DOI: 10.1002/chem.201406627

Communication

& Synthetic Methods

Copper-Catalyzed Trifluoromethylation of Trisubstituted Allylic and Homoallylic Alcohols Jian Lei, Xiaowu Liu, Shaolin Zhang, Shuang Jiang, Minhao Huang, Xiaoxing Wu,* and Qiang Zhu*[a] these methods. In addition, difunctionalization of alkenes that incorporates trifluoromethylation, such as oxytrifluoromethylation,[9] aminotrifluoromethylation,[10] orcarbotrifluoromethylation,[11, 12] is another important strategy to introduce CF3 to molecules.[13] However, mono- or disubstituted alkenes were used in most of these cases.

Abstract: An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni’s reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which b-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product.

Trifluoromethylated molecules are frequently found in pharmaceutical and agrochemical products owing to the unique ability of the trifluoromethyl (CF3) group in improving the metabolic stability, lipophilicity, and binding selectivity of the compound.[1] Consequently, methods of introducing a trifluoromethyl group into small molecules are of great importance.[2–5] In recent years, remarkable achievements have been made in the field of direct trifluoromethylation of alkenes, which can be attributed to both the advances of transition-metal-catalyzed transformations and the discovery of practical CF3-transfering reagents. In 2011, the groups of Buchwald, Wang, Liu, and Fu independently reported the trifluoromethylation of unactivated terminal alkenes by using Togni’s or Umemoto’s reagent as a CF3 source in the presence of copper salts.[6] Soon after, Qing’s group also realized a similar transformation by using a combination of copper(I)-thiophene-2-carboxylate (CuTc)/ TMSCF3/PhI(OAc)2.[7] Although these reactions are highly efficient and regioselective, the substrates are mostly restricted to terminal olefins containing allylic C H bonds to produce linear allyl CF3-substituted E alkenes. Only a few examples of unsubstituted cyclic or 1,1-disubstituted alkenes are shown in Wang’s report.[6c] To circumvent this limitation, Sodeoka and Gouverneur disclosed the trifluoromethylation of allylsilanes with multiple substituents on the double bond to produce various branched CF3 products.[8] However, the requirement of preinstalling a silyl group hampers the wide application of

Despite these methods, the trifluoromethylation of trisubstituted alkenes is still a challenging task, especially under copper catalysis.[14] Therefore, developing a general method to trifluoromethylate trisubstituted alkenes would be highly desirable. Herein, we report an efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols under mild conditions. The trifluoromethylated alcoholic products could be useful building blocks in the synthesis of more complex molecules of biological interests. During our recent investigation on trifluoromethylation-initiated aryl migration reactions,[12a] we found that the reaction of allylic alcohol 2 with Togni’s reagent (1)[15] did not give the desired 1,2-aryl migration product, that is ketone 3, when MeOH was used as a solvent in place of DMF. Instead, the branched CF3-substituted methyl ether 5 a was obtained in 7 % yield based on 19F NMR analysis. The detection of 4 a[16] in the crude products led us to assume that the trisubstituted alkene 4 a is an intermediate in the formation of 5 a under the reaction conditions. To support this hypothesis, trisubstituted allylic methyl ether 4 a was synthesized and subjected to a reaction under the conditions described in Table 1. To our delight, the same trifluoromethylated product 5 a was obtained in 23 % yield (entry 1). The isolated yield of 5 a could be improved to 50 % when the reaction was run in CH2Cl2 (entry 2). Surprisingly, when unpro-

[a] J. Lei, X. Liu, S. Zhang, S. Jiang, M. Huang, Prof. Dr. X. Wu, Prof. Dr. Q. Zhu Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences 190 Kaiyuan Avenue, Guangzhou 510530 (P. R. China) E-mail: [email protected] [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406627. Chem. Eur. J. 2015, 21, 1 – 5

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Communication Table 1. Selected optimization studies.[a]

Entry

Alkene

[Cu]

Solvent

Temp. [8C]

Yield of 5 [%][b]

1 2 3 4 5 6 7 8 9 10 11

4a 4a 4b 4b 4b 4b 4b 4b 4b 4b 4b

CuI CuI CuI CuI CuI CuI CuI CuI CuCl CuTc CuI

MeOH CH2Cl2 CH2Cl2 DCE CHCl3 MeOH DMF DMSO CH2Cl2 CH2Cl2 CH2Cl2

50 50 50 50 50 50 50 50 50 50 rt

23 56 (50)[c] 82 (79)[c] 47 65 38 13 44 65 56 66

[a] Reaction conditions: 4 a or 4 b (0.36 mmol, 1.2 equiv), Togni’s reagent (1, 0.3 mmol), [Cu] (10 mol %), solvent (1.5 mL), 16 h. [b] Determined by 19 F NMR spectroscopy using a,a,a-trifluorotoluene as an internal standard. [c] Isolated yield shown in parenthesis.

