A facile synthesis of 4-aryl-5-alkoxycarbonyl-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-3-hydroxy-2-(pyridin-2-yl)-indazoles and their nmr characterizations

Article abstract of DOI:10.3987/COM-07-11231

A series of N-pyridinyl tetrahydroindazoles have been synthesized by a convenient and regioseletive method by taking cyclic ²-ketoesters as scaffolds. An optimum reaction condition was achieved by monitoring the reaction in different reaction c

Full text of DOI:10.3987/COM-07-11231

HETEROCYCLES, Vol. 75, No. 3, 2008
537
HETEROCYCLES, Vol. 75, No. 3, 2008, pp. 537 - 554. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd September, 2007, Accepted, 12th November, 2007, Published online, 16th November, 2007. COM-07-11231
A FACILE SYNTHESIS OF 4-ARYL-5-ALKOXYCARBONYL-6-HYDROXY-
6-METHYL-4,5,6,7-TETRAHYDRO-3-HYDROXY-2-(PYRIDIN-2-YL)-
INDAZOLES AND THEIR NMR CHARACTERIZATIONS
Shanmugasundaram Amirthaganesan, Gopalakrishnan Aridoss,
Young Hwan Park, Jong Su Kim, Se Mo Son, and Yeon Tae Jeong∗
Division of Image and Information Engineering, Pukyong National University, Busan
608-739, Korea
Abstract - A series of N-pyridinyl tetrahydroindazoles have been synthesized by
a convenient and regioseletive method by taking cyclic β-ketoesters as scaffolds.
An optimum reaction condition was achieved by monitoring the reaction in
different reaction condition. One and two dimensional NMR spectroscopic
investigations evidenced the formation and structure of the compounds. Besides,
all the compounds have been achieved as a single isomer with pyridyl group at
N(2). A suitable reaction mechanism was proposed.
INTRODUCTION
Tetrahydroindazoles are cycloalkane derivatives of pyrazoles. Pyrazoles are well known skeleton having
much importance in the field of medicinal chemistry owing to their remarkable biological potencies.1−4
Moreover, substituted pyrazoles and pyrazole derivatives such as benzindazoles5 (aromatic derivatives of
pyrazoles), tetrahydroindazoles along with several substituents are also well known for their unique
pharmacological properties.6−8 Several reports have been proved that pyrazoles are being in annular
tautomerism9 and unsymmetrical pyrazoles and indazoles are showing regioisomerism with respect to N-
substitution like N-arylation10 and N-alkylation11 which are inevitably yielded a mixture of N(1) and N(2)
regioisomers with poor selectivities during substitutions. Numerous methods have been developed to
achieve a regioselective synthesis of N-substituted pyrazole derivatives and to crossover the harsh
reactionconditions.
∗ Corresponding author: Tel.: +8251 6201694; e-mail: ytjeong@pknu.ac.kr (Yeon Tae Jeong)

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HETEROCYCLES, Vol. 75, No. 3, 2008
Chemistry
Generally pyrazole ring have been synthesized by the reaction of β-dicarbonyl compounds with
hydrazine.1,12,13 Tetrahydroindazoles are usually prepared from cyclohexanone and its derivatives.14−18
Instead of cyclohexanones, 1,3-cylohexanedione and its derivatives were used to afford
tetrahydroindazole-4-ones.19-21 The reaction of Baylis-Hillman adduct and phenylhydrazine results in
diphenylpyrazole22 formation via the successive hydrazone formation, acid catalyzed cyclization, and
subsequent 1,3-hydrogen transfer. Heterogeneous catalysts have also been used for the synthesis of both
pyrazoles and tetrahydroindazoles derivatives (1,2-disubstituted cycloalkanopyrazole), starting from
hydrazine and 1,3-diketone.14b,23,24 Even though there are several methods, there is still a lack of general
and efficient methodologies for the regioselective synthesis of N-substituted tetrahydroindazoles with
various substituents in saturated ring.
Here, we described a convenient synthetic technique for the synthesis of 4-aryl-5-alkoxycarbonyl-6-
hydroxy- 6-methyl-4,5,6,7-tetrahydro-3-hydroxy-2(pyridin-2-yl)indazoles as a single isomer. We proved
that alicyclic keto esters are being suitable scaffolds for the regioselective synthesis of N-substituted
indazoles and the preferable reaction condition has been found. The formation of the series of title
compounds and their structural elucidations have been carried out by using NMR tool. 2,4-
Bis(alkoxycarbonyl)-3-aryl-5-hydroxy-5-methylcyclohexanoes25 have been used as a scaffolds and
2-hydrazinopyridine was used as hydrazine derivative, for its efficient reactivity and also in lieu of the
biological properties of the pyridyl moiety.
O
RO C
CO R
MeCOCH
2
2
2
MeNH2
Ar-CHO
OH
Me
Me
CO R
2
COCH
EtOH / heat
2
Ar
CO R
2
13 - 24
tolune / reflux
N
H+
HN
N
NH
2
N
N
2
1
N
N
N
3
O
8
HO
9
7
6
OH
Me
OH
Me
4
5
Ar
Ar
CO R
2
CO R
2
1 - 12
1 - 12
Scheme 1. Synthesis of compounds 1-12

