Synthesis of triazole-functionalized tetrahydroindazolones by 1,3-dipolar cycloadditions between azides and alkynes

Article abstract of DOI:10.1016/j.tetlet.2009.04.009

7-Azido-tetrahydroindazolones undergo efficient copper-catalyzed Huisgen 1,3-dipolar cycloaddition reactions with various alkynes leading to a straightforward synthesis of triazole-functionalized tetrahydroindazolones. The latter are interesting molecular

Full text of DOI:10.1016/j.tetlet.2009.04.009

Tetrahedron Letters 50 (2009) 3046–3049
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of triazole-functionalized tetrahydroindazolones by 1,3-dipolar
cycloadditions between azides and alkynes
*
Inta Strakova, Maris Turks , Andris Strakovs
¯
Faculty of Material Science and Applied Chemistry, Riga Technical University, 14/24 Azenes Str., Riga LV-1048, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
7-Azido-tetrahydroindazolones undergo efficient copper-catalyzed Huisgen 1,3-dipolar cycloaddition
reactions with various alkynes leading to a straightforward synthesis of triazole-functionalized tetra-
hydroindazolones. The latter are interesting molecular platforms in terms of medicinal chemistry.
Published by Elsevier Ltd.
Received 7 February 2009
Revised 20 March 2009
Accepted 3 April 2009
Available online 9 April 2009
Keywords:
Tetrahydroindazolones
Azides
Triazoles
Huisgen 1,3-dipolar cycloaddition
Tetrahydroindazoles (THIs), as a subclass of fused-pyrazoles,
have gained significant interest due to the broad spectrum of their
biological activity. Thus, 2-aryl derivatives of 4,5,6,7-THI have been
reported to be active as herbicides1 whilst their 5-carboxylic acid
derivatives possess anti-inflammatory properties.2 Additionally,
5-amino-4,5,6,7-tetrahydroindazoles possess dopaminergic activ-
ity3 and THI-substituted 3,5-dihydroxy-6-heptenoic acids have
shown HMG-CoA reductase inhibiting activity with IC50 = 3.0 nM.4
Tetrahydroindazolones of general structure 1a possess antitu-
mor activity while being less toxic than other available antitumor
drugs (Fig. 1).5 These derivatives have also shown other valuable
biological activities connected with cell proliferative disorders,
and in the treatment of Alzheimer’s disease. On the other hand,
cyclic P1-arginine side-chain mimetic.12 Additionally, tetra-
hydroindazolones have been used as intermediates for the
synthesis of selective and drug-like ligands for the opioid
r1
receptor.13
In the light of these facts, structural14 and synthetic interest in
the field of differently substituted 4,5,6,7-THIs has continued.15
Various
2-(2,6-dichloro-4-trifluoromethyl-phenyl)tetrahydroin-
dazoles16 and tetrahydroindazol-3-yl alanine derivatives,17 as well
as novel THI-based chiral auxiliaries,18 have been reported in the
last decade. Modern technologies have also been used in THI syn-
theses. For example, reactions under microwave irradiation have
been reported.19 Claramunt, Lopez, and co-workers20a studied the
synthesis and particularly the tautomeric equilibrium of tetra-
compounds 1b are known for their selectivity toward GABA-A
a
hydroindazolones related to those reported by us earlier20b
.
5 receptors and are useful for enhancing cognition.6 More recently,
other THI-3-carboxamides have been found to regulate the mitotic
motor protein, Eg5.7 Specific inhibition of the latter prevents
uncontrollable division of malignant cells. Furthermore, THIs 1c
were shown to be active against various carcinomas.8 Compounds
with the general formula 1d are potent inhibitors of Heat-Shock
Protein 90.9
Additionally, scaffolds similar to 1 have raised a theoretical
interest as privileged molecular platforms for the synthesis of
selective cyclooxygenase-2 inhibitors10 and searches in the THI
series have led to the discovery of inhibitors of bacterial type II
topoisomerases.11 The corresponding 4-deoxy-analogs of 1 have
been studied as thrombin inhibitors where THI acts as a heterobi-
triazole
6 R7 R8 R1
R1
R
R4
R3
N
N
7
R5
R4
6
5
1
7
4
6
5
1
N
N
3
3
4
R3
R2
R2
O
O
1a:5 R2 = H, Alk, c-Alkyl, Ar
1b:6,7 R2 = -C(O)NHAr
1c:8 R1 = -(CH2)n-Ar(Het)
1d:9 R1 = Ar, Het
1e
This work:
modifications at C(7)
via a triazole linker
* Corresponding author. Tel.: +371 67089251; fax: +371 67615765.
E-mail address: maris_turks@ktf.rtu.lv (M. Turks).
Figure 1. Generalized scaffolds of tetrahydroindazolones.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.04.009

