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Cite this: DOI: 10.1039/c4ob01739k Received 14th August 2014, Accepted 9th September 2014 DOI: 10.1039/c4ob01739k
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Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols: synthesis of β-aryl-γ-ketophosphonates† Xia Mi,a Chenyang Wang,a Mengmeng Huang,*a Yusheng Wu*a,b and Yangjie Wu*a
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Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols is achieved. A series of γ-ketophosphonates with different substituents were readily obtained. The mechanistic study indicated that the reaction was initiated by the addition of P-radicals, which sequentially undergo 1,2-migration of an aryl group to form C(Ar)– C(sp3) bonds.
γ-Ketophosphonates and their corresponding phosphonic acids have been established as useful tools in both synthetic1 and biological chemistry.2–6 For example, γ-ketophosphonates have been successfully employed as herbicides and fungicides (A and B),3 antihypertensive agents (C),4 and inhibitors of matrix-metalloproteinase (MMP-2) (D) (Fig. 1).5 The γ-ketophosphonic acid (E) is an inhibitor of 5-alanine levulinic acid dehydratase.6 Although some available methods7 have been developed for the preparation of γ-ketophosphonates, the conjugate addition of phosphonic acid derivatives or trialkyl phos-
Fig. 1
phites to α,β-unsaturated carbonyls is the most commonly employed approach.8 However, some problems exist with these procedures, such as poor selectivity, harsh conditions, multi steps, complicated starting materials or limited substrate scope. The addition of P-radicals to alkenes is a well-recognized and powerful tool for C(sp3)–P bond formation.9 Peroxides,10 azo compounds,11 R3B/O2,12 Ag/K2S2O8,13 Mn salts,14 etc. have been long known to generate phosphorus-centered radicals. Recently, cheap and nontoxic silver salts have attracted more and more attention from the point of view of economy and environment-friendliness and have been successfully utilized in the radical phosphorylation of alkenes.15 On the other hand, allylic alcohols have gained much attention in the synthesis of natural products because they can undergo 1,2migration of a C–C or C–H bond to generate a carbonyl group.16 Recently, Tu,17 Sodeoka18 and Wu19 groups independently reported the preparation of β-trifluoromethyl ketones from allylic alcohols, possible via intermediate A [eqn (1)]. Inspired by these results and based on our research interest,15d,20 we envisaged that α,α-diaryl allylic alcohols could be used as P-radical acceptors and would lead to the analogous intermediate B [eqn (2)] to provide β-aryl-γ-ketophosphonates. To the best of our knowledge, methods for the synthesis of this class of compounds are extremely limited.21 The concomitant formation of C(sp3)–P and C(sp3)–C(Ar) bonds in one molecule, the carbonphosphonation of alkenes, should serve as an ideal entry to β-aryl-γ-ketophosphonates. It is noteworthy that the radical
Examples of biologically significant γ-ketophosphonates.
