Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(I)-Catalyzed Oxydifluoroalkylation of Alkenes: A Route to Functionalization of Lactones Yang Da,§ Shengnan Han,§ Xiaoyong Du,§ Shaodong Liu, Lei Liu, and Jie Li* School of Pharmaceutical Science, Jiangnan University, Lihu Road 1800, 214122 Wuxi, P. R. China
Org. Lett. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 08/24/18. For personal use only.
S Supporting Information *
ABSTRACT: An efficient copper(I)-catalyzed oxydifluoroalkylation of unsaturated carboxylic acids has been developed under mild reaction conditions. Various α-bromodifluoromethyl substituted heterocycles, esters, amides, and ketones were successfully employed as the CF2 source. This cost-effective copper(I) catalysis provides expedient access to high valued lactones with ample substrate scope, wide functional group tolerance, and up to 98% yield.
F
alkenes with easily accessible bromodifluoromethyl substituted heterocycles, esters, amides, and ketones as the CF2 source. We initiated our research by exploring the optimal reaction conditions for the envisioned oxydifluoroalkylation of the benzoic acid 1a with 2a (Table 1). No reaction was detected in the presence of CuCl2 or CuBr2 (Table 1, entries 1−2).
luoroalkyl groups, such as difluoromethylene (CF2) and trifluoromethyl (CF3), are highly important structural motifs in numerous pharmaceuticals and agrochemicals.1 In this context, there is a continually strong demand for efficient and selective introduction of these groups into organic molecules. Catalytic fluoroalkylation has recently emerged as an attractive strategy in the synthesis of fluorinated compounds.2 Due to its user-friendly nature and facile postfunctionalizations, halogenated difluoroacetates (XCF2CO2Et, X = Br or I) have attracted considerable recent attention and turned out to be a better choice in the installation of CF2 structural motifs,3 as compared to the other synthetically difficult difluoroalkylation reagents, such as Me3SiCF2H,4 nBu3SnCF2H,5 (DMPU)2Zn(CF2H)2,6 and bis(difluoroacetoxy)iodo]benzene reagents.7 With the ubiquitous presence of lactone in various compounds with activities of relevance to biology or medicinal chemistry,8 the synthesis of fluoro-containing lactones has attracted increasing attention in recent years. Importantly, difunctionalization of unsaturated carboxylic acids,9 through a copper-catalyzed lactonization strategy, has emerged as a powerful tool for the lactone syntheses, such as oxytrifluoromethylation,10 oxyazidation, oxysulfonylation, oxyarylation,11 oxyamination,12 and oxysulfenylation.13 Among them, the remarkable copper-catalyzed oxytrifluoromethylation of unactivated alkenes has been developed with Togni’s reagent, as was reported by Buchwald.10,11 Subsequently, Koike and Akita demonstrated a highly efficient photoredox-catalysis for the synthesis of CF3-substituted lactones, using Umemoto’s reagent as the CF3 source of choice.14 Beyond that, a photoredoxcatalyzed cascade difluoroalkylation and intramolecular cyclization were only recently reported by Han, and the use of an expensive photocatalyst fac-[Ir(bpy)3] still represents drawbacks.15 Despite these remarkable advances in the synthesis of fluoro-containing lactones, copper-catalyzed oxydifluoroalkylation has still, unfortunately, proved elusive. Herein, we report a novel copper(I)-catalyzed oxydifluoroalkylation of simple © XXXX American Chemical Society
Table 1. Optimization for Copper-Catalyzed Oxydifluoroalkylation of Alkene 1aa
entry
[Cu] (mol %)
ligand
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13
CuCl2 (10) CuBr2 (10) Cu(OTf)2 (10) Cu(OAc)2 (10) Cu(MeCN)4PF4 (10) Cu2O (5) CuCl (10) CuBr (10) CuI (10) CuCN (10) Cu(OAc) (10) Cu(OAc) (10) Cu (10)
dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy dtbbpy
0 0c 40c 71 40 76 52 57 33 27 80 0−75d 40
dtbbpy
a
General reaction conditions: 1a (0.20 mmol, 1.0 equiv), 2a (0.40 mmol, 2.0 equiv), Cu2O (10.0 mol %), ligand (20.0 mol %), K2CO3 (0.2 mmol, 1.0 equiv), anhydrous MeCN (1.0 mL), under Ar, 70 °C, 12 h. bIsolated yield. c5 h. dWithout ligand or with other ligands (see Supporting Information for more details). dtbbpy = 4,4′-di-tert-butyl2,2′-dipyridine. Received: July 2, 2018
A
DOI: 10.1021/acs.orglett.8b02069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters However, a reaction was observed when using 10 mol % of Cu(OTf)2 or Cu(OAc)2 as the catalyst and 4,4′-di-tert-butyl2,2′-dipyridine (dtbbpy) as the ligand, the desired oxydifluoromethylated product 3aa was obtained in 40 and 71% yield, respectively (entries 3−4). Among a set of Cu(I) complexes, Cu2O and Cu(OAc) displayed the highest reactivity, furnishing the product 3aa in 76% and 80% yield, respectively (entries 5−11). After screening a variety of ligands, 4,4′-di-tertbutyl-2,2′-bipyridine (dtbbpy) proved to be the ideal ligand to a copper ratio of 1:1 (entries 11−12). Notably, a catalytic amount of Cu(0) can also be used as precatalyst in the presence of 4,4′di-tert-butyl-2,2′-bipyridine (entry 13). Having optimized the copper(I) catalyst, we subsequently tested its versatility in the oxydifluoroalkylation with various unsaturated carboxylic acids 1 (Scheme 1). A series of 2-
Scheme 2. Substrate Scope of Bromodifluoromethyl Substituted Heterocycles 2
Scheme 1. Substrate Scope of the Copper(I)-Catalyzed Oxydifluoroalkylation of Alkenes 1 Scheme 3. Copper(I)-Catalyzed Oxydifluoroalkylation with Bromodifluoroacetate 4a
a
With 5 mol % of Cu2O as the catalyst.
