Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro- 2H-indazol-3-yl)-carboxymides

Article abstract of DOI:10.1016/j.tetlet.2013.07.076

5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6, 7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthesized via Michael addition, Mannich reaction of the

Full text of DOI:10.1016/j.tetlet.2013.07.076

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetra-
hydro-2H-indazol-3-yl)-carboxymides
Chigalli N. Revanna b,c, Goravanahalli M. Raghavendra a, Kebbahalli N. Nandeesh a,
Doddamedur G. Bhadregowda b, , Kanchugarakoppal S. Rangappa a, Kempegowda Mantelingu a,
⇑
⇑
a Department of Studies in Chemistry, Manasagangothri, University of Mysore, Mysore 570006, India
b Yuvaraja’s College Mysore, University of Mysore, Mysore 570005, India
c Syngene International Limited, Jigini Link Road, Bangalore 560099, India
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-
c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthe-
sized via Michael addition, Mannich reaction of the difluorinated ethyl bromoacetate with a benzotria-
zole derivative, followed by a Dieckmann condensation. Starting from simple materials, this efficient
route which gives access to novel functionalized N-(5-allyl-7,7-dihalo)-4,5,6,7-tetrahydro-2H-indazol-
3-yl)-carboxymides, was explored and adapted for parallel synthesis, resulting in a compound library.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 13 March 2013
Revised 11 July 2013
Accepted 12 July 2013
Available online xxxx
Keywords:
Indazoles
Carboxymides
Fused pyrazoles
N-Aryl quinolines
Mannich reaction
Dieckmann condensation
Indazole and its derivatives have gained considerable impor-
tance in medicinal chemistry in view of their promising pharmaco-
logical properties.1,2 Several indazoles are found to exhibit
significant levels of activity as HIV protease inhibitors,3,4 serotonin
key hydrogen bonds with the enzyme. Several methods for the
synthesis of indazoles and their derivatives have been reported
in the literature.11–13 Most of them involve the construction of
the pyrazole moiety starting from preconstructed benzene deriva-
tives. On the other hand, methods based on pyrazole precursors,
more easily accessible, are briefly described in the literature.14
The introduction of fluorine atoms into organic molecules has pro-
ven to be a valuable tool for changing the physical and chemical
properties of the compound without major steric implications.15,16
In that respect, there is a growing demand for synthetic methods
5-HT1 , 5-HT25 and 5-HT3 receptor antagonists,6,7 and acetylholin-
a
esterase inhibitors,8 whereas 1-[3-(dimethylamino)-propyl]-
5-methyl-3-phenyl-1H-indazole (FS-32),9a MK-4827,9b and
compound 3 have been shown to be potent antidepressant drug
candidates and PARP-1 inhibitors.9c
Fipronil is a wide spectrum insecticide (Fig. 1).
Fused pyrazoles or tetrahydroindazoles have been reported to
inhibit protoporphyrinogen oxidase (PPO), an enzyme which cata-
lyzes the oxidation of protoporphyrinogen to protoporphyrin and
is the site of action of membrane disrupting herbicides.10 With
the aim of finding a new class of potent PARP-1 inhibitors, we de-
signed tetrahydroindazoles. The structure was designed bearing a
functionalizable site to allow the introduction of various substitu-
ents. We were particularly interested in 5-allyl-7,7-difluoro tetra-
hydroindazole derivatives. Early PARP-1 inhibitors were analogs
of 3-aminobenzamide. It was observed that amide functionality
was crucial for specific binding to the enzymatic site, forming three
O
NH2
O
NH2
F
N
N
N
N
F
NH
F
MK- 4827
3
CF3
NH2Cl
N
S
O
CF3
N
NC
⇑
Corresponding authors. Tel.: +91 821 2412191/2419661; fax: +91 821 2412191.
E-mail addresses: bhadre_chem@rediffmail.com (D.G. Bhadregowda), kmante-
Cl
Fipronil
lingu@yahoo.com (K. Mantelingu).
Figure 1. Bioactive indazoles (PARP inhibtors and insectiside).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.076
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2
C. N. Revanna et al. / Tetrahedron Letters xxx (2013) xxx–xxx
for the preparation of selectively fluorinated heterocyclic com-
pounds used in pharmaceutical and agrochemical industries.17
Consequently, fluorinated pyrazoles are of specific interest because
the introduction of a fluorine atom can drastically affect the biolog-
ical properties of this class of heterocyclic compounds.18,19 In con-
tinuation of our work on the development of bioactive synthetic
molecules20,21 and synthetic methodology,22–25 we were interested
in synthesizing tetrahydroindazoles which are analogs of MK-4827
and compound 3, both PARP-1 inhibitors. We now report an effi-
cient synthesis of N-(5-allyl-7,7-difluoro-2-(2,4-difluorophenyl)
tetrahydroindazole analogs involving, the Mannich reaction, Die-
ckmann cyclization, followed by cyclocondensation of (2-fluoro-
4-halogeno-phenyl)-hydrazine with the cyanoketone intermediate
(Scheme 1).
Our synthetic approach (Scheme 1) begins with the addition
of allylamine to acrylonitrile which gave compound 2. This one
was converted to benzotriazole derivative 5 by reaction with 4-
methoxy benzaldehyde and benzotriazole.26 Compound 7 was
prepared starting from 2-bromo-2,2-difluoroacetate via benzotri-
azole derivative 5 using the Mannich reaction in THF under
nitrogen. The Dieckmann condensation of 7 was optimized in
the presence of various bases (NaH, t-BuO-K, n-BuLi) and sol-
vents. The best yield in cyanoketone 8 was obtained by the
in situ generation of LDA at À78 °C. The reactivity of the ester
carbonyl toward the nucleophiles has increased due to the pres-
ence of the geminal-difluoro group. 5-allyl-3-amino-7,7-difluoro-
2-(2,4-dihalophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-
2H-pyrazolo[4,3-c]pyridine 10 was synthesized by the condensa-
tion of 2,4-diflurophenylhydrazine with cyanoketone 8. Several
syntheses of isomeric 4,5-fused bicyclicpyrazoles or tetrahydro-
indazoles have been reported.27,28 However, to the best of our
knowledge, there is no report for the synthesis of N-(5-allyl-
7,7-difluoro-1-(2,4-difluorophenyl) tetrahydroindazol analogs.
Here,29 we report an efficient, versatile, and convenient synthetic
route, which provides rapid access to 4,5,6,7-tetrahydro-2H-
indazoles.30 The cyclocondensation of hydrazines with the cyclic
b-cyanoketone 10 under neutral conditions generally leads to
N-(5-allyl-difluorophenyl)-4,5,6,7-tetrahydro-2H-indazole ana-
logs. The more reactive ketone and terminal NH2 group of the
arylhydrazine react first, leading to the formation of the corre-
sponding intermediate imine which is then cyclized to afford
compound 10. In order to attain the regioselectivity of these
reactions, we attempted many conditions like the reaction of
binucleophile phenylhydrazine with cyanoketone in the presence
of NaH. This was unsuccessful as we observed the decomposition
product. We also explored a strategy by using Boc protected
phenylhydrazine but we were unsuccessful. The primary amine
of 4,5,6,7-tetrahydraindazole 10 was derivatized to give the cor-
responding
N-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxam-
ides 12(a–k) by treatment of compound 10 with acyl chlorides.
These molecules are being evaluated as selective PARP-1 inhibi-
tors (Table 1).
In conclusion, we have developed an efficient strategy for the
synthesis of 5-allyl-3-amino-7,7-difluoro-2-(2,4-dihalophenyl)-6-
(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
10 as an important scaffold in the synthesis of PARP-1 inhibitors.
Our synthesis is a six-step strategy via 1,4-addition, Mannich reac-
tion, Dieckmann cyclization, and cyclocondensation of 2,4-dihalo-
phenylhydrazine with an intermediate cyanoketone. The method
is based on industrially accessible chemicals.
O
H
H
N
N
N
(i)
CN
+
N
+
CN
2
1
3
H
4
O
CN
N
CN
O
N
(iii)
N
(ii)
N
+
O
O
O
N
BrF2C
O
F
O
6
F
5
7
NH2
N
X
CN
H2N
N
N
NH
(iv)
X
(v)
X
+
N
O
F
F
F
F
O
O
10
8
9
X
X=F, Cl
R
NH
N
X
Y
N
F
X
(vi)
N
R
Cl
F
11 Y = O or S
O
12 (a-k)
Scheme 1. Synthesis of N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides. Reagents and conditions: (i) allyl amine, EtOH, rt; (ii) MeOH, rt; (iii) zinc
dust, trimethylsilyl chloride, THF, rt; (iv) diisopropyl amine, N-butyl lithium, THF; (v) EtOH, reflux; (vi) pyridine, rt.
Please cite this article in press as: Revanna, C. N.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.07.076

