Photoredox Divergent 1,2-Difunctionalization of Alkenes with gem

Letter pubs.acs.org/OrgLett

Photoredox Divergent 1,2-Difunctionalization of Alkenes with gemDibromides Jian Cheng,† Yixiang Cheng,† Jin Xie,*,† and Chengjian Zhu*,†,‡ †

State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China S Supporting Information *

ABSTRACT: The redox neutral photocatalytic divergent radical 1,2difunctionalization of a wide array of structurally varied alkenes with gem-dibromides is presented. On the basis of the electronic effect of alkenes, predictable 1,2-carboxygenation and 1,2-carbohalogenation of alkenes are readily available regardless of steric effect. This protocol affords a practical approach to the biologically important furan skeleton. It is distinguished by good regioselectivity, good functional group compatibility, and late-stage modification and thus signifies an important step forward to divergent radical difunctionalization of alkenes.

T

he rapid diversification of alkenes is bound to integrate small molecules into intricate molecular architectures.1 The radical 1,2-difunctionalization of alkenes can simultaneously construct two distinct chemical bonds. Its latent synthetic flexibility for a great variety of structurally diverse products has gained considerable momentum in recent years.2 The welldefined 1,2-difunctionalized strategy offers a powerful platform to construct valuable compounds. For example, radical 1,2dicarbofunctionalization,3 1,2-carboheterofunctionalization,4 and 1,2-diheterofunctionalization5 have been actively pursued. gem-Dihalides are versatile building blocks in organic synthesis and often are applied as carbene precursors. Historically, the difunctionalization of alkenes with gem-halides has proven to be reliable access to cyclopropane derivatives in the presence of Zn powder (Figure 1a).6 Very recently, Guo7a and Suero7b,c

Moreover, this protocol is distinguished by good functional group tolerance and late-stage application, complementing the existing alkene difunctionalization strategies. Initially, the reaction of p-methoxystyrene 1a and gemdibromomalonate 2a was chosen as the model reaction, and it afforded biologically important 2-arylated furan 3a in a good yield (Table 1). In recent years, oxidative furan synthesis from alkenes has attracted increasing attention.10 Despite advances, one major limitation associated with these strategies is the harsh reaction conditions (either high reaction temperature, stoichiometric sacrificial oxidative reagents, or high-valent metal salts), Table 1. Identification of the Optimal Conditionsa

Figure 1. Scenario of gem-dihalides with alkenes.

elegantly updated this transformation by means of visible-light photocatalytic cyclopropanation of alkenes in the presence of electron donors (reductant). Because of our longstanding interest in visible-light photocatalysis,8 herein we disclose a redox-neutral and divergent difunctionalization of alkenes with gem-dibromides (Figure 1b,c). Significantly, the resulting heterocyclic skeleton is a privileged unit in a diverse array of natural products and biologically important compounds.9 © 2017 American Chemical Society

entry

variation of conditions

yieldsb (%)

1 2 3 4 5 6 7 8

none MeCN instead of DMF K2CO3 instead of K2HPO4 2a (1 equiv) 2a (2 equiv) no 4 Å MS no photocatalyst in the dark

88 75 72 55 77 70 0 0

a

Standard conditions: Ir(ppy)3 (0.5 mol %), 1a (0.3 mmol), 2a (1.5 equiv), 4 Å molecular sieves (100 mg), K2HPO4 (2 equiv), DMF (2 mL), 5 W blue LEDs, rt, 8−10 h. bThe isolated yield after chromatography. Received: October 29, 2017 Published: November 14, 2017 6452

