A Practical Buchwald-Hartwig Amination of 2-Bromopyridines with Volatile Amines

Link: JOC ASAP

Jie Jack Li,* Zhi Wang, and Lorna H. Mitchell

Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development, Ann Arbor, Michigan 48105

This is a quick-read paper on a method to improve Buchwald-Hartwig amination using volatile amines as coupling partners.

The authors stated that in order to conduct an amination reaction of 2-bromopyridine using volatile amine such as methylamine (bp, -6.2 C), the process would have to utilize methyl benzylamine for amination and debenzylation of the coupling product (Scheme 1), which sometimes destroys that integrity of the molecule.

Another available method is to use methylamine-HCl salt as a precursor to the amine, as illustrated in Scheme 2. However, the process employs large excess of NaOt-Bu and cannot be applied to free amines.

The answer to these problems was to conduct the reaction in a sealed tube. Thus substrate, such as 1 was added with excess of volatile amine via condensation at -78 C, followed by addition of NaOt-Bu, Pd-catalyst and phosphine bidentate ligand in toluene. The tube was sealed and heated at 80 C overnight to give the desired product in 77% yield.

The volatilities of amines at 80 C in term of vapor pressure are as followed: methylamine, 20 atm; dimethylamine, 10 atm; ethylamine, 7.5 atm; and 3.5 atm for propylamine and cyclopropylamine.

The results of cross-couplings for other substrates are summarized in Table 1. In general, secondary amines gave better results than primary amines, presumably because the tertiary amines products were less readily to undergo further side-reactions, such as further cross-coulping, or N-oxidation with light.

And as seen in entry 10, 2-chloropyridine derivative did not work as well as the bromo counterpart in previous entries. The authors also noted that the current method did not yield any product with 2-chloropyridine and 2-bromopyridine.