Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives
by
Fátima C. Teixeira
1,*, 
Hélène Ramos
1,
Inês F. Antunes
1,
M. João M. Curto
1,
M. Teresa Duarte
2 and
Isabel Bento
3 1
INETI - Departamento de Tecnologia de Indústrias Químicas, Estrada do Paço do Lumiar, 22, 1649-038 Lisboa, Portugal
2
Instituto Superior Técnico, Centro de Química Estrutural, Complexo I, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
3
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Apartado 127, 2781-901 Oeiras, Portugal
*
Author to whom correspondence should be addressed.
Molecules 2006, 11(11), 867-889; https://doi.org/10.3390/11110867
Submission received: 4 October 2006
/
Revised: 30 October 2006
/
Accepted: 13 November 2006
/
Published: 14 November 2006
Abstract
:A series of indazoles substituted at the N-1 and N-2 positions with ester- containing side chains -(CH2)nCO2R of different lengths (n = 0-6, 9, 10) are described. Nucleophilic substitution reactions on halo esters (X(CH2)nCO2R) by 1H-indazole in alkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomer predominates. Basic hydrolysis of the ester derivatives allowed the synthesis of the corresponding indazole carboxylic acids. All compounds were fully characterised by multinuclear NMR and IR spectroscopies, MS spectrometry and elemental analysis; the NMR spectroscopic data were used for structural assignment of the N-1 and N-2 isomers. The molecular structure of indazol-2-yl-acetic acid (5b) was determined by X-ray diffraction, which shows a supramolecular architecture involving O2-H...N1 intermolecular hydrogen bonds.
Introduction
Indazoles constitute an important class of heterocycles that display interesting biological properties [1,2], such as anti-depressant [3], anti-inflammatory [4,5], analgesic and antipyretic [6], dopamine antagonistic [7], anti-tumor [8], anti-emetic [9] and anti-HIV activities [10]. The indazole ring system is also present in many other compounds such as herbicides, dyes or sweeteners like guanidine-1H-indazole [1,2,11]. Despite the many useful applications of indazole derivatives, indazole chemistry remains less studied compared to other heteroaromatic compounds, such as indole or benzimidazole.
Indazole is a ten-π electron aromatic heterocyclic system. Like the pyrazole molecule, indazole resembles both pyridine and pyrrole and its reactivity reflects this dual behaviour [1]. The indazole ring has two nitrogen atoms and presents annular tautomerism with regards to the position of the NH hydrogen atom. Due to the difference in energy between the tautomers, the 1H-tautomer (the benzenoid form 1a) predominates in the gas-phase, solution and solid state, and its derivatives are usually thermodynamically more stable than the corresponding 2H-forms (the quinonoid form 1b) (Figure 1) [1,2,12,13].
Figure 1.
Annular tautomerism of indazole (1a: benzenoid 1H-indazole tautomer; 1b: quinonoid 2H-indazole tautomer).
Figure 1.
Annular tautomerism of indazole (1a: benzenoid 1H-indazole tautomer; 1b: quinonoid 2H-indazole tautomer).
Several studies concerning the alkylation of 1H-indazole (1) reveal that the acidity or basicity of the medium, use of protic or aprotic solvents, as well as electronic and steric effects all affect the ratio of N-1 and N-2 alkylated isomers formed. Generally, the N-1 isomers are thermodynamically more stable, whereas the N-2 isomers are kinetically favoured [14]. Yamazaki [15] and Elguero [16] have reported the formation of both N-1 and N-2-acyl indazole derivatives, but they readily isomerize to afford the most stable isomer after equilibration. The regioselectivity of the reaction is also dependent on the nature of the alkylating agents used; recently Cheung et al. reported an efficient and regioselective synthesis of N-2 alkylated isomers using trimethyloxonium tetrafluoroborate or triethyloxonium hexafluorophosphonate as alkylating agents [17].
NMR spectroscopy is very useful to assign the structures of 1- and 2-substituted indazoles, as the 1H-NMR and 13C-NMR spectra of the two isomers are usually sufficiently different to be used as diagnostic tools to establish the position of substitution. 13C-NMR spectroscopy is usually a particularly good method to perform this assignment [1,2,14,16,17,18].
As part of a continuing effort to develop novel heterocyclic compounds with potential therapeutic biological activity, we are currently involved in the synthesis of a large number of indazole derivatives. The substitution at the different atoms of the six- and five membered rings with side chains with different length and functionalisation, can afford a large number of indazole derivatives, presenting a promising field to provide new derivatives with biological/therapeutical properties.
Here we report the synthesis, starting from 1H-indazole (1), of several indazole derivatives substituted at the N-1 and N-2 positions with side chains of different lengths and functionalised with ester or carboxylic acid groups. Their full characterization was achieved by IR and multinuclear NMR, mass spectrometry, mp and elemental analysis. The recrystallization of indazol-2-yl-acetic acid 5b afforded crystals suitable for X-ray diffraction studies, which confirm the proposed structure. Application of these compounds to the synthesis of novel biologically active compounds is under investigation and will be reported in due course.
Results and Discussion
Synthesis
The indazole ester derivatives 2 and 3 were obtained in different yields and ratios starting from 1H-indazole (1) by nucleophilic substitution reactions of the corresponding halo esters with different hydrocarbon chain lengths (Table 1).
| Series | n | Base (solvent) | X(CH2)nCO2R | 2 (%) | 3 (%) | 2 + 3 (%) | |
|---|---|---|---|---|---|---|---|
| X | R | ||||||
| a | 0 | Kt-BuO (THF) | Cl | Me | 99 | - | 99 |
| Kt-BuO (THF) | Cl | Et | (45)[a] | (10)[a] | |||
| b | 1 | Kt-BuO(THF) | Br | Et | 55 | 13 | 68 |
| K2CO3 (DMF) | Br | Et | 67 | 22 | 89 | ||
| Kt-BuO (THF) | Br | Et | (15)[a] | (15)[a] | |||
| c | 2 | NaH (THF) | Br | Et | 47 | 39 | 86 |
| K2CO3 (DMF) | Br | Et | 49 | 46 | 95 | ||
| Kt-BuO (THF) | Br | Et | (26)[a] | (18)[a] | |||
| d[b] | 3 | Kt-BuO (DMSO) | Br | Et | 49 | 12 | 61[c] |
| K2CO3 (DMF) | Br | Et | 59 | 37 | 96 | ||
| e[b] | 4 | K2CO3 (DMF) | Br | Et | 59 | 31 | 90 |
| f[b] | 5 | Kt-BuO (THF) | Br | Et | (39)[a] | (39)[a] | |
| K2CO3 (DMF) | Br | Et | 62 | 34 | 96 | ||
| g | 6 | K2CO3 (DMF) | Br | Et | 61 | 36 | 97 |
| h | 9 | K2CO3 (DMF) | Br | Me | 63 | 34 | 97 |
| i | 10 | K2CO3 (DMF) | Br | Me | 60 | 38 | 98 |
[a] Determined from the 1H-NMR spectra; [b] For the same reagents, the reactions were also performed using bases such as NaH (THF) (n = 3-5), nBuLi (THF) (n = 3, 5), KOH (MeOH) (n = 3) and pyridine (n = 3), but indazole 1 remained unreacted; [c] A complex mixture of products was also obtained.
For best results, the reaction was carried out on the anionic form of the 1H-indazole, readily obtained in situ by the action of a base (Kt-BuO, NaH, nBuLi, KOH, pyridine or K2CO3), in different solvents (THF, DMSO, MeOH or DMF). Compounds 2 and 3 were separated by column chromatography to provide the pure compounds, usually as pale yellow oils, in good to excellent yield. The N-1 isomers 2 were eluted first in each case and in all cases the N-1 isomers were the major isomers formed.
In these common nucleophilic displacement reactions, X in the compounds X(CH2)nCO2R corresponds to chloro or bromo atoms. When n≥1, the reactivity of chloroesters was lower than that of the corresponding bromoesters, so the latter were used. For n> 3 only the use of K2CO3 as base in DMF allows complete reactions. The reaction of indazole 1 with ClCO2Me in the presence of Kt-BuO, at room temperature, gave only the N-1 isomer 2a in excellent yield (99%). The synthesis of 2a was previously reported by Kingsbury et al. [19], who showed that the reaction of ClCO2Me with indazole 1 in the presence of an amine, such as pyridine or triethylamine, gave the N-1 isomer 2a (57%) at room temperature and the N-2 isomer at -78 °C. The synthesis of 2b, 2c, 3b and 3c, using also a nucleophilic displacement reactions with bromo esters, was first reported by Auwers in 1926 [20], but no spectroscopic characterisation has been described. During the course of this work, a patent referring to compounds 2d, 2e, 3d and 3e was published, but no spectroscopic data was given [21].
The esters 2 and 3 were subject to basic hydrolysis to afford the corresponding N-1 and N-2 indazole carboxylic acid derivatives (compounds 4 and 5, respectively), as white crystalline solids in good to excellent yields (Table 2 and Table 3). Indazol-2-yl-acetic acid 5b gave crystals suitable for an X-ray structural analysis (see Figure 2, below).
Table 2.
Physical-chemical characteristics and elemental analysis of indazole carboxylic acids 4b-i. ![Molecules 11 00867 i002]()
| N° | n | R | Yield (%) | mp (°C) | Formula | Analysis (%) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Calcd. | Found | ||||||||||
| C | H | N | C | H | N | ||||||
| 4b | 1 | Et | 97 | 186-188 1 | C9H8N2O2 | 61.36 | 4.58 | 15.90 | 61.32 | 4.52 | 15.85 |
| 4c | 2 | Et | 98 | 106-107 2 | C10H10N2O2 | 63.15 | 5.30 | 14.73 | 62.96 | 5.34 | 14.49 |
| 4d | 3 | Et | 93 | 60-62 | C11H12N2O2 | 64.69 | 5.92 | 13.72 | 64.71 | 5.97 | 13.74 |
| 4e | 4 | Et | 99 | 82-83 | C12H14N2O2 | 66.04 | 6.47 | 12.84 | 66.11 | 6.58 | 12.86 |
| 4f | 5 | Et | 100 | 69-70 | C13H16N2O2 | 67.22 | 6.94 | 12.06 | 67.42 | 6.99 | 11.97 |
| 4g | 6 | Et | 74 | 54-58 | C14H18N2O2 | 68.27 | 7.37 | 11.37 | 68.46 | 7.25 | 11.36 |
| 4h | 9 | Me | 93 | 78-81 | C17H24N2O2 | 70.80 | 8.39 | 9.71 | 70.67 | 8.49 | 9.65 |
| 4i | 10 | Me | 95 | 73-74 | C18H26N2O2 | 71.49 | 8.67 | 9.26 | 71.39 | 8.91 | 9.29 |
Table 3.
