Letter Cite This: Org. Lett. 2018, 20, 4975−4978
pubs.acs.org/OrgLett
Copper-Catalyzed Intermolecular Reductive Radical Difluoroalkylation−Thiolation of Aryl Alkenes Weiguang Kong,†,‡ Changjiang Yu,†,§ Hejun An,†,§ and Qiuling Song*,†,‡,§,∥ Institute of Next Generation Matter Transformation, ‡College of Chemical Engineering, and §College of Material Sciences Engineering, Huaqiao University, 668 Jimei Blvd, Xiamen, Fujian 361021, P. R. China ∥ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China Org. Lett. 2018.20:4975-4978. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 08/17/18. For personal use only.
†
S Supporting Information *
ABSTRACT: A novel radical-involved alkene difunctionalization catalyzed by the copper/B2pin2 system has been developed, leading to the difluoroalkylation−thiolation of aryl alkenes. The use of B2pin2 as an organic reductant enables the simultaneous installation of a C(sp3)−C(F2R) bond and a C(sp3)−S(R) bond across the CC bond of aryl alkenes by utilizing two electrophilic reactants. The reaction exhibits broad substrate scope, excellent diastereoselectivity, and moderate to good yields. Moreover, the reaction can be conducted on a gram scale with good yield achieved.
D
C(sp2) bonds across CC bonds using two electrophiles (Scheme 1, top).5
ifunctionalization of alkenes, which involves the installation of two vicinal functional groups in a single step, has been demonstrated to be a powerful tool in the preparation of polyfunctionalized compounds and valuable building blocks for natural and biologically active compounds.1 Among the reported methods, transition-metal-catalyzed radical difunctionalization of alkenes is featured as one of the most efficient pathways to realize this goal and has received much attention in recent decades. In this respect, nickelcatalyzed radical difluoroalkylation−arylation of enamides and radical alkylation−arylation of activated alkenes were, respectively, reported by Zhang and Baran in 2016.2 Coppercatalyzed radical difunctionalization alkenes developed by the groups of Sodeoka, Nevado, Buchwald, Liu, Wang, Zhang, etc. have also found broad applicability, and even some asymmetric versions of these transformations have been realized.3 From a formal point of view, all these reactions proceed in redox neutral conditions, with an electrophile and a nucleophile introduced to CC bonds successively. Moreover, oxidative radical difunctionalization of alkenes developed by Zhu and Li et al. allows the installation of two different nucleophiles across the CC bonds under oxidizing conditions.4 Despite the impressive success of the reactions mentioned above, more novel strategies are still highly desirable in order to broaden the scope of functional group implantation in CC bonds. In this scenario, Nevado and co-workers realized a nickelcatalyzed reductive dicarbofunctionalization of alkenes which enabled the direct formation of C(sp3)−C(sp3) and C(sp3)− © 2018 American Chemical Society
Scheme 1. Transition-Metal-Catalyzed Reductive Radical Difunctionalization of Alkenes
On the other hand, the formation of C−S bonds represents a key step in the synthesis of a broad range of biologically active molecules and functional materials, and many endeavors have been devoted to this area.6 We recently developed an unconventional reductive quenching cycle to realize the Received: July 4, 2018 Published: August 9, 2018 4975
DOI: 10.1021/acs.orglett.8b02091 Org. Lett. 2018, 20, 4975−4978
Letter
Organic Letters
were examined, and a small decrease in yield was observed when ligand L1 was replaced with structurally related L2 and L3; however, diphosphine ligand L4 could not catalyze the reaction (entries 6−8). Moreover, reductant also has a strong effect on the reaction. The reaction could not proceed without B2pin2 or using Zn powder instead of it, and an obvious decrease in yield was observed when 0.6 equiv of B2pin2 and CsF was used (entries 9−11). Finally, to our delight, with the amount of B2pin2 and CsF increased to 2 equiv and the reaction proceeding at 60 °C, 5aa could be delivered in 79% optimized yield (entry 12). With the optimized reaction conditions in hand, we set out to explore the substrate scope of this copper-catalyzed intermolecular reductive radical difluoroalkylation−thiolation of aryl alkenes. First, different aryl alkenes were investigated. As shown in Scheme 2, a series of styrenes, with various
