 70). 1307 This straightforward and environmentally friendly method allows accessing 1308 diphosphorylated quinoline compounds. Both electron-donating groups (-Me, -OMe)

1309 and electron-withdrawing groups (-Br, -NO2) at the 6-positions of the quinoline could 1310 afford the desired products in moderate to good yields. Unfortunately, some 1311 heterocyclic compounds, such as quinoxoline and benzothiophene, could only provide 1312 mono-phosphonation products. 1313

1314 1315 Figure 70. Photocatalytic synthesis of diphosphorous quinoline compounds. 57 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1316 Electrochemical organic synthesis, which uses electron as clean redox reagents, has 1317 been recognized as an efficient and environmentally benign strategy and attracted much 1318 attention of organic chemists in recent years. Although anodic oxidative phosphonation 1319 of arenes as an early example was reported by Effenberger and Kottmann, the 1320 electrochemical oxidative C-H phosphorylation is still underdeveloped. Recently, as an 1321 alternative to traditional transition-metal catalysis and photoredox catalysis, 1322 considerable progresses have achieved on electrochemical phosphorylation. In 2019, 1323 Sun and Zeng’s group[107] described an efficient method for the intermolecular 1324 electrochemically dehydrogenative C-H/P-H cross-coupling of quinoxaline-2(1H)-ones 1325 with P(O) compounds in an undivided cell under galvanostatic conditions (Figure 71). 1326 Besides, the protocol could be extended to the C(sp3)-H phosphonation of xanthenes. 1327 The method features mild reaction conditions, wide substrate scope and avoiding the 1328 utilization of transition metal catalysts. Notably, cyclic voltammetry analysis was 1329 performed to understand the possible reaction mechanism, and a radical pathway for 1330 the electrochemically oxidative phosphonation of quinoxaline-2(1H)-one reaction was 1331 proposed. 1332

1333 1334 Figure 71. Electrochemically dehydrogenative C-H/P-H cross-coupling. 1335 1336 Similar to the electrochemically oxidative phosphonation of quinoxaline-2(1H)-one, in 1337 2020, Subbarayappa and co-workers[108] reported the phosphonation of quinoxalines 1338 and quinoxalin-2(1H)-ones employing aerobic oxygen as green oxidant in the absence 1339 of external base and photocatalyst under visible light conditions at room temperature 1340 (Figure 72). In addition, alkyl or aryl phosphonates could be also tolerated in this 1341 regioselective C-P bond formation reaction under base/ligand-free conditions with good 1342 yields. The control experiment, adding radical scavengers TEMPO and BHT to the 58 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1343 reaction system under standard conditions, results in no desired products, suggesting 1344 the radical pathway. Various phosphonates (iPr, Et, Me, Bu and Bn) reacted with 1345 quinoxalines and quinoxalin-2(1H)-ones smoothly and generated the corresponding 1346 phosphonated products. A plausible reaction mechanism was proposed (Figure 72). 1347 Initially, phosphite radical intermediate was derived from alkyl or aryl phosphonate 1348 under aerobic condition in presence of visible light. Reaction between phosphite radical 1349 and quinoxaline gave a protonated radical cation intermediate in the presence of hydro 1350 peroxy radical. Further HAT and oxidation would lead to formation of the final desired 1351 product. 1352

1353 1354 Figure 72. Visible-light induced phosphonation of quinoxalines and 1355 quinoxalin-2(1H)-ones under aerobic metal-free conditions. 1356 1357 Indazoles are a class of important N-heterocycles which have received much attention 1358 due to their numerous pharmaceutical activities. In 2018, phosphonylation of 1359 2H-indazoles were explored by Hajra and co-workers[109] (Figure 73). The metal-free 1360 visible-light-induced C-H phosphonylation reaction which is employing 1361 diphenylphosphine oxides as P-radical precursors and rose bengal as the 1362 organophotoredox catalyst under ambient air at room temperature. A library of 1363 diphenyl(2-phenyl-2H-indazol-3-yl)phosphine oxides has been formed with broad 1364 functionalities in high yields.

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1365 1366 Figure 73. Visible-light-induced organophotoredox-catalyzed phosphonylation of 1367 2H-Indazoles with diphenylphosphine oxide. 1368 1369 Imidazo[1,2-a]pyridines are ubiquitous and key structural motif in N-heteroarenes 1370 which have been usually found in many commercially available drugs. The direct C-H 1371 functionalization of imidazo[1,2-a]pyridines represents an attractive method for the 1372 synthesis such highly valuable heteroaromatics. In 2020, Yu and coworker[110] reported 1373 a metal- and base-free procedure for the phosphoarylation of imidazo[1,2-a]pyridines 1374 with phosphine oxides (Figure 74). The reaction features mild and sustainable 1375 conditions, convenient operation, as well as good functional group compatibility. 1376 Besides, the authors proposed an energy transfer (EnT) process should be involved in 1377 the reaction. 1378

1379 1380 Figure 74. Phosphorylation of imidazo-fused heterocycles under metal-free conditions. 1381

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1382 Inspired by their previous work that cobaloxime could activate H-phosphine oxide into 1383 radical species under extremely mild reaction conditions, in 2020, Wu and 1384 co-workers[111] finished phosphorylation of enamines via cobaloxime catalysis under 1385 visible-light irradiation (Figure 75). The oxidation of diphenylphosphine oxide by 1386 excited cobaloxime catalyst produce phosphinoyl radical via a reductive quenching 1387 pathway, which undergoes cross-coupling with various enamines and enamides to give 1388 various β-phosphinoyl products in good to excellent yields. 1389

1390 1391 Figure 75. Cobaloxime catalysis for enamine phosphorylation with hydrogen 1392 evolution. 1393 1394 PHOSPHORYLATION OF OTHER SUBSTRATES 1395 Carbon-carbons are the most ubiquitous and fundamental chemical bonds in organic 1396 molecules. The selective cleavage of the C-C bonds and its subsequent transformation 1397 remains a major challenge to organic synthesis. In 2017, Peng, Ma and Dong’s group[112] 1398 developed a silver-catalyzed oxidative C(sp3)-P bond formation with 1,3-dicarbonyl 1399 compounds and H-phosphonates via C-C and P-H bond cleavage (Figure 76). The 1400 protocol exhibits a wide substrate scope, high functional group compatibility and 1401 exclusive selectivity. Preliminary mechanistic studies indicate that a radical process and 1402 a nucleophilic attack pathway may be involved in the C(sp3)-P bond formation and 1403 C(sp3)-C(CO) bond cleavage steps, respectively. A similar work involving 1404 Iron-catalyzed and air-mediated C(sp3)-H phosphorylation of 1,3-dicarbonyl 1405 compounds involving C-C bond cleavage was reported by Chen’s group[113].