I. Strakova et al. / Tetrahedron Letters 50 (2009) 3046–3049
3047
([1,2,3]triazol-1-yl)-4,5,6,7-tetrahydroindazol-4-ones 4a–h con-
taining phenyl, hydroxymethyl, hydroxypropyl, formyl, and eth-
oxycarbonyl functions at C(40) were obtained in good to excellent
yields.
N3
Ar
Ar
N
N
1. NBS, CCl4
2. NaN3, EtOH, H2O
N
N
R1
R1
Triazoles with R2 = CH2OH (4b, 4f), R2 = COOEt (4c),
R2 = (CH2)3OH (4e), and R2 = CHO (4h) are suitably functionalized
for further transformation.
O
2a-c
O
3a-c
2a, 3a: Ar = Ph, R1 = H
2b, 3b: Ar = Ph, R1 = Me
2c, 3c: Ar = 2-Py, R1 = Me
Reactions with ethyl propiolate were sluggish, gave mediocre
yields and often mixtures of regioisomers. The only exception
was starting material 3a, which provided product 4c in 70% iso-
lated yield. On the other hand, pyridyl derivative 3c gave insepara-
ble mixtures of products. Interesting results were obtained with
tetrahydroindazolone 3b. Thus, method A (80 °C, 22 h) gave full
conversion to triazoles 4i and 4j in a ratio of 74:26 and an isolated
yield of 91% (Scheme 3). In contrast, catalytic conditions at lower
temperature or thermal conditions furnished both regioisomers
in almost a 1:1 ratio. The structure of 4j was established unambig-
uously by single crystal X-ray diffraction.26 The structure of regio-
isomer 4i was confirmed from the 1H{1H} nuclear Overhauser
effect between H–C(7) and H–C(50) which was established to be
relatively small (1.5%). Triazole-functionalized THI 4c gave a
respective NOE of 2.3%.
Scheme 1. Synthesis of 7-azido THIs.
However, to the best of our knowledge, there are no reports
describing heterocyclic substituents/linkers at C(7) of the pharma-
cologically privileged structure 1. Hence, we decided to explore the
synthesis of C(7)-triazole derivatives of 1-aryl-6,6-dimethyl-4-
oxo-4,5,6,7-tetrahydroindazoles (1e). The latter correspond to the
general molecular platform 1 depicted in Figure 1.
Since the discovery of efficient catalysis of the Huisgen dipolar
cycloadditions between alkynes and azides,21 this reaction has be-
come important in the field of derivatization of different molecular
scaffolds. Moreover, triazoles themselves possess interesting bio-
logical activities.22
Thus, bromination of THIs 2a–c with N-bromosuccinimide
(NBS) in refluxing carbon tetrachloride followed by treatment with
NaN3 led to azides 3a–c as reported earlier (Scheme 1).23 We inves-
tigated two methods for the copper-catalyzed 1,3-dipolar cycload-
dition reaction. Method A utilizes the CuSO4ꢀ5H2O–Cu couple in
tert-butanol/water24 and method B uses CuSO4ꢀ5H2O with sodium
ascorbate in acetone/water.21a,25 The results are summarized in
Scheme 2 and Table 1.
As expected, dimethyl acetylenedicarboxylate underwent the
Huisgen cycloaddition under thermal conditions (Scheme 4). Tet-
rahydroindazole-substituted
1H-[1,2,3]triazole-4,5-dicarboxylic
acid dimethyl esters 4k and 4l were obtained in 59% and 40%
isolated yields, respectively.
Reaction of azide 3a and phenylacetylene according to method
A at 80 °C for eight hours provided phenyltriazole-functionalized
THI 4a in 85% yield. On the other hand, method B afforded 4a in
72% yield after 24 h at 20 °C. In general, higher temperatures and
longer reaction times gave better yields. 1-Phenyl/pyridyl-7-
nOe
E
1.5%
E
H
H
N3
O
N
Ph
N
N
Ph
N
+
N
N
N
R2
N
O
N
3b
4i, E = COOEt
4j
N3
O
N
Ar
Ar
a) 91%: 74
b) 76%: 58
c) 60%: 57
:
:
:
26
42
43
R2
Method
A or B
N
N
N
N
R1
R1
a) Method A (80 ºC, 22 h); b) EtOH, reflux, 22 h;
c) Method A (60 ºC, 21 h)
O
3a-c
4a-h
Scheme 3. Regioselectivity in the 1,3-dipolar cycloaddition of azide 3b and ethyl
Scheme 2. Synthesis of triazole-functionalized tetrahydroindazolones 4a–h.
propiolate.
Table 1
Triazole-functionalized tetrahydroindazolones 4a–i produced via methods A or B
Entry
Product 4
R1
Ar
R2
Method
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4c
4d
4e
4f
H
H
H
H
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
2-Py
2-Py
2-Py
Ph
Ph
CH2OH
COOEt
Ph
Aa (80 °C, 8 h)
Bb (20 °C, 24 h)
A (30 °C, 48 h)
A (80 °C, 11 h)
A (80 °C, 16 h)
A (80 °C, 5 h)
A (80 °C, 27 h)
A (80 °C, 12 h)
A (80 °C, 30 h)
85
72
60
70
87
89
89
98
53
172–173
175–176
189–190
180–181
148–149
52–55
215–216
189–190
183–185
(CH2)3OH
CH2OH
Ph
4g
4h
CHOc
a
CuSO4ꢀ5H2O, Cu, t-BuOH, H2O.
b
c
CuSO4ꢀ5H2O, sodium ascorbate, acetone, H2O.
The corresponding diethylacetal (R2 = CH(OEt)2) was employed as the reagent.