Physical-chemical characteristics and elemental analyses of indazole carboxylic acids 5a-i. ![Molecules 11 00867 i003]()
| N° | n | R | Yield (%) | mp (°C) | Formula | Analysis (%) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Calcd. | Found | ||||||||||
| C | H | N | C | H | N | ||||||
| 5b | 1 | Et | 96 | 254-256 1 | C9 H8N2O2 | 61.36 | 4.58 | 15.90 | 61.24 | 4.51 | 15.90 |
| 5c | 2 | Et | 98 | 147-149 2 | C10H10N2O2 | 63.15 | 5.30 | 14.73 | 63.05 | 5.37 | 14.70 |
| 5d | 3 | Et | 97 | 132-134 | C11H12N2O2 | 64.69 | 5.92 | 13.72 | 64.71 | 5.99 | 13.64 |
| 5e | 4 | Et | 98 | 112-114 | C12H14N2O2 | 66.04 | 6.47 | 12.84 | 65.92 | 6.18 | 12.74 |
| 5f | 5 | Et | 59 | 86-87 | C13H16N2O2 | 67.22 | 6.94 | 12.06 | 66.97 | 7.31 | 11.66 |
| 5g | 6 | Et | 62 | 77-78 | C14H18N2O2 | 68.27 | 7.37 | 11.37 | 68.15 | 7.38 | 11.27 |
| 5h | 9 | Me | 90 | 68 | C17H24N2O2 | 70.80 | 8.39 | 9.71 | 70.69 | 8.68 | 9.76 |
| 5i | 10 | Me | 93 | 82 | C18H26N2O2 | 71.49 | 8.67 | 9.26 | 71.53 | 8.68 | 9.15 |
Spectroscopic Characterization
The unambiguous assignment of indazole derivatives substituted at N-1 and N-2 was carried out by 1H- and 13C-NMR spectroscopy, DEPT and two-dimensional NMR techniques. The main resonances in the 1H-NMR spectra of 1H-indazole ester derivatives 2b-i in CDCl3 are: i) three resonances in the δ = 7.12-7.73 ppm region, usually as a two proton multiplet, a one proton doublet and a one proton triplet, which correspond to the 4-H to 7-H protons, ii) a singlet (or a doublet with J = 0.6 Hz) at δ = 7.98-8.04 ppm, which corresponds to the 3-H proton, iii) a triplet for the the NCH2 protons at δ = 4.36-5.13 ppm, and iv) resonances at δ = 1.22-3.65 ppm for the CH2 protons. The 1H-NMR spectrum of 1H-indazole ester derivative 2a (n = 0), with the ester carbonyl group bonded to the nitrogen atom of the indazole, shows all the resonances at higher frequency than those of compounds 2b-i, in particular the resonance of the 7-H proton, which appears at δ = 8.26 ppm, due to the deshielding effect of the ester carbonyl group.
The 1H-NMR spectra of the N-1 and N-2 isomers are very different. Spectral comparison shows that the resonances of the 3-H to 6-H protons in the N-2 isomers appear at lower frequency than in the corresponding 1N-isomers, but the resonance of the 7-H proton of the N-2 isomers appears at higher frequency, due to the deshielding effect of the N-1 lone pair. The 3-H proton in the N-2 isomers is shielded relative to the same proton in the N-1 isomer. The main resonances of the N-2 ester derivatives 3 are: i) four resonances in the δ = 7.06-7.71 ppm region, usually as two one proton doublets (4-H and 7-H) and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet, J = 0.6 Hz) at δ = 7.88-8.00 ppm, which corresponds to the 3-H proton, iii) a triplet for the the NCH2 protons at δ = 4.39-5.19 ppm, and iv) resonances at δ = 1.35-3.65 ppm for the CH2 protons.
The chemical shifts of the indazole protons in carboxylic acids 4 and 5 do not differ substantially from those in the corresponding esters 2 and 3, respectively. This is also the case for the side-chain protons.
The main resonances in the 1H-NMR spectra of the 1H-indazole carboxylic acid derivatives 4 in MeOD are: i) four resonances at δ = 7.12-7.76 ppm, usually as two one proton doublets (4-H and 7-H) and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet with J = 0.6 Hz) at δ = 7.98-8.04 ppm corresponding to the 3-H proton, iii) a triplet for the NCH2 protons at δ = 4.38-5.22 ppm, and iv) resonances at δ = 1.23-2.91 ppm for the CH2 protons. The 1H-NMR spectra of compounds 4d, 4e and 4f were also recorded in CDCl3. It was observed that the chemical shifts depend on solvents used, in particular the resonance of 7-H: in MeOD, it appears as a doublet at δ ≈ 7.53 ppm and in CDCl3 it appears as a two proton multiplet at δ ≈ 7.40 ppm (with the same chemical shift as the 6-H proton). The 1H-NMR spectrum of compound 4f was also recorded in DMSO and it showed no significant differences compared to the spectrum recorded in MeOD.
The main resonances in the 1H-NMR spectra of the 2H-indazole carboxylic acid derivatives 5c-i in MeOD are: i) four resonances in the δ = 7.03-7.74 ppm region, usually as two one proton doublets (4-H and 7-H) and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet with J = 0.6 Hz) at δ = 8.16-8.36 ppm, corresponding to the 3-H proton, iii) a triplet for the NCH2 protons at δ = 4.40-5.28 ppm, and iv) resonances at δ = 1.27-3.00 ppm for the CH2 protons. The 1H-NMR spectrum of carboxylic acid 5b was recorded in DMSO, but comparison with the spectra of 5c-i recorded in MeOD showed no significant differences. As observed for the N-1 isomer, the N-2 carboxylic acid derivatives 5 present 1H-NMR spectra similar to those of the corresponding ester derivatives 3, with the exception of the 3-H proton which is deshielded compared to the corresponding esters and N-1 isomers.
The main resonances in the 13C-NMR spectra in CDCl3 of 1H-indazole ester derivatives 2b-i (with the exception 2a) are: i) the resonances of C4 and C5 appear at δ ≈ 120-121 ppm, ii) C6 has a chemical shift of δ = 126 ppm, iii) C7 is the more shielded atom, with a chemical shift at δ = 108-109 ppm, iv) C3 appears at higher frequency, with a chemical shift at δ = 132-134 ppm; v) the quaternary C3a and C7a carbon atoms present different chemical shifts, with C7a at higher frequency (δ = 139 ppm) than C3a (δ = 123-125 ppm), vi) the CH2 carbon atom resonances appear at δ = 22.2-34.5 ppm, as expected, and vii) the CO carbon atom has a chemical shift of δ = 167-174 ppm and becomes more deshielded in compounds with longer hydrocarbon chains. In the case of compound 2a (n = 0), the chemical shift of carbon C7 is deshielded relative to the free indazole due to the ester group (Table 4).
Table 4.
13C-NMR chemical shifts (δ in ppm) of 1H-indazole 1, 1H-indazole esters 2a-i and 2H-indazole esters 3b-i in CDCl3.
| N° | n | R | C7 | C4 | C5 | C6 | C3 | C3a | C7a | CO | NCH2 | CH2 | OCH2CH3 | OCH3 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 110.0 | 120.4 | 120.1 | 125.8 | 133.4 | 122.8 | 139.9 | |||||||
| 2a | 0 | Me | 114.3 | 121.1 | 124.0 | 129.2 | 140.2 | 125.7 | 139.7 | 151.0 | 54.3 | |||
| 2b | 1 | Et | 108.6 | 121.1 | 120.8 | 126.6 | 134.1 | 124.1 | 140.0 | 167.8 | 50.1 | 61.6, 13.9 | ||
| 2c | 2 | Et | 109.0 | 120.9* | 120.5* | 126.3 | 133.5 | 123.9 | 139.5 | 171.1 | 44.1 | 34.5 | 60.8, 14.0 | |
| 2d | 3 | Et | 108.8 | 121.0* | 120.4* | 126.1 | 133.0 | 123.9 | 139.4 | 172.7 | 47.6 | 24.9, 30.9 | 60.4, 14.1 | |
| 2e | 4 | Et | 108.9 | 121.1* | 120.4* | 126.1 | 132.8 | 124.0 | 139.3 | 173.2 | 48.4 | 22.2, 29.2, 33.7 | 60.3, 14.2 | |
| 2f | 5 | Et | 108.8 | 121.0* | 120.3* | 126.0 | 132.7 | 123.9 | 139.3 | 173.4 | 48.5 | 24.5, 26.3, 29.4, 34.0 | 60.1, 14.1 | |
| 2g | 6 | Et | 108.9 | 121.1* | 120.3* | 126.0 | 132.7 | 123.9 | 139.3 | 173.7 | 48.7 | 24.7, 26.5, 28.7, 29.6, 34.2 | 60.2, 14.2 | |
| 2h | 9 | Me | 108.9 | 121.0 | 120.3 | 126.0 | 132.6 | 123.9 | 139.3 | 174.2 | 48.8 | 24.8, 26.8, 29.0, 29.1, 29.2, 29.8, 34.0 | 51.4 | |
| 2i | 10 | Me | 109.0 | 121.1* | 120.3* | 126.0 | 132.6 | 124.0 | 139.3 | 174.3 | 48.9 | 24.9, 26.8, 29.05, 29.13, 29.26, 29.31, 29.8, 34.1 | 51.4 | |
| 3b | 1 | Et | 117.6 | 120.3 | 122.1 | 126.4 | 124.4 | 122.2 | 149.2 | 167.2 | 54.5 | 62.2, 14.1 | ||
| 3c | 2 | Et | 117.1 | 120.1 | 121.51 | 125.9 | 123.5 | 121.5 | 148.9 | 170.7 | 48.7 | 34.9 | 60.8, 13.9 | |
| 3d | 3 | Et | 117.2 | 119.9 | 121.47 | 125.7 | 122.8 | 121.5 | 148.8 | 172.4 | 52.3 | 25.5, 30.7 | 60.4, 14.0 | |
| 3e | 4 | Et | 117.2 | 120.0 | 121.5 | 125.7 | 122.6 | 121.6 | 148.7 | 173.0 | 53.2 | 21.9, 29.8, 33.5 | 60.3, 14.1 | |
| 3f | 5 | Et | 117.3 | 119.9 | 121.5 | 125.7 | 122.5 | 121.6 | 148.8 | 173.4 | 53.4 | 24.3, 26.0, 30.2, 33.9 | 60.2, 14.1 | |
| 3g | 6 | Et | 117.3 | 120.0 | 121.5 | 125.7 | 122.5 | 121.7 | 148.8 | 173.6 | 53.6 | 24.7, 26.3, 28.5, 30.4, 34.1 | 60.2, 14.2 | |
| 3h | 9 | Me | 117.3 | 120.0* | 121.4* | 125.6 | 122.4 | 121.7 | 148.7 | 174.2 | 53.7 | 24.8, 26.6, 28.96, 28.98, 29.0, 29.1, 30.6, 34.0 | 51.4 | |
| 3i | 10 | Me | 117.4 | 120.0* | 121.5* | 125.7 | 122.5 | 121.7 | 148.8 | 174.3 | 53.8 | 24.9, 26.6, 29.04, 29.12, 29.24, 29.28, 30.6, 34.1 | 51.4 |
* These assignments may be reversed. The NMR assignment of the other compounds was done using two-dimensional NMR techniques.