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1406 1407 Figure 76. Silver-catalyzed oxidative C(sp3)-P bond formation via C-C and P-H bond 1408 cleavages. 1409 1410 In contrast to the above transition metal-catalyzed oxidative C(sp3)-P bond formation 1411 via C-C and P-H bond cleavages, in 2019, Kim and Wu’s group[114] reported a 1412 photosensitized C(sp3)-C(CO) bond cleavage and C-P bond formation of 1413 1,3-dicarbonyls with arylphosphine oxides (Figure 77). A series of β-ketophosphine 1414 oxides could be obtained in moderate to excellent yields. Control experiments, cyclic 1415 voltammetry and Stern-Volmer quenching experiments confirmed the reaction proceeds 1416 via a radical cascade reaction with chemoselective C-C bond cleavage to construct a 1417 C-P bond. The SET or the free radical chain reaction affords the critical active 1418 intermediates of PhCOO•, β-dicarbonyl radical and P-radical with the decomposition of 1419 BPO under visible light irradiation. The feasible reaction process was proposed. 1420 Initially, the excited state FI* of photo-catalyst FI could be formed under green LED 1421 irradiation. Next, there are three main pathways to generate the phosphinoyl radical: (a) 1422 to generate P-radical, the photoexcited FI* promotes the homolytic cleavage of the H-P 1423 bond of phosphine oxide via SET (Figure 77); (b) BPO could be reduced to the pioneer 1424 radical PhCOO• by the excited photocatalyst FI* via SET for gaining P-radical; (c) 1425 through tandem process involving the BPO decomposition and the free radical chain 1426 reaction, the active P-radical might also be generated from diphenylphosphine oxide. At 1427 the same time, β-dicarbonyls reacts with the photoexcited FI (FI*) providing the 1428 β-dicarbonyl radical. Subsequently, β-phosphonyl carbon radical intermediate (detected 1429 by ESI-MS) and enol could be gained from the reaction between the P-radical with 1430 β-diketone or β-dicarbonyl radical. In the presence of BPO or FI•+, the conversion of 1431 β-phosphonyl carbon radical intermediate to enol intermediate could occur. Then,

1432 electron-deficient carbonyl group was attacked by H2O to give geminal diols stabilized 62 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1433 by the intramolecular hydrogen bonds. The geminal diols underwent a proton transfer 1434 and C-C bond cleavage to produce desired products. 1435

1436 1437 Figure 77. Photosensitized C(sp3)-C(CO) bond cleavage and C-P bond formation of 1438 1,3-dicarbonyls with arylphosphine oxides. 1439 1440 P(O)-O and P(O)-N compounds are of greatly important organophosphorus compounds 1441 due to their broad applications in pharmaceuticals, agrochemicals, flame retardants and 1442 ligand scaffolds. Thus, much attention has been paid to the development of more 1443 efficient and versatile synthetic methodologies to access these compounds. The 1444 Atherton-Todd reaction, generating phosphoryl chlorides in situ by the halogenation of 1445 HP(O) compounds, is one of the most straightforward method for the phosphorylation

1446 of alcohols and amines. However, the use of highly toxic CCl4 as the halogenating 1447 reagent and the solvent enables the applications of reaction rather limited. In 2020, 1448 Chen’s group[115] reported a phosphoryl radical-initiated Atherton-Todd-type reaction

1449 under air (Figure 78). Notably, the utilization of less toxic CHCl3 as the halogenating

1450 reagent instead of highly toxic CCl4 and air as the radical initiator enables the method 1451 more environment and user friendly. The inexpensive, simple, and efficient synthesis of 1452 phosphinates, phosphinic amides, and phosphoramidates with high functional-group 1453 tolerance exhibits the potential application of this approach in organic chemistry. A 1454 plausible mechanism is illustrated in Figure 78. Initially, a phosphoryl radical is

1455 generated by the auto oxidation of the phosphoryl anion with O2, which generates from

1456 the deprotonation of P(O)-H compound. Then, the chlorine abstraction of CHCl3 by the 1457 phosphoryl radical gives rise to the dichloromethyl radical and phosphoryl chloride.

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1458 Eventually, a nucleophilic substitution reaction of a nucleophile reagent, such as 1459 alcohols and amines, with phosphoryl chloride affords the desired product. 1460

1461 1462 Figure 78. A phosphoryl radical-initiated Atherton-Todd-type reaction under open air. 1463 1464 Thiophosphate are also one of the most important classes of phosphorus-containing 1465 scaffold frequently occurring in pharmaceutically intriguing molecules. Therefore, the 1466 development of practical, efficient and green protocols for the synthesis of 1467 thiophosphate constitutes an important goal of contemporary organic chemistry. In 1468 2018, Wu and Li’s group[116] reported a visible light photoredox-catalyzed 1469 thiophosphate synthesis with methylene blue, leading to the products in moderate to 1470 good yields (Figure 79). Moreover, Stern-Volmer fluorescence quenching experiments 1471 were conducted to illustrate the possible reaction mechanism. 1472

1473 1474 Figure 79. Visible light photoredox catalyzed synthesis of thiophosphonate using 1475 methylene blue. 1476 64 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1477 Phosphonated azacyclic compounds containing P(O)-N bonds have shown wonderful 1478 applications in material chemistry, such as organic semiconductors and organic 1479 light-emitting diodes, due to their excellent electron donor-acceptor (D-A) properties. 1480 Therefore, the construction of P(O)-N bonds is synthetically important. Although some 1481 pioneering work has been established on the electrosynthesis of P(O)-N bonds by direct 1482 oxidative cross coupling of N-H/P-H, the substrates were only restricted to alkyl 1483 primary and secondary amines. In 2020, Liu and Jin’s group[117] presented an 1484 electrochemical dehydrogenative phosphorylation of nitrogen-containing heterocycles 1485 with imidazolium-based ionic liquid (DMMI = 1,3-dimethylimidazolium iodide) as 1486 electrolyte under mild reaction conditions (Figure 80). Diverse phosphorylation 1487 products of substituted carbazoles and indoles are constructed in moderate to excellent 1488 yields. The cyclic voltammogram (CV) experiments were also performed to investigate 1489 the reaction mechanism, and a plausible mechanism were proposed for the reaction. 1490 Initially, iodide radical is generated by the oxidation of iodide anion at the anode. Then, 1491 P(O)-H compound interacts with an iodide radical leading to the phosphonyl radical, 1492 which further couples with an iodide radical to form the intermediate P(O)-I compound. 1493 Meanwhile, the N-heterocycle anion is generated by the deprotonation of the starting

1494 material P(O)-H compound with Cs2CO3. The nucleophilic attack of P(O)-I compound 1495 by the N-heterocycle anion will result in the final desired product. Notably, reduction of 1496 the proton at the cathode will furnish the hydrogen gas. 1497

1498 1499 Figure 80. Electrochemical oxidative dehydrogenative phosphorylation of 1500 N-heterocycles.

