Water-promoted dehydrative coupling of 2-aminopyridines in heptane via a borrowing hydrogen strategy.

Taku Nakayama,Hidemasa Hikawa,Shoko Kikkawa,Isao Azumaya

doi:10.1039/d1ra04118e

Taku Nakayama, Hidemasa Hikawa + Show 2 more

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https://doi.org/10.1039/d1ra04118e

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Abstract

A synthetic method for dehydrative N-benzylation promoted by water molecules in heptane using a π-benzylpalladium system has been developed. The presence of water significantly accelerates carbon–nitrogen bond formation, which is accomplished in an atom-economical process to afford the corresponding N-monobenzylated products. A crossover experiment afforded H/D scrambled products, which is consistent with a borrowing hydrogen mechanism. Kinetic isotope effect measurements revealed that benzylic carbon–hydrogen bond cleavage was the rate-determining step.

Highlights

The borrowing hydrogen methodology has emerged as a promising greener synthetic strategy for straightforward carbon– nitrogen bond formation utilizing readily available and lowtoxicity benzyl alcohols instead of benzyl halides as coupling partners.[1]
In 2008, McLain et al showed that charge-based interactions play an important role in dipeptide association in aqueous solution.8b In non-polar organic solvents, reverse micelles (RMs), with the polar groups concentrated in the interior of the aggregate, are formed via the self-assembly of surfactant molecules.[9]
The strategy provides an efficient method for the facile synthesis of benzylaminopyridines, which are found in a wide variety of pharmaceuticals

Summary

Introduction

The borrowing hydrogen methodology has emerged as a promising greener synthetic strategy for straightforward carbon– nitrogen bond formation utilizing readily available and lowtoxicity benzyl alcohols instead of benzyl halides as coupling partners.[1] Various catalyst systems using iridium(III),[2] ruthenium(II),[3] or other metals[4] have been developed This strategy affords an attractive atom-economical pathway and is an appealing synthetic shortcut for constructing valuable products, the reactions generally require high temperatures, organic solvents and strong bases. The rst example of direct conversion of non-activated benzyl alcohols to the p-benzylPd(II) system has been developed in organic solvents, and applied to the dehydrative cross-coupling reaction This water-in-oil reaction system is substantially different from our previous method (an oil-in-water type reaction system) concerning the self-assembly between palladium catalysts and polar substrates (Scheme 1A vs B), and shows a signi cant advancement over our previous synthetic protocol for more sustainable chemistry. Since the reaction was completed in 4 h under an Ar atmosphere, oxygen was not essential to the borrowing hydrogen reaction (entry 17)

Reaction scope

Effect of water

Mechanistic studies

Mechanistic considerations

Conclusions