DOI: 10.1002/chem.201403447

Communication

& Trifluoromethylation

Dual Catalysis with Copper and Rhenium for Trifluoromethylation of Propargylic Alcohols: Efficient Synthesis of aTrifluoromethylated Enones Hiromichi Egami,[a, b, c] Takafumi Ide,[c] Masashi Fujita,[c] Toshifumi Tojo,[a, d] Yoshitaka Hamashima,*[c] and Mikiko Sodeoka*[a, b, e] Abstract: Trifluoromethylation of propargylic alcohols to provide (Z)-a-trifluoromethylated enones and b-unsubstituted a-trifluoromethylated enones proceeded with high yield and selectivity in the presence of CuI/Re2O7. The Z isomer was formed under kinetic control, though it is less stable than the E isomer in terms of steric repulsion.

The trifluoromethyl group has unique properties, and trifluoromethylation reactions have attracted significant interest in the pharmaceutical and agrochemical fields.[1, 2] Addition of a trifluoromethyl group to a C=C bond under oxidative conditions or with photo-redox catalysts has been actively investigated.[2–4] We have reported novel trifluoromethylations of simple alkenes, alkynes, and heteroaromatic compounds,[5] in which a copper or iron salt acts as an efficient catalyst for the trifluoromethylation reaction with Togni’s reagent 1.[6] Enone is also an important functional group in organic synthesis due to its versatile reactivity, and many methodologies have been developed for its construction.[7] Therefore, a-trifluoromethylated enones would serve as useful building blocks for the synthesis of bioactive compounds having a trifluoro-

[a] Dr. H. Egami, T. Tojo, Prof.Dr. M. Sodeoka Synthetic Organic Chemistry Laboratory RIKEN 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan) E-mail: [email protected] [b] Dr. H. Egami, Prof.Dr. M. Sodeoka Sodeoka Live Cell Chemistry Project, ERATO Japan Science and Technology Agency 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)

methyl group. However, suitable synthetic methods have not yet been well established for the synthesis of a-trifluoromethylated enones.[8] Allenol derivatives are expected to be good substrates for electrophilic trifluoromethylation (Scheme 1). However, allenols are usually unstable and preparation of allenol derivatives is sometimes difficult. Thus, we planned to utilize the Meyer– Schuster rearrangement, which provides enones from propargylic alcohols via an allenol intermediate.[9] The Meyer–Schuster rearrangement has been well studied from the viewpoint of the synthesis of highly substituted enones. However, there are only a few reports describing electrophilic trapping of allenol intermediates and their equivalents.[10] For example, Trost et al. developed a dual catalysis using a combination of p-allyl palladium chemistry and vanadium-catalyzed rearrangement of propargylic alcohols.[11] Recently, Gaunt and co-workers reported an arylative Meyer–Schuster rearrangement using diaryl iodonium salts with a copper catalyst to afford a variety of a-aryl a,b-unsaturated carbonyl compounds.[12] During the preparation of this paper, Liu and Tan reported the E-selective trifluoromethylation of propargylic alcohols via a Meyer–Schuster rearrangement using a copper catalyst alone, though a much longer reaction time and higher temperature were generally required.[13] As part of our research program to develop sequential reactions involving trifluoromethylation, we independently focused on a putative allenol intermediate and found a novel dual-catalytic system that is more effective than the single use of a copper catalyst alone. It is noteworthy that our reaction is Z-selective, and is thus complementary to Liu and Tan’s work. Herein we disclose a stereoselective trifluoromethylation of propargylic alcohols to provide (Z)-a-trifluoromethy-

[c] Dr. H. Egami, T. Ide, M. Fujita, Prof.Dr. Y. Hamashima School of Pharmaceutical Sciences University of Shizuoka 52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan) E-mail: [email protected] [d] T. Tojo Department of Bioengineering Tokyo Institute of Technology B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501 (Japan) [e] Prof.Dr. M. Sodeoka RIKEN Center for Sustainable Resource Science 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403447. Chem. Eur. J. 2014, 20, 12061 – 12065

Scheme 1. Trifluoromethylation of propargylic alcohol

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Communication reaction

conditions[a]

Table 1. Screening

of

Entry

[Cu]

Co-catalyst

Yield [%][b]

Z/E[c]

1 2 3 4[d] 5[e] 6 7 8 9 10

CuI CuI CuCl CuOAc Fe(OAc)2 CuI CuI CuI – CuI[f]

– Re2O7 Re2O7 Re2O7 Re2O7 MeReO3 MoO2(acac)2 VO(OSiPh3)3 Re2O7 Re2O7

33 89 71 73 53 77 68 62 trace 85

89:11 89:11 89:11 89:11 84:16 88:12 88:12 88:12 – 87:13

Table 2. (Z)-Selective

[a] The reactions were carried out with copper salt (20 mol %), co-catalyst (10 mol %) and Togni’s reagent (1.5 equiv) in CH2Cl2 on a 0.2 mmol scale, unless otherwise mentioned. [b] Isolated yield. [c] Determined by 19F NMR analysis of the crude mixture. [d] Run for 2.5 h. [e] Run for 3 h. [f] Run with 10 mol % of CuI.

