C O M M U N I C A T I O N S
Table 2. Amidation of Amines with Alcohols
Scheme 2. Mechanism for Ruthenium-Catalyzed Amide Formation
temperature, aniline and N-methylbenzylamine gave the amide in
low to moderate yield while the remaining portion of the alcohol
underwent self-condensation into the corresponding ester (entry 10
and 11).
The amidation presumably follows the mechanism in Scheme 2
and does not proceed through an intermediate ester. The latter was
confirmed by treating 2-phenylethyl 2-phenylacetate with benzyl-
amine and the catalyst, which afforded none of the amide in Table
2, entry 1. The reaction between benzaldehyde and benzylamine
under the same conditions led to exclusive formation of the cor-
responding imine and neither amide nor amine was observed. The
imine does not react in the presence of the catalyst and this did not
change by adding water or by conducting the reaction under a
dihydrogen atmosphere. Imine formation has never been detected
by GC in any of the experiments in Table 2. This indicates that the
reaction proceeds through an aldehyde, but that the aldehyde stays
coordinated to the metal (Scheme 2). Subsequent attack by the
amine affords the hemiaminal which also stays coordinated to the
metal. The amide is then formed after ꢀ-hydride elimination and
at no time is a free aldehyde or hemiaminal released from the
catalyst since this would lead to the formation of an unreactive
imine.
In conclusion, we have developed a novel method for the
amidation of amines with alcohols. The reaction is performed with
a simple catalyst prepared from a ruthenium precursor, an N-
heterocyclic carbene and a phosphine ligand. This system presents
new opportunities for the preparation of a key functional group in
organic chemistry.
a Isolated yield. b Ru(COD)Cl2 (2%), ligands (2%), and base (8%).
Acknowledgment. We thank the Danish National Research
Foundation for financial support.
c In mesitylene at 163 °C.
With these optimized conditions in place the scope and limitation
of the method could now be explored. A range of different primary
alcohols were reacted with primary amines to afford the corre-
sponding secondary amides in 60-100% isolated yield (Table 2,
entries 1-9).
Supporting Information Available: General experimental procedure
and compound characterization data. This material is available free of
References
Sterically unhindered alcohols and amines gave the amide in high
yield (entry 1 and 2). Benzyl alcohol was converted into benzamide
(entry 3) while hex-5-en-1-ol gave the hexanamide with concomitant
reduction of the olefin (entry 4). An optically pure amine could be
employed and the product showed no sign of racemization according
to optical rotation (entry 5). An aryl chloride also participated in
the amidation (entry 6) while essentially no reaction occurred with
the corresponding aryl bromide (data not shown). N-Benzyletha-
nolamine could be coupled with benzylamine in high yield (entry
7) which shows that the transformation is selective for a primary
amine. Optically pure N-benzyl-L-prolinol was converted into N,N′-
dibenzyl-L-prolinamide with no sign of epimerization (entry 8). The
amidation could also be carried out in an intramolecular fashion as
illustrated with the formation of γ-butyrolactam (entry 9). Aniline
and secondary amines, on the other hand, did not react with primary
alcohols at 110 °C. However, when the temperature was raised to
163 °C complete conversion of the alcohol was observed. At this
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