visible-light-induced thiotrifluoromethylation of terminal alkyl alkenes. However, aryl alkenes are not suitable for the reaction.7 In this context, the Cu/B2pin2 catalytic system developed by our group to realize radical difluoroalkylation reactions gave us inspiration.8 We speculated that a SET process between BrCF2CO2Et and the Cu(I)−Bpin intermediate, formed in situ from Cu/B2pin2 with the aid of base, would generate a CF2CO2Et radical and the Br−Cu(II)−Bpin intermediate. After the CF2CO2Et radical addition to aryl alkene and being trapped by the Br−Cu(II)−Bpin intermediate, the Bpin−Cu(III)−C(β-CF2CO2Et) intermediate was formed which then underwent reductive elimination to deliver the Cu(I)−C(β-CF2CO2Et) nucleophile intermediate. Finally, nucleophilic attack of the Cu(I)−C(β-CF2CO2Et) intermediate to benzenesulfonothioate (PhSO2SR) would afford the desired difluoroalkylation−thiolation product. Herein, we present the first example of a copper-catalyzed intermolecular reductive difunctionalization reaction which enables the simultaneous installation of a C(sp3)−C(F2R) bond and a C(sp3)−S(R) bond across the CC bond of aryl alkenes. Mild conditions, broad substrate scope, and excellent diastereoselectivity are features of this reaction (Scheme 1, bottom). We commenced the study with styrene 1a, S-phenyl benzenesulfonothioate 4a, and BrCF2CO2Et as the model substrates (Table 1) and systematically screened the influence
Scheme 2. Scope of Aryl Alkenesa
Table 1. Optimization of the Reaction Conditions
entry
change from the conditions above
yielda (%)
1 2 3 4 5 6 7 8 9 10 11 12
none K2CO3 instead of CsF KOtBu instead of CsF Cu2O instead of CuTc CuCl instead of CuTc L2 instead of L1 L3 instead of L1 L4 instead of L1 no B2pin2 Zn powder instead of B2pin2 B2pin2 (0.6 equiv) + CsF (0.6 equiv) B2pin2 (2 equiv) + CsF (2 equiv), 60 °C
55 28 33 54 52 51 52 N.D. N.D. N.D. 44 79 (73b)
a
GC yield. bIsolated yield.
a
1 or 2 or 3 (0.2 mmol), 4a (0.24 mmol), BrCF2CO2Et (0.24 mmol), CuTc (10 mol %), DTBBPY (10 mol %), B2pin2 (2.0 equiv), CsF (2.0 equiv), CH3CN, N2, 12 h, 60 °C.
substituents on the aromatic ring, were proved to be competent candidates in this transformation and provided the corresponding products 5aa−5sa in moderate to good yields. An array of functional groups such as alkyl, ester, ether, and halogens were well tolerated in the reactions. However, no product was detected for 4-vinylphenol, and only a trace amount of product was observed for 1-nitro-4-vinylbenzene. Moreover, good site selectivity was observed in the reaction. In the cases of 1r and 1s, which contain two different C−C unsaturated systems on the structure, only the styrene moieties reacted to give the corresponding products 5ra and 5sa in moderate yields, due to the relatively higher reactivity of the
of all reaction parameters (see Supporting Information for more details). It was found that the desired difluoroalkylation− thiolation product 5aa could be afforded in 55% yield in the presence of CuTc (10 mol %), L1 (DTBBPY, 10 mol %), B2Pin2 (1.2 equiv), and CsF (1.2 equiv) at rt under N2 (entry 1). Other bases such as K2CO3 and KOtBu led to inferior results (entries 2−3). The screening of Cu catalyst revealed that CuTc was the best choice, and other Cu salts, such as Cu2O and CuCl, could also promote the reaction, yet with somewhat lower yield (entries 4−5). Next, different ligands 4976
DOI: 10.1021/acs.orglett.8b02091 Org. Lett. 2018, 20, 4975−4978
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Organic Letters
heterocycles on benzenesulfonothioates was also studied: S(thiophen-2-yl) benzenesulfonothioate 2m posed no problem in the reaction to give 8am in 77% yield; however, pyridyl which had strong binding affinity to metal catalysts annihilated the reaction completely (8an). Another limitation of the present protocol was that S-alkyl benzenesulfonothioates such as 2o were unreactive in the reaction probably due to their weak electrophilicity. To further demonstrate the practicability of this coppercatalyzed intermolecular reductive radical difluoroalkylation− thiolation of aryl alkenes, a scale-up experiment of 4bromostyrene (1o) with S-phenyl benzenesulfonothioate (4a) and BrCF2CO2Et was performed. The desired product 5oa could be afforded at the gram scale with a yield comparable to smaller scale achieved (Scheme 4, eq 1). In