HETEROCYCLES, Vol. 75, No. 3, 2008
539
Entry
R
Ar
Ph
1
2
13
14
15
16
17
18
19
20
21
22
23
24
Me
Me
Me
Me
Me
Me
Me
Et
4-Cl-Ph
3
3-Cl-Ph
4
4-MeO-Ph
3,5-(MeO)2-Ph
3-NO2-Ph
3-PhOPh-Ph
Ph
5
6
7
8
9
Et
4-MeO-Ph
3-Cl-Ph
10
11
12
Et
Et
4-Cl-Ph
Et
4-NO2-Ph
RESULTS AND DISCUSSION
A series of N-pyridinyl tetrahydroindazoles were synthesized by the reaction of corresponding cyclic
ketoesters with 2-hydrazinopyridine as shown in the Scheme 1. It was helped us that the synthesis of
1H-indazoles from the reaction of cyclic ketoesters with the dinucleophile hydrazine, to find the optimum
reaction conditions and also for the structural elucidations of N-pyridylindazoles. The
1H-tetrahydroindazoles (25) synthesis has been carried out in EtOH medium by refluxing at 70-80 ˚C for
about two hours with good yield (75%). It was observed that there is no appreciable improvement in yield
by the addition of acid catalyst (acetic acid) or weak base (sodium acetate) and also by changing the
solvents. The resultant product was characterized by one and two dimensional NMR spectral results and
found as 5-methoxycarbonyl-6-hydroxy-6-methyl-4-phenyl-4,5,6,7-tetrahydro-3-hydroxy-1H-indazole
(25) as a single isomer.26
2
1
N
NH
3
8
5
HO
9
7
6
OH
Me
4
CO Me
2
25

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HETEROCYCLES, Vol. 75, No. 3, 2008
Table 1. Spectral assignments of 1H-indazole (25) recorded in DMSO-d6
Carbon chemical
shifts, δ (ppm)
Proton resonances,*
δ (ppm) and HSQC Correlations
HMBC Correlations
157.9, C-3
38.7, C-4
no correlations
4.06, H-4a
4.27, H-4a
7.25 (ph-ortho 2H), 2.73 (H-5a)
4.27 (H-4a), 2.98 (H-7e), 1.38 (Me
at C-6)
59.9, C-5
2.57, H-5a
2.76 (H-7a), 2.98 (H-7e),
1.38 (Me at C-6)
69.9, C-6
36.5, C-7
138.8, C-8
no correlations
2.52, H-7a; 2.77, H-7e
no correlations
2.73 (H-5a), 1.38 ( Me at C-6)
2.76 (H-7a), 2.98 (H-7e),
4.27 (H-4a), 1.38 ( Me at C-6)
4.27 (H-4a), 2.76 (H-7a),
2.98 (H-7e)
99.2, C-9
no correlations
28.4, Me at C-6
1.21 (Me at C-6)
2.76 (H-7a), 2.98 (H-7e)
2.73 (H-5a) weak
50.8, Me of CO2 Me
3.43 (Me of CO2Me)
172.0, C=O of
CO2Me
2.73 (H-5a), 4.27 (H-4a), 3.51 ( Me
of CO2 Me ), 2.98 (H-7e)
no correlations
7.07-7.21
126.0, 127.7, 128.0,
143.0 - phenyl ipso
4.27 (H-4a), 2.73 (H-5a)
no correlations for ipso carbon
* δ OH at C-6 (4.48 ppm), OH at C-3 (11.0 ppm) and N-H at 1 (9.0 ppm)
To find the optimum reaction condition, N-pyridyl tetrahydroindazoles synthesis was performed in
different solvents with and without the addition of acid or base catalyst (Table 1). The reaction was not
progressed in EtOH medium more than 5% and there was no improvement by the addition of acid or
base catalysts and also when allowed in prolonged heating. Also, very poor yield observed in methanol
medium suggested that the alcoholic medium is not a desirable solvent even for the hydrazone formation
from the condensation of hydrazinopyridine with cyclic ketoesters. When the reaction was carried out in
benzene or toluene, a substantial improvement in the yield was noted. Moreover, the addition of catalytic
amount of glacial acetic acid in toluene medium was found to be advantageous in enhancing the yield and
reducing the reaction time. Addition of excess acetic acid or HCl leads to the dehydration of OH at C-6. A
preliminary monitoring through TLC and GC/MS supports the formation of the product as a single isomer.

HETEROCYCLES, Vol. 75, No. 3, 2008
541
All the products were purified by the straight forward recrystalization in EtOH after evaporating the
solvent by vacuum distillation.
Table 2. Different reaction conditions and the results (for compounds 1 and 7)
toluene/s
EtOH
/AcOH
70-80 ˚C
30 h
MeOH/A benzene/
cOH AcOH
80-85 ˚C 75-80 ˚C
toluene/
AcOH
85-90 ˚C
6-8 h
EtOH
70-80 ˚C,
30 h
toluene
85-90 ˚C
24 h
odium
acetate
85-90 ˚C
24 h
Reaction
conditions
30 h
24 h
Yield
< 5%
< 5%
9-11%
35-40%
50-55%
ca. 55%
> 65%
The reaction mechanism was proposed with the support of literature and in connection with the
maintained reaction conditions. It is obvious that the direct condensation of pyridinyl hydrazine with the
keto functionality through its NH2 group is kinetically more favorable, subsequently the ester group
carbonyl should prefer bond formation with secondary amine nature like NH. The improvement in the
yield and lessen in reaction time duration after the addition of catalytic amount of acetic acid may be due
to the faster reaction rate of the NH2 condensation with keto group initially, after, followed by the
dehydration, cycloaddition through NH with ester group and hydrogen transfer yielded the
N-pyridinyltetrahydro indazole with the pyridinyl moiety positioned at N-2 (Scheme 2).
N
NH2
O
N
H
OH
NH
CO2R
NH
CO2R
N
OH
Me
tolune / reflux
H+
Ar
OH
Me
CO2R
Ar
CO2R
N
N
H
N
N
N
N
R
H
O
O
O
OR
OH
Me
OH
Me
Ar
Ar
CO2R
CO2R
N
N
O
N
N
N
N
HO
OH
Me
OH
Me
H
Ar
Ar
CO2R
CO2R
Scheme 2. Plausible mechanism for the formation of products 1-12

