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Communication

Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation

1
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
2
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile
3
Centro Interdisciplinario de Neurociencias, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago 8330024, Santiago, Chile
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(8), 2051; https://doi.org/10.3390/molecules23082051
Submission received: 7 July 2018 / Revised: 11 August 2018 / Accepted: 14 August 2018 / Published: 16 August 2018
(This article belongs to the Special Issue Recent Advances in Nitrogen-Containing Aromatic Heterocycles)

Abstract

:
Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.

Graphical Abstract

1. Introduction

The indazole ring is a heterocycle which, being an isostere of the indole ring, exhibits a very interesting medicinal chemistry potential. Having shown a broad variety of biological activities, this heterocycle could lead to the development of several pharmaceutical products [1]. Interestingly, the indazole nucleus is scarcely found in Nature, and to date, only three natural products containing this unit have been isolated: nigellicine [2], nigeglanine [3], and nigellidine [4]. For these reasons, the development of synthetic methodologies aimed at this aromatic moiety is an active area of research. Our research group has been conducting efforts to develop novel 5-HT6 receptor antagonists [5,6,7]. In this sense, we are very interested in preparing 5-HT6 receptor ligands based on the indazole nucleus, where a key intermediate in the envisaged synthetic route of these serotonergic ligands is 3-vinylindazole. The synthesis of this parent compound has been reported in some works, the first of them carrying out its preparation from synthetically complex precursors. In the 70s Igeta et al. obtained 3-vinylindazole through both thermal and basic decomposition of 1-(pyridazino [1,6-b]indazol-9(4aH)-yl)ethan-1-one with poor to moderate yields [8,9]. Another work from Tsuchiya’s group reported the synthesis of 3-vinyl indazole through a rearrangement of 3H-diazepines by thermo- or photo-stimulation in outstanding yields (95% and 90% respectively) [10]. Furthermore, Petrillo et al. described the preparation of 3-vinylindazole from o-allylphenylazosulfides in basic media with excellent yield [11] (Scheme 1).
However, despite the excellent reported yields, none of these works have dealt with obtaining C-5-substituted 3-vinylindazole derivatives. On the other hand, cross-coupling reactions have been widely studied as a way to perform palladium or nickel catalyzed vinylation reactions with aryl halide (or pseudohalide) substrates [12,13,14]. Nevertheless, despite the vast number of developed transition metal-catalyzed cross-coupling reactions, only a small fraction of these accommodate the attachment of a simple vinyl unit, with an aryl halide being used as the substrate an overwhelming number of times more than the heteroaryl halides [12]. On the other hand, in an outstanding work by Buchwald et al. the authors describe the arylation and heteroarylation of unprotected, nitrogen-rich heterocycles through a Suzuki cross-coupling reaction [15]. However, in this work the authors do not investigate the vinylation reaction over these substrates. In this sense, some reports have used cross-coupling reactions to functionalize the indazole ring as an attractive alternative to cyclization reactions. The most notable works in this area have been performed by Collot et al. [16,17,18,19,20,21,22]. In one of such works, the authors report the synthesis of a C-3 methyl acrylate-substituted indazole ring through a Heck cross-coupling reaction in order to easily obtain azatryptamines [18]. However, in the case of our compounds the presence of the ester function does not allow the easy preparation of our scaffold. More recently, the preparation of some 3-vinylindazole derivatives using cross-coupling reactions has been reported [23,24,25,26]. In one of them, the parent 3-vinylindazole was prepared in 60% yield from 3-bromo-1H-indazole via Stille coupling, the main drawback being the toxicity of the tin compounds used [23]. In another work by Sampson et al. the authors managed to prepare one 6-functionalized 3-vinylindazole with very good yield, but in a long time of reaction, via Suzuki cross-coupling in the context of the discovery of Polo-Like kinase 4 inhibitors as antitumoral agents [24]. In another example, the authors achieved the synthesis of 3-vinyl-1H-indazol-5-carboxylic acid methyl ester from the corresponding N-unprotected 3-iodoindazole via Suzuki cross-coupling under microwave irradiation at 160 °C in 40% yield [25]. Finally, in a patent by Li et al. the authors managed to prepare a highly functionalized 3-vinylindazole derivative in 39% yield using three equivalents of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane and 10 mol% of catalyst under conventional heating in a very long time of reaction [26]. Additionally, amongst the cross-couplings reactions, the Suzuki-Miyaura coupling is arguably the most important C-C-coupling method employed due to its broad substrate scope, high level of functional group tolerance, and, with modern catalysts, high turnover rates [15,27]. Considering all this gathered background, we set ourselves the goal of evaluating the vinylation reaction directly on the indazole nucleus through a Suzuki cross-coupling reaction and explore the influence of the electronic properties of the C-5 substituent on the indazole nucleus on the course of the reaction. Consequently, the following reaction sequence was proposed (Scheme 2).

2. Results and Discussions

2.1. Synthesis of Starting Materials

According to Scheme 2, the first step in the envisaged pathway involved the preparation of the 3-iodinated derivatives of several C-5 substituted commercial indazoles in a N,N-dimethyl-formamide (N,N-DMF) solution under standard basic conditions [16,18,28]. Thus, the corresponding 5-R-3-iodoindazole derivatives were obtained in excellent yields ranging from 87% to 100% (Scheme 3). An exception was 5-amino-3-iodoindazole; due to the high insolubility of the substrate in the reaction solvent, the product was obtained through a three-step sequence with a moderate final yield (49%). Said sequence involved: N-Boc protection of the aniline functionality (90%), iodination at C-3 (54%) and quantitative N-deprotection. Attempts to improve the yield of this iodination were infructuous.
As a previous step to the vinylation reaction assay, N1-protection of 3-iodoindazole derivatives with di-4-butyl dicarbonate (Boc2O) under ultrasound irradiation in basic media at room temperature was performed. The N1-Boc-3-iodoindazole products were quantitatively obtained in less than 5 min (Scheme 4).
This experiment was carried out in accordance with works that report that the 3-arylation of indazole requires the previous N1-protection of the NH group due to the competing N1-arylation reaction [16,29]. It is noteworthy to mention that the previously reported N-protection procedures apply ultrasound irradiation on aliphatic or aromatic amine substrates [30], which are inherently more basic than N-heterocyclic rings. On the other hand, experimental procedures that employ indazole as a substrate for N-protection use standard basic conditions, namely DMAP/Et3N in acetonitrile [18,31]. Thus, to our knowledge, this is the first report that employs ultrasound energy to N-protect the indazole nucleus.

