A novel and efficient synthesis of 3-aminomethyl-N-tosyl-indazoles

Article abstract of DOI:10.1016/j.tet.2010.09.069

A practical and environmentally friendly synthesis of 3-aminomethyl-N- tosyl-indazoles is developed. The in situ formed vinyl azines are reacted with amines to furnish amino functionalized anti-hydrazones in excellent yields. Subsequent copper-catalyzed cyclization at ambient temperature is effective and desired compounds are obtained in short reaction times. Also, the formation of bisindazoles is presented for the first time.

Full text of DOI:10.1016/j.tet.2010.09.069

Tetrahedron 66 (2010) 8854e8861
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and efficient synthesis of 3-aminomethyl-N-tosyl-indazoles
*
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Tuula Kylmala, Antti Hamalainen, Noora Kuuloja, Jan Tois , Robert Franzén
Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2010
Received in revised form 2 September 2010
Accepted 20 September 2010
Available online 24 September 2010
A practical and environmentally friendly synthesis of 3-aminomethyl-N-tosyl-indazoles is developed.
The in situ formed vinyl azines are reacted with amines to furnish amino functionalized anti-hydrazones
in excellent yields. Subsequent copper-catalyzed cyclization at ambient temperature is effective and
desired compounds are obtained in short reaction times. Also, the formation of bisindazoles is presented
for the first time.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Indazole
anti-Selective
Bisindazole
Cyclization
Copper
1. Introduction
their synthesis of indazole based peptide mimetics. 3-Indazole-
carboxaldehyde 10 was obtained by nitrosation-rearrangement10 of
3-Substituted indazole is a fragment present in a number of
biologically active compounds. Compound 1 has shown almost
equal activity against P388 leukemia as adriomycin.1 Indazole 2 has
potent inhibitory activity against DNA gyrase2 and 3-benzimidazole
derivative 3 was developed as an inhibitor of receptor tyrosine
kinases.3 Fluoroindazole 4 was found to be a potent anticoagulant,4
3-amino indazole 5 has been identified as a MCHr1 antagonist,5 and
indazole 6 has proven to be a promising lead as an inhibitor of
reverse transcriptase6 (Fig. 1).
the corresponding indole 11 under acidic conditions. The in-
termediates were used as obtained and yields of individual steps
were not reported. In the third route 7 was obtained by reduction of
the corresponding amide 12 with LiAlH4.11 3-Indazolecarboxamide
12 can be prepared from isatin in five steps. Although the hydro-
lysis/diazotization/reduction protocol12 usually gives the excellent
yields (>90%) the total yield of 7 remains only moderate.
Due to the wide range of pharmaceutical applications of
3-substituted indazoles, several efficient methods have been de-
veloped to obtain these heterocycles.7 Despite the variety of existing
methods, routes to 3-aminomethylindazoles have remained rela-
tively unexplored. To date, three distinct approaches have been
utilized to access 3-aminomethylindazoles of general type 7 (Fig. 2).
3-Bromomethylindazole 8 can be obtained by radical bromina-
tion of 3-methylindazole.1,2,6,8 Traditionally, the reaction has been
performed in CCl4 at reflux temperature for several hours. Usually
the indazole N1 nitrogen has been protected with tert-butylox-
ycarbonyl (Boc) and the yields have been moderate (60%), due to
formation of the dibrominated product. Substitution with primary
or secondary amines at room temperature afforded 7 in 40e75%
yields. Maryanoff et al.9 utilized reductive amination during
N
O
N
N
O
N
OMe
N
O
NH
N
NH
H2
N
N
H
N
Cl
N
O
Cl
N
H
N
HO
F
H
1
2
3
O
O
O
NH2
CN
F
N
N
N
N
HN
NC
O
MeO
F
F
N
N
NH2
N
N
H
N
H
N
O
4
5
6
* Corresponding author. Tel.: þ358 40 1981131; e-mail address: Jan.Tois@tut.fi
(J. Tois).
Fig. 1. Examples of pharmaceutically important indazoles.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.069

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R
R
O
Br
N
N
R
R
C-N amine
Reduction
N
R
R
N
R
N
R
R
N
N
N
N
R
8
R
12
R
7
O
Reductive amination
O
N
N
O
H
H
R
13
9
N
R
R
N
N
H
R
10
11
Fig. 2. Synthetic routes to 3-aminomethylindazoles.
Recently, we reported a practical and effective Z-selective syn-
thesis of o-bromo-acetophenone N-tosylhydrazones and subsequent
copper-catalyzed cyclization into 3-methylindazoles13 (Scheme 1).
We reasoned that utilization of amines instead of sodium
borohydride, followed by copper mediated cyclization would pro-
vide mild and rapid access to 3-aminomethylindazoles of general
type 7. Herein, we report our novel and environmentally friendly
route to 3-aminomethylindazoles. According to our knowledge this
is the first catalytic cyclization leading to 3-aminomethylindazoles.
respectively. These synthetically important conjugated dienes un-
dergo 1,4-addition with nucleophiles producing predominantly the
anti-products16 (Fig. 3).