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HETEROCYCLES, Vol. 75, No. 3, 2008
For all the compounds, 1H and 13C NMR spectra were recorded. For compound 1 HSQC,
HMBC, NOESY and for compound 8 HMBC spectra were also recorded. Mass spectrum was recorded
for compounds 1, 8, and 10.
Mass spectral analysis ensured the proposed molecular formulae with the observation of corresponding
molecular ion peaks at m/e 379, 393 and 423 respectively for the compounds 1, 8 and 10.
Structural elucidation through NMR
1H NMR results evidenced the formation of regioselective isomer. Proton resonances were investigated
through its chemical shift, multiplicity and coupling constants values. All the compounds recorded in
CDCl3 showed almost similar resonances for all the protons except the aromatic protons and ester group
protons with respect to the substituents, and the compound (6) recorded in DMSO-d6 having appreciable
difference in the chemical shift of OH at C-6 due to solvent effect. The pyridinyl protons resonances
observed in the aromatic region and the absence of one ester group signals observed in parent ketoesters
supports the cyclization. The calculated coupling constants from the four doublets observed in the
aliphatic region facilitated the assignments. A convenient assignment was made for the methylene and
methine protons on the basis of their coupling constants and position. Two doublets were observed in the
range of 2.74-2.77 ppm and 2.96-2.99 ppm with the coupling constants (J) of around 16Hz and another
two doublets in the range of 4.21-4.27 ppm and 2.66-2.73 ppm with the coupling constant of around 12Hz
showed closer proximity to the corresponding geminal and vicinal coupling constants of cyclohexane ring,
were conveniently assigned for methylene protons at C-7 and methine protons at C-4 and C-5 respectively.
Among the two methine protons, H-4a was assigned from its downfield resonance due to the deshielding
aroused from the fused ring formation at C-8 and C-9. Carbon resonances showed pyridyl carbons along
with the saturated ring carbons, aromatic carbons and ester carbons. The individual assignments of
carbons and protons, position of pyridinyl moiety and the stereochemistry of indazole have been
succeeded by NOESY, HSQC and HMBC spectrum.
From the HSQC (Figure 1) spectral results of compound 1 we have found that there are seven quaternary
carbons for the anticipated structure. The individual assignments of methyl, methylene and methine
carbons and their associated protons were carried out from their corresponding cross peaks observed at
1.38/28.7 ppm (Me at C-6), 3.51/51.5 ppm (Me of CO2Me), 2.76, 2.98/37.1 ppm (CH2 of C-7), 4.27/39.8
ppm (CH of C-4) and 2.73/59.0 ppm (CH of C-5). Pyridinyl protons and their respective carbons also
predicted from their corresponding cross peaks 8.09/144.8 ppm, 7.83/111.7 ppm, 139.7 ppm and
7.07/119.5 ppm. Likewise, aromatic protons were also assigned (Table 3).

HETEROCYCLES, Vol. 75, No. 3, 2008
543
Figure 1. HSQC spectrum of compound 1
Figure 2. HMBC spectrum of compound 1

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HETEROCYCLES, Vol. 75, No. 3, 2008
Figure 3. NOESY spectrum of compound 1
The HMBC (Figure 2) correlations observed for compound 1 furnished the quaternary carbons
assignments and also supports for the elucidation of structure. The individual assignment of three closer
carbon resonances achieved from their corresponding multiple bond correlations marked as δ 152.4 /H-4a,
δ 150.0/H-7a, H-7e, H-4a, Me at C-6 and δ 154.3/pyridinyl protons for C-3, C-8/C=N and ″C-1 (pyridinyl
ipso carbon) respectively. Remaining correlations supported for the individual assignments are tabulated
(Table-2). The HMBC correlations observed for compound 8 are given in Table 4.
The absence of OH (C-3) signal in 1H NMR recorded in CDCl3 is due to proton exchange with solvent, is
confirmed by recording compound (1) in DMSO-d6 in which the OH signal is observed at 11.7 ppm as a
broad singlet. The downfield shift observed for pyridinyl protons in DMSO-d6 was due to the strong
interaction between sulphoxide and nitrogen.
Although all the assignments of N-pyridinylindazoles were carried out from the observed NMR results, it
was further confirmed by comparing the one and two dimensional results observed for compound 1 with
1H-indazole 25 (Table-2). Apart from the solvent effect there was no appreciable difference found in the
proton resonances. But carbon resonances of C-3 and C-8 showed a significant difference. The upfield
shift of C-3 for about 5.5 ppm and the downfield shift of C-8 for about 11.2 ppm in N-pyridinylindazole
cleared the structure of the fused pyrazole ring with pyridinyl group positioned at N-2.

