Abstract:Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are selectively installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. The … Show more
“…Hence, the conversion of the NH 2 group into a modular and versatile leaving group would be highly desirable. In this sense, we turned our attention to heteroaryl chlorides since they have occupied a preferential place in synthetic routes due to the myriad of robust methods available for their chemical modification 9 . Fig.…”
Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)‒NH2 can be converted into C(sp2)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.
“…Hence, the conversion of the NH 2 group into a modular and versatile leaving group would be highly desirable. In this sense, we turned our attention to heteroaryl chlorides since they have occupied a preferential place in synthetic routes due to the myriad of robust methods available for their chemical modification 9 . Fig.…”
Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)‒NH2 can be converted into C(sp2)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.
“…2,3 Recently, we described a novel approach for the direct C-H-sulfonylation of pyridine and related N-heteroaromatics. 4 This process is based on activation of the pyridine ring with triflic anhydride (Tf2O) 5,6 followed by a 1, 4diazabicyclo[2.2.2]octane (DABCO) mediated addition of a sulfinate salt and rearomatization (Scheme 1a).…”
Section: Scheme 1 Para-selective Sulfonylation Of Pyridinementioning
The direct regioselective C-H-functionalization of simple, unfunctionalized pyridines is considered a long-standing challenge in heterocyclic chemistry. Herein, we report a novel one-pot protocol for the C4-selective sulfonylation of pyridines via triflic anhydride (Tf2O) activation, base-mediated addition of a sulfinic acid salt and subsequent elimination/rearomatization. Contrary to previous approaches employing tailored blocking groups, positional selectivity can be controlled by using N-methyl piperidine as simple, readily available external base. This method offers a highly modular and streamlined access to C4-sulfonylated pyridines
“…Recently, it has been employed with the aim of adding aromatic amines [ 34 , 67 ], alkylamines [ 48 , 76 ], cycloalkylamines [ 55 , 77 , 78 ], and substituted alkoxides [ 67 ]. In this respect, McNally, Paton, and co-workers designed an interesting way of coupling the 5-(diphenylphosphanyl)pyridine 118 to the position 7 of the fused pyrazole PP , generating the phosphonium salt 119 according to the authors [ 79 ]. This approach opens the door to a new functionalizations with weaker nucleophiles.…”
Section: Synthesis and Functionalizationmentioning
Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015–2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.
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