Harnessing the Polarizability of Conjugated Alkynes toward [2 + 2] Cycloaddition, Alkenylation, and Ring Expansion of Indoles

Abstract

Reported is the utilization of electronically biased conjugated alkynes in the development of highly diastereo- and regioselective dearomative [2 + 2] cycloadditions, alkenylations, and ring expansions of electron-rich indoles. Regioselective protonations of cross- and linear-conjugated alkynes were found to be crucial for accessing various cyclobutene-fused indoline and alkenylated indole derivatives. Furthermore, the facile ring expansion of [2 + 2] keto adducts, which were successfully synthesized from ynones, provided 1 H-benzo[ b]azepine scaffolds.

Alkyne–Alkene [2 + 2] cycloaddition based on visible light photocatalysis

“…Recently, a chiral UV sensitizer has been reported for enantioselective synthesis of cyclobutenes 7 . On the other hand, various alternative methods including Lewis acid- [8][9][10][11] and transition metal- [12][13][14][15][16] catalyzed syntheses of cyclobutenes have been developed. However, the requirement of specific functional groups on the substrates for activation remains as limitation.…”

One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles

“…gave 5-methyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole 4r (119 mg, 80%) as an amorphous brown solid, spectroscopically identical to that previously reported. 58 1-Hexyl-2,3-dimethylindole, 4s. By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.…”

Regiodivergent Trifluoromethanesulfonic Acid‐Promoted Cycloisomerizations of Ynenamines to Fused Indoles

“…Therefore, a proposed mechanism involved the generation of vinyl cationic intermediated A and A′ by the protonation of alkyne, as we have described in our recent report, followed by nucleophilic attack of the indole/C2‐phenyl ring and the subsequent ring closure via B (or B′ ) provides cyclized product as shown in Scheme . Although C2 phenyl substituent is influenced by adjacent strongly electron‐withdrawing Ts group, it should be nucleophilic enough to provide the 7‐memebered ring because the electron‐withdrawing effect will be mitigated on the phenyl ring by conjugation disconnection due to some degree of dihedral angle.…”

“…In our previous report, we presented a highly regioselective and stereospecific cycloisomerization of N‐alkynyl indoles to isoindolo[2,1‐ a ]indoles and indolo[2,1‐ a ]isoquinolines via transition‐metal‐catalyzed 5‐exo‐dig (pathway A ) and 6‐endo‐dig (pathway B ) cyclizations, respectively (Scheme a) . Along with our recently reported interesting transformations of ynenamides, we envisioned that the ynenamines derived from N‐alkynyl indoles (pathway C ) could also be regioselectively transformed into N‐fused indole derivatives through cycloisomerization reactions (Scheme b). Herein, we report electron‐withdrawing‐substituent‐controlled regioselective cycloisomerizations of ynenamines ( 2 and 3 ) to pyrrolo[3,2,1‐ ij ]quinolines ( 4 ) and benzo[3,4]azepino[1,2‐ a ]indoles ( 5 ) via 6‐endo‐dig cyclization (pathway D ) at the indole C7 position and 7‐endo‐dig cyclization (pathway E ) at the ortho position of a phenyl ring at the indole C2 position, respectively, promoted by TfOH.…”