.
Angewandte
Communications
DOI: 10.1002/anie.201300917
Synthetic Methods
Base-Catalyzed Synthesis of Substituted Indazoles under Mild,
Transition-Metal-Free Conditions**
Isabelle Thomꢀ, Claire Besson, Tillmann Kleine, and Carsten Bolm*
Coupling reactions are among the most versatile and efficient
sation of anilines and the condensation of benzaldehydes with
hydrazines, is desirable. Those methods often require an
excess of a highly toxic or unstable hydrazine,[6d,i,l] hydrazo-
ne,[6b,f] nitro,[6e] or diazo[6a,c,j] compound, and the reaction
conditions tend to be harsh and involve strong acids or high
temperatures.
[1]
À
À
À
methods for C C, C N, and C O bond formation. They
have enriched the toolbox of synthetic chemists with a great
number of inter- and intramolecular reactions for the step-
economical synthesis of complex and functionalized mole-
cules.
À
For the synthesis of N-heterocyclic compounds, C N
More recently, transition-metal-catalyzed syntheses of
indazoles have also been developed.[7–9] Most involve palla-
dium, copper, and iron salts or complexes, which are used in
combination with strong bases, such as lithium hexamethyl-
disilazide (LiHMDS) or tBuONa, at moderate to high
temperatures. Furthermore, the metal loading is generally
high, and the rather narrow substrate tolerance does not
enable the synthesis of 1-unsubstituted 1H-indazole deriva-
tives. Among the reported copper-catalyzed processes,[8]
a study by Tois, Franzꢀn, and co-workers caught our
attention.[8c] They had found that in the presence of a catalytic
system consisting of a combination of copper(I) iodide
coupling reactions are highly valuable; consequently, they
have quite frequently been used in the preparation of specific
polymers, dyes, and biologically active molecules to be used as
agrochemicals and drugs. They are most often catalyzed by
Pd-, Ni-, or Cu-based complexes, often at elevated temper-
atures.[2] Especially if applied in the synthesis of pharmaceut-
icals, the use of such transition-metal catalysts is controver-
sial, since they may remain in the products as trace impurities,
which have to be removed in tedious additional steps. Hence,
reaction protocols that enable the preparation of compounds
À
through inter- or intramolecular C N coupling reactions in
the absence of transition metals are attractive and considered
sustainable.[3] In this context, we previously reported various
base-mediated N-, O-, and S-arylation reactions, including
intramolecular ring-closing reactions to give heterocyclic
products.[4] We now wondered about a transition-metal-free
synthetic route to indazoles.
Compounds with an indazole framework display a wide
range of pharmacological activities,[5] from antiinflammatory
and antiarthritic activity to antifertility activity. Although
several procedures for the preparation of indazole derivatives
are known,[6] the discovery of new methods that are milder
than the classical routes, such as the diazotization or nitro-
(10 mol%),
N,N’-dimethylethylenediamine
(DMEDA;
30 mol%), and an excess of sodium carbonate, 1N-tosylinda-
zoles were formed in good yields from the corresponding
substituted (Z)-2-haloacetophenone N-tosylhydrazones.[10]
On the basis of our previous work,[4] we hypothesized that
an analogous transition-metal-free approach could be devel-
oped. Herein, we report the realization of this idea.
For the initial screening and optimization of the reaction
conditions, (Z)-2-bromoacetophenone N-tosylhydrazone
(1aa) was chosen as the substrate. Following the protocol
described by Tois, Franzꢀn, and co-workers, this starting
material was accessible in stereochemically homogeneous
form through a three-step reaction sequence.[8c,11] For the
envisaged transition-metal-free cyclization, various bases and
amines were tested, and the reaction parameters (temper-
ature, time) were altered. While our initial attempt to use the
previously applied “superbase” system consisting of KOH (or
KOtBu) in DMSO remained unsuccessful (Table 1, entries 1
and 2),[12] we were surprised to see that product formation
occurred in the presence of a simple DMEDA/K2CO3 mixture
(Table 1, entry 3). Only a catalytic amount of the diamine
(10 mol%) was required for the formation of indazole 2a in
high yield. The best reaction medium was toluene, which was
unexpected considering the low solubility of the applied
inorganic base in this rather nonpolar solvent.[13] Both
DMEDA (A1) and K2CO3 were essential reagents; in the
absence of either, no reaction occurred or the yield of 2a was
significantly lower (Table 1, entries 4–6).[14]
[*] I. Thomꢀ, Dr. T. Kleine, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
Dr. C. Besson
Institute of Inorganic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
[**] DFG funding within the Cluster of Excellence “Tailor-Made Fuels
from Biomass” (TMFB) at RWTH Aachen University is greatly
appreciated. I.T. acknowledges support by Dr. L. Pardo [University of
the Basque Country (UPV/EHU)]. We also thank Prof. Dr. M.
Heinrich (University of Erlangen-Nꢁrnberg), Prof. Dr. G. Gescheidt
(Graz University of Technology), and Dr. J. Wang (RWTH Aachen
University) for fruitful discussions. Prof. Dr. P. Kçgerler (RWTH
Aachen University) is acknowledged for ESR measurement time,
and we thank Prof. Dr. M. Rueping and C. Vermeeren (RWTH
Aachen University) for performing the isomer separation by
preparative supercritical fluid chromatography.
The next surprise related to the reaction temperature.
Assuming a low-to-moderate reactivity, we performed the
initial cyclization attempts at 1358C (Table 1, entries 1–6).
However, subsequent optimization studies revealed that the
Supporting information for this article is available on the WWW
2
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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