Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Abstract

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, Ciamician-Dennstedt (C-D) rearrangement remains limited to halocarbene precursors. Herein, we report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N-triftosylhydrazones. This one-pot, two-step protocol enables the insertion of various carbenes, including those previously unexplored in C-D skeletal editing chemistry, into indoles/pyrroles scaffolds to access 3-functionalized quinolines/pyridines. Mechanistic studies reveal a pathway involving the intermediacy of a 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative aromatization to form different carbon-atom insertion products.

Fig. 1. Ciamician-Dennstedt rearrangement reaction: background and development.

a The significance of heterocycle-to-heterocycle transmutation in successful drug discovery. b State-of-the-art methods for Ciamician-Dennstedt reaction. c This work: α-halogencarbene-free Ciamician-Dennstedt reaction through a mechanistically distinct approach.

Fig. 2. Skeletal ring-expansion of indoles with fluoroalkyl N-triftosylhydrazones.

a Direct carbon-atom insertion of indoles with fluoroalkyl carbenes. Conditions A: indole (0.3 mmol), TFHZ-Tfs (0.36 mmol), Tp^Br3Cu(CH₃CN) (10 mol%), NaH (0.72 mmol) in PhCF₃ at 60 °C under N₂ for 12 h. Conditions B: indole (0.3 mmol), DFHZ-Tfs (0.6 mmol), Tp^Br3Cu(CH₃CN) (10 mol%), Cs₂CO₃ (1.8 mmol) in DCM at 40 °C under N₂ for 24 h. b Defluorinative carbon-atom insertion of indoles with fluoroalkyl carbenes. Conditions C: indole (0.3 mmol), N-triftosylhydrazone (0.6 mmol), Tp^Br3Cu(CH₃CN) (10 mol%), NaH (1.8 mmol) in PhCF₃ at 60 °C under N₂ for 12 h. Isolated yields.

Fig. 3. Skeletal ring-expansion of indoles and pyrroles with functionalized N-triftosylhydrazones.

a Functionalized carbon-atom insertion of indoles. Reaction conditions: N-triftosylhydrazone (0.3 mmol), N-TBS indole (0.6 mmol), NaH (0.6 mmol) and Tp^Br3Ag(thf) (10 mol%) in PhCF₃ (10 mL) at 60 °C under N₂ for 12 h then TBAF (0.75 mmol) at 25 °C under air for 10 min. b One-carbon insertion of pyrroles. Reaction conditions: N-triftosylhydrazone (0.3 mmol), 1H-pyrrole (0.6 mmol), NaH (0.6 mmol) and Rh₂(esp)₂ (1 mol%) in PhCF₃ (5 mL) at 60 °C under N₂ for 12 h. Isolated yields. Rh₂(esp)₂, Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid). ^a80 °C. ^bCsF/DMSO instead of TBAF. ^cThe OH group in indole or N-triftosylhydrazone was protected by TBS and deprotected in the reaction conditions. ^dDCM instead of PhCF₃. ^eCsF/DMF instead of TBAF. ^f1 mol% Rh₂(esp)₂. ^gN-triftosylhydrazone derived from 3-(triisopropylsilyl)propiolaldehyde.

Fig. 4. Synthetic utility for the concise synthesis of bioactive molecules.

a The synthesis of potential anticancer agents 131 and 132. b Concise synthesis of bioactive molecules with one-carbon insertion as key step. c Further transformations of the one-carbon insertion products into bioactive molecules.

Fig. 5. Experimental studies and proposed mechanism for carbon-atom insertion of indoles with fluoroalkyl carbenes.

a Identification of the reaction intermediates. b Experiments to probe the source of the hydrogen atom incorporated in quinoline-3-carboxaldehyde. c Experiment to validate the process of imine-enamine tautomerization. d Probing source of oxygen atom incorporated into quinoline-3-carboxaldehyde. e Proposed reaction pathways for one-carbon insertion of indoles with fluoroalkyl carbenes.

Fig. 6. Computational studies.

a Free energy profiles for the formation of gem-difluoromethylene intermediate Int8. b Free energy profiles for Michael addition and CsF/DMSO-assisted formal 1,3-H transfer of Int8 leading to quinoline-3-carboxaldehyde 56. Calculations were carried out at the SMD(DMSO)-M06/6-31 G(d,p)-SDD(Cs) level of theory. Energies are in kcal/mol. Distances are in angstroms. Most hydrogen atoms in 3D structures are omitted for clarity.

Fig. 7. Investigations into the origin of chemoselectivity of Int8 and Int8-1 generated from CF₃- and CF₂CF₃-substituted carbenes, respectively.

a Michael addition of Int8 and Int8-1. b CsF/DMSO-assisted formal 1,3-H transfer of Int8 and Int8-1. Energies are in kcal/mol.