ð1Þ a College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China. E-mail: [email protected], [email protected], [email protected] b Tetranov Biopharm, LLC., 75 Daxue Road, Zhengzhou 450052, P. R. China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob01739k
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phosphinylation of α,α-diaryl allylic alcohols has been developed with stoichiometric amounts of silver salts.22 Herein, we report a silver-catalyzed carbonphosphonation of alkenes via 1,2-migration of α,α-diaryl allylic alcohols to prepare β-arylγ-ketophosphonates. Our previous study15d showed that the phosphonyl radicals could be easily generated from (RO)2P(O)H with a catalytic amount of silver salts. Based on this achievement, the model reaction of α,α-diphenyl allylic alcohol (1a) and diethyl H-phosphonate (2a) was carried out in the presence of AgNO3 (5 mol%) without any additive in CH3CN at 100 °C. Unfortunately, the desired product was not detected (Table 1, entry 1). When 0.5 equiv. of Mg(NO3)2·6H2O and 4 Å MS were employed as additives, the target product 3a was isolated in 33% yield (Table 1, entry 2). The product yield of 3a could reach 45% using 0.3 equiv. of Mg(NO3)2·6H2O (Table 1, entries 2–4). In an attempt to further increase the yield of this reaction, the loading of diethyl H-phosphonate (2a) was increased to 3 equiv. (Table 1, entry 5). The nitrate ion is essential to the reaction efficiency. Several other nitrates were tested, and 0.3 equiv. of Mg(NO3)2·6H2O could provide the highest yield of 62% (Table 1, entries 5–9). Increasing the amount of AgNO3 did not improve the yield further (Table 1, entries 10 and 11). Different silver catalysts were re-evaluated and proved to be less effective compared with AgNO3 (Table 1, entries 12 and 13). Other solvents, such as THF, DMF, toluene and dioxane,
Table 1
were applied instead of CH3CN, but no better results were obtained (Table 1, entries 14–17). Under these conditions, decreasing or increasing the reaction temperature led to lower yields (Table 1, entries 18 and 19). Without the silver catalyst, Mg(NO3)2·6H2O alone could not promote this reaction (Table 1, entry 20). With the optimized reaction conditions, the scope of the rearrangement reactions was explored with various α,α-diaryl allylic alcohols 1 (Table 2). The reaction could proceed well using dimethyl and diethyl H-phosphonates to form the corresponding products in moderate to good yields (3a, 3b). Subsequently, various symmetrical α,α-diaryl allylic alcohols Table 2 Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols via 1,2-migration of an aryl groupa,b
Optimization of conditionsa
Entry
Cat.
Additive
Solvent
Yieldb (%)
1c 2c,d 3c 4c,e 5 6 7 8 9 10 f 11g 12 13 14 15 16 17 18h 19i 20
AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 Ag2O Ag2CO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 —
— Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Cd(NO3)2·4H2O Ni(NO3)2·6H2O Co(NO3)2·6H2O NaNO3 Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF DMF Toluene Dioxane CH3CN CH3CN CH3CN
nr 33 45 35 62 39 55 35 23 40 39 46 57 55 Trace 29 36 44 36 Trace
Reaction conditions: 1a (0.5 mmol), 2a (3 equiv.), catalyst (5 mol%), additive (30 mol%), 4 Å MS (100 mg), solvent (3.0 mL), 100 °C (oil bath), N2 atmosphere for 18 h. b Isolated yields. c 2 equiv. HP(O)(OEt)2. d 50 mol% Mg(NO3)2·6H2O. e 20 mol% Mg(NO3)2·6H2O. f 10 mol% AgNO3. g 20 mol% AgNO3. h 110 °C (oil bath). i 90 °C (oil bath). a
Org. Biomol. Chem.