vinylbenzoic acids 1a−1f was efficiently transformed to the desired products 3aa−3fa in 62−95% yields. Notably, the unsaturated aliphatic carboxylic acids bearing different aryl or methyl substituents on the alkene were found to be viable substrates as well, undergoing the oxydifluoroalkylation reaction to afford the corresponding γ-lactones 3ga−3la in good to excellent yields, as was also observed when employing 1m as the substrate, delivering a δ-lactone 3ma in 81% yield. The scope of this method was further extended to different αbromodifluoromethyl substituted heterocycles 2 (Scheme 2). We have found that 2-(bromodifluoromethyl)benzo[d]thiazole 2a undergoes this oxydifluoroalkylation with alkenes (1a and 1h) to afford the desired products 3ab and 3hb in 57−91% yields. Moreover, the 2-(bromodifluoromethyl)benzo[d]oxazoles (2c−2f) bearing various substituents on the arene were effectively converted with different alkenes leading to the desired lactones in 57−93% yields. In consideration of the remarkably high catalytic efficacy of this copper(I)-catalyzed difunctionalization with 2-bromodifluoromethyl substituted heterocycles 2, we next sought to apply this protocol to the substrate of bromodifluoroacetate 4a (Scheme 3). We were delighted to find that 2-vinylbenzoic acids were smoothly transformed into the desired difluoroalkylated lactones 5aa−5fa. However, the product 5aa was obtained in a sharply decreasing yield when using chlorodifluoroacetate as the
a
CuBr (40 mol %) was used as the metal source.
fluorinating reagent. Moreover, the unsaturated aliphatic carboxylic acids were also successfully utilized for the oxidative difunctionalization under our optimized conditions, furnishing the desired γ-lactones 5ga−5ja and δ-lactones 5ma−5oa in moderate to good yields. Thereafter, the substrate scope of bromodifluoroacetamides 4b−4f was studied under the standard reaction conditions (Scheme 4a). Various substituted acetamides, such as morpholine, piperazine, pyrrolidine, diethylamine, and (S)-1-phenylethanamine, were proven to be viable substrates as well, furnishing the desired lactones in good to excellent yields. Remarkably, the alkene 1o was also successfully transformed into desired product 5ob with 50% yield in the presence of morpholine-substituted acetamide 4b. Remarkably, the efficient copper(I)-catalyzed oxydifluoroalkylation of unsaturated carboxylic acids was further extended to the bromodifluoromethyl substituted ketones (Scheme 4b). Aliphatic acid 1h was functionalized under our optimized conditions (40 mol % CuBr was used) to afford 5-exocyclized lactones 5hg−5hh in 62% and 68% yield, respectively. However, benzoic acid 1a B
DOI: 10.1021/acs.orglett.8b02069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Copper(I)-Catalyzed Oxydifluoroalkylation between Alkenes 1 and Bromodifluoroalkanes 4
Scheme 6. Proposed Catalytic Cycle
To summarize, we have reported an expedient route to access difluoroalkylated lactones through coppert(I)-catalyzed oxydifluoroalkylation between unsaturated carboxylic acids and various α-bromodifluoromethyl substituted heterocycles, esters, amides, and ketones. The highly valued CF2-containing lactones were obtained in moderate to excellent yields. Our simple and efficient catalytic system features mild reaction conditions, easily available substrates, and remarkable functional group tolerance.
a
CuBr (40 mol %) was used as the metal source.
underwent the difunctionalization process with CF2 reagent 4g in low yield. In order to understand the working mode of our copper(I)catalyzed oxydifluoroalkylation approach, we performed a series of control experiments with representative radical scavengers (Scheme 5). Importantly, a significantly reduced yield of 5aa
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02069. Experimental procedures, characterization data, and 1H, 13 C, and 19F NMR spectra for new compounds (PDF)
Scheme 5. Mechanistic Studies
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jie Li: 0000-0002-6912-3346 Author Contributions §
Y.D., S.H., and X.D. contributed equally.