tected allylic alcohol 4 b was used as a substrate, the corresponding CF3-containing product 5 b was isolated in 79 % yield (entry 3). Other combinations of solvent and copper salt resulted in a lower efficiency of the transformation (entries 4–10). Finally, the optimal reaction conditions were identified, which use Togni’s reagent as a CF3 source and CuI as catalyst (10 mol %) in CH2Cl2 at 50 8C. At room temperature, the yield of 5 b decreased to 66 % (entry 11). With the optimized conditions in hand, the substrate scope was then explored, firstly with trisubstituted styrene derivatives (Scheme 1). Both cyclic and acyclic phenyl-substituted allylic alcohols were trifluoromethylated to give 5 c–g in moderate to good yields. It is worth noting that products 5 e–g were formed in high selectivity in favor of the Z-configured product, probably owing to the bulkiness of the CF3-containing side chain. When an electron-rich aryl group was present, trifluoromethyl-substituted oxetane derivative 5 h’ was isolated as the major product together with the normal product 5 h. The oxetane product 5 h’ was derived from nucleophilic attack of the intramolecular alcoholic oxygen atom on the possible benzylic radical/cation intermediate that is stabilized by the electronrich arene. Although the yield of 5 h’ was low, this is the first example of a copper-catalyzed olefinic oxytrifluoromethylation in which the CF3 group is incorporated into the formed ring. Besides styrene-derived substrates, trisubstituted aliphatic allylic alcohols also underwent the allylic trifluoromethylation smoothly under the standard conditions (5 i–s). Particularly, the successful formation of 5 p and 5 q provides the first example of a copper-catalyzed trifluoromethylation of acyclic trialkylsubstituted alkenes. In addition, homoallylic alcohols were applied to the current protocol, giving the corresponding products 5 q and 5 r in good yields. In the case of 4 s, in which b-H elimination was prohibited, oxetane 5 s, formed by oxytrifluor&

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Chem. Eur. J. 2015, 21, 1 – 5

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Scheme 1. Cu-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols.[a] [a] Reaction conditions: 4 (0.36 mmol), 1 (0.3 mmol), CuI (10 mol %), CH2Cl2 (1.5 mL); isolated yields (average of two runs). [b] CuBr was used instead of CuI. [c] E/Z ratio determined by 19F NMR analysis of the crude mixtures. [d] The yield in parentheses was determined by 19F NMR analysis using a,a,a-trifluorotoluene as an internal standard. Several runs of preparative thin layer chromatography were necessary to remove the starting material 4 from the product owing to their very close polarity.

omethylation, was isolated in 44 % yield. In general, a variety of functional groups were well tolerated under the mild conditions. To investigate whether these reactions proceed by a radical pathway or not, we treated radical-clock substrates 4 t and 4 u under the standard conditions (Scheme 2). Products 5 b and

Scheme 2. Trifluoromethylation of radical-clock substrates.

5 u, formed by cyclopropane cleavage followed by a homolytic aromatic substitution (HAS), were isolated in 31 and 35 % yield, respectively.[17] This observation suggests that radical intermediates are involved in the transformation, which is consistent with our previous observation in the trifluoromethylationinitiated aryl migration reaction.[12a] 2

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Communication mary alcohols are versatile functionalities in chemical transformations, the use of these building blocks in medicinal and agrochemical chemistry could be expected.

Experimental Section General procedure CuI (5.7 mg, 0.03 mmol, 10 mol %) and Togni’s reagent (1, 94.8 mg, 0.3 mmol, 1.0 equiv) were added to an oven-dried, resealable screw-cap test tube. The tube was evacuated and backfilled with argon (this process was repeated three times). A solution of alcohol 4 (0.36 mmol, 1.2 equiv) in dry CH2Cl2 (1.5 mL) was added by using a syringe. Then, the reaction mixture was stirred at 50 8C for 16 h and CH2Cl2 (15 mL) was added. The organic layer was washed with a saturated ammonia solution (4  3 mL) and brine (5 mL), dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether/EtOAc from 20:1 to 5:1) to afford the corresponding trifluoromethylated compound 5.

Scheme 3. Confirmation of the role of the free hydroxyl group.[a] [a] The yield was determined by 19F NMR analysis using a,a,a-trifluorotoluene as an internal standard.