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), AgNO3 (5 mol%), Mg(NO3)2·6H2O (30 mol%), 4 Å MS (100 mg), CH3CN (3.0 mL), 100 °C (oil bath), N2 atmosphere for 18 h. b Isolated yields. c The total yields of two isomers. d The ratio was determined by 13C NMR analysis. e The ratio was determined by 1H NMR analysis. f The ratio was determined by 31P NMR analysis. a
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with para and meta substituents on the aryl ring were evaluated (3c–3m). It was found that diethyl H-phosphonates showed better reactivity than dimethyl H-phosphonates for all tested α,α-diaryl allylic alcohols. The p-methoxyphenyl-substituted substrate displayed poor reactivity, and no desired product was detected (3c). Comparing the α,α-diaryl allylic alcohols associated with electron-donating groups, the reaction of α,α-diaryl allylic alcohols substituted with electronwithdrawing groups gave better results, except for 3k. The substrate containing a strong electron-withdrawing group (CF3) on the meta position of aryl groups also proceeded smoothly, giving the target products in 63% and 53% yields respectively (3l, 3m). In order to determine which aryl group was being migrated preferentially, we turned our attention to unsymmetrical α,α-diaryl allylic alcohols. Gratifyingly, all rearrangements proceeded chemoselectively. For the substrate with a para substituent on the aryl ring, the more electron-deficient aryl group migrated preferentially to give the major product 3n and the minor product 3n′ in 67% yield with a ratio of 2.5 : 1. Compound 3o which was formed from the migration of a more electron-deficient CF3-substituted aryl ring was detected as the major product. In addition, ortho-substituted aryl rings migrated less effectively than para-substituted aryl groups (3p and 3p′). To certify the mechanism of this transformation, we performed chemical trapping of radicals. The reaction was suppressed in the presence of 1.0 equiv. of radical scavengers (TEMPO or BHT), and no target product was detected (Scheme 1). To our delight, an adduct of BHT and diethyl H-phosphonate was detected by ESI-MS, thus providing straightforward evidence of a phosphonyl radical formation (see ESI† for details). On the basis of the results obtained above and previous reports,15 a plausible mechanism was proposed as shown in Scheme 2. Firstly, a phosphonyl radical A, formed from diethyl H-phosphonate 2a and AgNO3, reacts with 1a to generate radical B. Subsequent migration of the electron-deficient aryl group via spiro[2,5]octadienyl radical C produces intermediate D. Single-electron transfer (SET) from D to silver(I) would release the desired product 3a with concomitant loss of a proton. In the presence of Mg(NO3)2, the silver(0) was oxidized to silver(I). In summary, a silver-catalyzed carbonphosphonation reaction of α,α-diaryl allylic alcohols with H-phosphonates is developed. The tandem reaction is valuable, as a series of γ-ketophosphonates were readily obtained using catalytic
Scheme 1
Radical-trapping experiments.
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Scheme 2
Possible mechanism.
amounts of silver salts. This method enables the construction of both C(sp3)–P and C(sp3)–C(Ar) bonds simultaneously. Further studies are underway to investigate the applications of these transformations. This work was supported by the National Natural Science Foundation (NSF) of China (no. 21172200 and 21302172).
Notes and references 1 (a) D. R. Marshall, P. J. Thomas and C. J. M. Stirling, J. Chem. Soc., Perkin Trans. 2, 1977, 1898; (b) C. Meier and W. H. G. Laux, Tetrahedron, 1996, 52, 589; (c) R. D. Norcross, P. Matt, H. C. Kolb and D. Bellus, Tetrahedron, 1997, 53, 10289; (d) D. Appleton, A. B. Duguid, S. K. Lee, Y. J. Ha, H. J. Ha and F. J. Leeper, J. Chem. Soc., Perkin Trans. 1, 1998, 89; (e) P. Page, C. Blonski and J. Perie, Bioorg. Med. Chem., 1999, 7, 1403; (f ) H. Krawczyk, K. Wasek, J. Kedzia, J. Wojciechowski and W. M. Wolf, Org. Biomol. Chem., 2008, 6, 308. 2 (a) M. Szelke, D. M. Evans and D. M. Jones, PCT Int. Appl., WO 94-GB1887 940831, 1994; Chem. Abstr., 1995, 123, 257409; (b) Y. Isomura, S. Sakamoto and T. Abe, Japan Patent Appl., JP 87-271433 871026, 1987; Chem. Abstr., 1989, 111, 174388. 3 I. Mori, G. Iwasaki, A. Scheidegger, S. Koizumi, K. Hayakawa and J. Mano, PCT Int. Appl., WO 92-JP485 920417, 1992; Chem. Abstr., 1993, 118, 124547. 4 D. S. Karanewsky and T. Dejneka, Eur. Pat. Appl., EP 87-104477 870326, 1987; D. S. Karanewsky and T. Dejneka, US Pat. Appl., US 844635, 1986; Chem. Abstr., 1988, 109, 129685. 5 H. C. E. Kluender, G. H. H. H. Benz, D. R. Brittelli, W. H. Bullock, K. J. Combs, B. R. Dixon, S. Schneider, J. E. Wood, M. C. Vanzandt, D. J. Wolanin and S. M. Wilhelm, US Pat. Appl., US 95-539409 951106, 1995; Chem. Abstr., 1998, 129, 161412.