2.2. Optimisation

Once N-protection had been carried out, the obtained N1-protected-3-iodoindazole (2a) was employed in the vinylation reaction assay with pinacol vinyl boronate under microwave irradiation, using Pd(PPh3)4 as a catalyst in basic media, replicating conditions described by Hopkins [29] (Table 1). The first attempt led to the intended product in a moderate yield of 60%, with the concomitant and expected loss of the Boc protecting group [32,33] (entry 1).
Afterwards, in an attempt to increase the yield of the reaction and to verify whether the vinylation reaction exhibits a similar behaviour to the arylation reaction previously described in the literature, the described vinylation reaction was tested employing non-N-protected 3-iodoindazole (1a) as a substrate under the same experimental conditions. Interestingly, under these conditions the yield of 3-vinylindazole increased to 75% (entry 2). Next, in order to explore whether the catalyst system could influence the course of the reaction or the ratio of the products, we also performed a vinylation reaction assay under microwave irradiation employing 3-iodoindazole (1a) and replicating previous conditions (namely, presence of aqueous base, 1,4-dioxane as solvent, and two equivalents of pinacol vinyl boronate) using different catalysts (entry 3–6) (Table 1). All the employed catalytic systems led to the C-3-vinylation of 3-iodoindazole 1a without the need of N-protection. Nevertheless, only PdCl2(PPh3)2 led to the complete conversion of the 3-iodoindazole substrate 1a, yielding a 50% of 3-vinylindazole 3a (entry 5). In all other cases, a significant amount of unreacted 3-iodoindazole 1a was recovered, carrying to a poor reaction yield. Thus, use of the Pd(OAc)2/XantPhos system led to a greater substrate recovery percentage than product yield (32% vs. 20% for 1a and 3a respectively) (entry 3, Table 1). On the other hand, Pd(OAc)2 afforded similar yields for both the vinylation product and the substrate (34% of 3a vs. 35% of 1a) but nevertheless the product yield was poor (entry 4, Table 1). Likewise, the nickel-based catalyst showed no improvement on the yield of the vinylation reaction; although it was possible to obtain the final reaction product, it was in a very low yield, and an important amount of the iodinated precursor was recovered (44% vs. 20% for 1a and 3a respectively) (entry 6, Table 1). Therefore, even though the obtainment of the product, using various catalytic systems, reveals the versatility and tolerability of the vinylation reaction in face of a lack of N-protection, the results achieved were poorer than those obtained when Pd(PPh3)4 was employed as a catalyst. In order to determine the optimum equivalents of Suzuki coupling partner for the vinylation reaction we proceeded to assay the reaction of compound 1a with one or three equivalents of pinacol vinyl boronate (entries 7 and 8). When one equivalent of the coupling partner was employed, 3-vinyl indazole was obtained in 48% yield, recovering 33% of 3-iodoindazole (entry 7). Alternatively, when we used three equivalents of the boron compound, 59% of 3-vinylindazole, without traces of 3-iodo-indazole, was obtained (entry 8). As an additional exploration of the reaction conditions, we carried out two more changes in the reaction’s parameters. First, we assayed the precursor (1a) increasing the temperature to 180 °C while keeping all other conditions unchanged. Under this temperature the C-3 vinylation product was the only isolated compound, but a slightly lower yield was observed than at 120 °C (68%, entry 9 vs. 75%, entry 2). We also carried out the vinylation of 1a at 120 °C in a longer reaction time, resulting in a poorer product yield (34%, entry 8 vs. 75%, entry 2). Overall, the best conditions for the vinylation reaction were those initially employed in this work, that is, two equivalents of the boron coupling partner, tetrakis triphenylphosphine palladium (0) as catalyst and microwave irradiation at 120 °C for 40 min (Table 1). Under these experimental conditions, the vinylation reaction proceeds with quantitative conversion of the reactant yielding 3-vinylindazole (3a) after chromatographic purification in a very good yield (entry 2, Table 1).

2.3. Scope

In order to evaluate the scope of these conditions, the vinylation reaction was tested on several N-unprotected 5-R-3-iodoindazoles encompassing a wide variety of both electron-withdrawing and electron-donating substituents (entries 2, 4 and 6–12, Table 2).
In all cases, the isolated product was the C-3-vinyl derivative, while no other competing product was detected. The obtained yields range from moderate to excellent (see Table 2). Despite the variability in electronic effects of the C-5 substituents, no correlation was observed either in the course of the reaction or in the yield of the reaction products, except for the opposing cases of the nitro (electron-withdrawing) (entry 2) and amino (electron-donating) (entry 12) groups (Table 2). Additionally, a few other N-protected derivatives was assayed in order to shed light on the unexpected behavior of this vinylation (entries 1, 3 and 5). In this sense, 3-iodo-5-nitroindazole, a more reactive substrate towards Suzuki cross coupling, was assayed with N-Boc protection under the optimized experimental conditions (entry 1). Surprisingly, the vinylation product was formed in a very poor yield (13%) with 3-iodo-5-nitro-1H-indazole being isolated as a co-product of the reaction in an 86% yield as consequence of N-deprotection reaction. However, by conducting a more exhaustive search of the literature, we find that a similar observation for the nitro analogue was previously reported Guillaumet et al. where the Suzuki arylation coupling of N-Boc 3-iodo-7-nitroindazole fails to give the C-3 arylation product, but the unprotected 3-iodo-7-nitro-1H-indazole is isolated in 95% [32]. Conversely, when unprotected 3-iodo-5-nitroindazole (1b) was employed, the vinylation product was obtained in excellent yield (87%) (entry 2). It seems to be that the nitro indazole derivatives are highly reactive towards N-deprotection. This is not surprising since the powerful electron withdrawing nitro group is at the right place for stabilisation of the anion generated by the Boc deprotection. One tentative explanation is that the N-deprotection for this analogue is so favored that occurs before the vinylation reaction and the side products generated by the cleavage of the Boc group poison the Pd-catalytic system [34]. However, more experiments to corroborate this hypothesis would be necessary [35].
Additionally, we used the N-Boc protected 5-bromo derivative (2c) (entry 3), and its unprotected counterpart (1c) (entry 4), both under the same conditions, obtaining the C-3-vinylation product in 43% and 60% yield respectively. Noteworthy that in the experiment with the N-Boc protected 5-bromo derivative (2c), we achieved to isolate a 5% of the 5-bromo-3-vinyl-N-protected derivative as only coproduct of the reaction, without observation of the C-5 vinylation product. Finally, as an additional proof of the reaction behavior, we performed the vinylation reaction with N-Boc protected 5-methoxy derivative (2d) (entry 5), and its unprotected counterpart (1d) (entry 6). The first example (entry 5) led to the isolation of the C-3-vinylation product in 46% yield and an additional 26% yield of the N-protected C-3-vinylation compound. The reaction with the unprotected precursor (entry 6) conduct to the preparation of the N-unprotected C-3 vinylation product in a 58% yield, corroborating the results obtained with the three previous examples (Table 1). Interestingly, compared to nitro compound, in the examples with 5-bromo and 5-methoxy derivatives the N-deprotection reaction possibly occurs after the vinylation reaction. Considering the absence of a strong electron-withdrawing group in these latter examples this hypothesis seems to be not very surprisingly. This is tentatively supported by the recovery of the N-Boc vinylated products for the 5-Br and 5-OMe analogues, isolated in 5% and 26% yield, respectively. The 5-OMe group being electron donating will be the most resistant to N-deprotection and this is supported by the higher amount of recovered N-Boc vinylated product vs. the 5-Br.
Next, with the aim of determining whether microwave heating was essential to the success of the reaction, we also performed the vinylation reaction of the unprotected derivatives 3-iodoindazole (1a), 5-nitro-3-iodoindazole (1b), 5-methoxy-3-iodoindazole (1d), 5-fluoro-3-iodoindazole (1e), and 5-methyl-3-iodoindazole (1g) under conventional heating conditions (entries 13–17, Table 2). In most cases, the reaction leads to the formation of the corresponding C-3 vinylation products (only fluoro derivative led to recovery of precursor (63% yield) and no isolation of the vinylation product), but in lower yields (except for 3g) and a longer reaction time than the procedure performed under microwave heating. The case of 5-methoxy-3-iodoindazole 1g is particularly noteworthy, as the work of Hopkins shows no arylation reaction of this 3-iodoindazole derivative under conventional heating (DME at 80 °C) [29]. However, the present conditions led, with an increment in heating temperature of only 20 °C, to the obtainment of the Suzuki cross-coupling product 3g in a very good (75%) yield.
The NMR analyses support the purity of the different synthesized compounds, the case of the amine derivatives being an exception (see supplementary materials). Both the 1H- and 13C-NMR spectra show a certain degree of impurities which could not be minimized despite the purification efforts carried out. On the other hand, the analyses of mass spectrometry support the success of the syntheses in all cases.
To the best of our knowledge, this is the first systematic study performing a vinylation cross-coupling reaction on the C-5 substituted indazole derivatives without N-protection of the indazole ring and without detection of the any other competing product.