conjugated alkenes. In addition, 2-vinylnaphthalene (1t) and 2vinylbenzo[b]thiophene (1u) were also suitable in the reactions with the corresponding products 5ta and 5ua obtained in 60% and 67% yields. Inspired by the above results, we next turned our attention to investigate the compatibility of polysubstituted styrenes in this difluoroalkylation−thiolation reaction. Generally, the 1,1-disubstituted styrenes exhibited similar reactivities with monosubstituted styrenes. They were smoothly difunctionalized with different para-substituted groups such as −Me, −SMe, −Bu, −Cl, and −CF3 (6aa−6fa). Likewise, 2-(prop-1-en-2-yl)naphthalene (2g) and 1-(prop-1-en-2-yl)naphthalene (2h) were effective for this transformation to give the desired products 6ga and 6ha in moderate yields. Moreover, the present protocol could also be applied to noncyclic or cyclic 1,2-disubstituted styrenes (3a−3f) and even 1,2,2-trisubstituted styrenes (3g). By contrast, these compounds showed slightly lower reactivity than monosubstituted and 1,1-disubstituted styrenes, except 1,2-dihydronaphthalene (3e) which provided the desired product 7ea in up to 74% yield. It is worth noting that almost exclusive anti-selectivity was observed for these reactants; synsubstituted products were obtained for (E)-1,2-disubstituted styrenes (3a−3b); and anti-substituted products were obtained for (Z)-1,2-disubstituted styrenes (3c−3f). The stereoscopic configurations of these products were confirmed by the X-ray crystallographic analysis of 7fa and 7ga. Subsequently, the substrate scope of benzenesulfonothioates was investigated. As depicted in Scheme 3, a variety of S-aryl
Scheme 4. Synthetic Applications
Scheme 3. Scope of Benzenesulfonothioatesa
addition, complex aryl alkenes such as estrone derivative 1v and 1w with a sugar moiety were also suitable candidates to participate in the reaction and afforded the corresponding products in good yields (eqs 2−3). Moreover, the −SR groups and −CF2CO2Et in the products are both convertible; as a representative example, 5oa could be oxidized to its sulfone derivatives 9 by m-CPBA in 78% yield and be reduced to its alcohol derivatives 10 by NaBH4 in 95% yield under mild conditions (eqs 4−5). Finally, radical trapping experiments were conducted to preliminarily probe into the mechanism of the reaction (Scheme 5). When the radical scavenger (TEMPO or 1,1diphenylethylene) was added into the reaction, it was totally suppressed, and radical trapping products 11 and 12 were all detected by GC-MS. BHT was also investigated, and the reaction was almost totally suppressed; however, the trapping product of the CF2CO2Et radical by BHT was not detected.
a
1a (0.2 mmol), 4 (0.24 mmol), BrCF2CO2Et (0.24 mmol), CuTc (10 mol %), DTBBPY (10 mol %), B2Pin2 (2.0 equiv), CsF (2.0 equiv), CH3CN, N2, 12 h, 60 °C.
benzenesulfonothioates could be used to participate in this copper-catalyzed intermolecular reductive radical difluoroalkylation−thiolation of aryl alkenes. For substrates with electrondonating groups, such as −Me and −OMe on the S-aryl ring, the desired products were afforded in 53−76% yields (8ab− 8ae). Moreover, better results were achieved with electronwithdrawing groups such as halogens and −CF3 on the S-aryl ring (8af−8ak). Meanwhile, the nitro group on the S-aryl ring, which is sensitive to the B2pin2/base revealed by Wu and coworkers,9 was well tolerated in our conditions to give the products in 76% yield (8al). The influence of aromatic
Scheme 5. Radical Trapping Experiments
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(2) (a) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 12270. (b) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016, 352, 801. (3) (a) Egami, H.; Shimizu, R.; Kawamura, S.; Sodeoka, M. Angew. Chem., Int. Ed. 2013, 52, 4000. (b) Kawamura, S.; Egami, H.; Sodeoka, M. J. Am. Chem. Soc. 2015, 137, 4865. (c) Kong, W.; Casimiro, M.; Fuentes, N.; Merino, E.; Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 13086. (d) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2013, 135, 14480. (e) Zhu, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 12655. (f) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 8069. (g) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.; Liu, X.-Y. J. Am. Chem. Soc. 2016, 138, 9357. (h) Wang, F.-L.; Dong, X.-Y.; Lin, J.-S.; Zeng, Y.; Jiao, G.-Y.; Gu, Q.-S.; Guo, X.-Q.; Ma, C.-L.; Liu, X.-Y. Chem. 2017, 3, 979. (i) Cheng, Y.-F.; Dong, X.-Y.; Gu, Q.-S.; Yu, Z.-L.; Liu, X.-Y. Angew. Chem. 2017, 129, 9009. (j) Li, Z.