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Copper-Catalyzed Cascade Addition/Cyclization: Highly Efficient Access to Phosphonylated Quinoline2,4(1H,3H)-diones Ya-Min Li,* Shi-Sheng Wang, Fuchao Yu, Yuehai Shen, Kwen-Jen Chang
DOI: 10.1039/x0xx00000x www.rsc.org/
A novel and facile Cu-catalyzed addition/cyclization cascade of o-cyanoarylacrylamide was developed. The process exhibits significant functional group tolerance, and provides an efficient and straightforward pathway for the synthesis of various phosphonylated quinoline-2,4(1H,3H)-diones. Organophosphorus compounds can be found in a wide range of biochemistry, medicinal chemistry, photoelectric materials, catalysis and organic synthesis.1 In light of their importance, the development of efficient C − P bond-forming method for the construction of phosphorus compounds is still a research focus up to now. In general, C−P bond formation relies on several classic reactions,2 for example, electrophilic phosphor reagents such as R2P(O)Cl with carbon nucleophile,2a Michaelis–Arbuzov reaction,2b,2c and addition of phosphines to carbon–carbon multiple bonds via radical or ionic pathways.2d Alone with the rapid development of organometallic chemistry, transition-metal-catalyzed coupling reactions3 and alkene, alkyne functionalization4 were developed as powerful strategies for C–P bond formation. However, most studies in this field focused on classic one-bond-forming reactions, very few P-containing cascade reactions have been reported,4e–j which can offer more environmentally benign and atom-economical processes. Therefore, the development of new transition-metal-catalyzed cascade reactions to build the C–P bond is highly desirable. The nitrile group is widely used in synthetic organic chemistry. For example, addition reactions to nitriles provided great opportunities for the synthesis of ketones. This addition reaction can be classified into two major types depending on the mechanism. The reaction can be initiated by the insertion of nitrile group from metal nucleophile such as Grignard reagents5 and lithium reagents.6 Many reports showed that the insertion of nitrile groups was carried out by stoichiometric early transition metal complexes, such as titanium,7 zirconium,8 scandium,9 molybdenum10 and tungsten.11 In recent years, catalytic insertion of nitriles was also reported, and different late transition metal catalysts have been developed for this insertion
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including Pd(II),12 Rh(I)13 and Ni(II).14 Another type of this transformation is radical addition. In general, radical additions to polar nitrile groups are not efficient because highly unstable iminyl radicals are generated.15 Nonetheless, this radical addition might be successful if the unstable iminyl radical intermediate can be effectively trapped.16 A number of metal reagents were successfully employed for the radical addition of nitrile. However, most of them are the early transition metal complexes such as titanium16a-c, samarium16d,e and manganese.16f Herein, we describe a novel Cucatalyzed cascade addition/cyclization reaction, where the cyclization was accomplished by an intramolecular addition of the carbon radical to the nitrile (Scheme 1). This transformation provides an efficient protocol for the synthesis of valuable phosphonylated quinoline-2,4(1H,3H)-diones. Quinoline-2,4-dione derivatives are a highly valuable class of heterocyclic compounds with remarkable biological activities such as antiplatelet, antibiotics, and herbicidal activities.17 Therefore, the development of a sustainable and atom-economic method for the synthesis of quinoline-2,4-dione derivatives is in demand.
Scheme 1 Cu-catalyzed addition/cyclization cascade To begin our study, anthranilonitrile-derived N-(2-cyanophenyl)N-methylmethacrylamide (1a) and readily available diphenylphosphine oxide were selected as the model substrates for the optimization of reaction conditions. When the reaction was performed in the presence of a stoichiometric amount of CuCl in CH3CN at 100 °C, the reaction afforded the desired quinoline-2,4dione (2a) in 72% isolated yield (Table 1, entry 1). Encouraged by this result, the reaction conditions of this cascade were further
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optimized. However, when the loading of CuCl was decreased to 10 mol %, the corresponding product (2a) was obtained only in 21% yield (entry 2). Metal nitrates are commonly used as efficient additives in C−P bond-forming reactions.4f–j Indeed, in the present reaction, the addition of Mg(NO3)2·6H2O significantly improved the conversion of the starting material, and the yield increased to 84% (entry 3). Different Cu and Ag salts such as CuBr, CuI, Cu2O, CuO, CuCl2, CuBr2, Cu(OAc)2, Cu(acac)2, Ag2CO3 and AgNO3 were screened; CuBr2 gave the best yield (93%) of 2a (entries 4–13). The additive also exerted a significant influence on the reaction. When Cu(NO3)2·3H2O, Ce(NO3)3·6H2O, and Zr(NO3)4·5H2O were investigated as the additive, the yield decreased (entries 14–16). Furthermore, the loading of Mg(NO3)2·6H2O could be decreased to 0.3 equiv and still provided an excellent yield (entry 17). The reaction also occurred at a lower temperature (80 °C), albeit in a lower yield (entry 18). Finally, other solvents such as toluene, DMF, DMSO, and 1,4-dioxane were screened, and the results indicate that this reaction proceeded most efficiently in CH3CN (entry 17 vs. entries 19–22). Control tests showed that no reaction occurred in the absence of either CuBr2 (entry 23) or Mg(NO3)2.6H2O (entry 24).
