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Metal-Catalyzed Synthesis of Heterocycles Bearing a Trifluoromethyl Group

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Metal-Catalyzed Synthesis of Heterocycles Bearing a Trifluoromethyl Group DOI 10.1515/pac-2013-1202 Pure Appl. Chem. 2014; 86(7): 1247–1256 Conference paper Mikiko Sodeoka* and Hiromichi Egami Metal-catalyzed synthesis of heterocycles bearing a trifluoromethyl group Abstract: The trifluoromethyl group has unique functional properties and is widely used not only in organic chemistry, but also in pharmaceutical and agrochemical science. Here we describe trifluoromethylation reactions of indoles and alkenes using Togni’s reagent. These reactions provide useful trifluoromethylated organic compounds, including heterocycles, with high efficiency. Keywords: alkenes; catalysis; copper; ICHC-24; indoles; trifluoromethylation. *Corresponding author: Mikiko Sodeoka, Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, e-mail: [email protected]; and RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; and Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Hiromichi Egami: Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; and School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Article note: A collection of invited papers based on presentations at the 24th International Congress on Heterocyclic Chemistry (ICHC-24), Shanghai, China, 8–13 September 2013. Introduction Introduction of a trifluoromethyl group into organic frameworks is an important strategy for improving metabolic stability, lipophilicity and selectivity of bioactive compounds in pharmaceutical and agrochemi- cal research [1]. The trifluoromethyl group can be introduced not only on sp2 carbon, but also on sp3 carbon [2, 3]. Construction of Csp2–CF3 bonds has been studied for a long time and recently a catalytic version of this transformation has been reported [2]. On the other hand, Csp3–CF3 bond formation generally utilizes the properties of the carbonyl group, though recently trifluoromethylation based on alkene transformation has been developed [3]. Since heterocyclic structures are frequently found in natural products and bioactive synthetic compounds [4], there is a particular need for methods to obtain heterocycles bearing a trifluoro- methyl group and also for direct introduction of a trifluoromethyl group into heterocycles at a late stage. Our group has investigated metal-catalyzed asymmetric fluorination reactions using the electrophilic fluorination reagent N-fluorobenzenesulfonimide (NFSI), and has synthesized optically active heterocycles bearing a fluorine atom on a chiral center [5]. But, there is increasing interest in trifluoromethylation of het- erocycles, especially catalytic trifluoromethylation coupled with construction of heterocycles [6]. Therefore, our focus has moved to the development of synthetic methods for heterocycles bearing a trifluoromethyl group. Herein, we present our recent work on trifluoromethylation of indoles and trifluoromethylation of alkenes to obtain trifluoromethylated heterocycles. Trifluoromethylation of indole derivatives The indole framework is a privileged core structure found in natural products and bioactive compounds, and trifluoromethylated indole derivatives are expected to show potent bioactivities [7]. They have generally been © 2014 IUPAC & De Gruyter 1248 M. Sodeoka and H. Egami: Trifluoromethylation for heterocycles prepared by utilizing indole synthetic methods, such as Fisher indole synthesis, with trifluoromethylated molecules [8, 9]. When we started to study trifluoromethylation chemistry, examples of direct trifluorometh- ylation of indoles were rare, though addition of trifluoromethyl radical generated from trifluoromethyl iodide to an indole under photo-irradiation had been reported [10]. Unfortunately, the efficiency of the method was only modest. Considering the potential utility of late-stage introduction of a functional group in biochemical studies, effective direct trifluoromethylation methods for indole derivatives would be very desirable [11, 12]. Therefore, we first examined trifluoromethylation of indoles [13]. Copper-catalyzed C2-trifluoromethylation of indoles We chose an electrophilic trifluoromethylation reagent, hypervalent iodine reagent 1 (Togni’s reagent) [14], for development of trifluoromethylation of indole derivatives, due to its nucleophilic character. Ini- tially, we treated 3-methylindole 2 with 1 under an argon atmosphere. However, the trifluoromethylation did not proceed. Togni’s reagent 1 contains a carboxylate moiety and Togni and co-workers have already III disclosed that coordination of oxygen of the carbonyl moiety to metal ion activated the I –CF3 bond and accelerated trifluoromethylation using 1 [14b]. Based on that report, we anticipated that a catalytic amount of metal ion might allow the target reaction to proceed. During screening of conditions, we found that use of CuOAc as a catalyst in MeOH provided the best results [13]. 