Experimental and Computational Study of 6-exo and 7-endo Cyclization of Aryl Radicals Followed by Tandem S_RN1 Substitution

Abstract

The reaction of N-allyl-N-(2-halobenzyl)-acetamides and derivatives was investigated in liquid ammonia under irradiation with the nucleophiles Me3Sn(-), Ph2P(-) and O2NCH2(-). Following this procedure, novel substituted 2-acetyl-1,2,3,4-tetrahydroisoquinolines and substituted 2-acetyl-2,3,4,5-tetrahydro-1H-benzo[c]azepines were obtained in good yields. These reactions are proposed to occur through the intermediacy of aryl radicals, which by intramolecular 6-exo or 7-endo attack to a double bond cyclize to give aliphatic radicals, which react along the propagation steps of the S(RN)1 chain cycle to afford the cyclic substituted compounds as main products. The reactions were modeled with DFT methods, which provide a rational understanding that relates the product distribution to the structure of the aliphatic radicals proposed as intermediates and the kinetic of their formation.

Copper(I)‐Catalyzed Synthesis of Chlorinated Tetrahydropyridazin‐3‐ones and 1,2‐Diazepan‐3‐ones from N‐Allyl‐N′‐trichloroacetylhydrazines

“…The first step involves the formation of a dichlorocarbo radical species after abstraction of a chlorine atom by CuCl/PMDETA. The selectivity in the cyclization step follows an order similar to that of recent observations by Peisino and Pierini26 for photo‐stimulated cyclizations of aryl radicals. They demonstrated by experiment and theoretical calculations that the regiochemistry of the 6‐ exo /7‐ endo radical ring closure could be controlled by an interplay of conformational effects (Baldwin’s rule) and the stability of the radical being formed (primary<secondary<tertiary).…”

“…A highly selective preparation of tetrahydropyridazin‐3‐ones by 6‐ exo cyclization could be realized by substituting the radical acceptor at the terminal position of the carbon‐carbon double bond. Selective 7‐ endo cyclization can also be achieved by changing the substitution at the double bond 26,27. The method has several advantages over previously known methods, as there is a considerable reduction in the number of steps for the preparation of such highly substituted heterocycles.…”

Iterative double cyclization reaction by SRN1 mechanism. A theoretical interpretation of the regiochemical outcome of diazaheterocycles

“…† † Calculations were performed using the Gaussian09 program, the B3LYP 38,39 DFT functional and the 6-31++G** basis set. The B3LYP functional and the 6-31+G*, 30,40 6-311+G*, 21,41 and 6-311+G** 40 basis sets have been previously tested for similar systems. All determinations were carried out with full geometry optimization, including for all cases the effect of the solvent through Tomasi's polarized continuum model (PCM) [42][43][44] as implemented in Gaussian09.…”

Photoinduced nucleophilic substitution of iodocubanes with arylthiolate and diphenylphosphanide ions. Experimental and computational approaches

“… 3 To facilitate reactions with good nucleophiles which are also poor electron donors, an entrainment compound can be added which is usually a good electron donor (reactive at initiation step) but kinetically slow for coupling as a nucleophile (non-reactive at propagation step). 1,21 Aliphatic radicals, for example 1-haloadamantyl or cyclopropyl, were generated from aliphatic carbanions in S RN 1-type reactions employing an entrainment agent, in DMSO 22 as well as in NH 3(l) 23 as solvents. Therefore in the reactions of 11 − with 2, we employed the anions of acetone or pinacolone (3,3-dimethylbutan-2-one) as entrainments, but the coupling was still unsuccessful in NH 3(l) .…”