Organic Letters
Letter
to unite both of these chemical processes in a step-economic and
operationally simple procedure that is amenable to preparing
substituted 3-aminoindazoles 3, starting from readily available
shelf-stable building blocks (Scheme 1, eq 4). Our envisioned
strategy consisted of a novel intramolecular Pd-catalyzed C−H
amination reaction with tosylhydrazonamides 2, which are
themselves derived from synthetic valuable and readily available
tertiary amides15,16 1 and hydrazides.
D).17 This experiment suggests by simple means that C−H bond
cleavage is not the rate-determining step.21
We were also eager to demonstrate that the N-Ts-3-
aminoindazole moiety is a versatile stepping stone for
subsequent functionalization reactions. To do so, we focused
our attention on diversifying the N-1 position by applying useful
synthetic transformations on 3a as a benchmark (Scheme 2). For
Scheme 2. Diversification of N-Ts-3-Diethylaminoindazole 3a
Initially, we carefully refined each of the parameters associated
with the amide activation step, as well as for the in situ
nucleophilic addition of the N-tosylhydrazide nucleophile.17
Following other well-established chemoselective Tf2O activation
protocols,18 an evaluation of various base additives was pursued
for the activation of 1a in the presence of 1.1 equiv of Tf2O in
CH2Cl2 at low temperatures. This tuning turned out to be
essential, as the incorporation of 2-methoxypyridine (2-MeO-
Py), a mild base additive, was mandatory for achieving an
appreciable yield (90%) of 2a (Table 1, Reaction A).13b,19 As a
proof of concept, stable tosylhydrazonamide 2a was submitted to
different transition-metal-catalyzed C−H amination conditions
in the presence of external oxidizing agents.17 Inspired by
extensive developments in oxidative C−H functionalizations,20
we were delighted to find that the desired C−N bond forming
reaction was achieved when the reaction was run under an
atmosphere of air in the presence of catalytic Pd(OAc)2 and two
equivalents of CsOPiv in refluxing toluene (Reaction B).
Unfortunately, the use of other oxidizing reagents and/or
catalytic amounts of ligand was detrimental to the reaction
conversion.17
After establishing efficient reaction conditions for both the
amide derivatization and intramolecular catalytic C−H amina-
tion reactions, the substrate scope was studied (Table 1). The
overall process was shown to be effective in the presence of
various amides, and it tolerates different substitution patterns on
both the aryl and nitrogen substituents of the benzamide moiety
(Table 1, entries 1−15). Cyclic and acyclic amines can be
incorporated at the C-3 position of the desired indazole, with
consistent yields for the preparation of the tosylhydrazonamides
and a more variable efficiency for the C−H functionalization
step. Indeed, varying the electronic properties at the para
position of the aryl ring on the benzamide moiety marginally
influenced Reaction A, while lower conversions were observed
for the C−H amination step (Table 1, entries 1−14). With
substrate 1o, which contains a meta substituent on the aryl ring,
the cyclization reaction produced a 4:1 mixture of regioisomers
(Table 1, Reaction B, entry 15). However, an ortho substitution
on the aryl ring was not tolerated in the amide derivatization step
(Table 1, Reaction A, entry 16).
example, the N-Ts protecting group was easily cleaved under
reductive conditions to yield the free base 3-aminoindazole 4a in
85% yield.22 Alkylation of the free amine in the presence of BnBr
affords 3-aminoindazole 4b in 65% yield. Furthermore, a
sequential one-pot deprotection−functionalization could be
performed by applying a Cu-catalyzed Buchwald−Hartwig
coupling to generate 4c in 79% yield in the presence of o-Me
substituted coupling partner.22a
In summary, we have developed a two-step process for the
rapid conversion of readily available tertiary amides into valuable
3-aminoindazoles. The disclosed synthetic strategy includes a
triflic-anhydride-mediated chemoselective derivatization, which
furnishes tosylhydrazonamide intermediates poised for subse-
quent intramolecular palladium catalyzed C−H aminations. The
optimized conditions allowed for the synthesis of substituted 3-
aminoindazoles with broad substitution patterns including the
complex 3-aminoindazobenzothiophene heterocycle. Moreover,
the resulting azole product can take part in additional useful
deprotection/functionalization reactions. These reactions pro-
vide rapid access to complex heterocyclic scaffolds, and
consequently, our synthetic strategy should be valuable to both
pharmaceutical and agrochemical industries, as it will signifi-
cantly impact the step-economy in the synthesis of bioactive
compounds.
The commercially available tosylhydrazide nucleophile can
also be replaced by other hydrazides with different electron-
withdrawing protecting groups at the N-1 position (Table 1,
entries 17 and 18). Remarkably, the transformation is also
productive in the presence of amide 1s bearing a benzothio-
phenyl group allowing for the formation of further diversified
cores, such as 3-aminoindazole heterocycle 3s (Table 1, entry
19). While Reaction A could be efficiently performed using
secondary amide 1t, the corresponding tosylhydrazonamide 2t
was not a suitable starting material for the C−H amination
reaction (Table 1, entry 20).17 Moreover, the KIE of the reaction
was determined to be 0.92 from an intramolecular C−H/C−D
functionalization competition employing substrate 2 bearing a
deuterium atom at the ortho position of the aryl ring (R1 = o-
ASSOCIATED CONTENT
* Supporting Information
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Optimization tables, experimental procedures, characterization
data, and copies of NMR spectra. The Supporting Information is
AUTHOR INFORMATION
Corresponding Author
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Org. Lett. XXXX, XXX, XXX−XXX
Cyr, Patrick
