Letter pubs.acs.org/OrgLett
6‑Phosphorylated Phenanthridines from 2‑Isocyanobiphenyls via Radical C−P and C−C Bond Formation Bo Zhang, Constantin Gabriel Daniliuc, and Armido Studer* Institute of Organic Chemistry, Westfälische Wilhems-University, Corrensstraße 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: A C−P bond and a C−C bond are formed in the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and commercially available P-radical precursors. The radical cascade reaction comprises addition of an oxidatively generated P-centered radical to the isonitrile functionality and subsequent homolytic aromatic substitution. Various 6-phosphorylated phenanthridines are formed in moderate to excellent yield. In contrast to the currently intensively investigated direct arene phosphorylation, the arene core is constructed with concomitant phosphorylation using this approach.
A
Scheme 1. Arene Phosphorylation and Formation of PSubstituted Phenanthridines
romatic organophosphorus compounds belong to a highly important class of compounds which have attracted considerable attention because of their wide application in organic synthesis,1 medicinal chemistry,2 and materials science.3 Recent studies have revealed that many heterocycles containing P-substituents show excellent bioactivity.4 In light of the importance of this compound class, there is continuing interest in the development of synthetic methods for C−P bond construction.5 Traditional methods for C−P bond formation rely on the reaction of organometallic reagents with an electrophilic P-reagent such as Ph2P(O)Cl (Scheme 1, a). Since the pioneering work of Hirao and co-workers in 1981,6 a transition-metal-catalyzed coupling reaction of aryl halides,7 triflates,8 tosylates,9 diazonium salts,10 and boronic acids11 with H-phosphonates has become a practical and valuable method for C(sp2)−P bond formation (Scheme 1, b). In recent years, transition-metal-catalyzed12 and radical13 arene CH phosphorylation, which provide a direct and atom economic approach to P-substituted arenes, have been studied intensively (Scheme 1, c). Although various methods for C(sp2)−P bond formation have been established, the development of alternative and complementary methods for C(sp2)−P bond construction is still highly desirable due to the importance of P-substituted arenes in various fields as mentioned above. Recently, aryl isonitriles have gained renewed attention as radical acceptors in cascade reactions for the construction of heteroarenes.14 Along these lines, we have disclosed that 2isocyanobiphenyls can be used as highly efficient CF3 radical acceptors for preparation of 6-trifluoromethylated phenanthridines.15a Moreover, 6-aroylated phenanthridines are readily prepared by reaction of acyl radicals with biarylisonitriles.15c Encouraged by these results, we decided to test whether biarylisonitriles can be used as P-radical acceptors in cascade reactions. Herein, we disclose the first results on the preparation of 6-Psubstituted phenanthridines by radical phosphorylation of © 2013 American Chemical Society
isonitriles (Scheme 1, d). The significance of the herein presented chemistry is 3-fold: (1) Although arylisonitriles are well established C-radical acceptors in cascade reactions,14 to our knowledge they have not been used as P-radical acceptors to date. (2) In contrast to the currently intensively studied arene phosphorylation, where C−P bond formation generally occurs at an intact arene ring, the presented chemistry comprises a phosphorylation with concomitant arene formation Received: November 11, 2013 Published: December 9, 2013 250
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azobisisobutyronitrile (AIBN) as initiator and oxidant (1.5 equiv), phenanthridine 3aa was not formed. We identified the phenanthridine derived from addition of the 2-cyanopropyl radical as the major product (entry 9).14c Various solvents were surveyed next, revealing that DMF is best suited to run this reaction to provide 3aa in 91% yield (Table 1, entries 2−4). The yield was decreased by using 1.5 equiv of 2a (Table 1, entry 5) and decreasing the amount of AgOAc led to an even worse result (Table 1, entry 6). With optimized conditions in hand, the scope and limitations of the synthesis of 6-phosphorylated phenanthridines were investigated (Figure 2). Variation of the arene that does not
and regiochemistry problems which may be observed in direct arene CH phosphorylation are not occurring using our approach. (3) In contrast to the reported methods, which proceed through single C−P bond-forming transformations, our process comprises a C−P bond along with a C−C bond formation. It has been reported that P-centered radicals can be generated from P−H derivatives with Mn(OAc)3 as oxidant.16,13c Based on these precedences, we initiated our studies by investigating radical phosphorylation of readily prepared isonitrile 1a with diphenylphosphine oxide 2a in the presence of Mn(OAc)3·2H2O as oxidant in AcOH at 100 °C for 4 h. Pleasingly, the targeted product 3aa was obtained in 37% yield (Table 1, entry 1). The structure of 3aa was unambiguously Table 1. Radical Phosphorylation of Isonitrile 1a under Various Conditionsa
entry
oxidant (equiv)
solvent
yieldb (%)
1 2 3 4 5c 6 7 8 9
Mn(OAc)3·2H2O (3) AgOAc (3) AgOAc (3) AgOAc (3) AgOAc (3) AgOAc (2) AgNO3 (0.2) + K2S2O8 (3) Bu4NI (0.2) + TBHP (3) AIBN (1.5)
AcOH AcOH CH3CN DMF DMF DMF DMF CH3CN DMF
37 79 77 91 78 30 22 12
a
All reactions were carried with 1a (0.2 mmol), 2a (0.4 mmol), and oxidant in solvent (1 mL) at 100 °C under Ar for 4 h. bIsolated yields. c Using 1.5 equiv of 2a.
