Direct Cupration of Fluoroform

Abstract

We have found the first reaction of direct cupration of fluoroform, the most attractive CF(3) source for the introduction of the trifluoromethyl group into organic molecules. Treatment of CuX (X = Cl, Br, I) with 2 equiv of MOR (M = K, Na) in DMF or NMP produces novel alkoxycuprates that readily react with CF(3)H at room temperature and atmospheric pressure to give CuCF(3) derivatives. The CuCl and t-BuOK (1:2) combination provides best results, furnishing the CuCF(3) product within seconds in nearly quantitative yield. As demonstrated, neither CF(3)(-) nor CF(2) mediate the Cu-CF(3) bond formation, which accounts for its remarkably high selectivity. The fluoroform-derived CuCF(3) solutions can be efficiently stabilized with TREAT HF to produce CuCF(3) reagents that readily trifluoromethylate organic and inorganic electrophiles in the absence of additional ligands such as phenanthroline. A series of novel Cu(I) complexes have been structurally characterized, including K(DMF)[Cu(OBu-t)(2)] (1), Na(DMF)(2)[Cu(OBu-t)(2)] (2), [K(8)Cu(6)(OBu-t)(12)(DMF)(8)(I)](+) I(-) (3), and [Cu(4)(CF(3))(2)(C(OBu-t)(2))(2)(μ(3)-OBu-t)(2)] (7).

Application of fluoroform in trifluoromethylation and difluoromethylation reactions

“…[40][41][42][43][44][45] All these research groups showed that HCF3 can react with CuCl in the presence of t-BuOK and DMF, or zinc bis-2,2,6,6-tetramethylpiperidide (TMP)2Zn, 1,3-dimethylpropyleneurea (DMPU) and phenanthroline to produce fluoroform-derived CuCF3, which was a good trifluoromethylating reagent for the trifluoromethylation, 5,46,47 and afforded the desired products 25-27 in moderate to excellent yields. 40 18 F as the precursor of CuCF2 18 F was described by Vugts and co-workers (Scheme 12). 48 Under the optimized reaction conditions, a broad range of aryl iodides and aryl boronic acids can be converted successfully into the desired products 28 in moderate to excellent yields in many cases.…”

Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

“…Most current processes for accessing CF 3 containing molecules are performed by carboxy or trichloromethyl group substitution using hazardous fluorinating reagents under harsh reaction conditions 6 . Cross-coupling reactions between organohalides [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] or boronic acids (or their esters) [25][26][27][28][29][30][31][32][33][34] and trifluoromethylating reagents are another common approach. Although CF 3 groups can be regioselectively introduced to aromatic rings in cross-coupling reactions, requirement of multiple steps for the preparation of aryl halides and boronic acids/esters and generation of stoichiometric amounts of metal salts decrease synthetic efficiency.…”

Recent advances in green fluorine chemistry

“…64 In 2011, Zanardi et al found that a mixture of CuCl and tBuOK in 1:2 ratio can effectively cuprate CF 3 H (Figure 29). 65 The resulting CuCF 3 readily reacts with ArI or ArB(OH) 2 to give the corresponding ArCF 3 . This protocol has been extended …”