Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals

Abstract

In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane systems was studied. Competition experiments in benzene at 80°C with brominated oxime ethers using Bu3SnH as...

Study of the Mechanism of 7‐exo‐trig Cyclizations of Aryl, Vinyl, and Alkyl Radicals on Oxime Ethers

“…Based on previous kinetic studies [16,22,23,31] and the determination of k c1a as 3.31 times faster than k ipso ‐a , we can calculate that the rate constant for 7‐ exo‐trig cyclization of aryl radical 17 a on an oxime ether is 1.0×10 8 s −1 , while the rate constant for ipso cyclization is 4.3×10 7 s −1 in benzene at 80 °C. These values indicate that the 7‐ exo‐trig process is controlled kinetically.…”

“…Moreover, the rate constant obtained in this work for the 7-exo-trig cyclization keeps the same order of magnitude (10 8 s À 1 ) of the rate constants reported for the 6-exo-trig cyclization of an aryl radical on C=C, [32] and for the 5-exo-trig cyclization of an aryl radical on an oxime ether. [16] DFT study for the 7-exo-trig cyclization and ipso addition of aryl and vinyl radicals on oxime ethers Geometry optimization and vibrational frequency calculations for all stationary points/minima and transition states (TS) of the investigated reaction pathways were performed at the UM06-2X/6-311 + G(d,p) level of theory in the presence of the SMD [33] continuum solvation model (benzene). Overall, both reaction pathways (7-exo-trig cyclization and ipso addition) followed by the radicals 17 a,b exhibit transition states with comparable geometries and conform to the Bürgi-Dunitz trajectory approach angle.…”

“…[4][5][6][7][8][9][10] Oxime ethers are recognized as radical acceptors, useful as valuable precursors for the synthesis of a wide variety of chemically and biologically relevant mono-and polycyclic compounds. [11][12][13][14][15][16][17] In this context, the determination of kinetic constants associated with intramolecular radical addition to oxime ethers is relevant, since it allows better control and optimization of reaction conditions, thus facilitating the development of new synthetic routes. This valuable information can be applied for the planning of complex molecular scaffolds through multiple sequential cyclizations.…”

“…Indeed, the formation of carbocyclic and heterocyclic ring systems through intramolecular cyclization processes of carbon‐centered radicals and π‐systems has made a significant contribution to synthetic chemistry [4–10] . Oxime ethers are recognized as radical acceptors, useful as valuable precursors for the synthesis of a wide variety of chemically and biologically relevant mono‐ and polycyclic compounds [11–17] . In this context, the determination of kinetic constants associated with intramolecular radical addition to oxime ethers is relevant, since it allows better control and optimization of reaction conditions, thus facilitating the development of new synthetic routes.…”

“…[20,21] Through these methods, Kim and Fallis determined the 5-and 6-exo-trig cyclization constants of alkyl radicals 3 onto oxime ethers to fall in the ranges of 1.5-4.2×10 7 s À 1 and 2.4-4.1×10 6 s À 1 , respectively (Scheme 1b). [22,23] In a recent study, [16] rate constants for the 5-exo-trig cyclization of aryl 5 and vinyl radicals 7 onto oxime ethers were reported using competition experiments, resulting in values of 9.9×10 8 s À 1 and 4.6×10 8 s À 1 , respectively (Scheme 1c,d). These constants were also predicted using DFT calculations and the conventional transition state theory (TST).…”