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6 (a) A. A. Patchett, N. A. Thornberry, H. G. Bull, D. Taub and K. E. Wilson, BCPC Monogr., 1989, 42, 109, (Prospects Amino Acid Biosynth. Inhib. Crop Prot. Pharm. Chem.); (b) P. K. Chakravarty, W. J. Greenlee, W. H. Parson, A. A. Patchett, P. Combs, A. Roth, R. D. Busch and T. N. Mellin, J. Med. Chem., 1989, 32, 1886. 7 (a) P. Savignac, A. Breque, F. Mathey, J.-M. Varlet and N. Collignon, Synth. Commun., 1979, 9, 287; (b) N.-S. Li, S. Yu and G. W. Kabalka, Organometallics, 1999, 18, 1811; (c) A. C. Verbicky and C. K. Zercher, J. Org. Chem., 2000, 65, 5615; (d) G. Pallikonda, M. Chakravarty and M. K. Sahoo, Org. Biomol. Chem., 2014, 12, 7140. 8 (a) G. H. Birum and G. A. Richardson, US Patent 3 113 139, 1963; Chem. Abstr., 1964, 60, 5551d; (b) D. Liotta, U. Sunay and S. Ginsberg, J. Org. Chem., 1982, 47, 2229; (c) D. Gorenstein and F. H. Westheimer, J. Am. Chem. Soc., 1970, 92, 634; (d) F. Ramirez, Synthesis, 1974, 90; (e) C. K. McClure and K.-Y. Jung, J. Org. Chem., 1991, 56, 2326; (f ) C. K. McClure and C. W. Grote, Tetrahedron Lett., 1991, 32, 5313. 9 Reviews for the addition of P-radicals to alkenes: (a) D. Leca, L. Fensterbank, E. Lacote and M. Malacria, Chem. Soc. Rev., 2005, 34, 858; (b) J.-L. Montchamp, Acc. Chem. Res., 2014, 47, 77. For example, see: (c) T. F. Herpin, W. B. Motherwell, B. P. Roberts, S. Roland and J.-M. Weibel, Tetrahedron, 1997, 53, 15085; (d) S. Deprele and J.-L. Montchamp, J. Org. Chem., 2001, 66, 6745; (e) O. Dubert, A. Gautier, E. Condamine and S. R. Piettre, Org. Lett., 2002, 4, 359; (f ) M. Jessop, A. F. Parsons, A. Routledge and D. Irvine, Tetrahedron Lett., 2003, 44, 479; (g) C. Lamarque, F. Beaufils, F. D. K. Schenkand and P. Renauda, Adv. Synth. Catal., 2011, 353, 1353; (h) C.-M. Jessop, A.-F. Parsons, A. Routledge and D. J. Irvine, Eur. J. Org. Chem., 2006, 1547; (i) V. Srinivas, E. Balaraman, K. V. Sajna and K. C. Kumara Swamy, Eur. J. Org. Chem., 2011, 4222. 10 For examples of peroxides as initiators: (a) E. F. Jason and E. K. Fields, J. Org. Chem., 1962, 27, 1402; (b) T. F. Herpin, W. B. Motherwell, B. P. Roberts, S. Roland and J.-M. Weibel, Tetrahedron, 1997, 53, 15085; (c) S. Deprele and J.-L. Montchamp, J. Org. Chem., 2001, 66, 6745; (d) J. M. Barks, B. C. Gilbert, A. F. Parsons and B. Upeandran, Tetrahedron Lett., 2001, 42, 3137; (e) O. Dubert, A. Gautier, E. Condamine and S. R. Piettre, Org. Lett., 2002, 4, 359; (f) C. Lamarque, F. Beaufils, F. Denes, K. Schenk and P. Renaud, Adv. Synth. Catal., 2011, 353, 1353. 11 For examples of azo compounds as initiators: (a) A. Robertson, C. Bradaric, C.-S. Frampton, J. McNulty and A. Capretta, Tetrahedron Lett., 2001, 42, 2609; (b) C.-M. Jessop, A. F. Parsons, A. Routledge and D. Irvine, Tetrahedron Lett., 2003, 44, 479; (c) T. Wada, A. Kondoh, H. Yorimitsu and K. Oshima, Org. Lett., 2008, 10, 1155. 12 For examples of R3B/O2 as initiators: (a) P. Rey, J. Taillades, J.-C. Rossia and G. Gros, Tetrahedron Lett., 2003, 44, 6169;