3-Substituted indole derivatives selectively provided C2-tri fluoromethylated products (Table 1). Although an electron-withdrawing group at the 3-position retarded the reaction, various functional groups were tolerant of these reaction condi- tions. The reactions of melatonin, tryptamine, and triptophan derivatives proceeded smoothly and the corresponding products were obtained in good to high yields. In addition, it was found that N-substituted indoles were good substrates. This reaction was also applicable to indole bearing no 3-substituent. When simple indole was subjected to our reaction, the chemical yield was only 35 %. However, the yields of the desired products were enhanced by the introduction of a substituent on the nitrogen. Notably, C2-trifluoromethylated products were obtained selectively in these reactions (Scheme 1). Table 1 Trifluoromethylation of indole derivatives. R2 R2 F C I O 3 R3 CuOAc (10 mol%) R3 O + CF3 N MeOH, rt, 6-24 h N R1 R1 Togni's reagent 1 2 3 Me Me Me Me MeO Br CF CF CF3 CF3 3 3 N N N N H H Me Bn 3a: 72 %a (88 %)b 3b: 74 %a (90 %)b 3c: 90 %a (95 %)b 3d: 67 %a (85 %)b NHBoc NHBoc MeO NHAc CO2Me CF3 CF3 CF3 N N N H H H 3e: 68 %a (76 %)b 3f: 79 %a (93 %)b 3g: 48 %a (86 %)b [a] Isolated yield. [b] The numbers in parentheses based on recovered starting material. M. Sodeoka and H. Egami: Trifluoromethylation for heterocycles 1249 H H F C I O 3 CuOAc (10 mol%) O + CF3 N MeOH, rt, 6 h N R Me 1 2h, R = Me 3h: 58 % a (62 %) b 2i, R = Bn 3i: 58 % a (76 %) b [a] Isolated yield. [b] The numbers in parentheses based on recovered starting material. Scheme 1 Trifluoromethylaiton of indoles bearing no substituent at the 3-position. CF CuOAc (10 mol%) 3 1 (1.2 eq.) CF3 + CF3 N MeOH, rt, 12 h N N H H TMS 2j 3k: 71 % 4k: 10 % CF CuOAc (10 mol%) 3 1 (1.2 eq.) CF3 + CF3 N MeOH, rt, 24 h N N TBDMS TBDMS TBDMS 2l 3l: 47 % 4l: 0% Scheme 2 Trifluoromethylation of N-silylated indole derivatives. Trifluoromethylation of indoles using trimethylsilyltriflate as a catalyst In the course of our studies to establish the effect of N-substituents on the trifluoromethylation of indole derivatives (vide supra), we encountered curious results (Scheme 2) [15]. Desilylated di-trifluoromethylated product 4k was obtained in 10 % yield when N-trimethylsilyl(TMS)-3-methylindole was used as the substrate, Table 2 Trifluoromethlation of indole derivatives using TMSOTf as a catalyst. R2 R2 CF3 R2 3 TMSOTf (20 mol%) 3 3 R 1 (1.3 equiv.) R R CF3 + CF3 N CH2Cl2, rt, 5 min N N R1 R1 R1 2 3 4 substrate product substrate product MeO NHAc 3k: 71%a 3f: 63%a 2k a 2f a N 4k: 7% N 4f: 10% H H MeO 3a: 60%a 3c: 75%a 2a a 2c a N 4a: 19% N 4c: 9% H Br 3b: 67%a 3m: 55%a 2b a 2m N 4b: 9% N 4m: 0% H TBDMS NHBoc 3e: 68%a 3h: 26%a N 2e 2h N 4e: 8%a N 4h: NDb N H 5 [a] Isolated yield. [b] Not detected. 1250 M. Sodeoka and H. Egami: Trifluoromethylation for heterocycles while the reaction of N-tert-butyldimethylsilyl(TBDMS)-3-methylindole afforded only the C2-trifluorometh- ylated product in 47 % yield with no di-trifluoromethylated product. It is noteworthy that the di-trifluoro- methylated product could be obtained only when desilylation was observed. Based on this phenomenon, we hypothesized that silyl cation could work as an effective catalyst for trifluoromethylation using Togni’s reagent 1. In line with our hypothesis, TMSOTf (a representative source of silyl cation species) was used as a cata- lyst. Dichloromethane (CH2Cl2) was chosen instead of MeOH, because TMSOTf was not stable in the protic solvent. The reaction with 2k was examined under the described conditions (Table 2, entry 1) [15]. It was found that the reaction using TMSOTf was much faster than the reaction using copper catalyst. Only 5 min was required for this transformation and 3k was isolated in 71 % yield, together with a 7 % yield of di-trif- luoromethylated product 4k. Encouraged by this result, we investigated various indole derivatives (Table 1). An electron-donating methoxy group on the phenyl ring afforded di-trifluoromethylated product 4a in 19 % yield, while mono-trifluoromethylated product 3a was obtained in 60 % yield (entry 2). Under these reaction conditions, various functional groups, such as an aryl bromide, amide, and N-silyl group, remained intact, as was the case in the reaction with CuOAc as a catalyst (entries 3–5, 7). Unfortunately, the reaction of indole 2h bearing no 3-substituent provided mainly dimerization product 5 in 47 % yield, though 3h was obtained in 26 % yield (entry 8). The by-product might have been formed due to the high acidity of the reaction medium. Interestingly, N-TBDMS tolerated the acidic environment and the di-trifluoromethylation product was not formed (entry 7). Oxy-trifluoromethylation of styrene derivatives Along with trifluoromethylation of heterocycles, we have investigated the trifluoromethylation of alkenes. During the trifluoromethylation of allylsilanes, methoxy-di-trifluoromethylation product 8 was observed when a substrate having an electron-rich aromatic ring was used (Scheme 3) [16].
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