HETEROCYCLES, Vol. 75, No. 3, 2008
545
Table 3. HSQC and HMBC Correlations of compound 1
Carbon chemical shifts
152.4, C-3
HSQC Correlations
no Correlations
4.27, H-4a
HMBC Correlations
4.27, H-4a
39.8, C-4
7.25 (ph-ortho 2H), 2.73 (H-5a)
4.27 (H-4a), 2.98 (H-7e),
1.38 (Me at C-6)
59.0, C-5
2.73, H-5a
2.76 (H-7a), 2.98 (H-7e),
1.38 (Me at C-6)
70.9, C-6
37.1, C-7
no Correlations
2.76, H-7a ; 2.98, H-7e
2.73 (H-5a), 1.38 (Me at C-6)
2.76 (H-7a), 2.98 (H-7e), 4.27 (H-4a), 1.38
(Me at C-6)
150.0, C-8
no correlations
97.4, C-9
no correlations
1.38 (Me at C-6)
4.27 (H-4a), 2.76 (H-7a), 2.98 (H-7e)
2.76 (H-7a), 2.98 (H-7e)
2.73 (H-5a) weak
28.7, Me at C-6
51.5, Me of CO2Me
3.51 (Me of CO2Me)
2.73 (H-5a), 4.27 (H-4a), 3.51 (Me of
CO2Me), 2.98 (H-7e)
175.4, C=O of CO2Me
no correlations
140.8, phenyl ipso
no correlations
no correlations
4.27 (H-4a), 2.73 (H-5a)
154.3, pyridinyl ipso
8.09, 7.83, 7.07 (pyridinyl protons)

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HETEROCYCLES, Vol. 75, No. 3, 2008
Table 4. HMBC Correlations of compound 7
Carbon chemical shifts, δ (ppm)
152.5, C-3
HMBC Correlations, δ (ppm)
4.26, H-4a
40.0, C-4
7.25 (ph-ortho 2H), 2.71 (H-5a),
58.8, C-5
70.9, C-6
37.2, C-7
4.26 (H-4a), 2.98 (H-7e), 1.40 (Me at C-6)
2.76 (H-7a), 2.98 (H-7e), 1.40 (Me at C-6)
2.71 (H-5a), 1.40 (Me at C-6)
2.76 (H-7a), 2.98 (H-7e), 4.26 (H-4a),
1.40 (Me at C-6)
150.1, C-8
97.5, C-9
4.26 (H-4a), 2.76 (H-7a), 2.98 (H-7e), 2.71 (H-5a)
28.7 (Me at C-6)
13.8 (Me of CO2Et)
60.6 (CH2 of CO2Et)
2.76 (H-7a), 2.98 (H-7e)
4.0 (CH2 of CO2Et)
0.97 (Me of CO2Et)
2.71 (H-5a), 4.26 (H-4a),
175.0, C=O of CO2Et
4.0 (CH2 of CO2Et), 2.98 (H-7e)
140.8, phenyl ipso
4.26 (H-4a), 2.71 (H-5a) - aromatic protons
8.09, 7.83, 7.06 (pyridinyl protons)
154.4, pyridinyl ipso
Stereochemistry of the products suggested from their calculated coupling constants of protons, and NOEs
(Figure 3) observed. Coupling constants of methylene protons at C-7 and methine protons H-4a and H-5a
are almost closer to the parent cyclic ketoesters suggested that the cycloalkane ring should be in chair
conformation (Figure 4). None of the NOEs observed for the pyridinyl protons with the saturated ring
protons, especially with H-7a and H-7e (Figure 5) proved that the pyridinyl ring should be positioned in
N(2).

HETEROCYCLES, Vol. 75, No. 3, 2008
547
N
N
2
N
H
N
1
HO
3
N2
1
N
OH
4
H
HO
8
3
Ph
OH
4
8
9
Ph
expected NOE
H 7e
6
MeO C
9
5
2
6
MeO C
Me
7
5
2
H
Me
7
H7a
H
CONCLUSION
A convenient and regioselective synthetic route to afford the N(2)-pyridyltetrahydroindazoles as a single
isomer from cyclic β-ketoesters was described. The reaction was consistent while using toluene as solvent
with the addition of catalytic amount of acetic acid by refluxing at 80-90 ˚C to get a series of products.
NMR analysis supports the pyridyl group at N(2) and C-3 having OH. The stereochemistry was found as
normal chair conformation.
EXPERIMENTAL
Melting points were measured in Electrothermal-9100 (Japan) instrument and were uncorrected. NMR
was recorded in CDCl3 (except 6 in DMSO-d6) with Me4Si as internal standard in JEOL (Japan) JNM
1
13
ECP-400 instrument operating at 400 MHz for H and 100.6 MHz for C. Mass spectrum was recorded
in JEOL, JMS-700.
General procedure for synthesis of 2,4-bis(alkoxycarbonyl)-3-aryl-5-hydroxy-5-methylcyclohexanoes
(13-24)
A mixture of acetoacetic esters (10 mmol), aromatic aldehydes (5 mmol) and methylamine (5 mmol) was
heated to boiling. The reaction mixture was kept for overnight. The separated solid was filtered and
recrystalized from EtOH.25
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-phenyl-4,5,6,7-tetrahydro-3-hydroxy-1H-
indazole(25)
A mixture of respective ketoester 13 (1 mmol) and hydrazine hydrate (1.3 mmol) in EtOH was refluxed for
2 h, and it was poured in ice. The separated solid was filtered and recrystalized from EtOH.