DOI: 10.1021/acs.orglett.7b03371 Org. Lett. 2017, 19, 6452−6455

Letter

Organic Letters which usually result in side reactions as well as poor functional group compatibility.11 In addition, these disadvantages seriously limit their synthetic applications in late-stage modifications. Therefore, this protocol developed in our efforts comprises a practical synthetic strategy, addressing the unsolved challenges in this area. After systematic screening of the reaction parameters, the optimum conditions were determined to be 0.5 mol % of Ir(ppy)3, 1.5 equiv of 2a, and 2 equiv of K2HPO4 with DMF as solvent under the irradiation of blue LEDs (λmax = 465 nm) for 8−10 h (Table 1, entry 1). Other solvents, bases, and changes to the equivalent ratio of 2a reduced the yield (Table 1, entries 2−5, and Supporting Information). In the absence of 4 Å molecular sieves, only 70% yield was obtained due to somewhat unidentified byproducts (Table 1, entry 6). Control experiments demonstrated that no desired product 3a was formed either in the absence of photocatalyst or without light irradiation (Table 1, entries 7 and 8). With the optimized reaction conditions in hand, a vast range of electron-rich styrenes and gem-dibromides were investigated (Scheme 1). Electron-donating substituents on the aromatic rings were essential to this transformation (3a−e and 3g−t), and styrene failed to produce 3f. Upon scale-up to 10 mmol, 3a was obtained in 83% yield, suggesting the protocol is amenable to preparation in gram scale under mild conditions. Notably, ortho-, meta-, and para-substituted styrenes uniformly underwent the 1,2-carboxygenation, affording the desired products in satisfying yields. It is distinguished by good regioselectivity and excellent functional group compatibility (3m−t). Admirable differentiation between aryl and alkyl alkenes (3k), aryl and conjugated alkenes (3p and 3q), as well as aryl alkenes and alkynes (3n) was achieved. Some acid- and oxidant-sensitive functional groups, such as acetal (3n and 3o), ester (3r), tertiary amine (3l, 3m and 3dd), allylic (3k), and thioether (3i) moieties, appeared intact under otherwise optimized reaction conditions, thus highlighting its synthetic advantages. The heteroaromatic reaction partners, such as thiofuran-, indole-, benzofuran-, and thiazole-substituted styrenes, tolerated the conditions well (3u− x). Several representative dibromomalonates were then evaluated (3y−aa). The unsuccessful gem-dibromides are also shown in Scheme 1 (see the Supporting Information). The internal styrene, trans-anethole, was indicative of low reactivity, with only 20% yield or so obtained. Besides styrenes, 1vinylpyrrolidin-2-one was a suitable substrate, albeit in 20% yield (3aa). To inspect the steric effect, further sterically encumbered 2,6disubstituted styrenes were subjected to the standard conditions (Scheme 1, lower part). All of the highly hindered 2,6disubstituted styrenes examined underwent the 1,2-carboxygenation readily to afford 3bb−gg in modest to good yields. The solid structure of 3cc was confirmed by X-ray crystal analysis. The method developed in our efforts contributes a convenient route to sterically congested 2-arylated furans, which remained one challenge in Pd-catalyzed diaryl coupling chemistry.12 The photoredox late-stage 1,2-carboxygenation of complex styrenes exclusively delivered the desired products 3hh and 3ii. Radical difluoroalkylation and trifluoromethylation of 3a further underlined its synthetic value (see the Supporting Information for details). Under otherwise standard conditions, when electron-poor and relatively weak electron-rich styrenes were subjected to these conditions, much to our surprise, 1,2-carbohalogenation of styrenes13 occurred instead of 1,2-carboxygenation, affording

Scheme 1. 1,2-Carboxygenation of Strong Electron-Rich Alkenesa

a

Standard conditions and isolated yield after chromatography.

building 1,3-dibromide blocks (Scheme 2). Both the electronwithdrawing functional groups (−Cl, −Br, −F, −CO2Me) and relatively weak electron-donating groups (−tBu, −naphthyl, −Me, −O2CMe) on the aromatic rings underwent the 1,2carbohalogenation reaction readily (4a−l). Interestingly, under the same reaction conditions, p-methoxystyrene underwent 1,2carboxygenation to produce 2-arylated furan 3a, and mmethoxystyrene underwent 1,2-carbohalogenation to offer 1,3dibromide 4i. This could be attributed to the stronger electrondonating ability of the methoxy group at the para-position on the phenyl ring. Notably, the aliphatic alkene also worked well (4m). Unfortunately, the 4-NO2-substituted styrene was not a suitable substrate (4n). During the exploration of the reaction scope of styrenes, we found some interesting competing experimental phenomena, 6453

