An efficient synthesis of 1-arylindazole-3-carboxamides using nitrile imines, isocyanides and 2-hydroxymethylbenzoic acid, followed by a chemoselective Buchwald–Hartwig intramolecular cyclization

Abstract

A convergent and efficient two-step synthesis of pharmaceutically relevant 1-arylindazole-3-carboxamides is reported. These molecules have been obtained in good to excellent yields (up to 98%) starting from a strategic reaction between isocyanides, 2-iodo-N-arylbenzohydrazonoyl chlorides and 2-hydroxymethylbenzoic acid followed by a chemoselective Buchwald–Hartwig intramolecular cyclization. This novel strategy provides an additional indazole synthesis to those already reported in literature both in the type of substrate as well as the substitution pattern obtainable in the products. Furthermore benzylisocyanide is herein reported for the first time as a convertible isocyanide providing an expeditious access to N-arylindazole-3-carbonitriles.

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Introduction

Several naturally occurring alkaloids and many bioactive synthetic compounds share as a common element the indazole nucleus.¹ According to their pattern of substitution, molecules containing the indazole ring have shown to possess different biological profiles spanning from anti-cancer compounds to serotonin 5-HT3 receptor antagonists.² In particular, substituted indazole-3-carboxamides have been disclosed as inhibitors of human neutrophil elastase,³ DNA intercalating agents,⁴ kinase inhibitors,⁵ selective sodium channel blockers,⁶ DGAT inhibitors,⁷ and NAMPT inhibitors⁸ (Fig. 1).

Fig. 1 Pharmaceutically relevant N-arylindazoles-3-carboxamides (numbers correspond to those reported in the patents).

Due to the pharmaceutical relevance of indazoles several methods of preparations have been reported in literature which depend on the pattern of substitution of the indazole ring.⁹ In particular 1-arylindazole-3-carboxamides 3 are prepared starting from the corresponding 1H-indazole-carboxylic acids 1 which are coupled with amines and then subjected to a Pd or Cu N-arylation. One disadvantage of this synthetic plan is that aryl substituted 1H-indazole-carboxylic acids require a multistep synthesis with poor overall efficiency¹⁰ (Scheme 1).

Scheme 1 Conventional synthesis of N-arylindazoles-3-carboxamides.

For this reason an efficient synthetic strategy based on the preparation of substituted indazoles without using 1H-indazole-carboxylic acids is welcomed.

Recently, in our on-going studies aimed at the discovery of novel multicomponent reactions, we reported the use of hydrazonoyl chlorides as imine aza-analogue in isocyanide-mediated multicomponent reactions.¹¹ Continuing our interest in this chemistry, we recognized that α-aminocarbonyl hydrazones 7, obtainable using the synthetic approach developed by us,^11a thanks to their atom connectivity and the presence of the hydrazone functional group can be exploited in a post-condensation modification using a Buchwald–Hartwing intramolecular amination to generate the substituted indazole ring 8 in two operationally simple reaction steps (Scheme 2).

Scheme 2 General structure of α-aminocarbonyl hydrazones and cyclic indazole derivatives.

Results and discussion

In order to test our hypothesis, we reacted 2-iodo-N′-phenylbenzohydrazonoyl chloride 9, cyclohexylisocyanide 10 and 2-hydroxymethylbenzoic acid (sacrificial acid) 6 in DCM at room temperature overnight to obtain α-aminocarbonyl hydrazone 11 in 65%. The reaction is triggered by the in situ generation of nitrile imine by a base-induced dehydrochlorination of hydrazonoyl chloride. The 2-hydroxymethylbenzoic acid behaves like a pseudo water molecule in order to overpass the poor reactivity of water on the nitrilium ion.¹² Subsequently, this linear intermediate was then reacted in classic Buchwald–Hartwing conditions to evaluate indazole 12 formation (Scheme 3). It is important to highlight that a priori both the hydrazone and the amide function could cyclize to give either the indazole or the indolone derivatives,¹³ both being at a suitable distance (5 centers) from the aromatic iodine atom of intermediate 11. Refluxing 11 in toluene, and in the presence of palladium acetate, Xantphos and cesium carbonate gave indeed the desired indazole 12 in 66% yield (entry 1, Table 1), and 12.5% of indolone derivative 13 coming from intramolecular amidation.

Scheme 3 3-CR affording α-aminocarbonyl hydrazones and test reaction for the formation of indazole derivatives.

Table 1 Optimization of indazole cyclization conditions

Entry	Solvent	Catalyst 10% mol	Ligand 7% mol	Yield of 12 (yield of 13)
1	Toluene	Pd(OAc)2	Xantphos	66% (12.5%)
2	Toluene	Pd(dppf)Cl2	Xantphos	48% (4%)
3	Toluene	CuI	N,N′-dimethylethylene diamine	22% (10%)
4	Toluene	Pd(dppf)Cl2	XPhos	38% (20%)
5	Toluene	Pd(PPh3)2Cl2	Tri-o-tolyl-phosphine	78% (traces)
6	1,4-Dioxan	Pd(PPh3)2Cl2	Tri-o-tolyl-phosphine	97% (traces)

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In order to optimize indazole formation we screened different palladium sources (entries 2, 4–6), ligands (entries 3–6), and solvents (entry 6), and we also tried copper catalyst in place of palladium (entry 3). With palladium catalysts (entries 1, 2 and 4–6) 1 equivalent of cesium carbonate has been used as base. With our satisfaction, we were able to obtain indazole 12 in 97% yields, which means a highly regioselective formation of indazole derivatives over indolone one, when intermediate 11 was refluxed in 1,4-dioxan in the presence of tri-o-tolylphosphine (0.1 equiv.), cesium carbonate (1 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.07 equiv.).