The anti-selectivity of this reaction has been explained by the
higher reactivity of the s-trans conformation in comparison to the
s-cis form.15c,e
Although the applications of nitrosostyrene are well reported by
Gilchrist,15f Hassner,17 Denmark,18 and very recently by Weinreb,19
the utilization of vinyl azines has remained relatively unexplored.
Selective a-fuctionalization of vinyl azines has been utilized mainly
R
N
in the field of carbohydrate chemistry.14bed In those examples the
intermediates have been isolated and reacted with different nucle-
ophiles. We decided to use ourown one-pot protocol,13 and react the
in situ formed vinyl azine with a range of amines. The amines used
functioned both as a base, by performing the needed deprotonation,
and as a nucleophile. Our investigation began with the preparation
Br
N
R
R
HN
H
N
NaBH4
R
Ts
N
NHTs
N
NHTs
R
R
R
H2O / CH3CN
H2O / CH3CN
Br
Br
Br
R
N
CuI
CuI
DMEDA
R
DMEDA
of five anti-aminomethyl N-tosylhydrazones 16aee. a-Brominated
EtOH/H2O
EtOH/H2O
N
N
R
R
o-bromoacetophenones20 14aed were reacted with p-toluene-
sulfonylhydrazide at room temperature in the presence of acid. After
stirring overnight, the intermediate products 15aed precipitated
out as a mixture of isomers and were filtered. The intermediates
were dissolved in acetonitrile, added to a stirred solution of the
amine (2 equiv). According to TLC, the reactions were usually com-
pleted in 30 min. The results are summarized in Table 1.
N
N
Ts
Ts
7
Scheme 1. Synthesis of 3-methyindazoles and 3-aminomethylindazoles.
2. Results and discussion
2.1. Synthesis of anti-hydrazones
With secondary amines the reaction proceeded smoothly, and the
desired amino functionalized anti-hydrazones were obtained in ex-
cellent yields. After aqueous work-up, the products were isolated in
pure form, and there was no need for chromatographic purifications.
Hydrazones and oximes, possessing a leaving group at the
a
-position, undergo an elimination reaction when treated with
basic reagents to form vinyl azines14 and
a
-nitrosostyrenes,15
B
H
1,4-addition
elimination
H
N
N
N
Nu
N
N
R
N
R
N
R
N
LG
Nu
R
s-cis vinyl azine
s-trans vinyl azine
hydrazone
hydrazone
anti-
B
elimination
1,4-addition
O
N
H
HO
Nu
O
N
N
O
N
LG
Nu
oxime
s-cis α-nitrosostyrene
s-trans α-nitrosostyrene
anti-oxime
Fig. 3. Analogous formation of anti-hydrazones and anti-oximes.

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Table 1
Synthesized anti-hydrazones
R
N
NHTs
N
O
R
Br
Br
TsNHNH2
amine
N
NHTs
R
R
R
AcCl, EtOH, RT, 16 h
H2O / CH3CN, RT, 30 min
Br
Br
Br
14a-d
15a-d
16a-e
Entry
1
Amine
Product
Yielda (%)
N
95
N
H
N
NHTs
16a
Br
O
O
N
2
87
N
H
N
NHTs
Br
16b
O
O
N
3
4
89
93
MeO
N
NHTs
N
H
Br
Br
16c
O
O
N
MeO
MeO
N
NHTs
N
H
16d
16e
O
O
N
5
98
O
O
N
NHTs
N
H
Br
a
Isolated yield after two steps.
Due to the success with secondary amines, we decided to
investigate primary amines as nucleophiles First, 15a was reacted
with benzylamine and as before, the reaction was complete in
30 min as shown by TLC. After aqueous work-up the crude
product was triturated with hexane/EtOAc-solution (1:1) and
a white solid was obtained. 1H NMR and ESI-MS indicated the
formation of a dimer 17a in 62% yield. For nitrosoalkenes the
dimer- or trimer-formation has been reported,15g but according to
our knowledge, this is the first example of anti-selective bishy-
drazone formation from vinyl azines. The reaction was next re-
peated with 3-(tert-butyldimethylsiloxy)-1-propylamine as the
nucleophile giving 17b in 81% isolated yield. When primary ar-
omatic amine, aniline, was subjected to the reaction a complex
mixture was obtained. Due to the lower basicity of aniline com-
pared to aliphatic amines, it was not capable of abstracting the
acidic proton and thus the vinyl azine intermediate was not
formed. We decided to induce vinyl azine formation by the ad-
dition of DBU, which is known to be a strong base but a poor
nucleophile. Our assumption was correct, and after 30 min 15a
was totally consumed giving bishydrazone 17c in 59% isolated
yield after column chromatography. In this case monohydrazone
18c was also obtained in 22% yield (Scheme 2).
2.2. Copper-catalyzed cyclization of anti-hydrazones into
3-aminomethyl-N-tosyl-indazoles
On the basis of our previous work on copper-catalyzed cy-
clizations,13,20 we decided to utilize N,N0-dimethylethylenedi-
amine, DMEDA, as a ligand and CuI as copper source. To our
delight, the catalytic system was found suitable also for amino
functionalized anti-hydrazones. The reactions were carried out
at room temperature in air, and in all entries full conversion was
achieved in less than 10 min with the results summarized in
Table 2.