Compared to the N-1 isomer 2 the N-2 isomers 3 present similar chemical shifts for CH2, CO, C6, C4 and C5 (Table 4). Other carbon atoms present large differences that allow the unequivocal assignment of both isomers: i) C7 (δ ≈ 117 ppm) and C7a (δ ≈ 148-149 ppm) are more deshielded in the N-2 isomer, with Δδ ≈ 8-9 and 9-10 ppm, respectively, ii) C3 (δ ≈ 122-124 ppm) and C3a (δ ≈ 121-122 ppm) are more shielded in these N-2 isomers, with Δδ ≈ 10 ppm (C3) and Δδ ≈ 2-3 ppm (C3a).
In the 13C-NMR spectra in MeOD, the differences between the N-1 and N-2 indazole carboxylic acids 4 and 5 are similar to those observed in the spectra of the ester derivatives: i) CH2, CO, C6, C5 and C4 have similar chemical shifts in both isomers, ii) C7 and C7a are deshielded in the N-2 isomers with Δδ ≈ 7 ppm (C7) and Δδ ≈ 10-11 ppm (C7a), iii) the C3 (δ ≈ 135 ppm in N-1 and δ ≈ 125 ppm in N-2 isomer) and C3a (δ ≈ 125 ppm in N-1 and δ ≈ 122-123 ppm in N-2 isomer) are more shielded in the N-2 than in the N-1 isomers (Table 5).
The 13C-NMR spectra in different deuterated solvents show similar patterns, with small differences in the chemical shifts, as were observed at higher frequencies in MeOD. Comparison of the spectra of indazole carboxylic acid derivatives 4d, 4e and 4f and indazole esters 2d, 2e and 2f in the same solvent (CDCl3), reveal no differences between their 13C-NMR spectra, with the exception of the CO carbon atom. These observations confirm that, despite the change in the functional groups of indazole derivatives (with no mesomeric effect towards the indazole ring) the chemical shifts of indazole ring carbon atoms remain constant, which allows the assignment of N-1 and N-2 isomers of carboxylic acid derivatives by 13C-NMR spectroscopy.
These spectroscopic data are in agreement with the 13C-NMR spectra of 1N- and 2N-substituted indazoles reported in the literature [1,2,8,11,12]. The structural assignments were ultimately confirmed by X-ray crystal structure analysis of compound 5b.
Table 5.
13C-NMR chemical shifts (δ in ppm) of 1H-indazole carboxylic acids 4b-i and 2H-indazole carboxylic acids 5b-i.
| N° | n | Solvent | C7 | C4 | C5 | C6 | C3 | C3a | C7a | CO | NCH2 | CH2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 4b | 1 | MeOD | 110.4 | 122.1 | 122.1 | 128.1 | 135.0 | 125.4 | 141.8 | 171.5 | 50.6 | |
| 4c | 2 | MeOD | 110.6 | 122.0* | 121.9* | 127.8 | 134.5 | 125.2 | 141.0 | 174.6 | 45.2 | 35.1 |
| 4d | 3 | MeOD | 110.3 | 122.2* | 121.9* | 127.8 | 134.1 | 125.2 | 141.0 | 174.6 | 48.6 | 26.2, 31.6 |
| 4d | 3 | CDCl3 | 108.9 | 121.3* | 120.7* | 126.6 | 132.9 | 123.7 | 139.4 | 177.6 | 47.4 | 24.7, 30.8 |
| 4e | 4 | MeOD | 110.3 | 122.1* | 121.8* | 127.7 | 133.8 | 125.2 | 140.9 | 177.0 | 49.2 | 23.3, 30.3, 34.3 |
| 4e | 4 | CDCl3 | 108.8 | 121.2* | 120.5* | 126.4 | 132.7 | 123.7 | 139.3 | 178.3 | 48.2 | 21.9, 29.0, 33.4 |
| 4f | 5 | MeOD | 110.4 | 122.2 | 121.8 | 127.7 | 133.8 | 125.1 | 140.9 | 177.4 | 49.3 | 25.6, 27.3, 30.6, 34.7 |
| 4f | 5 | CDCl3 | 108.9 | 121.2 | 120.5 | 126.3 | 132.7 | 123.8 | 139.3 | 178.9 | 48.5 | 24.2, 26.2, 29.4, 33.8 |
| 4f | 5 | DMSO | 109.6 | 120.8 | 120.3 | 125.9 | 132.4 | 123.4 | 139.2 | 174.4 | 47.9 | 24.1, 25.8, 29.2, 33.6 |
| 4g | 6 | MeOD | 110.4 | 122.1* | 121.8* | 127.7 | 133.7 | 125.1 | 140.9 | 177.5 | 49.4 | 25.8, 27.4, 29.7, 30.7, 34.7 |
| 4h | 9 | MeOD | 110.4 | 122.2* | 121.8* | 127.7 | 133.7 | 125.1 | 140.9 | 177.7 | 49.5 | 26.0, 27.7, 30.11, 30.18, 30.2, 30.3, 30.9, 34.9 |
| 4i | 10 | MeOD | 110.4 | 122.1 | 121.8 | 127.7 | 133.7 | 125.1 | 140.9 | 177.7 | 49.5 | 26.0, 27.7, 30.1, 30.27, 30.34, 30.4, 30.9, 34.9 |
| 5b | 1 | DMSO | 117.0 | 120.8 | 121.2 | 125.8 | 125.5 | 121.6 | 148.2 | 169.3 | 54.2 | |
| 5c | 2 | MeOD | 117.4 | 121.6 | 122.7 | 127.6 | 125.9 | 122.9 | 150.1 | 174.0 | 49.9 | 35.6 |
| 5d | 3 | MeOD | 117.4 | 121.6* | 122.7* | 127.5 | 125.5 | 123.1 | 150.1 | 176.2 | 53.4 | 27.0, 31.5 |
| 5e | 4 | MeOD | 117.3 | 121.5* | 122.6* | 127.5 | 125.4 | 123.1 | 149.9 | 176.9 | 53.9 | 23.0, 31.0, 34.2 |
| 5f | 5 | MeOD | 117.3 | 121.5 | 122.6 | 127.4 | 125.4 | 123.1 | 149.9 | 177.3 | 54.1 | 25.5, 27.1, 31.3, 34.6 |
| 5g | 6 | MeOD | 117.3 | 121.5* | 122.6* | 127.4 | 125.3 | 123.0 | 149.9 | 177.5 | 54.2 | 25.8, 27.2, 29.6, 31.4, 34.7 |
| 5h | 9 | MeOD | 117.3 | 121.5 | 122.6 | 127.4 | 125.3 | 123.1 | 149.9 | 177.7 | 54.3 | 26.0, 27.5, 30.0, 30.1, 30.2, 30.3, 31.6, 34.9 |
| 5i | 10 | MeOD | 117.3 | 121.5* | 122.6* | 127.4 | 125.3 | 123.1 | 149.9 | 177.7 | 54.3 | 26.1, 27.5, 30.1, 30.2, 30.3, 30.38, 30.41, 31.6, 35.0 |
* These assignments may be reversed. The NMR assignment of the other compounds was done using two-dimensional NMR techniques.
The IR spectra of compounds 2 and 3 show ν(C=O) stretching bands in the range of 1731-1748 cm-1 and ν(C-O) stretching bands in the 1171-1212 cm-1region. The ν(C=O) stretching band frequencies are similar in both the N-1 and N-2 isomers. The absence of the NH stretching band confirmed the substitution on the nitrogen atom. The IR spectra of indazole carboxylic acids 4 and 5 show broad bands in the 3500-2300 cm-1 region, corresponding to the hydrogen-bonded O-H characteristic of carboxylic acids. These bands overlap the C-H stretching region around 3000 cm-1. The spectra also showed ν(C=O) stretching bands at the usually lower frequency than the corresponding esters, in the 1689-1736 cm-1 region. In general, the ν(C=O) stretching bands reveal a shift to lower wavenumber with an increasing alkyl side chain directly linked to the nitrogen atom of indazole.
The electron impact (EI) mass spectra of all compounds show the [M]+ ions with relative abundances varying from 5 to 100% of the respective base peaks, with small molecular peaks for compounds with longer side chains. In most of the spectra, the ions with m/z values corresponding to [IndzCH2]+ and [IndzH]+ (IndzH-Indazole) are either the base peaks or have high relative abundances. The mass spectra of 1H- and 2H-indazole ester derivatives 2 and 3 are similar and their fragmentation generally involves the formation of [M-OR]+, [M-COOR]+ and [M-(CH2)nCOOR]+ ions. Mass spectra of the 1H- and 2H-indazole carboxylic acid derivatives 4 and 5 are also similar. Their fragmentation involves the formation of [M-COOH]+ and [M-(CH2)nCOOH]+ ions.
Molecular and crystal structure of 2-indazol-2-yl-acetic acid (5b)
2-Indazol-2-yl-acetic acid (5b, n = 1) was recrystallized from acetone/water solution to afford crystals suitable for X-ray diffraction studies. Compound 5b crystallizes in the centrosymetric space group P21/n, with one molecule per asymmetric unit. The ORTEP [23] view of the molecule, with the atomic numbering scheme, is given in Figure 2. Detailed bond distances and angles and other structural parameters, are given in Table 6.
Figure 2.
ORTEP [23] view of compound 5b showing the atomic labelling scheme and the relative positioning of the indazole ring and the carboxylic moiety.
Figure 2.
