A convenient synthesis and structural analysis of novel 4,5,6,7-tetrahydro-1H-indazoles

Article abstract of DOI:10.1007/s10593-010-0505-2

A new series of t-4-aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-tetrahydro-1 ^H-indazole-r-5-carboxylic acid isopropyl esters has been synthesized by adopting a conventional method from cyclic β-keto esters. 1^H, 13^C NMR, and IR s

Full text of DOI:10.1007/s10593-010-0505-2

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
A CONVENIENT SYNTHESIS AND STRUCTURAL ANALYSIS
OF NOVEL 4,5,6,7-TETRAHYDRO-1H-INDAZOLES
K. Murugavel1, S. Amirthaganesan2, R. T. Sabapathy Mohan1,3*
A new series of t-4-aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-tetrahydro-1H-indazole-r-5-carboxylic acid
isopropyl esters has been synthesized by adopting a conventional method from cyclic -keto esters. 1H,
13C NMR, and IR spectra for all the compounds were investigated. HMBC, HSQC, COSY, and NOESY
spectra of the representative compounds were studied. The stereochemistry of a six-membered ring of
the fused indazoles resembled that of keto esters. From the HMBC correlations the indazole structure
was confirmed as 1H-indazole.
Keywords: cyclic -keto esters, 1H-indazole, tetrahydroindazole, HMBC, NOESY spectra.
The universal requirements on heterocyclic compounds for their potential activities against
microorganisms and significance in the pharmaceutical field prompted us to synthesize indazoles from cyclic
keto esters. Several pathways have been described for the synthesis of indazoles [1–5].
Recently we reported the synthesis and structural studies of r-2,c-4-bis(alkoxycarbonyl)-t-3-aryl-
c-5-hydroxy-t-5-methylcyclohexanone by the condensation of acetoacetic esters with different aromatic aldehydes
in the presence of methylamine [6–8]. The conformation of the two isopropyl groups of compound 1 was also
studied with the help of X-ray crystallography of t-2-aryl-c-4-hydroxy-4-methyl-6-oxocyclohexane-r-1,c-3-di-
carboxylic acid diisopropyl ester [9]. The present paper describes the use of the above compounds [8] assynthons
for the preparation of 4,5,6,7-tetrahydro-1H-indazole. The synthesis of 4,5-trans-2-alkyl-4-hetaryl-5-ethoxy-
carbonyl(acetyl)-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-2H-indazole has been reported [10]. Nevertheless, the
published NMR spectral data apliesmoreto1H-indazolethan to 2H-indazole. N(2)-Substituted tetrahydro-
indazoles have been reported in [11].
Synthesis of 4,5,6,7-1H-indazoles involves two steps. The first step, condensation of isopropyl acetoacetate
with aromatic aldehydes in the presence of methylamine in ethanol, yielded cyclic -keto esters 1–7. They were
treated with hydrazine hydrate in ethanol under reflux to give compounds 8–14 (Scheme). The mechanism of
this second step was different from the expected one. Dehydration was faster than cyclization, and the cyclic
intermediates formed in the reaction course were unstable and easily underwent amido-imidol tautomerism,
yielding stable 1H-indazoles.
_______
* To whom correspondence should be addressed, e-mail: rteeyes@yahoo.com.
1Department of Chemistry, Annamalai University, Annamalainagar 608 002, India.
2Division of Image and Information Engineering, Pukyong National University, Busan, South Korea 608 739.
3Manonmaniyam Sundaranar University, Tirunelveli, Tamil Nadu, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 386-391, March, 2010. Original
article received June 27, 2009.
302
0009-3122/10/4603-0302©2010 Springer Science+Business Media, Inc.

The structure of the compounds was elucidated by IR, mass, and one- and two-dimensional NMR
spectra. Physical and analytical data of the synthesized compounds are given in Table 1.
