Trifluoromethylation of various aromatic compounds by CF3I in the presence of Fe(II) compound, H2O2 and dimethylsulfoxide

Kino, Tatsuhito; Yu, Na; Ohtsuka, Yoshihiro; Yamamoto, K.; Uraguchi, Daisuke; Tokuhisa, Kenji; Yamakawa, Tetsu

doi:10.1016/j.jfluchem.2009.09.007

Cited by 195 publications

(89 citation statements)

References 41 publications

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“…For cases where conversion was exceptionally low, a second portion of tBuOOH and CF 3 SO 2 Na could be added after 24 h to drive the reaction toward completion. Pyridines (1)(2)(3)(4)(5)(6)(7)14), pyrroles (8-9), indoles (10), pyrimidines (12), pyrazines (13,15), phthalazines (16), quinoxalines (17,18), deazapurine (24), thiadiazoles (11), uracils (19,25), xanthines (20)(21)(22), and pyrazolinopyrimidines (23) can all be directly trifluoromethylated with this simple procedure. It should be noted that several of the compounds in Fig.…”

Section: Initial Investigations Into Reaction Parametersmentioning

confidence: 99%

“…It should be noted that several of the compounds in Fig. 6 are previously undescribed chemical entities (see SI Appendix), whereas others are drugs (25) or trifluoromethylated derivatives thereof (7,10,(20)(21)(22)(23). In the case of trifluridine (25), this compound has been previously prepared either with an elaborate procedure involving gaseous CF 3 I as a slowly added radical source (at an elevated temperature under an inert atmosphere in the presence of a metal catalyst) (27), or through a three-step procedure involving protection, XeF 2 -mediated trifluoromethylation, and deprotection in 40% overall yield (28).…”

Section: Initial Investigations Into Reaction Parametersmentioning

confidence: 99%

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Innate C-H trifluoromethylation of heterocycles

Brueckl

Baxter

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

686

393

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Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF 3 I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.medicinal chemistry | C-H functionalization | synthetic methodology T he trifluoromethyl group is becoming an increasingly common trait among molecules found in billion-dollar pharmaceuticals, agrochemicals, liquid crystals, dyes, and polymers (1-6). The inclusion of this motif and the unique properties its presence elicits is a testament to the success of chemical synthesis, as it is notably absent in Nature. Methodologies for the trifluoromethylation of arenes can be divided into two general categories (Fig. 1A): those that functionalize the inherently reactive positions of the substrate ("innate trifluoromethylation") and those that utilize substrate prefunctionalization or a directing group ("programmed trifluoromethylation"). For most applications, "programmed" aryl trifluoromethylation holds a distinct advantage because it can selectively functionalize positions that are not naturally reactive. Indeed, incredibly powerful methods have recently emerged in this arena (10-18). On the other hand, methods that capitalize on innate reactivity avoid the complication of preparing prefunctionalized substrates. We became interested in exploring "innate" aryl trifluoromethylation during our recent studies in the area of direct C-H arylation of heterocycles (19) and quinones (20) using radicals derived from boronic acid precursors. Aromatic heterocycles containing the trifluoromethyl group represent an important subsection of molecules of practical interest, particularly for pharmaceuticals, and therefore previously undescribed methods for their rapid assembly are in high demand. Our goal was to identify a reagent that would circumvent the use of gaseous CF 3 I (21), a reagent that is often avoided in pharmaceutical settings. At the start of our work, the task of replacing this reagent for the innate trifluormethylation of nitrogen containing heterocycles remained an unmet challenge.As briefly illustrated in Fig. 1, we evaluated numerous reagents for the trifluoromethylation of 4-t-butylpyridine as a model compound, with the aim of exploring those that might p...

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Section: Initial Investigations Into Reaction Parametersmentioning

confidence: 99%

Section: Initial Investigations Into Reaction Parametersmentioning

confidence: 99%

Innate C-H trifluoromethylation of heterocycles

Brueckl

Baxter

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

686

393

View full text Add to dashboard Cite

show abstract

“…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. To overcome such drawbacks, direct C-H trifluoromethylation recently received much attention; however, examples of aromatic C-H trifluoromethylations are still limited [35][36][37][38][39][40][41][42][43][44][45][46] . These examples include the following: (1) directing groupassisted palladium 37,38 -or silver 39 -catalysed oxidative trifluoromethylation; (2) palladium 40 -or copper 41 -catalysed oxidative trifluoromethylation of heteroaromatic compounds; and (3) radical trifluoromethylation using NaSO 2 45,46 .…”

mentioning

confidence: 99%

“…To overcome such drawbacks, direct C-H trifluoromethylation recently received much attention; however, examples of aromatic C-H trifluoromethylations are still limited [35][36][37][38][39][40][41][42][43][44][45][46] . These examples include the following: (1) directing groupassisted palladium 37,38 -or silver 39 -catalysed oxidative trifluoromethylation; (2) palladium 40 -or copper 41 -catalysed oxidative trifluoromethylation of heteroaromatic compounds; and (3) radical trifluoromethylation using NaSO 2 45,46 . The drawback to approach (1), however, is the requirement for directing groups that are not necessary in the target molecules 39 , and in approaches (2) and (3), regioselectivity is generally difficult to control, especially in the case of sixmembered heteroaromatic compounds except when using substrates with substituent(s) to block the possible reaction site(s) [40][41][42][43][44][45][46] .…”

mentioning

confidence: 99%

“…These examples include the following: (1) directing groupassisted palladium 37,38 -or silver 39 -catalysed oxidative trifluoromethylation; (2) palladium 40 -or copper 41 -catalysed oxidative trifluoromethylation of heteroaromatic compounds; and (3) radical trifluoromethylation using NaSO 2 45,46 . The drawback to approach (1), however, is the requirement for directing groups that are not necessary in the target molecules 39 , and in approaches (2) and (3), regioselectivity is generally difficult to control, especially in the case of sixmembered heteroaromatic compounds except when using substrates with substituent(s) to block the possible reaction site(s) [40][41][42][43][44][45][46] . Specifically, trifluoromethylation reactions reported by Baran 42 and MacMillan groups 44 are of wide substrate scope.…”

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confidence: 99%

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