Letter pubs.acs.org/OrgLett
Benzylic C−H Trifluoromethylation via Photoenol Takafumi Ide, Shuya Masuda, Yuji Kawato, Hiromichi Egami, and Yoshitaka Hamashima* School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan S Supporting Information *
ABSTRACT: Photoenols generated in situ from ortho-methylsubstituted phenylketones such as benzophenones and acetophenones were trifluoromethylated with Togni reagent without any additive or catalyst. This trifluoromethylation reaction proceeded smoothly under photoirradiation conditions (365 nm). Various functional groups were tolerant of the reaction conditions. Interestingly, the trifluoromethyl group was exclusively introduced at the ortho-benzylic position. Mechanistic studies suggested that this reaction proceeds via formation of a photoenol, not via a radical pathway. Scheme 1. Reaction of o-Methylbenzophenones under Photoirradiation Conditions
T
he development of efficient synthetic methods for incorporating trifluoromethyl group(s) into organic materials is important because of the increasing interest in trifluoromethylated compounds in pharmaceutical, agrochemical, and materials sciences.1,2 Therefore, various approaches have been investigated, including electrophilic or radical trifluoromethylation of carbonyl compounds and C−C multiple bonds.3 Direct C−H trifluoromethylation is considered to be efficient and atom-economical.4 In the case of Csp2−H bonds of aromatic rings, transition-metal catalysis5 and radical chemistry6 have been used. On the other hand, only a few examples of Csp3−H trifluoromethylation have been reported, and most of them employed tetrahydroisoquinolines as starting materials.7,8 During the course of our studies of trifluoromethylation chemistry,9 we recently discovered a C−H trifluoromethylation of phenol derivatives.10 Stimulated by this finding, we became interested in the development of other types of Csp3−H trifluoromethylation reactions. ortho-Alkylbenzophenone derivatives are known to give the corresponding photoenols via generation of a ketyl radical intermediate by n-π* excitation and hydrogen atom abstraction (HAT) under photoirradiation conditions.11 Photoenols have been studied for direct functionalizations of benzylic Csp3−H bonds since the mid-20th century, and several types of electrophiles successfully undergo C−C bond-forming reactions (Scheme 1a).12 Based on these precedents, we envisioned that photoenols generated in situ would react with electrophilic trifluoromethylating reagents. In this paper, we disclose a novel benzylic Csp3−H trifluoromethylation of ortho-methyl-benzophenone and acetophenone derivatives under photoirradiation conditions without any additive (Scheme 1b). For optimization of the reaction conditions, 2-methylbenzophenone (1a) was chosen as a test substrate (Table 1). In reference to the precedent examples,12m,n an excess amount of the substrate was used in our reaction. First, the reaction was carried out with Togni reagent II (3)13 in dichloromethane (CH2Cl2) using an LED lamp at 365 nm (entry 1). The trifluoromethylated compound 2a was obtained in 58% yield. Polar solvents such as MeCN and DMF also provided 2a in © 2017 American Chemical Society
good yield (entries 2 and 3). Among the solvents tested, DMSO was found to be the solvent of choice (entries 1−4), and the reaction in DMSO afforded 2a in quantitative yield, to our delight (entry 4). The trifluoromethylated product was isolated by recycle gel permeation chromatography. We also investigated the reaction using other LED lamps, but other wavelengths (375 and 395 nm) proved ineffective (entries 5 and 6). The trifluoromethylating reagent also had a great impact on the reaction efficiency. Thus, while the reaction with Togni reagent I (4) provided 2a in 69% yield (entry 7), the desired product was not formed at all with Umemoto reagent 5 (entry 8).14 Unfortunately, reduction of the amount of substrate 1a resulted in lower yields (entries 9 and 10). According to the literature,12 the property of electrophilicity seems to be crucial for determining a suitable amount of benzophenone derivatives. For the reaction with 3, 3 equiv of benzophenone substrate were required, probably because of a high-energy short-lived photoenol intermediate. As shown in entry 11, the reaction did not proceed at all in the absence of photoirradiation. We next examined other o-methylbenzophenone derivatives under the optimized reaction conditions (Scheme 2). The reactions of ketones having an electron-donating group Received: June 28, 2017 Published: August 11, 2017 4452