3. Materials and Methods

3.1. General Information

All organic solvents used for the synthesis were of analytical grade. All reagents used were purchased from Sigma-Aldrich (St. Louis, MO, USA), Merck (Darmstadt, Germany) or AK Scientific (Union City, CA, USA) and were used as received. Melting points were determined on a Stuart Scientific SMP30 apparatus (Bibby Scientific Limited, Stone, UK) and are uncorrected. NMR spectra were recorded on anAvance III HD 400 instrument (Bruker, Billerica, MA, USA) at 400 MHz for 1H and 100 MHz for 13C-NMR spectra were recorded in DMSO-d6 unless otherwise indicated, using the solvent signal as reference. The chemical shifts are expressed in ppm (δ scale) downfield from tetramethylsilane (TMS), and coupling constants values (J) are given in Hertz. The IR spectra were obtained on a Bruker Vector 22 spectrophotometer using KBr discs. High resolution mass spectra were obtained on high resolution mass spectrometer Exactive™ Plus Orbitrap (ThermoFisher Scientific, Bremen, Germany) using electron impact ionization. Column chromatography was performed on Merck silica gel 60 (70–230 mesh). Thin layer chromatographic separations were performed on Merck silica gel 60 (70–230 mesh) chromatofoils. Ultrasonic reactions were performed on an ultrasound device Branson 2210R-MT Ultrasonic Cleaner (Marshall Scientific, Danbury, CT, USA). Suzuki cross coupling reactions were performed on a microwave oven Monowave 300 (Anton Paar, Graz, Austria).

