Pharmaceutical diversification via palladium oxidative addition complexes

Abstract

Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.

The Buchwald–Hartwig Amination After 25 Years

“…Chemie tBuXPhos ligand has been utilized to prepare stable oxidative addition palladium complexes of densely functionalized aryl halide substrates,complexes which then engaged in aseries of couplings,i ncluding C À Nc ouplings,i nt he context of drug discovery. [49] Concurrent with the development of biaryl monophosphine ligands,H artwig and co-workers examined the use of bulky trialkylphosphines as ligands for the Pd-catalyzed amination of aryl halides.T hus,t he use of PtBu 3 in ar atio 0.8:1 with respect to aP d 0 source initially allowed for the amination of aryl bromides and chlorides at either room temperature or slightly above,and enabled both the arylation of indoles and carbamates. [50] Further studies led to an improved catalyst through the use of air-stable dimeric palladium(I) complexes [PdBrL] 2 (13;L = PtBu 2 (1-Ad) or PtBu 3 ), which promoted the coupling of secondary alkylamines with aryl chlorides at room temperature within minutes (Scheme 6).…”

“…Weak organic amine bases could also be used as substitutes for strong inorganic bases in the presence of an electron‐deficient palladium complex ( 12 ) containing a dialkyl triarylphosphine ligand . Moreover, the t BuXPhos ligand has been utilized to prepare stable oxidative addition palladium complexes of densely functionalized aryl halide substrates, complexes which then engaged in a series of couplings, including C−N couplings, in the context of drug discovery …”

Mechanochemistry allows carrying out sensitive organometallic reactions in air: glove-box-and-Schlenk-line-free synthesis of oxidative addition complexes from aryl halides and palladium(0)

“…Palladium complexes obtained from oxidative addition reactions have been widely used in mechanistic studies,2 as catalyst precursors for several cross-coupling reactions3 and as stoichiometric aryl-group transfer reagents for the diversification of biomolecules and pharmaceuticals 4. Dialkylbiaryl phosphine-ligated palladium( ii ) complexes developed by Buchwald and co-workers are particularly useful reagents in these applications due to their high stability and ease of handling 2a–e,3a,4.…”

“…Palladium complexes obtained from oxidative addition reactions have been widely used in mechanistic studies,2 as catalyst precursors for several cross-coupling reactions3 and as stoichiometric aryl-group transfer reagents for the diversification of biomolecules and pharmaceuticals 4. Dialkylbiaryl phosphine-ligated palladium( ii ) complexes developed by Buchwald and co-workers are particularly useful reagents in these applications due to their high stability and ease of handling 2a–e,3a,4. One of the most common synthetic routes to these oxidative addition complexes involves reactions between the palladium(0) precursor (COD)Pd(CH 2 TMS) 2 (COD = 1,5-cyclooctadiene; TMS = trimethylsilyl) ( 1 )5 and aryl halides 2 in the presence of appropriate Buchwald-type ligands (Scheme 1).…”

“…One of the most common synthetic routes to these oxidative addition complexes involves reactions between the palladium(0) precursor (COD)Pd(CH 2 TMS) 2 (COD = 1,5-cyclooctadiene; TMS = trimethylsilyl) ( 1 )5 and aryl halides 2 in the presence of appropriate Buchwald-type ligands (Scheme 1). 2a–e,3a,4 According to the developed protocol reported by Buchwald et al , this procedure generally requires glove-box techniques, given that highly air-sensitive palladium(0) species are involved 3a,4c. These restrictions may, however, greatly reduce the practical utility of the obtained palladium complexes.…”