Synthesis of amides from esters and amines with liberation of H2 under neutral conditions

Article abstract of DOI:10.1021/ja109944n

Efficient synthesis of amides directly from esters and amines is achieved under mild, neutral conditions with the liberation of molecular hydrogen. Both primary and secondary amines can be utilized. This unprecedented, general, environmentally benign reaction is homogeneously catalyzed under neutral conditions by a dearomatized ruthenium-pincer PNN complex and proceeds in toluene under an inert atmosphere with a high turnover number (up to 1000). PNP analogues do not catalyze this transformation, underlining the crucial importance of the amine arm of the pincer ligand. A mechanism is proposed involving metal-ligand cooperation via aromatization-dearomatization of the pyridine moiety and hemilability of the amine arm.

Full text of DOI:10.1021/ja109944n

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pubs.acs.org/JACS
Synthesis of Amides from Esters and Amines with Liberation of H2
under Neutral Conditions
Boopathy Gnanaprakasam and David Milstein*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
S Supporting Information
b
ABSTRACT: Efficient synthesis of amides directly from
esters and amines is achieved under mild, neutral conditions
with the liberation of molecular hydrogen. Both primary and
secondary amines can be utilized. This unprecedented, general,
environmentally benign reaction is homogeneously catalyzed
under neutral conditions by a dearomatized ruthenium-pincer
PNN complex and proceeds in toluene under an inert atmo-
sphere with a high turnover number (up to 1000). PNP
analogues do not catalyze this transformation, underlining the
crucial importance of the amine arm of the pincer ligand. A
Figure 1. Dearomatized Ru-pincer complexes.
mechanism is proposed involving metal-ligand cooperation
via aromatization-dearomatization of the pyridine moiety and
hemilability of the amine arm.
catalyzes the dehydrogenative coupling of primary alcohols to acetals
or esters, and the reaction of alcohols with ammonia to selectively
form primary amines, also by a metal-ligand cooperation mecha-
nism, involving the central acridine ring.13
Here we report a novel catalytic amide synthesis from esters
and amines. This amidation reaction is general, efficient, and
environmentally benign. It proceeds under neutral reaction condi-
tions and results in high turnover numbers (up to 1000). Uniquely, it
generates H2 rather than an alcohol byproduct (eq 1).
arboxylic amides are of much importance in chemistry and
C
biology. Although several methods exist for the preparation
of amides, atom-economical syntheses under mild and neutral
conditions without waste generation or use of hazardous reagents
are a formidable challenge.1,2 A potentially attractive process is the
synthesis of amides from esters; however, stoichiometric amounts of
promoters or metal mediators are normally required.3 Very few cata-
lytic ester-amide exchange reactions have been reported,4,5 includ-
ing the use of Sb(OEt)3 (5-10 mol %) with azeotropic removal of
the methanol4a,b and the employment of group IV metal alkoxides in
conjunction with additives, such as the interesting catalytic system of
Zr(OtBu)4 (10 mol %) þ 1-hydroxy-7-azabenzotriazole (10 mol %)
reported by Porco.5 Reactions of amines with amides (transamida-
tion) catalyzed by Al(III) and group 4 metal complexes under mild
conditions were recently reported.6
We have discovered the atom-economical, environmentally
benign direct synthesis of amides from alcohols and amines with
liberation of H2, catalyzed by the dearomatized pincer complex
(PNN)Ru(II) 17 (Figure 1). Several interesting reports on amide
formation by dehydrogenative coupling of amines with alcohols
appeared later.8 Catalytic hydrogenation of amides to alcohols and
amines was also reported very recently.9 Complex 1 and the analo-
gous (PNP)Ru(II) complexes 2a, 2b catalyze also the dehydro-
genative coupling of primary alcohols to form esters,10a,10b the hydro-
genation of esters to alcohols,10d the dehydrogenation of secondary
alcohols to ketones,10c and, very recently reported, the acylation of
secondary alcohols with esters.10f Unlike complex 1, complexes 2a,2b
catalyze the coupling of amines with alcohols to form imines, rather
than amides, with liberation of H2.11 Mechanistically, these catalytic
reactions operate by a new mode of metal-ligand cooperation,
involving aromatization-dearomatization of the pyridine-based core
of the pincer ligand.12 An acridine-based pincer-ruthenium complex
When a benzene solution containing 10 mmol of pyrrolidine,
10 mmol of ethyl acetate, and 0.01 mmol of complex 1 was refluxed
under an argon atmosphere, quantitative conversion of pyrrolidine
was observed by GC after 28 h, to give N-acetylpyrrolidine (charac-
terized by NMR and GC-MS) in 98% isolated yield after column
purification (Table 1, entry 1). The same results were obtained when
the reaction was carried out in refluxing toluene. Reaction of ethyl
acetate with morpholine in benzene under reflux resulted after 36 h
in 69% conversion, and the corresponding amide was isolated in 67%
yield (Table 1, entry 2). Refluxing of 1-methyl piperazine, ethyl
acetate, and benzene in the presence of complex 1 provided the
amide in 52% isolated yield (Table 1, entry 3).
Exploring the scope of the ester amidation reaction, various
esters and amines were examined. Refluxing a toluene solution
containing butyl butyrate (5 mmol), piperidine (10 mmol), and 0.1
mol % of the PNN complex 1 under an argon atmosphere for 19 h
resulted in 100% conversion of piperidine as observed by GC