The starting materials 16aee, 17aec, and 18c were simply
slurried in EtOH/H2O (1:1 for entries 1e5 and 2:1 for entries
6e9), treated with Na2CO3, and stirred for 2 min. DMEDA (0.7 M
solution in EtOH) and CuI were added and the reactions moni-
tored by TLC (hexane/EtOAc 1:1 or 2:1). After aqueous work-up
products 19e25 and 27 were obtained in excellent yields with no
need for chromatographic purification. Compound 26 was
obtained in moderate yield, even though 100% conversion was
observed, because a mixture of 17c and 18c was used as the
starting material and chromatographic separation of 26 and 27
was difficult.

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Br
N
NHTs
N
15a
NH2
N
(1)
NHTs
H2O / CH3CN
Br
17a (62%)
TBSO
Br
N
NHTs
N
15a
N
(2)
TBSO
NH2
NHTs
H2O / CH3CN
Br
17b (81%)
Br
NH
N
NHTs
N
15a
NH2
N
N
NHTs
+
(3)
NHTs
H2O / CH3CN
Br
18c (22%)
Br
17c (59%)
Scheme 2. anti-Selective formation of bishydrazones.
Table 2
Formation of 3-aminomethyl-N-tosyl-indazoles
CuI (10 mol%)
R
R
DMEDA (30 mol%)
Na2CO3 (2.2 equiv.)
N
R'
R'
N
NHTs
EtOH/H2O
Br
N
RT, 10 min
Ts
19 - 27
16a-e 17a-c 18c
,
,
Entry
R
R0
H
Product
Yielda (%)
N
1
92
N
N
N
Ts
19
O
N
O
N
2
H
100
N
N
Ts
20
99
O
N
O
N
MeO
3
OMe
N
N
21
Ts
(continued on next page)

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Table 2 (continued)
Entry
R
R0
Product
Yielda (%)
O
N
O
N
MeO
4
di-OMe
92
N
N
MeO
Ts
22
O
N
O
N
O
5
eOCH2Oe
95
N
O
N
Ts
23
Ts
N
N
N
N
6
H
98
N
NHTs
N
N
Br
Ts
24
TBSO
OTBS
Ts
N
N
N
N
7
H
95
N
NHTs
N
N
Br
Ts
25
Ts
N
N
N
N
N
8
H
54
N
N
NHTs
Br
Ts
26
NH
NH
9
H
100
N
N
27
Ts
a
Isolated yield.
3. Conclusion
in aqueous conditions producing the desired indazoles in excellent
yields. Further investigations to extend this strategy to other nu-
cleophiles and utilization of bisindazoles as metal ligands are cur-
rently underway in our laboratory.
In summary, we have extended our previously reported catalytic
cyclization13 method to the synthesis of 3-aminomethyl-N-tosyl-
indazoles. This approach offers a rapid and convenient alternative
to the existing synthetic routes toward 3-aminomethylindazole.
The in situ formed highly reactive vinyl azines underwent 1,4-
addition with a variety of amines producing, selectively, the anti-
hydrazones. When primary amines were utilized as nucleophiles
novel bishydrazones were formed in good yields. In case of aro-
matic amines addition of DBU was needed to induce the vinyl azine
formation. Effective copper-catalyzed cyclizations were performed
4. Experimental
4.1. General
All commercially available chemicals and solvents were used as
received and reactions were carried out in air. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were measured using Varian Mercury

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300 spectrometer. Chemical shifts are reported as
d
values (ppm)
m, N]CCH2N), 2.43 (3H, s, Me), 2.43e2.35 (4H, m, 2ꢁCH2NCH2). 13
C
relative to tetramethylsilane, which was used as internal standard.
High resolution mass spectra were acquired with Micromass LCT
instrument and ESI-MS with ESI-TOF Waters LCT Premier XE in-
strument. Thin-layer chromatography (TLC) was performed on pre-
coated aluminum plates. Silica gel 60, particle size 0.040e0.063 mm,
was used for column chromatography. Melting points were de-
termined with a Stuart SMP10 apparatus and are uncorrected.
NMR (75 MHz, CDCl3, 21 ꢀC)
d
(ppm): 150.9,149.3,144.3,135.4,131.5,
129.5, 128.4, 124.8, 115.8,111.7, 110.7, 67.0, 63.7, 56.5, 56.3, 53.6, 21.8.
HRMS (EI): Mþ, found 511.0790. C21H26BrN3O5S requires 511.0777.