DOI: 10.1021/acs.orglett.7b03371 Org. Lett. 2017, 19, 6452−6455

Letter

Organic Letters Scheme 2. 1,2-Carbohalogenation of Electron-Poor and Relatively Weak Electron-Rich Styrenesa

a b

Standard conditions and isolated yield after chromatography. Competing 1,2-difunctionalization of styrenes.

which further indicated that the 1,2-difunctionalization of styrenes with gem-bromides were predominantly controlled by the electronic effect of alkenes. For example, when styrene 1u was employed, 1,2-carboxygenation product 3u was obtained in 33% yield and 1,2-carbohalogenation product 4o was obtained in 26% yield (Scheme 2, lower part). When 1-(benzyloxy)-2,4divinylbenzene 5 was used, the vinyl unit on the para-position of benzyloxyunderwent 1,2-carboxygenation, while the vinyl unit on the ortho-position underwent 1,2-carbohalogenation. The reason behind this may be due to the conjugation effect of multiple aromatic rings, decreasing the electron density on the second carbon−carbon double bond. Therefore, in general, for more electron-rich styrenes, the 1,2-carboxygenation is predominant; in contrast, the 1,2-carbohalogenation is favorable. Some mechanistic experiments are shown in Figure 2a,b. It was found that BHT, TEMPO (radical inhibitor), and 1,4dinitrobenzne (DNB, electron-transfer scavenger) could inhibit the model reaction, and a trace amount of trapped byproducts was detected by HRMS analysis, thus indicating an electrontransfer-triggered radical pathway (Figure. 2a). To further probe the radical intermediate, a radical-clock experiment with (1cyclopropylvinyl)benzene 9 was tested (Figure. 2b). The doublering-opening product 10A was isolated in 20% yield with a trace amount of concomitant 10B. The result unambiguously indicated that it would be a tandem alkyl radical generation from 2a rather than the direct formation of a carbene intermediate at first. A tentative mechanism for divergent 1,2-difunctionalization of styrene is proposed in Figure 2d. Under irradiation with visible light, the photoexcited *Ir(ppy)3 [E(*IrIV/III) = −1.73 V vs SCE]14 undergoes a SET process with gem-dibromomalonate 2a [E1/2red = −1.44 V vs SCE] to generate Ir(IV) species and monobromomalonate radical 11. The resulting radical 11 immediately adds to alkene 1 to give alkyl radical 12. The electronic effect of substituents on the phenyl rings plays an important role for selective 1,2-carboxygenation and 1,2carbohalogenation. A close look into the benzylic radical reduction potential indicates that the electron-push effect on

Figure 2. Mechanistic studies and proposed mechanism.

styrene arenes would facilitate single-electron oxidation of benzylic radical to its cation species (Figure 2c).15 For more electron-rich alkenes, the radical intermediate 12b subsequently donates one electron to the Ir(IV) species [E(IrIV/III) = 0.77 V vs SCE]14 to furnish intermediate 13 after deprotonation from the corresponding cation. For styrenes bearing an electron-withdrawing group or relatively weak electron-donating group, the single-electron oxidation rate of a benzylic radical becomes sluggish, and therefore, the Br-atom transfer is much more favorable,13b initiating the radical chain propagation and forming 4g.16 Notably, although at present we cannot isolate the reactive intermediate 13, it can be successfully detected by HRMS analysis.17 This indicates that once 13 is generated, rapid intramolecular transformation occurs to keep it at a low concentration. Accordingly, 13 immediately undergoes the second photocatalytic cycle with photoexcted *IrIII to form radical 14. Its mesomeric form, benzylic radical 15, is readily oxidized by SET with IrIV to generate benzylic cation 16, which undergoes electrocyclization18 and subsequent deprotonation to deliver the expected 2-arylated furan 3a. Alternatively, SET 6454

