A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions.

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields.

Pyrazoline and pyrazole derivatives have demonstrated a broad spectrum of interesting biological properties, and some of them were shown to have analgesic, anti-hyperglycemic, hypotensive,

Reaction of Nitroindazoles 1a-1d with 1,2-Dibromoethane
The reaction of the nitroindazoles 1a-1d with 1,2-dibromoethane performed at room temperature, in acetone and in the presence of Cs 2 CO 3 (1.1 equiv.) afforded the corresponding N-bromoethylnitroindazoles 2 and 4 and the N-vinyl-nitroindazoles 3 and 5 (Scheme 1) in overall yields ranging from 68% to 82%. The starting nitroindazoles 1 were obtained in excellent yields by diazotization of the adequate 2-methyl-nitroanilines according to the procedure described by Noelting (Scheme 1) [41].
The conditions indicated in Scheme 1 (cesium carbonate/acetone, room temperature) were selected considering that in the optimisation studies performed with derivative 1b (see Table 1), the N-bromoethylnitroindazoles 2b and 4b and the elimination products 3b and 5b were obtained in just 1 h of reaction in reasonable amounts. From the results summarised in Table 1, it is patent that the distribution of the products 2b-5b is strongly dependent on the experimental conditions used.
The first experiments were performed with 1b and using KOH (1 equiv.) in acetone at room temperature; such conditions gave rise, after 48 h, to the synthesis of compound 2b and to 3b, respectively, in 39% and 9% yields (entry 1). Two other products 4b and 5b were obtained; those are due to the reaction of the N-2 of the indazole moiety, the vinyl derivative 5b being obtained in higher yield than 4b (25% versus 12%).

Scheme 1. Synthetic access to N-bromoethyl-nitro-indazoles and N-vinyl-nitro-indazoles.
In a previous study performed with 4-nitroindazole 1a at low temperature (0 °C), only the substituted compounds 2a and 4a were obtained in a total yield of 58% [39]. Therefore, the elimination process with higher activation energy than the substitution route [42] is favoured by the higher temperature used in the reactions reported in the present work. It was also observed (entries 2 and 3) that the formation of the elimination products was strongly favoured when the reactions were performed in the presence of three equiv. of KOH either at room temperature (4 h of reaction) or at reflux (2 h of reaction). In fact, under these conditions, only traces of 4b were detected, and the yield of 3b increased to 25% and 21%, respectively. The change of the solvent to tetrahydrofuran (THF) or methanol had no positive effect on the yield/distribution of the products obtained. When methanol was used (entry 5) it was not observed the full consumption of the starting material and a significant amount was recovered (ca. 35%). Table 1. Conditions studied for the optimization of the N-alkylation reaction of compound 1b and yields of compounds 2b-4b.
In the reactions performed in acetone and 1 equiv. of Cs2CO3 (entry 6), compound 2b was isolated in 35% in just 1 h of reaction time and its elimination product 3b in 6% yield; under those Scheme 1. Synthetic access to N-bromoethyl-nitro-indazoles and N-vinyl-nitro-indazoles.
In a previous study performed with 4-nitroindazole 1a at low temperature (0 • C), only the substituted compounds 2a and 4a were obtained in a total yield of 58% [39]. Therefore, the elimination process with higher activation energy than the substitution route [42] is favoured by the higher temperature used in the reactions reported in the present work. It was also observed (entries 2 and 3) that the formation of the elimination products was strongly favoured when the reactions were performed in the presence of three equiv. of KOH either at room temperature (4 h of reaction) or at reflux (2 h of reaction). In fact, under these conditions, only traces of 4b were detected, and the yield of 3b increased to 25% and 21%, respectively. The change of the solvent to tetrahydrofuran (THF) or methanol had no positive effect on the yield/distribution of the products obtained. When methanol was used (entry 5) it was not observed the full consumption of the starting material and a significant amount was recovered (ca. 35%).  1  Acetone  KOH  48  39  9  12  25  2  Acetone  KOH a  4  29  25  Traces  17  3  Acetone  KOH b  2  27  21  Traces  19  4  THF  KOH b  72  30  11  14  10  5  MeOH  KOH b  120 c  15  Traces  7  Traces  6  Acetone  Cs 2 CO 3  1  35  6  12  15  7  Acetone  K 2 CO 3  68  47  10  20  8 a 3 equiv. KOH; b 3 equiv. KOH, reflux. c Recovery of a significant amount of starting material 1b.
