A new synthesis of β-keto amides by reduction of Passerini adducts

Article abstract of DOI:10.1016/j.tetlet.2004.11.041

The Passerini reaction between glyoxals, isocyanides and acetic acid forms β-keto acyloxyamides, which are readily transformed in β-keto amides by reductive deacetoxylation with zinc. The versatility of this procedure, which allows introducing different groups both in position-3 and the amide nitrogen, makes it ideal for its use in diversity-oriented synthesis, in combination with subsequent complexity generation reactions.

Full text of DOI:10.1016/j.tetlet.2004.11.041

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 23–26
A new synthesis of b-keto amides by reduction of Passerini adducts
Ana G. Neo,a Jose Delgado,a Cecilia Polo,a Stefano Marcaccinib and Carlos F. Marcosa,*
a
´ ´ ´
Laboratorio de Quımica Organica y Bioorganica, LOBO, Departamento de Quımica Organica, Facultad de Veterinaria,
´
Universidad de Extremadura, 10071 Caceres, Spain
´
´
Dipartimento di Chimica Organica ‘Ugo Schiff ’, Universita di Firenze 50019 Sesto Fiorentino FI, Italy
b
`
Received 27 September 2004; revised 2 November 2004; accepted 8 November 2004
Abstract—The Passerini reaction between glyoxals, isocyanides and acetic acid forms b-keto acyloxyamides, which are readily trans-
formed in b-keto amides by reductive deacetoxylation with zinc. The versatility of this procedure, which allows introducing different
groups both in position-3 and the amide nitrogen, makes it ideal for its use in diversity-oriented synthesis, in combination with sub-
sequent complexity generation reactions.
Ó 2004 Elsevier Ltd. All rights reserved.
Diversity-oriented synthesis (DOS) has received much
attention lately as a tool for the exploration of the chem-
ical space of molecular structures.1 The aim of DOS is to
obtain collections of small molecules as complex and
diverse as possible. The screening of such molecular
libraries, searching for perturbing effects on disease-
related biological pathways, may eventually lead to the
identification of therapeutic protein targets, which can
be modulated by small organic molecules. The develop-
ment of effective strategies in DOS is therefore very
important in finding new pharmacological targets.2
Multicomponent reactions (MCRs) are privileged in
the generation of molecular complexity, and have pro-
ven to be very useful in DOS.3,4 A remarkable feature
of MCRs is their capability to generate multifunctional
compounds from simple monofunctional starting mate-
rials. Multifunctional reagents, in turn, serve as advan-
tageous starting materials for the construction of
libraries of more complex molecules.
or functional groups. On the other hand, reductive
removal of the acyloxy group in the 2-acyloxy-3-keto
amides (4) coming from the Passerini condensation of
arylglyoxals would give b-keto amides (5), containing
an active methylene group suitable for further function-
alization. In fact, b-keto amides (5) have proven to be
versatile building blocks in the synthesis of different
heterocycles, as pyrroles,10 indoles,11 tetrahydroquino-
lines,12 dihydropyrimidones,13 dihydrofuranodiones
and succinimides.14 So, this strategy would, in theory,
allow preparing a wide range of heterocyclic structures.
Several methods have been previously reported for the
synthesis of b-keto amides (5). The most general ones
are based on nucleophilic amidation of electrophiles,
as b-keto acids,15 b-keto esters,16 b-keto thioesters,17
ketene dimers,18 dioxinones19 or acylated MeldrumÕs
acids.20 Other approaches include condensation of
ketone enolates with isocyanates21 or activated carba-
mates,22 condensation of amide enolates with esters23
or acyl chlorides,24 isoxazolium salts fragmentation,25
and enzymatic hydrolysis of b-keto nitriles.26 Neverthe-
less, many of these methods have limitations, as they in-
volve very specific or low yielding reactions, use harsh
reaction conditions, or require difficult syntheses of the
starting materials.
As part of our research in the use of MCRs for the syn-
thesis of heterocyles,5 we were able to prepare several
furan,6 indole6a and oxazole7 derivatives by the Passerini
condensation8 of arylglyoxals, carboxylic acids and iso-
nitriles, followed by suitable post-condensation trans-
formations.9 However, this method is limited to the
use of carboxylic acids containing particular structures
Rosenfeld has reported the deacetoxylation of esteroid
ketol acetates using zinc in refluxing glacial acetic acid.27
A modification of this method, using ultrasounds, has
been applied to the cleavage of sesquiterpene c-enone-
lactones.28 In our case, we envisaged that the reductive
Keywords: Multicomponent reactions; Isocyanides; Amido-ketones;
Ultrasounds.
*
Corresponding author. Tel.: +34 927 257158; fax: +34 927 257110;
e-mail: cfernan@unex.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.041

