Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones

Abstract

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3‐(chloromethylene)oxindoles via the chloroacylation of alkyne‐tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene‐tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2‐quinolinones.

BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling

“…We were pleased to see that our method was also applicable towards the synthesis of γ-lactams 4a and 4b with complete Z-selectivity, as confirmed by X-ray crystallography of 4a. This reversal in stereoselectivity, previously observed for related HFIP-promoted reactions run in the absence of a metal catalyst, 16 can now be explained by density functional theory (DFT) studies (vide infra). To demonstrate the utility of our method towards the synthesis of medicinally relevant compounds, we prepared oxindoles 2aa-2ab, which upon PMB deprotection provided access to the 3-fluoro-derivatives (5aa-5ab) of known protein kinase inhibitors.…”

“…The use of an alkynes as the π-acceptor would provide a direct route to tetrasubstituted alkenyl fluorides, which are present in a number of bioactive compounds, serving as amide bond bioisosteres and enol mimics. 14 The intramolecular chlorocarbamoylation of alkynes has been previously reported by Lautens and co-workers using Pd catalysts 15 or stoichiometric HFIP 16 (cheme 1b). These methods provide entry to 3-(chloromethylene)oxindoles, which are precursors to pharmaceutically relevant compounds through C-Cl bond functionalization.…”

“…23 Changing the counteranion to PF6 -(entry 2) or cation to tropylium (entry 3) led to inferior results. Pd 0 catalysts known to promote the chlorocarbamoylation of alkynes [15][16] could not effect the desired reaction (Table S2); however, Pd(MeCN)4(BF4)2 provided 2a in moderate yield (entry 4). An improved yield of 67% was obtained with HBF4•OEt2 (entry 5), 24 although other Brønsted acids were unable to promote the chemistry (entries 6-8).…”

Accessing Unsymmetrically Linked Heterocycles through Stereoselective Palladium‐Catalyzed Domino Cyclization

“…The absence of 3 a rules out a potential addition/elimination mechanism on the chlorinated methylene oxindole. [15,16] The product was observed when this experiment was performed using a palladium catalyst (see SI for details). This corroborates that the intermediacy of a vinyl-Pd II species in the catalytic cycle (see SI for proposed mechanism).…”

Stereoselective Construction of Unsymmetrically Linked Heterocycles via Palladium-Catalyzed Alkyne Insertion/Cycloimidoylation Cascade

“…Alkyne-tethered carbamoyl chlorides were established as efficient synthons to forge methylene oxindole derivatives through an anionic-capture cascade (Scheme a). In 2015, Lautens and co-workers developed a Pd 0 -/Pd II -catalyzed intramolecular chlorocarbamoylation reaction of alkynes, offering access to E -methylene oxindoles, in which the R 2 group of alkyne was restricted to bulky groups such as TMS and TBS (Scheme b) . Later on, access to Z -products was achieved under Pd II /Pd IV catalysis (Scheme c) .…”