Synthesis of N -Methyl-6-heterocyclic-1-oxoisoindoline Derivatives by Microwave Assisted Buchwald-Hartwig Amination

: An rapid and efficient microwave assisted Pd(II) catalyzed protocol for the preparation of N -methyl-6-heterocyclic-1-oxoisoindoline derivatives by Buchwald-Hartwig amination with an overall yield 68-85% has been described.


Introduction
Oxoisoindoline derivatives plays an important role in organic chemistry due to their wide range of biological applications.Isoindolinone like structures are very good antiviral drugs for the treatment of cold 1 important anti-inflammatory agents 2 analgesic agents 3 and recent study reveals that 3-oxoisoindoline-4-carboxamide core structure, displayed a good activity as poly (ADP-ribose) polymerase (PARP) inhibitors 4 .
Microwave-assisted amination of aromatic halides has become a powerful methodology for the construction of aryl amine intermediates useful for the synthesis of biologically active molecules 5 .Microwave-assisted organic synthesis has gained considerable attention over the past decade and these advances have also found application in the pursuit of pharmaceutically active agents 6,7 .The power and complexity of reactions adapted to microwave methods has grown over the past few years in particular, expanding the scope of their use from simple acceleration of coupling reactions to include more elegant applications such as the acceleration of momentous metal-catalyzed transformations 8 .

General procedures for the synthesis of the N-methyl 6-heterocyclic-1oxoisoindoline (7a-l)
A high pressure microwave 5 mL process vial was loaded with 6 (1 equiv) and amine (1.2 equiv in anhydrous toluene/t-BuOH (5:1).2-(2'-Di-tert-butylphosphine) biphenylpalladium(II) acetate (5 mol%) and NaO-t-Bu (1.5 equiv) were added and then the process vial was evacuated, backfilled with argon and sealed.The mixture was kept at 140 o C for 15 min (including the ramp time).After cooling, the mixture was diluted with ethyl acetate, filtered through celite and the solvent was removed under reduced pressure.The product was isolated by flash chromatography on silica gel with hexane/ethyl acetate solvent mixtures.

Conclusion
In conclusion, the use of microwave irradiation allowed a rapid and high-yield preparation of N-methyl-6-heterocyclic-1-oxoisoindoline derivatives.We carried out the Buchwald amination with alkyl and aryl amines using Pd(II) catalyst by conventional protocol as well as by microwave irradiation.Dramatic improvements on excellent yields using microwave irradiation were observed.Different reaction conditions, quantities of substrates and solvents were tested to develop a simple and reproducible Buchwald amination methodology.Our interest was to optimize the construction of alkyl or aryl amine intermediates which may useful for the synthesis of biologically active molecules and the studies is under progress.

1 H
NMR spectra were recorded in DMSO-d 6 solvent on varian XL-300 MHz spectrometers/ varian XL-400 MHz (chemical shifts are given in parts per million (ppm)).