O
HN
N
CO2Pr-i
MeNH2
EtOH
OH
Ar
2MeCOCH2CO2Pr-i
+
ArCHO
NH2NH2·H2O
HO
Me
HO
Me
Ar
CO2Pr-i
1–7
i
CO2Pr-
8–14
1, 8 Ar = Ph;2, 9 Ar = p-FC6H4;3, 10 Ar = p-MeOC6H4; 4, 11 Ar = p-Me2NC6H4;
5, 12 Ar = p-ClC6H4;6, 13 Ar = m-O2NC6H4; 7, 14 Ar = m-PhOC6H4
The structure of the indazoles prepared could be t-4-aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-tetrahydro-
1H-indazole-r-5-carboxylic acid isopropyl ester or the respective 2H-indazole derivative.
2
H 1
2
1
N
N
H
N
N
8
9
8
7
3
9
HO
7
3
OH
Me
HO
OH
Me
6
4
Ar
5
6
4
Ar
5
CO Pr-
i
2
i
CO2Pr-
1H-indazole
2H-indazole
In the HMBC spectrum the cross peak (38.7/7.07–7.02 ppm) reveals that the aromatic protons show
13
multiple bond correlations with the cyclohexanone ring carbon at 38.7 ppm. Hence, the C resonance at 38.7
ppm has been assigned to C-4. In the HSQC spectrum the one-bond correlation (38.7/4.06 ppm) between C-4
and H-4a confirms that the doublet at 4.06 ppm is due to H-4a. Hence, another doublet with a diaxial coupling
constant around 10 Hz to 2.57 ppm is conveniently assigned to H-5a. Once H-5a is assigned, from the HSQC
spectrum (59.9/2.57 ppm) the 13C resonance at 59.9 ppm is confirmed to be due to C-5. Among the two doublets
TABLE 1. Physical and Analytical Characteristics of Compounds 8-14
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
m/z [M+H+] mp, °C
Yield, %
C
H
N
8
C18H22N2O4
C18H21FN2O4
C19H24N2O5
C20H27N3O4
C18H21ClN2O4
C18H21N3O6
C24H26N2O5
65.60
65.45
62.27
62.06
63.51
63.32
64.59
64.32
59.42
59.26
57.74
57.59
68.44
68.23
7.20
6.71
6.12
6.08
6.79
6.71
7.35
7.29
5.84
5.80
5.07
5.64
6.22
6.20
8.67
8.48
8.21
8.04
7.94
7.77
11.52
11.25
7.91
7.68
11.39
11.19
6.81
6.63
331
349
361
374
365
376
423
218
238
218
125
243
250
215
82
78
75
70
80
75
70
9
10
11
12
13
14
303

due to H-7a and H-7e the doublet at 2.52 ppm has NOE with H-4a and H-5a in the NOESY spectrum. Therefore
the doublet at 2.52 ppm is assigned to H-7a, while the chemical shift of H-7e is 2.77 ppm. Based on the one-bond
correlation between H-7a and H-7e with C-7 in HSQC, the C-7 resonance is fixed as 36.5 ppm. In the HSQC the
13C resonance at 69.9 ppm has no correlations with protons and hence it is due to quaternary carbon C-6.
13
Among the quaternary carbon resonances 99.2, 138.8, 143.8, and 159.9, the C resonance at 143.0 ppm
has a multiple-bond correlation (143.0/7.07-7.29 ppm) with aromatic protons in the HMBC and hence that
13
resonance is assigned to C-1' (ipso carbon of the Ar ring). The C resonance at 99.2 ppm shows cross peaks
(99.2/4.06 and 99.2/2.57 ppm) with H-5a and hence that resonance has been assigned to C-9.
The assignment of 13C resonances C-3 and C-8 determines whether the compound is 1H-indazole or
2H-indazole. If the indazole is 2H-indazole, then C-8 is C=N and the 13C resonance must be 157.9 ppm. This 13C
resonance should exhibit multiple-bond correlations with H-7a, H-7e, and methyl protons at C-6 in HMBC.
13
If the indazole is 1H-indazole, then C-3 is C=N and the C resonance 157.9 ppm assigned to C-3 and C-8
must be 138.8 ppm. Further, the 13C resonance 138.8 ppm (C-8) must exhibit a multiple-bond correlation with H-
7a, H-7e, and methyl protons at C-6 in HMBC.
