Monoselective o-C–H Functionalizations of Mandelic Acid and α-Phenylglycine

Abstract

Pd-catalyzed C–H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd(II)/Pd(IV) and Pd(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers.

CH Bond Arylation of Diamondoids Catalyzed by Palladium(II) Acetate

“…The best conversions were obtained using hexafluoroisopropanol (HFIP). [36] The amount of catalyst Pd(OAc) 2 was reduced to 5 mol % with just a slight decrease of conversion to 3 a (Table 1, entry 17). The optimized reaction conditions were Pd(OAc) 2 (5 mol %) as the catalyst, 1.5 equiv of the aryl halide 2, AgOAc (1.3 equiv) as the base in HFIP at 110 8C.…”

Carboxylic Acids as Directing Groups for C−H Bond Functionalization

“…The redox‐neutral C−H arylation of arylacetic acids has been slow to develop. In 2015, Yu and co‐workers described the Pd(OAc) 2 ‐catalyzed ortho ‐arylation of mandelic acid derivatives by using aryl iodides as part of a thorough study of multiple C−H functionalization reactions of these substrates . The reaction conditions were mild enough to tolerate various sensitive functional groups, while yielding only monosubstituted products without epimerization of the vulnerable chiral center.…”

“…Ligand‐enabled Fujiwara–Moritani reactions have also been successfully applied to the olefination of mandelic acid. The selectivity mono‐ vs. disubstitution could be modulated by prolonging the reaction time without leading to racemization . From a detailed mechanistic study of C−H olefination of arylacetic acids, the authors concluded that the addition of an appropriate amino acid ligand triggers a switch in mechanism from C−H bond cleavage by electrophilic palladation to proton abstraction, which was the key toward better reactivity and selectivity .…”

“…As part of a study on Pd(OAc) 2 ‐catalyzed ortho ‐functionalization of arylacetic acids with several moieties, Yu and co‐workers described a single example of the acetoxylation of a mandelic acid derivative by using PhI(OAc) 2 as stoichiometric oxidant . A Pd II –Pd IV catalytic cycle is likely at work in these conditions.…”

Palladium‐Catalyzed Remote ortho‐CH Alkenylation of Alkyl Aryl Sulfones: Access to Densely Functionalized Indane Derivatives

“…Interestingly, consistent with the known influence of steric effects in the site selectivity of many C À H functionalizations, [22] the introduction of a substituent at the benzylic position in both substrates allowed a very high monoalkenylation reaction while improving the yield (9 and 10, 87% and 74%, respectively, entries 4 and 5). Remarkably, in contrast to the majority of reported C À H alkenylation reactions for which the diolefination of substrates bearing two equivalent ortho-C À H bonds is a persistent problem, [23] this approach allowed for facile and high yielding formation of the monoalkenylated products of benzyl and phenethyl 2-pyridyl sulfones with excellent ortho-regiocontrol and mono-/disubstitution selectivity using 1.1 equiv, of the alkene. [24] The key directing role of the (2-pyridyl)sulfonyl unit was established through a control experiment showing the complete lack of reactivity of the related benzyl phenyl sulfone (1b) when submitted to the reaction with phenyl vinyl sulfone under otherwise identical reaction conditions to those in Table 1, the reaction leading to exclusive recovery of starting material even after a prolonged time (Scheme 2).…”