Ytterbium triflate catalyzed synthesis of β-enaminones

Article abstract of DOI:10.1016/j.tetlet.2007.02.064

β-Enaminones have been synthesized in very good yield under solvent-free conditions from differently substituted amines and β-diketones in the presence of Yb(OTf)₃ as catalyst. The method is applicable to cyclic and acyclic ketones, aromatic an

Full text of DOI:10.1016/j.tetlet.2007.02.064

Tetrahedron Letters 48 (2007) 2717–2720
Ytterbium triflate catalyzed synthesis of b-enaminones
Francesco Epifano,a,* Salvatore Genoveseb and Massimo Curinib
aDipartimento di Scienze del Farmaco, Via dei Vestini 31, 66013 Chieti Scalo (CH), Italy
bDipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Via del Liceo, 06123 Perugia, Italy
Received 10 January 2007; revised 12 February 2007; accepted 13 February 2007
Available online 16 February 2007
Abstract—b-Enaminones have been synthesized in very good yield under solvent-free conditions from differently substituted amines
and b-diketones in the presence of Yb(OTf)3 as catalyst. The method is applicable to cyclic and acyclic ketones, aromatic and ali-
phatic amines without differences.
ꢀ 2007 Elsevier Ltd. All rights reserved.
b-Enaminones have been extensively used as key inter-
mediates in organic synthesis.1 In particular they have
been employed as synthons of a wide variety of hetero-
cycles2 and pharmaceutical compounds having anti-epi-
leptic,3 molluscicidal and larvicidal activities4 and as
intermediates for the synthesis of naturally occurring
alkaloids.5 Despite the importance of b-enaminones as
valuable biologically active compounds, their synthesis
has received to date little attention. The most well-
known and exploited route to b-enaminones involves
the direct condensation of b-dicarbonyl compounds
with amines in refluxing aromatic hydrocarbons with
azeotropic removal of water.6 Other improved proce-
dures have been subsequently reported and include the
reaction of amines with b-dicarbonyl compounds sup-
ported on silica under microwave irradiation,7 montmo-
rillonite K-10 and ultrasounds,8 the reaction catalyzed
by NaAuCl4,9 bismuth(III) trifluoroacetate,10 erbium
triflate11 or zirconium(IV) chloride,12 cyclization of
aminoacids,13 reductive cleavage of silylisoxazoles,14
the direct condensation of primary amines and b-di-
ketones in water.15 A detailed survey of all methods for
the synthesis of the title compounds have been recently
reported.12 Unfortunately many of these processes suffer
major or minor limitations such as drastic reaction con-
ditions, low yields, tedious work-up procedures, low
selectivity, co-occurrence of several side reactions and
need of chromatography for purification of adducts.
Moreover, in the case of some of the Lewis acid cata-
lyzed reactions, no recycling of the catalyst renders these
methods environmentally unsound, especially with
regard to a potential large-scale synthesis. So although
different methods are available for the synthesis of
b-enaminones, development of another facile, high-
yielding, nonpolluting preparation is still of great
importance.
During the last 15 years, rare earth metal triflates have
been found as unique Lewis acids in that they are water
tolerant reusable catalysts and they can effectively pro-
mote several carbon–carbon and carbon–heteroatom
bond formation reactions in high yield.16 As a part of
our ongoing studies aimed to explore the utility of
lanthanide triflate catalyzed reactions under solvent-
free conditions,17 we decided to investigate the use of
Yb(OTf)3 as a catalyst for the preparation of b-enami-
nones using some reaction conditions recently reported
for the synthesis of b-keto enol ethers (Scheme 1).17
Although Jenner reported in 1996 a procedure aimed
to obtain the title compounds under the catalysis of
Yb(OTf)3,18 results reported in this work is mainly
focused on the use of secondary amines as starting mate-
rials, while results employing primary amines are not re-
ported or gave no desired product or not satisfactory
yields, with the only exception of using 2,4-pentanedione
O
O
Yb(OTf)3
R
NH2
+
Keywords: Amine; b-Enaminone; b-Dicarbonyl compounds; Hetero-
geneous catalysis; Ytterbium triflate.
O
NHR
*
Corresponding author. Tel.: +39 08712555321; fax: +39
08713555315; e-mail: fepifano@unich.it
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.064

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F. Epifano et al. / Tetrahedron Letters 48 (2007) 2717–2720
Table 1. Yb(OTf)3 catalyzed formation of b-enaminones
Reactant
Amine
Product
Yielda (%)
O
1,3-Cyclohexanedione
Morpholine
99
N
O
1
O
1,3-Cyclohexanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
Isopropyl amine
Cyclohexyl amine
Aniline
97
93
99
NHiPr
2
O
NHcC6H11
3
O
NHPh
4
O
1,3-Cyclohexanedione
n-Butyl amine
99
99
NHnBu
5
O
O
Acetylacetone
Morpholine
N
O
6
NHiPr
Acetylacetone
Isopropyl amine
98
7
O
O
O
NHcC6H11
Acetylacetone
Acetylacetone
Acetylacetone
Cyclohexyl amine
99
99
99
8
NHPh
Aniline
9
NHnBu
n-Butyl amine
10

