Synthesis of Amidomethyltrifluoroborates and Their Use in Cross-Coupling Reactions

Abstract

Amidomethyltrifluoroborates were successfully synthesized in a one-pot fashion and used in cross-coupling reactions with a wide variety of aryl and heteroaryl chlorides.Amidomethylarenes are commonly found in a variety of biologically active compounds (Figure 1).1 Several strategies have been developed to obtain amidomethyl-containing products such as nucleophilic displacement,2 reductive N-alkylation,3 and more commonly amidation.4 These methods follow a consonant reactivity pattern based on the nucleophilicity of the nitrogen. Recently, cross-coupling reactions using N,Ndialkylaminomethyltrifluoroborates were described to access the analogous aminomethyl moiety.5 This approach provides access to amines using a C-C bond connection strategy complementary to existing C-N bond-forming approaches.The N,N-dialkylaminomethyltrifluoroborates used in previous coupling efforts were obtained by a direct S N 2 displacement of the halides of potassium halomethyltrifluoroborates. Unfortunately, amidomethyltrifluoroborates cannot be accessed in this manner, and thus it was necessary to develop a different approach to the trifluoroborate starting materials. The strategy chosen was based on previous work pioneered by Matteson,6 in which substituted boronate esters were obtained from halomethylboronate esters via intramolecular nucleophilic displacement and one carbon homologation of in situ generated LiCHX 2 or LiCH 2 X species (X = Cl, Br, I).7 The "ate" complex resulting from initial attack of the nucleophile at the boron atom is followed by α-transfer to the neighboring carbon to form the elaborated boronate ester (Figure 2).8Amidomethylboronate esters have been synthesized following this strategy,9 but only a few examples were reported, and poor to moderate yields were observed for the formation of α-unsubstituted products in a process that required two to three steps.9f , 10 Furthermore, apart

Organotrifluoroborates: Another Branch of the Mighty Oak

“…Thus, amidomethyltrifluoroborates (eq 38), 47 Boc-protected (1°and 2°) aminomethyltrifluoroborates (eqs 39 and 40), 48 sulfonamidomethyltrifluoroborates (eq 41), 49 N-trifluoroboratomethylisoindolin-1-ones (eq 42), 50 and imidomethyltrifluoroborates 51 have all been prepared and cross-coupled effectively with a variety of aryl electrophiles, including halides, various sulfonates, 47,48a,49,50,52 and sulfamates (eq 43). 53 β-Heteroatomically substituted organometallic synthons present a different set of challenges centered about their inherent stability.…”

α‐Arylation/Heteroarylation of Chiral α‐Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross‐Coupling Catalysis

“…Our group has established an interest in the development of complementary aminomethylating [7,14–18] and related [19,20] cross-coupling procedures that take advantage of the vast number of commercially available aryl halides by using air- and moisture stable N -trifluoroboratomethyl derivatives in cross-coupling reactions. Based on this strategy, a preparation of enantiopure aminomethylarenes was sought.…”

Palladium-Catalyzed Cross-Coupling Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides

“…Supplementary material (i.e., full experimental details and copies of 1 H, 13 C, 19 F, and 11 B spectra for all compounds synthesized) associated with this article can be accessed on the publisher's website.…”

“…These methylaminotrifluoroborate nucleophiles have proven to be effective coupling partners in variety of Suzuki-Miyaura coupling reactions. [16][17][18][19][20][21][22][23][24] One drawback of methylaminotrifluoroborates is that coupling reaction conditions are usually not general in nature and typically need to be developed for each unique application. Because there are numerous reaction variables (e.g., substrate, solvent mixture, catalyst, ligand, base, temperature, time) screening for reaction protocols often benefits from the use of high-throughput facilities.…”