α-Tertiary Dialkyl Ether Synthesis via Reductive Photocatalytic α-Functionalization of Alkyl Enol Ethers

Abstract

The photocatalytic construction of C(sp 3)-rich α-tertiary dialkyl ethers through the reductive αfunctionalization of alkyl enol ether substrates with conjugated alkenes in the presence of a Hantzsch ester terminal reductant under blue LED irradiation, is described. Pivoting on oxocarbenium ion generation via an initial TMSClfacilitated protic activation of the enol ether substrate, subsequent single electron transfer delivers the key nucleophilic αoxy tertiary radical capable of productively combining with a variety of alkene substrates. The new reductive functionalization strategy was simple to perform, efficient, broad in scope with respect to both alkene acceptor and enol ether donor fragments and delivered a wide range of complex α-tertiary dialkyl ether architectures. Scheme 4. Proposed mechanism for the photocatalytic α-functionalization of enol ethers Single electron transfer from the iridium(II) species (E°1/2 =-1.37 V) to the oxocarbenium ion (E°1/2 (calc) =-1.12 V) gives rise to the nucleophilic α-oxy radical 31 which then undergoes Giese-type addition with the conjugated alkene to produce the γ-amino radical. Subsequent intramolecular HAT and then intermolecular HAT permits termination, delivering the α-tertiary dialkyl ether 3a. This HAT can take place from either HE radical cation (shown, Scheme 4, right), or HEH•, rendering either HP+ or HE radical cation as the potential respective proton sources for the corresponding mechanisms (see ESI for more details). Aligned to previous investigations, the pathway shown is most likely in operation. 32 In conclusion, a mild photocatalytic reductive αfunctionalization of alkyl enol ethers has been developed. Through Lewis acid-assisted protic activation of the enol ether to generate the corresponding oxocarbenium ion and subsequent single electron reduction, we have identified a new approach to access the α-oxy dialkyl radical. This reactive intermediate was shown to engage in Giesetype coupling reactions with a wide range of alkene substrates to deliver 33 examples of α-tertiary dialkyl ether architectures. Work to understand the source of the acidity and applying this concept to further reaction systems is currently underway.

Metal-free deoxygenative coupling of alcohol-derived benzoates and pyridines for small molecules and DNA-encoded libraries synthesis

“…Control experiments showed that light and sodium acetate were crucial for the formation of the desired product; the starting benzoate ester 3 was completely recovered in both cases, while 4-cyanopyridine 9 was intact only in the former. Therefore, we propose that sodium acetate favours β-scission fragmentation by deprotonating the radical cation of the Hantzsch ester (p K a,calc in DMSO = 3.0) 14 after SET or through proton-coupled electron transfer (PCET), 15 thus inhibiting unproductive back electron transfer.…”

Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

“…Furthermore, the utility of our approach was showcased by adapting the method to apply to intramolecular examples and secondary amides, which we highlighted in the late stage functionalization of an API. DFT studies established that the energetic balance between hydrolytic stability of the iminium ion and an accessible reduction potential were key for the successful transition of the reactive intermediate between the hydrosilylation and photocatalytic reductive processes …”

C–H functionalisation tolerant to polar groups could transform fragment-based drug discovery (FBDD)

“…Routes to access sterically hindered ethers worth noting include, metal-free iodonium salt-mediated arylation of phenols, 63,64 and photocatalytic and electrochemical-mediated routes to alkyl ethers. 65,66 Of particular interest is the late-stage C–H thianthrenation chemistry reported by Ritter et al ( Fig. 8b(iii) ).…”

“…At the time there were no available options for growth via late-stage modication and this meant that any SAR exploration around the phenyl-group required a lengthy de novo synthesis. Routes to access sterically hindered ethers worth noting include, metal-free iodonium salt-mediated arylation of phenols,63,64 and photocatalytic and electrochemical-mediated routes to alkyl ethers 65,66. Of particular interest is the late-stage C-H thianthrenation chemistry reported by Ritter et al (Fig.8b(iii)) 62.…”