confirmed by X-ray analysis (Figure 1). Motivated by this result, we further optimized the radical cascade reaction by varying the oxidant and solvent.
Figure 1. X-ray structure of 3aa (thermals ellipsoids are shown with 30% probability).
Figure 2. Various 6-phosphorylated phenanthridines prepared ((a) regioisomer ratio = 7:1).
We found that yield was improved by using AgOAc17 as an oxidant (Table 1, entry 2). Other oxidants which should allow for generation of P-radicals from the corresponding P−H compounds such AgNO3/K2S2O813b and Bu4NI/TBHP18 were also investigated, but the reaction did not work well under these conditions (Table 1, entries 7 and 8). With α,α′-
carry the isonitrile functionality was studied first (see 3ba−ha). We found that the reactions with substrates bearing electronwithdrawing and also electron-donating substituents at the para position proceeded well, and the corresponding products 3ba− ha were isolated in moderate to good yields (45−80%, Figure 2). Slightly lower but still good yields were obtained for the 251
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ortho-substituted systems, probably for steric reasons (3ja and 3ka, Figure 2). A heteroarene such as pyridine was also tolerated in the biaryl moiety and product 3la was isolated in 54% yield. To investigate the regioselectivity of this cascade reaction, meta-substituted arylisonitriles 1m−o were prepared and successfully converted to the corresponding products 3ma− oa in moderate to good yields. Whereas 3ma was formed with good regioselectivity (7:1, selectivity was readily determined by 31 P NMR spectroscopy), products 3na and 3oa were obtained with complete regiocontrol. Cyclization preferably occurred at the position distal to the meta substituent (in Figure 2 only the major isomer is shown for 3ma). Arylisonitriles bearing substituents at the arene moiety containing the isonitrile functionality also underwent smooth addition/cyclization to form the corresponding products in moderate to good yields (3qa and 3ra, Figure 2). Finally, we showed that ethyl phenylphosphinate (2b) is also a suitable P-radical precursor for this transformation and phenanthridine 3ab was isolated in 85% yield (Figure 2). A plausible reaction mechanism is depicted in Scheme 2. It is known that P-centered radicals can be generated from
development of the presented method and its application toward the synthesis of bioactive compounds.
