γ-Amino phosphonates via the photocatalytic α-C–H alkylation of primary amines

Photoredox-HAT Catalysis for Primary Amine α-C–H Alkylation: Mechanistic Insight with Transient Absorption Spectroscopy

“…The kinetics of electron transfer from azide anions (present as dissolved TBAA) to photoexcited 4CzIPN were determined directly by observing the rate of loss of excited-state absorption by the 4CzIPN. For the TBAA concentrations used in TVAS studies, which are comparable to those employed in the photoredox reactions of Cresswell and co-workers, − the electron transfer reaction involves the S 1 excited state of 4CzIPN, and not the longer-lived T 1 state. This bimolecular ET reaction was found to be diffusion-limited, consistent with a large thermodynamic driving force for electron transfer from N 3 – to the orbital vacancy created by electronic excitation of 4CzIPN.…”

“…Organic photocatalysts (OPCs) offer a sustainable and complementary alternative to the archetypal ruthenium- and iridium-based polypyridyl complexes applied in visible-light-mediated synthesis − and controlled polymerization. − One of many exciting advances in this area is the use of OPCs to drive catalytic derivatizations of C­(sp 3 )–H bonds, circumventing the need for prefunctionalized organic substrates. − While some OPCs, such as eosin Y, possess excited states capable of directly abstracting hydrogen atoms from C­(sp 3 )–H bonds, a more typical (and modular) approach is to employ a discrete hydrogen-atom transfer (HAT) cocatalyst that may be photooxidized. , In this vein, one of our research groups (Cresswell and co-workers) recently discovered that azide ion (N 3 – ) is an unusually effective HAT catalyst for the challenging photocatalytic α-C–H alkylation of unprotected, primary alkylamines (Figure a) . The reported alkylation reactions employed acrylates as coupling partners for the synthesis of γ-amino esters (and their derived γ-lactams), with subsequent studies extending the chemistry to vinyl phosphonates and styrenes as radical acceptors. Cresswell and co-workers proposed the photoredox-HAT cycle depicted in Figure b for all of these transformations.…”

Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap “BecaP”

“…In particular, due to their profound biological activity, phosphonic acids and esters are found in numerous pharmaceuticals and agrochemicals (Scheme A). , Methods to access organophosphonates commonly involve two electron processes, where C–P bond formation is achieved through the reaction of nucleophilic phosphites or H-phosphonates with electrophilic halides or CX bonds, or reactions of electrophilic phosphorus­(V) reagents with organometallics . One electron processes are also known; however, their application to the synthesis of alkyl phosphonates typically involves the reaction of phosphorus-centered radicals with alkenes (Scheme B, top). , In contrast, C–P bond formation by addition of alkyl radicals to phosphorus reagents is rather underdeveloped (Scheme B, bottom) . While highly reactive aryl radicals add rapidly to trialkyl phosphites, yielding aryl phosphonates after β-scission of the intermediate phosphoranyl radicals, the lower reactivity of alkyl radicals means that they either do not react or undergo unproductive reversible addition .…”

29th Annual GP2A Medicinal Chemistry Conference

“…Alexander J. Cresswell Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.; a.j.cresswell@bath.ac.uk My group has recently found that primary alkylamines without N-protection can be employed directly in photoredox catalysis to form new C-C bonds αto nitrogen, using a variety of radicophiles as coupling partners [100,101]. This is a key advance for amine synthesis, providing a highly simplifying disconnection for α-tertiary amines and saturated azacycles, including spirocycles.…”