In the reactions performed in acetone and 1 equiv. of Cs 2 CO 3 (entry 6), compound 2b was isolated in 35% in just 1 h of reaction time and its elimination product 3b in 6% yield; under those conditions, the vinyl derivative 5b was isolated in slightly better yield (15%) than compound 4b (12%). Interestingly, the preferential formation of the N-bromoethylnitroindazole 4b towards its elimination product 5b (20% vs. 8%) can be obtained in the reaction performed with K 2 CO 3 at room temperature, although a longer reaction time was required (68 h) until the full consumption of the starting nitroindazole 1b has been detected (entry 7). With this base, an improvement in the yield of 2b to 47% was observed, and 3b was isolated in 10% yield.
The conditions of entry 6 were extended to the other nitroindazoles since these conditions showed the best relationship between the reaction time and total yield. In general, the product distribution and the moderate selectivity towards N-1 was maintained (Scheme 1). The N-bromoethylnitroindazoles 2a-2d (34-44%) were always isolated as the major products and in much higher yields than the corresponding elimination derivatives 3a-3d (1-6%), while the yield values of 4a-4d (12-19%) were obtained in the same range of the vinyl derivatives 5a-5d (15-20%). The elimination reaction leading to the N-vinyl substituted derivatives is strongly favoured in the N-2 alkylated derivatives, probably due to higher instability of the corresponding N-bromoethyl-nitroindazole [43,44].
The 1 H-NMR spectra of derivatives 2a-2d and 4a-4d are consistent with N-alkylated indazole derivatives with a bromoethyl moiety showing, in the aliphatic region, two characteristic triplets at ca. δ 5.0 ppm and δ 4.0 ppm due to the resonances of the methylene protons. The 13 C-NMR spectra of isomers 2a-2d and 4a-4d showed two signals at ca. δ 50 and δ 32 ppm due to the resonances of the two methylene carbons from the bromoethyl moiety. The assignments of these signals were confirmed by DEPT 135 studies.
The 1 H-NMR spectra of N-substituted vinylic products 3a-3d and 5a-5d present in the aliphatic region two doublets of doublets due to the resonances of the methylene protons from the vinylic units at ca. δ 5.8 ppm and δ 5.1 ppm for derivatives 3a-3d, while for compounds 5a-5d these signals are slightly deshielded to ca. δ 6.2 ppm and δ 5.4 ppm. The resonance of the methinic proton from the vinylic group generates a doublet of doublets signal ranging from δ 7.9 to δ 7.3 ppm. These three NMR signals present characteristic constant couplings due to the geminal (J gem ≈ 1 Hz), cis (J cis ≈ 9 Hz) and trans (J trans ≈ 15 Hz) correlations between the three protons from the vinyl unit. The resonances of all the remaining protons from the nitroindazole moiety generate signals in the aromatic region, as expected, being the proton from the position 3 of the pyrazolic ring (δ 9.2-8.2 ppm) the most deshielded one.
Additionally, the 13 C-NMR spectra of the compounds 3a-3d and 5a-5d present the signals due to the resonance of the methinic carbons from the alkene groups at ca. δ 130 ppm. The signals corresponding to the resonances of the secondary carbons from the vinylic double bonds were easily identified by DEPT 135 NMR spectra ranging from δ 107.4 to δ 100.5 ppm.
The structures of all compounds isolated from the alkylation/elimination reactions of nitroindazoles 1a-1d with 1,2-dibromoethane were confirmed by ESI(+) mass spectrometry, showing the peaks corresponding to the expected [M] +• or [M + H] + molecular ions.