24
A. G. Neo et al. / Tetrahedron Letters 46 (2005) 23–26
deacyloxylation of 2-acyloxy-3-keto amides (4) with zinc
would be facilitated by the complexation of a zinc atom
by the two carbonyl groups of the substrate.
water promotes the precipitation of the products, which
can then be isolated by filtration and, according to our
experience, directly used in further reactions. However,
purification by column chromatography was systemati-
cally carried out, in order to get reproducible yields
and analytically pure samples. Cleavage of the acetoxy
group was evidenced by the loss of the carboxylic
C@O stretching peak at around 1750cmꢀ1 in the IR
spectra. In this way, b-keto amides (5) are obtained, in
good or excellent yields, and essentially pure, as showed
by TLC analysis, and confirmed in one case by HPLC
(UV detection at 214 and 300nm). Though, in most of
the cases tautomerization takes place in solution, so
NMR spectra show peaks corresponding to the minor
enol form, in addition to the main signals corresponding
to the major keto form.22,24,26 Their structures were con-
firmed by the usual analytical and spectroscopic
methods.
With all these considerations in mind, we propose a
straightforward method for the preparation of b-keto
amides (5) by a Passerini three-component condensa-
tion, followed by zinc promoted removal of the acid
component.
The combination of glyoxals (1) with isocyanides (2) and
acetic acid (3) gave the expected Passerini three-compo-
nent adducts (4; Table 1). The reaction is conveniently
performed by mixing the three components in diethyl
ether and stirring at room temperature for 3 days. Typ-
ically, the yields are moderate to good and, in most of
the cases, the adduct precipitates in the reaction med-
ium, and is isolated with high degree of purity by simple
filtration. Though, in a few cases, hexane is added to the
reaction medium in order to induce precipitation of the
product.
In this two-step process, only the fragments coming
from the aldehyde and isocyanide components are pres-
ent in the final structure. The acid component is useful
in the construction of the desired molecular skeleton
and the acetoxy on the Passerini adduct is actually
masking an active methylene group, which is just re-
vealed after the reduction with zinc. The transformation
of the Passerini adducts into b-keto amides could be
used as a branching strategy in DOS.29
Subsequent reduction of the Passerini adducts takes
place almost instantaneously, in extraordinarily mild
conditions, using activated zinc in a mixture of saturated
aqueous ammonium chloride and methanol. Addition of
Table 1. Synthesis of b-keto amides
O
O
It is noteworthy that, the cleavage of the acetyl group
takes place in aqueous medium, in very mild conditions,
as anticipated. We propose a mechanism in which an ini-
tial complexation of a zinc atom with the ketone and
amide carbonyl groups in the Passerini adduct takes
place. The formation of this complex forces a flat con-
formation of the bidentate ligand, facilitating the dona-
tion of a pair of electrons from zinc to the ketone
oxygen. This results in the formation of the correspond-
ing conjugated zinc enolate and the concomitant release
of the acetate leaving group. Neutralization and tauto-
merization gives the final b-keto amides (Scheme 1).
O
O
O
R' NC
R'
·
)
)
)
Zn
Et2O
R
N
H
H
(2)
+
R'
R
R
N
H
O
aq NH4Cl
CH3COOH
O
MeOH
O
(1)
(3)
(4)
R0
(5)
4, 5
R
% 4a
% 5b
1
a
C6H5
C6H11
C6H11
C6H11
C6H11
C5H11
C5H11
PhCH2
PhCH2
PhCH2
PhCH2
tBu
74
73
76
77
73
68
60
74
63
82
89
81
66
81
69
78
67
75
75
82
74
83
71
68
66
70
69
84
73
80
76
67
87
94
85
95
95
74
2
3
4
6
7
5
8
9
b
c
d
e
f
4-Me–C6H4
4-Cl–C6H4
4-Br–C6H4
C6H5
4-Br–C6H4
C6H5
g
h
i
4-Me–C6H4
4-Cl–C6H4
4-Br–C6H4
C6H5
As many different arylglyoxals and isocyanides are easily
available, a wide variety of substituents can be intro-
duced both in position-3 and in the amide nitrogen.
From this point of view, the present route appears to
be more versatile than many of the earlier approaches
to b-keto amides. On the other hand, it is experimentally
very simple, and both the Passerini adducts and the final
b-keto amides can be easily isolated with a reasonable
grade of purity by filtration. Hence, although our method
10
11
12
13
14
15
16
17
18
19
j
k
l
4-Me–C6H4
4-Br–C6H4
C6H5
tBu
tBu
m
n
o
p
q
r
2,6-Me2Ph
2,6-Me2Ph
2,6-Me2Ph
2,6-Me2Ph
2,6-Me2Ph
4-(MeO)–Ph
4-Me–C6H4
4-(MeO)–C6H4
4-Cl–C6H4
4-Br–C6H4
C6H4
s
a 5mmol of each acetic acid and the corresponding arylglyoxal and
isocyanide were stirred 72h in Et2O at room temperature. Filtration
and washing with i-PrOH and i-Pr2O yielded the product pure
enough to be used in the following reaction.
b 8mmol of Zn dust in 8mL of saturated aqueous NH4Cl is activated
by irradiation 5min in a sonication bath; 2mmol of the starting
Passerini adduct dissolved in 32mL of methanol was then added, and
the mixture was stirred 30min at room temperature. Zn was filtered
off, 100mL of water was added, and the resulting white precipitate
was filtered, dried under vacuum and purified by flash column
chromatography. The yields have not been optimized.
Zn
Zn
O
O
O
O
O
O
O
NH4Cl
H2O
Zn
R'
R'
R'
R
N
H
R
N
H
R
N
H
·
)
)
)
O
O
O
Scheme 1. Proposed mechanism for the zinc deacetoxylation of b-keto
amides.

