Copper-catalyzed aerobic oxidative cyclization of hydrazones to pyrazolidinones

Article abstract of DOI:10.1002/ejoc.201100261

N-Aryl hydrazones participate, under copper catalysis, in a [3+2] cycloaddition/aerobic oxidation cascade reaction to form pyrazolidinones. The starting hydrazones were prepared by three-component coupling of allylic amines, acyl chlorides, and aryl diazonium salts. Copyright

Full text of DOI:10.1002/ejoc.201100261

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100261
Copper-Catalyzed Aerobic Oxidative Cyclization of Hydrazones to
Pyrazolidinones
Aurélie Dos Santos,[a] Laurent El Kaïm,*[a] Laurence Grimaud,*[a] and Caroline Ronsseray[a]
Keywords: Hydrazones / Cycloaddition / Oxidation / Copper / Multicomponent reactions
N-Aryl hydrazones participate, under copper catalysis, in a
[3+2] cycloaddition/aerobic oxidation cascade reaction to
form pyrazolidinones. The starting hydrazones were pre-
pared by three-component coupling of allylic amines, acyl
chlorides, and aryl diazonium salts.
group can easily be introduced by appropriate choice of the
nucleophile as the third component of this diazonium–
ketene coupling.
Introduction
In the context of environment-friendly processes, the
concept of atom and step efficiency has led academic chem-
ists to join their industrial colleagues in their long-lasting
efforts towards cost reductions. This trend has brought
about a rebirth of many old reactions, which can now be
adapted to the new paradigms of modern chemistry. With
such a focus on sustainable chemistry, impressive develop-
ments in the field of multicomponent reactions (MCRs),[1]
cascades,[2] as well as aerobic processes[3] have emerged
these last few years. We recently disclosed a two-step syn-
thesis of complex polycyclic systems through an isocyanide-
based MCR and an oxidative process involving either palla-
dium or copper.[4] In combination with our long-established
interest in hydrazone chemistry,[5] we became interested in
MCR/oxidative strategies by exploiting hydrazone chemis-
try.
Scheme 1. Three-component access to hydrazonocarboxylic acids.
Hydrazono amide 1a, prepared in 74% isolated yield
from the corresponding acyl chloride and diallylamine, was
heated in acetic acid in air by using a catalytic amount of
copper acetate (Scheme 2). Under these conditions, pyraz-
olidinone 2a could be obtained in 29% yield.
Results and Discussion
Hydrazone derivatives are known to be very sensitive to
oxidation and many aerobic oxidative transformations into
ketones are reported.[6] Looking closely at the mechanism
of these oxidative degradations, we speculated that a proper
allyl moiety would allow trapping of some reactive interme-
diates. Such functionalized substrates may be easily synthe-
sized through coupling between aryl diazonium salts and
ketene–pyridines – obtained by treating acyl chlorides with
pyridine – as reported earlier (Scheme 1).[7] Indeed, an allyl
[a] DCSO-UMR 7652: CNRS-ENSTA-Ecole Polytechnique,
Laboratoire Chimie et Procédés,
Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris Cedex 15, France
Fax: +33-1-45528322
E-mail: laurent.elkaim@ensta-paristech.fr
grimaud@dcso.polytechnique.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100261.
Scheme 2. Copper-catalyzed oxidative cyclization of 1a.
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A. Dos Santos, L. El Kaïm, L. Grimaud, C. Ronsseray
SHORT COMMUNICATION
Such an oxidative cyclization was rather appealing and, Table 1. Cu-catalyzed oxidative cyclizations.
to the best of our knowledge, unprecedented. We first con-
firmed that the copper salts were mandatory for this reac-
tion, as under heating in acetic acid, only the Fischer indole
product was isolated at temperatures over 100 °C.[7] When
dimethylformamide, acetonitrile, or ethanol was tested as
the solvent, either no reaction took place or a complex mix-
ture was obtained. Trials with 1a using palladium acetate
or copper triflate as catalyst in various solvents also failed
to give any product. We finally achieved the best yield by
using a mixture of acetic acid/water/DMF in a 70:20:10 ra-
tio (Table 1). Under these conditions, we formed the ex-
pected pyrazolidinones in moderate to good yields for vari-
ous allylamine, acyl chloride, and diazonium salt inputs, ex-
cept for the nitrophenyl hydrazone derivative (Table 1, En-
try 2), which failed to react.