Table 2 Substrate scope a,b
Table 1 Reaction conditions screeninga
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18c 19d 20e 21f 22g 23 24 a
catalyst (mol %) CuCl (100) CuCl (10) CuCl (10) CuBr (10) CuI (10) Cu2O (10) CuO (10) CuCl2 (10) CuBr2 (10) Cu(OAc)2 (10) Cu(acac)2 (10) Ag2CO3 (10) AgNO3 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10)
additive (equiv) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Cu(NO3)2.3H2O (0.5) Ce(NO3)3.6H2O (0.5) Zr(NO3)4.5H2O (0.5) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) -
yield (%) b c (%) 72 21 84 84 trace 69 73 67 93 73 76 43 82 31 64 24 94 81 48 56 51 67 0 0
Reaction conditions: 1a (0.30 mmol), HP(O)Ph 2 (0.60 mmol), catalyst,
and additive in solvent (3.0 mL) at 100 °C for 10 h under N 2 . c
d
yield. 80 °C. Toluene was used as the solvent.
e
b
Isolated
DMF was used as the
solvent. f DMSO was used as the solvent. g 1,4-Dioxane was used as the solvent.
2 | J. Name., 2012, 00, 1-3
a
Unless otherwise noted, all the reactions were carried out in the presence of
0.30 mmol of 1a–1v, HP(O)R32 (2.0 equiv), 10 mol % catalyst and 0.3 equiv Mg(NO3)2·6H2O in 3.0 mL CH3CN at 100 °C under N2. b Yield of the isolated product.
With the optimized reaction conditions (Table 1, entry 17), the substrate scope and limitations of the addition/cyclization cascade were investigated, and the results are summarized in Table 2. Initially, different protecting groups on the N atom were evaluated: N-(2-cyanophenyl)-N-acrylamides bearing methyl and benzyl protecting groups participated well in this transformation; however, the reactions of acetylated and unprotected substrates failed (2a–2c). Next, the effect of substituents at the N-aryl moiety was investigated (2d–2q). The electronic properties of the substituents had no significant influence on the efficiency of the reaction. Both electrondonating and -withdrawing substituents were tolerated in this cascade, and most of the substrates were successfully converted into the desired products in good to excellent yields. However, the steric
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Journal Name hindrance effect was obvious on the transformation reactivity. For example, N-(3-bromo-2-cyanophenyl)-N-methylmethacrylamide, bearing a Br atom at the ortho position of the nitrile group, afforded the corresponding product 2f in 38% yield, whereas the substrate containing a Br atom at the meta position of the nitrile group afforded the corresponding product 2j in 91% yield. Notably, halo functional groups such as Cl and Br were well tolerated in the reaction, thus offering opportunities for further modification at the halogenated positions. The substrates with two substituents on the benzonitrile moieties also reacted well with Ph2P(O)H (2p and 2q). Next, the effect of the substituents on olefins was evaluated. A series of α-substituted olefins bearing different functional groups such as benzyl, phenyl, ester, and phthalimide were compatible with the optimal conditions, affording the desired products 2r − 2u in moderate to good yields. Heterocyclic substrate pyridineacrylamide also underwent the reaction smoothly, affording product 2v in 91% yield. Unlike diphenylphosphine oxide, the reaction of diethyl phosphite failed under the standard conditions. However, the reaction proceeded when AgNO3 was used as the catalyst to afford 2w in 59% yield. It is worth noting that the reaction was also readily scaled up with similar efficiency. For instance, the reaction at the 6.0 mmol scale afforded the corresponding product 2a in 87% yield. (see the ESI†). In order to probe the possible mechanism of the cascade reaction, several radical-trapping experiments were carried out (Scheme 2). When the reactions were conducted in the presence of 1.5 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the radical scavenger, the reaction progress was remarkably suppressed, and only trace amounts of the desired products were detected, even after longer reaction times. The addition of 1,1-diphenylethylene led to a complete reaction, yielding the alkenyl diphenylphosphine oxide 3 in 19% yield. Furthermore, the reaction of diene 4 afforded cyclized product 5 under the optimized conditions. These results suggest that the transformation may involve a radical process.