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1501 1502 CONCLUSION AND OUTLOOK 1503 The growing awareness for the importance of organophosphorus compounds gives a 1504 strong and renewed relevance to the development of P-centered radical-based reactions. 1505 Owing to their versatile reactivity of P-centered radicals in various transformations, 1506 considerable progresses have been achieved in the transition metal-mediated and 1507 photoredox-catalyzed phosphorylation reaction. Besides, it is worth noting that 1508 electrochemical phosphorylation has also emerged as an efficient approach for the 1509 construction of organophosphorus compounds. In particular, over the past decade, 1510 phosphorus radical-initiated phosphorylation of unsaturated compounds, such as 1511 alkenes, alkynes and isocyanides, through merging with transition-metal catalysis, 1512 photocatalysis and electrochemistry, has become one of the most appealing strategies to 1513 build structurally diverse organophosphorus compounds. Furthermore, cross-coupling 1514 reactions with X-H (X = C, N, O, S) bonds and (pseudo)halides involving phosphorus 1515 radicals have also transformed into a powerful protocol for the efficient synthesis of 1516 otherwise uneasily accessible organophosphorus compounds. Despite myriad recent 1517 advances have been made in this fast-growing research arena, some limitations or 1518 restrictions and challenges remains to be addressed in the future, in order to improve 1519 practicality and versatility of these methods. First of all, the types and sources of 1520 phosphorus radical are still limited, thus the expanding the types and sources of 1521 phosphorus radical are worth exploring. Second, the usage of transition-metal salts or 1522 organometallic reagents in most cases of the phosphorylation reactions, which might 1523 hamper its further application in industry, enables the development of more 1524 environmentally sustainable approaches highly demanding. Third, the development of 1525 enantioselective C-P bond formation reactions would be another hugely fascinating 1526 field. Overall, there are still many challenges and problems in the field of construction 1527 of organophosphorus compounds, which need to be resolved, and deserve to attract 1528 more attention of chemists. 1529 1530 DECLARATIONS 1531 Acknowledgments

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1532 We sincerely thank all leading chemists and co-workers involved in the development of

1533 phosphorus radical-based phosphorylation reactions.

1534 1535 Authors’ contributions 1536 Wrote the paper: Liu J, Xiao HZ and Fu Q. 1537 Guide this work, gave valuable suggestions and discussion for the review and revised 1538 the paper: Fu Q and Yu DG. 1539 1540 Availability of data and materials 1541 Not applicable. 1542 1543 Financial support and sponsorship 1544 This work was supported by Natural Science Foundation of China (No. 21772129; No. 1545 22001220), and the Fundamental Research Funds for the Central Universities. 1546 1547 Conflicts of interest 1548 All authors declared that there are no conflicts of interest. 1549 1550 Ethical approval and consent to participate 1551 Not applicable. 1552 1553 Consent for publication 1554 Not applicable. 1555 1556 Copyright 1557 © The Author(s) 2021. 1558 1559 REFERENCES

1560 1. Tang W, Zhang X. New chiral phosphorus ligands for enantioselective

1561 hydrogenation. Chem Rev 2003;103:3029-70. [DOI: 10.1021/cr020049i]

67 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1562 2. Demmer CS, Krogsgaard-Larsen N, Bunch L. Review on modern advances of

1563 chemical methods for the introduction of a phosphonic acid group. Chem Rev

1564 2011;111:7981-8006. [DOI: 10.1021/cr2002646]

1565 3. Duffy MP, Delaunay W, Bouit PA, Hissler M. π-Conjugated phospholes and their

1566 incorporation into devices: components with a great deal of potential. Chem Soc Rev

1567 2016;45:5296-310. [DOI: 10.1039/C6CS00257A]

1568 4. Van der Jeught S, Stevens CV. Direct phosphonylation of aromatic azaheterocycles.

1569 Chem Rev 2009;109:2672-702. [DOI: 10.1021/cr800315j]

1570 5. Shao C, Xu W, Li L, Zhang X. Recent Advances of Transition Metal-Catalyzed P-C

1571 Coupling Reactions. Chin J Org Chem 2017;37:335. [DOI: 10.6023/cjoc201608030]

1572 6. Gao Y, Tang G, Zhao Y. Recent progress toward organophosphorus compounds

1573 based on phosphorus-centered radical difunctionalizations. Phosphorus, Sulfur, and

1574 Silicon and the Related Elements 2017;192:589-96. [DOI:

1575 10.1080/10426507.2017.1295965]

1576 7. Lan X, Wang N, Xing Y. Recent Advances in Radical Difunctionalization of Simple

1577 Alkenes: Recent Advances in Radical Difunctionalization of Simple Alkenes. Eur J

1578 Org Chem 2017;2017:5821-51. [DOI: https://doi.org/10.1002/ejoc.201700678]

1579 8. Gao Y, Tang G, Zhao Y. Recent Advances of Phosphorus-Centered Radical

1580 Promoted Difunctionalization of Unsaturated Carbon-Carbon Bonds. Chin J Org Chem

1581 2018;38:62. [DOI: 10.6023/cjoc201708023]

1582 9. Cai B, Xuan J, Xiao W. Visible light-mediated C P bond formation reactions.

1583 Science Bulletin 2019;64:337-50. [DOI: https://doi.org/10.1016/j.scib.2019.02.002]

1584 10. Chen L, Liu X, Zou Y. Recent Advances in the Construction of

1585 Phosphorus‐Substituted Heterocycles, 2009-2019. Adv Synth Catal 2020;362:1724-818.

1586 [DOI: https://doi.org/10.1002/adsc.201901540]

1587 11. Ung SP, Mechrouk VA, Li C. Shining Light on the Light-Bearing Element: A Brief

1588 Review of Photomediated C-H Phosphorylation Reactions. Synthesis 2021;53:1003-22.

1589 [DOI: 10.1055/s-0040-1705978]

68 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1590 12. Leca D, Fensterbank L, Lacôte E, Malacria M. Recent advances in the use of

1591 phosphorus-centered radicals in organic chemistry. Chem Soc Rev 2005;34:858-65.

1592 [DOI: 10.1039/B500511F]

1593 13. Rueping M, Zhu S, Koenigs RM. Photoredox catalyzed C-P bond forming

1594 reactions-visible light mediated oxidative phosphonylations of amines. Chem Commun

1595 (Camb) 2011;47:8679-81. [DOI: 10.1039/C1CC12907D]

1596 14. Kingston C, Palkowitz MD, Takahira Y, et al. A Survival Guide for the

1597 "Electro-curious". Acc Chem Res 2020;53:72-83. [DOI: 10.1021/acs.accounts.9b00539]

1598 15. Budnikova YH, Gryaznova TV, Grinenko VV, Dudkina YB, Khrizanforov MN.