4.2.5. (E)-N0-(1-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2-morpholino-
ethylidene)-4-methylbenzenesulfonohydrazide (16e). Yellow oil. 1H
NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm): 7.82 (2H, d, J 8.7 Hz, ArH),
7.33e7.28 (2H, d, J 8.7 Hz, ArH), 7.01 (1H, s, ArH), 6.42 (1H, s, ArH),
6.05 (2H, s, OCH2O), 3.57 (4H, t, J 5.0 Hz, 2ꢁCH2CH2O), 3.21 (2H, m,
N]CCH2N), 2.43 (3H, s, Me), 2.38e2.34 (4H, m, 2ꢁCH2NCH2). 13C
4.2. General procedure for the preparation of anti-
hydrazones 16aee
NMR (75 MHz, CDCl3, 21 ꢀC)
d (ppm): 156.0,150.0,148.4,144.1,135.4,
Acetyl chloride (0.4 g, 0.36 mL, 5.1 mmol, 5.1 equiv) was added
slowly to 4 mL EtOH at 0 ꢀC. Stirring was continued for 30 min at
0
130.0, 128.2, 113.4, 111.4, 109.0, 102.6, 66.9, 53.6, 25.4, 21.7, 16.9.
HRMS (EI): Mþ, found 495.0470. C20H22BrN3O5S requires 495.0464.
ꢀC and 30 min at room temperature. -Bromo-acetophenones20
a
(14aed, 1.0 mmol, 1 equiv) were dissolved in ethanol (6 mL) and
added to acidic EtOH-solution followed by p-toluenesulfonylhy-
drazide (0.48 g, 2.6 mmol, 2.6 equiv). The reactions were stirred
overnight (ca. 18 h) at room temperature. The intermediate prod-
ucts (15aed) precipitated out as a mixture of isomers and were
filtered. Compounds 15aed (0.5 mmol, 1 equiv) were dissolved in
acetonitrile (10 mL) and added portion wise to a stirred mixture of
amine (1.0 mmol, 2 equiv) in water/CH3CN (10 mL/10 mL). After
30 min stirring at room temperature, the reactions were complete
according to TLC, wherein the mixtures were poured into water and
the aqueous solutions extracted with EtOAc (3ꢁ20 mL). Combined
organics were washed with water (20 mL) and saturated NaCl-so-
lution (20 mL), dried over Na2SO4, and filtered. After removal of
solvents the desired products (16aee) were obtained in pure form.
4.2.6. (N0,N00E,N0,N00E)-N0,N00-((2,2-Benzylazanediyl)bis(1-(2-bromo-
phenyl)ethan-2-yl-1-ylidene))bis(4-methylbenzenesulfonohydrazide)
(17a). Benzylamine (0.107 g, 1 mmol, 2 equiv) was dissolved in
H2O/CH3CN (10 mL/10 mL). Compound 15a (0.22 g, 0.5 mmol,
1 equiv) was dissolved in CH3CN (10 mL) and added to the amine
solution during 5 min. After 30 min stirring at room temperature
the reaction was complete according to TLC (eluent hexane/EtOAc
1:1). Reaction mixture was poured in water and aqueous solution
was extracted with EtOAc (3ꢁ25 mL). Combined organics were
washed with brine (2ꢁ25 mL) and dried over Na2SO4. The solvent
was evaporated in vacuo and the residue was triturated with hex-
ane/EtOAc-solution (1:1, 15 mL). Compound 17a (0.13 g, 62%) was
obtained as white powder after filtration. Mp 130e132 ꢀC. 1H NMR
(300 MHz, acetone-d6, 21 ꢀC)
d (ppm): 7.82e7.77 (4H, m, ArH), 7.56
(2H, t, J 7.9 Hz, ArH), 7.38e7.17 (9H, m, ArH), 7.12e6.99 (3H, m, ArH),
6.89e6.73 (2H, m, ArH), 6.57(2H, t, J 6.0 Hz, ArH), 3.76e3.12 (6H, m,
2ꢁN]CCH2N and PhCH2N), 2.35 (6H, s, 2ꢁMe). 13C NMR NMR
4.2.1. (E)-N0-(1-(2-Bromophenyl)-2-(piperidin-1-yl)ethylidene)-4-
methylbenzenesulfonolhydrazide (16a). Yellowsolid,mp144e145 ꢀC.
1H NMR (300 MHz, CDCl3, 21 ꢀC)
d
(ppm): 7.81 (2H, d, J 8.3 Hz, ArH),
(75 MHz, acetone-d6, 21 ꢀC)
d (ppm): 152.8, 152.4, 144.0, 143.9,
7.57 (1H, d, J 8.0 Hz, ArH), 7.36e7.25 (4H, m, ArH), 6.96 (1H, d, J 7.5 Hz,
ArH), 3.33e3.13 (2H, m, N]CCH2N), 2.42 (3H, s, Me), 2.26e2.21 (4H,
m, 2ꢁNCH2CH2),1.45e1.32 (6H, m, 3ꢁCH2). 13C NMR (75 MHz, CDCl3,
138.7, 137.5, 136.9, 136.8, 134.5, 134.1, 133.1, 133.0, 131.1, 131.0, 130.6,
130.3, 129.6, 128.8, 128.5, 128.3, 128.1, 127.9, 126.9, 120.6, 58.4, 57.2,
20.8. ESI-MS: MþNaþ, found 860.
21 ꢀC)
d (ppm): 152.9, 144.1, 135.3, 133.3, 131.3, 129.7, 129.5, 128.2,
120.2, 63.6, 54.4, 25.8, 24.1, 21.7. HRMS (ESI): MHþ, found 450.0862.
