Transition-Metal-Free Amination of Pyridine-2-sulfonyl Chloride and Related N-Heterocycles Using Magnesium Amides

Abstract

A new transition-metal-free amination of pyridine-2-sulfonyl chloride and related N-heterocycles using magnesium amides of type RNMgCl·LiCl is reported. Additionally, the directed ortho-magnesiation of pyridine-2-sulfonamides using TMPMgCl·LiCl was investigated. Reaction of the magnesium intermediates with various electrophiles and subsequent amination using magnesium amides led to a range of 2,3-functionalized pyridines. Also, cyclization reactions providing an aza-indole and an aza-carbazole were carried out.

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

“…Thesulfone-magnesium exchange was paired with aconjugate addition to install contiguous tertiary and quaternary centers (Scheme 4). Condensing pyridylsulfonylacetonitrile (14)with benzaldehyde afforded the alkenesulfonylnitrile 18. Unlike most alkenenitriles , [23] 18 engaged in afacile conjugate addition upon addition of PhLi.…”

“…Overcoming the deprotonation by replacing the phenylsulfone with a2-pyridylsulfone (14;Scheme 3) was predicated on the strong chelation of organometallics with 2-pyridines [14] to anchor the nucleophilic alkyl group proximal to the Although no exchange occurred on addition of iPrMgCl to 15 a,t he more nucleophilic Bu 3 MgLi triggered as mooth sulfone-magnesium exchange between À15 8 8Ca nd À5 8 8C [15] (15 a!16 a!17 a). Tr apping the magnesiated nitrile 17 a with BnBr,a satest electrophile,e fficiently afforded the quaternary nitrile 4a.A lternatively,t he exchange was equally efficacious with BuLi (5 min, À78 8 8C) affording al ithiated nitrile that was benzylated to afford 4a (Scheme 3).…”

“…[21] Thes ulfone-metal exchange of 15 h and 15 i are an intriguing pair (Table 1, entries 14 and 15). Condensing pyridylsulfonylacetonitrile (14)with benzaldehyde afforded the alkenesulfonylnitrile 18. [22] In contrast, as ulfone-magnesium exchange with 15 i triggered af acile 5-exo-tet cyclization to afford the cyclopentylcarbonitrile 4p (entry 15).…”

“…[22] In contrast, as ulfone-magnesium exchange with 15 i triggered af acile 5-exo-tet cyclization to afford the cyclopentylcarbonitrile 4p (entry 15). Theefficacy of the conjugate addition likely stems from chelation with the sulfone [12] and pyridine, [14] promoting conjugate addition via the six-membered complex 19.T he resultant lithiated nitrile was efficiently trapped with methyl iodide to afford the sulfonyl nitrile 15 j,ab,b-disubstituted nitrile.S tandard sulfonemagnesium exchange of 15 j and subsequent methylation afforded the quaternary nitrile 4q (82 %yield). Condensing pyridylsulfonylacetonitrile (14)with benzaldehyde afforded the alkenesulfonylnitrile 18.…”

“…Overcoming the deprotonation by replacing the phenylsulfone with a2-pyridylsulfone (14;Scheme 3) was predicated on the strong chelation of organometallics with 2-pyridines [14] to anchor the nucleophilic alkyl group proximal to the Scheme 1. Nitrile-based metalation-alkylation strategies.…”