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13
14
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17 18 19 20 21 22
(b) S. Gouanlt-Bironneau, S. Deprele, A. Sutor and J.-L. Montchamp, Org. Lett., 2005, 7, 5909. For examples of Ag/K2S2O8 as initiators: (a) F. Effenberger and H. Kottmann, Tetrahedron, 1985, 41, 4171; (b) C.-B. Xiang, Y.-J. Bian, X.-R. Mao and Z.-Z. Huang, J. Org. Chem., 2012, 77, 7706; (c) X. Mao, X. Ma, S. Zhang, H. Hu, C. Zhu and Y. Cheng, Eur. J. Org. Chem., 2013, 4245. For examples of Mn salts as initiators: (a) O. Tayama, A. Nakano, T. Iwahama, S. Sakaguchi and Y. Ishii, J. Org. Chem., 2004, 69, 5494; (b) T. Kagayama, A. Nakano, S. Sakaguchi and Y. Ishii, Org. Lett., 2006, 8, 407; (c) X. Mu, J. Zou, Q. Qian and W. Zhang, Org. Lett., 2006, 8, 5291; (d) X. Pan, J. Zou and W. Zhang, Mol. Diversity, 2009, 13, 421; (e) X. Pan, J. Zou, G. Zhang and W. Zhang, Chem. Commun., 2010, 46, 1721; (f ) W. Xu, J. Zou and W. Zhang, Tetrahedron, 2010, 51, 2639; (g) X. Pan, L. Wang, J. Zou and W. Zhang, Chem. Commun., 2011, 47, 7875; (h) G. Wang, C. Wang and J. Zou, J. Org. Chem., 2011, 76, 6088; (i) W. B. Sun, Y. F. Ji, X. Pan, S. Zhou, J. Zou and W. Zhang, Synthesis, 2013, 1529; ( j) F. Zhang, L. Wang, C. Zhang and Y. Zhao, Chem. Commun., 2014, 50, 2046; (k) H. C. Fisher, O. Berger, F. Gelat and J. L. Montchamp, Adv. Synth. Catal., 2014, 356, 1199. For examples of Ag-mediated radical phosphorylation of alkenes: (a) W. Wei and J.-X. Ji, Angew. Chem., Int. Ed., 2011, 50, 9097; (b) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian and S.-D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; (c) C. Zhang, Z. Li, L. Zhu, L. Yu, Z. Wang and C. Li, J. Am. Chem. Soc., 2013, 135, 14082; (d) X. Mi, C. Wang, M. Huang, J. Zhang, Y.-S. Wu and Y.-J. Wu, Org. Lett., 2014, 16, 3356. (a) B.-M. Wang and Y.-Q. Tu, Acc. Chem. Res., 2011, 44, 1207; (b) Z.-L. Song, C.-A. Fan and Y.-Q. Tu, Chem. Rev., 2011, 111, 7523; (c) E. Zhang, Y.-Q. Tu, C.-A. Fan, X. Zhao, Y.-J. Jiang and S.-Y. Zhang, Org. Lett., 2008, 10, 4943; (d) Q.-W. Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu and Z.-M. Chen, Angew. Chem., Int. Ed., 2009, 48, 8572; (e) Z.-M. Chen, Q.-W. Zhang, Z.-H. Chen, H. Li, Y.-Q. Tu, F.-M. Zhang and J.-M. Tian, J. Am. Chem. Soc., 2011, 133, 8818; (f ) H. Li, F.-M. Zhang, Y.-Q. Tu, Q.-W. Zhang, Z.-M. Chen, Z.-H. Chen and J. Li, Chem. Sci., 2011, 2, 1839; (g) H. Zheng, S. Ghanbari, S. Nakamura and D. G. Hall, Angew. Chem., Int. Ed., 2012, 51, 6187. Z.-M. Chen, W. Bai, S.-H. Wang, B.-M. Yang, Y.-Q. Tu and F.-M. Zhang, Angew. Chem., Int. Ed., 2013, 52, 9781. H. Egami, R. Shimizu, Y. Usui and M. Sodeoka, Chem. Commun., 2013, 49, 7346. X. Liu, F. Xiong, X. Huang, L. Xu, P. Li and X. Wu, Angew. Chem., Int. Ed., 2013, 52, 6962. X. Mi, M. Huang, J. Zhang, C. Wang and Y.-J. Wu, Org. Lett., 2013, 15, 6266. S. H. Kim, S. H. Kim, H. J. Kim and N. J. Kim, Bull. Korean Chem. Soc., 2013, 34, 989. X.-Q. Chu, Y. Zi, H. Meng, X.-P. Xu and S.-J. Ji, Chem. Commun., 2014, 50, 7642.