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ASSOCIATED CONTENT
* Supporting Information S
Experimental details and characterization data for the products. This material is available free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Deutsche Forschungs-gemeinschaft (DFG) for support of our work. REFERENCES
(1) For some reviews, see: (a) Organic Phosphorus Compounds; Kosolapoff, G. M., Maier, L., Eds.; Wiley-Interscience: New York, 1972. (b) Corbridge, D. E. C. Phosphorus: Chemistry, Biochemistry and Technology, 6th ed.; CRC Press: London, 2013. (c) Kolio, D. T. Chemistry and Application of H-Phosphonates; Elsevier Science: Oxford, 2006. (d) Quin, L. D. A Guide to Organophosphorus Chemistry; WileyInterscience: Hoboken, NJ, 2000. (e) Bhattacharta, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415. (f) Giorgio, C.; Gianmauro, O.; Gerard, A. P. Tetrahedron 2003, 59, 9471. (g) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (2) (a) Sivendran, S.; Jones, V.; Sun, D.; Wang, Y.; Grzegorzewicz, A. E.; Scherman, M. S.; Napper, A. D.; McCammon, J. A.; Lee, R. E.; Diamond, S. L.; McNeil, M. Bioorg. Med. Chem. 2010, 18, 896. (b) Dang, Q.; Liu, Y.; Cashion, D. K; Kasib-hatla, S. R.; Jiang, T.; Taplin, F.; Jacintho, J. D.; Li, H.; Sun, Z.; Fan, Y.; DaRe, J.; Tian, F.; Li, W.; Gibson, T.; Lemus, R.; van Poelje, P. D.; Potter, S. C.; Erion, M. D. J. Med. Chem. 2011, 54, 153. (c) Chen, X.; Kopecky, D. J.; Mihalic, J.; Jeffries, S.; Min, X.; Heath, J.; Deignan, J.; Lai, S.; Fu, Z.; Guimaraes, C.; Shen, S.; Li, S.; Johnstone, S.; Thibault, S.; Xu, H.; Cardozo, M.; Shen, W.; Walker, N.; Kayser, F.; Wang, Z. J. Med. Chem. 2012, 55, 3837. (3) (a) Steininger, H.; Schuster, M.; Kreuer, K. D.; Kaltbeitzel, A.; Bingol, B.; Meyer, W. H.; Schauff, S.; Brunklaus, G.; Maier, J.; Spiess, H. W. Phys. Chem. Chem. Phys. 2007, 9, 1764. (b) Kirumakki, S.; Huang, J.; Subbiah, A.; Yao, J.; Rowland, A.; Smith, B.; Mukherjee, A.; Samarajeewa, S.; Clearfield, A. J. Mater. Chem. 2009, 19, 2593. (c) Spampinato, V.; Tuccitto, N.; Quici, S.; Calabrese, V.; Marletta, G.; Torrisi, A.; Licciardello, A. Langmuir 2010, 26, 8400. (4) For selected exampes, see: (a) Li, X. S.; Zhang, D. W.; Pang, H.; Shen, F.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett. 2005, 7, 4919. (b) Yu, X.; Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12, 743. (5) (a) Schwan, A. L. Chem. Soc. Rev. 2004, 33, 218. (b) Jeught, S. V. D.; Stevens, C. V. Chem. Rev. 2009, 109, 2672. (c) Glueck, D. S. Top. Organomet. Chem. 2010, 31, 65. (d) Tappe, F. M. J.; Trepohl, V. T.; Oestreich, M. Top. Synthesis 2010, 3037. (e) Montchamp, J.-L. Acc. Chem. Res. 2013, DOI: 10.1021/ar400071v. (6) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis 1981, 56. (7) For selected examples, see: (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315. (b) Kalek, M.; Ziadi, A.; Stawinski, J. Org. Lett. 2008, 10, 4637. (c) Deal, E. L.; Petit, C.; Montchamp, J.-L. Org. Lett. 2011, 13, 3270. (d) Zhang, X. H.; Liu, H. Z.; Hu, X. M.; Tang, G.; Zhu, J.; Zhao, Y. Org. Lett. 2011, 13, 3478. (e) Rummelt, S. M.; Ranocchiari, M.; Bokhoven, J. A. Org. Lett. 2012, 14, 2188. (f) Xu, K.; Yang, F.; Zhang, G.; Wu, Y. Green. Chem. 2013, 15, 1055. (g) Zhao, Y.-L.; Wu, G.-J.; Li, Y.; Gao, L.-X.; Han, F.-S. Chem.Eur. J. 2012, 18,
Scheme 2. Proposed Reaction Mechanism
diarylphosphine oxides with Ag-based oxidants.17,19b We therefore believe that diphenylphosphine oxide 2a is first oxidized by the AgI salt to generate the corresponding Pcentered radical and Ag0. Note that a silver mirror is formed during reaction. Addition of the P-radical to the isonitrile functionality in 1 then gives the imidoyl radical A, which undergoes cyclization to generate cyclohexadienyl radical B.20 Subsequently, radical B gets oxidized by the AgI salt to give cyclohexadienyl cation E through a single electron transfer (SET). Finally, E gets deprotonated to afford the product 3. In summary, we have demonstrated a novel approach to the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and the commercially available diphenylphosphine oxide as P radical precursor. Various 6-phosphorylated phenanthridines were obtained in moderate to excellent yield. In contrast to the currently intensively investigated arene phosphorylation, in which C−P bond formation occurs at an intact arene, our process comprises a phosphorylation with concomitant arene formation. The phenanthridine core structure is an important structural element which is present in many natural products that show different biological activities.21 We anticipate further 252
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Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119. (d) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6, 263.
