The Synthesis of Highly Functionalized Pyrroles: A Challenge in Regioselectivity and Chemical Reactivity

Abstract

Pyrrole-containing compounds play an eminent role in nature. Since the development of the pyrrole synthesis by Knorr and Paal at the end of the 19^th century, the synthesis and study of modified pyrroles has become an active field of chemical research spanning from natural product synthesis, through medicinal chemistry, and on to material science. For example, the synthetic availability of porphyrins and their artificial analogues and isomers in the second half of the last century led to important insights into the function of this prominent molecule in nature. In the last few years, synthetic pyrrole-containing biomacromolecules and intelligent materials such as pyrrole-based conducting polymers have come into focus. All this research requires the efficient synthesis of highly functionalized pyrroles. However, even after more than 100 years since the pioneering work by Paal and Knorr, the synthesis of highly functionalized pyrroles remains challenging. Often, the yields are low and the regioselectivity is only modest. We present here an overview of some recent work in this area, including some of our own research.

1 Introduction

2 Monosubstitution of Pyrrole

2.1 N-Substitution

2.2 α-Substitution

2.3 β-Substitution

3 Disubstitution of Already-Functionalized Pyrroles

3.1 Temporary Substituents

3.2 Permanent Substituents

4 Interconversion of Substituents

4.1 Transformations Involving Carbonyl Groups

4.2 Radical α-Halogenation

4.3 Radical β-Halogenation

4.4 Regioselective Transesterification

5 Direct Synthesis of Substituted Pyrroles via Cyclization Reactions­

5.1 Knorr, Paal-Knorr and Hantzsch Reactions

5.2 Modified Knorr Reactions

5.3 Other Pyrrole Syntheses

6 Application of Highly Functionalized Pyrroles in Supramolecular Chemistry

7 Conclusions

Key words

pyrroles - heterocycles - cyclizations - regioselectivity - radical reactions

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Schmuck, C. unpublished results.