Nickel‐Catalyzed CH Arylation of Azoles with Haloarenes: Scope, Mechanism, and Applications to the Synthesis of Bioactive Molecules

Abstract

Novel nickel-based catalytic systems for the C-H arylation of azoles with haloarenes and aryl triflates have been developed. We have established that Ni(OAc)(2)/bipy/LiOtBu serves as a general catalytic system for the coupling with aryl bromides and iodides as aryl electrophiles. For couplings with more challenging electrophiles, such as aryl chlorides and triflates, the Ni(OAc)(2)/dppf (dppf = 1,1'-bis(diphenylphosphino)ferrocene) system was found to be effective. Thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles can be used as the heteroarene coupling partner. Upon further investigation, we discovered a new protocol for the present coupling using Mg(OtBu)(2) as a milder and less expensive alternative to LiOtBu. Attempts to reveal the mechanism of this nickel-catalyzed heterobiaryl coupling are also described. This newly developed methodology has been successfully applied to the syntheses of febuxostat (a xanthine oxidase inhibitor that is effective for the treatment of gout and hyperuricemia), tafamidis (effective for the treatment of TTR amyloid polyneuropathy), and texaline (a natural product having antitubercular activity).

Palladium‐Catalyzed Direct Cyclopropylation of Heterocycles

“…An alternative pathway involving external attack of an indole on p-allylpalladium complexes is less likely.Itwould have led to allylation at C3, more nucleophilic site of indole. [30] It was this mechanistic insight that led us to try similar couplings with thiophenes,which have C À Hbonds with pK a values below 30 in DMSO.Indeed they reacted well in the presence of KOMe (see Scheme 3c). [29] TheH-D exchange process was accompanied by partial ring opening of benzox-azole.T he ring-opened form existed as an isonitrile (34 % yield;N MR) in a[ D 6 ]benzene solution.…”

Oxazole

“…A complementary methodology uses aryl iodides as coupling partners under argon at lower temperatures (85 • C vs. 120 • C) and lower base loading, albeit with longer reaction times (36 h vs. 2-4 h) (eq 34). 53 Similarly to the previous account, Ni(cod) 2 was also an effective catalyst, and it was proposed that Ni II is first reduced to Ni 0 before it undergoes oxidative addition into the Ar-I bond. Base-mediated nickelation of the Ar-Ni II -I species then produces Ar-Ni II -oxazole.…”

Intermolecular direct arylation of five-membered ring heterocycles by non-activated aryl chlorides

“…Unfortunately, only one example of aryl chloride use was described. Furthermore, Itami has developed a method for nickel-catalyzed azole arylation by aryl bromides and chlorides [13]. Benzothiazole can be arylated with a variety of aryl chlorides by employing a Ni(OAc) 2 catalyst in combination with dppf ligand and t-BuOLi base at 140°C in dioxane (Scheme 8).…”