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Scheme 3 Possible mechanism of addition/cyclization cascade In summary, a novel Cu-catalyzed cascade addition/cyclization reaction was developed, where the cyclization was accomplished by an intramolecular addition of the carbon radical to the nitrile. This radical mediated cascade reaction is not only efficient and general, but also functional group compatible. This protocol provides a practical synthetic method for the construction of phosphonylated quinoline2,4(1H,3H)-diones. Further investigation of the reaction mechanism and synthetic applications are underway. Financial support from the National Natural Science Foundation of China (No. 21402071) and the Foundation of Kunming University of Science and Technology (No. KKSY201426046) is greatly appreciated.
Notes and references Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, P. R. China. E-mail: [email protected]. †
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. Electronic Supplementary Information (ESI) available: Experimental procedures, characterization of new compounds, copies of 1 H,
13
C,
31
P
19
and F NMR spectra. See DOI: 10.1039/c000000x/ 1
Scheme 2 Radical-trapping experiments
(a) D. T. Kolio, Chemistry and Application of H-Phosphonates, Elsevier Science, Amsterdam, 2006; (b) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447-5674; (c) A. George
The detailed reaction mechanism remains to be clarified. However, according to the experimental results and previous reports,3g–k,8d–f a plausible pathway is proposed (Scheme 3). First, diphenylphosphine oxide is oxidized by copper salt to generate phosphonyl radical A and a low valent copper species. After the low copper species
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Copper-Catalyzed Cascade Addition/Cyclization: Highly Efficient Access to Phosphonylated Quinoline2,4(1H,3H)-diones Ya-Min Li,* Shi-Sheng Wang, Fuchao Yu, Yuehai Shen, Kwen-Jen Chang
DOI: 10.1039/x0xx00000x www.rsc.org/
A novel and facile Cu-catalyzed addition/cyclization cascade of o-cyanoarylacrylamide was developed. The process exhibits significant functional group tolerance, and provides an efficient and straightforward pathway for the synthesis of various phosphonylated quinoline-2,4(1H,3H)-diones. Organophosphorus compounds can be found in a wide range of biochemistry, medicinal chemistry, photoelectric materials, catalysis and organic synthesis.1 In light of their importance, the development of efficient C − P bond-forming method for the construction of phosphorus compounds is still a research focus up to now. In general, C−P bond formation relies on several classic reactions,2 for example, electrophilic phosphor reagents such as R2P(O)Cl with carbon nucleophile,2a Michaelis–Arbuzov reaction,2b,2c and addition of phosphines to carbon–carbon multiple bonds via radical or ionic pathways.2d Alone with the rapid development of organometallic chemistry, transition-metal-catalyzed coupling reactions3 and alkene, alkyne functionalization4 were developed as powerful strategies for C–P bond formation. However, most studies in this field focused on classic one-bond-forming reactions, very few P-containing cascade reactions have been reported,4e–j which can offer more environmentally benign and atom-economical processes. Therefore, the development of new transition-metal-catalyzed cascade reactions to build the C–P bond is highly desirable. The nitrile group is widely used in synthetic organic chemistry. For example, addition reactions to nitriles provided great opportunities for the synthesis of ketones. This addition reaction can be classified into two major types depending on the mechanism. The reaction can be initiated by the insertion of nitrile group from metal nucleophile such as Grignard reagents5 and lithium reagents.6 Many reports showed that the insertion of nitrile groups was carried out by stoichiometric early transition metal complexes, such as titanium,7 zirconium,8 scandium,9 molybdenum10 and tungsten.11 In recent years, catalytic insertion of nitriles was also reported, and different late transition metal catalysts have been developed for this insertion
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including Pd(II),12 Rh(I)13 and Ni(II).14 Another type of this transformation is radical addition. In general, radical additions to polar nitrile groups are not efficient because highly unstable iminyl radicals are generated.15 Nonetheless, this radical addition might be successful if the unstable iminyl radical intermediate can be effectively trapped.16 A number of metal reagents were successfully employed for the radical addition of nitrile. However, most of them are the early transition metal complexes such as titanium16a-c, samarium16d,e and manganese.16f Herein, we describe a novel Cucatalyzed cascade addition/cyclization reaction, where the cyclization was accomplished by an intramolecular addition of the carbon radical to the nitrile (Scheme 1). This transformation provides an efficient protocol for the synthesis of valuable phosphonylated quinoline-2,4(1H,3H)-diones. Quinoline-2,4-dione derivatives are a highly valuable class of heterocyclic compounds with remarkable biological activities such as antiplatelet, antibiotics, and herbicidal activities.17 Therefore, the development of a sustainable and atom-economic method for the synthesis of quinoline-2,4-dione derivatives is in demand.