1599 Eco-efficient electrocatalytic C-P bond formation. Pure and Applied Chemistry

1600 2017;89:311-30. [DOI: doi:10.1515/pac-2016-1001]

1601 16. Bezzenine-Lafollée S, Gil R, Prim D, Hannedouche J. First-Row Late Transition

1602 Metals for Catalytic Alkene Hydrofunctionalisation: Recent Advances in C-N, C-O and

1603 C-P Bond Formation. Molecules 2017;22:1901.

1604 17. Yoo W, Kobayashi S. Hydrophosphinylation of unactivated alkenes with secondary

1605 phosphine oxides under visible-light photocatalysis. Green Chem 2013;15:1844. [DOI:

1606 10.1039/C3GC40482J]

1607 18. Wang N, Ye L, Li Z, et al. Hydrofunctionalization of alkenols triggered by the

1608 addition of diverse radicals to unactivated alkenes and subsequent remote hydrogen

1609 atom translocation. Org Chem Front 2018;5:2810-4. [DOI: 10.1039/C8QO00734A]

1610 19. Yuan Z, Wang S, Li M, et al. Visible light induced hydrophosphinylation of

1611 unactivated alkenes catalyzed by salicylaldehyde. Green Chem 2021;23:3600-6. [DOI:

1612 10.1039/D1GC00374G]

1613 20. Li YM, Sun M, Wang HL, Tian QP, Yang SD. Direct annulations toward

1614 phosphorylated oxindoles: silver-catalyzed carbon-phosphorus functionalization of

1615 alkenes. Angew Chem Int Ed Engl 2013;52:3972-6. [DOI:

1616 https://doi.org/10.1002/anie.201209475]

69 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1617 21. Li Y, Shen Y, Chang K, Yang S. Metal-free oxidative arylphosphination of

1618 activated N-substituted-N-arylacrylamide derivatives using K2S2O8. Tetrahedron

1619 2014;70:1991-6. [DOI: https://doi.org/10.1016/j.tet.2014.01.065]

1620 22. Zhao J, Li P, Li X, Xia C, Li F. Straightforward synthesis of functionalized

1621 chroman-4-ones through cascade radical cyclization-coupling of

1622 2-(allyloxy)arylaldehydes. Chem Commun (Camb) 2016;52:3661-4. [DOI:

1623 10.1039/C5CC09730D]

1624 23. Liu Q, Lu W, Xie G, Wang X. Metal-free synthesis of phosphinoylchroman-4-ones

1625 via a radical phosphinoylation-cyclization cascade mediated by K2S2O8. Beilstein J Org

1626 Chem 2020;16:1974-82. [DOI: 10.3762/bjoc.16.164]

1627 24. Liang D, Ge D, Lv Y, Huang W, Wang B, Li W. Silver-Catalyzed Radical

1628 Arylphosphorylation of Unactivated Alkenes: Synthesis of 3-Phosphonoalkyl Indolines.

1629 J Org Chem 2018;83:4681-91. [DOI: 10.1021/acs.joc.8b00450]

1630 25. Liu X, Sun K, Lv Q, et al. Silver-mediated radical phosphorylation/cyclization of N

1631 -allylbenzamides to access phosphoryl-substituted dihydroisoquinolones. New J Chem

1632 2019;43:12221-4. [DOI: 10.1039/C9NJ02833A]

1633 26. Liu X, Sun K, Chen X, et al. Visible‐Light‐Promoted Transition‐Metal‐Free

1634 Approach toward Phosphoryl‐Substituted Dihydroisoquinolones via Cascade

1635 Phosphorylation/Cyclization of N ‐Allylbenzamides. Adv Synth Catal 2019;361:3712-7.

1636 [DOI: https://doi.org/10.1002/adsc.201900544]

1637 27. Liu J, Zhao S, Song W, et al. Silver-Catalyzed Carbon-Phosphorus

1638 Functionalization for Polyheterocycle Formation. Adv Synth Catal 2017;359:609-15.

1639 [DOI: https://doi.org/10.1002/adsc.201600850]

1640 28. Gorre R, Enagandhula D, Balasubramanian S, Akondi SM. Visible-light-driven

1641 metal-free aerobic synthesis of highly diastereoselective phosphinoylpyrroloindoles.

1642 Org Biomol Chem 2020;18:1354-8. [DOI: 10.1039/C9OB02730K]

1643 29. Li Y, Zhu Y, Yang S. Visible-light-induced tandem phosphorylation cyclization of

1644 vinyl azides under mild conditions. Org Chem Front 2018;5:822-6. [DOI:

1645 10.1039/C7QO01004D]

70 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1646 30. Sun K, Si Y, Chen X, et al. Synthesis of Phosphoryl‐Substituted Benzimidazo[2,1‐

1647 a ]isoquinolin‐6(5 H )‐ones from 2‐Arylbenzoimidazoles and Diarylphosphine Oxides.

1648 Asian J Org Chem 2019;8:2042-5. [DOI: 10.1002/ajoc.201900570]

1649 31. Jiang SS, Xiao YT, Wu YC, Luo SZ, Song RJ, Li JH. Manganese(Ⅲ)-promoted

1650 tandem phosphinoylation/cyclization of 2-arylindoles/2-arylbenzimidazoles with

1651 disubstituted phosphine oxides. Org Biomol Chem 2020;18:4843-7. [DOI:

1652 10.1039/D0OB00877J]

1653 32. Fu Q, Bo ZY, Ye JH, et al. Transition metal-free phosphonocarboxylation of

1654 alkenes with carbon dioxide via visible-light photoredox catalysis. Nat Commun

1655 2019;10:3592. [DOI: 10.1038/s41467-019-11528-8]

1656 33. Jiang Y, Liu J, Fu Q, Yu Y, Yu D. Visible-Light-Driven Phosphonoalkylation of

1657 Alkenes. Synlett 2021;32:378-82.

1658 34. Chu XQ, Zi Y, Meng H, Xu XP, Ji SJ. Radical phosphinylation of α,α-diaryl allylic

1659 alcohols with concomitant 1,2-aryl migration. Chem Commun (Camb) 2014;50:7642-5.

1660 [DOI: 10.1039/C4CC02114B]

1661 35. Mi X, Wang C, Huang M, Wu Y, Wu Y. Silver-catalyzed carbonphosphonation of

1662 α,α-diaryl allylic alcohols: synthesis of β-aryl-γ-ketophosphonates. Org Biomol Chem

1663 2014;12:8394-7. [DOI: 10.1039/C4OB01739K]

1664 36. Yin Y, Weng WZ, Sun JG, Zhang B. Eosin Y-catalyzed, visible-light-promoted

1665 carbophosphinylation of allylic alcohols via a radical neophyl rearrangement. Org

1666 Biomol Chem 2018;16:2356-61. [DOI: 10.1039/C8OB00231B]

1667 37. Li C, Qi Z, Yang Q, Qiang X, Yang S. Visible-Light-Catalyzed

1668 Phosphonation-Annulation: an Efficient Strategy to Synthesize

1669 β-Phosphonopyrrolidines and β-Phosphonolactones: Visible-Light-Catalyzed

1670 Phosphonation-Annulation: an Efficient Strategy to Synthesize

1671 β-Phosphonopyrrolidines and β-Phosphonolactones†. Chin J Chem 2018;36:1052-8.