For the incorporation of triazole units in the nitroindazole core (Scheme 2) it was selected the N-bromoethylnitroindazole 2b that was efficiently converted into the required 5-nitroindazole azide 6 (88%) by reaction with an excess of sodium azide in DMF. The structure of this synthon was confirmed by mass spectrometry and 1 H-NMR and 13     The excellent performance of 6 in this CuAAC reactions prompted us to extend our study to 1,3diethynylbenzene (Scheme 3). With this terminal alkyne, the reaction leads to the formation of 1,4disubstituted triazole 8 and the bis-nitroindazolyl-triazole 9 in 23% and 58% yields, respectively. These two adducts were easily separated by column chromatography using hexane-ethyl acetate as solvent (Scheme 3). In this series of compounds, the success of the reaction was easily confirmed from the 1 H-NMR spectra analysis. It shows the resonance of the protons from the ethylenic bridge as two multiplets at δ 5.10-5.01 ppm and δ 5.00-4.92 ppm and a remarkable singlet in the aromatic region due to the resonance of the proton from the triazole ring. In the 1 H-NMR spectrum of compound 8, an additional peak at δ 4.25 ppm due to the resonance of the proton from the alkyne unit was observed. The resonance of the two carbons from the triple bond generates two characteristic peaks at δ 83.1 and δ 81.2 ppm in the 13 C-NMR spectrum. The copper(I)-catalysed 1,3-dipolar cycloaddition reactions involving the azide 6 were performed in the presence of the terminal alkynes, 1-ethynylbenzene, 1-ethynyl-4-methylbenzene, 1-ethynyl-4-metoxybenzene and 1-ethynyl-4-nitrobenzene (Scheme 2). All these reactions were accomplished at room temperature in a mixture of tert-butyl alcohol-water (1:1) using sodium ascorbate as the reducing agent and CuSO 4 as the copper source. After reaction times ranging from 12 to 16 h, the desired adducts 7a-7d were isolated in excellent yields (71-87%) ( Table 2). The yield of the CuAAC reaction and the consequent formation of the 1,4-disubstituted triazole ring is favoured by the presence of electron donor groups instead of electron-withdrawing groups in the para position of the phenyl ring from the alkyne reagent. The excellent performance of 6 in this CuAAC reactions prompted us to extend our study to 1,3-diethynylbenzene (Scheme 3). With this terminal alkyne, the reaction leads to the formation of 1,4-disubstituted triazole 8 and the bis-nitroindazolyl-triazole 9 in 23% and 58% yields, respectively. These two adducts were easily separated by column chromatography using hexane-ethyl acetate as solvent (Scheme 3).  The excellent performance of 6 in this CuAAC reactions prompted us to extend our study to 1,3diethynylbenzene (Scheme 3). With this terminal alkyne, the reaction leads to the formation of 1,4disubstituted triazole 8 and the bis-nitroindazolyl-triazole 9 in 23% and 58% yields, respectively. These two adducts were easily separated by column chromatography using hexane-ethyl acetate as solvent (Scheme 3). In this series of compounds, the success of the reaction was easily confirmed from the 1 H-NMR The structure of all the newly synthesised compounds were unambiguously confirmed by using 1D ( 1 H and 13 C spectra) and 2D [( 1 H, 1 H) COSY, ( 1 H, 13 C) HSQC and ( 1 H, 13 C) HMBC] NMR techniques, and by mass spectrometry (see experimental section and supporting information SI, Figures S72-S97).
In this series of compounds, the success of the reaction was easily confirmed from the 1 H-NMR spectra analysis. It shows the resonance of the protons from the ethylenic bridge as two multiplets at δ 5.10-5.01 ppm and δ 5.00-4.92 ppm and a remarkable singlet in the aromatic region due to the resonance of the proton from the triazole ring. In the 1 H-NMR spectrum of compound 8, an additional peak at δ 4.25 ppm due to the resonance of the proton from the alkyne unit was observed. The resonance of the two carbons from the triple bond generates two characteristic peaks at δ 83.1 and δ 81.2 ppm in the 13 C-NMR spectrum.
The structure of each the indazole-triazole derivatives 7b and 9 were unambiguously established by single-crystal X-ray diffraction studies (vide infra).

1,3-Dipolar Cycloaddition Reactions of N-Vinyl-Nitroindazoles with Nitrile Imines
Considering the easy accessibility to N-vinylnitroindazoles we envisaged an extra functionalization of the indazole nucleus with pyrazoline units by using the vinyl moiety to trap nitrile imines generated from the ethyl hydrazono-α-bromoglyoxylates (Scheme 4).
Considering the easy accessibility to N-vinylnitroindazoles we envisaged an ext nctionalization of the indazole nucleus with pyrazoline units by using the vinyl moiety to tra trile imines generated from the ethyl hydrazono-α-bromoglyoxylates (Scheme 4).