3.2. Syntheses and Characterization Procedures

Molecules 23 02051 i003
3-Iodo-1H-indazole (1a). 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole (3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol) in DMF (7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 × 30 mL). The solid was left to dry at 30 °C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100%; m.p.: 136–138 °C (lit.: [36] 134–136 °C); IR (KBr) ν (cm−1): 3086 (NH); 424 (C-I). 1H-NMR δ (ppm): 13.50 (1H, s, H-1); 7.55 (1H, d, J = 8.6 Hz, H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR δ (ppm): 140.41; 127.22; 126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497, Found: 243.9499.
Molecules 23 02051 i004
3-Iodo-5-nitro-1H-indazole (1b). Prepared from 5-nitro-1H-indazole (3 g, 18.4 mmol), iodine (9.0 g, 35.46 mmol), potassium hydroxide (3.87 g, 69.00 mmol) and DMF (7 mL) to give 5.31 g of a pale yellow solid. Yield: 100%; m.p.: 216–217 °C (lit.: [22] 214 °C); IR (KBr) ν (cm−1): 3200 (NH); 1528 (NO2 asymmetrical); 1335 (NO2 symmetrical); 424 (C-I). 1H-NMR δ (ppm): 14.13 (1H, s, H-1); 8.30 (1H, d, J = 1.8 Hz, H-4); 8.23 (1H, dd, J = 9.2 and 2.1 Hz, H-6); 7.75 (1H, d, J = 9.2, H-7). 13C-NMR δ (ppm): 142.99; 142.52; 126.77; 122.42; 118.57; 112.18; 97.67; HRMS calculated for C7H4IN3O2: 288.9348, Found: 288.9353.
Molecules 23 02051 i005
5-Bromo-3-iodo-1H-indazole (1c). Prepared from 5-bromo-1H-indazole (1 g, 5.07 mmol), iodine (2.5 g, 9.85 mmol), potassium hydroxide (1.07 g, 19.06 mmol) and DMF (4 mL) to give 1.63 g of a pale yellow solid. Yield: 100%; m.p.: 209–210 °C (lit.: [22] 196 °C); IR (KBr) ν (cm−1): 3124 (NH); 424 (C-I and C-Br). 1H-NMR δ (ppm): 13.69 (1H, s, H-1); 7.60 (1H, s, H-4); 7.57–7.50 (2H, m, H-6 and H-7). 13C-NMR δ (ppm): 139.24; 129.98; 128.46; 122.59; 113.46; 112.74; 92.47; HRMS calculated for C7H4BrIN2: 321.8603, Found: 321.8617.
Molecules 23 02051 i006
3-Iodo-5-methoxy-1H-indazole (1d). Prepared from 5-methoxy-1H-indazole (0.2 g, 1.35 mmol), iodine (0.7 g, 2.76 mmol), potassium hydroxide (284 mg, 5.06 mmol) and DMF (3 mL) to give 0.34 g of a pale brown solid. Yield: 90%; m.p.: 162–163 °C (lit.: [22] 178–179 °C); IR (KBr) ν (cm−1): 3185 (NH); 1288 (C-O); 424 (C-I). 1H-NMR δ (ppm): 13.36 (1H, s, H-1); 7.46 (1H, d, J = 8.9 Hz, H-7); 7.08 (1H, d, J = 8.8 Hz, H-6); 6.76 (1H, s, H-4); 3.82 (3H, s, OCH3). 13C-NMR δ (ppm): 154.71; 136.16; 127.13; 119.51; 111.74; 99.24; 92.25; 55.45; HRMS calculated for C8H7IN2O: 273.9603, Found: 273.9599.
Molecules 23 02051 i007
5-Fluoro-3-iodo-1H-indazole (1e). Prepared from 5-fluoro-1H-indazole (0.2 g, 1.47 mmol), iodine (0.75 g, 2.95 mmol), potassium hydroxide (0.31 g, 5.52 mmol) and DMF (3 mL) to give 0.33 g of a pale brown solid. Yield: 87%; m.p.: 158–159 °C (lit.: [37] 166 °C); IR (KBr) ν (cm−1): 3171 (NH); 1165 (C-F); 424 (C-I). 1H-NMR δ (ppm): 13.61 (1H, s, H-1); 7.61 (1H, dd, J = 9.0 and 4.1 Hz, H-7); 7.32 (1H, td, J = 9.1 and 2.1 Hz, H-6); 7.17 (1H, dd, J = 8.7 and 1.7 Hz, H-4). 13C-NMR δ (ppm): 157.51 (d, J = 237.3 Hz); 137.56; 126.96 (d, J = 10.4 Hz); 116.84 (d, J = 27.5 Hz); 112.41 (d, J = 9.7 Hz); 104.44 (d, J = 24.2 Hz); 92.69 (d, J = 5.8 Hz); HRMS calculated for C7H4FIN2: 261.9403, Found: 261.9408.
Molecules 23 02051 i008
5-Chloro-3-iodo-1H-indazole (1f). Prepared from 5-chloro-1H-indazole (0.2 g, 1.31 mmol), iodine (0.65 g, 2.56 mmol), potassium hydroxide (275 mg, 4.90 mmol) and DMF (3 mL) to give 0.33 g of a pale brown solid. Yield: 90%; m.p.: 182–183 °C; IR (KBr) ν (cm−1): 3125 (NH); 710 (C-Cl); 424 (C-I). 1H-NMR δ (ppm): 13.69 (1H, s, H-1); 7.60 (1H, d, J = 8.7 Hz, H-7), 7.46–7.40 (2H, m, H-4 and H-6). 13C-NMR δ (ppm): 139.10; 127.82; 127.64; 125.77; 119.48; 112.51; 92.64; HRMS calculated for C7H4ClIN2: 277.9108, Found: 277.9116.
Molecules 23 02051 i009
3-Iodo-5-methyl-1H-indazole (1g). Prepared from 5-methyl-1H-indazole (0.2 g, 1.51 mmol), iodine (0.75 g, 2.95 mmol), potassium hydroxide (318 mg, 5.67 mmol) and DMF (3 mL) to give 0.36 g of a pale brown solid. Yield: 93%; m.p.: 159–160 °C; IR (KBr) ν (cm−1): 3186 (NH); 2916 (C-H); 424 (C-I). 1H-NMR δ (ppm): 13.37 (1H, s, H-1); 7.44 (1H, d, J = 8.2 Hz, H-7); 7.25 (1H, d, J = 8.1 Hz, H-6); 7.18 (1H, s, H-4); 2.41 (3H, s, CH3). 13C-NMR δ (ppm): 139.12; 130.43; 129.33; 127.10; 119.24; 110.31; 92.59; 20.91; HRMS calculated for C8H7IN2: 257.9654, Found: 257.9659.
Molecules 23 02051 i010
3-Iodo-1H-indazole-5-carbonitrile (1h). Prepared from 1H-indazole-5-carbonitrile (0.2 g, 1.4 mmol), iodine (0.7 g, 2.76 mmol), potassium hydroxide (295 mg, 5.26 mmol) and DMF (3 mL) to give 0.34 g of a white solid. Yield: 91%; m.p.: 206–207 °C; IR (KBr) ν (cm−1): 3340 (NH); 2283 (CN); 424 (C-I). 1H-NMR δ (ppm): 13.99 (1H, s, H-1); 8.04 (1H, s, H-7); 7.73 (2H, s, H-4 and H-6). 13C-NMR δ (ppm): 141.53; 129.27; 127.39; 126.73; 119.30; 112.25; 103.73; 95.36. HRMS calculated for C8H4IN3: 268.9450, Found: 268.9455.
Molecules 23 02051 i011
tert-Butyl (3-iodo-1H-indazol-5-yl)carbamate (1i). Prepared from tert-butyl(1-H-indazol-5-yl)carbamate (0.35 g, 1.5 mmol), iodine (0.75 g, 2.95 mmol), potassium hydroxide (316 mg, 5.63 mmol) and DMF (3 mL). The brown solid obtained was purificated by column chromatography on silica gel using n-hexane/ethyl acetate 1:1 v/v to obtain 0.29 g of pure product as brown crystalline plates. Yield: 54%; m.p.: 181–182 °C; IR (KBr) ν (cm−1): 3348 (NH); 1750 (C=O); 1157 (C-O); 424 (C-I). 1H-NMR δ (ppm): 13.35 (1H, s, H-1); 9.40 (1H, s, H-5); 7.70 (1H, s, H-4); 7.44 (1H, d, J = 8.9 Hz, H-8); 7.38 (1H, d, J = 8.9 Hz, H-7); 1.50 (9H, s, H-6). 13C-NMR δ (ppm): 153.05; 136.82; 133.63; 126.91; 120.89; 110.71; 107.38; 92.78; 79.04; 28.19; HRMS calculated for C12H14IN3O2: 359.0131, Found: 359.0128.
Molecules 23 02051 i012