1672 [DOI: https://doi.org/10.1002/cjoc.201800360]

1673 38. Wang C, Huang X, Liu X, Gao S, Zhao B, Yang S. Photo-induced phosphorus

1674 radical involved semipinacol rearrangement reaction: Highly synthesis of

71 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1675 γ-oxo-phosphonates. Chinese Chemical Letters 2020;31:677-80. [DOI:

1676 10.1016/j.cclet.2019.08.011]

1677 39. Jin S, Sun S, Yu JT, Cheng J. The Silver-Promoted Phosphonation/Alkynylation of

1678 Alkene Proceeding with Radical 1,2-Alkynyl Migration. J Org Chem

1679 2019;84:11177-85. [DOI: 10.1021/acs.joc.9b01088]

1680 40. Zhang PZ, Zhang L, Li JA, Shoberu A, Zou JP, Zhang W. Phosphinoyl Radical

1681 Initiated Vicinal Cyanophosphinoylation of Alkenes. Org Lett 2017;19:5537-40. [DOI:

1682 10.1021/acs.orglett.7b02621]

1683 41. Zhang G, Fu L, Chen P, Zou J, Liu G. Proton-Coupled Electron Transfer Enables

1684 Tandem Radical Relay for Asymmetric Copper-Catalyzed Phosphinoylcyanation of

1685 Styrenes. Org Lett 2019;21:5015-20. [DOI: 10.1021/acs.orglett.9b01607]

1686 42. He Y, Won J, Kim J, et al. One-pot bifunctionalization of unactivated alkenes,

1687 P(O)-H compounds, and N -methoxypyridinium salts for the construction of β-pyridyl

1688 alkylphosphonates. Org Chem Front 2018;5:2595-603. [DOI: 10.1039/C8QO00689J]

1689 43. Buquoi JQ, Lear JM, Gu X, Nagib DA. Heteroarene Phosphinylalkylation via a

1690 Catalytic, Polarity-Reversing Radical Cascade. ACS Catal 2019;9:5330-5. [DOI:

1691 10.1021/acscatal.9b01580]

1692 44. Lear JM, Buquoi JQ, Gu X, Pan K, Mustafa DN, Nagib DA. Multi-component

1693 heteroarene couplings via polarity-reversed radical cascades. Chem Commun (Camb)

1694 2019;55:8820-3. [DOI: 10.1039/C9CC03498F]

1695 45. Shen J, Zhang Y, Yu Y, Wang M. Metal-free visible-light-induced

1696 photoredox-catalyzed intermolecular pyridylation/phosphinoylation of alkenes. Org

1697 Chem Front 2021;8:901-7. [DOI: 10.1039/D0QO01218A]

1698 46. Maryanoff BE, Reitz AB. The Wittig olefination reaction and modifications

1699 involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected

1700 synthetic aspects. Chem Rev 1989;89:863-927. [DOI: 10.1021/cr00094a007]

1701 47. Wei W, Ji JX. Catalytic and direct oxyphosphorylation of alkenes with dioxygen

1702 and H-phosphonates leading to β-ketophosphonates. Angew Chem Int Ed Engl

1703 2011;50:9097-9. [DOI: 10.1002/anie.201100219]

72 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1704 48. Zhou M, Zhou Y, Song Q. Cu/Fe-Cocatalyzed Formation of β-Ketophosphonates

1705 by a Domino Knoevenagel-Decarboxylation-Oxyphosphorylation Sequence from

1706 Aromatic Aldehydes and H-Phosphonates. Chemistry 2015;21:10654-9. [DOI:

1707 10.1002/chem.201501226]

1708 49. Chen X, Chen X, Li X, et al. Acetonitrile-dependent oxyphosphorylation: A mild

1709 one-pot synthesis of β-ketophosphonates from alkenyl acids or alkenes. Tetrahedron

1710 2017;73:2439-46. [DOI: https://doi.org/10.1016/j.tet.2017.03.026]

1711 50. Fu Q, Yi D, Zhang Z, et al. Copper-catalyzed aerobic oxidative coupling of ketones

1712 with P(O)-H compounds leading to β-ketophosphine oxides. Org Chem Front

1713 2017;4:1385-9. [DOI: 10.1039/C7QO00202E]

1714 51. Zhang Z, Yi D, Fu Q, et al. Copper catalyzed one-pot synthesis of β-ketophosphine

1715 oxides from ketones and H-phosphine oxides. Tetrahedron Letters 2017;58:2417-20.

1716 [DOI: 10.1016/j.tetlet.2017.05.005]

1717 52. Liang W, Zhang Z, Yi D, et al. Copper-Catalyzed Direct Oxyphosphorylation of

1718 Enamides with P(O)-H Compounds and Dioxygen. Chin J Chem 2017;35:1378-82.

1719 [DOI: https://doi.org/10.1002/cjoc.201700189]

1720 53. Nan G, Yue H. Direct synthesis of β-ketophosphine oxides via copper-catalyzed

1721 difunctionalization of alkenes with H-phosphine oxides and dioxygen. Tetrahedron

1722 Letters 2018;59:2071-4. [DOI: https://doi.org/10.1016/j.tetlet.2018.04.042]

1723 54. Wang H, Fu Q, Zhang Z, Gao M, Ji J, Yi D. Hydrochloric Acid-Promoted

1724 Copper/Iron-Cocatalyzed Deesterifica-tive Oxyphosphorylation of 2-Substituted

1725 Acrylates with H-Phosphine Oxides. Chin J Org Chem 2018;38:1977. [DOI:

1726 10.6023/cjoc201805027]

1727 55. Feng S, Li J, He F, et al. A copper-catalyzed radical coupling/fragmentation

1728 reaction: efficient access to β-oxophosphine oxides. Org Chem Front 2019;6:946-51.

