Z-Selective synthesis of o-bromoacetophenone N-tosylhydrazones and formation of 3-methylindazoles in aqueous ethanol

Article abstract of DOI:10.1016/j.tetlet.2010.05.024

A practical and effective Z-selective synthesis of o-bromoacetophenone N-tosylhydrazones is developed. Subsequent cyclization of Z-tosylhydrazones to furnish 3-methylindazoles is accomplished with the aid of copper and DMEDA in aqueous ethanol. Cyclization reactions are complete at ambient temperature in 10 min to afford the desired compounds in excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.05.024

Tetrahedron Letters 51 (2010) 3613–3615
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Z-Selective synthesis of o-bromoacetophenone N-tosylhydrazones and
formation of 3-methylindazoles in aqueous ethanol
a
Tuula Kylmälä a, Sandra Udd b, Jan Tois a, , Robert Franzén
*
a Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
b Research and Development, Fermion Oy/Orion group, Koivu-Mankkaan tie 6 A, 02200 Espoo, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and effective Z-selective synthesis of o-bromoacetophenone N-tosylhydrazones is developed.
Subsequent cyclization of Z-tosylhydrazones to furnish 3-methylindazoles is accomplished with the aid
of copper and DMEDA in aqueous ethanol. Cyclization reactions are complete at ambient temperature in
10 min to afford the desired compounds in excellent yields.
Received 3 March 2010
Revised 26 April 2010
Accepted 7 May 2010
Available online 12 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Indazole
Z-Selective
Copper
Among the myriad methods for the preparation of indazoles,1
one of the most elegant routes is the catalytic cyclization of hydra-
zones derived from o-halogenated aromatic carbonyl compounds.2
Although modern methods offer several advantages over classical
indazole syntheses, there is still a demand for improvement when
taking reaction time, reaction temperature, and yields into ac-
count. Recently, Inamoto et al.2d examined the reactivity of N-
tosylhydrazones in Pd-catalyzed indazole formation. The desired
indazole was obtained from the Z-isomer in excellent yield while
the E-isomer was totally decomposed under the same conditions.
The decomposition pathway was not further investigated, but the
possibility of a base-mediated Bamford–Stevens reaction cannot
be ruled out.3
When o-bromoacetophenone was treated with p-toluenesulfo-
nyl hydrazide in the presence of acid, Z- and E-isomers were ob-
tained in a ratio of 1:4.6.2d The predominance of the E-isomer
was also reported by Bunnel and Fuchs.4 To avoid the loss of start-
ing material and to take full advantage of the rapid cyclization of
the Z-isomer we decided to investigate the Z-selective synthesis
of o-bromoacetophenone N-tosylhydrazones. Recently, we re-
ported a Z-selective synthesis of o-bromoacetophenone oximes5
and a similar approach was attempted for N-tosylhydrazones
(Scheme 1). To our delight, this route was found to be also suitable
for N-tosylhydrazones and probably proceeds in an analogous
manner.6 Formation of the Z-hydrazone is initiated by abstraction
of the acidic proton leading to an N-tosyl-vinyl-diazene. Subse-
quent Michael addition of a hydride nucleophile then provides
the desired Z-hydrazone (Scheme 2).
We decided to prepare four o-brominated N-tosylhydrazones
adorned with electron-donating substituents and one o-fluorinated
N-tosylhydrazone (Table 1). We reasoned that if catalytic cycliza-
tion of these electron-rich starting materials (3a–d?4a–d) oc-
curred then the possible SNAr-pathway would be minimized. On
the other hand, the fluorinated hydrazone 3e would favor the
SNAr-mechanism and disfavor the catalytic pathway.
After successful preparation of the Z-tosylhydrazones 3a–e, we
began screening the cyclization conditions as indicated in Table 2.
Our goal was to develop a cyclization which occurs at ambient
temperature, thus all the reactions were carried out without exter-
nal heating, in air. At first the non-catalytic pathway was ruled out
(entries 1 and 2). When N-tosylhydrazones 3a and 3e were treated
with base and DMEDA in the absence of CuI, no formation of 4a
Br
N
Br
O
TsNH2NH2
AcCl
NHTs
R
R
EtOH, 0 oC to RT, 17 h
X
X
2a-e
1a-e
NaBH4
N
R
NHTs
H2O / CH3CN, RT, 30 min
X
3a-e
* Corresponding author. Tel.: +358 40 1981131.
E-mail address: Jan.Tois@tut.fi (J. Tois).
Scheme 1. Z-Selective synthesis of N-tosylhydrazones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.024

