N-Heteroarylation of Chiral α-Aminoesters by Means of Palladium-Catalyzed Buchwald–Hartwig Reaction

Abstract

N-Heteroaryl-α-amino acid derivatives are valuable pharmacological agents as peptidomimetics. Classical SNAr methods using acid catalysis and elevated temperatures could not be extended to various α-amino acids and fairly electrophilic heterocyclic partners. Here, we report a mild and versatile method of N-heteroarylation of chiral α-aminoesters without racemization, involving Buchwald-Hartwig conditions. It could be extended to various α-amino acids and azines. This efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF receptor ligands.

Development of a Method for the N-Arylation of Amino Acid Esters with Aryl Triflates

“…The N- arylation of amino acids and esters through nucleophilic aromatic substitution 4 or hypervalent iodine chemistry 5 has been reported, along with other more indirect methods for the preparation of arylated amino acids. 6 Transition metal catalyzed N -arylation of amino acids and esters using aryl (pseudo)halides constitutes another direct approach to these compounds.…”

N‐Heteroarylation of Optically Pure α‐Amino Esters using the Pd‐PEPPSI‐IPentCl‐o‐picoline Pre‐Catalyst

“…More recently,t ransition-metal-catalyzed aminationso f (hetero)aryl halides with optically pure amines has emerged as an alternativea pproach fort he preparation of aromatic amines of high enantio-purity. [7][8][9] Copper-catalyzed Ullmann-typer eactions have, in certain cases, provent ob ee ffective in preparing optically enhanced arylamines from amino acids;h owever the substrate scope for the oxidative addition partnersh as been limited to the use of aryl bromides and iodides with no reports on the use of heteroaryl halides or aryl chlorides. [7,[10][11][12][13] In addition, strong heating (usually > 80 8C) alongw ith prolonged reactiont imes are typicallyr equired.…”

“…While the advento fP d-catalyzeda mination reactions has obviated the substrate scope limitation associated with copper-catalyst systems, there exist only af ew reports on Pd-catalyzedN -(hetero)arylation of optically pure a-amino acids(esters). [9,14,15] However,r etention of stereochemistry of the product still remains as ignificant challengew ith Pd catalysis, as racemization of the a-chirala mines can occur through b-hydride elimination (BHE) duringt he catalytic cycle. [8] One way to overcome this challenge is through ligandd esign.…”

“…Bulky phosphine ligands, which have been reportedt of acilitate fast reductive elimination (RE) ands uppress BHE, have been successfully employed in these amination reactions,c oupling av arietyo f( hetero)aryl halides with a-amino acids(esters) in moderate-to-excellent yields. [9,14,15] However, these catalysts ystemsg enerally requiret emperaturesi ne xcess of 90 8Ctoa chieve acceptable levels of conversion to product.Primary a-amino acids(esters) (i.e.,R O 2 CCH(NH 2 )R')h ave an additional selectivity concern as over-arylation of the amine can occur taking the desired monoarylation product (RO 2 CCH(NHAr)R')t ot he diarylated product( RO 2 CCH(NAr 2 )R'). For example,t he use of a-amino acids(esters) with relatively less bulky alkyl groups at the a-carbon (e.g.,m ethyl and benzyl vs. isopropyl and sec-butyl) have been shown to decreaset he efficiency of theset ransformations, with significant amountso fd i-N-arylated products being reported.…”

“…For example,t he use of a-amino acids(esters) with relatively less bulky alkyl groups at the a-carbon (e.g.,m ethyl and benzyl vs. isopropyl and sec-butyl) have been shown to decreaset he efficiency of theset ransformations, with significant amountso fd i-N-arylated products being reported. [9] Further, the chiral integrity of the a-aminoa cids(esters) wasn ot preserved, presumably due to faster rates of BHE over RE. [14] Thus, ac atalysts ystem that is capable of couplinga ryl halides with optically pure a-aminoa cids(esters)w ith high enantio-retention, which is also selective for monoarylation, has yet to be developed.Recently,w er eported dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI- [a] S.…”