DOI: 10.1021/acs.orglett.7b01971 Org. Lett. 2017, 19, 4452−4455
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
entry
solvent
hν (nm)
[CF3+]
yield (%)b
1 2 3 4 5 6 7 8 9d 10e 11f
CH2Cl2 MeCN DMF DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
365 365 365 365 375 395 365 365 365 365 −
3 3 3 3 3 3 4 5 3 3 3
58 69 64 quant (98)c 30 34 69 0 54 55 0
afforded the trifluoromethylated products in good yields (2b, 2c, and 2d). The halogen atoms were tolerant of this reaction, and 2e and 2f were obtained in 56% and 55% yields, respectively. It was found that a 1,3-dioxolane unit remained intact to give the corresponding product 2g in 75% yield. Interestingly, reaction of a benzophenone derivative bearing two methyl groups at both ortho-positions gave only monotrifluoromethylated product 2h. In addition, the orthomethyl group was selectively trifluoromethylated in high yield even in the presence of an additional methyl group at the metaor para-position (2i and 2j). An electron-donating methoxy group on the reacting benzene ring reduced the reaction efficiency, but the desired product 2k was obtained in 21% yield. Furthermore, 2-phenyl-2′-methyl-acetophenone 1l and 2′-methylacetophenone 1m were applicable to the present reaction, affording 2l and 2m in 32% and 49% yields, respectively. Although the product was inseparable from the remaining starting material, ortho-ethyl substituted benzophenone was also trifluoromethylated in 29% NMR yield. Unfortunately, a complex mixture was obtained when otolualdehyde was reacted with 3 under photoirradiation conditions. The reaction of 4,4′-dimethylbenzophenone did not give the desired Csp3−H trifluoromethylated compound, suggesting that the ortho-methyl group is essential for the generation of photoenol. To obtain information regarding the reaction mechanism, we examined the reaction in the presence of radical scavengers (Scheme 3). Tetramethylpiperidine N-oxide (TEMPO) and
a
The reactions were carried out with a trifluoromethylating reagent (1 equiv) and 1a (3 equiv) in the described solvent (0.1 M) under an argon atmosphere, unless otherwise mentioned. bDetermined by 1H NMR analysis using 1,2-dibromoethane as an internal standard. c Isolated yield. dRun with 1.1 equiv of 1a. eRun with 1.5 equiv of 1a. f Run without photoirradiation.
Scheme 2. Substrate Scope
Scheme 3. Mechanistic Studies for C−H Trifluoromethylation
a
3,5-di-tert-butyl-4-hydroxytoluene (BHT) did not retard the desired trifluoromethylation reaction. In the case of TEMPO, the product was still obtained in a comparable yield (74%) and only 20% of TEMPO−CF3 adduct was formed.15 The CF3trapping product of BHT was not detected. Notably, compounds derived from the reaction between substrate and radical scavengers were not detected at all in the above reactions. These results strongly suggest that an ionic pathway is predominantly involved in this reaction, not a radical pathway, which is in accord with our working hypothesis. NMR experiments were also conducted. After irradiation of the DMSO-d6 solution of 3 for 1 h, decomposition of 3 was slightly observed. In addition, some nonreactive o-methylbenzophenone derivatives16 were found to accelerate the decomposition reaction. The electronic nature of the generated photoenol or its transient excited triplet state depends on the substituents, which may have a strong influence on the reaction course. When the decomposition of 3 is predominant, single
a
Determined by 1H NMR analysis using 1,2-dibromoethane as an internal standard. The values in parentheses are isolated yields. 4453
DOI: 10.1021/acs.orglett.7b01971 Org. Lett. 2017, 19, 4452−4455
Organic Letters
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electron transfer from the photoenol or its excited state to 3 might occur in preference to nucleophilic attack of the photoenol on the hypervalent iodine moiety of 3 (Figure 1).
