Ni-Catalyzed Regio- and Enantioselective Domino Reductive Cyclization: One-Pot Synthesis of 2,3-Fused Cyclopentannulated Indolines

Abstract

Transition-metal-catalytic domino reactions represent important advances in synthetic organic chemistry. Their development benefits synthesis by providing highly efficient and step-economical methods to complex molecules with impressive selectivity. Herein, a Ni-catalyzed domino reductive cyclization of acrylamides with alkynyl bromides is reported, enabling rapid assembly of a range of substituted 2,3-fused cyclopentannulated indolines. Preliminary mechanistic studies revealed that tricyclic indolines are afforded through a highly regioselective migratory insertion of 1,3-diynes, which are formed from the homocoupling of alkynyl bromides, into the in situ generated σ-alkyl-Ni­(II) species, followed by nucleophilic addition of the resulting alkenyl nickel to unactivated amides. Most importantly, a highly regio- and enantioselective reductive cyclization of acrylamides and internal alkynes has also been developed. This transformation takes place under mild conditions with high efficiency, providing a rapid access to structurally diverse cyclopentannulated indolines in synthetically useful yields with high regioselectivity (>20/1) and enantioselectivity (27 examples, 82–96% ee).

Synthesis of bridged tricyclo[5.2.1.01,5]decanes via nickel-catalyzed asymmetric domino cyclization of enynones

“…Transmetallation of arylboronic acid with the chiral nickel species A (X could be acetate, hydroxide or 2,2,2-trifluoroethoxide) gives the arylnickel complex B. The 1,2-addition of arylnickel species to the triple bond to form an alkenylnickel intermediate C. An intramolecular migratory insertion of alkenylnickel C into double bond affords the σ-alkylnickel intermediate D [61][62][63][64] . A subsequent nucleophilic cyclization of the resulting σ-alkylnickel species D onto one of the ketones leads to nickel alkoxide species E, followed by protonolysis to regenerate the catalytical active nickel catalyst and release the desired tricyclo [5.2.1.0 1,5 ]decane product 3.…”

Nickel-Catalyzed Site- and Stereoselective Reductive Alkylalkynylation of Alkynes

“…and DMA as solvent under ambient conditions (Table 1, entry 1). Switching the reducing agent to Zn or tetrakis(dimethylamino)ethylene (TDAE) led to poor yields of 4a with excessive by-product formation from 1a cyclotrimerization 65 and 2a homocoupling [63][64] (Table 1, In order to enhance the catalytic efficiency and/or suppress the undesired formation of diyne by-products, [63][64] various additives were experimented as detailed in Table 1, entries 710.…”

“…Our motivation to pursue this approach is twofold: (1) The greater variety of N-(acyloxy)phthalimides accessible from aliphatic carboxylic acids (vs. alkyl halides) means that diverse aliphatic units (tertiary, secondary, primary) can be incorporated; (2) The ability of NHPI esters to promote challenging alkylalkynylations in which alkyl halides fail to deliver, by minimizing rampant undesired pathways arising from homocoupling [63][64] and cross-coupling 14,16 of the alkynyl halide and NHPI ester reactants, as well as alkyne cyclotrimerization 65 (see Fig. 4 for further discussion).…”

The Use of Domino Reactions for the Synthesis of Chiral Rings

“…Finally, asymmetric nickel catalysis was employed in 2019 by Kong et al in a novel one-pot synthesis of chiral 2,3-fused cyclopentannulated indolines 170. 50 As illustrated in Scheme 47, these highly substituted products arose from the domino reaction occurring between internal alkynes 145 and acrylamides 171, which were performed in the presence of a combination of NiCl 2 (DME) and chiral Pybox ligand 172 as the catalyst system and Mn as the reducing agent. These biologically interesting products were obtained as single regioisomers in variable yields (26-88%) and uniformly excellent enantioselectivities (85-96% ee).…”