Notes
(14%) was obtained when employing 20 mol % of TEMPO as the radical scavenger. However, the desired transformation was completely stopped by introducing stoichiometric TEMPO into the catalytic system, as was also observed in the presence of 2.0 equiv of 1,1-diphenylethylene. Thus far, these findings can be rationalized in terms of a radical-involved pathway. Based on our mechanistic investigations and previous mechanistic insights,10−12,16 we propose that the catalytic cycle involves an initial single electron transfer (SET) from Cu(I)Ln (A) to 2 (4), along with a subsequent addition of •CF2R into unsaturated carboxylic acid 1 to form a difluoroalkyl radical intermediate B and Cu(II)Ln species. Thereafter, there are two possible pathways for the final C−O bond formation. Oxidation of B occurs to generate the carbocation intermediate C and regenerate the active copper(I) catalyst. Then, the final product 3 (5) was delivered through an intramolecular nucleophilic attack (Scheme 6, path a). Another pathway involves a cyclic Cu(III) intermediate D, and the reductive elimination of D under basic conditions affords the final product (Scheme 6, path b).
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant No. 21602083) and the Fundamental Research Funds for the Central Universities (JUSRP51703A).
■
REFERENCES
(1) (a) Begue, J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley: Hoboken, 2008. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (2) For recent reviews: (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. (b) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (c) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214. (d) Chen, P.; Liu, G. Synthesis 2013, 45, 2919. (e) Alonso, C.; de Marigorta, E. M.; Rubiales, G.; Palacios, F. Chem. C
DOI: 10.1021/acs.orglett.8b02069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Rev. 2015, 115, 1847. (f) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683. (h) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650. (i) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826. (j) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X. Chem. - Eur. J. 2015, 21, 12836. (k) Pannecoucke, X.; Poisson, T. Synlett 2016, 27, 2314. (l) Pan, X.; Xia, H.; Wu, J. Org. Chem. Front. 2016, 3, 1163 Selected examples:. (m) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 1881. (n) Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 10202. (o) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2016, 138, 15547. (p) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (3) Recent examples: (a) Wang, X.; Zhao, S.; Liu, J.; Zhu, D.; Guo, M.; Tang, X.; Wang, G. Org. Lett. 2017, 19, 4187. (b) Liao, J.; Fan, L.; Guo, W.; Zhang, Z.; Li, J.; Zhu, C.; Ren, Y.; Wu, W.; Jiang, H. Org. Lett. 2017, 19, 1008. (c) Guo, W.-H.; Luo, Z.-J.; Zeng, W.; Zhang, X. ACS Catal. 2017, 7, 896. (d) Lai, Y.-L.; Lin, D.-Z.; Huang, J.-M. J. Org. Chem. 2017, 82, 597. (e) Zhang, Y.; Ye, S.; Ji, M.; Li, L.; Guo, D.; Zhu, G. J. Org. Chem. 2017, 82, 6811. (f) Chen, H.; Wang, J.; Wu, J.; Kuang, Y.; Wu, F. J. Fluorine Chem. 2017, 200, 41. (g) Tarui, A.; Shinohara, S.; Sato, K.; Omote, M.; Ando, A. Org. Lett. 2016, 18, 1128. (h) He, Y.-T.; Li, L.-H.; Wang, Q.; Wu, W.; Liang, Y.-M. Org. Lett. 2016, 18, 5158. (i) Li, G.; Cao, Y.-X.; Luo, C.-G.; Su, Y.-M.; Li, Y.; Lan, Q.; Wang, X.-S. Org. Lett. 2016, 18, 4806. (j) Chen, F.; Hashmi, A. S. K. Org. Lett. 2016, 18, 2880. (k) Hua, H.-L.; Zhang, B.