9622. (h) For radical phosphanylation of aryl halides, see Vaillard, S. E.; Mück-Lichtenfeld, C.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6533. (i) Bruch, A.; Ambrosius, A.; Fröhlich, R.; Studer, A.; Guthrie, D. B.; Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 11452. (j) Bruch, A.; Fukazawa, A.; Yamaguchi, E.; Yamaguchi, S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 12094. (8) Petrakis, K. S.; Nagabhushan, T. L. J. Am. Chem. Soc. 1987, 109, 2831. (9) Luo, Y.; Wu, J. Organometallics 2009, 28, 6823. (10) Berrino, R.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Stabile, P. Org. Biomol. Chem. 2010, 8, 4518. (11) (a) Andaloussi, M.; Lindh, J.; Sävmarker, J.; Sjöberg, P. J. R.; Larhed, M. Chem.Eur. J. 2009, 15, 13069. (b) Hu, G.; Chen, W.; Fu, T.; Peng, Z.; Qiao, H.; Cao, Y.; Zhao, Y. Org. Lett. 2013, 15, 5362. (c) Zhuang, R.; Xu, J.; Cai, Z.; Tang, G.; Fang, M.; Zhao, Y. Org. Lett. 2011, 13, 2110. (12) (a) Li, C.; Yano, T.; Ishida, N.; Murakami, M. Angew. Chen., Int. Ed. 2013, 52, 9801. (b) Feng, C.-G.; Ye, M.; Xiao, K.-J.; Li, S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 9322. (c) Hou, C.; Re, Y.; Lang, R.; Hu, X.; Xia, C.; Li, F. Chem. Commun. 2012, 48, 5181. (d) Kuninobu, Y.; Yoshida, T.; Takai, K. J. Org. Chem. 2011, 76, 7370. (13) (a) Mao, X.; Ma, X.; Zhang, S.; Hu, H.; Zhu, C.; Cheng, Y. Eur. J. Org. Chem. 2013, 4245. (b) Xiang, C.-B.; Bian, Y.-J.; Mao, X.-R.; Huang, Z.-Z. J. Org. Chem. 2012, 77, 7706. (c) Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2006, 8, 407. (14) Previous examples: (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863. (b) Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. 1996, 34, 2683. (c) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, T. Tetrahedron 1995, 51, 9045. (d) Yamago, S.; Miyazoe, H.; Coto, R.; Hashidume, M.; Sawazaki, T.; Yoshida, I. J. Am. Chem. Soc. 2001, 123, 3697. (e) Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875. Recent studies: (f) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem., Int. Ed. 2012, 51, 11363. (g) Mitamura, T.; Iwata, K.; Ogawa, A. J. Org. Chem. 2011, 76, 3880. For reviews, see: (h) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (i) Spagnolo, D.; Nanni, D. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons: Chichester, 2012; Vol. 2, p 1019. (15) (a) Zhang, B.; Mück-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2013, 52, 10792. For a similar work on the synthesis of 6-trifluoromethylphenanthridines via trifluoromethylation of isonitriles, see: (b) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846. (c) Leifert, D.; Daniliuc, C. G.; Studer, A. Org. Lett. 2013, DOI: 10.1021/ol403147v. (16) (a) Zhou, J.; Zhang, G.-L.; Zou, J.-P.; Zhang, W. Eur. J. Org. Chem. 2011, 3412. (b) Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem. Commun. 2010, 46, 1721. (c) Pan, X.-Q.; Wang, Lu.; Zou, J.-P.; Zhang, W. Chem. Commun. 2011, 47, 7875. (d) Tayama, O.; Nakano, A.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 5494. For a review, see: (e) Snider, B. B. Chem. Rev. 1996, 96, 339. (17) (a) Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, Z.; Li, C. J. Am. Chem. Soc. 2013, 135, 14082. (b) Unoh, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chen. Int. Ed. 2013, 52, 12975. (c) Wang, H.; Li, X.; Wu, F.; Wan, B. Synthesis 2012, 941. (18) Review: Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 979. See also: Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928. (19) For reviews on P-centered radicals, see: (a) Leca, D.; Fensterbank, L.; Lacote, E.; Malacria, M. Chem. Soc. Rev. 2005, 34, 858. (b) Baralle, A.; Baroudi, A.; Daniel, M.; Fensterbank, L.; Goddard, J.-P.; Lacote, E.; Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons: Chichester, 2012; Vol. 2, p 767. (20) Alternatively, A might be directly oxidized with the AgI salt to the corresponding cation, which will then undergo an electrophilic aromatic substitution to eventually provide 3. (21) For selected exampes, see: (a) Simeon, S.; Rios, J. L.; Villar, A. Pharmazie 1989, 44, 593. (b) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223. (c) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.; 253
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6‑Phosphorylated Phenanthridines from 2‑Isocyanobiphenyls via Radical C−P and C−C Bond Formation Bo Zhang, Constantin Gabriel Daniliuc, and Armido Studer* Institute of Organic Chemistry, Westfälische Wilhems-University, Corrensstraße 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: A C−P bond and a C−C bond are formed in the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and commercially available P-radical precursors. The radical cascade reaction comprises addition of an oxidatively generated P-centered radical to the isonitrile functionality and subsequent homolytic aromatic substitution. Various 6-phosphorylated phenanthridines are formed in moderate to excellent yield. In contrast to the currently intensively investigated direct arene phosphorylation, the arene core is constructed with concomitant phosphorylation using this approach.