Scheme 1 Cu-catalyzed addition/cyclization cascade To begin our study, anthranilonitrile-derived N-(2-cyanophenyl)N-methylmethacrylamide (1a) and readily available diphenylphosphine oxide were selected as the model substrates for the optimization of reaction conditions. When the reaction was performed in the presence of a stoichiometric amount of CuCl in CH3CN at 100 °C, the reaction afforded the desired quinoline-2,4dione (2a) in 72% isolated yield (Table 1, entry 1). Encouraged by this result, the reaction conditions of this cascade were further
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optimized. However, when the loading of CuCl was decreased to 10 mol %, the corresponding product (2a) was obtained only in 21% yield (entry 2). Metal nitrates are commonly used as efficient additives in C−P bond-forming reactions.4f–j Indeed, in the present reaction, the addition of Mg(NO3)2·6H2O significantly improved the conversion of the starting material, and the yield increased to 84% (entry 3). Different Cu and Ag salts such as CuBr, CuI, Cu2O, CuO, CuCl2, CuBr2, Cu(OAc)2, Cu(acac)2, Ag2CO3 and AgNO3 were screened; CuBr2 gave the best yield (93%) of 2a (entries 4–13). The additive also exerted a significant influence on the reaction. When Cu(NO3)2·3H2O, Ce(NO3)3·6H2O, and Zr(NO3)4·5H2O were investigated as the additive, the yield decreased (entries 14–16). Furthermore, the loading of Mg(NO3)2·6H2O could be decreased to 0.3 equiv and still provided an excellent yield (entry 17). The reaction also occurred at a lower temperature (80 °C), albeit in a lower yield (entry 18). Finally, other solvents such as toluene, DMF, DMSO, and 1,4-dioxane were screened, and the results indicate that this reaction proceeded most efficiently in CH3CN (entry 17 vs. entries 19–22). Control tests showed that no reaction occurred in the absence of either CuBr2 (entry 23) or Mg(NO3)2.6H2O (entry 24).
Table 2 Substrate scope a,b
Table 1 Reaction conditions screeninga
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18c 19d 20e 21f 22g 23 24 a
catalyst (mol %) CuCl (100) CuCl (10) CuCl (10) CuBr (10) CuI (10) Cu2O (10) CuO (10) CuCl2 (10) CuBr2 (10) Cu(OAc)2 (10) Cu(acac)2 (10) Ag2CO3 (10) AgNO3 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10) CuBr2 (10)
additive (equiv) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Mg(NO3)2.6H2O (0.5) Cu(NO3)2.3H2O (0.5) Ce(NO3)3.6H2O (0.5) Zr(NO3)4.5H2O (0.5) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) Mg(NO3)2.6H2O (0.3) -
yield (%) b c (%) 72 21 84 84 trace 69 73 67 93 73 76 43 82 31 64 24 94 81 48 56 51 67 0 0
Reaction conditions: 1a (0.30 mmol), HP(O)Ph 2 (0.60 mmol), catalyst,
and additive in solvent (3.0 mL) at 100 °C for 10 h under N 2 . c
d
yield. 80 °C. Toluene was used as the solvent.
e
b
Isolated
DMF was used as the
solvent. f DMSO was used as the solvent. g 1,4-Dioxane was used as the solvent.