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HETEROCYCLES, Vol. 75, No. 3, 2008
General procedure for synthesis 4-aryl-5-alkoxycarbonyl-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazoles (1-12)
A mixture of cyclic keto ester (1 mmol) and 2-hydrazinopyridine(1.2 mmol) in dry toluene with the
addition of catalytic amount of acetic acid were refluxed for about 6-8 h under nitrogen atmosphere.
Duration of the reaction period varied for every reaction, and it was monitored by TLC. After completion
of the reaction, the solvent was evaporated under vacuum and the resultant residue was recrystalized from
EtOH.
Synthesis of t(5)-methoxycarbonyl-t(6)-hydroxy-c(6)-methyl-r(4)-phenyl-4,5,6,7-tetrahydro-3-
hydroxy-2-(pyridin-2-yl)indazole (1): This compound was obtained as white crystals (284 mg, 75%)
1
with mp 157-158 ˚C. EI-MS (70 eV): m/e = 379 (M+), 302 (bp), 262, 78. H NMR (400 MHz, CDCl3):
δ = 7.23-7.33 (m, 5H, ArH), 4.27 (d, 3J = 11.0 Hz, 1H, H-4a), 2.73 (d, 3J = 11.0 Hz, 1H, H-5a), 2.76 (d,
2J = 16.84 Hz, 1H, H-7a), 2.98 (d, 2J = 16.88 Hz, 1H, H-7e), 1.38 (s, 3H, Me at C-6), 3.36 (bs, 1H, OH at
C-6), 3.51 (s, 3H, Me of CO2Me), 8.09 (d, 1H, PyH), 7.83 (m, 2H, PyH), 7.07 (t, 1H, PyH) ppm.
13C NMR(100.6 MHz, CDCl3):δ = 152.4 (C-3), 39.8 (C-4), 59.0 (C-5), 70.9 (C-6), 37.1 (C-7), 150.0
(C-8), 97.4 (C-9), 28.7 (Me at C-6), 51.5 (Me of CO2Me), 175.4 (C=O), 140.8 (ipso Ph-C), 127.0, 127.8,
128.3 (Phenyl), 154.3 (ipso Py-C), 111.7, 139.7, 119.5, 144.8 (Pyridyl) ppm. Anal. Calcd for C21H21N3O4
(379.41): C 66.48, H 5.58, N 11.08. Found: C 66.51, H 5.57, N 11.06.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(pyridinyl)indazole (2): This compound was obtained as white solid (289 mg, 70%) with mp
143-145 ˚C. 1H NMR (400 MHz, CDCl3): δ = 7.25-7.29 (m, 5H, ArH), 4.26 (d, 3J = 11.36 Hz, 1H, H-4a),
3
2
2
2.68 (d, J = 11.0 Hz, 1H, H-5a), 2.76 (d, J = 16.84 Hz, 1H, H-7a), 2.98 (d, J = 16.84 Hz, 1H, H-7e),
1.38 (s, 3H, Me at C-6), 3.17 (bs, 1H, OH at C-6), 3.55 (s, 3H, Me of CO2Me), 8.12 (d, 1H, PyH), 7.84
13
(m, 2H, PyH), 7.09 (t, 1H, PyH) ppm. C NMR (100 MHz, CDCl3): δ = 152.5 (C-3), 39.2 (C-4), 58.9
(C-5), 71.0 (C-6), 37.1 (C-7), 149.9 (C-8), 96.9 (C-9), 28.7 (Me at C-6), 51.7 (Me of CO2Me),175.2
(C=O), 139.5 (ipso Ph-C), 128.6, 129.2, 132.6 (Phenyl), 154.3 (ipso Py-C), 111.7, 139.8, 119.6, 144.9
(Pyridyl). Anal. Calcd for C21H20ClN3O4 (413.85): C 60.95, H 4.87, N 10.15. Found: C 60.98, H 4.86,
N 10.14.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(m-chlorophenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (3): This compound was obtained as grayish white powder (297 mg,
72%) with mp 194-196 ˚C. 1H NMR (400 MHz, CDCl3): δ = 7.13-7.15, 7.23-7.26 (m, 5H, ArH), 4.25 (d,
3J = 11.36 Hz, 1H, H-4a), 2.69 (d, 3J = 11.36 Hz, 1H, H-5a), 2.75 (d, 2J = 16.84 Hz, 1H, H-7a), 2.98 (d,
2J = 16.84 Hz, 1H, H-7e), 1.38 (s, 3H, Me at C-6), 3.35 (bs, 1H, OH at C-6), 3.55 (s, 3H, Me of CO2Me),

