Elsevier

Tetrahedron

Volume 67, Issue 47, 25 November 2011, Pages 9063-9066
Tetrahedron

Synthesis of 5-bromo-6-methyl imidazopyrazine, 5-bromo and 5-chloro-6-methyl imidazopyridine using electron density surface maps to guide synthetic strategy

https://doi.org/10.1016/j.tet.2011.08.090Get rights and content

Abstract

Small heteroaromatic rings are valuable monomers in drug discovery that can enable rapid access to novel and desirable chemical space. Installation of a synthetic handle on a heteroaromatic core may be difficult if steric and electronic factors are not in alignment with the desired transformation. Described are practical routes for the construction of 5-bromo-6-methyl imidazopyrazine (1) as well as 5-bromo and 5-chloro-6-methyl imidazopyridines (2a and 2b), which were developed using electron density surface maps encoded with ionization potential to guide synthetic strategy.

Graphical abstract

Small heteroaromatic rings are valuable monomers in drug discovery that can enable rapid access to novel and desirable chemical space. Installation of a synthetic handle on a heteroaromatic core may be difficult if steric and electronic factors are not in alignment with the desired transformation. Described are practical routes for the construction of 5-bromo-6-methyl imidazopyrazine (1) as well as 5-bromo and 5-chloro-6-methyl imidazopyridines (2a and 2b), which were developed using electron density surface maps encoded with ionization potential to guide synthetic strategy.

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Introduction

Small halogenated heteroaromatic ring systems are valuable monomers because of their ability to participate in established cross-couplings including the Heck, Stille, and Suzuki reactions.1 As part of a chemistry initiative to increase the diversity of our available low molecular weight heteroaryl monomer set, we were interested in developing a practical construction of the novel heterocycles imidazopyrazine 1 and imidazopyridines 2a and 2b (Eq. 1). Formation of the fused imidazole ring was planned by reaction of chloroacetaldehyde with a 2-amino pyrazine or pyridine, such as in 5 or 6. One anticipated challenge with this approach was regioselective installation of the requisite halogen handle at the sterically and electronically disfavored C(5) position.

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Results and Discussion

Brominating reagents, such as N-bromosuccinimide (NBS) and bromine, react with heterocycles via electrophilic aromatic halogenation (EAH) at the site of greatest electron density.2 The electronic properties of a ring system are dictated by the heteroatom substitution pattern and pendant electron donating or withdrawing functionality. Protonated or hydrogen-bonded heterocycles can have vastly different charge distributions and orbital energies relative to their neutral counterparts. Imidazo[1,2-a

General

NMR spectra were recorded on a Bruker Avance II spectrometer (1H: 400 MHz, 13C: 100 MHz) at 25 °C, using CDCl3, CD3OD or DMSO-d6 as the solvent. Chemical shifts are reported in parts per million (ppm) relative to solvent (CDCl3: 7.27 and 77.0 ppm; DMSO-d6: 2.50 and 39.51 ppm; CD3OD: 3.31 and 49.2 ppm in 1H and 13C NMR, respectively). IR spectra were recorded on an FT-IR type Nicolet 380 spectrometer and are reported in cm−1. Mass spectra were recorded using the ESI+ method on an Agilent G1969A

Acknowledgements

We would like to acknowledge Professors Justin Dubois and Andy Myers, colleagues: Heather Frost, Bruce Rogers, Jinhua Yang, Jinlong Wang as well as all other members of Team Cobra (Past and Present) for their helpful discussions.

References and notes (11)

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