C20H25BrN3O2S requires 450.0851.
4.2.7. (N0,N00E,N0,N00E)-N0,N00-(2,20-(3-(tert-Butyldimethylsilyloxy)pro-
pylazanediyl)bis(1-(2-bromophenyl)ethan-2-yl-1-ylidene))bis
(4-methylbenzenesulfonohydrazide) (17b). Compound 15a (0.22 g,
0.5 mmol,1 equiv) and 3-(tert-butyldimethylsiloxy)-1-propylamine
(0.19 g, 1 mmol, 2 equiv) were subjected to conditions similar to 17a
described above. Crude product was purified by column chroma-
tography (hexane/EtOAc 2:1/1:1). Compound 17b (0.19 g, 81%)
was obtained as a white solid. Mp 71e73 ꢀC. 1H NMR (300 MHz,
4.2.2. (E)-N0-(1-(2-Bromophenyl)-2-morpholinoethylidene)-4-meth-
ylbenzenesulfonohydrazide (16b). White solid, mp 161e162 ꢀC. 1H
NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm): 7.80 (2H, d, J 8.3 Hz, ArH),
7.60 (1H, d, J 8.0 Hz, ArH), 7.41e7.26 (4H, m, ArH), 6.97 (1H, d, J
7.5 Hz, ArH), 3.54 (4H, t, J 4.6 Hz, 2ꢁCH2CH2O), 3.25 (2H, m, N]
CCH2N), 2.43 (3H, s, Me), 2.37e2.31 (4H, m, 2ꢁCH2NCH2). 13C NMR
CDCl3, 21 ꢀC)
d (ppm): 7.85 (4H, m, ArH), 7.61e7.57 (2H, m, ArH),
(75 MHz, CDCl3, 21 ꢀC)
d
(ppm): 152.1, 144.2, 135.2, 133.4, 133.3,
7.37e7.15 (10H, m, ArH), 6.63e6.56 (2H, m, ArH), 3.65e3.24 (6H, m,
2ꢁN]CCH2N and CH2OSi), 2.73e2.27 (8H, m, NCH2CH2 and 2ꢁMe),
1.39e1.19 (2H, m, CH2CH2CH2), 0.89 (9H, s, 3ꢁCCH3), ꢂ0.01 (6H, s,
131.4, 129.6, 129.5, 128.3, 128.2, 120.3, 66.9, 63.5, 53.5, 21.7. HRMS
(EI): Mþ, found 451.0571. C19H22BrN3O3S requires 451.0565.
m, 2ꢁSiCH3). 13C NMR (75 MHz, CDCl3, 21 ꢀC)
d (ppm): 153.4, 152.9,
4.2.3. (E)-N0-(1-(2-Bromophenyl-5-methoxyphenyl)-2-morpholino-
144.3, 144.2, 135.4, 135.4, 133.3, 133.0, 131.3, 130.2, 129.8, 129.7,
129.6, 128.3, 128.2, 128.1, 120.4, 120.0, 60.9, 60.5, 58.8, 26.1, 21.8,
18.3, ꢂ5.16, ꢂ7.91. ESI-MS: MHþ, found 920.
ethylidene)-4-methylbenzenesulfonohydrazide (16c). Colorless oil.
1H NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm): 7.83 (2H, d, J 8.3 Hz, ArH),
7.49 (1H, d, J 8.9 Hz, ArH), 7.31 (2H, d, J 8.0 Hz, ArH), 6.87 (1H, dd, J
8.9, 3.0 Hz, ArH), 6.52 (1H, d, J 3.0 Hz, ArH), 3.80 (3H, s, OMe), 3.58
(4H, t, J 5.1 Hz, 2ꢁCH2CH2O), 3.26 (2H, m, N]CCH2N), 2.43 (3H, s,
Me), 2.43e2.35 (4H, m, 2ꢁCH2NCH2). 13C NMR (75 MHz, CDCl3,
4.2.8. (N0,N00E,N0,N00E)-N0,N00-(2,20-(Phenylazanediyl)bis(1-(2-bromo-
phenyl)ethan-2-yl-1-ylidene))bis(4-methylbenzenesulfonohydrazide)
(17c) and (E)-N0-(1-(2-bromophenyl)-2-(phenylamino)ethylidene)-4-
methylbenzenesulfonohydrazide (18c). 1,8-Diazabicyclo[5.4.0]undec-
7-ene (DBU) (0.09 mL, 0.6 mmol, 1.2 equiv) and aniline (0.093 g,
1 mmol, 2 equiv) were dissolved in H2O/CH3CN (10 mL/10 mL).
Compound 15a (0.22 g, 0.5 mmol, 1 equiv) was dissolved in CH3CN
(10 mL) and added to the amine solution during 5 min. After 30 min
stirring at room temperature the reaction was complete according to
TLC (eluent hexane/EtOAc 2:1). Reaction mixture was poured in water
and aqueous solutionwasextracted with EtOAc (3ꢁ25 mL). Combined
organics were washed with brine (2ꢁ25 mL) and dried over Na2SO4.