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Cite this: DOI: 10.1039/c4ob01739k Received 14th August 2014, Accepted 9th September 2014 DOI: 10.1039/c4ob01739k
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Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols: synthesis of β-aryl-γ-ketophosphonates† Xia Mi,a Chenyang Wang,a Mengmeng Huang,*a Yusheng Wu*a,b and Yangjie Wu*a
www.rsc.org/obc
Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols is achieved. A series of γ-ketophosphonates with different substituents were readily obtained. The mechanistic study indicated that the reaction was initiated by the addition of P-radicals, which sequentially undergo 1,2-migration of an aryl group to form C(Ar)– C(sp3) bonds.
γ-Ketophosphonates and their corresponding phosphonic acids have been established as useful tools in both synthetic1 and biological chemistry.2–6 For example, γ-ketophosphonates have been successfully employed as herbicides and fungicides (A and B),3 antihypertensive agents (C),4 and inhibitors of matrix-metalloproteinase (MMP-2) (D) (Fig. 1).5 The γ-ketophosphonic acid (E) is an inhibitor of 5-alanine levulinic acid dehydratase.6 Although some available methods7 have been developed for the preparation of γ-ketophosphonates, the conjugate addition of phosphonic acid derivatives or trialkyl phos-
Fig. 1
phites to α,β-unsaturated carbonyls is the most commonly employed approach.8 However, some problems exist with these procedures, such as poor selectivity, harsh conditions, multi steps, complicated starting materials or limited substrate scope. The addition of P-radicals to alkenes is a well-recognized and powerful tool for C(sp3)–P bond formation.9 Peroxides,10 azo compounds,11 R3B/O2,12 Ag/K2S2O8,13 Mn salts,14 etc. have been long known to generate phosphorus-centered radicals. Recently, cheap and nontoxic silver salts have attracted more and more attention from the point of view of economy and environment-friendliness and have been successfully utilized in the radical phosphorylation of alkenes.15 On the other hand, allylic alcohols have gained much attention in the synthesis of natural products because they can undergo 1,2migration of a C–C or C–H bond to generate a carbonyl group.16 Recently, Tu,17 Sodeoka18 and Wu19 groups independently reported the preparation of β-trifluoromethyl ketones from allylic alcohols, possible via intermediate A [eqn (1)]. Inspired by these results and based on our research interest,15d,20 we envisaged that α,α-diaryl allylic alcohols could be used as P-radical acceptors and would lead to the analogous intermediate B [eqn (2)] to provide β-aryl-γ-ketophosphonates. To the best of our knowledge, methods for the synthesis of this class of compounds are extremely limited.21 The concomitant formation of C(sp3)–P and C(sp3)–C(Ar) bonds in one molecule, the carbonphosphonation of alkenes, should serve as an ideal entry to β-aryl-γ-ketophosphonates. It is noteworthy that the radical
Examples of biologically significant γ-ketophosphonates.