In comparison, nearly no reaction occurred for trisubstituted alkene 4 v lacking a free hydroxyl group (Scheme 3). When the hydroxyl group in 4 p was protected as a methyl ether (4 w), the yield of 5 w dropped to 55 %, demonstrating the critical role of the free hydroxy group in the transformation. When the OH group was one more carbon atom away from the double bond as in 4 x, the NMR yield of 5 x decreased to 37 %. Based on these observations, a plausible mechanism was proposed in Scheme 4. Initially, the copper(I) catalyst reacts

Acknowledgements We are grateful to the National Science Foundation of China (21202168, 21472190) for financial support of this work. Keywords: (homo)allylic alcohols · branched products · copper · radical reactions · trifluoromethylation [1] a) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; c) T. Yamazaki, T. Taguchi, I. Ojima in Fluorine in Medicinal Chemistry and Chemical Biology (Ed.: I. Ojima), Wiley, Chichester, 2009. [2] For selected reviews, see: a) T. Umemoto, Chem. Rev. 1996, 96, 1757; b) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470; c) T. Besset, C. Schneider, D. Cahard, Angew. Chem. Int. Ed. 2012, 51, 5048; Angew. Chem. 2012, 124, 5134; d) A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8950; Angew. Chem. 2012, 124, 9082; e) H. Egami, D. Sodeoka, Angew. Chem. Int. Ed. 2014, 53, 8294; Angew. Chem. 2014, 126, 8434; f) C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765; g) J. Charpentier, N. Fruh, A. Togni, Chem. Rev. 2015, 115, 650; h) E. Merino, C. Nevado, Chem. Soc. Rev. 2015, 43, 6598. [3] For selected reports on (hetero)aryl CF3 bond formations, see: a) M. Oishi, H. Kondo, H. Amii, Chem. Commun. 2009, 1909; b) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010, 328, 1679; c) T. Knauber, F. Arikan, G.-V. Rçschenthaler, L. J. Gooßen, Chem. Eur. J. 2011, 17, 2689; d) O. A. Tomashenko, E. C. Escudero-Adn, M. M. Belmonte, V. V. Grushin, Angew. Chem. Int. Ed. 2011, 50, 7655; Angew. Chem. 2011, 123, 7797; e) C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen, C.T. Zhang, Y.-C. Gu, J.-C. Xiao, Angew. Chem. Int. Ed. 2011, 50, 1896; Angew. Chem. 2011, 123, 1936; f) T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. Int. Ed. 2012, 51, 540; Angew. Chem. 2012, 124, 555; g) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 8436; h) X. Wang, Y. Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2013, 135, 10330. [4] For recent selected examples on sp3 C CF3 bond formations, see: a) P. Novk, A. Lishchynskyi, V. V. Grushin, J. Am. Chem. Soc. 2012, 134, 16167; b) M. Hu, C. Ni, J. Hu, J. Am. Chem. Soc. 2012, 134, 15257; c) H. Kawai, T. Furukawa, Y. Nomura, E. Tokunaga, N. Shibata, Org. Lett. 2012, 14, 5330; d) Y. Miyake, S.-I. Ota, Y. Nishibayashi, Chem. Eur. J. 2012, 18, 13255; e) G. K. S. Prakash, P. V. Jog, P. T. D. Batamack, G. A. Olah, Science 2012, 338, 1324; f) A. T. Herrmann, L. L. Smith, A. Zakarian, J. Am. Chem. Soc. 2012, 134, 6976; g) C.-B. Liu, W. Meng, F. Li, S. Wang, J. Nie, J.-A. Ma, Angew. Chem. Int. Ed. 2012, 51, 6227; Angew. Chem. 2012, 124, 6331; h) Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012,

Scheme 4. Proposed mechanism.

with Togni’s reagent (1) to generate a CF3 radical and a CuII species. Subsequent addition of the CF3 radical to alkene 4 at the less-substituted end of the double bond provides intermediate B.[14b, e, f] Single-electron transfer (SET) from the resulting carbon radical to the copper(II), which coordinates to oxygen, forms carbon cation intermediate C and regenerates CuI.[18] Subsequently, the alkene product is formed by elimination of a proton. When the proton elimination is retarded or prohibited, the oxetane derivative is obtained by nucleophilic addition of the hydroxyl group. In summary, we have developed a mild and general coppercatalyzed trifluoromethylation method by using trisubstituted allylic and homoallylic alcohols as substrates. A variety of branched CF3-containing products can be efficiently constructed from readily available trisubstituted allylic and homoallylic alcohols. Furthermore, the CF3-substituted oxetanes formed by this new method could find application in the synthesis of other useful CF3-containing heterocycles. Since alkenes and priChem. Eur. J. 2015, 21, 1 – 5

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Received: December 24, 2014 Revised: February 17, 2015 Published online on && &&, 0000

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Communication

COMMUNICATION & Synthetic Methods J. Lei, X. Liu, S. Zhang, S. Jiang, M. Huang, X. Wu,* Q. Zhu* && – && An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni’s reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-

Chem. Eur. J. 2015, 21, 1 – 5

substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which b-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product.

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Copper-Catalyzed Trifluoromethylation of Trisubstituted Allylic and Homoallylic Alcohols

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Copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols.

An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This st...
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