analysis, with the exclusive formation of 1-(piperidin-1-yl)butan-1-
one in 94% isolated yield after purification by alumina column
Received: November 5, 2010
Published: January 19, 2011
r
2011 American Chemical Society
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Table 1. Aminolysisa of Esters Catalyzed by the Ruthenium-PNN* Complex 1 Using Amines
a Complex 1 (0.01 mmol), ester (5 mmol), amine (10 mmol), and toluene/benzene (3 mL) were refluxed at an oil bath at a temperature of 135 °C in a
Schlenk tube. Conversion of amine was analyzed by GC using m-xylene as an internal standard. b Benzene was used as a solvent.
chromatography (Table 1, entry 4). Similarly, refluxing a toluene
solution containing butyl butyrate and morpholine or N-methylpi-
perazine in the presence of complex 1 resulted in 100% conversion
of the amine, with the isolation of the corresponding amides in 95%
and 94% yields, respectively. Refluxing of excess butyl butyrate and
piperazine in toluene led the bis-acylation of the piperazine,
providing the corresponding bis-amide in 56% isolated yield.
Interestingly, unlike the traditional methods, this amidation
reaction forms H2 rather than alcohol byproduct, resulting in the
irreversible incorporation of both the acyl and alkoxo parts of the
starting ester into the product amide. This is useful when symme-
trical esters are utilized. This result is accounted for in the proposed
mechanism (see later), with no need to invoke intermediacy of the
free alcohol. Significantly, the turnover number of the ester-amide
exchange reaction using the dearomatized pincer complex 1 is high
(up to 1000), as compared with 10-20 turnovers in the few
reported catalytic ester-amide exchange reactions.4,5,14
To explore the synthetic utility of this reaction, pentyl penta-
noate was reacted with various amines. The reaction of pentyl
pentanoate with piperidine gave 100% conversion, with the
isolation of the amide in 96% yield. Upon refluxing a toluene
solution of morpholine or N-methyl piperazine with pentyl
pentanoate, the corresponding amide was produced in 96%
and 94% isolated yields, respectively. Likewise, reaction of hexyl
hexanoate with pyrrolidine, piperidine, or morpholine under
reflux conditions of toluene afforded the complete conversion
of the amines, with isolated excellent yield of the corresponding
amides.
Next, the reactions were also studied with primary amines.
The reaction of ethyl butyrate and hexyl amine in the presence of
0.1 mol % of 1under refluxing toluene led to 100% conversion of the
amine, with the isolation the corresponding amide in 97% yield.
Similarly, reaction of pentyl pentanoate with 4-methylbenzyl amine
in toluene reflux yielded 100% conversion, with isolation of the
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alkoxo parts of the substrate ester into the product amide with
liberation of H2. The reaction results in high turnover numbers,
up to 2 orders of magnitude higher than those reported for the
few catalytic ester amidation reactions. Both primary and sec-
ondary amines can be utilized.15
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
david.milstein@weizmann.ac.il
’ ACKNOWLEDGMENT
This research was supported by the European Research
Council under the FP7 framework (ERC No 246837), by the
Israel Science Foundation, by the MINERVA Foundation, and
by the Kimmel Center for Molecular design. D.M. is the holder of
the Israel Matz Professorial Chair of Organic Chemistry.
Figure 2. Plausible mechanism for the ester amidation reaction.
corresponding amide in 98% yield. These reactions did not lead to
any alcohol as waste product.
Interestingly, the dearomatized PNP complexes 2a, 2b, analo-
gous to complex 1 except for not having a “hemilabile” amine
arm, did not catalyze the amidation reaction. Thus, heating a
solution of pentyl pentanoate, piperidine, and 2 or 3 in toluene
under reflux for 24 h resulted in no reaction. This indicates that
the hemilabile amine arm is essential for ester amidation catalysis.
The reactions were also studied without a solvent. Thus,
heating the solutions containing pentyl pentanoate, piperidine,
and RuPNN complex 1 at 135 °C resulted in only 52% conver-
sion.
Although at present we do not have sufficient mechanistic
data, a plausible catalytic cycle for the ester amidation is
presented in Figure 2. This mechanism accounts for the striking
observation that, while 1 is an excellent catalyst, the seemingly
similar complexes 2a, 2b are catalytically inert. We propose that
N-H activation of the dearomatized complex 1 forms the
aromatized coordinatively saturated species A, as we have pre-
viously observed with complex 2b.12c Dissociation of the hemi-
labile amine arm and coordination of the ester forms inter-
mediate B. This is difficult with the PNP complexes 2a, 2b under the
reaction conditions, and hence they do not catalyze this reaction.
Intramolecular nucleophilic attack by the amido ligand at the
carbonyl group of the ester results in formation of the amide and
generation of the alkoxy intermediate C. β-H elimination generates
the Ru dihydride complex D, bearing a coordinated aldehyde.
Nucleophilic attack of the amine on the aldehyde followed by
liberation of H2 (via proton-hydride interaction) gives intermediate
E, which upon β-H elimination forms the trans dihydride inter-
mediate F, with liberation of a second molecule of the amide.
Dihydrogen loss from intermediate F regenerates catalyst 1. Based
on this mechanism, one cycle accounts for the generation of two
amide molecules and two H2 molecules, with no intermediacy of
free alcohol.
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