ð1Þ a College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China. E-mail: [email protected], [email protected], [email protected] b Tetranov Biopharm, LLC., 75 Daxue Road, Zhengzhou 450052, P. R. China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob01739k
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phosphinylation of α,α-diaryl allylic alcohols has been developed with stoichiometric amounts of silver salts.22 Herein, we report a silver-catalyzed carbonphosphonation of alkenes via 1,2-migration of α,α-diaryl allylic alcohols to prepare β-arylγ-ketophosphonates. Our previous study15d showed that the phosphonyl radicals could be easily generated from (RO)2P(O)H with a catalytic amount of silver salts. Based on this achievement, the model reaction of α,α-diphenyl allylic alcohol (1a) and diethyl H-phosphonate (2a) was carried out in the presence of AgNO3 (5 mol%) without any additive in CH3CN at 100 °C. Unfortunately, the desired product was not detected (Table 1, entry 1). When 0.5 equiv. of Mg(NO3)2·6H2O and 4 Å MS were employed as additives, the target product 3a was isolated in 33% yield (Table 1, entry 2). The product yield of 3a could reach 45% using 0.3 equiv. of Mg(NO3)2·6H2O (Table 1, entries 2–4). In an attempt to further increase the yield of this reaction, the loading of diethyl H-phosphonate (2a) was increased to 3 equiv. (Table 1, entry 5). The nitrate ion is essential to the reaction efficiency. Several other nitrates were tested, and 0.3 equiv. of Mg(NO3)2·6H2O could provide the highest yield of 62% (Table 1, entries 5–9). Increasing the amount of AgNO3 did not improve the yield further (Table 1, entries 10 and 11). Different silver catalysts were re-evaluated and proved to be less effective compared with AgNO3 (Table 1, entries 12 and 13). Other solvents, such as THF, DMF, toluene and dioxane,
Table 1
were applied instead of CH3CN, but no better results were obtained (Table 1, entries 14–17). Under these conditions, decreasing or increasing the reaction temperature led to lower yields (Table 1, entries 18 and 19). Without the silver catalyst, Mg(NO3)2·6H2O alone could not promote this reaction (Table 1, entry 20). With the optimized reaction conditions, the scope of the rearrangement reactions was explored with various α,α-diaryl allylic alcohols 1 (Table 2). The reaction could proceed well using dimethyl and diethyl H-phosphonates to form the corresponding products in moderate to good yields (3a, 3b). Subsequently, various symmetrical α,α-diaryl allylic alcohols Table 2 Silver-catalyzed carbonphosphonation of α,α-diaryl allylic alcohols via 1,2-migration of an aryl groupa,b
Optimization of conditionsa
Entry
Cat.