HETEROCYCLES, Vol. 75, No. 3, 2008
549
8.11 (d, 1H, PyH), 7.84 (m, 2H, PyH), 7.08 (t, 1H, PyH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 152.5
(C-3), 39.6 (C-4), 58.8 (C-5), 70.9 (C-6), 37.1 (C-7), 149.8 (C-8), 96.6 (C-9), 28.6 (Me at C-6), 51.6 (Me
of CO2Me), 175.1 (C=O), 143.1 (ipso Ph-C), 134.1, 129.5, 127.9, 127.2, 126.1 (Phenyl), 154.3 (ipso
Py-C), 111.7, 139.8, 119.6, 144.9 (Pyridyl). Anal. Calcd for C21H20ClN3O4 (413.85): C 60.95, H 4.87,
N 10.15. Found: C 6.98, H 4.89, N 10.14.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(p-methoxyphenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (4): This compound was obtained as white needles (306 mg, 75%)
1
with mp 191-192 ˚C. H NMR (400 MHz, CDCl3): δ = 7.05-7.09, 7.79-7.85 (m, 5H, ArH), 4.23 (d,
3J = 11.36 Hz, 1H, H-4a), 2.70 (d, 3J = 11.36 Hz, 1H, H-5a), 2.75 (d, 2J = 16.88 Hz, 1H, H-7a), 2.97 (d,
2J = 16.84 Hz, 1H, H-7e), 1.38 (s, 3H, Me at C-6), 3.34 (bs, 1H, OH at C-6), 3.54 (s, 3H, Me of CO2Me),
8.11 (d, 1H, PyH), 7.83 (m, 2H, PyH), 7.07 (t, 1H, PyH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 152.4
(C-3), 39.0 (C-4), 59.2 (C-5), 70.9 (C-6), 37.2 (C-7), 150.1 (C-8), 97.6 (C-9), 28.7 (Me at C-6), 51.6 (Me
of CO2Me), 175.5 (C=O), 132.9 (ipso Ph-C), 128.7, 113.7, 158.4 (Phenyl), 55.0 (Ph-OMe), 154.4 (ipso
Py-C), 111.7, 139.7, 119.4, 144.8 (Pyridyl). Anal. Calcd for C22H23N3O5 (409.44): C 64.54, H 5.66,
N 10.26. Found: C 64.51, H 5.68, N 10.28.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(2,4-methoxyphenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (5): This compound was obtained as white needles (351 mg, 80%)
1
3
with mp 181-183 ˚C. H NMR (400 MHz, CDCl3): δ = 6.36-6.40 (m, 3H, ArH), 4.21 (d, J = 11.32 Hz,
1H, H-4a), 2.72 (d, 3J = 10.96 Hz, 1H, H-5a), 2.75 (d, 2J = 15.04 Hz, 1H, H-7a), 2.97 (d, 2J = 16.84 Hz,
1H, H-7e), 1.37 (s, 3H, Me at C-6), 3.35 (bs, 1H, OH at C-6), 3.57 (s, 3H, Me of CO2Me), 8.12 (d, 1H,
13
PyH), 7.84 (m, 2H, PyH), 7.08 (t, 1H, PyH) ppm. C NMR (100.6 MHz, CDCl3): δ = 152.5 (C-3), 40.0
(C-4), 58.9 (C-5), 71.0 (C-6), 37.1 (C-7), 150.0 (C-8), 97.0 (C-9), 28.7 (Me at C-6), 51.6 (Me of CO2Me),
175.4 (C=O), 98.8, 105.8, 143.5, 160.6 (Phenyl), 55.1 (2,4-MeO -Ph), 154.3 (ipso Py-C), 111.7, 139.7,
119.5, 144.9 (Pyridyl). Anal. Calcd for C23H25N3O6 (439.46): C 62.86, H 5.73, N 9.56. Found: C 62.89,
H 5.75, N 9.57.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(m-nitrophenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (6): This compound was obtained as yellow crystals (288 mg, 68%)
1
with mp 223-226 ˚C. H NMR (400 MHz, DMSO-d6): δ = 7.56, 7.66, 8.0, 8.08 (m, 5H, ArH), 4.22 (d,
3
2
3J = 9.88 Hz, 1H, H-4a), 2.85 (d, J = 10.6 Hz, 1H, H-5a), 2.63 (d, J = 16.84 Hz, 1H, H-7a), 2.96 (d,
2J = 16.84 Hz, 1H, H-7e), 1.28 (s, 3H, Me at C-6), 4.87 (bs, 1H, OH at C-6), 3.46 (s, 3H, Me of CO2Me),
8.37 (d, 1H, PyH), 8.20 (m, 2H, PyH), 7.17 (t, 1H, PyH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 152.5
(C-3), 39.2 (C-4), 58.4 (C-5), 69.5 (C-6), 39.0 (C-7), 149.0 (C-8), 96.6 (C-9), 28.1 (Me at C-6), 51.1 (Me
of CO2Me), 171.9 (C=O), 147.7, 144.6, 135.4, 129.5, 122.6, 121.5 (Phenyl and ipso Py-C), 111.0, 138.8,

