Transition‐Metal‐Free BF₃‐Mediated Oxidative and Non‐Oxidative Cross‐Coupling of Pyridines

Abstract

We report a BF3-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF3⋅OEt2 as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines.

Hydrohalogenation of Ethynylpyridines Involving Nucleophilic Attack of a Halide Ion

“…Next, substituent effects of the pyridine ring were studied because electron-donating groups increase the basicity of the ring nitrogen and electron-withdrawing groups diminish the electron density of the ethynyl group. 11 In the case of 3Ka , the reaction was suppressed, and severe conditions were required because stabilization of the pyridinium cation by the electron-donating group, especially in the case of 3Ka , could not diminish the electron density of the ethynyl group sufficiently (entries 10 and 11, Scheme 3). On the other hand, electron-withdrawing groups promoted the reactivity for hydrochlorination to afford the corresponding products 5Ma and 5Na in moderate yields (entries 12 and 13).…”

Synthesis and Utility of Dihydropyridine Boronic Esters

“…Tr aditional Chichibabin reactions involve the addition of nucleophiles to activated pyridines,a lthough they generally show poor regioselectivity (Scheme 1a). [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).…”

“…[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.…”

Dearomatization of Transition Metal-Coordinated N-Heterocyclic Ligands and Related Chemistry

“…In 2013 and 2014 Knochel and co-workers reported nucleophilic additions to pyridines mediated by BF 3 . 31,32 They found that the formation of pyridine-BF 3 adducts has a dramatic effect on the reaction course. Indeed, some reactions do not occur without the presence of BF 3 and, in other instances, the regioselectivity towards the product of addition to the 4-position is attributed to BF 3 complexation.…”