The ethyl hydrazono-α-bromoglyoxylates 10a-10e selected to generate in situ the correspondin aryl-C-ethoxycarbonylnitrile imines 11a-11e were obtained using the approach developed b amilton and co-workers. The preparation of the nitrile imine precursors was carried out by th action of ethyl acetoacetate with the adequate diazonium salts followed by bromination of th sulting azoacetoacetic esters [51].
The cycloaddition reactions involving the indazole 3b and the N-aryl-C-ethoxycarbonylnitri ines 11a-11e were performed in dichloromethane at room temperature, in the presence of Cs2CO equiv.). After 24 h of reaction, it was observed by TLC the total, or almost total, consumption e starting indazole and this being accompanied by the formation of the main product. After th orkup and purification of the reaction mixture by column chromatography, we were able nclude by a detailed spectroscopic analysis that the major products were the pyrazolin cloadducts 12a-12e which were isolated in yields ranging from 63% to 83%. It is worth to refer th neither case was isolated the corresponding pyrazole derivative from the dehydrogenation of th razoline ring from derivatives 12a-12e. When the reaction was performed with the vinyl-nitroindazole 3c and the nitrile imine 11 tained in situ from the corresponding ethyl hydrazono-α-bromoglyoxylates 10d, the expecte razoline derivative 13 (Figure 1) was obtained in 81% yield. This yield is similar to the one obtaine ith the indazole 3b, showing that the position of the electron-withdrawing nitro group in th dazole moiety does not have a significant influence in the reaction yield. The ethyl hydrazono-α-bromoglyoxylates 10a-10e selected to generate in situ the corresponding N-aryl-C-ethoxycarbonylnitrile imines 11a-11e were obtained using the approach developed by Hamilton and co-workers. The preparation of the nitrile imine precursors was carried out by the reaction of ethyl acetoacetate with the adequate diazonium salts followed by bromination of the resulting azoacetoacetic esters [51].
The cycloaddition reactions involving the indazole 3b and the N-aryl-C-ethoxycarbonylnitrile imines 11a-11e were performed in dichloromethane at room temperature, in the presence of Cs 2 CO 3 (2 equiv.). After 24 h of reaction, it was observed by TLC the total, or almost total, consumption of the starting indazole and this being accompanied by the formation of the main product. After the workup and purification of the reaction mixture by column chromatography, we were able to conclude by a detailed spectroscopic analysis that the major products were the pyrazoline cycloadducts 12a-12e Molecules 2020, 25, 126 7 of 18 which were isolated in yields ranging from 63% to 83%. It is worth to refer that in neither case was isolated the corresponding pyrazole derivative from the dehydrogenation of the pyrazoline ring from derivatives 12a-12e.
When the reaction was performed with the vinyl-nitroindazole 3c and the nitrile imine 11d, obtained in situ from the corresponding ethyl hydrazono-α-bromoglyoxylates 10d, the expected pyrazoline derivative 13 (Figure 1) was obtained in 81% yield. This yield is similar to the one obtained with the indazole 3b, showing that the position of the electron-withdrawing nitro group in the indazole moiety does not have a significant influence in the reaction yield. Scheme 4. Reaction of N-vinyl-nitroindazole 3b with nitrile imines 11a-e. hen the reaction was performed with the vinyl-nitroindazole 3c and the nitrile imine ed in situ from the corresponding ethyl hydrazono-α-bromoglyoxylates 10d, the expe oline derivative 13 (Figure 1) was obtained in 81% yield. This yield is similar to the one obta the indazole 3b, showing that the position of the electron-withdrawing nitro group in ole moiety does not have a significant influence in the reaction yield.  The resonances due to the protons from the indazole core were not significantly affected by the presence of the introduced pyrazoline unit. Important diagnostic peaks confirming the presence of the pyrazoline unit are the two double doublets at ca. δ 7.58-7.76 ppm and δ 3.82-3.85 ppm and a multiplet at ca. δ 3.33-3.38 ppm, corresponding respectively to the pyrazoline protons H , H and H . In the aliphatic region, there is also the expected quartet (ca. δ 4.3 ppm) and triplet (ca. δ 1.3 ppm) due to the resonance of the protons from the ethyl ester group. The 13 C-NMR spectra show a distinctive signal near δ 161 ppm corresponding to the resonance of the carbonyl carbon from the ethyl ester group. The structure of the cycloadduct 13 was also unequivocally established by single-crystal X-ray diffraction studies (vide infra).