DOI: 10.1021/acs.orglett.7b03371 Org. Lett. 2017, 19, 6452−6455

Letter

Organic Letters

T. M.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 10555. (f) Meng, L.; Zhang, G.; Liu, C.; Wu, K.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 10195. (g) Hartmann, M.; Li, Y.; Studer, A. J. Am. Chem. Soc. 2012, 134, 16516. (h) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. Am. Chem. Soc. 2011, 133, 4160. (i) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem., Int. Ed. 2014, 53, 12064. (j) Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (5) Selected examples: (a) Yang, Y.; Song, R. J.; Ouyang, X. H.; Wang, C. Y.; Li, J. H.; Luo, S. Angew. Chem., Int. Ed. 2017, 56, 7916. (b) Molnar, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 5004. (c) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y. F.; Jiao, N. J. Am. Chem. Soc. 2015, 137, 6059. (d) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kürti, L.; Falck, J. R. Science 2014, 343, 61. (e) Schroder, K.; Join, B.; Amali, A. J.; Junge, K.; Ribas, X.; Costas, M.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 1425. (f) Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz, K. Angew. Chem., Int. Ed. 2011, 50, 9478. (g) Hu, X.; Chen, J.; Wei, Q.; Liu, F.; Deng, Q.; Beauchemin, A.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 12163. (6) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. (7) (a) Zhang, Y.; Qian, R.; Zheng, X.; Zeng, Y.; Sun, J.; Chen, Y.; Ding, A.; Guo, H. Chem. Commun. 2015, 51, 54. (b) del Hoyo, A. M.; Herraiz, A. G.; Suero, M. G. Angew. Chem., Int. Ed. 2017, 56, 1610. (c) del Hoyo, A. M.; García Suero, M. Eur. J. Org. Chem. 2017, 2017, 2122. (8) (a) Xu, P.; Wang, G. Q.; Zhu, Y.; Li, W.; Cheng, Y.; Li, S. H.; Zhu, C. Angew. Chem., Int. Ed. 2016, 55, 2939. (b) Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2017, 56, 7266. (c) Cheng, J.; Li, W.; Duan, Y.; Cheng, Y.; Yu, S.; Zhu, C. Org. Lett. 2017, 19, 214. (9) Ye, Q.; Xie, S.; Huang, M.; Huang, W.; Lu, J.; Ma, Z. J. Am. Chem. Soc. 2004, 126, 13940. (10) In 2016, Wu’s group reported an elegant photoredox multisubstituted furan synthesis from styrene and α-chloroaryl ketone with external strong oxidant K2S2O8: (a) Wang, S.; Jia, W. L.; Wang, L.; Liu, Q.; Wu, L. Z. Chem. - Eur. J. 2016, 22, 13794. Indeed, to prepare the similar furans without oxidants, Rh-catalyzed [3 + 2] cyclization of alkynes with potentially explosive diazo compounds is a choice: (b) Davies, H. M. L.; Romines, K. R. Tetrahedron 1988, 44, 3343. Other strategies under harsh conditions: (c) Dey, A.; Ali, M. A.; Jana, S.; Hajra, A. J. Org. Chem. 2017, 82, 4812. (d) Wu, Y.; Huang, Z. Y.; Luo, Y.; Liu, D.; Deng, Y.; Yi, H.; Lee, J. F.; Pao, C. W.; Chen, J. L.; Lei, A. W. Org. Lett. 2017, 19, 2330. (e) Yang, Y. Z.; Yao, J. Z.; Zhang, Y. H. Org. Lett. 2013, 15, 3206. (f) Liu, L.; Sun, K.; Ji, X. Y.; Zhou, Y. B.; Yin, S. F. Tetrahedron 2017, 73, 2698. (g) Ishikawa, S.; Noda, Y.; Wada, M.; Nishikata, T. J. Org. Chem. 2015, 80, 7555. (11) Liu, C.; Yuan, J. W.; Gao, M.; Tang, S.; Li, W.; Shi, R. Y.; Lei, A. W. Chem. Rev. 2015, 115, 12138. (12) Ligand Design in Metal Chemistry: Reactivity and Catalysis;Stradiotto, M., Lundgren, R. J., Eds.; John Wiley & Sons, Ltd.: Chichester, UK. 2016. (13) (a) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. Am. Chem. Soc. 2011, 133, 4160. (b) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem., Int. Ed. 2014, 53, 12064. (14) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. Chem. Rev. 2013, 113, 5322. (15) Sim, B. A.; Griller, D.; Wayner, D. D. M. J. Am. Chem. Soc. 1989, 111, 754. (16) Magagnano, G.; Gualandi, A.; Marchini, M.; Mengozzi, L.; Ceroni, P.; Cozzi, P. G. Chem. Commun. 2017, 53, 1591. (17) We tried to prepare 13 from 2-(4-methoxystyryl)malonate with NBS or dibromotetrachloroethane utilizing LDA or KOtBu, but the reaction became very messy owing to unidentified side reactions. See the Supporting Information for details. (18) The ring closure to furan from benzylic cation 16 may be formulated as an electrocyclic process (Nazarov type).