F. Epifano et al. / Tetrahedron Letters 48 (2007) 2717–2720
2719
Table 1 (continued)
Reactant
Amine
Product
Yielda (%)
O
NHnBu
Benzoylacetone
n-Butyl amine
98
Ph
11
O
NHPh
Benzoylacetone
Aniline
99
Ph
12
a Yields of pure isolated products, characterized by IR, GC–MS, 1H NMR and 13C NMR.
as substrate. In addition better yields were obtained only
by application of a high-pressure procedure (300 MPa)
and carrying out reactions in a toxic and polluting
solvent such as chloroform.
NMR analysis and NOE experiments, except in the case
of using morpholine as starting amine to give compound
6 where a (E) geometry was obtained. The (Z) configu-
ration may be thermodynamically favoured by the
formation of an intramolecular hydrogen bond forma-
tion between oxygen atom of the carbonyl and the NH
residue yielding a six-member pseudocycle, while the
driving force in determining the geometry of the double
bond in compound 6 is the sterically more bulky
morpholine ring to assume a trans position with respect
to the carbonyl group. Finally we employed also b-di-
ketones with two different substituents, such as the
commercially available benzoylacetone. In all cases we
obtained selectively the adduct deriving from a nucleo-
philic attack of the amine to the carbonyl bearing a
methyl group.19 In contrast to data reported by
Jenner,18 our methodology is of general applicability,
leading in very good yield to the desired product starting
from differently substituted b-diketones and primary or
secondary amines.
We initially tested this type of reaction using cyclic b-
diketones as starting materials. The reaction was carried
out in neat at room temperature for 12 h using commer-
cially available 1,3-cyclohexanedione (2.0 mmol) and
amine (2.0 mmol) in the presence of Yb(OTf)3 hydrate
(0.01 mmol) as catalyst. After addition of NaOH 1 N
to precipitate Yb(III) as the corresponding hydroxide,
the desired product was obtained after filtration and
extraction with Et2O (3 · 2 mL). Results are summa-
rized in Table 1 and show that primary and secondary
amines, aromatic and aliphatic with linear, branched
or cyclic N-substituents, react without any significative
difference to give the corresponding b-enaminones in
good to nearly quantitative yield. Uncatalyzed reac-
tions, carried out in solvent-free conditions, gave in all
cases the desired product, after the same time, in yields
ranging from 40% to 55%. Loading of the catalyst high-
er than 0.01 mmol did not decrease reaction times signi-
ficantly. The degree of purity of each product was
analyzed by GC/MS spectrometry, using a Hewlett
Packard 6890 gas chromatograph equipped with a
12.5 m · 0.25 mm MetSil column coupled to HP Chem-
Station Software. The carrier gas was helium at a pres-
sure of 3.5 kg/cm2 and the column temperature was
programmed from 50 to 270 ꢁC at 10 ꢁC/min. The chro-
matogram was obtained using a reporting integrator.
Mass spectra were obtained from a GC–MS system,
operating in the EI mode at 70 eV, equipped with a
12.5 m · 0.25 mm MetSil column and an HP 5973 Mass
Selective Detector, using the same chromatographic
conditions reported above. The column was connected
to the mass spectrometer ion source via an open split
interface heated at 250 ꢁC.
From every reaction the catalyst have been recovered by
precipitation as Yb(OH)3, filtration and transformation
into triflate salt as already described.13 Recycled in this
way, the catalyst could be reused several times without
any loss of activity.
In conclusion we disclosed an easy environmentally
sound method for the synthesis of b-enaminones start-
ing from differently substituted 1,3-diketones and
amines under the catalysis of Yb(OTf)3. The simple
work-up procedure, mild reaction conditions and high
yields make our methodology a valid contribution to
the existing processes in the field of b-enaminones syn-
thesis. Further investigations into the scope and other
applications of Yb(OTf)3 promoted reactions are now
in progress in our laboratories and will be reported in
due course.
Employing linear b-diketones as substrates, such
commercially available acetylacetone, using the same
reaction conditions as above, the corresponding
b-enaminones were obtained in very good yield. From
linear b-diketones we also obtained the corresponding
Synthesis of b-enaminones. A typical procedure: A mix-
ture of b-diketone (2.0 mmol) and amine (2.0 mmol)
was well stirred with Yb(OTf)3 (0.01 mmol) at room
temperature for 12 h. NaOH 1 N (2 mL) was added,
the white precipitate filtered and the resulting solution
extracted with Et2O (3 · 2 mL). Collected organic
phases were dried over anhydrous Na2SO4 and the
b-enaminones having
a (Z) configuration of the
carbon–carbon double bond, as determined by 1H

2720
F. Epifano et al. / Tetrahedron Letters 48 (2007) 2717–2720
solvent evaporated to dryness to give the desired
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13
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Acknowledgements
Financial support from MIUR National Project ‘Svilup-
po di processi sintetici ecocompatibili nella sintesi orga-
nica’, COFIN 2004 is gratefully acknowledged. Authors
also wish to thank Dr. Paola Pisani and Dr. Maria
Grazia Lamagna for their helpful and friendly
collaboration.
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