ORTEP [23] view of compound 5b showing the atomic labelling scheme and the relative positioning of the indazole ring and the carboxylic moiety.
| N1-C7a | 1.349(2) | C3a-C4 | 1.421(2) |
| N1-N2 | 1.3526(19) | C8-C9 | 1.516(2) |
| N2-C3 | 1.334(2) | C5-C4 | 1.355(3) |
| N2-C8 | 1.446(2) | C5-C6 | 1.408(3) |
| C7a-C3a | 1.413(2) | C7-C6 | 1.360(3) |
| C7a-C7 | 1.413(3) | C9-O1 | 1.200(2) |
| C3a-C3 | 1.384(3) | C9-O2 | 1.307(2) |
| C7a-N1-N2 | 104.08(12) | N2-C8-C9 | 112.22(14) |
| C3-N2-N1 | 113.32(14) | C4-C5-C6 | 121.66(18) |
| C3-N2-C8 | 127.88(16) | C5-C4-C3a | 118.2(2) |
| N1-N2-C8 | 118.73(14) | C6-C7-C7a | 117.5(2) |
| N1-C7a-C3a | 111.07(15) | N2-C3-C3a | 107.08(16) |
| N1-C7a-C7 | 128.05(17) | C7-C6-C5 | 122.1(2) |
| C3a-C7a-C7 | 120.86(16) | O1-C9-O2 | 125.35(16) |
| C3-C3a-C7a | 104.44(14) | O1-C9-C8 | 124.33(15) |
| C3-C3a-C4 | 135.92(18) | O2-C9-C8 | 110.32(14) |
| C7a-C3a-C4 | 119.64(17) |
Angle between planes
C3a-C3-N1-N2-C7a and C9-O1-O2 87.2(1)
Torsion angles
N2-C8-C9-O1 10.0(3) N1-N2-C8-C9 87.99(19)
N2-C8-C9-O2 -169.98(15) C3-N2-C8-C9 -88.9(2)
Hydrogen bond
D-H…A D-H H...A D...A D-H..A
O2-H2...N1[a] 1.02(3) Å 1.68(3) Å 2.677(2) Å 164(3)o
[a]- symmetry operation 1/2-x,1/2+y,3/2-z
The molecular structure of the indazole is similar to that of related compounds reported in the literature [24]. As expected, the indazole moiety is planar, with maximum deviations of 0.0052(9) Å in the N1 atom. Atom C8 is still within the indazole least square plane, but the carboxyl group (COOH) is oriented perpendicularly, forming an angle of 87.2(1)° with the five membered pyrazole ring. The plane containing the COOH group bisects the indazole almost as a mirror plane, but no disorder was found in the molecule. The values of the torsion angles N2-C8-C9-O1 [10.0(3)°] and N2-C8-C9-O2 [-169.98(15)°], showing the planarity of the fragment, as well as N1-N2-C8-C9 [87.99(19)°] and C3-N2-C8-C9 [-88.9(2)°] support the relative orientation of the carboxy moiety described above.
The secondary structure of compound 5b presents a one dimensional zigzag chain, due to the short O2-H...N1 intermolecular hydrogen bond [2.677(2) Å with an angle of 164(3)°], which is preferably observed, instead of the ![Molecules 11 00867 i004]()
main pattern found in carboxylic acid derivatives (C-O-H…O-C-O-H…O contacts) [25]. The one-dimensional zigzag chain along the b axis obtained with a C(6) synthon as well as the weak π…π contacts [~ 2.75(4) Å] within neighbouring chains are shown in the packing diagrams of Figure 3 (a, b and c, respectively). The supramolecular motif found in the crystal structure of compound 5b agrees with the data in the literature, either for 1H-unsubstituted indazoles [26] where N-H…N hydrogen bonds are responsible for the supramolecular pattern, or with pyrazole [27] or even with pyrazole carboxylic acid derivatives [28] where the usual hydrogen bond ring pattern ![Molecules 11 00867 i004]()
[25] is not found, due to the strength of this heteromeric intermolecular interaction [29].
main pattern found in carboxylic acid derivatives (C-O-H…O-C-O-H…O contacts) [25]. The one-dimensional zigzag chain along the b axis obtained with a C(6) synthon as well as the weak π…π contacts [~ 2.75(4) Å] within neighbouring chains are shown in the packing diagrams of Figure 3 (a, b and c, respectively). The supramolecular motif found in the crystal structure of compound 5b agrees with the data in the literature, either for 1H-unsubstituted indazoles [26] where N-H…N hydrogen bonds are responsible for the supramolecular pattern, or with pyrazole [27] or even with pyrazole carboxylic acid derivatives [28] where the usual hydrogen bond ring pattern [25] is not found, due to the strength of this heteromeric intermolecular interaction [29].
Figure 3.
(a) and (b) View along axis a and b respectively, showing the C(6) hydrogen bond synthon, responsible for the zigzag chain. (c) Packing diagram along axis c shows the weak interaction between the zigzag neighbouring chains, due to the π…π contacts (drawings done with Mercury) [24b].
Figure 3.
(a) and (b) View along axis a and b respectively, showing the C(6) hydrogen bond synthon, responsible for the zigzag chain. (c) Packing diagram along axis c shows the weak interaction between the zigzag neighbouring chains, due to the π…π contacts (drawings done with Mercury) [24b].
Conclusions
A series of seventeen esters and sixteen carboxylic acids with side chains with different length derived from indazole substituted at N-1 and N-2, is reported. General synthetic routes to these compounds have been described and their full spectroscopic characterization and structural features have been presented. Spectroscopic data were used to assign the substitution patterns and the major differences in these data are pointed out. Recrystallization of compound 5b (n = 1) gave crystals suitable for X-ray crystal structure analysis. Application of these compounds to the synthesis of novel biologically active compounds will be described in a subsequent paper.
Experimental
General
Reagents were used as purchased and were purified when necessary according to standard procedures [30]. 7-Bromoheptanoic acid ethyl ester was a gift from CU Chemie Uetikon GmbH (Germany). Column chromatography was performed on silica gel (230-400 Mesh) under a positive pressure of nitrogen. Melting points were determined on a Reichert Thermovar melting point apparatus and are uncorrected. NMR spectra were recorded on a Bruker AMX 300 spectrometer (1H at 300 MHz, 13C at 75 MHz). Chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. The assignment of 1H- and 13C- multiplicities was done using a DEPT sequence, two-dimensional NMR (HETCOR and COSY) and irradiations techniques (Table 4 and Table 5). Infrared spectra were recorded on a Perkin Elmer FT-IR 1725xIR Fourier Transform spectrophotometer using either thin films on NaCl plates (film) or KBr discs (KBr) as stated. Only the characteristic bands are quoted in cm-1. Low-resolution mass spectra (MS) were recorded on a Kratos 25 RF or a Thermo Quest model GCQplus spectrometer. High-resolution mass spectra (HRMS) were obtained on a VG AutoSpect M instrument. Elemental analyses were performed on a CE instrument EA 1110CHNS-O or a Fisons EA-1108 elemental analyser (for compounds 4 and 5 see Table 2 and Table 3). Although compounds 2a-e [19,20,21], 3b-e [20,21], 4b-e [20,21,31] and 5b-e [20,21] have been noted previously in the literature, no full spectroscopic characterisation has been reported, therefore the full characterisation of these compounds is described herein.
General procedure 1 (using Kt-BuO as base). Kt-BuO (1.6 eq.) was added to a solution of indazole 1 (1 eq.) in THF at 0 oC. The reaction mixture was warmed to r.t., stirred over 1 h. and then recooled to 0 oC. After 15 min., excess X(CH2)nCO2R was added and the reaction mixture was allowed to warm to r.t. and stirred for 0.5-4 h. The solvent was removed under reduced pressure and the residue was redissolved in EtOAc, washed successively with water and brine and dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo. The resulting oil was purified by column chromatography (2:3 ether/petroleum ether).
General procedure 2 (using K2CO3 as base): A mixture of indazole 1 (1 eq.) and K2CO3 (3-10 eq.) in DMF was stirred at 80 oC. After 30 min., excess X(CH2)nCO2R was added and the reaction mixture was stirred for 4-24 h. at 80 oC. Upon cooling, the mixture was acidified with 10% aqueous HCl solution and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous MgSO4. After filtration, the solvent was removed in vacuo and the resulting oil was purified by column chromatography (2:3 ether/petroleum ether).
Indazole-1-carboxylic acid methyl ester (2a)
Following general procedure 1, reaction of indazole 1 (200 mg, 1.69 mmol) in THF (10 mL), Kt-BuO (260 mg, 2.73 mmol) and ClCO2CH3 (0.13 mL, 1.69 mmol) for 30 min. gave compound 2a (290 mg, 99%) as a white solid, mp 56-58 °C (Lit. [19] 58-60 °C); IR (KBr): 3013 (C-H)Ar, 2958 (C-H), 1736 (C=O), 1611, 1457 (C=C, C=N) cm-1; 1H NMR (CDCl3): δ 4.13 (s, 3 H, OCH3), 7.36 (t, J = 7.8, 1 H, 5-H or 6-H), 7.58 (dt, J = 7.8 and 0.9, 1 H, 5-H or 6-H), 7.76 (d, J = 7.8, 1 H, 4-H), 8.20 (s, 1 H, 3-H), 8.26 (d, J = 8.4, 1 H, 7-H); MS (EI): m/z (%)= 176 (100) [M]+, 145 (4) [M-OMe]+, 118 (19) [IndzH]+, 117 (9) [M-CO2Me]+; Anal. Calcd. for C9H8N2O2: C 61.36, H 4.58, N 15.90. Found: C 61.31, H 4.61, N 15.74.
Indazol-1-yl-acetic acid ethyl ester (2b) and indazol-2-yl-acetic acid ethyl ester (3b)
Following general procedure 1, reaction of indazole 1 (500 mg, 4.23 mmol) in THF (10 mL), Kt-BuO (665 mg, 5.93 mmol) and BrCH2CO2Et (0.56 mL, 5.08 mmol) for 2 h. gave compounds 2b (474 mg, 55%) and 3b (110 mg, 13%) as pale yellow oils. Compound 2b: IR (film): 3064 (C-H)Ar, 2983, 2940 (C-H), 1748 (C=O), 1619, 1504, 1470, 1435 (C=C, C=N), 1210 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.21 (t, J = 7.2, 3 H, OCH2CH3), 4.18 (q, J = 7.2, 2 H, OCH2CH3), 5.13 (s, 2 H, NCH2CO2Et), 7.15 (m, 1 H, 5-H), 7.33 (m, 2 H, 6-H and 7-H), 7.72 (dd, J = 8.1 and 0.6, 1 H, 4-H), 8.04 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 204 (27) [M]+, 131 (100) [M-CO2Et]+, 118 (2) [IndzH]+; HRMS (EI): calcd. for [M]+ (C11H12N2O2): 204.0899, found 204.0893. Compound 3b: IR (film): 3121, 3065 (C-H)Ar, 2984, 2941 (C-H), 1746 (C=O), 1630, 1520, 1475, 1429 (C=C, C=N), 1212 (C-O) cm-1; 1H-NMR (CDCl3): 1.28 (t, J = 7.2, 3 H, OCH2CH3), 4.25 (q, J = 7.2, 2 H, OCH2CH3), 5.19 (s, 2 H, NCH2CO2Et), 7.09 (t, J = 7.2, 1 H, 5-H), 7.29 (m, 1 H, 6-H), 7.66 (d, J = 8.4, 1 H, 4-H), 7.68 (dd, J = 8.7 and 0.6, 1 H, 7-H), 8.00 (s, 1 H, 3-H); MS (EI): m/z (%) = 204 (64) [M]+, 131 (100) [M-CO2Et]+, 118 (11) [IndzH]+; HRMS (EI) calcd. for [M]+ (C11H12N2O2): 204.0899, found 204.0903. Following general procedure 2, indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL), K2CO3 (10.53 g, 76.18 mmol) and BrCH2CO2Et (4.2 mL, 38.1 mmol) gave compound 2b (3.49 g, 67%) and compound 3b (1.16 g, 22%) after reacting for 24 h.