21 ꢀC)
d (ppm): 159.6, 151.7, 144.3, 135.3, 134.4, 134.1, 129.6, 128.4,
117.4, 115.1, 110.3, 66.9, 63.4, 55.8, 53.6, 21.8. HRMS (EI): Mþ, found
481.0676. C20H24BrN3O4S requires 481.0671.
4.2.4. (E)-N0-(1-(2-Bromo-4,5-dimethoxyphenyl)-2-morpholinoethy-
lidene)-4-methylbenzenesulfonohydrazide (16d). Colorless oil. 1H
NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm): 7.84 (2H, d, J 8.4 Hz, ArH), 7.31
(2H, d, J 8.0 Hz, ArH), 7.02 (1H, s, ArH), 6.48 (1H, s, ArH), 3.90 (3H, s,
OMe), 3.83 (3H, s, OMe), 3.60e3.55 (4H, m, 2ꢁCH2CH2O), 3.24 (2H,

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The solvent was evaporated in vacuo and the residue was triturated
with hexane/EtOAc-solution (2:1,15 mL). White solid 17c (0.12 g, 59%)
was filtered. Mp 194e195 ꢀC. 1H NMR (300 MHz, DMSO-d6, 21 ꢀC)
d (ppm): 7.78 (2H, d, J 8.4 Hz, ArH), 7.61 (1H, s, ArH), 7.25 (1H, s,
ArH), 7.21 (2H, d, J 8.0 Hz, ArH), 4.04 (3H, s, OMe), 3.92 (3H, s, OMe),
3.77 (2H, s, N]CCH2N), 3.62 (4H, t, J 4.6 Hz, 2ꢁCH2CH2O),
2.38e2.34 (7H, m, 2ꢁNCH2CH2 and Me). 13C NMR (75 MHz, CDCl3,
d
(ppm): 10.4 (2H, m, NH), 7.63e7.54 (6H, m, ArH), 7.34e7.20 (8H, m,
ArH), 6.89e6.40 (7H, m, ArH), 4.00e3.68 (4H, m, 2ꢁN]CCH2N), 2.32
21 ꢀC)
d (ppm): 152.2, 151.0, 147.9, 145.2, 137.6, 129.8, 127.5, 118.8,
(6H,s,2ꢁMe).13CNMR(75MHz, DMSO-d6,21ꢀC)
d
(ppm): 151.2,148.3,
101.4, 95.5, 67.1, 56.6, 56.3, 55.7, 53.6, 21.7. HRMS (EI): Mþ, found
431.1509. C21H25N3O5S requires 431.1515.
143.1, 136.2, 133.7, 132.5, 131.1, 130.0, 129.2, 128.7, 127.9, 127.4, 120.5,
116.5, 111.8, 55.3, 55.2, 21.1. ESI-MS: MþNaþ, found 846. Compound
18c (0.05 g, 22%) was obtained as a orange solid after column chro-
matography (hexane/EtOAc 2:1). Mp 134e136 ꢀC. 1H NMR (300 MHz,
4.3.5. 3-(Morpholinomethyl)-1-tosyl-1H-[1,3]dioxolo[4,5-f]indazole
(23). Off-white solid, mp 150e152 ꢀC. 1H NMR (300 MHz, CDCl3,
CDCl3, 21 ꢀC)
d (ppm): 7.76 (2H, d, J 8.3 Hz, ArH), 7.59 (1H, d, J 7.6 Hz,
21 ꢀC)
d (ppm): 7.8 (2H, d, J 8.4 Hz, ArH), 7.58 (1H, s, ArH), 7.23 (2H,
ArH), 7.44 (1H, br s, NH), 7.34e7.23 (4H, m, ArH), 7.08 (2H, t, J 7.4 Hz,
ArH), 6.88 (1H, m, ArH), 6.72e6.66 (1H, m, ArH), 6.54 (2H, d, J 8.3 Hz,
ArH), 4.3e4.0 (3H, m, N]CCH2N and NH), 2.42 (3H, s, Me). 13C NMR
d, J 8.6 Hz, ArH), 7.18 (1H, s, ArH), 6.07 (2H, s, OCH2O), 3.72 (2H, s,
N]CCH2N), 3.62 (4H, t, J 4.6 Hz, 2ꢁCH2CH2O), 2.38e2.34 (7H, m,
2ꢁNCH2CH2 and Me). 13C NMR (75 MHz, CDCl3, 21 ꢀC)
d (ppm):
(75 MHz, CDCl3, 21 ꢀC)
d (ppm): 152.8, 147.2, 144.2,135.2,133.6,132.7,
150.8, 146.2, 145.3, 138.5, 134.5, 129.8, 127.6, 120.4, 102.4, 99.1, 94.1,
67.1, 55.6, 53.6, 21.7. HRMS (EI): Mþ, found 415.1206. C20H21N3O5S
requires 415.1202.