3-Iodo-1H-indazol-5-amine (1j). To a solution of tert-butyl (3-iodo-1-H-indazol-5-yl)carbamate (0.2 g, 0.56 mmol) (1i) and trifluoroacetic acid (5 mL, 65.34 mmol) in CH2Cl2 (5 mL) was stirred vigorously for 2 h at room temperature. After stirring, the reaction was neutralized to pH = 7 using NaOH 1M and the organic layer was extracted with ethyl acetate (3 × 20 mL) The combined organic layers were dried over anhydrous sodium sulfate and removal of the solvent under vacuum afforded a 144 mg of pure product as a black solid. Yield: 100%; m.p.: 178–179 °C; IR (KBr) ν (cm−1): 3375 (NH); 424 (C-I). 1H-NMR δ (ppm): 13.07 (1H, s, H-1); 7.25 (1H, d, J = 8.8 Hz, H-7), 6.85 (1H, dd, J = 8.8 and 1.7 Hz, H-6); 6.44 (1H, s, H-4); 5.01 (2H, br s, H-5). 13C-NMR δ (ppm): 143.46; 134.79; 127.96; 119.39; 110.91; 99.83; 90.59; HRMS calculated for C7H6IN3: 258.9606, Found: 258.9602.
Molecules 23 02051 i013
tert-Butyl 3-iodo-1H-indazole-1-carboxylate (2a). A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), di-tert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonic irradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with anhydrous sodium sulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals. Yield: 100%; m.p.: 93–95 °C; IR (KBr) ν (cm−1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) δ (ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H, t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR δ (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96; 114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.
Molecules 23 02051 i014
tert-Butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (2b). Prepared from 3-iodo-5-nitro-1H-indazole (0.2 g, 0.69 mmol), di-tert-butyldicarbonate (0.17 g, 0.78 mmol) and triethylamine (1 mL) to give 0.27 g of a pale yellow solid. Yield: 100%; m.p.: 144–145 °C; IR (KBr) ν (cm−1): 1744 (C=O); 1528 (NO2 asymmetrical); 1381 and 1342 (NO2 symmetrical); 1258 (C-O); 617 (C-I). 1H-NMR δ (ppm): 8.49 (1H, br s, H-4); 8.32 (1H, br s, H-7); 8.25 (1H, br s, H-6); 1.66 (9H, s, CH3). 13C-NMR δ (ppm): 147.11; 144.13; 141.57; 129.78; 124.83; 118.31; 115.39; 105.88; 86.23; 27.56; HRMS calculated for C12H12IN3O4: 388.9872, Found: 388.9871.
Molecules 23 02051 i015
tert-Butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (2c). Prepared from 5-bromo-3-iodo-1H-indazole (0.2 g, 0.62 mmol), di-tert-butyldicarbonate (0.15 g, 0.69 mmol) and triethylamine (1 mL) to give 0.27 g of a pale yellow solid. Yield: 100%; m.p.: 152–153 °C; IR (KBr) ν (cm−1): 1750 (C=O); 1157 (C-O); 424 (C-I and C-Br). 1H-NMR (CDCl3) δ (ppm): 8.01 (1H, d, J = 8.8 Hz, H-7); 7.66 (1H, d, J = 9.2 Hz, H-6); 7.64 (1H, s, H-4); 1.64 (9H, s, CH3). 13C-NMR δ (ppm): 148.14; 138.67; 133.15; 131.89; 124.69; 117.56; 116.15; 101.11; 86.13; 28.23; HRMS calculated for C12H12BrIN2O2: 421.9127, Found: 421.9128.
Molecules 23 02051 i016
tert-Butyl 3-iodo-5-methoxy-1H-indazole-1-carboxylate (2d). Prepared from 3-iodo-5-methoxy-1H-indazole (0.1 g, 0.365 mmol), di-tert-butyldicarbonate (0.08 g, 0.366 mmol) and triethylamine (1 mL) to give 119 mg of a pale yellow solid. Yield: 88%; m.p.: 130–131 °C; IR (KBr) ν (cm−1): 1740 (C=O); 1298 (H3C-O); 1157 (C-O); 424 (C-I). 1H-NMR (CDCl3) δ (ppm): 8.01 (1H, d, J = 9.1 Hz, H-7); 7.22 (1H, dd, J = 9.1 and 2.4 Hz, H-6); 6.82 (1H, d, J = 2.2 Hz, H-4); 3.93 (3H, s, OCH3); 1.74 (9H, s, CH3). 13C-NMR δ (ppm): 157.902; 148.32; 134.85; 130.95; 121.12; 115.58; 102.20; 101.71; 85.45; 55.86; 28.21; HRMS calculated for C13H15IN2O3: 374.0127, Found: 374.0118.
Molecules 23 02051 i017
3-Vinyl-1H-indazole (3a). Method a: A mixture of 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.27 mL, 1.62 mmol), tetrakis triphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and 1,4-dioxane (7 mL), were placed in a microwave glass tube and purged with nitrogen. The closed tube was placed under microwave irradiation to 120 °C for 40 min. After irradiation was completed, the reaction was stopped by dilution using 50 mL of brine. The organic layer was extracted with ethylacetate (3 × 45 mL) and the combined organic layers were dried over anhydrous sodium sulfate. Removal of the solvent under vacuum afforded a brown oil crude residue. The oil was purified by column chromatography on silica gel (hexane/ethylacetate 7:3) to yield 89 mg of white crystalline plates. Yield: 75%.
Method b: Prepared from tert-butyl 3-iodo-1H-indazole-1-carboxylate (0.2 g, 0.58 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.27 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 50 mg of a crystalline plates: Yield: 60%.
Method c: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 1 equivalent of vinyl boronic acid pinacol ester (0.14 mL, 0.823 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 58 mg of a crystalline plates. Yield: 48%.
Method d: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 3 equivalents of vinyl boronic acid pinacol ester (0.42 mL, 2.47 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using the previously described microwave method to obtain 70 mg of a crystalline plates. Yield: 59%.
Method e: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), palladium (II) acetate (5 mol%, 9 mg, 0.041 mmol), Xantphos (5 mol%, 24 mg, 0.041 mmol) an aqueous solution of potassium phosphate 1M (2 mL) and dioxane (7 mL) using microwave method described above to obtain 23 mg of a crystalline plates. Yield: 20%.
Method f: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), palladium (II) acetate (5 mol%, 9 mg, 0.041 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 40 mg of a crystalline plates. Yield: 34%.
Method g: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), bis(triphenylphosphine)palladium (II) dichloride (5 mol%, 29 mg, 0.041 mmol), triphenylphosphine (5 mol%, 11 mg, 0.041 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 58 mg of a crystalline plates. Yield: 49%.