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of

propargylic

alcohols[a]

[a] The reactions were carried out with CuI (20 mol %), Re2O7 (10 mol %) and Togni’s reagent (1.5 equiv) in CH2Cl2 on a 0.2 mmol scale.

lated enones and b-unsubstituted a-trifluoromethylated enones in a mild Cu/Re dual-catalytic system (Scheme 1). In order to find suitable reaction conditions, secondary propargylic alcohol 2 a was selected as a test substrate (Table 1). The reaction with CuI/Togni’s reagent system provided the desired product 3 a in moderate yield, and the substrate 2 a was recovered in 32 % yield (entry 1).[5] Unidentified by-products were detected by 1H NMR analyses of the crude mixture. We considered that the side reactions were attributable to the slow reaction rate of the Meyer–Schuster rearrangement. Therefore, Re2O7 was added to the reaction mixture to accelerate the rearrangement.[9, 14] To our delight, the reaction was completed at 40 8C after only 2 h, affording 3 a in 89 % yield with 89:11 Z/E ratio (entry 2).[15] Among the copper catalysts screened, CuI provided the best result (entries 2–4). Fe(OAc)2 could promote the reaction, albeit with moderate yield (entry 5). MeReO3,[6d] MoO2(acac)2 and VO(OSiPh3)3 also worked as co-catalysts, though the yields were lower than that obtained with Re2O7 (entries 6–8). When the reaction was carried out without CuI, only a trace amount of 3 a was detected (entry 9).[16] In this case, both the 2-iodobenzoyl ester of 2 a (24 %) and the normal Meyer–Schuster product (41 %) were obtained, and most of the Togni’s reagent was decomposed to give trifluoromethyl 2-iodobenzoate. These results strongly indicate that the combination of copper ion and rhenium oxide is essential for this reaction. Decreasing the amount of CuI did not affect the reaction efficiency, and comparable results were obtained (entry 10). Having established the optimized reaction conditions, the generality of the reaction was investigated by using various substrates (Table 2). The reaction was not affected by an orthosubstituent on the aryl ring, and compound 3 c was obtained in 78 % yield. The thiophene ring of 2 d did not react under these conditions, and the desired product 3 d was obtained Chem. Eur. J. 2014, 20, 12061 – 12065

trifluoromethylation

with good efficiency. Bulkier substituents at the R2 position did not have a significant impact on the reactivity or selectivity (3 e–3 g). It should be noted that all the reactions examined in Table 2 gave the trifluoromethylated compound 3 with Z configuration as the major product, whereas the E form was generally the major product under Liu and Tan’s conditions. Encouraged by these results, we examined the reactions of primary propargylic alcohols, which have not been reported to date (Table 3). We found that terminal enones having a trifluoromethyl group at the a-position were successfully obtained in good yield. The reaction without Re2O7 provided 5 a in 31 % yield and the starting material 4 a was recovered in 30 % yield.

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Table 3. Trifluoromethylation

of

primary

propargylic

alcohols[a]

[a] The reactions were carried out with CuI (20 mol %), Re2O7 (10 mol %) and Togni’s reagent (1.5 equiv) in CH2Cl2 on a 0.2 mmol scale.

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication This clearly indicates that the addition of rhenium oxide is effective for primary alcohols to smoothly promote the desired trifluoromethylation. TBS-ether and aryl halides were tolerant of these reaction conditions (5 b, 5 e, 5 f). Interestingly, the di-trifluoromethylated product was detected as a by-product. The second trifluoromethyl group might be incorporated through hydrotrifluoromethylation. For example, 6 c was obtained in 8 % yield in the reaction of 4 c. Notably, this is the first report of successful transformation of primary propargylic alcohols to b-unsubstituted atrifluoromethylated enones. To obtain information regarding the stereoselectivity of this trifluoromethylation, the time course of the Z/E ratio was monitored by NMR analysis in the reaction of 2 a under the optimized conditions (Table 1, entry 2 and Figure 1). The Z/E ratio dramatically decreased with increasing reaction time. Although isolated 3 a did not undergo isomerization in the absence of the catalyst, the Z/E ratio decreased in the presence of the Cu/Re catalysts and Togni’s reagent.