Additive
Solvent
Yieldb (%)
1c 2c,d 3c 4c,e 5 6 7 8 9 10 f 11g 12 13 14 15 16 17 18h 19i 20
AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 Ag2O Ag2CO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 —
— Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Cd(NO3)2·4H2O Ni(NO3)2·6H2O Co(NO3)2·6H2O NaNO3 Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O Mg(NO3)2·6H2O
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF DMF Toluene Dioxane CH3CN CH3CN CH3CN
nr 33 45 35 62 39 55 35 23 40 39 46 57 55 Trace 29 36 44 36 Trace
Reaction conditions: 1a (0.5 mmol), 2a (3 equiv.), catalyst (5 mol%), additive (30 mol%), 4 Å MS (100 mg), solvent (3.0 mL), 100 °C (oil bath), N2 atmosphere for 18 h. b Isolated yields. c 2 equiv. HP(O)(OEt)2. d 50 mol% Mg(NO3)2·6H2O. e 20 mol% Mg(NO3)2·6H2O. f 10 mol% AgNO3. g 20 mol% AgNO3. h 110 °C (oil bath). i 90 °C (oil bath). a
Org. Biomol. Chem.
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), AgNO3 (5 mol%), Mg(NO3)2·6H2O (30 mol%), 4 Å MS (100 mg), CH3CN (3.0 mL), 100 °C (oil bath), N2 atmosphere for 18 h. b Isolated yields. c The total yields of two isomers. d The ratio was determined by 13C NMR analysis. e The ratio was determined by 1H NMR analysis. f The ratio was determined by 31P NMR analysis. a
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with para and meta substituents on the aryl ring were evaluated (3c–3m). It was found that diethyl H-phosphonates showed better reactivity than dimethyl H-phosphonates for all tested α,α-diaryl allylic alcohols. The p-methoxyphenyl-substituted substrate displayed poor reactivity, and no desired product was detected (3c). Comparing the α,α-diaryl allylic alcohols associated with electron-donating groups, the reaction of α,α-diaryl allylic alcohols substituted with electronwithdrawing groups gave better results, except for 3k. The substrate containing a strong electron-withdrawing group (CF3) on the meta position of aryl groups also proceeded smoothly, giving the target products in 63% and 53% yields respectively (3l, 3m). In order to determine which aryl group was being migrated preferentially, we turned our attention to unsymmetrical α,α-diaryl allylic alcohols. Gratifyingly, all rearrangements proceeded chemoselectively. For the substrate with a para substituent on the aryl ring, the more electron-deficient aryl group migrated preferentially to give the major product 3n and the minor product 3n′ in 67% yield with a ratio of 2.5 : 1. Compound 3o which was formed from the migration of a more electron-deficient CF3-substituted aryl ring was detected as the major product. In addition, ortho-substituted aryl rings migrated less effectively than para-substituted aryl groups (3p and 3p′). To certify the mechanism of this transformation, we performed chemical trapping of radicals. The reaction was suppressed in the presence of 1.0 equiv. of radical scavengers (TEMPO or BHT), and no target product was detected (Scheme 1). To our delight, an adduct of BHT and diethyl H-phosphonate was detected by ESI-MS, thus providing straightforward evidence of a phosphonyl radical formation (see ESI† for details). On the basis of the results obtained above and previous reports,15 a plausible mechanism was proposed as shown in Scheme 2. Firstly, a phosphonyl radical A, formed from diethyl H-phosphonate 2a and AgNO3, reacts with 1a to generate radical B. Subsequent migration of the electron-deficient aryl group via spiro[2,5]octadienyl radical C produces intermediate D. Single-electron transfer (SET) from D to silver(I) would release the desired product 3a with concomitant loss of a proton. In the presence of Mg(NO3)2, the silver(0) was oxidized to silver(I). In summary, a silver-catalyzed carbonphosphonation reaction of α,α-diaryl allylic alcohols with H-phosphonates is developed. The tandem reaction is valuable, as a series of γ-ketophosphonates were readily obtained using catalytic
Scheme 1
Radical-trapping experiments.
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Scheme 2
Possible mechanism.
amounts of silver salts. This method enables the construction of both C(sp3)–P and C(sp3)–C(Ar) bonds simultaneously. Further studies are underway to investigate the applications of these transformations. This work was supported by the National Natural Science Foundation (NSF) of China (no. 21172200 and 21302172).
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