Three-component reaction using the Bestmann-Ohira reagent: A regioselective synthesis of phosphonyl pyrazole rings

Article abstract of DOI:10.1002/anie.200906781

BOR-n to run: A new one-pot multicomponent reaction involving the use of an aldehyde, a cyanoacid derivative, and the Bestmann-Ohira reagent (BOR) has been developed for the synthesis of substituted phosphonyl pyrazoles. This process was also combined with a copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition to generate five new bonds and two heterocyclic rings in a one-pot fashion. Chemical Equation Presented

Full text of DOI:10.1002/anie.200906781

Communications
DOI: 10.1002/anie.200906781
Synthetic Methods
Three-Component Reaction Using the Bestmann–Ohira Reagent:
A Regioselective Synthesis of Phosphonyl Pyrazole Rings**
Kishor Mohanan, Anthony R. Martin, Loic Toupet, Michael Smietana,* and Jean-
Jacques Vasseur
Organophosphorus compounds continue to attract much
attention because of their various potent biological activ-
ities.[1] In particular, phosphonates are important synthetic
derivatives which can often act as phosphate and carboxylic
acid mimics, and interfere with enzymatic processes. Much of
nent reactions (MCR), which allow the formation of multiple
bonds in a one-pot fashion and give access to complex
molecules without isolating or purifying the intermediates,
represent an attractive alternative.[12] Being operationally
simple and atom-economical, these processes use simple
substrates and offer additional opportunities for subsequent
transformations that will increase the molecular complexity
and the structural diversity.
this activity has been attributed to the relatively inert nature
[1]
À
of the C P bond, which is not as easily hydrolyzed as
À
compared to the P O bond found in phosphates. The
synthesis and biological activities of important natural and
non-natural phosphonate derivatives, including phospho-
nated azaheterocycles and nucleotides, has been reviewed
recently.[2,3] In view of the importance of heterocycles bearing
a phosphonate group, new synthetic methods that would
allow straightforward access to these versatile building blocks
are needed.[1,4,5] Among the various bioactive heterocycles,
the pyrazole moiety remains of great interest because of its
wide applications in the pharmaceutical and agrochemical
industry.[6,7] In addition, pyrazoles also play a central role in
coordination chemistry.[8] In the plethora of existing method-
ologies for the synthesis of pyrazole derivatives,[9] a vast
majority relies on either the condensation of hydrazine with
1,3-difunctional compounds,[9a,b] or the 1,3-dipolar cycloaddi-
tions of diazo compounds with triple bonds.[9c,d] Although a
large number of new pyrazole syntheses that complement
efficiently the traditional approaches[9e–l] have been reported
in recent years, relatively few examples are known for the
preparation of phosphonyl pyrazoles, and the existing meth-
ods are often limited by the number of steps and the harsh
conditions needed.[10] Recently, an attractive procedure has
been described wherein 5-phosphonyl pyrazoles are obtained
from nitroalkenes. However, the reaction is restricted to aryl
and heteroaryl nitroalkenes which are usually not commer-
cially available.[11] Therefore, there remains a need for
identifying improved methods for the synthesis of phosphonyl
pyrazole scaffolds employing simple building blocks and a
minimal number of synthetic steps. To this end, multicompo-
Recently, we reported the one-pot synthesis of triazoles
from aldehydes using the Bestmann–Ohira reagent (BOR)[13]
which is more commonly used to prepare alkynes from
aldehydes under mild reaction conditions (MeOH/K2CO3).[14]
Encouraged by the straightforward access to these valuable
chemical motifs, we were interested in exploiting the synthetic
potential offered by this unique reagent. In particular, we
have been exploring the possibility of achieving the con-
struction of diversely substituted 5-phosphonyl pyrazoles
through a convergent MCR strategy. Based on a domino
Knoevenagel condensation/formal 1,3-dipolar cycloaddition
sequence, this three-component process involving the combi-
nation of readily available reactants (aldehyde, BOR, and
cyanoacetic derivatives[15]) should generate small molecules
with a high degree of skeletal and functional diversity and
demonstrate for the first time that the BOR could be used in
MCRs.
To achieve this goal, preliminary experiments were
performed with unsaturated nitrile 1a, which was prepared
by reaction of malononitrile and 4-bromobenzaldehyde in the
presence of tBuOK (Scheme 1, R = p-Br).[16] When 1a was
reacted with the BOR under the same conditions (tBuOK/
MeOH) phosphonyl pyrazole 2a was obtained as a single
tautomer in 74% yield. This product suggested that a formal
1,3-dipolar cycloaddition took place between the in situ
generated anion of the BOR and 1a with a subsequent
elimination of a cyano group.
Considering the reactivity of the BOR towards aldehydes,
we needed to demonstrate that the Knoevenagel condensa-
tion of malononitrile with an aldehyde was faster than the
homologation reaction. To our delight, the one-pot three-
component reaction between BOR, p-bromobenzaldehyde,
[*] Dr. K. Mohanan, A. R. Martin, Dr. M. Smietana, Dr. J. J. Vasseur
Institut des Biomolꢀcules Max Mousseron (IBMM), UMR 5247
CNRS-Universitꢀ Montpellier 1 et Universitꢀ Montpellier 2
Place Eugꢁne Bataillon, 34095 Montpellier (France)
Fax: (+33)4-6714-2029
E-mail: msmietana@univ-montp2.fr
Dr. L. Toupet
Institut de Physique (IPR), UMR 6521 CNRS-Universitꢀ de Rennes 1
35042 Rennes (France)
[**] L’Universitꢀ de Montpellier 2 (K.M.), the MENRT (A.R.M.), and the
CNRS are gratefully acknowledged for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906781.
Scheme 1. Access to phosphonyl pyrazole from aldehydes.