3-Indazol-1-yl-propionic acid ethyl ester (2c) and 3-indazol-2-yl-propionic acid ethyl ester (3c)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL), K2CO3 (10.53 g, 76.18 mmol) and Br(CH2)2CO2Et (4.9 mL, 38.1 mmol) for 4 h. gave compounds 2c (2.72g, 49%) and 3c (2.53 g, 46%) as pale yellow oils. Compound 2c: IR (film): 3062 (C-H)Ar, 2982, 2938 (C-H), 1734 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1192 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.16 (t, J = 7.2, 3 H, OCH2CH3), 2.96 (t, J = 6.9, 2 H, CH2CH2CO2Et), 4.08 (q, J = 7.2, 2 H, OCH2CH3), 4.67 (t, J = 6.9, 2 H, NCH2), 7.13 (t, J = 7.5, 1 H, 5-H), 7.38 (dt, J = 7.5 and 1.2, 1 H, 6-H), 7.48 (dd, J = 8.7 and 0.6, 1 H, 7-H), 7.70 (d, J = 8.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); MS (EI): m/z (%) = 218 (90) [M]+, 173 (58) [M-OEt]+, 145 (31) [M-CO2Et]+, 131 (100) [M-CH2CO2Et]+, 118 (45) [IndzH]+; HRMS (EI) calcd. for [M]+ (C12H14N2O2): 218.1055, found 218.1054. Compound 3c: IR (film): 3121, 3062 (C-H)Ar, 2982, 2938 (C-H), 1733 (C=O), 1628, 1517, 1471, 1446 (C=C, C=N), 1201 (C-O) cm-1; 1H- NMR (CDCl3): 1.21 (t, J = 7.2, 3 H, OCH2CH3), 3.03 (t, J = 6.6, 2 H, CH2CH2CO2Et), 4.11 (q, J = 7.2, 2 H, OCH2CH3), 4.69 (t, J = 6.6, 2 H, NCH2), 7.06 (t, J = 7.5, 1 H, 5-H), 7.27 (t, J = 8.7, 1 H, 6-H), 7.63 (d, J = 8.4, 1 H, 4-H), 7.68 (d, J = 8.7, 1 H, 7-H), 7.99 (s, 1 H, 3-H); MS (EI): m/z (%) = 218 (75) [M]+, 173 (24) [M-OEt]+, 145 (45) [M-CO2Et]+, 131 (42) [M-CH2CO2Et]+, 118 (100) [IndzH]+; HRMS (EI) calcd. for [M]+ (C12H14N2O2): 218.1055, found 218.1047. The reaction was also performed using general procedure 1. Analysis of the 1H-NMR spectrum of the crude product indicated the presence of 2c, 3c and 1 in the ratio 15:15:70.
4-Indazol-1-yl-butyric acid ethyl ester (2d) and 4-indazol-2-yl-butyric acid ethyl ester (3d)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL), K2CO3 (10.53 g, 76.18 mmol) and Br(CH2)3CO2Et (5.4 mL, 38.1 mmol) for 24 h. gave compounds 2d (3.49 g, 59%) and 3b (2.16 g, 37%) as pale yellow oils. Compound 2d: IR (film): 3063 (C-H)Ar, 2981, 2939 (C-H), 1731 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1190 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.21 (t, J = 7.2, 3 H, OCH2CH3), 2.19-2.32 (m, 4 H, CH2CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.45 (t, J = 6.6, 2 H, NCH2), 7.13 (dt, J = 7.5 and 0.9, 1 H, 5-H), 7.38 (m, 2 H, 6-H and 7-H), 7.71 (d, J = 8.1, 1 H, 4-H), 7.99 (s, 1 H, 3-H); MS (EI): m/z (%) = 232 (75) [M]+, 187 (100) [M-OEt]+, 159 (9) [M-CO2Et]+, 145 (22) [M-CH2CO2Et]+, 131 (76) [M-(CH2)2CO2Et]+, 118 (20) [IndzH]+; HRMS (EI) calcd. for [M]+ (C13H16N2O2): 232.1212, found 232.1212. Compound 3d: IR (film): 3119, 3061 (C-H)Ar, 2982, 2980 (C-H), 1730 (C=O), 1628, 1515, 1469, 1445 (C=C, C=N), 1186 (C-O) cm-1; 1H- NMR (CDCl3): δ 1.22 (t, J = 7.2, 3 H, OCH2CH3), 2,30 (m, 4 H, CH2CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.46 (t, J = 6.6, 2 H, NCH2), 7.06 (dt, J = 7.5 and 0.6, 1 H, 5-H), 7.27 (m, 1 H, 6-H), 7.63 (d, J = 8.7, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H), 7.88 (s, 1 H, 3-H); MS (EI): m/z (%) = 232 (68) [M]+, 187 (47) [M-OEt]+, 159 (7) [M]+, 145 (17) [M-CH2CO2Et]+, 131 (100) [M-(CH2)2CO2Et]+, 118 (36) [IndzH]+; HRMS (EI) calcd. for [M]+ (C13H16N2O2): 232.1212, found 232.1218. The reaction was also performed using general procedure 1. Analysis of the 1H-NMR spectrum of the crude product indicated the presence of 2d, 3d and 1 in the ratio 26:18:56.
5-Indazol-1-yl-pentanoic acid ethyl ester (2e) and 5-indazol-2-yl-pentanoic acid ethyl ester (3e)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL), K2CO3 (10.53 g, 76.18 mmol) and Br(CH2)4CO2Et (4.7 mL, 33.02 mmol) for 24 h. gave compounds 2e (3.67 g, 59%) and 3e (1.95 g, 31%) as pale yellow oils. Compound 2e: IR (film): 3062 (C-H)Ar, 2982, 2939 (C-H), 1732 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1184 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.22 (t, J = 7.2, 3 H, OCH2CH3), 1.60-1.70 (m, 2 H, CH2CH2CO2Et), 1.93-2.03 (m, 2 H, NCH2CH2), 2.32 (t, J = 7.2, 2 H, CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.40 (t, J = 7.2, 2 H, NCH2), 7.13 (dt, J = 7.2 and 1.8, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.73 (td, J = 8.1 and 0.9, 1 H, 4-H), 7.99 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 246 (27) [M]+, 201 (56) [M-OEt]+, 173 (10) [M-CO2Et]+, 131 (100) [M-(CH2)3CO2Et]+, 118 (30) [IndzH]+; HRMS (EI) calcd. for [M]+ (C14H18N2O2): 246.1368, found 246.1362. Compound 3e: IR (film): 3119, 3061 (C-H)Ar, 2980, 2942 (C-H), 1731 (C=O), 1630, 1516, 1469, 1446 (C=C, C=N), 1186 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.22 (t, J = 7.2, 3 H, OCH2CH3), 1.59-1.69 (m, 2 H, CH2CH2CO2Et), 2.00-2.10 (m, 2 H, NCH2CH2), 2.32 (t, J = 7.2, 2 H, CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.41 (t, J = 6.9, 2 H, NCH2), 7.06 (dt, J = 7.5 and 0.9, 1 H, 5-H), 7.27 (m, 1 H, 6-H), 7.63 (td, J = 8.4 and 0.9, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H), 7.89 (s, 1 H, 3-H); MS (EI): m/z (%) = 246 (62) [M]+, 201 (63) [M-OEt]+, 173 (35) [M-CO2Et]+, 159 (4) [M-CH2CO2Et]+, 145 (11) [M-(CH2)2CO2Et]+, 131 (100) [M-(CH2)3CO2Et]+, 118 (62) [IndzH]+; HRMS (EI) calcd. for [M]+ (C14H18N2O2): 246.1368, found 246.1367.
6-Indazol-1-yl-hexanoic acid ethyl ester (2f) and 6-indazol-2-yl-hexanoic acid ethyl ester (3f)
Following general procedure 2, reaction of indazole 1 (200 mg, 1.69 mmol) in DMF (2 mL), K2CO3 (2.34 g, 16.93 mmol) and Br(CH2)5CO2Et (0.6 mL, 3.39 mmol) for 5 h. gave compounds 2f (276 g, 62%) and 3f (150 mg, 34%) as pale yellow oils. Compound 2f: IR (film): 3061 (C-H)Ar, 2979, 2938, 2865 (C-H), 1731 (C=O), 1616, 1499, 1465, 1446 (C=C, C=N), 1181 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.22 (t, J = 7,2, 3 H, OCH2CH3), 1.34 (m, 2 H, CH2), 1.65 (m, 2 H, CH2CH2CO2Et), 1.94 (m, 2 H, NCH2CH2), 2.27 (t, J = 7.5, 2 H, CH2CO2Et), 4.09 (q, J = 7.2, 2 H, OCH2CH3), 4.38 (t, J = 7.2, 2 H, NCH2), 7.13 (dt, J = 7.2 and 1.8, 1 H, 5-H), 7.37 (m, 2 H, 6-H and 7-H), 7.73 (dd, J = 8.4 and 0.9, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 260 (11) [M]+, 215 (20) [M-OEt]+, 187 (4) [M-CO2Et]+, 173 (14) [M-CH2CO2Et]+, 131 (100) [M-(CH2)4CO2Et]+, 118 (14) [IndzH]+; HRMS (EI) calcd. for [M]+ (C15H20N2O2): 260.1525, found 260.1526. Compound 3f: IR (film): 3119, 3062 (C-H)Ar, 2980, 2938 (C-H), 1732 (C=O), 1628, 1516, 1465 (C=C, C=N), 1186 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.29 (t, J = 7.2, 3 H, OCH2CH3), 1.35 (m, 2 H, CH2), 1.67 (m, 2 H, CH2CH2CO2Et), 2.03 (m, 2 H, NCH2CH2), 2.28 (t, J = 7.5, 2 H, CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.40 (t, J = 7.2, 2 H, NCH2), 7.07 (t, J = 7.8, 1 H, 5-H), 7.27 (t, J = 7.8, 1 H, 6-H), 7.64 (d, J = 8.4, 1 H, 4-H), 7.70 (d, J = 8.7, 1 H, 7-H), 7.89 (s, 1H, 3-H); MS (EI): m/z (%) = 260 (67) [M]+, 215 (61) [M-OEt]+, 187 (28) [M-CO2Et]+, 173 (78) [M-CH2CO2Et]+, 131 (100) [M-(CH2)4CO2Et]+, 118 (61) [IndzH]+; HRMS (EI) calcd. for [M]+ (C15H20N2O2): 260.1525, found 260.1525. The reaction was also performed using general procedure 1. Analysis of the 1H-NMR spectrum of the crude product indicated the presence of 2f, 3f and 1 in the ratio 39:39:22.