Method h: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), [1,2-bis(diphenylphosphino)ethane]dichloro nickel (II) (5 mol%, 22 mg, 0.041 mmol), ethylenebis(diphenylphosphine) (5 mol%, 16 mg, 0.041 mmol), an aqueous solution of potassium phosphate 1M (2 mL) and dioxane (7 mL) using microwave method described above to obtain 24 mg of a crystalline plates. Yield: 20%.
Method i: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above, but at a reaction temperature of 180 °C, to obtain 80 mg of a crystalline plates. Yield: 68%.
Method j: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.28 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above, but with a reaction time of 60 min, to obtain 40 mg of a crystalline plates. Yield: 34%.
Method k: Prepared from 3-iodoindazole (0.1 g, 0.41 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.1 mL, 0.81 mmol), tetrakistriphenylphosphine palladium (26 mg, 0.023 mmol), an aqueous solution of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using method a described above, but employing conventional heating, to obtain 26 mg of a crystalline plates: Yield: 44%.
m.p.: 104–105 °C (lit.: [11] 115.5–116.5 °C); IR (KBr) ν (cm−1): 3047 (NH); 1620 (C=C). 1H-NMR (CDCl3) δ (ppm): 11.32 (1H, s, H-1); 7.95 (1H, d, J = 8.2 Hz, H-7); 7.48 (1H, d, J = 8.4 Hz, H-4); 7.40 (1H, t, J = 7.6 Hz, H-6); 7.21 (1H, t, J = 7.5 Hz, H-5); 7.13 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1′); 6.16 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.58 (1H, d, Jcis = 11.4 Hz, H-2′). 13C-NMR (CDCl3) δ (ppm): 144.18; 141.59; 128.90; 127.03; 121.48; 121.14; 121.00; 117.18; 110.30; HRMS calculated for C9H8N2: 144.0687, Found: 144.0681.
Molecules 23 02051 i018
5-Nitro-3-vinyl-1H-indazole (3b). Method a: Prepared from 3-iodo-5-nitro-1H-indazole (0.2 g, 0.69 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.23 mL, 1.35 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 0.113 g of a pale brown solid. Yield: 87%.
Method b: Prepared from tert-butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (0.2 g, 0.514 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.17 mL, 1.03 mmol), tetrakistriphenylphosphine palladium (35 mg, 0.03 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 13 mg of a pale brown solid: Yield: 13%.
Method c: Prepared from 3-iodo-5-nitro-1H-indazole (0.18 g, 0.62 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.21mL, 1.24 mmol), tetrakistriphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using method a described above, but employing conventional heating, to give 24 mg of pale brown solid. Yield: 21%.
m.p.: 166–168 °C; IR (KBr) ν (cm−1): 3179 (NH); 1620 (C=C); 1528 (NO2 asymmetrical); 1335 (NO2 symmetrical). 1H-NMR δ (ppm): 13.75 (1H, s, H-1); 8.93 (1H, s, H-4); 8.20 (1H, d, J = 8.6 Hz, H-7); 7.71 (1H, d, J = 9.2 Hz, H-6); 7.14 (1H, dd, Jtrans = 17.8 Hz and Jcis =11.4 Hz, H-1′); 6.19 (1H, d, Jtrans = 17.8 Hz, H-3′); 5.58 (1H, d, Jcis = 11.4 Hz, H-2′).13C-NMR δ (ppm): 145.12; 142.97; 141.89; 127.65; 121.14; 119.61; 118.21; 117.95; 111.31; HRMS calculated for C9H7N3O2: 189.0538, Found: 189.0535.
Molecules 23 02051 i019
5-Bromo-3-vinyl-1H-indazole (3c). Method a: Prepared from 5-bromo-3-iodo-1H-indazole (0.2 g, 0.621 mmol), 2 equivalent of vinyl boronic acid pinacol ester (0.21 mL, 1.24 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 82 mg of a pale yellow solid. Yield: 60%.
Method b: Prepared from tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (0.2 g, 0.47 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.16 mL, 0.96 mmol), tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 45 mg of a pale yellow solid: Yield: 43%.
m.p.: 250–251 °C; IR (KBr) ν (cm−1): 3112 (NH); 1689 (C=C); 424 (C-Br). 1H-NMR (CDCl3) δ (ppm): 11.68 (1H, s, H-1); 8.03 (1H, s, H-4); 7.44 (1H, d, J = 8.8 Hz, H-7); 7.32 (1H, d, J = 8.8 Hz, H-6); 7.01 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1′); 6.07 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.57 (1H, d, Jcis = 11.5 Hz, H-2′). 13C-NMR (CDCl3) δ (ppm): 143.45;140.15; 130.21; 128.12; 123.48; 122.54; 117.83; 114.66; 111.77; HRMS calculated for C9H7BrN2: 221.9793, Found: 221.9797.
Molecules 23 02051 i020
5-Methoxy-3-vinyl-1H-indazole (3d). Method a: Prepared from 3-iodo-5-methoxy-1H-indazole (0.2 g, 0.73 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.24 mL, 1.43 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 74 mg of a pale yellow solid. Yield: 58%.
Method b: Prepared from tert-butyl 3-iodo-5-methoxy-1H-indazole-1-carboxylate (0.135 g, 0.361 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.12 mL, 0.72 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.018 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 29 mg of a pale yellow solid. Yield: 46%.
Method c: Prepared from 3-iodo-5-methoxy-1H-indazole (0.2 g, 0.73 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.24 mL, 1.43 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7.0 mL) using method described above, but employing conventional heating, to obtain 96 mg of a pale yellow solid. Yield: 75%.
m.p.: 88–89 °C; IR (KBr) ν (cm−1): 3155 (NH); 1635 (C=C); 1219 (C-O). 1H-NMR δ (ppm): 12.95 (1H, s, H-1); 7.44 (1H, d, J = 8.9 Hz, H-7); 7.33 (1H, s, H-4); 7.06–6.96 (2H, m, H-6 and H-1’); 6.02 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.41 (1H, d, Jcis = 11.5 Hz, H-2′); 3.82 (1H, s, OCH3). 13C-NMR δ (ppm): 154.50; 141.71; 137.02; 129.38; 120.70; 118.05; 114.90; 111.47; 100.02; 55.50; HRMS calculated for C10H10N2O: 174.0793, Found: 174.0788.
Molecules 23 02051 i021
5-Fluoro-3-vinyl-1H-indazole (3e). Method a: Prepared from 5-fluoro-3-iodo-1H-indazole (0.2 g, 0.763 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 58 mg of a pale yellow solid. Yield: 47%.