The HMBC spectrum of indazole proves that there are multiple-bond correlations between 13C
13
resonance 138.8 ppm and H-7a, H-7e, and methyl protons at C-6. Therefore, the C resonance 138.8 ppm is
assigned to C-8 and the compound is 1H-indazole. This has been proved beyond doubt by X-ray structure study
[12]. The spectral and crystal study of indazole proves that it is t-4-aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-
tetrahydro-1H-indazole-r-5-carboxylic acid isopropyl ester.
Re-examination of NMR spectral data of 4,5-trans-2-alkyl-5-ethoxycarbonyl(acetyl)-4-hetaryl-
6-methyl-4,5,6,7-tetrahydro-2H-indazole suggests that based on the assignment of C-13 chemical shifts of C-3 and
C-8 (mentioned as C-7 in [10]) the indazoles reported then must be 1H-indazoles and not 2H-indazoles.
Based on the observed chemical shifts and coupling constants, the indazoles obtained adopt a normal
chair conformation with axial orientation of OH group at C-6 and equatorial orientation of other substituents
like in cyclic -keto esters.
H
O
H
H
Me
H
N
i
-PrOOC
N
H
CH
C
Ar
H
OH
Conformation of t-4-aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-tetrahydro-1H-indazole-r-5-carboxylic
acid isopropyl ester
EXPERIMENTAL
The progress of the reaction and compound purity were checked by TLC. Melting points were
1
13
determined in open capillaries and are uncorrected. H and C NMR spectra were recorded on a Bruker AMX
1
13
400 NMR spectrometer (400 and 100 MHz for H and C NMR spectra, respectively). HMBC, HSQC, and
NOESY spectra were recorded on a Bruker DRX 500 NMR spectrometer. DMSO-d6 was used as a solvent.
Mass spectra were recorded on a JEOL DX 303 and HP-5889A mass engine. Elemental analyses were
performed on Perkin–Elmer CHNS/O analyzer.
Compounds 1-7 were prepared by adopting the literature procedure [8].
Synthesis of t-4-Aryl-3,c-6-dihydroxy-6-methyl-4,5,6,7-tetrahydro-1H-indazole-r-5-carboxylic
Acid Isopropyl Ester (General Method). t-3-Aryl-r-2,c-4-bis(isopropoxycarbonyl)-c-5-hydroxy-t-5-methyl-
304

cyclohexanone (100 mmol) was dissolved in hot ethanol (25 ml) and after addition of hydrazine hydrate (150
mmol) the reaction mixture was heated under reflux for 2 h. Then the reaction mixture was cooled and poured
onto crushed ice, and the precipitate was filtered off, dried, and recrystallized from ethanol.
3,c-6-Dihydroxy-6-methyl-t-4-phenyl-4,5,6,7-tetrahydro-1H-indazole-r-5-carboxylic Acid Isopropyl
1
Ester (8). IR spectrum,  cm–1: 3494, 3327 (OH and NH), 1700 (CO), 1618 (C=N). H NMR spectrum, , ppm (J,
Hz): 0.77 (3H, d, J = 6.2, CH3CH); 1.05 (3H, d, J = 6.2, CHCH2); 1.21 (3H, s, 6-CH3); 2.50 (2H, m, H-5a and H-
7a); 2.74 (1H, d, J = 16.0, H-7e); 4.00 (1H, d, J = 10.4, H-4a); 4.34 (1H, s, 6-OH); 4.73 (1H, m, CHCH3); 7.13
(5H, m, Ar); 9.05 (1H, br. s, H-1); 10.95 (1H, br. s, 3-OH).
The presence of labile protons, OH proton at C-3, NH proton, and OH proton at C-6 was confirmed by
recording the 1H NMR spectrum after adding D2O.