A
Scheme 1. Arene Phosphorylation and Formation of PSubstituted Phenanthridines
romatic organophosphorus compounds belong to a highly important class of compounds which have attracted considerable attention because of their wide application in organic synthesis,1 medicinal chemistry,2 and materials science.3 Recent studies have revealed that many heterocycles containing P-substituents show excellent bioactivity.4 In light of the importance of this compound class, there is continuing interest in the development of synthetic methods for C−P bond construction.5 Traditional methods for C−P bond formation rely on the reaction of organometallic reagents with an electrophilic P-reagent such as Ph2P(O)Cl (Scheme 1, a). Since the pioneering work of Hirao and co-workers in 1981,6 a transition-metal-catalyzed coupling reaction of aryl halides,7 triflates,8 tosylates,9 diazonium salts,10 and boronic acids11 with H-phosphonates has become a practical and valuable method for C(sp2)−P bond formation (Scheme 1, b). In recent years, transition-metal-catalyzed12 and radical13 arene CH phosphorylation, which provide a direct and atom economic approach to P-substituted arenes, have been studied intensively (Scheme 1, c). Although various methods for C(sp2)−P bond formation have been established, the development of alternative and complementary methods for C(sp2)−P bond construction is still highly desirable due to the importance of P-substituted arenes in various fields as mentioned above. Recently, aryl isonitriles have gained renewed attention as radical acceptors in cascade reactions for the construction of heteroarenes.14 Along these lines, we have disclosed that 2isocyanobiphenyls can be used as highly efficient CF3 radical acceptors for preparation of 6-trifluoromethylated phenanthridines.15a Moreover, 6-aroylated phenanthridines are readily prepared by reaction of acyl radicals with biarylisonitriles.15c Encouraged by these results, we decided to test whether biarylisonitriles can be used as P-radical acceptors in cascade reactions. Herein, we disclose the first results on the preparation of 6-Psubstituted phenanthridines by radical phosphorylation of © 2013 American Chemical Society
isonitriles (Scheme 1, d). The significance of the herein presented chemistry is 3-fold: (1) Although arylisonitriles are well established C-radical acceptors in cascade reactions,14 to our knowledge they have not been used as P-radical acceptors to date. (2) In contrast to the currently intensively studied arene phosphorylation, where C−P bond formation generally occurs at an intact arene ring, the presented chemistry comprises a phosphorylation with concomitant arene formation Received: November 11, 2013 Published: December 9, 2013 250
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azobisisobutyronitrile (AIBN) as initiator and oxidant (1.5 equiv), phenanthridine 3aa was not formed. We identified the phenanthridine derived from addition of the 2-cyanopropyl radical as the major product (entry 9).14c Various solvents were surveyed next, revealing that DMF is best suited to run this reaction to provide 3aa in 91% yield (Table 1, entries 2−4). The yield was decreased by using 1.5 equiv of 2a (Table 1, entry 5) and decreasing the amount of AgOAc led to an even worse result (Table 1, entry 6). With optimized conditions in hand, the scope and limitations of the synthesis of 6-phosphorylated phenanthridines were investigated (Figure 2). Variation of the arene that does not
and regiochemistry problems which may be observed in direct arene CH phosphorylation are not occurring using our approach. (3) In contrast to the reported methods, which proceed through single C−P bond-forming transformations, our process comprises a C−P bond along with a C−C bond formation. It has been reported that P-centered radicals can be generated from P−H derivatives with Mn(OAc)3 as oxidant.16,13c Based on these precedences, we initiated our studies by investigating radical phosphorylation of readily prepared isonitrile 1a with diphenylphosphine oxide 2a in the presence of Mn(OAc)3·2H2O as oxidant in AcOH at 100 °C for 4 h. Pleasingly, the targeted product 3aa was obtained in 37% yield (Table 1, entry 1). The structure of 3aa was unambiguously Table 1. Radical Phosphorylation of Isonitrile 1a under Various Conditionsa
entry
oxidant (equiv)
solvent
yieldb (%)
1 2 3 4 5c 6 7 8 9
Mn(OAc)3·2H2O (3) AgOAc (3) AgOAc (3) AgOAc (3) AgOAc (3) AgOAc (2) AgNO3 (0.2) + K2S2O8 (3) Bu4NI (0.2) + TBHP (3) AIBN (1.5)
AcOH AcOH CH3CN DMF DMF DMF DMF CH3CN DMF
37 79 77 91 78 30 22 12
a
All reactions were carried with 1a (0.2 mmol), 2a (0.4 mmol), and oxidant in solvent (1 mL) at 100 °C under Ar for 4 h. bIsolated yields. c Using 1.5 equiv of 2a.
