Buchwald‐Hartwig Amination of Coordinating Heterocycles Enabled by Large‐but‐Flexible Pd‐BIAN‐NHC Catalysts**

Abstract

A new class of large‐but‐flexible Pd‐BIAN‐NHC catalysts (BIAN=acenaphthoimidazolylidene, NHC=N‐heterocyclic carbene) has been rationally designed to enable the challenging Buchwald‐Hartwig amination of coordinating heterocycles. This robust class of BIAN‐NHC catalysts permits cross‐coupling under practical aerobic conditions of a variety of heterocycles with aryl, alkyl, and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron‐deficient heterocycles containing multiple heteroatoms with BIAN‐INon (N,N′‐bis(2,6‐di(4‐heptyl)phenyl)‐7H‐acenaphtho[1,2‐d]imidazol‐8‐ylidene) as the most effective ligand. Studies on the ligand structure and electronic properties of the carbene center are reported. The study should facilitate the discovery of even more active catalyst systems based on the unique BIAN‐NHC scaffold.

Selective Buchwald–Hartwig arylation ofC-amino-1,2,4-triazoles and other coordinating aminoheterocycles enabled by bulky NHC ligands and TPEDO activator

“…[1][2][3][4][5][6][7] Despite the great progress in the development of efficient catalytic systems for a wide combination of amines and electrophiles, polynitrogen heteroaromatic compounds still remain challenging substrates for Buchwald-Hartwig cross-coupling. [8][9][10][11][12] The decreased reactivity of polynitrogen aminoheterocycles can usually be explained by the low nucleophilicity of amino groups combined with the multidentate character of these substrates as well as their arylation products, which are prone to coordinate with metal centers via endocyclic N atoms and thus hinder reductive elimination, oxidative addition, and Pd(II) to Pd(0) reduction at the activation stage. [9][10][11][12][13] 1,2,4-Triazole is a highly demanded scaffold in medicinal chemistry [14][15][16][17][18][19][20] and material sciences.…”

“…[8][9][10][11][12] The decreased reactivity of polynitrogen aminoheterocycles can usually be explained by the low nucleophilicity of amino groups combined with the multidentate character of these substrates as well as their arylation products, which are prone to coordinate with metal centers via endocyclic N atoms and thus hinder reductive elimination, oxidative addition, and Pd(II) to Pd(0) reduction at the activation stage. [9][10][11][12][13] 1,2,4-Triazole is a highly demanded scaffold in medicinal chemistry [14][15][16][17][18][19][20] and material sciences. [21][22][23][24] For example, arylamino-1,2,4-triazoles, such as the anticancer [25][26][27][28] and anti-SARS-CoV-2 [29][30][31][32] drug Bemcentinib (R428), anticancer agents JNJ-7706621 33,34 and K00546, 34,35 and antidepressant JNJ-39393406, [36][37][38] are currently under clinical trials (Fig.…”

“…Organ and co-workers described the use of Pd-PEPPSI-IPent Cl precatalyst for the (het)arylation of aminopyridines, 10 Wu, Qiu and co-workers reported new precatalyst (SIPr) Ph2 Pd(cin)Cl efficient in room temperature Buchwald-Hartwig cross-coupling of various (hetero)aryl chlorides with multinitrogen heteroaryl amines, 11 and Szostak, Liu and co-workers successfully applied Pd-BIAN-NHC complexes for catalysis of (hetero)arylation of various coordinating aminoheterocycles. 12 However, to the best of our knowledge, arylation of C-amino-1,2,4-triazoles under catalysis with Pd/NHC complexes has never been studied before. Herein, we report a facile approach to diverse 3(5)-(hetero)arylamino-1,2,4-triazoles via Pd/NHC-catalyzed (hetero)arylation of 3(5)-amino-1,2,4-triazoles enabled by the bulky NHC-ligand and new efficient Pd (II) to Pd(0) reductant (Scheme 1).…”

“…8–12 The decreased reactivity of polynitrogen aminoheterocycles can usually be explained by the low nucleophilicity of amino groups combined with the multidentate character of these substrates as well as their arylation products, which are prone to coordinate with metal centers via endocyclic N atoms and thus hinder reductive elimination, oxidative addition, and Pd( ii ) to Pd(0) reduction at the activation stage. 9–13…”

“…Organ and co-workers described the use of Pd-PEPPSI-IPent Cl precatalyst for the (het)arylation of aminopyridines, 10 Wu, Qiu and co-workers reported new precatalyst (SIPr) Ph2 Pd(cin)Cl efficient in room temperature Buchwald–Hartwig cross-coupling of various (hetero)aryl chlorides with multinitrogen heteroaryl amines, 11 and Szostak, Liu and co-workers successfully applied Pd-BIAN-NHC complexes for catalysis of (hetero)arylation of various coordinating aminoheterocycles. 12…”