Construction of Boronated γ‐Lactams via Palladium‐Catalyzed Intramolecular Boryldifluoroalkylation of Alkenes

Abstract

An approach for the preparation of boronated γ-lactams via palladium-catalyzed boryldifluoroalkylation of alkenes with α-bromodifluoroacetamides was developed. This method exhibits good functional group tolerance. Various boronated products were obtained in moderate to good yields for 1 h. Mechanistic studies indicated that this reaction may involve an intramolecular radical cascade cyclization process.

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

“…Finally, the intermediates B were captured by diselenides 52 to further generate the target products 53 and selenyl radicals, which can be converted into R 2 SeBr depending on the reduction of Cu(II) to Cu(I) [25]. In 2018 and 2020, the research groups of Mai, Lu, and Liu developed a practical access to the synthesis of 4-benzyl-α,α-difluoro-γ-lactams 60 or 4-boronated α,α-difluoro-γ-lactams 63 by the reactions of α-bromodifluoroacetamides 58 or 61 with arylboronic acids 59 or B 2 pin 2 62 using Ni(OTf) 2 or Pd(PPh 3 ) 4 as catalyst (Scheme 12) [27,28]. A series of arylboronic acids 59 bearing various substituents such as 3-CH 3 CO, 3,5-dimethoxy, 4-CO 2 Me, 3-CO 2 Et, 4-BocNH, 4-CH 3 SO 2 , 4-t-Bu, 4-F, 3-CH 3 , 4-Cl, and 4-CF 3 , were examined to react with α-bromodifluoroacetamides 58 containing different aryl groups on the N atom to afford the desired products 4-benzyl-α,α-difluoro-γ-lactams 60 in 57%-94% yields catalyzed by Ni(OTf) 2 , ligand L, and PPh 3 in the presence of K 2 CO 3 as base in 1,4-dioxane at 80 C for 8 h [27].…”

“…A plausible mechanism for the synthesis of 4-boronated α,α-difluoro-γ-lactams 63 was proposed by Liu and co-workers, as shown in Scheme 13 [28]. First of all, the interaction of Pd(0) with α-bromodifluoro acetamides 61 generated Pd(I)X and radical intermediates A, which were rapidly converted into the intermediates B through an intramolecular cyclization.…”

“…A series of arylboronic acids 59 bearing various substituents such as 3‐CH 3 CO, 3,5‐dimethoxy, 4‐CO 2 Me, 3‐CO 2 Et, 4‐BocNH, 4‐CH 3 SO 2 , 4‐ t ‐Bu, 4‐F, 3‐CH 3 , 4‐Cl, and 4‐CF 3 , were examined to react with α‐bromodifluoroacetamides 58 containing different aryl groups on the N atom to afford the desired products 4‐benzyl‐α,α‐difluoro‐γ‐lactams 60 in 57%–94% yields catalyzed by Ni(OTf) 2 , ligand L , and PPh 3 in the presence of K 2 CO 3 as base in 1,4‐dioxane at 80°C for 8 h [27]. The α‐bromodifluoroacetamides 61 bearing 4‐CH 3 , 3‐CH 3 , 4‐Et, 3‐Et, 4‐CH 3 O, 4‐ i ‐Pr, 4‐ t ‐Bu, 4‐F, 3‐F, 4‐Cl, 3‐Cl, 4‐CF 3 O, 3‐CF 3 , 4‐Ph, 3,4‐dimethyl, 3,5‐dimethyl, or 3‐CH 3 ‐4‐F group on the benzene ring of N atom all worked well and reacted with B 2 pin 2 62 in the presence of Pd(PPh 3 ) 4 and Cs 2 CO 3 to afford the corresponding 4‐boronated α,α‐difluoro‐γ‐lactams 63 in moderate to good yields (40%–75%) [28]. However, when the substituents of N atom of α‐bromodifluoroacetamides 61 were changed to 2‐CH 3 Ph, benzyl, or naphthyl, the reactions were not ideal, and only trace products 63 were given [28].…”

“…The α‐bromodifluoroacetamides 61 bearing 4‐CH 3 , 3‐CH 3 , 4‐Et, 3‐Et, 4‐CH 3 O, 4‐ i ‐Pr, 4‐ t ‐Bu, 4‐F, 3‐F, 4‐Cl, 3‐Cl, 4‐CF 3 O, 3‐CF 3 , 4‐Ph, 3,4‐dimethyl, 3,5‐dimethyl, or 3‐CH 3 ‐4‐F group on the benzene ring of N atom all worked well and reacted with B 2 pin 2 62 in the presence of Pd(PPh 3 ) 4 and Cs 2 CO 3 to afford the corresponding 4‐boronated α,α‐difluoro‐γ‐lactams 63 in moderate to good yields (40%–75%) [28]. However, when the substituents of N atom of α‐bromodifluoroacetamides 61 were changed to 2‐CH 3 Ph, benzyl, or naphthyl, the reactions were not ideal, and only trace products 63 were given [28].…”

Et2Zn-Mediated Radical (3 + 2) Cycloaddition of Vinyl Azides with Ethyl Iododifluoroacetate to Access 3,3-Difluoro-γ-lactams

“…However, these reports are restricted by the relatively narrow scope of substrates. In recent years, an increasing interest in radical cyclization reactions has led to the development of efficient protocols to synthesize various functionalized α,α-difluoro-γ-lactams through radical-mediated processes. − For instance, radical cascade cyclization of alkenes catalyzed by transition metals, such as copper, nickel, and palladium, was developed to rapidly assemble CF 2 -decorated γ-lactams. Furthermore, Zhu et al demonstrated a novel photoredox/iodide catalytic system toward these compounds via aminodifluoroalkylation of alkenes (Scheme a1) .…”