X-Ray Diffraction
Single-crystal X-ray diffraction analysis was used to study the structural features of three of the reported compounds in this paper, namely compounds 7b, 9 and 13. The N-substituted triazolo-nitroindazole 7b crystallises in the centrosymmetric monoclinic space group P2 1 /n with the asymmetric unit being composed of a whole molecular unit as depicted in Figure 2. The small number of hydrogen bonding donors and acceptors in this compound leads to a close packing in the solid-state achieved, mainly, by weak hydrogen bonding interactions of the C-H···N and C-H···O types, having typical geometrical parameters: d C···N distances found in the 3. bonding interactions [dC···N distances found in the 3.237(3)-3.530(3) Å range with <(CHN) interaction angles ranging from 123 to158°; the dC···O distances were found instead in the 3.291(4)-3.594(3) Å range with the corresponding <(CHO) interaction angles in the range 132-168°]. Interestingly, despite the presence of a high number of aromatic moieties, only a few highly offset π···π contacts are observed, all between aromatic rings within the molecular unit [intercentroid distances of dπ···π = 3.5320(14)-3.7007(15) Å].  From the reaction of derivative 6 with 1,3-diethynylbenzene, we were able to crystallise the bis-nitroindazolyl-triazole 9. Despite its intrinsic molecular symmetry, 9 crystallises in the triclinic P-1 space group, with the asymmetric unit being composed of a complete molecular unit ( The pyrazoline-indazole cycloadduct 13 crystallises in the noncentrosymmetric monoclinic space group P2 1 . The asymmetric unit is composed of a whole molecular unit containing one asymmetric carbon (C14, denoted with an asterisk in Figure 2). The crystal quality and the absence of heavy atomic elements did not allow a precise calculation of the Flack parameter. However, we believe that the crystal should consist of a racemic mixture since there is no reason for the performed reaction to exhibit any enantiomeric excess. As for the previous compounds, the close packing of 13 is achieved by weak C-H···N and C-H···O hydrogen-bonding interactions [d C···N distances found in the 3.160(6)-3.329(6) Å range with <(CHN) interaction angles ranging from 115 to164 • ; d C···O distance of 3.288(6) Å with the corresponding <(CHO) interaction angle of 128 • ]. No π···π contacts are observed.

General Remarks
Melting points were measured using a B-540 melting point apparatus (Buchi, Flawil, Switzerland). Electrospray ionization mass spectra (ESI) were acquired with a Micromass Q-Tof 2 (Micromass, Manchester, UK), operating in the positive ion mode, equipped with a Z-spray source, an electrospray probe and a syringe pump. Source and desolvation temperatures were 80 • C and 150 • C, respectively. Capillary voltage was 3000 V. The spectra were acquired at a nominal resolution of 9000 and at cone voltages of 30 V. Nebulisation and collision gases were N 2 and Ar, respectively. Compound solutions in methanol were introduced at a 10 µL min −1 flow rate. 1 H and 13 C solution NMR spectra were recorded on an Avance 300 spectrometer at 300.13 and 75.47 MHz, respectively (Bruker, Wissembourg, France). DMSO-d 6 was used as solvent and tetramethylsilane (TMS) as the internal reference; the chemical shifts are expressed in δ (ppm) and the coupling constants (J) in Hertz (Hz). Unequivocal 1 H assignments were made using 2D COSY ( 1 H/ 1 H), while 13 C assignments were made on the basis of 2D HSQC ( 1 H/ 13 C) and HMBC (delay for long-range J C/H couplings were optimized for 7 Hz) experiments. Elemental analyses were performed on a CHNS-932 apparatus (LECO, Madrid, Spain). Column chromatography was carried out using silica gel (Merck, 35-70 mesh). Analytical TLC was carried out on 0.2 mm thick sheets precoated with silica gel 60 (Merck, city, Darmstadt, Germany). All chemicals were used as supplied. Solvents were purified or dried according to the literature procedures [52].