Figure 2. Proposed mechanism.

Figure 1. Time course of Z/E ratio during the reaction of 2 a.

These results clearly indicate that the Z isomer was kinetically formed in our reaction. Furthermore, the trifluoromethylation of silyl allenyl ether 7[17] was conducted under the described conditions [Eq. (1)]. Although the corresponding trifluoromethylated product was obtained in only 27 % yield, the E-configured product was formed as a major isomer.[15] If the reaction proceeds via an allenol intermediate, the trifluoromethylation would be expected to occur at the less hindered face of the silyl enolate of 7, affording the E isomer as a major product. This result strongly supports the idea that an allenol intermedi-

ate is unlikely to be involved in our Cu/Re dual catalysis. This is in striking contrast to the reaction mechanism proposed by Liu and Tan, even though their reaction conditions and ours seem similar. To explain the above results, we propose an alternative reaction mechanism, as illustrated in Figure 2. After coordination of Chem. Eur. J. 2014, 20, 12061 – 12065

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the alkyne moiety of the substrate to an electrophilic active species, oxetene intermediate I would be generated via a 4endo-dig cyclization with the alcoholic oxygen (path a). Although the precise nature of the active species is not clear at the moment, we assume that it might be formed by reaction of a Cu/Re complex generated in situ with Togni’s reagent. Then, a ring-opening reaction would occur in an outward manner to minimize the steric repulsion caused by the alkyl group (A), resulting in the formation of key intermediate III.[18] Finally, the product would be released by C–CF3 bond-forming reductive elimination to give the Z form in a stereoselective manner. Another possibility is path b. A rhenium–propargylic alcohol complex formed in situ would undergo six-membered ring formation in combination with an electrophilic active species to activate the alkyne of the substrate, affording intermediate II. The fragmentation of II would give key intermediate III. This fragmentation is expected to occur via transition state model B with the substituent at the b-position directed away from the ring. Reaction via an allenol interemediate IV would also be involved (path c), because the Meyer–Schuster rearrangement proceeded when the reaction was run without CuI. However, path c should be a minor pathway in our reaction, since only a trace amount of 3 a was formed (entry 9 of Table 1). Further study is required to distinguish definitively between the above two proposals. In summary, we have developed an efficient trifluoromethylation of propargylic alcohols with Togni’s reagent to provide a-trifluoromethylated enones in the presece of CuI and Re2O7 dual catalysts. The reaction of secondary propargylic alcohols proceeded in a Z-selective manner, under kinetic control. In addition, primary propargylic alcohols were good substrates, affording terminal a-trifluoromethylated enones, which are expected to be useful building blocks for the synthesis of bioac-

12063

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication tive molecules. Further investigation of this reaction system is ongoing.

Experimental Section Trifluoromethylation of propargylic alcohol with CuI and Re2O7: CuI (7.6 mg, 20 mol %), Re2O7 (9.7 mg, 10 mol %), and Togni’s reagent 1 (94.8 mg, 1.5 equiv) were weighed and added to a Schlenk flask, which had been flame-dried under vacuum. The flask was evacuated and back-filled with argon. Then, dichloromethane (1 mL) and 2 a (35.2 mg, 0.2 mmol) were added. The reaction mixture was stirred for 2 h at 40 8C and diluted with ethyl acetate (5 mL). The solution was washed with aqueous saturated NaHCO3 and brine. The organic layer was dried over MgSO4. After filtration, the organic solvent was evaporated and the residue was subjected to column chromatography on silica gel (hexane/ethyl acetate = 20:1) to give the trifluoromethylated product 3 a (43.4 mg, 89 %) as a colorless oil.