A. G. Neo et al. / Tetrahedron Letters 46 (2005) 23–26
25
"
"
"
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Synthesis 2003, 1471; (c) Do¨mling, A. Curr. Opin. Chem.
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O
O
O
O
R'
R'
+
R
N
H
N
H
R
´
7, 143; (e) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt,
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Scheme 2. Formal double-Umpolung disconnection for the synthesis
of b-keto amides.
involves two separate reaction steps, in some cases it
may be advantageous relative to apparently more
straightforward procedures, as the one-step thermal
reaction of b-keto esters with primary amines; for exam-
ple, in combinatorial chemistry applications. Several
examples combining different arylglyoxals and aliphatic
an aromatic isocyanides are reported in Table 1 and the
yields for both the Passerini condensation and zinc
reduction are given. All the isocyanides employed were
obtained from commercial sources, while glyoxals were
made by oxidation of the corresponding acetophenones
with HBr in DMSO.30
In summary, a simple and versatile two-step synthesis of
b-keto amides has been developed. This method for-
mally involves the formation of a new bond between a
b-keto-carbocation and a carbamoyl anion. This means
that the b-keto amide moiety is built through an unusual
double Umpolung process (Scheme 2). To our knowl-
edge, such disconnection has never been employed be-
fore in the preparation of b-keto amides. The use of
recyclable polymer supported carboxylic acids in the
Passerini condensation, which would spare the sacrificial
use of acetic acid, is currently under research in our
laboratory.
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Acknowledgements
´
We thank financial support from the Consejerıa de San-
idad y Consumo (03/72) and Consejerıa de Educacion
´
Ciencia y Tecnologıa (2PR04A003) of the Junta de
Extremadura and FEDER.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2004.
11.041.
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