Palladium-catalyzed concerted [4 + 1] cyclization of prop-2-yn-1-ones and isocyanides

Synthesis of trifluoromethyl or trifluoroacetyl substituted heterocyclic compounds from trifluoromethyl‐α,β‐ynones

“…From 2012 to 2021, Pd(OAc) 2 ‐, CH 3 ONa‐, AgOTf‐ or light‐promoted cyclization of ynones 3c , 3 , or 3d with p ‐methylaniline 32 , methyl thioglycolate 39 , diketone 41 , mesitaldehyde 43 , or multi‐step reactions directly with 1,1,1‐trifluoro‐4‐phenylbut‐3‐yn‐2‐one 3c as the starting reactant to synthesize trifluoromethyl‐pyrroles 33 , 34 , and 38 , trifluoromethyl‐thiophenes 40 , trifluoromethyl‐dihydrofuran 42 , or trifluoromethyl‐isochromanone 44 has been described by the research groups of Chen, You, Qiu, Maas, Nenajdenko, Singh, and Takaki (Scheme 10). [ 51–56 ] Palladium acetate was used as catalyst in the multicomponent reaction of ynone 3c , p ‐methylaniline 32 , isocyanide t ‐BuNC, and water in the presence or absence of KOAc to afford the target product 33 or 34 in 69% or 72% yield. [ 51,52 ] 1,1,1‐Trifluoro‐ N ‐methyl‐4‐phenylbut‐3‐yn‐2‐imine 35 derived from 1,1,1‐trifluoro‐4‐phenylbut‐3‐yn‐2‐one 3c , reacted with MeOTf in CH 2 Cl 2 at room temperature for 2–3 days to give 91% yield of N , N ‐dimethyliminium triflate 36 , which was treated with PPh 3 in CH 2 Cl 2 to afford 91% yield of aminoallene 37 , eventually generating 1‐methyl‐4‐phenyl‐2‐(trifluoromethyl)pyrrole 38 in 61% yield in CH 3 CN at 65°C for 16–24 hr.…”

“…[ 51–56 ] Palladium acetate was used as catalyst in the multicomponent reaction of ynone 3c , p ‐methylaniline 32 , isocyanide t ‐BuNC, and water in the presence or absence of KOAc to afford the target product 33 or 34 in 69% or 72% yield. [ 51,52 ] 1,1,1‐Trifluoro‐ N ‐methyl‐4‐phenylbut‐3‐yn‐2‐imine 35 derived from 1,1,1‐trifluoro‐4‐phenylbut‐3‐yn‐2‐one 3c , reacted with MeOTf in CH 2 Cl 2 at room temperature for 2–3 days to give 91% yield of N , N ‐dimethyliminium triflate 36 , which was treated with PPh 3 in CH 2 Cl 2 to afford 91% yield of aminoallene 37 , eventually generating 1‐methyl‐4‐phenyl‐2‐(trifluoromethyl)pyrrole 38 in 61% yield in CH 3 CN at 65°C for 16–24 hr. [ 53 ] Trifluoromethyl‐thiophenes 40 can be synthesized in 42–84% yields from the reactions of trifluoromethyl‐α,β‐ynones 3 and methyl thioglycolate 39 using CH 3 ONa as base in methanol at room temperature.…”

“…From 2012 to 2021, Pd(OAc) 2 -, CH 3 ONa-, AgOTf-or light-promoted cyclization of ynones 3c, 3, or 3d with p-methylaniline 32, methyl thioglycolate 39, diketone 41, mesitaldehyde 43, or multi-step reactions directly with 1,1,1-trifluoro-4-phenylbut-3-yn-2-one 3c as the starting reactant to synthesize trifluoromethyl-pyrroles 33, 34, and 38, trifluoromethyl-thiophenes 40, trifluoromethyldihydrofuran 42, or trifluoromethyl-isochromanone 44 has been described by the research groups of Chen, You, Qiu, Maas, Nenajdenko, Singh, and Takaki (Scheme 10). [51][52][53][54][55][56] Palladium acetate was used as catalyst in the multicomponent reaction of ynone 3c, p-methylaniline 32, isocyanide t-BuNC, and water in the presence or absence of KOAc to afford the target product 33 or 34 in 69% or 72% yield. [51,52] [53] Trifluoromethyl-thiophenes 40 can be synthesized in 42-84% yields from the reactions of trifluoromethyl-α,β-ynones 3 and methyl thioglycolate 39 using CH 3 ONa as base in methanol at room temperature.…”

“…[51][52][53][54][55][56] Palladium acetate was used as catalyst in the multicomponent reaction of ynone 3c, p-methylaniline 32, isocyanide t-BuNC, and water in the presence or absence of KOAc to afford the target product 33 or 34 in 69% or 72% yield. [51,52] [53] Trifluoromethyl-thiophenes 40 can be synthesized in 42-84% yields from the reactions of trifluoromethyl-α,β-ynones 3 and methyl thioglycolate 39 using CH 3 ONa as base in methanol at room temperature. [54] The AgOTf-catalyzed reaction of ynone 3c with diketone 41 in the presence of (R)-BINAP as ligand in CH 2 Cl 2 at -60 C for 48 hr delivered trifluoromethyl-dihydrofuran 42 in 58% yield with 44% ee.…”

“…[56] Chen, qiu, and coworkers proposed a plausible mechanism for the synthesis of trifluoromethyl-pyrrole 34, as shown in Scheme 11. [52] First of all, the condensation between 1,1,1-trifluoro-4-phenylbut-3-yn-2-one 3c and p-methylaniline 32 produced imine A, which reacted with t-BuNC through a [4 + 1] cycloaddition to give furan cation palladium species B. Then, furan cation palladium species B occurred to go through another imidoylation to deliver imidoylpalladium species C, further treated with water to afford bicyclo[3.2.0]hept-4-ene D, which was added by palladium to form the intermediate E. Finally, under the action of H + , the intermediate E was converted to the transition state F, which can be further isomerized into the final product 34.…”