A plausible mechanism involves a copper-triggered [3+2]
cycloaddition to form pyrazolidine copper complex B,
which in turn might be oxidized under air pressure[8]
(Scheme 3). The oxidation process to pyrazolidinone could
involve transient diazenium salt C, followed by the acti-
vation of the α-CH2 group through the hydrolysis of re-
arranged hydrazonium D (resulting from acid-catalyzed
prototropy). Hydrazones are known to undergo [3+2] cy-
cloadditions with alkenes under thermal[9] or acidic condi-
tions[10] as well as under Lewis acid activation.[11] Though
CuII salts are well known for inducing aerobic oxidative
processes, their behavior in such a type of cycloaddition has
not been reported before. The lack of any cycloadduct when
the reaction is performed in the absence of copper is a good
indication of its catalytic role in both steps of the cascade.
This [3+2] cycloaddition/oxidation path is further endorsed
by the following experiments using hydrazone 1g: When
BF3·OEt2 was added to 1g in CH2Cl2 at room temperature,
related pyrazolidine 3g was obtained in quantitative iso-
lated yield. The following oxidation in acetic acid in air and
copper catalysis led to pyrazolidinone 2g, resulting in the
same yield as the one-pot process (Scheme 4). An interest-
ing observation bringing some further insight into the com-
plexity of the oxidation process was made when working on
3g with different solvent systems. When 3g was heated in air
in acetonitrile in the presence of copper acetate, aldehyde 4g
was formed in 56% yield. The formation of this aldehyde
may be explained by ring opening of intermediate E or F.
The different behavior in acetic acid and acetonitrile is
probably associated with faster prototropy performed on F
when the reaction is performed in an acidic medium.
Even if all these elements seem to corroborate this mech-
anistic proposition, an alternative pathway may still be
taken into account for the formation of diazenium C
(Scheme 3). Indeed, prior oxidation of the starting hydra-
zone to form an azoacetate, which can then cyclize under
activation by a Lewis acid, may explain the formation of
intermediate C. A similar type of cycloaddition with α-chlo-
roazo derivatives was recently reported by Brewer et al.[12]
In the same study, they observed fast rearrangement of di-
azenium salts into hydrazonium salts, not unlike our propo-
sition for the conversion of C into D (Scheme 3).
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Cu-Catalyzed Aerobic Oxidative Cyclization of Hydrazones
Scheme 3. Possible mechanism for the formation of pyrazolidinone.
Scheme 4. Mechanistic insight into the oxidative cascade.
Considering the whole synthetic sequence, we were ple- in modest isolated yield (Scheme 5). In this reaction, ini-
ased to find a process that features three important aspects tially formed pyrazolidinone 2a is slowly converted into 5a
of green chemistry: a multicomponent reaction followed by through a mechanism involving either an intermediate diaz-
a post-condensation cascade reaction involving an aerobic enium trapped by the electron-rich thiophene or copper-
process. Recently, many cascade reactions involving oxi- triggered C–H activation of the heteroaryl moiety.[15] Al-
dation steps have been disclosed thanks to the use of more
tolerant oxidants such as hypervalent iodine derivatives.[13]
These sequences have been described for the direct use of
alcohols or amines in reactions usually involving carbonyl
derivatives (such as Wittig or Mannich reactions). In most
aerobic oxidative cascades involving cycloadditions, the oxi-
dation step is usually a fast final dehydrogenation leading
to aromatic systems.[14] In the case of this pyrazolidinone
synthesis, the presence of quaternary carbon atoms in the
cycle prevents its aromatization, along with the formation
of compounds too stable to offer much synthetic develop-
ment. Indeed, the introduction of a new carbonyl moiety in
the five-membered heterocyclic ring system can be associ-
ated with various transformations such as fragmentations
close to the one depicted in Scheme 4. More interestingly,
starting with hydrazone 1a, we could observe, under pro-
longed heating, a complex cascade of multiple oxidation
and cyclization steps to form tetracyclic pyrazolidinone 5a Scheme 5. Oxidative cascade to tetracyclic pyrazolidinone 3a.