13C NMR spectrum, , ppm: 20.6 (CH3 i-Pr); 20.8 (CH3 i-Pr); 27.6 (6-CH3); 35.8 (C-7); 39.6 (C-4); 58.9
(C-5); 65.9 (CH i-Pr); 69.3 (C-6); 98.7 (C-9); 125.2–127.5 (Ar); 138.2 (C-8); 142.5 (ipso-C); 157.3 (C-3); 171.31
(C=O).
t-4-p-Fluorophenyl-3,c-6-dihydroxy-6-methyl-1H-indazole-r-5-carboxylic Acid Isopropyl Ester (9). IR
spectrum,  cm–1: 3437, 3267 (OH and NH);1721 (CO group);1619 (C=N).1H NMR spectrum,, ppm(J, Hz):0.82
(3H, d, J = 6.1, CH3CH);1.09 (3H, d, J = 6.2, CH3CH); 1.21 (3H, s, 6-CH3); 2.52 (2H, m, H-5a and H-7a); 2.76
(1H, d, J = 16.1, H-7e); 4.03 (1H, d, J = 10.6, H-4a); 4.42 (1H, s, 6-OH); 4.76 (1H, m, CHCH3); 7.117.04 (4H,
m, Ar); 8.92 (1H, br. s, NH); 11.10 (1H, br. s, 3-OH). 13C NMR spectrum, , ppm: 21.1 (CH3 i-Pr); 21.3 (CH3 i-Pr);
28.1 (6-CH3); 36.4 (C-7); 40.1 (C-4); 59.4 (C-5); 66.5 (CH i-Pr); 69.8 (C-6); 99.2 (C-9); 113.9–129.8 (Ar); 138.7
(C-8); 157.7 (C-3); 159.4, 161.8 (ipso-C-1); 171.6 (C=O).
3,c-6-Dihydroxy-t-4-p-methoxyphenyl-6-methyl-1H-indazole-r-5-carboxylic Acid Isopropyl Ester (10).
IR spectrum,  cm–1: 3446, 3316 (OH and NH); 1700 (C=O); 1608 (C=N). 1H NMR spectrum, , ppm (J, Hz): 0.89
(3H, d, J = 6.2, CH3CH); 1.15 (3H, d, J = 6.2, CH3CH); 1.22 (3H, s, 6-CH3); 2.49 (2H, m, H-5a and H-7a); 2.74 (H,
d, J = 16.0, H-7e); 3.70 (3H, s, OCH3); 3.97 (1H, d, J = 10.3, H-4a); 4.43 (1H, s, 6-OH), 4.76 (1H, m, CHCH3),
6.77-6.99 (4H, m, Ar); 8.80 (1H, br. s, NH); 11.05 (1H, br. s, 3-OH). 13C NMR spectrum, , ppm: 21.2 (CH3 i-Pr);
21.4 (CH3 i-Pr); 28.1 (6-CH3); 36.3 (C-7); 39.9 (C-4); 54.8 (OCH3); 59.6 (C-5); 66.4 (CH i-Pr); 69.8 (C-6);
112.9–128.9 (Ar); 134.5, 157.4 (C-ipso); 138.6 (C-8); 157.8 (C-3); 171.9 (C=O).
t-4-p-(N,N-Dimethylamino)phenyl-3,c-6-dihydroxy-6-methyl-1H-indazole-r-5-carboxylic Acid Iso-
propyl Ester (11). IR spectrum,  cm–1: 3447, 3286 (OH and NH); 1723 (CO); 1613 (C=N). 1H NMR spectrum, , ppm
(J, Hz): 0.87 (3H, d, J = 6.1, CH3CH i-Pr); 1.11 (3H, d, J = 6.2, CH3CH); 1.21 (3H, s, 6-CH3); 2.45 (1H, d,
J = 10.9, H-5a); 2.50 (1H, d, J = 15.9, H-7a); 3.72 (1H, d, J = 15.9, H-7e); 3.92 (1H, d, J = 10.9, H-4a); 4.28
(1H, s, 6-OH); 4.77 (1H, m, CHCH3); 2.74 (6H, s, N(CH3)2); 6.58–6.89 (4H, m, Ar). 13C NMR spectrum, , ppm:
21.3 (CH3 i-Pr); 21.5 (CH3 i-Pr); 28.3 (6-CH3); 36.4 (C-7); 40.2 (N–CH3); 40.3 (C-4); 59.9 (C-5); 66.5 (CH i-Pr);
70.0 (C-6); 99.8 (C-9); 112.1–130.5 (Ar); 138.7 (C-8); 149.0 (C-ipso); 158.0 (C-3); 172.2 (C=O).
t-4-p-Chlorophenyl-3,c-6-dihydroxy-6-methyl-1H-indazole-r-5-carboxylic Acid Isopropyl Ester (12).