1729 [DOI: 10.1039/C9QO00006B]

1730 56. Gu J, Cai C. Cu(i)/Fe(Ⅲ)-Catalyzed C-P cross-coupling of styrenes with

1731 H-phosphine oxides: a facile and selective synthesis of alkenylphosphine oxides and

73 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1732 β-ketophosphonates. Org Biomol Chem 2017;15:4226-30. [DOI:

1733 10.1039/C7OB00505A]

1734 57. Moghaddam FM, Daneshfar M, Azaryan R, Pirat J. Copper ferrite nanoparticles

1735 catalyzed formation of β-Ketophosphonates via oxyphosphorylation of styrenes with

1736 H-phosphonates: A DFT study on UV-vis absorption spectra. Catalysis

1737 Communications 2020;141:106015. [DOI:

1738 https://doi.org/10.1016/j.catcom.2020.106015]

1739 58. Shi Y, Chen R, Guo K, et al. Visible light-promoted metal-free aerobic

1740 oxyphosphorylation of olefins: A facile approach to β-ketophosphine oxides.

1741 Tetrahedron Letters 2018;59:2062-5. [DOI: 10.1016/j.tetlet.2018.04.040]

1742 59. Qian HF, Li CK, Zhou ZH, Tao ZK, Shoberu A, Zou JP. Visible Light-Mediated

1743 Photocatalytic Metal-Free Cross-Coupling Reaction of Alkenyl Carboxylic Acids with

1744 Diarylphosphine Oxides Leading to β-Ketophosphine Oxides. Org Lett

1745 2018;20:5947-51. [DOI: 10.1021/acs.orglett.8b02639]

1746 60. Jung HI, Kim DY. Visible light-mediated photocatalytic phosphorylation of vinyl

1747 azides: A mild synthesis of β-ketophosphine oxides. Synthetic Communications

1748 2020;50:380-7. [DOI: 10.1080/00397911.2019.1696364]

1749 61. Li M, Zhang Q, Hu D, et al. Catalyst-free direct difunctionalization of alkenes with

1750 H-phosphine oxides and dioxygen: a facile and green approach to β-hydroxyphosphine

1751 oxides. Tetrahedron Letters 2016;57:2642-6. [DOI:

1752 https://doi.org/10.1016/j.tetlet.2016.05.019]

1753 62. Peng P, Lu Q, Peng L, Liu C, Wang G, Lei A. Dioxygen-induced oxidative

1754 activation of a P-H bond: radical oxyphosphorylation of alkenes and alkynes toward

1755 β-oxy phosphonates. Chem Commun (Camb) 2016;52:12338-41. [DOI:

1756 10.1039/C6CC06881B]

1757 63. Yi D, Fu Q, Chen S, et al. Copper-catalyzed direct hydroxyphosphorylation of

1758 electron-deficient alkenes with H-phosphine oxides and dioxygen. Tetrahedron Letters

1759 2017;58:2058-61. [DOI: 10.1016/j.tetlet.2017.04.042]

74 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1760 64. Chen Y, Chen Y, Lu S, Li Z. Copper-catalyzed three-component

1761 phosphorylation-peroxidation of alkenes. Org Chem Front 2018;5:972-6. [DOI:

1762 10.1039/C7QO01045A]

1763 65. Shen J, Xiao B, Hou Y, et al. Cobalt(Ⅱ)‐Catalyzed Bisfunctionalization of Alkenes

1764 with Diarylphosphine Oxide and Peroxide. Adv Synth Catal 2019;361:5198-209. [DOI:

1765 10.1002/adsc.201900873]

1766 66. Zhou SF, Li DP, Liu K, Zou JP, Asekun OT. Direct radical acetoxyphosphorylation

1767 of styrenes mediated by manganese(Ⅲ). J Org Chem 2015;80:1214-20. [DOI:

1768 10.1021/jo5023298]

1769 67. Ryzhakov D, Jarret M, Baltaze JP, Guillot R, Kouklovsky C, Vincent G. Synthesis

1770 of 3,3-Spirocyclic 2-Phosphonoindolines via a Dearomative Addition of Phosphonyl

1771 Radicals to Indoles. Org Lett 2019;21:4986-90. [DOI: 10.1021/acs.orglett.9b01516]

1772 68. Yang B, Hou S, Ding S, et al. Cerium(Ⅳ)-Promoted Phosphinoylation-Nitratation

1773 of Alkenes. Adv Synth Catal 2018;360:4470-4. [DOI: 10.1002/adsc.201800985]

1774 69. Zhang C, Li Z, Zhu L, Yu L, Wang Z, Li C. Silver-catalyzed radical

1775 phosphonofluorination of unactivated alkenes. J Am Chem Soc 2013;135:14082-5.

1776 [DOI: 10.1021/ja408031s]

1777 70. Zhang HY, Mao LL, Yang B, Yang SD. Copper-catalyzed radical cascade

1778 cyclization for the synthesis of phosphorated indolines. Chem Commun (Camb)

1779 2015;51:4101-4. [DOI: 10.1039/C4CC10267C]

1780 71. Li JA, Zhang PZ, Liu K, Shoberu A, Zou JP, Zhang W. Phosphinoyl

1781 Radical-Initiated α,β-Aminophosphinoylation of Alkenes. Org Lett 2017;19:4704-6.

1782 [DOI: 10.1021/acs.orglett.7b02183]

1783 72. Wang Y, Wang W, Tang R, Liu Z, Tao W, Fang Z. Iron(Ⅲ)-catalyzed radical

1784 α,β-aminophosphinoylation of styrenes with diphenylphosphine oxides and anilines.

1785 Org Biomol Chem 2018;16:7782-6. [DOI: 10.1039/C8OB02151A]

1786 73. Xu J, Li X, Gao Y, et al. Mn(Ⅲ)-mediated phosphonation-azidation of alkenes: a

1787 facile synthesis of β-azidophosphonates. Chem Commun (Camb) 2015;51:11240-3.

1788 [DOI: 10.1039/C5CC03995A]

75 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1789 74. Ma X, Chiou M, Ge L, et al. Iron phthalocyanine-catalyzed radical

1790 phosphinoylazidation of alkenes: A facile synthesis of β-azido-phosphine oxide with a

1791 fast azido transfer step. Chinese Journal of Catalysis 2021;42:1634-40. [DOI:

1792 https://doi.org/10.1016/S1872-2067(21)63847-0]

1793 75. Tao ZK, Li CK, Zhang PZ, Shoberu A, Zou JP, Zhang W. Phosphinoyl

1794 Radical-Initiated 1,2-Bifunctional Thiocyanodiphenylphosphinoylation of Alkenes. J

1795 Org Chem 2018;83:2418-24. [DOI: 10.1021/acs.joc.7b02929]

1796 76. Huang T, Saga Y, Guo H, Yoshimura A, Ogawa A, Han LB. Radical

1797 Hydrophosphorylation of Alkynes with R2P(O)H Generating Alkenylphosphine Oxides:

1798 Scope and Limitations. J Org Chem 2018;83:8743-9. [DOI: 10.1021/acs.joc.8b01042]

1799 77. Wang H, Li Y, Tang Z, et al. Z-Selective Addition of Diaryl Phosphine Oxides to