Acknowledgements

[5]

This work was supported in part by Project Funding from RIKEN and the NOVARTIS Foundation (Japan) for the Promotion of Science. We thank TOSOH F-TECH, INC. for generous gift of Ruppert–Prakash reagent. Keywords: copper · dual catalyst · enone · rhenium · trifluoromethyl [1] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications, Wiley-VCH, Weinheim, 2004; b) J.-P. Bgu, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley-VCH, Weinheim, 2008; c) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Oxford, 2009; d) P. Jeschke, ChemBioChem 2004, 5, 570 – 589; e) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Mller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637 – 643; f) M. Shimizu, T. Hiyama, Angew. Chem. 2005, 117, 218 – 234; Angew. Chem. Int. Ed. 2005, 44, 214 – 231; g) M. Schlosser, Angew. Chem. 2006, 118, 5558 – 5572; Angew. Chem. Int. Ed. 2006, 45, 5432 – 5446; h) C. Isanbor, D. O’Hangan, J. Fluorine Chem. 2006, 127, 303 – 319; i) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886; j) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359 – 4369; k) V. Gouverneur, K. Mller, Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications, Imperial College Press, London 2012. [2] For selected reviews on trifluoromethylation, see: a) M. A. McClinton, D. A. McClinton, Tetrahedron 1992, 48, 6555 – 6666; b) T. Umemoto, Chem. Rev. 1996, 96, 1757 – 1777; c) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757 – 786; d) T. Billard, B. R. Langlois, Eur. J. Org. Chem. 2007, 891 – 897; e) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1 – PR43; f) A. D. Dilman, V. V. Levin, Eur. J. Org. Chem. 2011, 831 – 841; g) S. Roy, B. T. Gregg, G. W. Gribble, V.-D. Le, S. Roy, Tetrahedron 2011, 67, 2161 – 2195; h) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475 – 4521; i) X.-F. Wu, H. Neumann, M. Beller, Chem. Asian J. 2012, 7, 1744 – 1754; j) A. Studer, Angew. Chem. 2012, 124, 9082 – 9090; Angew. Chem. Int. Ed. 2012, 51, 8950 – 8958; k) Y. Ye, M. S. Snaford, Synlett 2012, 23, 2005 – 2013; l) T. Liu, Q. Shen, Eur. J. Org. Chem. 2012, 6679 – 6687; m) Y. Mac, E. Magnier, Eur. J. Org. Chem. 2012, 2479 – 2494; n) S. BarataVallejo, A. Postigo, Coord. Chem. Rev. 2013, 257, 3051 – 3069; o) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. 2013, 125, 8372 – 8423; Angew. Chem. Int. Ed. 2013, 52, 8214 – 8264. [3] H. Egami, M. Sodeoka, Angew. Chem. Int. Ed. DOI: 10.1002/ anie.201309260. [4] For selected recent reports on trifluoromethylation of C=C bonds, see: a) A. T. Parsons, S. L. Buchwald, Angew. Chem. 2011, 123, 9286 – 9289; Chem. Eur. J. 2014, 20, 12061 – 12065

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Communication

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Chem. Eur. J. 2014, 20, 12061 – 12065

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[16] Rhenium-catalyzed trifluoromethylation of aromatic compounds with Togni’s reagent, see: E. Mejia, A. Togni, ACS Catal. 2012, 2, 521 – 527. [17] The allenol compound 7 could not be purified due to its instability. Therefore, we used the compound without purification. See Supporting Information for details. [18] a) W. R. Dolbier Jr., H. Koroniak, K. N. Houk, C. Sheu, Acc. Chem. Res. 1996, 29, 471 – 477; b) M. Shindo, S. Mori, Synlett 2008, 2231 – 2243.

Received: May 7, 2014 Published online on July 30, 2014

12065

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Dual catalysis with copper and rhenium for trifluoromethylation of propargylic alcohols: efficient synthesis of α-trifluoromethylated enones.

Trifluoromethylation of propargylic alcohols to provide (Z)-α-trifluoromethylated enones and β-unsubstituted α-trifluoromethylated enones proceeded wi...
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norbornenes from divinyl ketones.
The synthetic methods of trifluoromethylated cyclopentadienes/fulvenes/norbornenes have been developed using 3-CF3-1,4-dien-3-ols as the synthons, which can be easily prepared by the regiospecific 1,2-addition of the Ruppert–Prakash reagent (TMSCF3)

cyclization of imides: synthesis of α-trifluoromethylated amine derivatives.
Tryptamine- and phenethylamine-derived imides were selectively monotrifluoromethylated using CF3TMS. Subsequent methanesulfonic acid mediated cyclization of the intermediate hemiaminals afforded the α-trifluoromethylated amine derivatives via the for

1-Trifluoromethylated isoquinolines via radical trifluoromethylation of isonitriles.
A simple and efficient approach to biologically important 1-trifluoromethylated isoquinolines starting with readily prepared β-aryl-α-isocyano-acrylates and the commercially available Togni reagent as the CF3 radical precursor is described. These tra