Organic Letters
Letter
a
Here we describe the development of a novel and direct
synthesis for the selective construction of 3-amino-2H-
indazoles 12 based on a Pd-catalyzed domino reaction using
readily available 2-halobenzonitriles 8 and monosubstituted
hydrazines 9 (Scheme 1).
Table 1. Optimization of Reaction Conditions
Scheme 1. Strategy for the Palladium-Mediated Access to 3-
Amino-2H-indazoles
Cat.
mol %
Lig.
mol
Ph-NH-NH
(equiv)
Yield
(%)
2
N
X
Solvent
1
2
3
4
5
6
7
8
9
Br
Br
Cl
I
Br
Br
Br
Br
Br
Br
Cl
Br
10
10
10
10
10
10
5
5
7
7
5
20
20
20
20
20
20
10
10
14
14
10
20
2
2
2
2
3.5
3.5
3.5
3.5
4.7
4.7
5
toluene
85
86
67
63
95
66
67
60
68
63
91
74
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1,4-dioxane
toluene
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1
1
1
0
1
2
10
5
a
Although a number of transition-metal-catalyzed couplings
between aryl halides and amides, amines, hydrazides, and
hydrazones are known, only a few couplings employing
All reactions were performed in anhydrous solvent at 100−110 °C
for 2−4 h. Yield of the isolated product after flash chromatography on
silica gel or reversed phase HPLC.
15−17,21,26
hydrazines have been published.
We therefore set
out to develop a regioselective transition-metal-catalyzed
coupling of monosubstituted hydrazines 9 with 2-halobenzoni-
triles 8, to provide the N,N′-disubstituted hydrazines 10
needed for the cyclization to 12.
The subsequent hydroamination/5-exo-dig-cyclization step
toward the formation of the 3-imino-1,2-dihydro-3H-indazole
With these optimized reaction conditions, we then explored
the scope of the reaction using various monosubstituted
hydrazines 9 and reacting them with 2-bromo- or 2-
chlorobenzonitrile (8a and b) (Scheme 2). The 2H-indazoles
12 were formed in good to moderate yields (Scheme 2, 12a−
v), and importantly the domino reaction sequence was also
found to proceed with nonaromatic hydrazines as well
(Scheme 2). Although full conversion was observed by
LCMS, the isolated yield was moderate after the purification.
Besides free hydrazines their corresponding HCl salts could
also be employed in the reaction when additional Cs CO is
1
1 was a further critical step, as other cyclization pathways, e.g.
6-endo-dig) and (5-endo-dig), are also favored by the
Baldwin rules giving rise to other products like 1,2-dihydro-
aza)cinnolines and N-azaindole. We started by screening for
suitable reaction conditions for the coupling of 2-bromo (8a),
-chloro (8b), or 2-iodobenzonitrile (8c) and phenyl
hydrazine (9a) to afford 2-phenyl-3-amino-2H-indazole
12a) in the presence of palladium, phosphine ligand and a
(
(
2
3
2
added (Scheme 2). This result is of great practical significance,
as most commercially available hydrazines are sold as their
more stable hydrochloride salts, eliminating the need to
liberate and handle the free hydrazines.
(
base. By varying the palladium source, solvents, and base, we
found the desired coupling to proceed smoothly within just a
few hours and with complete regioselectivity employing a
PdCl /tBu PHBF (1:2) catalyst at 110 °C and Cs CO as
To further expand the scope of the domino reaction, a
variety of hydrazines with electron-donating or -withdrawing
groups at different positions were reacted. Electron-with-
drawing groups such as CF , F, OCF , methane sulfonyl,
2
3
4
2
3
base. The optimal solvents were found to be 1,4-dioxane and
toluene.
3
3
naphtyl, or nitrile in the 4-position attached to the phenyl
hydrazine accelerate the reaction, and the desired products
were obtained in good to excellent yields of up to 83% while,
e.g., Cl substitution formed the desired products 12h and 12r
in moderate yield (Scheme 2). Some electron-donating
substituents such as benzyloxy formed the corresponding 3-
amino-2H-indazole in moderate to good yield (Scheme 2),
whereas isopropyl, methyl, and dioxolyl afforded good yields
(Scheme 2) except for the 2-ethyl substituted hydrazine which
only provided a 34% yield, presumably due to increased steric
hindrance (Scheme 2).
Decreasing the catalyst loading to 5 mol % still afforded the
desired 3-amino-2H-indazole 12a in good yield (Table 1,
entries 7−10), but 5 equiv of phenyl hydrazine (9a) were
required for high yields (Table 1, entries 11 and 12 and SI
Table S1). Albeit the catalyst loading could be decreased to 5
mol % without a significant drop in yield (Table 1, entries 7
and 8), 10 mol % with 3.5 equiv as well as 2 equiv of hydrazine
generally provided the most robust conditions for further
development without strict handling precautions. 2-Bromo, 2-
chloro, and 2-iodobenzonitriles (8a−c) were found to react
similarly with phenyl hydrazine (9a) to afford 2-phenyl-3-
amino-2H-indazole (12a) (Table 1, entries 2−5). The free
choice of halogen is clearly a major synthetic advantage, as it
significantly increases the pool of available 2-halobenzonitriles
substrates. Control experiments in the absence of either
palladium, ligand, or base led in all cases to no detectable
To explore the scope and versatility of this synthesis with
regard to substituted 2-halobenzonitriles 8, we performed the
reaction with phenyl hydrazine (9a). Several substituted 2-
halobenzonitriles bearing methyl, methoxy, monofluoro,
difluoro, CF , chloro, and unprotected amine groups were
3
compatible with the reaction conditions and produced the
desired 3-amino-2H-indazoles 13 in very good to moderate
yields. The use of methyl substituents in the 6- and 4-position
B
Org. Lett. XXXX, XXX, XXX−XXX
Alsalim, Rana
