Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts

Abstract

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

Cobalt bis(acetylacetonate)–tert-butyl hydroperoxide–triethylsilane: a general reagent combination for the Markovnikov-selective hydrofunctionalization of alkenes by hydrogen atom transfer

“…Sulfonyl oximes 6a and 6b [32] afforded the carbon–carbon coupled products 4j and 4k in 60% and 48% yields, respectively (Table 1, entries 11 and 12, respectively). Recently, our laboratory reported a formal intermolecular hydroheteroarylation using N- methoxy heteroarenium salts by Co(acac) 2 -mediated HAT [33–34]. In the original reports, 36 discrete unactivated alkenes were coupled with 38 different heteroarenium salts under mild conditions [33–34].…”

“…Recently, our laboratory reported a formal intermolecular hydroheteroarylation using N- methoxy heteroarenium salts by Co(acac) 2 -mediated HAT [33–34]. In the original reports, 36 discrete unactivated alkenes were coupled with 38 different heteroarenium salts under mild conditions [33–34]. A representative example comprises the coupling of methallyl p -methoxybenzoate ( 3a ) with N -methoxypyridinium methyl sulfate ( 6c ) to form the hydropyridylation product 4l in 66% yield and as a 4.7:1 ratio of regioisomers (Table 1, entry 13).…”

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…[28] These nucleophilic radicals then add to N-methoxypyridinium salts,u sed in large excess (5 equivalents), to afford the desired C4-or C2-monoalkylated pyridines in moderate to good yields [Scheme 9, Eq. [28] These nucleophilic radicals then add to N-methoxypyridinium salts,u sed in large excess (5 equivalents), to afford the desired C4-or C2-monoalkylated pyridines in moderate to good yields [Scheme 9, Eq.…”

“…[28] This procedure could be extended to the direct alkylation of N-methoxyimidazolium salts to afford the corresponding 2-alkylimidazoles in moderate yields,with the main limitation lying in the lower availability of the starting N-methoxyimidazolium salts compared to the corresponding imidazoles [Scheme 33, Eq. [28] This procedure could be extended to the direct alkylation of N-methoxyimidazolium salts to afford the corresponding 2-alkylimidazoles in moderate yields,with the main limitation lying in the lower availability of the starting N-methoxyimidazolium salts compared to the corresponding imidazoles [Scheme 33, Eq.…”

Visible‐Light‐Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N‐Alkoxypyridinium Salts

“…[16] We were pleased to observe that pyridyl groups possessing methyl, substituted aryl, methoxy,f luoro,c hloro,b romo,o re ster groups reacted well to afford the desired 4-heteroaryl products under the optimized reaction conditions.C hloro and bromo groups were intact under the standard reaction conditions to provide products 2n and 2o,r espectively,t hus enabling further synthetic functionalizations.T he radical coupling was also compatible with various heteroarenes, allowing the construction of 2r, 2s, 2t, 2u,a nd 2v.F or example,s ubstrates prepared from quinolines could be subjected to these reaction conditions and generated the corresponding products 2r and 2s.T he utility of the present method was further broadened by the reaction with the pyridyl-substituted substrate,w hich provided the bipyridyl product 2u.T his product is ar emarkable finding,b ecause 2,2'-bipyridines,key structures in various ligands,are typically difficult to prepare by transition metal-mediated reactions because of the severe poisoning of the metal catalyst. [18] Asubstrate with an ester group in its alkyl appendage was tested, and the C4-heteroarylated product 2ad was exclusively formed, indicating that the positional selectivity is solely determined by the 1,5-HATp rocess.P yridyl groups could be introduced to nonactivated, simple cyclohexyl groups (2af and 2ag)i ng ood yield. [18] Asubstrate with an ester group in its alkyl appendage was tested, and the C4-heteroarylated product 2ad was exclusively formed, indicating that the positional selectivity is solely determined by the 1,5-HATp rocess.P yridyl groups could be introduced to nonactivated, simple cyclohexyl groups (2af and 2ag)i ng ood yield.…”