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Chemistry Letters Vol.36, No.11 (2007)
Synthesis of 3-Amino-substituted N-Alkylindazoles via Palladium(II)-catalyzed
Intramolecular N-Arylation of Tosylhydrazines
N. Suryakiran, P. Prabhakar, and Y. Venkateswarluꢀ
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 5000 07, India
(Received July 20, 2007; CL-070766; E-mail: luchem@iict.res.in)
An efficient synthesis of 3-amino-substituted N-alkyl
indazoles is described. Reaction of readily available o-halo
aryl hydrazines with palladium(II) acetate and cupper(I) iodide
in the presence of a base afforded the corresponding 3-sub-
stituted N-tosylindazoles in excellent yields. These products
were further functionalized after detosylation with Na–Hg,
followed by alkylation to afford 3-amino-substituted N-alkyl-
indazoles.
N
X
H
N
N
Ts
PdII 3 mol %
N
R'
R'
N
CuI 1 mol %
K2CO3 2 equiv.
N
2
1
Ts
Scheme 1.
N
N
1) Na–Hg/MeOH
2) MeI/NaH/THF
R'
R'
The indazole ring is an important pharmacophore in medic-
inal chemistry due to its association with various potent biolog-
ically active molecules.1 In fact, compounds containing the inda-
zole skeleton are known to show a variety of biological proper-
ties, such as high binding affinity for estrogen receptor,2 inhibi-
tion of protein kinases like C-ꢀ, 5-HT2, 5HT3 receptor
antagonism,3 HIV protease inhibition,4 anti-inflammatory,5 and
as anti-tumor agents.6 Thus, the search for an efficient synthesis
of the indazole ring system has been a longstanding goal. Several
methods for the synthesis of indazoles have been reported in lit-
erature. They include intramolecular amination of N-aryl-N0-(o-
halobenzyl)hydrazines,7 hydrazones of 2-halobenzaldehydes,
and 2-haloacetophenones.8 However, these methods have limit-
ed success in the case of synthesis of 3-amino-substituted N-
alkyl indazoles.
The palladium-catalyzed aromatic carbon–nitrogen bond
forming reactions by the cross coupling of aryl halides and
amines has recently had an upsurge as a useful synthetic tool;
various N-aryl amines can be prepared by this protocol.9 Where-
as, by intramolecular N-arylation ca affords a variety of nitrogen
heterocycles.7,8 In this connection, some synthetic routes have
been reported for the synthesis of indazoles. Herein, we report
an efficient synthesis of 3-amino-substituted N-alkylindazoles
via palladium(II)-catalyzed intramolecular N-arylation of tosyl-
hydrazines.
N
N
N
N
2
3
Me
Ts
Scheme 2.
Table 1. Optimization of reaction conditions on the intramolec-
ular N-arylation of N-(o-chlorophenyl)morpholinomethylidene-
N0-tosylhydrazine 1 in 1,4-dioxane at 60 ꢁC
Entry PdII (mol %) CuI (mol %) Time/h Yield/%
1
2
3
4
5
6
7
8
9
20
15
10
5
1
2
3
3
3
—
—
—
—
20
10
5
6
6
6
6
2
2
1
1
1
75
70
50
50
96
96
95
95
95
3
1
N
CuI
+
N
N
Pd(o)
Ts
N
X
In this report (Schemes 1 and 2), we have described an effi-
cient method for the synthesis of 3-amino-substituted N-alkylin-
dazoles via palladium(II) acetate-catalyzed intramolecular N-
arylation of tosylhydrazines. The amino-substituted intermediate
1 was readily prepared from the corresponding tosylhydrazone10
and which on intramolecular N-arylation with palladium(II)
acetate (3 mol %) and cupper(I) iodide (1 mol %) in the presence
of 2 equiv. of K2CO3 at 60 ꢁC in 1,4-dioxane yielded the
corresponding 3-amino-substituted N-tosylindazoles 2 in 95%
(Scheme 1, Table 2, Entry 1). In order to optimize the reaction
conditions, we varied the amount of palladium(II) acetate and
cupper(I) iodide. In the absence of cupper(I) iodide, more
amount of palladium(II) acetate was needed and the formation
of product was low (Table 1, Entries 1–4). However, using
1 mol % of cupper(I) iodide gave interesting results (Table 1,
Entry 9). We believe that cupper(I) iodide forms complex
H
N
Ts
N
N
N
Ts
N
N
H
CuII
N
Ts
N
PdII-X
PdII-X
CuI
Scheme 3. Plausible mechanism.
with nitrogen of tosylhydrazine and facilitates the reaction
(Scheme 3). Encouraged by these findings we have carried
out the reaction using 3 mol % of palladium(II) acetate and
Copyright Ó 2007 The Chemical Society of Japan
Suryakiran
