The Reductive Amination of Aldehydes with Monoalkylureas

Two similar methods for the synthesis of unsymmetrical N,N -disubstituted ureas by the reductive amination of aldehydes with monoalkylureas or urea have recently been reported. 

Reductive amination of aldehydes with monoalkylureas in the presence of titanium(lV) isopropoxide and sodium borohydride in THF represents a viable, laboratory-scale route to unsymmetrical N,N -disubstituted ureas in 39-94% yield. 

Titanium(IV) isopropoxide behaves as the Lewis acid as well as as an efficient acid scavenger, and is compatible with a variety of functional groups, such as lactams, acetamides, acetals, and tert-butyldimethylsilyl ethers. Unfortunately, aldehydes with an a-hydrogen do not undergo selective reactions [791]. 

A rather similar method based on reductive alkylation of urea involves the use of trimethylsilyl chloride (TMSCl) as the catalyst in the condensation step and again utilizes sodium borohydride as the reducing agent [792]. Under these conditions, the parent urea can be converted into monosubstituted as well as disubstituted ureas in yields of 60-92%. 

Although both of these methods offer some advantages over the previous ones and are able to produce a variety of unsymmetrical substituted ureas without the use of gas-phase or highly toxic reagents, they share a major drawback in that they generate large amounts of waste salts. 

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