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

Abstract

A robust, mild, and efficient method for the Pd-catalyzed N-heteroarylation of optically pure α-amino esters was developed. Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](o-picoline)palladium(II) (Pd-PEPPSI-IPent -o-picoline; PEPPSI=pyridine enhanced pre-catalyst preparation, stabilization, and initiation) was shown to effectively couple a variety of amino acids as the tert-butyl ester with heteroaryl chlorides in high yields and with excellent stereoretention of the acidic proton adjacent to the ester. Control experiments revealed that racemization is base-mediated, with no evidence of Pd-mediated β-hydride elimination when using Pd-PEPPSI-IPent , and that racemization occurs only after the product is formed, that is, the non-arylated starting amino ester does not deprotonate under our reaction conditions. Studies also revealed that increasing the steric bulk of the ester moiety on the amino acid (e.g., ethyl to tert-butyl) drastically slows racemization of the product.

Transition Metal‐Free N‐Arylation of Amino Acid Esters with Diaryliodonium Salts

“…Substrates 1 c and 1 d could also be arylated with less activated diaryliodonium salts, providing the phenylated and tert ‐butyl‐substituted products 3 s – 3 v . The reactions with valine ester 1 d gave consistently higher yields than the corresponding reactions with 1 c , a trend that has also been reported in previous N ‐arylations [2a, 12a, 13b] …”

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

“…Stereoretentive N ‐arylation is a challenging transformation for amino acid esters [12–16] . Although transition metal‐catalyzed N ‐arylation of amines with aryl halides is practical for synthesizing aryl amines, [17–19] it cannot be easily applied to stereoretentive reactions of amino acid esters (Scheme 1a); this N ‐arylation is limited by racemization and other side reactions from stoichiometric or excess amounts of strong base reagents [13–16] .…”

“…2‐Tetralone reacted to afford the desired N ‐naphthyl product ( 3 ah ) in high yield with 99 % ee. Furthermore, N ‐benzylated 4‐ and 3‐piperidones 2 i and 2 j produced the 4‐ and 3‐pyridine derivatives 3 ai and 3 aj , respectively [14] . In this interesting transformation, it is assumed that the N ‐pyridyl group is introduced via consecutive condensation and dehydrogenative aromatization involving N ‐debenzylation by the Pd catalyst.…”

“…[9][10][11] Stereoretentive N-arylation is a challenging transformation for amino acid esters. [12][13][14][15][16] Although transition metal-catalyzed N-arylation of amines with aryl halides is practical for synthesizing aryl amines, [17][18][19] it cannot be easily applied to stereoretentive reactions of amino acid esters (Scheme 1a); this Narylation is limited by racemization and other side reactions from stoichiometric or excess amounts of strong base reagents. [13][14][15][16] In contrast, the catalytic N-arylation of amines with cyclohexanones is a promising method that can be applied to the synthesis of amino acid esters (Scheme 1b).…”

“…[12][13][14][15][16] Although transition metal-catalyzed N-arylation of amines with aryl halides is practical for synthesizing aryl amines, [17][18][19] it cannot be easily applied to stereoretentive reactions of amino acid esters (Scheme 1a); this Narylation is limited by racemization and other side reactions from stoichiometric or excess amounts of strong base reagents. [13][14][15][16] In contrast, the catalytic N-arylation of amines with cyclohexanones is a promising method that can be applied to the synthesis of amino acid esters (Scheme 1b). [20][21][22][23][24] Unlike transition metal-catalyzed CÀ N couplings using aryl halides, this reaction proceeds under neutral conditions in the absence of base reagents and will, therefore, be compatible with basesensitive amino acid compounds.…”