between benzylic radical 15 and 2a would constitute a radical chain pathway to produce radical 11 and cation 16. In summary, a practical synthetic strategy for redox-neutral divergent 1,2-difunctionalization of a diverse array of styrenes was developed. Based on the electronic effect of alkenes, predictable 1,2-carboxygenation and 1,2-carbohalogenation can be achieved. The sterically demanding 2,6-disubstituted aromatic and heteroaromatic styrenes are good reaction partners. It also provides a powerful route to biologically important heterocyclic skeletons and versatile 1,3-dibromide building blocks. The mild conditions, ready scale-up ability, and practical late-stage modification of complex molecules make this protocol very promising, representing a significant advance toward divergent radical 1,2-difunctionalization of alkenes.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03371. Experimental procedures, X-ray crystal data of 3cc, and characterization data for all of the new products (PDF) Accession Codes

CCDC 1563593 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yixiang Cheng: 0000-0001-6992-4437 Jin Xie: 0000-0003-2600-6139 Chengjian Zhu: 0000-0003-4465-9408 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 21732003, 21702098, 21372114, 21672099, 21474048, and 21472084) for supporting this research.

■

REFERENCES

(1) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (2) (a) Yin, G.; Mu, X.; Liu, G. Acc. Chem. Res. 2016, 49, 2413. (b) Koike, T.; Akita, M. Acc. Chem. Res. 2016, 49, 1937. (c) Wang, X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712. (3) Selected examples: (a) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (b) Garcia-Dominguez, A.; Li, Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835. (c) Ouyang, X. H.; Song, R. J.; Hu, M.; Yang, Y.; Li, J. H. Angew. Chem., Int. Ed. 2016, 55, 3187. (d) Tasker, S. Z.; Jamison, T. F. J. Am. Chem. Soc. 2015, 137, 9531. (4) Selected examples: (a) Wang, D.; Wu, L.; Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 6811. (b) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 3708. (c) Liu, Y. Y.; Yang, X. H.; Song, R. J.; Luo, S.; Li, J. H. Nat. Commun. 2017, 8, 14720. (d) Cheng, Y. F.; Dong, X. Y.; Gu, Q. S.; Yu, Z. L.; Liu, X. Y. Angew. Chem., Int. Ed. 2017, 56, 8883. (e) Bunescu, A.; Ha, 6455

DOI: 10.1021/acs.orglett.7b03371 Org. Lett. 2017, 19, 6452−6455