N-alkylation of Nitroindazole Derivatives 1a-d with 1,2-Dibromoethane. General Procedure
To a solution of the appropriate nitroindazole 1a-1d (100 mg, 0.62 mmol) in acetone (10.0 mL) it was added a small excess of cesium carbonate (1.1 equiv., 0.67 mmol, 218 mg). Then, the 1,2-dibromoethane alkylating agent (1.1 equiv., 0.67 mmol, 58 µL) was added dropwise and the resulting reactional mixture was maintained under stirring at room temperature until the TLC control showed the total consumption of the starting material (1 h). Then, the solvent was evaporated and the crude product was purified by column chromatography (silica gel) using hexane:toluene (1:1) as the eluent.   A mixture of 1-(2-bromoethyl)-5-nitro-1H-indazole (2b, 0.1 g, 0.37 mmol) and sodium azide NaN 3 (10 equiv., 3.7 mmol, 130 µL) in 5 mL of DMF was maintained under stirring at room temperature for 24 h. After this period, the TLC control confirmed the disappearance of the starting material and the formation of a main product. Then, the reaction mixture was washed with water and the desired product was extracted with diethyl ether. The organic layer was separated, dried under Na 2 SO 4 and the solvent evaporated under reduced pressure. The residue was crystallized in hexane affording compound 6 pure in 88% yield. Yield: 88% (78.

General Procedure for 1,3-Dipolar Cycloaddition of Azides with Terminal Alkynes
To a stirred solution of azide 6 (0.1 g, 0.43 mmol) and the appropriate terminal alkynes (0.64 mmol) in 5 mL of a mixture H 2 O/t-BuOH (1:1), it was added copper sulphate (0.02 mmol) and sodium ascorbate (0.04 mmol). The reaction mixture was stirred at room temperature until the TLC control showed the total consumption of the starting material (12-16 h). After this period, the reaction mixture was washed with water and the organic phase was extracted with dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The desired products 7a-7d were obtained pure after crystallization in ethanol. The compounds 8 and 9 were purified by column chromatography (silica gel) using hexane:ethyl acetate (1:1) as the eluent.  3.5. General Procedure for 1,3-Dipolar Cycloaddition Reactions of N-Vinyl-Nitroindazoles with Nitrile Imines to Give Access to Compounds 12a-12e A solution of 5-nitro-1-vinyl-1H-indazole 3b or 6-nitro-1-vinyl-1H-indazole, 3 (0.02 g, 0.10 mmol) and the appropriate hydrazonyl bromide 10a-10e (1.5 equiv., 0.15 mmol) in dichloromethane (5 mL) was treated with cesium carbonate (0.20 mmol) and then stirred for 24 h at room temperature. After this period, the solvent was removed, and the crude product was purified by column chromatography on silica gel (EtOAc:hexane 2:8) to afford the corresponding products 12a-12e. (for the three first families of groups) or 1.5×U eq (for the methyl groups) of the parent non-hydrogen atoms. Structural drawings have been created using the software package Crystal Impact Diamond [61].
Crystal data for 7b: C 18

Conclusions
In summary, the N-alkylation of nitroindazole derivatives with dibromoethane afforded N-(2-bromoethyl)and N-vinyl-nitro-1H-indazoles. The distribution of the N-substituted derivatives depends on the experimental conditions although the N-1 bromoethyl derivatives are always isolated as the major components. The elimination reaction at N-2 seems to be more favourable than the elimination reaction at the N-1 position. Both types of derivatives showed to be excellent templates for further functionalization via 1,3-dipolar cycloaddition approaches.
The N-bromoethylnitroindazole derivative 2c after being efficiently converted into the corresponding azide 6 afforded, in the presence of terminal ethynylbenzene derivatives and under CuAAC conditions, the expected triazolo derivatives in yields ranging from 71 to 87%. This reaction seems to be favoured by the presence of electron-donating groups in the ethynylbenzene derivative.
The reaction of the N-vinyl-nitroindazole 3b with N-aryl-C-ethoxycarbonylnitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates, afforded the corresponding nitroindazole-pyrazoline derivatives 12 with yields ranging from 63 to 87%. The presence of the nitro group in a different position of the indazole core did not seem to affect its reactivity as dipolarophile since derivative 13 was also obtained in excellent yield from the nitroindazole 3c. The expected regioselectivity in these cycloaddition reactions was further supported by single-crystal X-ray diffraction analysis with some single crystals of the compounds obtained.