Photocatalytic intramolecular radical cyclization involved synergistic SET and HAT: synthesis of 3,3-difluoro-γ-lactams

Abstract

A mild and metal-free protocol for visible-light induced intramolecular radical cyclization of N-allyl(propargyl)-2-bromo-2,2-difluoro-N-arylacetamide has been developed.

Photoredox catalysis in the synthesis of γ- and δ-lactams from N-alkenyl trichloro- and dichloroacetamides

“…Having in mind the mechanism proposed for the photocatalyzed processes reported previously, [9][10][11][12][13] we decided to run the reaction in the absence of any amines. Thus, 1a was irradiated in a mixture of THF/acetone or in THF and in the presence of fac-Ir(ppy) 3 alone.…”

“…Moreover, to the best of our knowledge, there are few examples describing the synthesis of γ-lactams from α-haloamides under photoredox catalysis. Among these are: (a) the visible light photoredox catalyzed cyclization of α-chloroenamides in the presence of Ir(ppy) 2 (dtb-bpy)PF 6 , 9 (b) the synthesis of 3,3-difluoro-γ-lactams achieved from N -allyl(propargyl)-2-bromo-2,2-difluoroacetamides in the presence of fluorescein and under white LEDs, 10 and (c) the intermolecular photoredox catalytic atom transfer radical cyclization (ATRC) of 1,6-dienes and α-haloketones for the synthesis of 4-bromooctahydroindol-2-ones. 11 In addition, 3,3-disubstituted oxindoles were prepared under photoredox catalysis in the presence of fac -Ir(ppy) 3 12,15 and finally an intermolecular aminodifluoroalkylation of alkenes was reported in the synthesis of difluoro-γ-lactams using the same catalyst and blue LEDs.…”

Advances in the synthesis of α,α‐difluoro‐γ‐lactams

“…Based on this, in 2018 and 2021, the report of synthesizing α,α‐difluoro‐γ‐lactams by visible‐light‐induced intramolecular radical cyclization or consecutive synthesis process appeared, as shown in Scheme 2 [9,10]. Sun, Su, Jin, and co‐workers showed that a variety of N ‐allyl(but‐3‐en‐1‐yl)‐2‐bromo‐2,2‐difluoroacetarylamines 1 and N ‐propargyl‐2‐bromo‐2,2‐difluoroacetarylamines 3 were well tolerated to provide the corresponding 4‐substituted α,α‐difluoro‐γ‐lactams 2 and 4 in moderate to excellent yields ( 2 : 39%–83%, 4 : 42%–89%) in the presence of fluorescein as photocatalyst, pentamethyl diethylenetriamine (PMDETA) as organoamine, and 1,2‐dichloroethane (DCE) as solvent at room temperature for 10–24 h [9].…”

“…Based on this, in 2018 and 2021, the report of synthesizing α,α‐difluoro‐γ‐lactams by visible‐light‐induced intramolecular radical cyclization or consecutive synthesis process appeared, as shown in Scheme 2 [9,10]. Sun, Su, Jin, and co‐workers showed that a variety of N ‐allyl(but‐3‐en‐1‐yl)‐2‐bromo‐2,2‐difluoroacetarylamines 1 and N ‐propargyl‐2‐bromo‐2,2‐difluoroacetarylamines 3 were well tolerated to provide the corresponding 4‐substituted α,α‐difluoro‐γ‐lactams 2 and 4 in moderate to excellent yields ( 2 : 39%–83%, 4 : 42%–89%) in the presence of fluorescein as photocatalyst, pentamethyl diethylenetriamine (PMDETA) as organoamine, and 1,2‐dichloroethane (DCE) as solvent at room temperature for 10–24 h [9]. In 2018, Wang et al used 2‐bromo‐2,2‐difluoro‐ N ‐alkyl‐ N ‐(1H‐indol‐3‐yl)acetamides 5 as raw materials and adopted visible‐light‐induced consecutive synthesis such as difluoromethylative dearomatization, hydroxylation, and oxidation to prepare the products gem ‐difluorinated spiro‐γ‐lactam oxindoles 6 in up to 85% yields [10].…”

“…A plausible mechanism for this intramolecular radical cyclization was proposed by Sun, Su, Jin, and co‐workers, as shown in Scheme 3 [9]. First, under the irradiation of light, the photocatalyst fluorescein was activated to the excited state, then quenched by PMDETA to afford [PMDETA]˙ + and reduced fluorescein.…”