A practical one-pot procedure for the synthesis of N-H isoquinolones

A practical one-pot procedure for the synthesis of N–H isoquinolones

Shaonan Lu ,Yingfu Lin ,Hongban Zhong,Kang Zhao,Jianhui Huang ⇑

Tianjin Key Laboratory for Modern Drug Delivery &High-Efficiency,School of Pharmaceutical Science and Technology,Tianjin University,92Weijin Road,Nankai District,Tianjin,China

a r t i c l e i n f o Article history:

Received 9December 2012Revised 23January 2013Accepted 1February 2013

Available online 9February 2013Keywords:

C–H activation Isoquinolone

N–O bond cleavage Organometallics Pd-catalysis

a b s t r a c t

A practical one-pot procedure for the preparation of N–H isoquinolones has been developed.This 2-step process via C–H activation of N -alkoxyl benzamides and NaH-mediated dealkoxylation reaction has been demonstrated to be a high yielding alternative methodology for the efficient synthesis of a wide range of representative N–H isoquiolones.In addition,the experimental precedent supported mechanism of the dealkoxylation reaction was also proposed.

Ó2013Elsevier Ltd.All rights reserved.

1.Introduction

There have been a considerable number of syntheses of isoqui-nolones using modern directing group associated direct C–H func-tionalization reactions in the last 3years.1,2Among these amide directed and associated isoquinolone syntheses,when alkoxyl benzamide was utilized as the substrate,both C–H bond activation (Scheme 1,Eq.A,marked in red)and N–O bond cleavage (Scheme 1,Eq.A,marked in blue)were observed for Rh 3a,b -and Ru 4b,d -catalysed N–H isoquiolone syntheses.2,3

More recently we have reported new approaches using relatively cheap Pd-catalysts for the tailoring of these isoquinolones.5a,b Inter-estingly,we have found that under our Pd-catalysed conditions,when alkoxyl benzamides reacted with alkynes,the alkoxyl groups were retained without N–O bond cleavage detected and N–OR 1iso-quinolones were achieved instead of N–H isoquiolones.(Scheme 1,Eq.B)

As an alternative methodology to Rh 3-and Ru 4-catalysed N–H isoquiolone syntheses,our research interests have moved to the developement of a Pd-catalysed approach for the access of these versatile intermediates.Herein we report our latest discovery to-wards the practical synthesis of N–H isoquinolones via a two-step one-pot procedure from N-alkoxybenzamides.After Pd-catalysed isoquinolone ring formation,the reaction mixture was treated with NaH for deprotection to give N-unsubstituted isoquinolone.In

addition,a plausible N–O bond cleavage reaction mechanism was also proposed at the end of the article.2.Results and discussion

2.1.Base screening for the demethoxylation reaction

Initial attempts on the direct one step synthesis of N–H isoqui-nolone by the introduction of inorganic bases were not successful.Only less than 10%of demethoxylated product was obtained in most of the cases when cheap readily available inorganic bases KOH,Na 2CO 3,NaOAc,K 3PO 4and NaH were employed.

0040-4039/$-see front matter Ó2013Elsevier Ltd.All rights reserved./10.1016/j.tetlet.2013.02.003

⇑Corresponding author.Tel.:+862227405316;fax:+862227404031.

E-mail address:jhuang@ (J.Huang).

These two authors contributed equally to this work.