Regioselective bromination: Synthesis of brominated methoxyquinolines

Abstract

Simple synthetic methods are described for the synthesis of valuable polyfunctional brominated methoxyquinolines 10–13, 20–21, and 24–25. Three regioselective routes are described for convenient preparation of brominated methoxyquinolines at the C-2, C-3, and C-5 positions with consecutive reaction steps under mild reaction conditions using molecular bromine. While bromination of 6-bromo-8-methoxy-1,2,3,4-tetrahydroquinoline (8) selectively gave 3,6-dibromo-8-methoxyquinoline (10) and 3,5,6-tribromo-8-methoxyquinoline (11), the reaction of 6,8-dimethoxy-1,2,3,4-tetrahydroquinoline (9) resulted in the formation of 3-bromo-6,8-dimethoxyqinoline (12) and tribromide 13. On the other hand, direct bromination of 6-methoxy- 17 and 6,8-dimethoxyquinoline (19) gave 5-bromo derivatives 20 and 21. However, the reaction 3,6-dimethoxyquinoline (8) resulted in dibromination to form 2,5-dibromoquinoline (24). This process selectively led to functionalization of the quinoline ring at both the C-2 and C-5 positions.

Introduction

Developments in the synthesis of new quinoline derivatives are progressing and expanding hugely due to their pharmaceutical importance. Applications of quinoline derivatives have become widespread from anticancer drugs to almost every branch of medicinal chemistry.1, 2, 3 A variety of heterocyclic ring systems for anticancer activity have been widely reported by a number of researchers to develop new approaches to a variety of heterocyclic ring systems, especially including 3-substituted quinoline derivatives.³

Several methods for the synthesis of haloquinolines have been reported, including direct halogenation, which always suffers from poor regioselectivity and overhalogenation,⁴ but only a few methods for the regioselective synthesis of 3-haloquinolines are known.⁵ The development of a new synthetic method for preparing halogen-containing quinolines would enable the synthesis of diverse quinoline frameworks because the halogen atom could enhance biological activity in many cases⁶ and could also be used for further functionalization in preparing other molecules.7, 8

There has been enormous interest in developing efficient methods for the synthesis of quinoline derivatives considering their significant applications in the field of bioorganic, industrial, and synthetic organic chemistry. The Skraup, Friedländer, Doebner–von Miller, and Combes syntheses8, 9 of quinoline derivatives are important classical synthetic approaches. Almost all synthetic strategies are based on metal catalyzed cyclizations or acid catalyzed cycloadditions.⁹ However, quinoline synthesis has important disadvantages, such as harsh reaction conditions and highly acidic media,¹⁰ that make it tedious to isolate the product from the crude mixture. For instance, the Skraup procedure includes reactions of meta- or 3,4-disubstituted anilines normally giving a mixture of regioisomers difficult to isolate. Most of these methods are not fully satisfactory with respect to yield,11, 12, 13 reaction conditions,11, 13 generality,13, 14 and practical use.11, 13 These synthetic problems have encouraged researchers to develop a practical efficient procedure for the synthesis of these important heterocycles.¹⁵

It is interesting that despite the considerable synthetic and biological interest in quinoline derivatives, very few general synthetic routes are available starting from quinoline or tetrahydroquinoline cores themselves. Recently, we have found that the bromination reaction of substituted 1,2,3,4-tetrahydroquinolines is a good starting point for functionalizing both rings. In our previous publications, brominated tetrahydroquinolines were transformed to their respective derivatives.9, 16 Bromination of 6-bromo-8-cyano-1,2,3,4-tetrahydroquinoline gave corresponding 3-brominated quinoline derivatives (Scheme 1).¹⁶ This methodology uses neither metal catalyzed cyclizations nor acid catalyzed cycloadditions. The process constitutes a rapid and convenient method for obtaining selective brominated aromatic compounds as the sole products in high yields.

This work presented herein is a continuation of our ongoing research and focuses on the synthesis of polyfunctional quinolines, starting from methoxy 1,2,3,4-tetrahydroquinoline, which provides an efficient synthesis of brominated derivatives at C-3 and C-5 (Scheme 1). We are also interested in investigation of the biological activity and structure–activity relationship (SAR) results because the synthesized quinoline derivatives exhibited promising anticancer activities and interesting SARs (Scheme 2).9, 17, 18, 19, 20