282412 Benign Alkylation of Amines by Alcohols (AAA)

Wednesday, October 31, 2012: 2:36 PM
Allegheny III (Westin )
Luka Tallon1, Klaus Hellgardt2 and Mimi Hii1, (1)Chemistry, Imperial College London, London, United Kingdom, (2)Chemical Engineering, Imperial College London, London, United Kingdom

Benign Alkylation of Amines by Alcohols (AAA)

Luka Tallon, Klaus Hellgardt, Mimi Hii

In recent years the increasing concern for the environment and concepts such as ‘e-factor' and ‘atom economy', have catalysed the integration of sustainable development and green chemistry. In particular, the activation of alcohols for nucleophilic substitution was identified by the American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable as one of the key reactions where improvements are required. For example, it has been estimated that 64% of all nitrogen substitutions constitute amine alkylations in the pharmaceutical industry.

Two commonly used approaches for the activation of an OH group towards nucleophilic substitution are by protonation or conversion to a halide/sulfonate. However, protonation often causes the incoming nucleophile to become deactivated in acidic environment and halogenation generates a large quantity of waste products. In both cases, over-alkylation (formation of tertiary amines from primary amines) is also a recurring problem.

A ‘hydrogen borrowing' methodology offers an alternative, benign approach to the activation of alcohols; in this presentation we will discuss the Alkylation of Amines by Alcohols (AAA) using this process.

Hydrogen borrowing is a form of transfer hydrogenation; a catalyst, [M], is employed both as a hydrogen acceptor and donor (Figure 1). During the reaction, hydrogen is abstracted from the alcohol to form the more reactive carbonyl, which is then condensed with the amine to form an imine intermediate, to which the catalyst then returns hydrogen to form the newly alkylated amine.







Figure 1: N- Alkylation of amine using hydrogen borrowing methodology

This system has clear advantages over previous routes for the activation of alcohols. Only water is generated as a by-product therefore achieving an enhanced environmental profile.

Very recently the work from our research group has shown that by using heterogeneous Au/TiO2, highly selective direct alkylation of a range of amines under aerobic conditions can be achieved using a flow reactor (Figure 2).

Figure 2: Continuous flow alkylation of amine over heterogeneous Au catalysts

The scope of this system will be demonstrated, including details on the synthesis of Piribedil.  Although higher temperatures and 50 bar pressure are required, the method involves no use of co-catalysts such as [RuCl2(p-cymene)]2 .

Figure 3: Facile Piribedil synthesis over Au based catalyst

Additionally, we wish to highlight that the reaction of optically pure α-methylbenzylamine and benzyl alcohol proceeds with complete retention of configuration to give the substituted product (Figure 4).



Figure 4: Reaction of optically pure α-methylbenzylamine and benzyl alcohol.


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