To Protonate or Alkylate? Stereoselective Brønsted Acid Catalysis of CC Bond Formation Using Diazoalkanes

Abstract

A new means to activate diazoalkanes has been discovered and applied broadly over the past few years. Brønsted acids, both achiral and chiral, have been used to promote the formation of carbon-carbon and carbon-heteroatom bonds with a growing number of diazoalkane derivatives. Aside from their straightforward ability to build structural and stereochemical complexity in innovative new ways, these transformations are remarkable owing to their ability to skirt competitive diazo protonation--a reaction that has long been used to prepare esters efficiently and cleanly from carboxylic acids. In cases where achiral Brønsted acids are used, high diastereoselection can be achieved. Meanwhile, chiral Brønsted acids can deliver products with both high diastereo- and enantioselectivity. More recently, systems have emerged that combine Brønsted acids and either Lewis acids or transition metals to promote carbon-carbon bond formation from diazoalkanes.

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

“…7,8,9,10,11 However, there is little evidence in the literature with regard to the existence of the diazonium ion intermediate or the identity of rate-limiting step in this mechanism. 7b,11 Based on our experimental KIEs, we propose that reversible formation of the catalyst bound diazonium ion intermediate ( gauche 3a’/anti 3a ’) could be followed by an irreversible S N 2-like ring-closure step (rate-limiting step) to form the aziridine with concomitant elimination of N 2 (Scheme 4).…”

Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acids

“…Thef ormation of carboxylate esters by the reaction of carboxylic acids with diazo compounds,m ost commonly diazomethane (R 2 ,R 3 = H), is one of the most well-known reactions of diazo compounds. [4] Ther eaction proceeds by initial protonation of the diazo carbon atom to form ad iazonium cation [4a, 5] (1), which can react directly with an ucleophile or carboxylate [Scheme 1, Eq. (1), pathway a], or can lose nitrogen to give amore stable phenonium ion [6] 3 if the diazo compound has an eighboring phenyl group,f or example,R 2 = CH 2 Ph.…”

Conversion of Azides into Diazo Compounds in Water

“…1 Moreover, C -protonation gives rise to diazonium ions, which are highly reactive alkylating agents. 2 Thermal or photochemical generation of carbenes, along with transition metal-mediated carbenoid formation, facilitates addition to double bonds and insertion into C– H,O–H, and N–H bonds. 3 This broad reactivity makes diazo compounds attractive for applications in chemical biology, having special promise in the labeling of proteins 4,5 and as tunable reactants in 1,3-dipolar cycloaddition reactions with cycloalkynes.…”