7-Indazol-1-yl-heptanoic acid ethyl ester (2g) and 7-indazol-2-yl-heptanoic acid ethyl ester (3g)
Following general procedure 2, reaction of indazole 1 (500 mg, 4.23 mmol) in DMF (5 mL), K2CO3 (2.92 g, 21.20 mmol) and Br(CH2)6CO2Et (1.64 mL, 8.46 mmol) for 5 h. gave compounds 2g (714 mg, 61%) and 3g (422 mg, 36%) as pale yellow oils. Compound 2g: IR (film): 3061 (C-H)Ar, 2979, 2936, 2859 (C-H), 1731 (C=O), 1615, 1499, 1465, 1424 (C=C, C=N), 1180 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.23 (t, J = 7.2, 3 H, OCH2CH3), 1.33 (m, 4 H, 2×(CH2)), 1.57 (m, 2 H, CH2), 1.93 (m, 2 H, CH2), 2.25 (t, J = 7.5, 2 H, CH2CO2Et), 4.10 (q, J = 7.2, 2 H, OCH2CH3), 4.37 (t, J = 6.9, 2 H, NCH2), 7.13 (dt, J = 7.2 and 1.5, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 274 (7) [M]+, 229 (11) [M-OEt]+, 187 (17) [M-CH2CO2Et]+, 173 (6) [M-(CH2)2CO2Et]+, 131 (100) [M-(CH2)5CO2Et]+, 118 (22) [IndzH]+; HRMS (EI) calcd. for [M]+ (C16H22N2O2): 274.1681, found 274.1680. Compound 3g: IR (film): 3061 (C-H)Ar, 2979, 2933, 2859 (C-H), 1731 (C=O), 1628, 1515, 1466, 1446 (C=C, C=N), 1185 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.24 (t, J = 7.2, 3 H, OCH2CH3), 1.35 (m, 4 H, 2×(CH2)), 1.61 (m, 2 H, CH2CH2CO2Et), 2.02 (m, 2 H, NCH2CH2), 2.27 (t, J = 7.2, 2 H, CH2CO2Et), 4.11 (q, J = 7.2, 2 H, OCH2CH3), 4.40 (t, J = 7.2, 2 H, NCH2), 7.07 (t, J = 7.2, 1 H, 5-H), 7.27 (m, 1 H, 6-H), 7.64 (d, J = 8.4, 1 H, 4-H), 7.64 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.89 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 274 (15) [M]+, 229 (21) [M-OEt]+, 187 (27) [M-CH2CO2Et]+, 173 (5) [M-(CH2)2CO2Et]+, 131 (100) [M-(CH2)5CO2Et]+, 118 (21) [IndzH]+; HRMS (EI) calcd. for [M]+ (C16H22N2O2): 274.1681, found 274.1679.
10-Indazol-1-yl-decanoic acid methyl ester (2h) and 10-indazol-2-yl-decanoic acid methyl ester (3h)
Following general procedure 2, reaction of indazole 1 (1.00 g, 8.46 mmol) in DMF (10 mL), K2CO3 (5.85 g, 42.30 mmol) and Br(CH2)9CO2Me (2.96 mL, 12.69 mmol) for 12 h. gave compounds 2h (1.53 g, 63%) and 3h (825 mg, 34%) as pale yellow oils. Compound 2h: IR (film): 3061 (C-H)Ar, 2928, 2855 (C-H), 1739 (C=O), 1616, 1499, 1465, 1435 (C=C, C=N), 1196 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.26 (m, 10 H, 5×(CH2)), 1.56 (m, 2 H, CH2), 1.94 (m, 2 H, CH2), 2.28 (t, J = 7.2, 2 H, CH2CO2CH3), 3.65 (s, 3 H, OCH3), 4.36 (t, J = 6.9, 2 H, NCH2), 7.12 (dt, J = 7.2 and 1.5, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (d, J = 0.3, 1 H, 3-H); MS (EI): m/z (%) = 302 (20) [M]+, 271 (15) [M-OMe]+, 243 (2) [M-CO2Me]+, 229 (23) [M-CH2CO2Me]+, 187 (12) [M-(CH2)4CO2Me]+, 173 (16) [M-(CH2)5CO2Me]+, 131 (100) [M-(CH2)8CO2Me]+, 118 (34) [IndzH]+; HRMS (EI) calcd. for [M]+ (C18H26N2O2): 302.1994, found 302.1985. Compound 3h: IR (film): 3060 (C-H)Ar, 2928, 2855 (C-H), 1739 (C=O), 1628, 1515, 1466, 1436 (C=C, C=N), 1196 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.27 (m, 10 H, 5×(CH2)), 1.59 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 2.28 (t, J = 7.2, 2 H, CH2CO2CH3), 3.65 (s, 3 H, OCH3), 4.39 (t, J = 7.2, 2 H, NCH2), 7.06 (m, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.64 (d, J = 8.4, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H), 7.89 (s, 1 H, 3-H); MS (EI): m/z = 302 (68) [M]+, 271 (35) [M-OMe]+, 229 (54) [M-CH2CO2Me]+, 187 (42) [M-(CH2)4CO2Me]+, 173 (37) [M-(CH2)5CO2Me]+, 131 (100) [M-(CH2)8CO2Me]+, 118 (91) [IndzH]+; HRMS (EI) calcd. for [M]+ (C18H26N2O2): 302.1994, found 302.1992.
11-Indazol-1-yl-undecanoic acid methyl ester (2i) and 11-indazol-2-yl-undecanoic acid methyl ester (3i)
Following general procedure 2, reaction of indazole 1 (1.02 g, 8.61 mmol) in DMF (10 mL), K2CO3 (5.85 g, 42.33 mmol) and Br(CH2)10CO2Et (3.06 mL, 12.68 mmol) for 7 h. gave compounds 2i (1.64 g, 60%) as a white solid and 3i (1.04 g, 38%) as a pale yellow oil. Compound 2i: mp 52-54 °C; IR (KBr): 3058 (C-H)Ar, 2914, 2847 (C-H), 1741 (C=O), 1617, 1495, 1466, 1438 (C=C, C=N), 1176 (C-O) cm-1; 1H-MR (CDCl3): δ 1.28 (m, 12 H, 6×(CH2)), 1.60 (m, 2 H, CH2), 1.92 (m, 2 H, CH2), 2.29 (t, J = 7.5, 2 H, CH2CO2CH3), 3.66 (s, 3 H, OCH3), 4.37 (t, J = 7.2, 2 H, NCH2), 7.13 (t, J = 7.2, 1 H, 5-H), 7.38 (m, 2 H, 6-H and H-7), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 316 (6) [M]+, 243 (11) [M-(CH2)CO2Me]+, 187 (7) [M-(CH2)5CO2Me]+, 173 (11) [M-(CH2)6CO2Me]+, 131 (100) [M-(CH2)9CO2Me]+, 118 (41) [IndzH]+. Anal. Calcd. for C19H28N2O2: C 72.12, H 8.92, N 8.85. Found: C 72.15, H 8.87, N 8.79. Compound 3i: IR (film): 3060 (C-H)Ar, 2922, 2855 (C-H), 1732 (C=O), 1628, 1515, 1465, 1435 (C=C, C=N), 1771 (C-O) cm-1; 1H-NMR (CDCl3): δ 1.25 (m, 12 H, 6×(CH2)), 1.60 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 2.29 (t, J = 7.5, 2 H, CH2CO2CH3), 3.65 (s, 3 H, OCH3), 4.40 (t, J = 7.2, 2 H, NCH2), 7.06 (m, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.64 (td, J = 8.7 and 0.9, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.6, 1 H, 7-H), 7.90 (d, J = 0.6, 1 H, 3-H); MS (EI): m/z = 316 (78) [M]+, 285 (40) [M-OMe]+, 243 (72) [M-CH2CO2Me]+, 187 (42) [M-(CH2)5CO2Me]+, 173 (39) [M-(CH2)6CO2Me]+, 131 (100) [M-(CH2)9CO2Me]+, 118 (90) [IndzH]+; HRMS (EI) calcd. for [M]+ (C19H28N2O2): 316.2151, found 316.2154.
General procedure 3: Indazole ester derivative (2 or 3) (1 eq.) and excess aqueous NaOH solution (10 M) was stirred at reflux for 1-5 h. After cooling, the mixture was acidified with 10% aqueous HCl solution and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. The resulting solid was purified by recrystallisation from ethyl acetate/petroleum ether. The following compounds were prepared following this procedure:
Indazol-1-yl-acetic acid (4b)
Reaction of compound 2b (2.42 g, 11.86 mmol) in aqueous NaOH solution (10 M, 10 mL) for 5 h. gave compound 4b (2.02 g, 97%) as white crystals, mp 186-188 °C (Lit. [20] 185-186 °C (H2O)); IR (KBr): 3300-2300 (COO-H), 3112 (C-H)Ar, 2943 (C-H) 1736 (C=O), 1618, 1507, 1464 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 5.22 (s, 2 H, NCH2), 7.17 (dt, J = 7.5 and 0.9, 1 H, 5-H), 7.42 (dt, J = 7.2 and 0.9, 1 H, 6-H), 7.51 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.76 (d, J = 7.5, 1 H, 4-H), 8.04 (d, J = 0.6, 1 H, 3-H); MS (EI): m/z (%) = 176 (33) [M]+, 131 (100) [M-CO2H]+.