confirmed by X-ray analysis (Figure 1). Motivated by this result, we further optimized the radical cascade reaction by varying the oxidant and solvent.
Figure 1. X-ray structure of 3aa (thermals ellipsoids are shown with 30% probability).
Figure 2. Various 6-phosphorylated phenanthridines prepared ((a) regioisomer ratio = 7:1).
We found that yield was improved by using AgOAc17 as an oxidant (Table 1, entry 2). Other oxidants which should allow for generation of P-radicals from the corresponding P−H compounds such AgNO3/K2S2O813b and Bu4NI/TBHP18 were also investigated, but the reaction did not work well under these conditions (Table 1, entries 7 and 8). With α,α′-
carry the isonitrile functionality was studied first (see 3ba−ha). We found that the reactions with substrates bearing electronwithdrawing and also electron-donating substituents at the para position proceeded well, and the corresponding products 3ba− ha were isolated in moderate to good yields (45−80%, Figure 2). Slightly lower but still good yields were obtained for the 251
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ortho-substituted systems, probably for steric reasons (3ja and 3ka, Figure 2). A heteroarene such as pyridine was also tolerated in the biaryl moiety and product 3la was isolated in 54% yield. To investigate the regioselectivity of this cascade reaction, meta-substituted arylisonitriles 1m−o were prepared and successfully converted to the corresponding products 3ma− oa in moderate to good yields. Whereas 3ma was formed with good regioselectivity (7:1, selectivity was readily determined by 31 P NMR spectroscopy), products 3na and 3oa were obtained with complete regiocontrol. Cyclization preferably occurred at the position distal to the meta substituent (in Figure 2 only the major isomer is shown for 3ma). Arylisonitriles bearing substituents at the arene moiety containing the isonitrile functionality also underwent smooth addition/cyclization to form the corresponding products in moderate to good yields (3qa and 3ra, Figure 2). Finally, we showed that ethyl phenylphosphinate (2b) is also a suitable P-radical precursor for this transformation and phenanthridine 3ab was isolated in 85% yield (Figure 2). A plausible reaction mechanism is depicted in Scheme 2. It is known that P-centered radicals can be generated from
development of the presented method and its application toward the synthesis of bioactive compounds.
■
ASSOCIATED CONTENT
* Supporting Information S
Experimental details and characterization data for the products. This material is available free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Deutsche Forschungs-gemeinschaft (DFG) for support of our work. REFERENCES
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Scheme 2. Proposed Reaction Mechanism
diarylphosphine oxides with Ag-based oxidants.17,19b We therefore believe that diphenylphosphine oxide 2a is first oxidized by the AgI salt to generate the corresponding Pcentered radical and Ag0. Note that a silver mirror is formed during reaction. Addition of the P-radical to the isonitrile functionality in 1 then gives the imidoyl radical A, which undergoes cyclization to generate cyclohexadienyl radical B.20 Subsequently, radical B gets oxidized by the AgI salt to give cyclohexadienyl cation E through a single electron transfer (SET). Finally, E gets deprotonated to afford the product 3. In summary, we have demonstrated a novel approach to the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and the commercially available diphenylphosphine oxide as P radical precursor. Various 6-phosphorylated phenanthridines were obtained in moderate to excellent yield. In contrast to the currently intensively investigated arene phosphorylation, in which C−P bond formation occurs at an intact arene, our process comprises a phosphorylation with concomitant arene formation. The phenanthridine core structure is an important structural element which is present in many natural products that show different biological activities.21 We anticipate further 252
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Organic Letters
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