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HETEROCYCLES, Vol. 75, No. 3, 2008
119.8 (Pyridyl). Anal. Calcd for C21H20N4O6 (424.41): C 59.43, H 4.75, N 13.20. Found: C 59.47, H 4.76,
N 13.21.
Synthesis of 5-methoxycarbonyl-6-hydroxy-6-methyl-4-(m-phenoxyphenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (7): This compound was obtained as white needles (339 mg, 72%)
1
with mp 201-203 ˚C. H NMR (400 MHz, CDCl3): δ = 6.91-7.09, 7.24-7.30 (m, 5H, ArH), 4.26 (d,
3J = 11.36 Hz, 1H, H-4a), 2.70 (d, 3J = 11.36 Hz, 1H, H-5a), 2.73 (d, 2J = 16.84 Hz, 1H, H-7a), 2.96 (d,
2J = 16.84 Hz, 1H, H-7e), 1.37 (s, 3H, Me at C-6), 3.32 (bs, 1H, OH at C-6), 3.56 (s, 3H, Me of CO2Me),
13
8.12 (d, 1H, PyH), 7.81 (m, 2H, PyH), 6.91-7.09 (m, 1H, PyH) ppm. C NMR (100.6 MHz, CDCl3):
δ = 152.4 (C-3), 39.6 (C-4), 58.9 (C-5), 70.9 (C-6), 37.1 (C-7), 149.9 (C-8), 97.0 (C-9), 28.6 (Me at C-6),
51.6 (Me of CO2Me), 175.1(C=O), 157.5, 156.7, 143.1, 129.6, 129.4, 123.1, 122.6, 119.0, 118.0, 117.9
(Phenyl), 154.3 (ipso Py-C), 111.7, 139.7, 119.5, 144.8 (Pyridyl). Anal. Calcd for C27H25N3O5 (471.5):
C 68.78, H 5.34, N 8.91. Found: C 68.80, H 5.34, N 8.90.
Synthesis of 5-ethoxycarbonyl-6-hydroxy-6-methyl-4-phenyl-4,5,6,7-tetrahydro-3-hydroxy-2-(2-
pyridinyl)indazole (8): This compound was obtained as white crystals (290 mg, 74%) with mp EI-MS
1
(70 eV): m/e = 393 (M+), 302 (bp), 262, 121, 78. H NMR (400 MHz, CDCl3): δ = 7.25-7.32 (m, 5H,
3
3
2
ArH), 4.26 (d, J = 11.36 Hz, 1H, H-4a), 2.71 (d, J = 11.36 Hz, 1H, H-5a), 2.76 (d, J = 16.84 Hz, 1H,
H-7a), 2.98 (d, 2J = 16.84 Hz, 1H, H-7e), 1.40 (s, 3H, Me at C-6), 3.41 (bs, 1H, OH at C-6), 0.97 (t, 3H,
Me of CO2Et),4.0 (m, 2H, CH2 of CO2Et), 8.09 (d, 1H, PyH), 7.83 (m, 2H, PyH), 7.06 (m, 1H, PyH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 152.5 (C-3), 40.0 (C-4), 58.8 (C-5), 70.9 (C-6), 37.2 (C-7), 150.1
(C-8), 97.5 (C-9), 28.7 (Me at C-6), 13.8 (Me of CO2Et), 60.6 (CH2 of CO2Et), 175.0 (C=O), 140.8 (ipso
Phenyl), 128.3, 128.0, 126.9 (Phenyl-C), 154.4 (ipso Py-C), 111.7, 139.7, 119.4, 144.9 (Pyridyl).
Anal. Calcd for C22H23N3O4 (393.44): C 67.16, H 5.89, N 10.68. Found: C 67.18, H 5.90, N 10.69.
Synthesis of 5-ethoxycarbonyl-6-hydroxy-6-methyl-4-(p-methoxyphenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (9): This compound was obtained as white needles (334 mg, 79%)
1
with mp 173-175 ˚C. EI-MS (70 eV): m/e = 423 (M+), 332 (bp), 292, 262, 166, 121, 78. H NMR (400
3
MHz, CDCl3): δ = 6.84-6.86, 7.16-7.19 (m, 5H, ArH), 4.23 (d, J = 11.36 Hz, 1H, H-4a), 2.68 (d,
2
3J = 11.36 Hz, 1H, H-5a), 2.74 (d, 2J = 16.84 Hz, 1H, H-7a), 2.97 (d, J = 17.20 Hz, 1H, H-7e), 1.39 (s,
3H, Me at C-6), 3.38 (bs, 1H, OH at C-6), 1.02 (t, 3H, Me of CO2Et), 4.03 (m, 2H, CH2 of CO2Et), 3.79
(s, 3H, MeO-Ph) 8.10 (d, 1H, PyH), 7.82 (m, 2H, PyH), 7.06 (m, 1H, PyH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 152.5 (C-3), 39.1 (C-4), 59.1 (C-5), 70.9 (C-6), 37.2 (C-7), 150.1 (C-8), 97.8 (C-9), 28.7 (Me
at C-6), 13.9 (Me of CO2Et), 60.6 (CH2 of CO2Et), 55.1 (MeO-Ph), 175.1 (C=O), 158.4, 132.9, 128.9,
113.7 (Phenyl-C), 154.4 (ipso Py-C), 111.7, 139.7, 119.4, 144.9 (Pyridyl). Anal. Calcd for C23H25N3O5
(423.46): C 65.24, H 5.95, N 9.92. Found: C 65.22, H 5.96, N 9.91.

