A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent(Cl) catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination.
The ability to cross-couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to β-hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non-rearranged) cross-coupled product with aryl or heteroaryl oxidative-addition partners, none have shown reliable selectivity with five-membered-ring heterocycles. In this report, a new, rationally designed catalyst, Pd-PEPPSI-IHept(Cl), is demonstrated to be effective in selective cross-coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo-fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.
Herein we report the first example of (hetero)arylation of ammonia using a monoligated palladium-NHC complex. The new, rationally designed, precatalyst (DiMeIHept Cl )Pd(allyl)Cl featuring highly branched alkyl chains has been shown to be effective in selective aminations across a range of challenging substrates, including nitrogencontaining heterocycles and those featuring base-sensitive functionality. The less bulky Pd-PEPPSI-IPent Cl precatalyst performs well for ortho-substituted aryl halides, giving monoarylated products in high yield with good selectivity.
A silica-supported precatalyst, Pd-PEPPSI-IPent-SiO , has been prepared and evaluated for its proficiency in the Negishi cross-coupling of hindered and electronically deactivated coupling partners. The precatalyst Pd-PEPPSI-IPent loaded onto packed bed columns shows high catalytic activity for the room-temperature coupling of deactivated/hindered biaryl partners. Also for the first time, the flowed Csp -Csp coupling of secondary alkylzinc reagents to (hetero)aromatics has been achieved with high selectivity with Pd-PEPPSI-IPent-SiO . These couplings required residence times as short as 3 minutes to effect completion of these challenging transformations with excellent selectivity for the nonrearranged product.
Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IHept(Cl) ), a new, very bulky yet flexible Pd-N-heterocyclic carbene (NHC) complex has been evaluated in the cross-coupling of secondary alkylzinc reactants with a wide variety of oxidative addition partners in high yields and excellent selectivity. The desired, direct reductive elimination branched products were obtained with no sign of migratory insertion across electron-rich and electron-poor aromatics and all forms of heteroaromatics (five and six membered). Impressively, there is no impact of substituents at the site of reductive elimination (i.e., ortho or even di-ortho), which has not yet been demonstrated by another catalyst system to date.
A series of substrate analogues has been used determine which chemical moieties of the substrate, phosphoenolpyruvate (PEP) contribute to the allosteric inhibition of rabbit muscle pyruvate kinase (M1-PYK) by phenylalanine. Replacing the carboxyl group of the substrate with a methyl alcohol, or removing the phosphate altogether, greatly reduces substrate affinity. However, removal of the carboxyl group is the only modification tested that removes the ability to allosterically reduce Phe binding. From this, it can be concluded that the carboxyl group of PEP is responsible for energetic coupling with Phe binding in the allosteric sites.
An efficient total synthesis of the annulated indole natural product (±)-cis-trikentrin B was accomplished by means of a regioselectively generated 6,7-indole aryne cycloaddition via selective metal-halogen exchange from a 5,6,7-tribromoindole. The unaffected C-5 bromine was subsequently used for a Stille cross-coupling to install the butenyl side chain and complete the synthesis. This strategy provides rapid access into the trikentrins and the related herbindoles, and represents another application of this methodology to natural products total synthesis. The required 5,6,7-indole aryne precursor was prepared using the Leimgruber-Batcho indole synthesis.
A silica‐supported precatalyst, Pd‐PEPPSI‐IPent‐SiO2, has been prepared and evaluated for its proficiency in the Negishi cross‐coupling of hindered and electronically deactivated coupling partners. The precatalyst Pd‐PEPPSI‐IPent loaded onto packed bed columns shows high catalytic activity for the room‐temperature coupling of deactivated/hindered biaryl partners. Also for the first time, the flowed Csp3–Csp2 coupling of secondary alkylzinc reagents to (hetero)aromatics has been achieved with high selectivity with Pd‐PEPPSI‐IPent‐SiO2. These couplings required residence times as short as 3 minutes to effect completion of these challenging transformations with excellent selectivity for the nonrearranged product.
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