1800 Alkynes via Photoredox Catalysis. ACS Catal 2018;8:10599-605. [DOI:

1801 10.1021/acscatal.8b02617]

1802 78. Liu WQ, Lei T, Zhou S, et al. Cobaloxime Catalysis: Selective Synthesis of

1803 Alkenylphosphine Oxides under Visible Light. J Am Chem Soc 2019;141:13941-7.

1804 [DOI: 10.1021/jacs.9b06920]

1805 79. Hou H, Zhou B, Wang J, et al. Stereo- and Regioselective

1806 cis-Hydrophosphorylation of 1,3-Enynes Enabled by the Visible-Light Irradiation of

1807 NiCl2(PPh3)2. Org Lett 2021;23:2981-7. [DOI: 10.1021/acs.orglett.1c00626]

1808 80. Zhang P, Zhang L, Gao Y, et al. Copper-catalyzed tandem

1809 phosphination-decarboxylation-oxidation of alkynyl acids with H-phosphine oxides: a

1810 facile synthesis of β-ketophosphine oxides. Chem Commun (Camb) 2015;51:7839-42.

1811 [DOI: 10.1039/C5CC01904D]

1812 81. Chen X, Li X, Chen XL, et al. A one-pot strategy to synthesize β-ketophosphonates:

1813 silver/copper catalyzed direct oxyphosphorylation of alkynes with H-phosphonates and

1814 oxygen in the air. Chem Commun (Camb) 2015;51:3846-9. [DOI:

1815 10.1039/C4CC10312B]

76 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1816 82. Yi N, Wang R, Zou H, He W, Fu W, He W. Copper/Iron-Catalyzed Aerobic

1817 Oxyphosphorylation of Terminal Alkynes Leading to β-Ketophosphonates. J Org

1818 Chem 2015;80:5023-9. [DOI: 10.1021/acs.joc.5b00408]

1819 83. Zhou M, Chen M, Zhou Y, et al. β-ketophosphonate formation via aerobic

1820 oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonates. Org

1821 Lett 2015;17:1786-9. [DOI: 10.1021/acs.orglett.5b00574]

1822 84. Zhou Y, Rao C, Mai S, Song Q. Substituent-Controlled Chemoselective Cleavage

1823 of C═C or Csp(2)-C(CO) Bond in α,β-Unsaturated Carbonyl Compounds with

1824 H-Phosphonates Leading to β-Ketophosphonates. J Org Chem 2016;81:2027-34. [DOI:

1825 10.1021/acs.joc.5b02887]

1826 85. Tao ZK, Li CK, Li JA, Shoberu A, Zhang W, Zou JP. Copper-Catalyzed Vicinal

1827 Cyano-, Thiocyano-, and Chlorophosphorylation of Alkynes: A Phosphinoyl

1828 Radical-Initiated Approach for Difunctionalized Alkenes. Org Lett 2021;23:4342-7.

1829 [DOI: 10.1021/acs.orglett.1c01286]

1830 86. Zhang P, Gao Y, Zhang L, et al. Copper-Catalyzed Cycloaddition between

1831 Secondary Phosphine Oxides and Alkynes: Synthesis of Benzophosphole Oxides. Adv

1832 Synth Catal 2016;358:138-42. [DOI: 10.1002/adsc.201500667]

1833 87. Quint V, Morlet-Savary F, Lohier JF, Lalevée J, Gaumont AC, Lakhdar S.

1834 Metal-Free, Visible Light-Photocatalyzed Synthesis of Benzo[b]phosphole Oxides:

1835 Synthetic and Mechanistic Investigations. J Am Chem Soc 2016;138:7436-41. [DOI:

1836 10.1021/jacs.6b04069]

1837 88. Zhu XT, Zhao Q, Liu F, et al. Silver-mediated radical 5-exo-dig cyclization of

1838 2-alkynylbenzonitriles: synthesis of phosphinylated 1-indenones. Chem Commun

1839 (Camb) 2017;53:6828-31. [DOI: 10.1039/C7CC01666B]

1840 89. Hou H, Xu Y, Yang H, et al. Visible-Light Mediated Hydrosilylative and

1841 Hydrophosphorylative Cyclizations of Enynes and Dienes. Org Lett 2020;22:1748-53.

1842 [DOI: 10.1021/acs.orglett.0c00024]

77 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1843 90. Huang WB, Ren FY, Wang MW, Qiu LQ, Chen KH, He LN. Cu(Ⅱ)-Catalyzed

1844 Phosphonocarboxylative Cyclization Reaction of Propargylic Amines and Phosphine

1845 Oxide with CO2. J Org Chem 2020;85:14109-20. [DOI: 10.1021/acs.joc.0c02172]

1846 91. Liu XC, Chen XL, Liu Y, et al. Visible-Light-Induced Metal-Free Synthesis of

1847 2-Phosphorylated Thioflavones in Water. ChemSusChem 2020;13:298-303. [DOI:

1848 https://doi.org/10.1002/cssc.201902817]

1849 92. Li CX, Tu DS, Yao R, Yan H, Lu CS. Visible-Light-Induced Cascade Reaction of

1850 Isocyanides and N-Arylacrylamides with Diphenylphosphine Oxide via Radical C-P

1851 and C-C Bond Formation. Org Lett 2016;18:4928-31. [DOI:

1852 10.1021/acs.orglett.6b02413]

1853 93. Yang W, Li B, Zhang M, et al. Metal-free photo-induced radical C-P and C-S bond

1854 formation for the synthesis of 2-phosphoryl benzothiazoles. Chinese Chemical Letters

1855 2020;31:1313-6. [DOI: 10.1016/j.cclet.2019.10.022]

1856 94. Liu Y, Chen XL, Li XY, et al. 4CzIPN-tBu-Catalyzed Proton-Coupled Electron

1857 Transfer for Photosynthesis of Phosphorylated N-Heteroaromatics. J Am Chem Soc

1858 2021;143:964-72. [DOI: 10.1021/jacs.0c11138]

1859 95. Liao LL, Gui YY, Zhang XB, et al. Phosphorylation of Alkenyl and Aryl C-O

1860 Bonds via Photoredox/Nickel Dual Catalysis. Org Lett 2017;19:3735-8. [DOI:

1861 10.1021/acs.orglett.7b01561]

1862 96. Zhu DL, Jiang S, Wu Q, et al. Visible-Light-Induced Nickel-Catalyzed P(O)-C(sp2)

1863 Coupling Using Thioxanthen-9-one as a Photoredox Catalysis. Org Lett 2021;23:160-5.

1864 [DOI: 10.1021/acs.orglett.0c03892]

1865 97. Hou H, Zhou B, Wang J, et al. Visible-light-induced ligand to metal charge transfer

1866 excitation enabled phosphorylation of aryl halides. Chem Commun (Camb)