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a
Unless otherwise noted, all the reactions were carried out in the presence of
0.30 mmol of 1a–1v, HP(O)R32 (2.0 equiv), 10 mol % catalyst and 0.3 equiv Mg(NO3)2·6H2O in 3.0 mL CH3CN at 100 °C under N2. b Yield of the isolated product.
With the optimized reaction conditions (Table 1, entry 17), the substrate scope and limitations of the addition/cyclization cascade were investigated, and the results are summarized in Table 2. Initially, different protecting groups on the N atom were evaluated: N-(2-cyanophenyl)-N-acrylamides bearing methyl and benzyl protecting groups participated well in this transformation; however, the reactions of acetylated and unprotected substrates failed (2a–2c). Next, the effect of substituents at the N-aryl moiety was investigated (2d–2q). The electronic properties of the substituents had no significant influence on the efficiency of the reaction. Both electrondonating and -withdrawing substituents were tolerated in this cascade, and most of the substrates were successfully converted into the desired products in good to excellent yields. However, the steric
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Journal Name hindrance effect was obvious on the transformation reactivity. For example, N-(3-bromo-2-cyanophenyl)-N-methylmethacrylamide, bearing a Br atom at the ortho position of the nitrile group, afforded the corresponding product 2f in 38% yield, whereas the substrate containing a Br atom at the meta position of the nitrile group afforded the corresponding product 2j in 91% yield. Notably, halo functional groups such as Cl and Br were well tolerated in the reaction, thus offering opportunities for further modification at the halogenated positions. The substrates with two substituents on the benzonitrile moieties also reacted well with Ph2P(O)H (2p and 2q). Next, the effect of the substituents on olefins was evaluated. A series of α-substituted olefins bearing different functional groups such as benzyl, phenyl, ester, and phthalimide were compatible with the optimal conditions, affording the desired products 2r − 2u in moderate to good yields. Heterocyclic substrate pyridineacrylamide also underwent the reaction smoothly, affording product 2v in 91% yield. Unlike diphenylphosphine oxide, the reaction of diethyl phosphite failed under the standard conditions. However, the reaction proceeded when AgNO3 was used as the catalyst to afford 2w in 59% yield. It is worth noting that the reaction was also readily scaled up with similar efficiency. For instance, the reaction at the 6.0 mmol scale afforded the corresponding product 2a in 87% yield. (see the ESI†). In order to probe the possible mechanism of the cascade reaction, several radical-trapping experiments were carried out (Scheme 2). When the reactions were conducted in the presence of 1.5 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the radical scavenger, the reaction progress was remarkably suppressed, and only trace amounts of the desired products were detected, even after longer reaction times. The addition of 1,1-diphenylethylene led to a complete reaction, yielding the alkenyl diphenylphosphine oxide 3 in 19% yield. Furthermore, the reaction of diene 4 afforded cyclized product 5 under the optimized conditions. These results suggest that the transformation may involve a radical process.
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Scheme 3 Possible mechanism of addition/cyclization cascade In summary, a novel Cu-catalyzed cascade addition/cyclization reaction was developed, where the cyclization was accomplished by an intramolecular addition of the carbon radical to the nitrile. This radical mediated cascade reaction is not only efficient and general, but also functional group compatible. This protocol provides a practical synthetic method for the construction of phosphonylated quinoline2,4(1H,3H)-diones. Further investigation of the reaction mechanism and synthetic applications are underway. Financial support from the National Natural Science Foundation of China (No. 21402071) and the Foundation of Kunming University of Science and Technology (No. KKSY201426046) is greatly appreciated.
Notes and references Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, P. R. China. E-mail: [email protected]. †
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. Electronic Supplementary Information (ESI) available: Experimental procedures, characterization of new compounds, copies of 1 H,
13
C,
31
P
19
and F NMR spectra. See DOI: 10.1039/c000000x/ 1
Scheme 2 Radical-trapping experiments
(a) D. T. Kolio, Chemistry and Application of H-Phosphonates, Elsevier Science, Amsterdam, 2006; (b) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447-5674; (c) A. George
The detailed reaction mechanism remains to be clarified. However, according to the experimental results and previous reports,3g–k,8d–f a plausible pathway is proposed (Scheme 3). First, diphenylphosphine oxide is oxidized by copper salt to generate phosphonyl radical A and a low valent copper species. After the low copper species
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