3048
I. Strakova et al. / Tetrahedron Letters 50 (2009) 3046–3049
In conclusion, we have developed a straightforward synthesis of
O
MeO
O
O
triazole-functionalized tetrahydroindazolones that are interesting
molecular platforms in terms of medicinal chemistry. In order to
use these structures for conjugation with compounds from natural
sources (carbohydrates, peptides, etc.) and/or oligomerization,
homochiral forms of the corresponding azido-THIs 3a–c are re-
quired. Studies toward this end are underway in our laboratory
and will be reported in due course.
MeO
MeO
N
N
N3
N
O
N
N
OMe
N
N
EtOH, 78 ºC
7 h
R1
R1
O
O
4k: R1 = H; 59%
3a: R1 = H
Acknowledgments
4l: R1 = Me; 40%
3b: R1 = Me
The authors thank Syntagon Baltic for analytical support, Dr. S.
Belyakov for X-ray structures, and Dr. S. R. Dubbaka for helpful dis-
cussions. Financial support of this work by the Latvian Council of
Science (Grant No. 09.1222) and European Social Fund within the
National Program ‘Support for the Doctoral Study Program and
Postdoctoral Research’ is gratefully acknowledged.
Scheme 4. Thermal 1,3-dipolar cycloaddition of 7-azido-THIs 3a,b with dimethyl
acetylenedicarboxylate.
Next, we turned our attention to 7-bromo-1-phenyl-4,5,6,7-tet-
rahydroindazol-4-one 3d (Scheme 5). This substrate formed elim-
ination and aromatization products when treated with sodium
azide under standard conditions. As a consequence, we were un-
able to isolate the required azide. However, a one-pot procedure
which involved heating bromide 3d, NaN3, and phenylacetylene
in the presence of the copper-couple according to method A pro-
vided the expected triazole 4m in 86% yield.27
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.009.
The spectroscopic and physical properties (1H NMR and mass
spectra, and/or CHN analysis) of all new compounds were fully
consistent with the assigned structures.28 The chemical shifts of
H–C(7) depend on both the N(1) substituents of the THIs, and
C(4,5) of the triazole. The presence of a methoxycarbonyl group
at the latter position shifts H–C(7) upfield (6.13 ppm relative to
TMS). On the contrary, the presence of the N(1)-pyridyl group re-
sults in a downfield shift (6.70 ppm relative to TMS). On the other
hand, both H–C(5) show a typical AB system with 2J ꢁ 17 Hz.
Our further research is connected with the synthesis and bio-
logical activity evaluation of THI oligomers and conjugates with
natural scaffolds. To this end, we have pursued initial dimerization
experiments of THIs via extended bis-triazole-linkers. Thus, THI-
azide 3a underwent double 1,3-dipolar cycloaddition to provide a
diastereomeric mixture of dimer 5 in 86% yield (Scheme 6).
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Scheme 6. Synthesis of a THI dimer with an extended bis-triazole-linker.

I. Strakova et al. / Tetrahedron Letters 50 (2009) 3046–3049
3049
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