131.8, 129.6, 129.4, 129.2, 128.6, 128.0, 120.4, 117.8, 113.1, 48.9, 22.7.
HRMS (EI): Mþ, found 457.0465. C21H20BrN3O2S requires 457.0460.
4.3.6. N-Benzyl-1-(tosyl-1H-indazol-3-yl)-N-((1-tosyl-1H-indazol-
4.3. General procedure for the preparation of indazoles
19e27
3-yl)methyl)methanamine(24). Colorless oil. 1H NMR (300 MHz,
CDCl3, 21 ꢀC)
d (ppm): 8.16 (2H, d, J 8.3 Hz, ArH), 7.72 (4H, d, J
8.4 Hz, ArH), 7.50 (2H, t, J 7.1 Hz, ArH), 7.23e7.20 (3H, m, ArH),
7.07 (2H, t, J 8.3 Hz, ArH), 6.99e6.92 (8H, m, ArH), 3.74 (4H, s,
2ꢁN]CCH2N), 3.29 (2H, s, PhCH2N), 1.97 (6H, s, 2ꢁMe). 13C NMR
Hydrazone (0.1 mmol, 1 equiv) was slurried in EtOH/H2O (1:1,
1 mL) and Na2CO3 (0.22 mmol, 2.2 equiv) was added. The mixture
wasstirredat roomtemperaturefor 2 min, DMEDA (0.7 M solutionin
(75 MHz, CDCl3, 21 ꢀC)
d (ppm): 152.3, 145.5, 142.2, 138.3, 134.2,
ethanol, 43 ml, 30 mol %) was added followed by CuI (2 mg,10 mol %).
129.8, 129.7, 129.5, 128.4, 127.6, 127.4, 125.7, 124.2, 121.8, 113.8,
58.6, 50.0, 21.4. HRMS (ESI): MHþ, found 676.2054. C37H34N5O4S2
requires 676.2052.
After 10 min no starting material was observed on TLC. Reaction
mixture was poured in water (50 mL) and the aqueous solution
extracted with EtOAc (3ꢁ25 mL). The combined organics were
washed with 5% aqueous NH3-solution (3ꢁ10 mL), brine (2ꢁ25 mL)
and dried over Na2SO4. The solvent was evaporated in vacuo. Com-
pounds 19e25 and 27 were obtained as pure form and compound 26
was purified by column chromatography (hexane/EtOAc 2:1).
4.3.7. 3-(tert-Butyldimethylsilyloxy)-N,N-bis((1-tosyl-1H-indazol-
3-yl)methyl)propan-1-amine (25). Colorless oil. 1H NMR
(300 MHz, CDCl3, 21 ꢀC)
d (ppm): 8.26 (2H, d, J 8.4 Hz, ArH), 7.88
(4H, d, J 8.4 Hz, ArH), 7.63 (2H, t, J 7.1 Hz, ArH), 7.38 (2H, d, J 7.1 Hz,
ArH), 7.24 (2H, t, J 7.1 Hz, ArH), 7.15 (4H, d, J 8.4 Hz, ArH), 3.90 (4H,
s, 2ꢁN]CCH2N), 3.35e3.28 (2H, m, CH2OSi), 2.51e2.45 (2H, m,
NCH2CH2), 2.20 (6H, s, 2ꢁMe), 1.75e1.62 (2H, m, CH2CH2CH2),
0,88 (9H, s, 3ꢁCCH3), 0.00 (6H, s, 2ꢁSiCH3). 13C NMR (75 MHz,
4.3.1. 3-(Piperidin-1-ylmethyl)-1-tosyl-1H-indazole
(19). Yellow
d (ppm): 8.17
solid, mp 112e115 ꢀC. 1H NMR (300 MHz, CDCl3, 21 ꢀC)
(1H, d, J 8.5 Hz, ArH), 7.95 (1H, d, J 8.0 Hz, ArH), 7.82 (2H, d, J 8.4 Hz,
ArH), 7.52 (1H, m, ArH), 7.30 (1H, m, ArH), 7.20 (2H, d, J 8.1 Hz, ArH),
3.80 (2H, s, N]CCH2N), 2.33e2.28 (7H, m, 2ꢁNCH2CH2 and Me),
CDCl3, 21 ꢀC)
d (ppm): 152.1, 145.3, 141.8, 134.2, 129.7, 129.3, 127.4,
1.52e1.41 (4H, m, 2ꢁNCH2CH2), 1.40e1.32 (2H, m, CH2CH2CH2). 13
C
125.5, 124.0, 121.7, 113.5, 61.2, 51.1, 50.7, 30.5, 25.9, 21.4, 18.2,
ꢂ5.38. HRMS (ESI): MHþ, found 758.2852. C39H48N5O5SiS2 re-
quires 758.2866.
NMR (75 MHz, CDCl3, 21 ꢀC)
d (ppm): 152.1, 145.1, 141.7, 141.7, 134.6,
129.7, 129.2, 127.5, 126.2, 124.0, 122.3, 113.4, 54.6, 26.1. HRMS (ESI):
MHþ, found 370.1574. C20H24N3O2S requires 370.1589.