C. N. Revanna et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
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H3C
12a
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H
N
12h
Cl
12i
12j
F
F
O
O
12k
F
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Acknowledgements
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The authors are grateful to the University Grants Commission
(UGC) and the Government of India for financial support to KM
the project vides No.F. 39-710/2011 (SR) dated 21-01-2011. C.N.R.
thanks Dr. P. Sathyashankar, and Dr. Subhendu Kumar Mohanty,
Syngene International Pvt. Ltd (Bangalore) for valuable suggestions.
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30. General procedure for the synthesis of 12(a–k). To a solution of 5-allyl-3-amino-
7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-
2H-pyrazolo[4,3-c]pyridine 10 (0.2 g, 0.462 mmol) in pyridine (2 mL) at 0 °C
under nitrogen, acid chloride (0.555 mmol) was added. The reaction mixture
was stirred overnight at room temperature, and monitored by TLC. After
completion of the reaction, 10% NaHCO3 solution (4 mL) was added and the
aqueous layer was extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and concentrated. The
crude product was purified by column chromatography on silica gel by using
hexane:ethyl acetate (1:1) as eluent.
Supplementary data
Supplementary data (relevant spectra (1H NMR, 13C NMR spec-
tra) for all compounds and 19F NMR spectra for key intermediates
7, 8, 10a, 10b and 12a–k) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.076.
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Please cite this article in press as: Revanna, C. N.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.07.076