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and malononitrile in the presence tBuOK in anhydrous
methanol at room temperature afforded 3-cyano-4-p-bromo-
phenyl-5-dimethoxyphosphonyl pyrazole (2a) in 88% yield
(Scheme 2), whereas the two-step sequence gave only 57%
Scheme 2. One-pot access to phosphonyl pyrazoles and X-ray structure
of 2a.
overall yield. As 1.2 equivalents of malononitrile are used in
both experiments, the modest yield obtained in the two-step
sequence might come from consecutive reactions of the
initially formed Knoevenagel adduct and the excess of
nucleophile.[17] The structure of 2a was unambiguously
established by NMR and single-crystal X-ray analysis.[18]
Notably, the 1H NMR spectrum of the crude reaction mixture
did not reveal the presence of any major side product. This
reaction was therefore selected to establish optimum exper-
imental conditions. An initial base and solvent screen
revealed that the use of KOH and MeOH led to the best
results, thereby generating phosphonyl pyrazole 2a in 95%
yield (see Table S1 in the Supporting Information). Interest-
ingly, K2CO3 led mostly to the unwanted alkyne.
The scope of this unique one-pot three-component
phosphonyl pyrazole synthesis was next investigated. As
depicted in Scheme 3, the reaction proceeded effectively with
several substituted aromatic derivatives and was not found to
be dependent upon the electronic features of the substituents.
In many cases, the phosphonyl pyrazoles could be isolated in
greater than 90% yield after column chromatography on
silica gel. The flexibility of the process allows the strategic
placement of functional groups. For instance, examples 6 and
8 which contain chlorine atoms and a boronic acid group
respectively, were easily prepared and could be additionally
derivatized thereby providing a convenient alternative for the
generation of a broad range of analogues.[9d] The scope of the
MCR was additionally surveyed by probing the changes on
the aldehydes; for example 9, 10a, and 11 demonstrate that
ferrocenyl, heteroaromatic, and aliphatic aldehydic substrates
respectively, could also be used. Interestingly, when the a,b-
unsaturated octenaldeyde was treated under identical con-
Scheme 3. Three-component synthesis of phosphonyl pyrazoles. The
yields are for the isolated product.
ditions, phosphonyl pyrazole 12 was formed in 85% yield with
no detectable formation of the Michael addition side product.
The scope of the reaction was expanded by varying the nature
of the active cyanoacid derivative. In this context, ethyl-
cyanoacetate was found to be a good substrate allowing access
to 3-carbomethoxy-5-phosponyl pyrazoles 2b, 3b, and 13
after transesterification under the reaction conditions. Nota-
bly, in these specific cases we found that longer reaction times
were needed to reach completion, however the yields
remained unaffected. Another way to extend the scope of
the present MCR was to apply the reaction to cyanoaceta-
mide derivatives. Interestingly, the reactions between alde-
hydes, the BOR, and cyanoacetamide or N-benzyl-2-cyanoa-
cetamide were successful as the expected phosphonylpyra-
zoles 3c, 3d, and 10b were obtained in very good yields. In
these cases, the substituents on the cyanoacetamide did not
seem to have an influence on the reactivity. Hence, by varying
both the aldehyde and the cyanoacid components, a wide
variety of substituted phosphonylpyrazoles could be readily
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Communications
prepared. As expected the use of (phenylsulfonyl)acetonitrile
with benzaldehyde and the BOR led only to 3a as a result of
the higher stability of the phenylsulphinate anion compared
with that of cyanide (pKa values of phenylsulphinic acid and
hydrogen cyanide in water are 2.1 and 9.2, respectively).[19]
The only unmatched results were obtained with less activated
cyanoacetic derivatives. Indeed, under the reaction conditions
phenylbutyronitrile, benzylcyanide, and trimethylsilylaceto-
nitrile led to the formation of the homologated alkyne.
Nonetheless, these examples confirm that the Knoevenagel
condensation is indeed the first step in this reaction sequence.
As demonstrated by 1H and 31P NMR analysis, pyrazoles 2–13
did not exhibit tautomerism in solution.
Scheme 5. One-pot MCR/CuAAC sequence.
In summary, we have developed a simple and completely
regioselective one-pot Knoevenagel condensation/formal 1,3-
dipolar cycloaddition reaction which generates 5-phosphonyl
À
Our postulated mechanism for this reaction is shown in
Scheme 4. This proposal accounts for the facts that the
reaction rate is solvent-dependent whereas it is almost
unaffected by electron-withdrawing or electron-donating
groups on the starting aldehyde. Therefore, we assume that
this formal 1,3-cycloaddition is based on a Michael-type 1,4-
addition of the dimethyl (diazomethyl)phosphonate anion B
pyrazole scaffolds through the formation of two C C bonds
À
and one C N bond. To the best of our knowledge this
represents the first example in which the Bestmann–Ohira
reagent is used: 1) in a multicomponent reaction and 2) in the
presence of an aldehyde without leading to the expected
homologated alkyne. Attractive features of this domino
process are its versatility, the readily available starting
material needed, and the efficiency in creating a complex
core in a single operation. The scope of the reaction was
expanded with the development of an efficient MCR/CuAAC
reaction sequence in single step. This highly flexible method-
ology should provide a quick and easy access to libraries of
molecules of pharmaceutical or agrochemical interests.
Received: December 1, 2009
Revised: February 23, 2010
Published online: March 26, 2010
Keywords: click chemistry · cycloaddition · heterocycles ·
.
multicomponent reactions · phosphonates
Scheme 4. Proposed mechanism for the formation of pyrazoles.
Bn=benzyl.
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