4.3.8. N,N-Bis((1-tosyl-1H-indazol-3-yl)methyl)aniline (26). Light
yellow solid, mp 168e169 ꢀC. 1H NMR (300 MHz, CDCl3, 21 ꢀC)
4.3.2. 4-((1-Tosyl-1H-indazol-3-yl)methyl)morpholine (20). White
solid, mp 100 ꢀC. 1H NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm): 8.18 (1H,
d
(ppm): 8.14 (2H, d, J 7.7 Hz, ArH), 7.75 (4H, d, 8.3 Hz, ArH),
7.51e7.41 (5H, m, ArH), 7.18e7.01 (9H, m, ArH), 6.89 (2H, d, J 7.8 Hz,
ArH), 6.74 (1H, t, J 7.3 Hz, ArH), 4.72 (4H, s, 2ꢁN]CCH2N), 2.28 (6H,
d, J 9.0 Hz, ArH), 7.93 (1H, d, J 8.0 Hz, ArH), 7.83 (2H, d, J 8.4 Hz, ArH),
7.55 (1H, m, ArH), 7.32 (1H, m, ArH), 7.22 (2H, d, J 8.6 Hz, ArH), 3.84
(2H, s, N]CCH2N), 3.62 (4H, t, J 4.6 Hz, 2ꢁCH2CH2O), 2.40 (4H, t, J
4.6 Hz, 2ꢁCH2NCH2), 2.34 (3H, s, Me). 13C NMR (75 MHz, CDCl3,
s, 2ꢁMe). 13C NMR (75 MHz, CDCl3, 21 ꢀC)
d (ppm): 150.9, 145.3,
141.8, 134.4, 129.8, 129.8, 129.4, 129.2, 127.5, 125.0, 124.3, 121.2,
119.3, 116.1, 113.6, 49.0, 21.7. HRMS (ESI): MHþ, found 662.1897.
C36H32N5O4S2 requires 662.1896.
21 ꢀC)
d (ppm): 151.1, 145.3, 141.7, 134.6, 129.8, 129.4, 127.5, 125.8,
124.1, 122.0, 113.5, 67.0, 55.5, 53.6, 21.7. HRMS (EI): Mþ, found
371.1294. C19H21N3O3S requires 371.1304.
4.3.9. N-((1-Tosyl-1H-indazol-3-yl)methyl)aniline
(27). Orange
(ppm):
solid, mp 143e146 ꢀC. 1H NMR (300 MHz, CDCl3, 21 ꢀC)
d
4.3.3. 4-((5-Methoxy-1-tosyl-1H-indazol-3-yl)methyl)morpholine
(21). Yellow sticky paste. 1H NMR (300 MHz, CDCl3, 21 ꢀC)
d (ppm):
8.19 (1H, d, J 9.3 Hz, ArH), 7.81e7.71 (3H, m, ArH), 7.51 (1H, m,
ArH), 7.27e7.11 (5H, m, ArH), 7.10e6.65 (3H, m, ArH), 4.82 (2H, br
s, N]CCH2NH), 2.34 (3H, s, Me). 13C NMR (75 MHz, CDCl3, 21 ꢀC)
8.06 (1H, d, J 8.8 Hz, ArH), 7.79 (2H, d, J 8.3 Hz, ArH), 7.23 (1H, m,
ArH), 7.20e7.15 (3H, m, ArH), 3.85 (3H, s, OMe), 3.80 (2H, s, N]
CCH2N), 3.63 (4H, t, J 4.5 Hz, 2ꢁCH2CH2O), 2.38 (4H, t, J 4.5 Hz,
2ꢁCH2NCH2), 2.34 (3H, s, Me). 13C NMR (75 MHz, CDCl3, 21 ꢀC)
d
(ppm): 145.3, 134.5, 129.9, 129.6, 129.3, 127.5, 124.3, 120.9, 118.2,
113.7, 21.7. HRMS (EI): Mþ, found 377.1199. C21H19N3O2S requires
377.1198.
d
(ppm): 156.9, 150.9, 145.2, 137.1, 130.0, 129.5, 127.8, 127.3, 126.8,
120.3, 115.0, 102.5 67.1, 56.0, 53.6, 21.7. HRMS (EI): Mþ, found
401.1416. C20H23N3O4S requires 401.1409.
Acknowledgements
4.3.4. 4-((5,6-Dimethoxy-1-tosyl-1H-indazol-3-yl)methyl)morpho-
The Academy of Finland, for financial support (110043), is
gratefully acknowledged.
line (22). Yellow sticky paste. 1H NMR (300 MHz, CDCl3, 21 ꢀC)

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12. Crestey, F.; Stiebling, S.; Legay, R.; Collot, V.; Rault, S. Tetrahedron 2007, 63,
419e428.
13. Kylmala, T.; Udd, S.; Tois, J.; Franzén, R. Tetrahedron Lett. 2010, 51, 3613e3615.
Supplementary data
€ €
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.09.069.
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N
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anti = E
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