3-Indazol-1-yl-propionic acid (4c)
Reaction of compound 2c (2.72 g, 12.45 mmol) in aqueous NaOH solution (10 M, 10 mL) for 3 h. gave compound 4c (2.32 g, 98%) as white crystals, mp 106-107 °C (Lit. [20] 105.5-106.5 °C (C6H6/petroleum ether)); IR (KBr): 3300-2300 (COO-H), 2932 (C-H), 1718 (C=O), 1655, 1618, 1502, 1466 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 2.91 (t, J = 6.9, 2 H, CH2CO2H), 4.65 (t, J = 6.6, 2 H, NCH2), 7.13 (t, J = 7.8, 1 H, 5-H), 7.39 (t, J = 7.8, 1 H, 6-H), 7.59 (d, J = 8.1, 1 H, 7-H), 7.71 (d, J = 8.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); MS (EI): m/z (%) = 190 (20) [M]+, 131 (100) [M-CH2CO2H]+, 118 (9) [IndzH]+.
4-Indazol-1-yl-butyric acid (4d)
Reaction of compound 2d (3.49 g, 15.02 mmol) in aqueous NaOH solution (10 M, 15 mL) for 3 h. gave compound 4d (2.85 g, 93%) as white crystals, mp 60-62 °C; IR (KBr): 3300-2400 (COO-H), 3057 (C-H)Ar, 2948 (C-H), 1690 (C=O), 1616, 1497, 1463 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 2.10-2.27 (m, 4 H, CH2CH2), 4.45 (t, J = 6.9, 2 H, NCH2), 7.13 (t, J = 7.8, 1 H, 5-H), 7.39 (m, 1 H, 6-H), 7.54 (d, J = 8.4, 1 H, 7-H), 7.73 (dd, J = 8.1 and 0.9, 1 H, 4-H), 8.00 (s, 1 H, 3-H); 1H NMR (CDCl3): δ 2.23 (m, 2 H, NCH2CH2), 2.35 (t, J = 7.2, 2 H, CH2CO2H), 4.49 (t, J = 6.6, 2 H, NCH2), 7.13 (dt, J = 7.2 and 0.9, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 8.02 (s, 1 H, 3-H); MS (EI): m/z (%) = 204 (14) [M]+, 131 (100) [M-(CH2)2CO2H]+, 118 (9) [IndzH]+.
5-Indazol-1-yl-pentanoic acid (4e)
Reaction of compound 2e (216 mg, 0.879 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h. gave compound 4e (189 mg, 99%) as white crystals, mp 82-83 °C; IR (KBr): 3500-2400 (COO-H), 3108 (C-H)Ar, 2931 (C-H), 1712 (C=O), 1617, 1501, 1454 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.55 (m, 2 H, CH2CH2CO2H), 1.92 (m, 2 H, NCH2CH2), 2.27 (t, J = 7.2, 2 H, CH2CO2H), 4.40 (t, J = 6.9, 2 H, NCH2), 7.12 (t, J = 7.5, 1 H, 5-H), 7.38 (t, J = 8.1, 1 H, 6-H), 7.53 (d, J = 8.7, 1 H, 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); 1H-NMR (CDCl3): δ 1.66 (m, 2 H, CH2), 1.99 (m, 2 H, CH2), 2.37 (t, J = 7.2, 2 H, CH2CO2H), 4.41 (t, J = 6.9, 2 H, NCH2), 7.14 (dt, J = 7.2 and 2.1, 1 H, 5-H), 7.40 (m, 2 H, 6-H and 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 8.02 (s, 1 H, 3-H); MS (EI): m/z (%) = 218 (16) [M]+, 131 (100) [M-(CH2)3CO2H]+, 118 (19) [IndzH]+.
6-Indazol-1-yl-hexanoic acid (4f)
Reaction of compound 2f (1.35 g, 5.19 mmol) in aqueous NaOH solution (10 M, 5 mL) for 2 h. gave compound 4f (1.20 g, 100%) as white crystals, mp 69-70 °C; IR (KBr): 3500-2350 (COO-H), 3058, 3042 (C-H)Ar, 2969, 2936, 2871 (C-H), 1691 (C=O), 1638, 1617, 1498, 1438 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.30 (m, 2 H, CH2), 1.60 (m, 2 H, CH2CH2CO2H), 1.92 (m, 2 H, NCH2CH2), 2.22 (t, J = 7.2, 2 H, CH2CO2H), 4.40 (t, J = 7.2, 2 H, NCH2), 7.13 (t, J = 7.1, 1 H, 5-H), 7.39 (dt, J = 7.8 and 0.9, 1 H, 6-H), 7.53 (d, J = 8.7, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); 1H-NMR (CDCl3): δ 1.38 (m, 2 H, CH2), 1.67 (m, 2 H, CH2CH2CO2H), 1.95 (m, 2 H, NCH2CH2), 2.33 (t, J = 7.2, 2 H, CH2CO2H), 4.40 (t, J = 7.2, 2 H, NCH2), 7.14 (dt, J = 6.9 and 2.1, 1 H, 5-H), 7.40 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); 1H-NMR (DMSO): δ 1.22 (m, 2 H, CH2), 1.49 (m, 2 H, CH2CH2CO2H), 1.80 (m, 2 H, NCH2CH2), 2.14 (t, J = 7.2, 2 H, CH2CO2H), 4.37 (t, J = 6.9, 2 H, NCH2), 7.10 (dt, J = 6.9 and 0.9, 1 H, 5-H), 7.35 (dt, J = 7.8 and 0.9, 1 H, 6-H), 7.63 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 8.03 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 232 (13) [M]+, 173 (19) [M-CH2CO2H]+, 131 (100) [M-(CH2)4CO2H]+, 118 (25) [IndzH]+.
7-Indazol-1-yl-heptanoic acid (4g)
Reaction of compound 2g (720 mg, 2.61 mmol) in aqueous NaOH solution (10 M, 2.5 mL) for 2 h. gave compound 4g (474 mg, 74%) as white crystals, mp 54-58 °C; IR (KBr): 3350-2400 (COO-H), 3041 (C-H)Ar, 2929, 2908, 2855 (C-H), 1701 (C=O), 1614, 1561, 1462 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.30 (m, 4 H, 2×(CH2)), 1.51 (m, 2 H, CH2), 1.90 (m, 2 H, CH2), 2.22 (t, J = 7.2, 2 H, CH2CO2H), 4.39 (t, J = 6.9, 2 H, NCH2), 7.13 (dt, J = 7.8 and 0.9, 1 H, 5-H), 7.39 (dt, J = 7.8 and 0.9, 1 H, 6-H), 7.53 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 7.98 (d, J = 0.6, 1 H, 3-H); MS (EI): m/z (%) = 246 (12) [M]+, 187 (21) [M-CH2CO2H]+, 131 (100) [M-(CH2)5CO2H]+, 118 (31) [IndzH]+.
10-Indazol-1-yl-decanoic acid (4h)
Reaction of compound 2h (1.02 g, 3.36 mmol) in aqueous NaOH solution (10 M, 3.0 mL) for 2 h. gave compound 4h (913 mg, 93%) as white crystals, mp 78-81 °C; IR (KBr): 3360-2400 (COO-H), 3041 (C-H)Ar, 2932, 2915, 2845 (C-H), 1689 (C=O), 1615, 1497, 1467, 1428 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.24 (m, 10 H, 5×(CH2)), 1.54 (m, 2 H, CH2), 1.87 (m, 2 H, CH2), 2.23 (t, J = 7.5, 2 H, CH2CO2H), 4.39 (t, J = 6.9, 2 H, NCH2), 7.13 (t, J = 7.5, 1 H, 5-H), 7.38 (t, J = 7.5, 1 H, 6-H), 7.52 (d, J = 8.4, 1 H, 7-H), 7.73 (dd, J = 8.4 and 0.9, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 288 (13) [M]+, 229 (11) [M-CH2CO2H]+, 187 (9) [M-(CH2)4CO2H]+, 173 (14) [M-(CH2)5CO2H]+, 131 (100) [M-(CH2)8CO2H]+, 118 (51) [IndzH]+.
11-Indazol-1-yl-undecanoic acid (4i)
Reaction of compound 2i (755 mg, 2.39 mmol) in aqueous NaOH solution (10 M, 3 mL) for 2 h. gave compound 4i (686 mg, 95%) as white crystals, mp 73-74 °C; IR (KBr): 3350-2400 (COO-H), 3041 (C-H)Ar, 2921, 2849 (C-H), 1691 (C=O), 1615, 1497, 1464, 1428 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.23 (m, 12 H, 6×(CH2)), 1.54 (m, 2 H, CH2CH2CO2H), 1.86 (m, 2 H, NCH2CH2), 2.24 (t, J = 7.5, 2 H, CH2CO2H), 4.38 (t, J = 6.9, 2 H, NCH2), 7.12 (dt, J = 7.8 and 0.9, 1 H, 5-H), 7.38 (dt, J = 7.8 and 1.2, 1 H, 6-H), 7.51 (dd, J = 8.4 and 0.6, 1 H, 7-H), 7.72 (dd, J = 8.1 and 0.9, 1 H, 4-H), 7.98 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 302 (6) [M]+, 243 (7) [M-CH2CO2H]+, 187 (6) [M-(CH2)5CO2H]+, 173 (10) [M-(CH2)6CO2H]+, 131 (100) [M-(CH2)9CO2H]+, 118 (59) [IndzH]+.
Indazol-2-yl-acetic acid (5b)
Reaction of compound 3b (100 mg, 0.49 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h. gave compound 5b (83 mg, 96%) as white crystals, mp 254-256 °C (Lit. [20] 257 °C (dec.)); IR (KBr): 3300-2300 (COO-H), 3130 (C-H)Ar, 2986, 2944 (C-H), 1719 (C=O), 1628, 1517, 1481 (C=C, C=N) cm-1; 1H-NMR (DMSO): δ 5.29 (s, 2 H, NCH2), 7.03 (t, J = 7.5, 1 H, 5-H), 7.24 (t, J = 8.7, 1 H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.71 (d, J = 8.4, 1 H, 4-H), 8.36 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 176 (5) [M]+, 131 (100) [M-CO2H]+, 118 (34) [IndzH]+.
3-Indazol-2-yl-propionic acid (5c)
Reaction of compound 3c (2.53 g, 11.61 mmol) in aqueous NaOH solution (10 M, 10 mL) for 2.5 h. gave compound 5c (2.16 g, 98%) as white crystals, mp 147-149 °C (Lit. [20] 148-149 °C (H2O)); IR (KBr): 3300-2300 (COO-H), 3128 (C-H)Ar, 2927 (C-H), 1708 (C=O), 1626, 1516, 1476 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 3.00 (t, J = 6.6, 2 H, CH2CO2H), 4.68 (t, J = 6.6, 2 H, NCH2), 7.04 (t, J =7.5, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.57 (dd, J = 8.9 and 0.9, 1 H, 7-H), 7.64 (d, J = 8.4, 1 H, 4-H), 8.18 (s, 1 H, 3-H); MS (EI): m/z (%) = 190 (29) [M]+, 145 (7) [M-CO2H]+, 131 (13) [M-CH2CO2H]+, 118 (100) [IndzH]+.
