Transition-Metal-Free BF₃-Mediated Regioselective Direct Alkylation and Arylation of Functionalized Pyridines Using Grignard or Organozinc Reagents

Abstract

A formal regioselective cross-coupling of various pyridines with alkyl and aryl groups can be achieved by a BF3·OEt2-mediated addition of Grignard or organozinc reagents to pyridines bearing various substituents (chloro, bromo, cyano, vinyl, phenyl, carbethoxy, nitro, etc.) followed by an oxidative aromatization mediated by chloranil. Good regioselectivity and wide functional group tolerance make this method very versatile for the preparation of polyfunctional pyridines. No transition-metal catalyst is required in these coupling reactions.

Alkylation of Pyridines at Their 4‐Positions with Styrenes plus Yttrium Reagent or Benzyl Grignard Reagents

“…For example, nucleophilic addition of organometallic reagents to pyridines takes place mostly at their 2-or 4-positions, among which the former appears more feasible, but the selectivity is often difficult to control. [1][2][3][4][5] A similar issue is also found in the alkylation of pyridines through CÀH bond activation, in which the reaction preferentially occurs at the 2-position of pyridines, [11,12] likely facilitated by the initial interaction between the metal reagents and the pyridine nitrogen. Thus, the highly regioselective substitution of pyridines at the 4-position has been less frequently encountered [4,5,12] and still calls for newer, simpler, or more dependable methods using inexpensive reagents.…”

“…As nucleophilic addition at the 2-position of pyridines is more common than that at 4-position, [1][2][3][4][5] the exclusive addition of benzylmetal species at the 4-position as shown in Scheme 2 should be synthetically quite useful.…”

“…For the benzylmetal species, we chose the convenient ones, Grignard reagents, [1][2][3][4][5] and initiated the investigation, results of which are summarized in Table 3. When 2-ethylpyridine (1 a) (1 equiv) and 1-[p-(tert-butyl)phenyl]ethylmagnesium chloride (12 a) (2 equiv) were heated at reflux in THF for 18 h (Table 3, entry 3), the desired 4-alkylated pyridine 4 h was isolated in 74 % yield.…”

Synthesis and Utility of Dihydropyridine Boronic Esters

“…[2][3][4] Enhanced regioselectivity has been observed by Knochel and co-workers by using substrates with electron-withdrawing groups at C3. [5] Alternatively,M inisci reactions feature addition of alkyl or aryl radicals to aheteroarene.P oor regioselectivity is usually observed, and the 2-substituted products generally predominate (Scheme 1b). [6] Tr ansition metal catalyzed coupling reactions can also generate substituted pyridines,but they do not provide dearomatized products.…”

“…Accordingly,weused amixed zinc reagent derived from the zinc chloride and tert-butyl magnesium chloride and achieved good yields of the ester 32. [5] Additionally,a lkyl, aryl, and vinyl Grignard reagents provided the pyridines in high yields.T wo cyclopropyl Grignard reagents were incorporated without any evidence of ring opening (41, 42). Overall, the reaction is notable for its ability to 1) incorporate sp 3 -, sp 2 -, and sp-hybridized carbon nucleophiles,2 )accommodate organolithium, organozinc, and organomagnesium reagents,a nd 3) introduce electrophilic functional groups including nitriles and esters.…”