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August 13, 2007
Volume 85, Number 33
p. 10

Organic Synthesis

Easier, Cleaner Route To Amides

Simple coupling reaction involves alcohols and amines

Bethany Halford

DESPITE THEIR FUNDAMENTAL ROLE in chemical and biochemical systems, amides are tough to make. Routes to this functional group usually employ toxic reagents, such as thionyl chloride; require corrosive acidic or basic conditions; and often generate unwanted by-products.

courtesy of david milstein
From left, Milstein, Gunanathan, and Ben-David alongside their ruthenium pincer catalyst.

Now, using a pincerlike ruthenium catalyst, chemists in Israel have managed to make amides simply by coupling alcohols and amines (Science 2007, 317, 790). The procedure is both clean and selective, the researchers say, eschewing the harsh reagents and conditions usually required to make amides and creating H2 gas as the only by-product. Furthermore, the reaction could have applications in the synthesis of industrially important polyamides such as Kevlar.

"This is an exciting advance in the synthesis of amides, using alcohols as the acylating partner," says Jonathan Williams, a professor at England's University of Bath. "The low catalyst loading and absence of a hydrogen acceptor make this a very attractive, environmentally benign process."

The reaction, developed by David Milstein, Chidambaram Gunanathan, and Yehoshoa Ben-David of the Weizmann Institute of Science, relies on a new type of ruthenium catalyst. The catalyst contains a dearomatized pyridine ligand that's covalently bound to an armlike tertiary amine ligand. "It operates in a unique way, involving cooperation between the metal and the ligand," Milstein explains. "The catalytic cycle includes reversible aromatization of the pyridine backbone and reversible opening of the amine 'arm.' "

In previous work, Milstein's group used a similar catalyst to couple alcohols to form esters via a hemiacetal intermediate. "This got us thinking that amide formation might be possible if an amine was added to the alcohol, since formation of a hemiaminal in this case is expected to be more favorable than that of a hemiacetal," Milstein says.

Their reasoning proved to be correct. The reaction of amines and alcohols in the presence of the ruthenium catalyst generates both aromatic and aliphatic amides in good to excellent yields.

The proposed mechanism for the transformation begins with catalytic dehydrogenation of the alcohol to the corresponding aldehyde. The aldehyde and the amine then form a hemiaminal that associates with the ruthenium catalyst. β-Hydride elimination from this intermediate produces the desired amide and a trans ruthenium dihydride complex, which, in turn, eliminates H2, thereby regenerating the catalyst.

The amidation reaction is sensitive to steric hindrance at the α position of either the alcohol or the amine, the researchers report. Substitution at that position results in lower yields and ester by-products. The reaction is also selective for primary amines. Experiments using secondary amines gave no amides but instead produced esters from self-coupling of the alcohol.

For future work, Milstein plans to extend the amidation reaction to the preparation of amide polymers and industrially important amides, he says.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society