4-Indazol-2-yl-butyric acid (5d)
Reaction of compound 3d (143 mg, 0.62 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h. gave compound 5d (122 mg, 97%) as white crystals, mp 132-134 °C; IR (KBr): 3450-2300 (COO-H), 3119 (C-H)Ar, 2937 (C-H), 1698 (C=O), 1626, 1508, 1474, (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 2.26 (m, 4 H, CH2CH2CO2H), 4.49 (t, J = 6.6, 2 H, NCH2), 7.06 (t, J = 7.8, 1 H, 5-H), 7.28 (t, J = 8.1, 1H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.67 (d, J = 8.4, 1 H, 4-H), 8.19 (s, 1 H, 3-H); MS (EI): m/z (%) = 204 (28) [M]+, 131 (100) [M-(CH2)2CO2H]+, 118 (55) [IndzH]+.
5-Indazol-2-yl-pentanoic acid (5e)
Reaction of compound 3e (168 mg, 0.68 mmol) in aqueous NaOH solution (10 M, 2 mL) for 2 h. gave compound 5e (134 mg, 90%) as white crystals, mp 112-114 °C; IR (KBr): 3450-2300 (COO-H), 3129 (C-H)Ar, 2944 (C-H), 1701 (C=O), 1636, 1508, 1458 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.55 (m, 2 H, CH2CH2CO2H), 2.00 (m, 2 H, NCH2CH2), 2.30 (t, J = 7.2, 2 H, CH2CO2H), 4.41 (t, J = 6.9, 2 H, NCH2), 7.05 (t, J = 8.1, 1 H, 5-H), 7.26 (t, J = 8.7, 1 H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.66 (d, J = 8.4, 1 H, 4-H), 8.16 (d, J = 1.5, 1 H, 3-H); MS (EI): m/z (%) = 218 (5) [M]+, 173 (3) [M-CO2H]+, 131 (24) [M-(CH2)3CO2H]+, 118 (11) [IndzH]+, 61 (100).
6-Indazol-2-yl-hexanoic acid (5f)
Reaction of compound 3f (1.05 mg, 4.04 mmol) in aqueous NaOH solution (10 M, 3 mL) for 2 h. gave compound 5f (553 mg, 59%) as white crystals, mp 86-87 °C; IR (KBr): 3330-2400 (COO-H), 3131 (C-H)Ar, 2948, 2867 (C-H), 1717 (C=O), 1626, 1517, 1466, 1451 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.31 (m, 2 H, CH2), 1.62 (m, 2 H, CH2CH2CO2H), 1.98 (m, 2 H, NCH2CH2), 2.25 (t, J = 7.2, 2 H, CH2CO2H), 4.41 (t, J = 7.2, 2 H, NCH2), 7.04 (t, J = 7.2, 1 H, 5-H), 7.26 (t, J = 7.2, 1 H, 6-H), 7.57 (d, J = 8.7, 1 H, 7-H), 7.66 (d, J = 8.4, 1 H, 4-H), 8.16 (s, 1 H, 3-H); MS (EI): m/z (%) = 232 (23) [M]+, 173 (50) [M-CH2CO2H]+, 131 (100) [M-(CH2)4CO2H]+, 118 (82) [IndzH]+.
7-Indazol-2-yl-heptanoic acid (5g)
Reaction of compound 3g (251 mg, 1.28 mmol) in aqueous NaOH solution (10 M, 1.5 mL) for 30 min. gave compound 5g (195 mg, 62%) as white crystals, mp 77-78 °C; IR (KBr): 3350-2400 (COO-H), 3127 (C-H)Ar, 2934, 2857 (C-H), 1707 (C=O), 1629, 1515, 1465, 1433 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.32 (m, 4 H, 2×(CH2)), 1.56 (m, 2 H, CH2), 1.96 (m, 2 H, CH2), 2.24 (t, J = 7.2, 2 H, CH2CO2H), 4.40 (t, J = 7.2, 2 H, NCH2), 7.05 (t, J = 7.5, 1 H, 5-H), 7.27 (t, J = 7.5, 1 H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.66 (d, J = 8.4, 1 H, 4-H), 8.16 (s, 1 H, 3-H); MS (EI): m/z (%) = 246 (26) [M]+, 187 (51) [M-CH2CO2H]+, 173 (18) [M-(CH2)2CO2H]+, 131 (100) [M-(CH2)5CO2H]+, 118 (78) [IndzH]+.
10-Indazol-2-yl-decanoic acid (5h)
Reaction of compound 3h (710 mg, 2.35 mmol) in aqueous NaOH solution (10 M, 2.5 mL) for 2 h. gave compound 5h (611 mg, 90%) as white crystals, mp 68 °C; IR (KBr): 3350-2400 (COO-H), 3128 (C-H)Ar, 2922, 2850, (C-H), 1711 (C=O), 1627, 1515, 1469, 1432 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.27 (m, 10 H, 5×(CH2)), 1.55 (m, 2 H, CH2), 1.97 (m, 2 H, CH2), 2.24 (t, J = 7.2, 2 H, CH2CO2H), 4.41 (t, J = 6,9, 2 H, NCH2), 7.05 (t, J = 7.5, 1 H, 5-H), 7.27 (t, J = 7.2, 1 H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.67 (d, J = 8.4, 1 H, 4-H), 8.18 (s, 1 H, 3-H); MS (EI): m/z (%) = 288 (33) [M]+, 229 (20) [M-CH2CO2H]+, 187 (20) [M-(CH2)4CO2H]+, 173 (21) [M-(CH2)5CO2H]+, 131 (97) [M-(CH2)8CO2H]+, 118 (100) [IndzH]+.
11-Indazol-1-yl-undecanoic acid (5i)
Reaction of compound 3i (311 mg, 0.98 mmol) in aqueous NaOH solution (10 M, 1.5 mL) for 2 h. gave compound 5i (276 mg, 93%) as white crystals, mp 82 °C; IR (KBr): 3500-2390 (COO-H), 3127 (C-H)Ar, 2935, 2916, 2848 (C-H), 1708 (C=O), 1629, 1515, 1462, 1434 (C=C, C=N) cm-1; 1H-NMR (MeOD): δ 1.27 (m, 12 H, 6×(CH2)), 1.56 (m, 2 H, CH2), 1.98 (m, 2 H, CH2), 2.25 (t, J = 7.5, 2 H, CH2CO2H), 4.42 (t, J = 7.2, 2 H, NCH2), 7.05 (t, J = 7.2, 1 H, 5-H), 7.27 (t, J = 7.5, 1 H, 6-H), 7.57 (d, J = 8.7, 1 H, 7-H), 7.67 (dd, J = 8.1 and 0.6, 1 H, 4-H), 8.19 (s, 1 H, 3-H); MS (EI): m/z (%) = 302 (18) [M]+, 243 (16) [M-CH2CO2H]+, 187 (17) [M-(CH2)5CO2H]+, 173 (18) [M-(CH2)6CO2H]+, 131 (98) [M-(CH2)9CO2H]+, 118 (100) [IndzH]+.
X-ray data analysis of compound 5b
Data were collected in a CAD-4, equipped with a rotating anode, using Cu radiation (λ=1.5418 Å). Cell dimensions were determined from the setting angles of 25 reflections. Data were corrected for Lorentz and polarization effects. The structure was solved by direct methods using SIR97 [32] and refined using SHELXL [33] within the WinGX suite of programs [34]. Non-hydrogen atoms were refined anysotropically and H atoms were identified from the Fourier difference map and allowed to refine freely. The crystal data and refinement parameters are summarized in Table 7.
CCDC 279230 contains the supplementary crystallographic data on this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK; E-mail: deposit@ccdc.cam.ac.uk.
| Empirical formula | C9 H8 N2O2 |
| Formula weight | 176.17 |
| Temperature | 293(2) K |
| Wavelength | 1.54184 A |
| Crystal system, space group | Monoclinic, P21/n |
| Unit cell dimensions | a = 9.615(2) Å |
| b = 8.524(2) Å β = 92.420(10)° | |
| c = 10.109(6) Å | |
| Volume | 827.8(6) A3 |
| Z, Calculated density | 4, 1.414 Mg/m3 |
| Absorption coefficient | 0.855 mm-1 |
| F(000) | 368 |
| Crystal size | 0.5 × 0.4 × 0.2 mm |
| Theta range for data collection | 6.80 to 59.39 deg. |
| Limiting indices | -10<=h<=0, -9<=k<=0, -11<=l<=11 |
| Reflections collected / unique | 1281 / 1201 [R(int) = 0.0134] |
| Completeness to theta = 59.39 | 99.2% |
| Absorption correction | None |
| Refinement method | Full-matrix least-squares on F2 |
| Data / restraints / parameters | 1201 / 0 / 151 |
| Goodness-of-fit on F2 | 1.134 |
| Final R indices [I>2sigma(I)] | R1 = 0.0411, wR2 = 0.0980 |
| R indices (all data) | R1 = 0.0571, wR2 = 0.1054 |
| Extinction coefficient | 0.017(2) |
| Largest diff. peak and hole | 0.210 and -0.223 e. Å-3 |
Acknowledgments
We thank Fundação para a Ciência e a Tecnologia (POCTI, POCI and FEDER programs) for provision of funding (Projects POCTI/QUI/39368/ 2001 and POCI/QUI/55508/2004).
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Teixeira, F.C.; Ramos, H.; Antunes, I.F.; Curto, M.J.M.; Duarte, M.T.; Bento, I. Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives. Molecules 2006, 11, 867-889. https://doi.org/10.3390/11110867
AMA Style
Teixeira FC, Ramos H, Antunes IF, Curto MJM, Duarte MT, Bento I. Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives. Molecules. 2006; 11(11):867-889. https://doi.org/10.3390/11110867
Chicago/Turabian StyleTeixeira, Fátima C., Hélène Ramos, Inês F. Antunes, M. João M. Curto, M. Teresa Duarte, and Isabel Bento. 2006. "Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives" Molecules 11, no. 11: 867-889. https://doi.org/10.3390/11110867
APA StyleTeixeira, F. C., Ramos, H., Antunes, I. F., Curto, M. J. M., Duarte, M. T., & Bento, I. (2006). Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives. Molecules, 11(11), 867-889. https://doi.org/10.3390/11110867
