Regioselective Control of the S_NAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

Abstract

The SNAr reaction of 2,4-dichloropyrimidines, further substituted with an electron-withdrawing substituent at C-5, has selectivity for substitution at C-4. Here we report that tertiary amine nucleophiles show excellent C-2 selectivity. In situ N-dealkylation of an intermediate gives the product that formally corresponds to the reaction of a secondary amine nucleophile at C-2. This reaction is practical (fast under simple reaction conditions, with good generality for tertiary amine structure and moderate to excellent yields) and significantly expands access to pyrimidine structures.

Direct Access to 2‐Aminobenzoxazinones via Ph3P‐I2 Mediated Deoxygenative Amination of Isatoic Anhydrides with Tertiary Amines

“…It is also worth mentioning that the dealkylation by the in situ generated halide anion in “counterattack fashion” has been found to be efficient strategies for various organic transformations including S N Ar amination of heteroaryl chlorides in which similar selectivity toward N ‐debenzylation has been observed [23a,b,27] …”

Predicting solvent effects in ionic liquids: Extension of a nucleophilic aromatic substitution reaction on a benzene to a pyridine

“…Triethylamine is considered to be a non‐nucleophilic base and usually tertiary amines require harsher conditions than those used here to participate in S N Ar reactions, although there are reports of tertiary amines acting as nucleophiles for S N Ar reactions for activated electrophiles . To overcome the problem of reaction of the pyridine 3 with triethylamine, the concentration of triethylamine was decreased (to 1.1 equivalents of pyridine 3 ) in solution.…”

Photoredox Catalyzed Dealkylative Aromatic Halogen Substitution with Tertiary Amines

“…The reaction proceeds via the photoredox generation of the aryl radical, which interacts with the amine followed by loss of electron and elimination of one group from the ammonium fragment. Classical uncatalyzed nucleophilic substitution reactions of chlorine or heavier halogens with tertiary amines are known but proceed under thermal conditions [ 29 , 30 , 31 , 32 ], while such reactions of fluorides have not been described.…”