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yoshitaka Hamashima: 0000-0002-6509-8956 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant for Platform for Drug Discovery, Informatics and Structural Life Science from and AMED and Grant-in-Aid for Scientific Research (B) (No. 16H05077). We thank TOSOH F-TECH, Inc. for a generous gift of Ruppert-Prakash reagent.
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Figure 1. Proposed mechanism.
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013. (b) Gouverneur, V.; Müller, K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications; Imperial College Press: London, 2012. (c) Ojima, I. Fluorin in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Oxford, 2009. (2) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (c) Bégué, J.-P.; BonnetDelpon, D. J. Fluorine Chem. 2006, 127, 992. (d) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (e) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (f) Purser, S.; Moore, P. R.; Swallowb, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (g) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071. (3) For selected reviews on trifluoromethylations, see: (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) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (e) Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513. (f) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294. (g) Charpentier, J.; Früh, N.; Togni, A. Chem. Rev. 2015, 115, 650. (h) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683. (i) Koike, T.; Akita, M. Acc. Chem. Res. 2016, 49, 1937. (4) For recent selected reviews on C−H functionalizations, see: (a) Huang, X.; Groves, J. T. ACS Catal. 2016, 6, 751. (b) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900. (c) Santiago, J. V.; Machado, A. H. L. Beilstein J. Org. Chem. 2016, 12, 882. (d) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 10578. (5) For selected reports, see: (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (b) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 14682. (c) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. - Eur. J. 2011, 17, 6039. (d) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298. (e) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 11948. (f) Zhang, L.S.; Chen, K.; Chen, G.; Li, B.-J.; Luo, S.; Guo, Q.-Y.; Wei, J.-B.; Shi, Z.J. Org. Lett. 2013, 15, 10. (6) For selected reports, see: (a) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525. (b) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (c) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224. (d) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14411. (e) Cai, S.; Chen, C.; Sun, Z.; Xi, C. Chem. Commun. 2013, 49, 4552. (f) Ilchenko, N. O.; Janson, P. G.; Szabó, K. J. Chem. Commun. 2013, 49, 6614. (g) Xie, J.; Yuan, X.; Abdukader, A.; Zhu, C.; Ma, J. Org. Lett. 2014, 16, 1768.
This idea may explain our results: For instance, considerably different results were obtained between 1d and 1k, irrespective of similar UV−vis spectra (Scheme 2). Furthermore, the original peaks of 3 in DMSO-d 6 did not shift and decomposition of 3 was not observed after photoirradiation even in the presence of simple benzophenone. These results suggest that the substrate ketone and the excited biradical species did not induce the decomposition of the Togni reagent 3 strongly. Finally, the proposed mechanism is illustrated in Figure 1.12,17 First, the substrate ketone is excited by photoirradiation. The resulting triplet-state oxygen radical abstracts the hydrogen atom at the ortho-benzylic position. Subsequently, intersystem crossing (ISC) would occur rapidly to give a photoenol.18 Radical trapping experiments strongly suggest that the reaction of radical intermediates with a trifluoromethyl radical is less likely, and ISC is much faster than single electron transfer from the biradical intermediate. Then, the photoenol would attack the hypervalent iodine of the Togni reagent 3 followed by reductive elimination 3g to give the trifluoromethylated compound 2. In summary, we have developed a metal-free C−H trifluoromethylation of o-methyl-(di)aryl ketones under photoirradiation conditions. This reaction reached completion at room temperature within 1 h without any additive, providing the corresponding benzylic trifluoromethylation product selectively in moderate to good yield. Radical trapping experiments suggested that the photoenol is the key intermediate in this reaction. To our knowledge, this is the first report of the reaction between photoenol and hypervalent iodine reagents. Further studies to improve the efficiency of the reaction are underway in our laboratory.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01971. Typical experimental procedure and characterization of products (PDF) 4454
DOI: 10.1021/acs.orglett.7b01971 Org. Lett. 2017, 19, 4452−4455
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DOI: 10.1021/acs.orglett.7b01971 Org. Lett. 2017, 19, 4452−4455