IR spectrum, , cm–1: 3415, 3274 (OH and NH); 1607 (C=O); 1614 (C=N). 1H NMR spectrum, , ppm (J, Hz): 0.84
(3H, d, J = 6.1, CH3CH); 1.10 (3H, d, J = 6.1, CH3CH); 1.24 (3H, s, 6-CH3); 2.52 (2H, m, H-5a and H-7a); 2.77
(1H, d, J = 15.9, H-7e); 4.03 (1H, d, J = 10.5, H-4a), 4.48 (1H, s, 6-OH); 4.77 (1H, m, CHCH3); 7.11-7.27 (4H, m,
13
Ar); 9.05 (1H, br. s, NH); 11.10 (1H, br. s, 3-OH). C NMR spectrum, , ppm: 21.3 (CH3 i-Pr); 21.5 (CH3 i-Pr);
28.3 (6-CH3); 36.5 (C-7); 41.1 (C-4); 59.3 (C-5); 66.7 (CH i-Pr); 99.1 (C-9); 127.59–130.10 (Ar); 138.9 (C-8);
141.9, 149.9 (C-ipso); 157.8 (C-3); 171.6 (C=O).
3,c-6-Dihydroxy-6-methyl-t-4-m-nitrophenyl-1H-indazole-r-5-carboxylic Acid Isopropyl Ester (13). IR
spectrum,  cm–1: 3492, 3273 (OH and NH); 1705 (C=O); 1613 (C=N). 1H NMR spectrum, , ppm (J, Hz): 0.80 (3H, d, J
= 6.0, CH3CH); 1.09 (3H, d, J = 6.1, CH3CH); 1.27 (3H, s, 6-CH3); 2.54 (1H, d, J = 15.9, H-7a); 2.62 (1H, d,
J = 10.6, H-5a); 2.84 (1H, d, J = 15.9, H-7e); 4.21 (1H, d, J = 10.3, H-4a); 4.55 (1H, s, 6-OH); 4.77 (1H, m,
CHCH3); 7.54–8.07 (4H, m, Ar); 9.12 (1H, br. s, NH); 11.20 (1H, br. s, 3-OH). 13C NMR spectrum, , ppm: 21.2 (CH3
i-Pr); 21.4 (CH3 i-Pr); 28.1 (6-CH3); 36.5 (C-7); 40.2 (C-4); 59.0 (C-5); 66.9 (CH i-Pr); 98.5 (C-9); 121.2-135.4
(Ar); 145.5, 147.5 (C-ipso); 157.8 (C-3); 139.2 (C-8); 171.1 (C=O).
305

3,c-6-Dihydroxy-6-methyl-t-4-m-phenoxyphenyl-1H-indazole-r-5-carboxylic Acid Isopropyl Ester (14).
1
IR spectrum,  cm–1: 3498, 3324 (OH and NH); 1698 (C=O); 1617 (C=N). H NMR spectrum, , ppm (J, Hz): 0.89
(3H, d, J = 6.1, CH3CH); 1.10 (3H, d, J = 6.1, CH3CH); 1.23 (3H, s, 6-CH3); 2.50 (1H, d, J = 15.9, H-7a); 2.52
(1H, d, J = 10.3, H-5a); 2.76 (1H, d, J = 15.9, H-7e); 4.03 (1H, d, J = 10.3, H-4a); 4.40 (1H, s, 6-OH); 4.78 (1H,
m, CHCH3); 6.7–7.3 (Ar); 9.25 (1H, br. s, NH); 11.02 (1H, br. s, 3-OH). 13C NMR spectrum, , ppm: 21.4 (CH3 i-Pr);
21.5 (CH3 i-Pr); 28.2 (6-CH3); 36.4 (C-7); 40.0 (C-4); 59.4 (C-5); 66.7 (CH i-Pr); 69.9 (C-6); 116.9-129.8 (Ar);
145.2, 157.2 (C-ipso); 138.8 (C-8); 157.9 (C-3); 171.7 (C=O).
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