(467g) Benign Alkylation of Amines by Alcohols (AAA)

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.