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551
Synthesis of 5-ethoxycarbonyl-6-hydroxy-6-methyl-4-(m-chlorophenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (10): This compound was obtained as white solid (286 mg, 67%) with
mp 163-166 ˚C. 1H NMR (400 MHz, CDCl3): δ = 7.15-7.17, 7.23-7.26 (m, 5H, ArH), 4.25 (d, 3J = 11.36
Hz, 1H, H-4a), 2.66 (d, 3J = 11.36 Hz, 1H, H-5a), 2.75 (d, 2J = 16.84 Hz, 1H, H-7a), 2.98 (d, 2J = 16.84
Hz, 1H, H-7e), 1.40 (s, 3H, Me at C-6), 3.39 (bs, 1H, OH at C-6), 1.02 (t, 3H, Me of CO2Et), 4.03 (m, 2H,
13
CH2 of CO2Et), 8.11 (d, 1H, PyH), 7.84 (m, 2H, PyH), 7.08 (m, 1H, PyH) ppm. C NMR (100.6 MHz,
CDCl3): δ = 152.5 (C-3), 39.7 (C-4), 58.7 (C-5), 70.9 (C-6), 37.1 (C-7), 149.9 (C-8), 96.8 (C-9), 28.6 (Me
at C-6), 13.9 (Me of CO2Et), 60.7 (CH2 of CO2Et), 174.8 (C=O), 143.1, 134.1, 126.2, 127.1, 128.1
(Phenyl-C), 154.3 (ipso Py-C), 111.7, 139.8, 119.6, 144.9 (Pyridyl). Anal. Calcd for C22H22ClN3O4
(427.88): C 61.75, H 5.18, N 9.82. Found: C 61.78, H 5.20, N 8.83.
Synthesis of 5-ethoxycarbonyl-6-hydroxy-6-methyl-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-
hydroxy-2-(2-pyridinyl)indazole (11): This compound was obtained as white solid (311 mg, 73%) with
mp 187-189 ˚C. 1H NMR (400 MHz, CDCl3): δ = 7.19-7.21, 7.26-7.29 (m, 5H, ArH), 4.25 (d, 3J = 11.36
Hz, 1H, H-4a), 2.66 (d, 3J = 11.36 Hz, 1H, H-5a), 2.75 (d, 2J = 16.88 Hz, 1H, H-7a), 2.99 (d, 2J = 16.84
Hz, 1H, H-7e), 1.40 (s, 3H, Me at C-6), 3.33 (bs, 1H, OH at C-6), 1.02 (t, 3H, Me of CO2Et), 4.03 (m, 2H,
13
CH2 of CO2Et), 8.12 (d, 1H, PyH), 7.83 (m, 2H, PyH), 7.09 (m, 1H, PyH) ppm. C NMR (100.6 MHz,
CDCl3): δ = 152.5 (C-3), 39.4 (C-4), 58.8 (C-5), 71.0 (C-6), 37.1 (C-7), 149.9 (C-8), 97.1 (C-9), 28.7 (Me
at C-6), 13.9 (Me of CO2Et), 60.8 (CH2 of CO2Et), 174.8 (C=O), 139.5, 128.5, 129.4, 132.6 (Phenyl-C),
154.4 (ipso Py-C), 111.7, 139.8, 119.6, 144.9 (Pyridyl). Anal. Calcd for C22H22ClN3O4 (427.88): C 61.75,
H 5.18, N 9.82. Found: C 61.78, H 5.19, N 9.82.
Synthesis of 5-ethoxycarbonyl-6-hydroxy-6-methyl-4-(p-nitrophenyl)-4,5,6,7-tetrahydro-3-hydroxy-
2-(2-pyridinyl)indazole (12): This compound was obtained as yellow crystals (284 mg, 65%) with mp
167-169 ˚C. 1H NMR (400 MHz, CDCl3): δ = 7.42-7.44, 8.16-8.18 (m, 5H, ArH), 4.39 (d, 3J = 11.36 Hz,
1H, H-4a), 2.68 (d, 3J = 11.36 Hz, 1H, H-5a), 2.77 (d, 2J = 16.88 Hz, 1H, H-7a), 2.99 (d, 2J = 16.88 Hz,
1H, H-7e), 1.41 (s, 3H, Me at C-6), 3.32 (bs, 1H, OH at C-6), 1.0 (t, 3H, Me of CO2Et), 4.03 (m, 2H, CH2
of CO2Et), 8.11 (d, 1H, PyH), 7.84 (m, 2H, PyH), 7.1 (m, 1H, PyH) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 152.5 (C-3), 39.7 (C-4), 58.3 (C-5), 71.0 (C-6), 37.1 (C-7), 149.7 (C-8), 96.3 (C-9), 28.6 (Me at C-6),
14.0 (Me of CO2Et), 60.9 (CH2 of CO2Et), 174.3 (C=O), 148.9, 147.0, 129.0, 123.6 (Phenyl-C), 154.2
(ipso Py-C), 111.7, 139.9, 119.7, 144.9 (Pyridyl). Anal. Calcd for C22H22N4O6 (438.43): C 60.27, H 5.06,
N 12.78. Found: C 60.27, H 5.07, N 12.77.

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ACKNOWLEDGEMENT
This research work was supported by the Program for the Training of Graduate students in Regional
Innovation which was conducted by the Ministry of Commerce Industry, Energy of the Korean
Government and the second stage of BK21 program.
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