RESUMEN
The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.
Asunto(s)
Compuestos Organometálicos/química , Piridinas/síntesis química , Zinc/química , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular , Análisis de Componente Principal , Piridinas/químicaRESUMEN
A wide range of air-stable, solid, polyfunctional aryl and heteroarylzinc pivalates were efficiently prepared by either magnesium insertion or Hal/Mg exchange followed by transmetalation with Zn(OPiv)2 (OPiv = pivalate). By reducing the amount of LiCl the air stability could be significantly enhanced compared with previously prepared reagents. An alternative route is directed magnesiation using TMPMgClâ LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) followed by transmetalation with Zn(OPiv)2 or, for very sensitive substrates, direct zincation by using TMPZnOPiv. These zinc reagents not only show excellent stability towards air, but they also undergo a broad range of C-C bond-formation reactions, such as allylation and carbocupration reactions, as well as addition to aldehydes and 1,4-addition reactions. Acylation reactions can be performed by using an excess of TMSCl to overcome side reactions of the omnipresent pivalate anion.
Asunto(s)
Compuestos Organometálicos/química , Ácidos Pentanoicos/química , Zinc/química , Catálisis , Técnicas de Química Sintética/métodos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Ácidos Pentanoicos/síntesis químicaRESUMEN
The pivalates RZnOPivâ Mg(OPiv)Xâ n LiCl (OPiv=pivalate; R=aryl; X=Cl, Br, I) stand out amongst salt-supported organometallic reagents, because apart from their effectiveness in Negishi cross-coupling reactions, they show more resistance to attack by moist air than conventional organometallic compounds. Herein a combination of synthesis, coupling applications, X-ray crystallographic studies, NMR (including DOSY) studies, and ESI mass spectrometric studies provide details of these pivalate reagents in their own right. A p-tolyl case system shows that in [D8]THF solution these reagents exist as separated Me(p-C6H4)ZnCl and Mg(OPiv)2 species. Air exposure tests and X-ray crystallographic studies indicate that Mg(OPiv)2 enhances the air stability of aryl zinc species by sequestering H2O contaminants. Coupling reactions of Me(p-C6H4)ZnX (where X=different salts) with 4-bromoanisole highlight the importance of the presence of Mg(OPiv)2. Insight into the role of LiCl in these multicomponent mixtures is provided by the molecular structure of [(THF)2Li2(Cl)2(OPiv)2Zn].
RESUMEN
Treatment of pyridines, quinoline and methylthiopyrazine with the frustrated Lewis pair TMPMgCl·BF(3) (1) leads to organotrifluoro borates which react readily with a variety of aromatic aldehydes in the absence of a transition metal catalyst.
RESUMEN
A wide range of aryl and heteroaryl zinc pivalates bearing sensitive functionalities were prepared by selective metalation using TMPZnOPivâ¢LiCl, a new hindered zinc amide base. The new zinc reagents are easy-to-handle solids, which maintain their activity almost entirely (>95%) after 4 h of air exposure and smoothly undergo Negishi cross-couplings and reactions with various electrophiles such as Cu(I)-catalyzed acylations and allylations.
RESUMEN
Quinine, nicotine, and related electron-rich amino-substituted pyridines were readily metalated using LiCl-solubilized TMP (2,2,6,6-tetramethylpiperidyl) bases in the presence of BF(3)·OEt(2). A full pyridine functionalization of all five positions of the pyridine ring can be realized by using an appropriate combination of TMP bases in the presence or absence of BF(3)·OEt(2).