Novel Synthesis of Pyrido[2,1-a]isoindoles via a Three-Component Assembly Involving Benzynes

Abstract

A novel three-component assembly involving benzynes has been developed for the synthesis of pyrido[2,1-a]isoindoles in moderate yields. Reaction conditions have been optimized and the scope of the reaction has been studied. A plausible mechanism has been proposed to account for the three-component reaction.

Key words

three component - benzyne - aryne - pyrido[2,1-a]iso­indole

References and Notes

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• 14a All the reactions were carried out under the nitrogen atmosphere in oven-dried flasks. MeCN was distilled from CaH₂ using benzophenone as the indicator. 2-Bromo-1-(4-methoxyphenyl)ethanone, 2-bromo-1-(4-ethylphenyl)-ethanone, 2-bromo-1-(4-nitrophenyl)ethanone, 2-bromo-1-(4-chlorophenyl)ethanone were prepared according to the method described in: Ismail MA. Brun R. Wenzler T. Tanious FA. Wilson WD. Boykin DW. J. Med. Chem.  2004,  47:  3658 
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• 14c

  Other materials were purchased from common commercial sources and used without additional purification. ^¹H NMR spectra were recorded at 400 MHz using TMS as internal standard. ^¹³C NMR spectra were recorded at 100 MHz using TMS as internal standard. Mass spectroscopy data of the reaction product were collected on an HRMS (EI) instrument.

13

The CCDC number of the X-ray structure is 701719.

15

General Procedure of the Three-Component Reaction: An oven-dried flask was charged with 2-bromo-1-phenyl-ethanone (0.6 mmol), pyridine (1.0 mmol), CsF (1.5 mmol) and MeCN (3 mL). Benzyne precursor (0.5 mmol) in MeCN (2 mL) was added dropwise under the protection of N₂. The reaction mixture was then allowed to react at 80 ˚C for 2 h. After the completion of the reaction, the mixture was cooled to r.t. and filtered through a pad of celite. The solvent was then removed in vacuum, and the final product was obtained by flash chromatography on a silica gel column as a yellow powder.