A General and Selective Copper‐Catalyzed Cross‐Coupling of Tertiary Grignard Reagents with Azacyclic Electrophiles

Abstract

Bulky heterocycles: A highly selective catalytic cross‐coupling reaction of tertiary Grignard reagents with chloroazacycles provides a shortcut to heterocyclic building blocks for applications in pharmaceutical chemistry and supramolecular chemistry, or as ligand precursors in transition‐metal catalysis (see scheme).

Structures, Mechanisms, and Results in Bifunctional Catalysis and Related Species Involving Proton Transfer

“…Our success in creating efficient and highly active catalysts for alkyne hydration and alkene isomerization ( Fig. 1) which both feature tert-butylated heterocycles has spurred recent improvements from the Hintermann labs in synthesis of pyridyl halides and phosphines with tert-alkyl or 2,6-disubstituted aryl groups next to nitrogen [27,47,48]. In summary, the ability to vary catalyst structure, particularly the steric environment around the basic or coordinating nitrogen, allows one to fine-tune reactivity in many ways.…”

2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine

“…This side-product will be commented upon in detail later. The bulky triazinylamines 8b/c and 2-pyrimidylamine 9a emerged from similar S N Ar reactions of chlorinated precursors [25] and the respective amines. Pyrimidylamine 9b was prepared by condensation of the bdiketone with guanidine [44], while 2-aminotriazines 8d-8g with less bulky substituents R were synthesized from nitriles (RCN) and guanidine according to Kabbe et al (Scheme 3b) [45].…”

“…Triazinylamines 8 and pyrimidylamines 9 were obtained by several methods: first, reaction of chlorotriazine 1 [25] with aqueous ammonia in ethanol gave 2-aminotriazine 8a, accompanied by a trace of ethoxy derivative 10a (Scheme 3a). This side-product will be commented upon in detail later.…”

“…We have recently introduced a copper-catalyzed crosscoupling of doubly or triply halogenated azacycles with tertiary alkyl Grignard reagents that gave direct access, among a variety of products, to 2-alkylated 4,6-dichloro-1,3,5-triazines and 2,4-dialkylated 6-chloro-1,3,5-triazines, and thus to bulky azacyclic building blocks with electrophilic sites for further synthetic manipulation [25]. The building blocks obtained using that methodology have led, inter alia, to new syntheses of geometrically restrained selenacalix [3] triazines [26], bulky ligands for studying organometallic coordination chemistry [27,28], metal complexes for dye-sensitized solar cells [29][30][31], ligands for transition metal catalysis [32], or building blocks for medicinal chemistry [33,34].…”

“…Di-tert-butyl-6-ethoxy-1,3,5-triazine (10a, C 13 H 23 N 3 O) 2-Chloro-4,6-di-tert-butyl-1,3,5-triazine (1[25]; 5.00 g, 22.0 mmol) was added to a solution of 1.…”