-L.; Li, X.-H.; Wang, N.; Yang, N.-Y.; Liu, X.-Y. Angew. Chem., Int. Ed. 2016, 55, 15100. (k) Hemric, B. N.; Shen, K.; Wang, Q. J. Am. Chem. Soc. 2016, 138, 5813. (l) Shen, K.; Wang, Q. J. Am. Chem. Soc. 2017, 139, 13110. (m) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu, Q.; Zhang, Q. Angew. Chem., Int. Ed. 2013, 52, 2529. (n) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.; Zhang, Q. Angew. Chem., Int. Ed. 2014, 53, 11079. (o) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 1881. (p) Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 10202. (q) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2016, 138, 15547. (r) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, Pi; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (s) Wang, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G. Angew. Chem., Int. Ed. 2017, 56, 2054. (t) Chen, Z.-M.; Bai, W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew. Chem., Int. Ed. 2013, 52, 9781. (u) Liu, X.; Xiong, F.; Huang, X.; Xu, L.; Li, P.; Wu, X. Angew. Chem., Int. Ed. 2013, 52, 6962. (v) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 1790. (w) Sequeira, F. C.; Turnpenny, B. W.; Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49, 6365. (4) (a) Bunescu, A.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 3132. (b) Ha, T. M.; Chatalova-Sazepin, C.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9249. (c) Fan, J.-H.; Wei, W.-T.; Zhou, M.-B.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2014, 53, 6650. (d) Ouyang, X.-H.; Song, R.-J.; Hu, M.; Yang, Y.; Li, J.-H. Angew. Chem., Int. Ed. 2016, 55, 3187. (e) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.; Li, J.-H. Nat. Commun. 2017, 8, 14720. (f) Zhou, S.-F.; Li, D.-P.; Liu, K.; Zou, J.-P.; Asekun, O. T. J. Org. Chem. 2015, 80, 1214. (5) García-Domínguez, A.; Li, Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835. (6) (a) Block, E. Reactions of Organosulfur Compounds; Academic Press: New York, 1978. (b) Townsend, D. M.; Tew, K. D.; Tapiero, H. Biomed. Pharmacother. 2004, 58, 47. (c) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239. (d) Meadows, D. C.; Gervay-Hague, J. Vinyl sulfones. Med. Res. Rev. 2006, 26, 793. (e) Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23, 4347. (f) Majumdar, P.; Pati, A.; Patra, M.; Behera, R. K.; Behera, A. K. Chem. Rev. 2014, 114, 2942. (g) Lee, C.F.; Liu, Y.-C.; Badsara, S. S. Chem. - Asian J. 2014, 9, 706. (h) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem. 2016, 16, 1200. (7) Kong, W.; An, H.; Song, Q. Chem. Commun. 2017, 53, 8968. (8) (a) Ke, M.; Feng, Q.; Yang, K.; Song, Q. Org. Chem. Front. 2016, 3, 150. (b) Ke, M.; Song, Q. J. Org. Chem. 2016, 81, 3654. (c) Ke, M.; Song, Q. Adv. Synth. Catal. 2017, 359, 384. (d) Ke, M.; Song, Q. Chem. Commun. 2017, 53, 2222. (e) Fu, W.; Song, Q. Org. Lett. 2018, 20, 393. (9) Lu, H.; Geng, Z.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Org. Lett. 2016, 18, 2774.
These experiments suggested that the CF2CO2Et radical was generated in the reaction. In summary, the first copper-catalyzed reductive radical difunctionalization reaction has been established to realize the difluoroalkylation−thiolation of aryl alkenes. The use of B2pin2 as an organic reductant is crucial to the reaction and avoids the generation of stoichiometric metallic waste. The reaction exhibits broad substrate scope, excellent diastereoselectivity, and moderate to good yields. Moreover, the reaction can be conducted on a gram scale with good yield achieved. The asymmetric version of this transformation is in progress.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02091. Experimental procedures and characterization data (PDF) Accession Codes
CCDC 1834217 and 1849374 contain 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Qiuling Song: 0000-0002-9836-8860 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation (21772046), Program of Innovative Research Team of Huaqiao University (Z14X0047), the Recruitment Program of Global Experts (1000 Talents Plan), and the Natural Science Foundation of Fujian Province (2016J01064) is gratefully acknowledged. We also thank the Instrumental Analysis Center of Huaqiao University for analysis support. W. K. thanks the Subsidized Project for Cultivating Postgraduates’ Innovative Ability in Scientific Research of Huaqiao University.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02091 Org. Lett. 2018, 20, 4975−4978