Method b: Prepared from 5-fluoro-3-iodo-1H-indazole (0.08 g, 0.305 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.075 mL, 0.61 mmol), tetrakistriphenylphosphine palladium (17 mg, 0.015 mmol), an aqueous solution of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using method a described above, but employing conventional heating, to obtain 50 mg of the precursor 5-fluoro-3-iodo-1H-indazole: Yield of recovery: 63%.
m.p.: 104–105 °C; IR (KBr) ν (cm−1): 3163 (NH); 1636 (C=C); 1118 (C-F). 1H-NMR (CDCl3) δ (ppm): 11.73 (1H, s, H-1); 7.52 (1H, dd, J = 8.9 and 1.7 Hz, H-4); 7.41 (1H, dd, J = 9.0 and 4.2 Hz, H-7); 7.17 (1H, td, J = 8.9 and 2.0 Hz, H-6); 7.05 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1′); 6.05 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.56 (1H, d, Jcis = 11.5 Hz, H-2′). 13C-NMR (CDCl3) δ (ppm): 158.39 (d, J = 238.8 Hz), 144.04 (d, J = 5.5 Hz), 138.52, 128.38, 121.01 (d, J = 10.0 Hz), 117.25, 111.49 (d, J = 9.7 Hz), 105.21 (d, J = 24.1 Hz); HRMS calculated for C9H7FN2: 162.0593, Found: 162.0590.
Molecules 23 02051 i022
5-Chloro-3-vinyl-1H-indazole (3f). Prepared from 5-chloro-3-iodo-1H-indazole (0.2 g, 0.722 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.24 mL, 1.42 mmol), tetrakistriphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 77 mg of a yellow solid. Yield: 60%; m.p.: 131–132 °C; IR (KBr) ν (cm−1): 3181 (NH); 1628 (C=C); 649 (C-Cl). 1H-NMR δ (ppm): 13.28 (1H, s, H-1); 8.05 (1H, s, H-4); 7.56 (1H, d, J = 8.8 Hz, H-7); 7.37 (1H, d, J = 8.7 Hz, H-6); 7.01 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1′); 6.08 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.46 (1H, d, Jcis = 11.5 Hz, H-2′). 13C-NMR δ (ppm): 142.00; 139.72; 128.57; 126.56; 125.45, 121.23, 119.60, 116.29, 112.17; HRMS calculated for C9H7ClN2: 178.0298, Found: 178.0296.
Molecules 23 02051 i023
5-Methyl-3-vinyl-1H-indazole (3g). Method a: Prepared from 3-iodo-5-methyl-1H-indazole (0.2 g, 0.775 mmol), 2 equivalent of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 60 mg of a pale brown solid. Yield: 49%.
Method b: Prepared from 3-iodo-5-methyl-1H-indazole (0.095 g, 0.368 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.090 mL, 0.736 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.018 mmol), an aqueous solution of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using method a described above, but employing conventional heating, to obtain 10 mg of a pale brown solid. Yield: 17%.
m.p.: 88–89 °C; IR (KBr) ν (cm−1): 3179 (NH); 2916 (C-H); 1628 (C=C). 1H-NMR (CDCl3) δ (ppm): 11.63 (1H, s, H-1); 7.72 (1H, s, H-4); 7.37 (1H, d, J = 8.5 Hz, H-7); 7.24–7.11 (2H, m, H-1′ and H-6); 6.16 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.57 (1H, d, Jcis = 11.4 Hz, H-2′); 2.50 (3H, s, CH3). 13C-NMR (CDCl3) δ (ppm):143.28; 140.28; 130.84; 129.02; 128.96; 121.38; 119.96; 116.69; 110.12; 21.58; HRMS calculated for C10H10N2: 158.0844, Found: 158.0840.
Molecules 23 02051 i024
5-Cyano-3-vinyl-1H-indazole (3h). Prepared from 5-cyano-3-iodo-1H-indazole (0.2 g, 0.743 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.25 mL, 1.48 mmol), tetrakistriphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 77 mg of a white solid. Yield: 61%; m.p.: 156–157 °C; IR (KBr) ν (cm−1): 3209 (NH); 2222 (CN); 1612 (C=C). 1H-NMR δ (ppm): 13.59 (1H, s, H-1); 8.63 (1H, s, H-4), 7.68 (2H, s, H-7 and H-6); 7.04 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1′), 6.21 (1H, d, J = 18.0 Hz, H-3′), 5.53 (1H, d, J = 11.5 Hz, H-2′). 13C-NMR δ (ppm): 143.56; 142.01; 128.38; 128.01; 127.43; 119.99; 119.82; 117.82; 111.98; 103.29; HRMS calculated for C10H7N3: 169.0640, Found: 169.0637.
Molecules 23 02051 i025
tert-Butyl (3-vinyl-1H-indazol-5-yl)carbamate (3i). Prepared from tert-butyl (3-iodo-1-H-indazol-5-yl) carbamate (0.2 g, 0.56 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.19 mL, 1.12 mmol), tetrakistriphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 80 mg of a White solid. Yield: 55%; m.p.: 189–190 °C; IR (KBr) ν (cm−1): 3356 (NH); 1700 (C=O); 1636 (C=C); 1165 (C-O). 1H-NMR δ (ppm): 12.96 (1H, s, H-1); 9.30 (1H, s, H-5); 8.13 (1H, s, H-4); 7.45–7.37 (2H, m, H-8 and H-7); 6.98 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.4 Hz, H-1′); 5.92 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.44 (1H, d, Jcis = 11.4 Hz, H-2′); 1.49 (9H, s, H-6). 13C-NMR δ (ppm): 153.18; 141.83; 137.80; 133.36; 129.70; 120.33; 119.92; 114.88; 110.54; 107.98; 78.91; 28.22; HRMS calculated for C14H17N3O2: 259.1321, Found: 259.1330.
Molecules 23 02051 i026
5-Amino-3-vinyl-1H-indazole (3j). Method a: Prepared from 5-amino-3-iodo-1H-indazole (1j, 0.2 g, 0.77 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis- triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL), to give 44 mg of a brown solid. Yield: 36%.
Method b: A solution of tert-butyl (3-vinyl-1H-indazol-5-yl) carbamate (3i, 145 mg, 0.4 mmol) and trifluoroacetic acid (2 mL, 26.13 mmol) in CH2Cl2 (2 mL) was stirred vigorously for 2 h at room temperature. After stirring, the reaction was neutralized to pH = 7 using NaOH 1M and the organic layer was extracted with ethyl acetate (3 × 20 mL) The combined organic layers were dried with anhydrous sodium sulfate and removal of the solvent under vacuum afforded a 80 mg of pure product as a brown solid. Yield: 100%; m.p.: 157–158 °C; IR (KBr) ν (cm−1): 3461 (NH); 1682 (C=O). 1H-NMR δ (ppm):12.64 (1H, s, H-1); 7.24 (1H, d, J = 8.7 Hz, H-7); 7.00 (1H, s, H-4); 6.91 (1H, dd, Jtrans = 18.0 and Jcis = 11.5 Hz, H-1′); 6.80 (1H, d, J = 8.8 Hz, H-6); 5.84 (1H, d, Jtrans = 18.0 Hz, H-3′); 5.34 (1H, d, Jcis = 11.5 Hz, H-2′); 4.87 (2H, s, H5). 13C-NMR δ (ppm): 143.20; 140.39; 135.83; 130.33; 121.46; 118.02; 113.61; 110.81; 100.76; HRMS calculated for C9H9N3: 159.0796, Found: 159.0792.