3614
T. Kylmälä et al. / Tetrahedron Letters 51 (2010) 3613–3615
Table 2
H
H
Screening of the cyclization conditionsa
H
B
H
Br
catalyst (10 mol%)
DMEDA (30 mol%)b
H
N
N
N
Ts
N
Ts
H
base (2.2 equiv)
N
N
X
X
NHTs
solvent, RT
N
X
4a
Ts
3a or 3e
Yield%c
H
B H
H
Entry
X
Solvent
Base
Catalyst
1
2
3
4
5
6
7
8
Br
F
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
—
—
—
—
—
H2O
N
N
N
Br
Br
Br
Br
F
Br
Br
Br
Br
Br
Br
Br
PdCl2
Pd(OAc)2
Pd/C
CuI
CuI
CuI
CuI
CuI
CuI
CuI
6d
—
NHTs
X
Ts
X
—
26d
—
Scheme 2. Mechanism for the Z-selective formation of N-tosylhydrazones.
—
t-BuONa
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
96
95
96
95
98
54d
—
9
was observed even after 12 h. According to TLC and the 1H NMR
spectrum of the recovered starting material no isomerization took
place under these conditions. Several reports in which fluorine has
been used as a leaving group exist, but all involve external heating
or the use of excess hydrazine.7 Palladium-catalysts were found to
be inefficient for our model reaction (entries 3–5). However, when
3a was treated with DMEDA and CuI without t-BuONa the desired
indazole 4a was detected after 12 h (entry 6). As expected there
was no evidence of cyclization when 3e was subjected to similar
conditions (entry 7).
10
11
12
13
14e
EtOH/H2O (1:1)
H2O
EtOH/H2O (1:1)
CuI
CuI
a
b
c
See the Supplementary data for details concerning the reaction conditions.
0.7 M solution in THF or EtOH.
Isolated yield.
Determined by 1H NMR spectroscopy of the crude reaction mixture.
Compound 3a-E was used as the reactant.
d
e
Next we used the conditions employed for benzisoxazoles5 (en-
try 8) and the reaction proceeded smoothly and was complete in
10 min. After work-up, compound 4a was obtained in 96% yield
with no need for chromatographic purification. Comparison of
the estimated pKa values of hydrazone 3a and the corresponding
oxime8 indicated that a milder base could be utilized. Thus, t-BuO-
Na was replaced with Cs2CO3 and Na2CO3 (entries 9 and 10),
respectively, and to our delight, our assumption was correct and
the desired indazoles were formed in 10 min and in excellent
yields. Finally, we wanted to see if THF could be replaced by safer
and environmentally friendly solvents. Indeed, the reaction was ra-
pid when EtOH was used as the solvent (entry 11). Despite the fact
that conversion was fast and the yields were excellent we were still
concerned about the heterogeneity of the reaction media. This
could cause problems when the reaction is performed on larger
scale. To enhance the solubility of the inorganic reagents we used
aqueous ethanol as the solvent (entry 12). The reaction proceeded
as a clear solution and 4a was isolated as the sole product in 98%
yield. Full conversion was achieved in this case in 10 min. When
only water was utilized as the solvent the reaction did not proceed
to completion (entry 13). Finally, E-tosylhydrazone 3a-E was
subjected to the optimized conditions to examine the possible
Table 3
Preparation of 5- and 6-substituted indazoles
CuI (10 mol%)
DMEDA (30 mol%)
Na2CO3 (2.2 equiv)
N
Table 1
N
R
R
NHTs
Synthesized o-halogenated N-tosylhydrazones
N
EtOH/H2O 1:1
RT, 10 min
Br
Entry
1
Product
Yield%a
98
3a-d
Ts
4a-d
Entry
1
Product
Yield%a
N
3a
3b
3c
3d
3e
NHTs
Br
N
4a
4b
4c
4d
98
98
99
95
N
MeO
Ts
N
2
3
4
5
66
90
82
76
NHTs
MeO
Br
N
N
Ts
2
3
4
MeO
MeO
N
NHTs
Br
N
MeO
MeO
N
N
Ts
O
O
NHTs
Br
O
O
N
N
Ts
N
NHTs
F
Isolated yield after two steps.
a
a
Isolated yield.

T. Kylmälä et al. / Tetrahedron Letters 51 (2010) 3613–3615
3615
equilibrium9 between 3a-E and 3a-Z, however, formation of 4a
was not observed after 12 h at room temperature (entry 14).
The substituted N-tosylhydrazones 3a–d were subjected to the
optimized conditions and the results are collected in Table 3. In all
entries the reaction was complete in 10 min and the pure indazoles
were isolated without chromatography.
In summary, we have developed a facile strategy for the prepa-
ration of Z-configured N-tosylhydrazones. These compounds can
be utilized efficiently as precursors for the copper-catalyzed syn-
thesis of 3-methylindazoles under mild conditions. We believe that
this easy access to Z-hydrazones will open new possibilities for
metal-catalyzed C–H activation protocols. Further investigations
to extend this strategy to other substituents at the 3-position are
currently in progress in our laboratory and the results will be pre-
sented in due course.
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Acknowledgments
The Academy ofFinland, for financial support (110043), is grate-
fully acknowledged. We also thank Mr. Mikko Mäkelä for valuable
assistance with pKa estimations.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, and 1H and 13C NMR spectra for new compounds are
available) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.05.024.
N
N
NHTs
OH
Br
pKa~ 9.22
Br
pKa~ 11.20
References and notes
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Stambuli, J. P. Org. Lett. 2007, 10, 1021–1023.
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