1867 2021;57:5702-5. [DOI: 10.1039/D1CC01858B]

1868 98. Tang L, Wen L, Sun T, et al. Solvent-Controlled Copper-Catalyzed Radical

1869 Decarboxylative Coupling for Alkenyl C(sp2)-P Bond Formation. Asian J Org Chem

1870 2017;6:1683-92. [DOI: 10.1002/ajoc.201700434]

78 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1871 99. Xue JF, Zhou SF, Liu YY, Pan X, Zou JP, Asekun OT. Manganese(Ⅲ)-mediated

1872 alkenyl C(sp2)-P bond formation from the reaction of β-nitrostyrenes with dialkyl

1873 phosphites. Org Biomol Chem 2015;13:4896-902. [DOI: 10.1039/C5OB00404G]

1874 100. Yuan J, Yang L, Mao P, Qu L. Silver-catalyzed synthesis of

1875 2-arylvinylphosphonates by cross-coupling of β-nitrostyrenes with H-phosphites. RSC

1876 Adv 2016;6:87058-65. [DOI: 10.1039/C6RA19002B]

1877 101. Zhou P, Jiang Y, Zou J, Zhang W. Manganese(Ⅲ) Acetate Mediated Free-Radical

1878 Phosphonylation of Flavones and Coumarins. Synthesis 2012;44:1043-50. [DOI:

1879 10.1055/s-0031-1289748]

1880 102. Yuan J, Li Y, Yang L, et al. Silver-catalyzed direct Csp2-H radical

1881 phosphorylation of coumarins with H-phosphites. Tetrahedron 2015;71:8178-86. [DOI:

1882 10.1016/j.tet.2015.08.026]

1883 103. Yu X, Ge B, Zhang Y, Wang X, Wang D. Silver-Mediated Phosphonylation of

1884 C(sp2)-H Bonds with P-H Bonds: Direct C-H Functionalization of Ferrocenyl Anilides

1885 and Dialkyl Phosphites under Palladium- and Copper-Free Conditions. Asian J Org

1886 Chem 2016;5:1253-9. [DOI: 10.1002/ajoc.201600296]

1887 104. Luo K, Chen YZ, Yang WC, Zhu J, Wu L. Cross-Coupling Hydrogen Evolution

1888 by Visible Light Photocatalysis Toward C(sp(2))-P Formation: Metal-Free C-H

1889 Functionalization of Thiazole Derivatives with Diarylphosphine Oxides. Org Lett

1890 2016;18:452-5. [DOI: 10.1021/acs.orglett.5b03497]

1891 105. Qiao H, Sun S, Zhang Y, et al. Merging photoredox catalysis with transition metal

1892 catalysis: site-selective C4 or C5-H phosphonation of 8-aminoquinoline amides. Org

1893 Chem Front 2017;4:1981-6. [DOI: 10.1039/C7QO00305F]

1894 106. Xiong Y, Zhang Y, Qi L, Jiang M, Zhang J, Wang T. Photocatalytic Synthesis of

1895 Diphosphorous Quinoline Compounds. Asian J Org Chem 2020;9:292-5. [DOI:

1896 10.1002/ajoc.201900717]

1897 107. Li K, Jiang Y, Xu K, Zeng C, Sun B. Electrochemically dehydrogenative C-H/P-H

1898 cross-coupling: effective synthesis of phosphonated quinoxalin-2(1H)-ones and

1899 xanthenes. Green Chem 2019;21:4412-21. [DOI: 10.1039/C9GC01474H]

79 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1900 108. Rawat D, Kumar R, Subbarayappa A. Visible-light induced phosphonation of

1901 quinoxalines and quinoxalin-2(1H)-ones under aerobic metal-free conditions. Green

1902 Chem 2020;22:6170-5. [DOI: 10.1039/D0GC02168G]

1903 109. Singsardar M, Dey A, Sarkar R, Hajra A. Visible-Light-Induced

1904 Organophotoredox-Catalyzed Phosphonylation of 2 H-Indazoles with

1905 Diphenylphosphine Oxide. J Org Chem 2018;83:12694-701. [DOI:

1906 10.1021/acs.joc.8b02019]

1907 110. Gao F, Sun K, Chen XL, et al. Visible-Light-Induced Phosphorylation of

1908 Imidazo-Fused Heterocycles under Metal-Free Conditions. J Org Chem

1909 2020;85:14744-52. [DOI: 10.1021/acs.orglett.0c01709]

1910 111. Lei T, Liang G, Cheng YY, Chen B, Tung CH, Wu LZ. Cobaloxime Catalysis for

1911 Enamine Phosphorylation with Hydrogen Evolution. Org Lett 2020;22:5385-9. [DOI:

1912 10.1021/acs.orglett.0c01709]

1913 112. Li L, Huang W, Chen L, Dong J, Ma X, Peng Y. Silver-Catalyzed Oxidative C()-P

1914 Bond Formation through C-C and P-H Bond Cleavage. Angew Chem Int Ed Engl

1915 2017;56:10539-44. [DOI: https://doi.org/10.1002/anie.201704910]

1916 113. Ou Y, Huang Y, Liu Y, et al. Iron‐Catalyzed and Air‐Mediated C(sp3)-H

1917 Phosphorylation of 1,3‐Dicarbonyl Compounds Involving C-C Bond Cleavage. Adv

1918 Synth Catal 2020;362:5783-7. [DOI: https://doi.org/10.1002/adsc.202001020]

1919 114. Zhao X, Huang M, Li Y, Zhang J, Kim JK, Wu Y. Stepwise photosensitized

1920 C(sp3)-C(CO) bond cleavage and C-P bond formation of 1,3-dicarbonyls with

1921 arylphosphine oxides. Org Chem Front 2019;6:1433-7. [DOI: 10.1039/C9QO00075E]

1922 115. Ou Y, Huang Y, He Z, et al. A phosphoryl radical-initiated Atherton-Todd-type

1923 reaction under open air. Chem Commun (Camb) 2020;56:1357-60. [DOI:

1924 10.1039/C9CC09407E]

1925 116. Zhang H, Zhan Z, Lin Y, et al. Visible light photoredox catalyzed thiophosphate

1926 synthesis using methylene blue as a promoter. Org Chem Front 2018;5:1416-22. [DOI:

1927 10.1039/C7QO01082F]

80 Page X of 6 Liu et al. Chem Synth Year;Volume:Number│http://dx.doi.org/10.20517/cs.2021.xx

1928 117. Dong X, Wang R, Jin W, Liu C. Electrochemical Oxidative Dehydrogenative

1929 Phosphorylation of N-Heterocycles with P(O)-H Compounds in Imidazolium-Based

1930 Ionic Liquid. Org Lett 2020;22:3062-6. [DOI: 10.1021/acs.orglett.0c00814] 1931

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