Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds

Abstract

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2CR2) across a carbon–carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Vinyl Azides as Radical Acceptors in the Vitamin B12-Catalyzed Synthesis of Unsymmetrical Ketones

“… 18 While investigating the mechanism of azidoalkylation of alkenes with diazoacetate, the Doyle group proposed that the addition of α-ester radicals to vinyl azides, followed by denitrogenative fragmentation and hydrolysis, afforded ketones in 47% yield. 19 The synthesis of unsymmetrical, linear ketones, however, remained elusive. On the basis of this reactivity mode and the fact that vitamin B 12 generates radicals from electrophiles, we envisaged that they should react with vinyl azides to give iminyl species that in turn will transform into ketones.…”

Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes

“…Since the electronic characteristics of the diazo group could be reversed from nucleophilic to electrophilic through the formation of the diazomethyl radical, [10a, 11] we considered whether electron‐neutral or even electron‐rich alkenes could be incorporated with the diazocarbon radical intermediate utilizing this umpolung strategy, [12] thereby providing a general methodology that would provide an alternative strategy for cycloaddition of alkenes that are unreactive towards dipolar cycloaddition. Previously, we reported radical‐mediated strategies for the functionalization of alkenes with diazo compounds [13] . The diazo compounds were transformed to carbon radical species through proton‐coupled electron transfer (PCET) process in which N 2 was released.…”

“…This observation can be rationalized by the direct decomposition of diazo substrate 2 a when a strong carboxylic acid was used (bubbles were observed when TfOH was added to the reaction system suggesting proton-denitrogenation), while low conversion occurred when other weak acids were used. Moreover, alternative oxidants such as 70 % TBHP in H 2 O (THYDRO) or cumyl hydroperoxide led to reduced yield (Table 1, entries 13,14), while di-tert-butyl peroxide (DTBP) failed to give the desired product 3 a (Table 1, entry 12). It should be mentioned that in addition to the desired 3 a, byproducts 4 a, 5 and 6 were also observed under some of these reaction conditions.…”

Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes

“…Previously, we reported radical-mediated strategies for the functionalization of alkenes with diazo compounds. [13] The diazo compounds were transformed to carbon radical species through proton-coupled electron transfer (PCET) process in which N 2 was released. The formation of the carbon-centered radicals from diazo compounds have also been reported by other groups, but in each of these processes dinitrogen is released.…”

“…This observation can be rationalized by the decomposition of diazo substrate 2 a when a strong carboxylic acid was used (bubbles were observed when TfOH was added to the reaction system suggesting proton-denitrogenation), while low conversion occurred when other weak acids were used. Moreover, alternative oxidants such as 70 % TBHP in H 2 O (THYDRO) or cumyl hydroperoxide led to reduced yield (Table 1, entries 13,14), while di-tert-butyl peroxide (DTBP) failed to give the desired product 3 a (Table 1, entry 12). It should be mentioned that in addition to the desired 3 a, byproducts 4 a, 5 and 6 were also observed under some of these reaction conditions.…”