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SHORT COMMUNICATION
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though low yielding, this transformation represents an im-
pressive cascade with copper-catalyzed oxidative steps of
high synthetic value.
[2]
[3]
Conclusions
As a conclusion, we have disclosed a new aerobic oxidat-
ive cascade sequence involving hydrazones. The starting
materials were prepared by a three-component coupling of
acyl chlorides with aryl diazonium salts and allylamines.
The whole process involves multiple reactive pathways de-
pending on the choice of solvent. Dealing with the develop-
ment of new aerobic oxidations, hydrazine derivatives are
of special interest, as their easy oxidation may be used to
functionalize the carbon atoms linked to the nitrogen
atoms. We have already exploited this property in an aero-
bic cyclization of amidrazones into triazoles.[16] Presently,
we are further studying the mechanism of these reactions
to extend these strategies to other families.
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Experimental Section
Typical Experimental Procedure for 2a: To a 0.06-m solution of hy-
drazone 1a in DMF/H2O/CH3COOH (10:20:70) was added
Cu(OAc)2 (20 mol-%). The resulting mixture was heated at 80 °C
under an atmosphere of argon. The solution was then adjusted to
pH 6 with an aqueous solution of sodium hydrogencarbonate. Af-
ter extraction of the aqueous solution with AcOEt, the organic
layers were washed with water, dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The crude product was isolated
by flash chromatography on silica gel (petroleum ether/Et2O, 20:80
+ 2% TEA). M.p. 149–150 °C. 1H NMR (400 MHz,CDCl3): δ =
7.54 (s, 1 H), 7.51 (d, J = 8.3 Hz, 1 H), 7.18 (dd, J = 5.1, 1.0 Hz,
1 H), 7.14 (d, J = 8.3 Hz, 1 H), 6.95 (dd, J = 5.1, 3.5 Hz, 1 H),
6.87–6.86 (m, 1 H), 5.72 (ddt, J = 16.4, 10.1, 6.1 Hz, 1 H), 5.27 (d,
J = 10.1 Hz, 1 H), 5.23 (d, J = 16.4 Hz, 1 H), 5.01 (br. s, 1 H), 4.03
(dd, J = 15.2, 6.1 Hz, 1 H), 3.93 (dd, J = 15.2, 6.1 Hz, 1 H), 3.73
(d, J = 10.4 Hz, 1 H), 3.57 (dd, J = 10.4, 6.8 Hz, 1 H), 3.24 (d, J
= 6.8 Hz, 1 H), 3.14–2.99 (m, 2 H), 2.37–2.30 (m, 2 H), 2.28 (s, 3
H), 2.25 (s, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 173.5,
168.1, 143.4, 137.7, 135.6, 134.5, 131.5, 130.3, 127.4, 125.1, 124.1,
120.8, 119.6, 117.1, 66.2, 47.3, 46.2, 46.0, 35.6, 24.9, 20.4,
[7]
[8]
L. El Kaim, L. Grimaud, C. Ronsseray, Synlett 2010, 2296–
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When the reaction was performed in an open flask, degrada-
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obtained by using commercially available DMF (reagent
grade), heating under an argon atmosphere. Under such condi-
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[9]
[10]
[11]
19.7 ppm. IR (thin film): ν = 3211, 2924, 1684, 1507, 1440, 1422,
˜
1351, 1273 cm–1. HRMS: calcd for C22H25N3O2S 395.1667; found
395.1672.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for all new
compounds.
Acknowledgments
[12]
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We thank the Ecole Nationale Supérieure de Techniques Avancées
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Cu-Catalyzed Aerobic Oxidative Cyclization of Hydrazones
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Received: February 25, 2011
Published Online: May 2, 2011
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