-S.; He, Y.-T.; Qiu, Y.-F.; Hu, J.-Y.; Yang, Y.C.; Liang, Y.-M. Chem. Commun. 2016, 52, 10396. (l) Prieto, A.; Melot, R.; Bouyssi, D.; Monteiro, N. ACS Catal. 2016, 6, 1093. (m) Ke, M.; Song, Q. J. Org. Chem. 2016, 81, 3654. (n) Wang, J.-X.; Wu, J.-J.; Chen, H.; Zhang, S.-W.; Wu, F.-H. Chin. Chem. Lett. 2015, 26, 1381. (o) Shao, C.; Shi, G.; Zhang, Y.; Pan, S.; Guan, X. Org. Lett. 2015, 17, 2652. (p) Belhomme, M.-C.; Bayle, A.; Poisson, T.; Pannecoucke, X. Eur. J. Org. Chem. 2015, 2015, 1719. (q) Ge, S.; Chaladaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4149. (r) Caillot, G.; Dufour, J.; Belhomme, M.-C.; Poisson, T.; Grimaud, L.; Pannecoucke, X.; Gillaizeau, I. Chem. Commun. 2014, 50, 5887. (s) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.; Zhang, X. J. Am. Chem. Soc. 2014, 136, 1230. (t) Belhomme, M.-C.; Poisson, T.; Pannecoucke, X. J. Org. Chem. 2014, 79, 7205. (u) Belhomme, M.-C.; Poisson, T.; Pannecoucke, X. Org. Lett. 2013, 15, 3428. (v) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406. (w) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560. (x) Zou, X.; Wu, F.; Shen, Y.; Xu, S.; Huang, W. Tetrahedron 2003, 59, 2555. (4) (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524. (b) Jiang, X.-L.; Chen, Z.-H.; Xu, X.-H.; Qing, F.-L. Org. Chem. Front. 2014, 1, 774. (c) Gu, Y.; Leng, X.-B.; Shen, Q. Nat. Commun. 2014, 5, 5405. (d) Chang, D.; Gu, Y.; Shen, Q. Chem. - Eur. J. 2015, 21, 6074. (5) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090. (6) Serizawa, H.; Ishii, K.; Aikawa, K.; Mikami, K. Org. Lett. 2016, 18, 3686. (7) Sakamoto, R.; Kashiwagi, H.; Maruoka, K. Org. Lett. 2017, 19, 5126. (8) (a) Kaiser, C.; Spagnuolo, C. J.; Adams, T. C.; Audia, V. H.; Dupont, A. C.; Hatoum, H.; Lowe, V. C.; Prosser, J. C.; Sturm, B. L.; Noronha-Blob, L. J. Med. Chem. 1992, 35, 4415. (b) Lambert, J. D.; Rice, J. E.; Hong, J.; Hou, Z.; Yang, C. S. Bioorg. Med. Chem. Lett. 2005, 15, 873. (c) Janecki, T. Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity; Wiley-VCH: Weinheim, 2013. (d) Ye, L.-W.; Shu, C.; Gagosz, F. Org. Biomol. Chem. 2014, 12, 1833. (9) (a) Castellanos, A.; Fletcher, S. P. Chem. - Eur. J. 2011, 17, 5766. (b) Denmark, S. E.; Kuster, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938. (c) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. 2013, 49, 7985 Recent examples:. (d) Griffin, J. D.; Cavanaugh, C. L.; Nicewicz, D. A. Angew. Chem., Int. Ed. 2017, 56, 2097. (e) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492. (f) Denmark, S. E.; Collins, W. R. Org. Lett. 2007, 9, 3801. (g) Niu, W.; Yeung, Y.-Y. Org. Lett. 2015, 17, 1660. (h) Xu, C.; Shen, Q. Org. Lett. 2015, 17, 4561.
(10) (a) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462. (b) Zhu, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 12655. (11) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 8069. (12) (a) Hemric, B. N.; Shen, K.; Wang, Q. J. Am. Chem. Soc. 2016, 138, 5813. (b) Xie, J.; Wang, Y.-W.; Qi, L.-W.; Zhang, B. Org. Lett. 2017, 19, 1148. (13) Du, B.; Wang, Y.; Mei, H.; Han, J.; Pan, Y. Adv. Synth. Catal. 2017, 359, 1684. (14) Yasu, Y.; Arai, Y.; Tomita, R.; Koike, T.; Akita, M. Org. Lett. 2014, 16, 780. (15) Sha, W.; Zhang, W.; Ni, S.; Mei, H.; Han, J.; Pan, Y. J. Org. Chem. 2017, 82, 9824. (16) Li, Y.; Liu, J.; Zhao, S.; Du, X.; Guo, M.; Zhao, W.; Tang, X.; Wang, G. Org. Lett. 2018, 20, 917.
D
DOI: 10.1021/acs.orglett.8b02069 Org. Lett. XXXX, XXX, XXX−XXX
