Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
2‑Position-Selective Trifluoromethylthiolation of Six-Membered Heteroaromatic Compounds Ryuhei Muta,‡ Takeru Torigoe,†,‡ and Yoichiro Kuninobu*,†,‡ †
Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan Department of Molecular and Material Sciences, Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan
‡
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S Supporting Information *
ABSTRACT: The regioselective C−H trifluoromethylthiolation of six-membered heteroaromatic compounds via nucleophilic attack of a CF3S source on the electrophilically activated six-membered heteroaromatic ring was developed. The reaction proceeds in good yield with good functional group tolerance, even on a gram-scale. The key to the successful regioselective transformation is the presence of an additive (2,4-dinitrobenzenesulfonyl chloride). The regioselective trifluoromethylthiolation of quinidine derivative is also demonstrated. Trifluoromethylthiolation, followed by S-oxidation, affords the corresponding sulfones.
T
pyridine and quinoline derivatives have been obtained via the deprotonation of pyridine and quinoline derivatives and their subsequent trifluoromethylthiolation using a trifluoromethanesulfenamide reagent (Scheme 1c).6 2-Trifluoromethylthiopyridine derivatives have also been obtained via nucleophilic trifluoromethylthiolation of aryl halides using a trifluoromethyl copper reagent (Scheme 1d).7 The trifluoromethyl copper complex can be generated in situ using a catalytic amount of CuCl, bipyridyl, Me3SiCF3, and Na2S2O3. 2-Trifluoromethylthiopyridine can be synthesized via the trifluoromethylthiolation of 2-iodopyridine under copper catalysis (Scheme 1e).8 Trifluoromethylthio groups can also be introduced into pyridine skeletons via a directing group-assisted coppermediated C−H trifluoromethylthiolation reaction (Scheme 1f).9 Herein, we report the regioselective C−H trifluoromethylthiolation of pyridine, quinoline, and their related compounds (Scheme 1g).10 We initially investigated the regioselective C−H trifluoromethylthiolation of quinoline based on our previously reported study.11−13 However, the desired reaction did not proceed using quinoline N-oxide or quinoline N-oxide·BF2CF3 complex with AgSCF3 (or a mixture of AgSCF3 and an additive; see the Supporting Information for details). Subsequently, we changed the additive used to electrophilically activate the quinoline ring. The reaction of quinoline Noxide (1a) with AgSCF3 in the presence of 1.1 equiv of o-NsCl in toluene at 25 °C for 16 h gave a mixture of 2-, 3-, and 4trifluoromethylthiolated quinolines (2a, 3a, and 4a, respectively) in yields of 19%, 4%, and 5%, respectively (Table 1, entry 1). The yield of 2a increased by changing the solvent (Table 1, entries 2−6) with acetonitrile affording the best
he trifluoromethylthio group (SCF3) is an important functional group found in many pharmaceuticals and agrochemicals. 1 The lipophilicity and bioavailability of bioactive molecules are enhanced upon introducing SCF3 group(s).2 Therefore, many recently developed bioactive molecules contain SCF3 group(s) (Figure 1).
Figure 1. Several examples of bioactive molecules with a trifluoromethylthio group.
Several methods have been used to synthesize aromatic and heteroaromatic compounds bearing trifluoromethylthio groups (Scheme 1).3 2-Trifluoromethylthiopyridine can be synthesized via trifluoroacetylation of thiohydroxamic acid, followed by a decarboxylative rearrangement (Scheme 1a).4 There have been several reports on the S-trifluoromethylation of dithiodipyridine using trifluoroiodomethane as a trifluoromethylation reagent (Scheme 1b).5 Trifluoromethylthiolated © XXXX American Chemical Society
Received: April 27, 2019
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DOI: 10.1021/acs.orglett.9b01474 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Table 1. Investigation of Several Solvents and Additivesa
Scheme 1. Several Examples of C−H Trifluoromethylthiolation
a
1a (0.20 mmol) was treated with a solution of AgSCF3 (1.1 equiv) and an additive (1.1 equiv) in a solvent (1.0 mL) at 25 °C. bIsolated yield.
(CH3CN, δ = −20.9 ppm) was significantly shifted to −45.7 ppm upon mixing with 2,4-dinitrobenzenesulfonyl chloride, and AgCl was not formed as a white precipitate during the reaction. These results indicate that complex A (Scheme 4) must be an important intermediate. In addition, the reaction of 1a with 4-(NO2)C6H4SO2SCF3 (5) gave 2a in