4. Conclusions

We have prepared ten, nine of them novel, C-5 substituted 3-vinylindazole derivatives through an easy, simple, fast and reproducible Suzuki cross-coupling reaction between unprotected 3-iodoindazoles and pinacol vinyl boronate with yields ranging from moderate to excellent. The vinylation reaction without N-protection herein presented shows tolerance concerning: (i) the electronic properties of the C-5 substituent on the indazole nucleus, (ii) the use of conventional heating, and (iii) the use of diverse catalytic systems. Despite such tolerance, the best conditions for this reaction were identified as: microwave irradiation, Pd(PPh3)4 as a catalyst, 120 °C, and 40 min of reaction time. In all reported cases the main isolated product was the C-3 vinyl derivative without detection of the any other competing product. With this methodology in hand, vinylated indazoles may be directly and selectively obtained without the need of N-protection.

Supplementary Materials

The Supplementary Materials are available online. Figure S1: 1H-NMR spectrum of 1a. Figure S2: 13C-NMR spectrum of 1a. Figure S3: 1H-NMR spectrum of 1b. Figure S4: 13C-NMR spectrum of 1b. Figure S5: 1H-NMR spectrum of 1c. Figure S6: 13C-NMR spectrum of 1c. Figure S7: 1H-NMR spectrum of 1d. Figure S8: 13C-NMR spectrum of 1d. Figure S9: 1H-NMR spectrum of 1e. Figure S10: 13C-NMR spectrum of 1e. Figure S11: 1H-NMR spectrum of 1f. Figure S12: 13C-NMR spectrum of 1f. Figure S13: 1H-NMR spectrum of 1g. Figure S14: 13C-NMR spectrum of 1g. Figure S15: 1H-NMR spectrum of 1h. Figure S16: 13C-NMR spectrum of 1h. Figure S17: 1H-NMR spectrum of 1i. Figure S18: 13C-NMR spectrum of 1i. Figure S19: 1H-NMR spectrum of 1j. Figure S20: 13C-NMR spectrum of 1j. Figure S21: 1H-NMR spectrum of 2a. Figure S22: 13C-NMR spectrum of 2a. Figure S23: 1H-NMR spectrum of 2b. Figure S24: 13C-NMR spectrum of 2b. Figure S25: 1H-NMR spectrum of 2c. Figure S26: 13C-NMR spectrum of 2c. Figure S27: 1H-NMR spectrum of 2d. Figure S28: 13C-NMR spectrum of 2d. Figure S29: 1H-NMR spectrum of 3a. Figure S30: 13C-NMR spectrum of 3a. Figure S31: 1H-NMR spectrum of 3b. Figure S32: 13C-NMR spectrum of 3b. Figure S33: 1H-NMR spectrum of 3c. Figure S34: 13C-NMR spectrum of 3c. Figure S35: 1H-NMR spectrum of 3d. Figure S36: 13C-NMR spectrum of 3d. Figure S37: 1H-NMR spectrum of 3e. Figure S38: 13C-NMR spectrum of 3e. Figure S39: 1H-NMR spectrum of 3f. Figure S40: 13C-NMR spectrum of 3f. Figure S41: 1H-NMR spectrum of 3g. Figure S42: 13C-NMR spectrum of 3g. Figure S43: 1H-NMR spectrum of 3h. Figure S44: 13C-NMR spectrum of 3h. Figure S45: 1H-NMR spectrum of 3i. Figure S46: 13C-NMR spectrum of 3i. Figure S47: 1H-NMR spectrum of 3j. Figure S48: 13C-NMR spectrum of 3j.

Author Contributions

G.R.-G. formulated the research idea, designed the synthetic route of compounds, analyzed the data and wrote the manuscript; Compounds were synthesized and purified by G.V. and B.D.; C.A.T. contributed with organic reagents and analytical tools, and participated in manuscript preparation.

Funding

This research was funded by DIPOG of the Chemistry Faculty-Pontificia Universidad Católica de Chile grant number 3913-189-81 and 3913-529-81.

Acknowledgments

We also acknowledge the invaluable assistance of R. Tapia and R. Rojas by facilitating the microwave equipment.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Scheme 1. First reported syntheses of 3-vinylindazole: (A) Igeta’s work [8]; (B) Tsuchiya group’s work [10] and (C) report of the Petrillo group [11].
Scheme 1. First reported syntheses of 3-vinylindazole: (A) Igeta’s work [8]; (B) Tsuchiya group’s work [10] and (C) report of the Petrillo group [11].
Molecules 23 02051 sch001
Scheme 2. Synthetic pathway to prepare 5-R-3-vinylindazole derivatives.
Scheme 2. Synthetic pathway to prepare 5-R-3-vinylindazole derivatives.
Molecules 23 02051 sch002
Scheme 3. Iodination reaction of commercial indazole.
Scheme 3. Iodination reaction of commercial indazole.
Molecules 23 02051 sch003
Scheme 4. N1-protection of 3-iodoindazole derivatives using ultrasound irradiation.
Scheme 4. N1-protection of 3-iodoindazole derivatives using ultrasound irradiation.
Molecules 23 02051 sch004
Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
Molecules 23 02051 i001
EntryReactantReaction ConditionsxTime/Temp (°C)Yield a (%)
12aPd(PPh3)4/Na2CO3240 min/12060
21aPd(PPh3)4/Na2CO3240 min/12075
31aPd(OAc)2/XantPhos, K3PO4240 min/12020
41aPd(OAc)2, Na2CO3240 min/12034
51aPd(PPh3)2Cl2/PPh3, Na2CO3240 min/12050
61aNiCl2(dppe)/dppe, K3PO4240 min/12020
71aPd(PPh3)4/Na2CO3140 min/12048
81aPd(PPh3)4/Na2CO3340 min/12059
91aPd(PPh3)4/Na2CO3240 min/18068
101aPd(PPh3)4/Na2CO3260 min/12034
Reaction conditions: 5 mol % of catalyst, aqueous base, 1,4-dioxane, µW. a Yield corresponding to the purified products.
Table 2. Results of the vinylation reaction of several 5-R-3-iodoindazole derivatives.
Table 2. Results of the vinylation reaction of several 5-R-3-iodoindazole derivatives.
Molecules 23 02051 i002
EntryReactantRR′HeatingProductYield a (%)
12bNO2BocµW3b13 b
21bNO2HµW3b87
32cBrBocµW3c43 c
41cBrHµW3c60
52dOCH3BocµW3d46 d
61dOCH3HµW3d58
71eFHµW3e47
81fClHµW3f60
91gCH3HµW3g49
101hCNHµW3h61
111iNHBocHµW3i55
121jNH2HµW3j36 (55) e
131aHHconventional3a44
141bNO2Hconventional3b21
151dOCH3 conventional3d75
161eFHconventional3e0
171gCH3Hconventional3g17
Reaction conditions: pinacol vinyl boronate (2 eq), Pd(PPh3)4 (5–6 mol %), Na2CO3 (2N), 1,4-dioxane, µW, 120 °C, 40 min (entries 1–12). Conventional heating, 101 °C, 3 h (entries 13–17). a Yields corresponding to the purified products. b 3-iodo-5-nitro-1H-indazole was obtained as the major product in 86% yield. c 5-bromo-3-vinyl-N-protected derivative was isolated as only coproduct in 5% yield. d N-boc-3-vinyl-5-methoxy-1H-indazole was obtained as coproduct in 26% yield. e 55% yield for 5-amino-3-vinylindazole 3j corresponds to that obtained by deprotection of 3i.

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MDPI and ACS Style

Vera, G.; Diethelm, B.; Terraza, C.A.; Recabarren-Gajardo, G. Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation. Molecules 2018, 23, 2051. https://doi.org/10.3390/molecules23082051

AMA Style

Vera G, Diethelm B, Terraza CA, Recabarren-Gajardo G. Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation. Molecules. 2018; 23(8):2051. https://doi.org/10.3390/molecules23082051

Chicago/Turabian Style

Vera, Gonzalo, Benjamín Diethelm, Claudio A. Terraza, and Gonzalo Recabarren-Gajardo. 2018. "Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation" Molecules 23, no. 8: 2051. https://doi.org/10.3390/molecules23082051

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