Despite the reported examples of both intermolecular¹⁴ and intramolecular^9b hydrazone N-arylation (Scheme 4), to our knowledge this is the first example of a regioselective hydrazone palladium catalyzed cyclization in the presence of an amide bond.

Scheme 4 Examples of inter- and intra-molecular hydrazine N-arylation reported in literature.

To evaluate the scope of this cyclization, we synthesized five different hydrazonoyl chlorides^11a (9, 14–17) and we selected six isocyanides (10, 18–22) as starting inputs (Fig. 2), to form a library of α-aminocarbonyl hydrazones (31–74% yields) (Fig. 3). Aliphatic hydrazonoyl chlorides are much less stable than aromatic ones and did not react successfully in this reaction (poor yield, by-products formation and difficult purification procedure).

Fig. 2 Starting materials for the synthesis of α-aminocarbonyl hydrazones.

Fig. 3 Synthesized library of linear α-aminocarbonyl hydrazones.

We then reacted the intermediate hydrazones using the optimized conditions to get eleven different substituted 1-arylindazole-3-carboxamides in good to excellent yields (48–98%) (Fig. 4).

Fig. 4 Synthesized library of indazole cyclic derivatives.

The reaction proved to be quite general in scope as the presence of both aliphatic (34–37, 39–41, 43 and 44) and aromatic (38, 42) carboxamides gave good yields. Only electron-withdrawing nitrile group on the hydrazone aromatic ring in derivatives 40, 41 and 42 showed to decrease yields to 65, 64 and 48%, respectively.

A working hypothesis for the formation of hydrazone derivatives is depicted in Scheme 5. The hydrazonoyl chlorides 4 readily form the nitrilimine, which is the active 1,3-dipolar species and is attacked by the isocyanide carbon atom to form a nitrilium ion. The latter is then attacked by the carboxylate function of sacrificial acid 6 to give an unstable imidate: the hydroxy-function cyclize into the C=O carbonyl to give the N-arylhydrazono-acetamides 7 and phthalide. In this reaction sacrificial acid 6 enables to overcome the poor nucleophilicity of water towards the nitrilium ion. 6 behaves indeed like a pseudo water molecule, as it traps the nitrilium ion and then undergoes an intramolecular cyclization to deliver one oxygen atom to the product, as water would, and the aromatic lactone phthalide.

Scheme 5 Proposed reaction mechanism for the synthesis of hydrazono-acetamide derivative 7.

In order to further expand the scope of the reaction we tried a direct conversion of N-arylindazole-3-carboxamides to N-arylindazole-3-carbonitriles. The synthesis of such derivatives is usually accomplished in two or more steps, with overall yields of 26–44% and the use of harsh reaction conditions, with Zn- or Cu-containing waste¹⁵ or promoted by tri-n-butyltin chloride and palladium.¹⁶ An alternative two-step route, based on a primary amide formation and subsequent dehydration to nitrile (overall yield 63%) has been reported for the synthesis of p38 kinase inhibitors.⁵ Dealing with their biological activities, N-arylindazole-3-carbonitrile derivatives have been described also as xanthine oxidase inhibitors¹⁵ and as low nanomolar bradykinin receptor antagonists.¹⁶ We speculated indeed that a one-step conversion of the reported N-arylindazole-3-carboxamides to N-arylindazole-3-carbonitrile could be useful to further enlarge the size and the variability of the synthesizable libraries. So, by reacting N-arylindazole-3-carboxamide 37 in POCl₃ at 150 °C in a sealed tube for 4 h we were able to get N-arylindazole-3-carbonitrile 45 in 96% yield (Scheme 6).¹⁷

Scheme 6 Conversion of N-arylindazole-3-carboxamides to N-arylindazole-3-carbonitriles.

To our knowledge, this transformation accounts for the first application of benzylisocyanide as a convertible isocyanide.

Conclusions

In conclusion we developed a novel, concise two-step synthesis for the construction of 1-aryl-indazoles-3-carboxamides performing a reaction between isocyanides, 2-iodo-N-arylbenzohydrazonoyl chlorides and 2-hydroxymethylbenzoic followed by a regioselective intramolecular hydrazone palladium catalyzed cyclization. Furthermore benzyl-isocyanide was unconventionally employed as a convertible isocyanide for the synthesis of biologically interesting N-arylindazole-3-carbonitriles. The present work step forward the consideration of post-condensation modifications of isocyanide-based reactions as a pass-holder to gain a direct access not only to medicinally relevant compounds, but still to the exploitation of the full potential of landmark transformations as the Buchwald–Hartwig reactions.

Experimental section

General

Commercially available reagents and solvents were used without further purification. Dichloromethane was dried by distillation from P₂O₅ and stored over activated molecular sieves (4 Å). When necessary the reactions were performed in oven-dried glassware under a positive pressure of dry nitrogen. Melting points were determined in open glass capillaries and are uncorrected. All the compounds were characterized by IR. ¹H and ¹³C APT NMR were recorded on a 400 MHz. High-resolution ESI-MS spectra were performed on a Thermo LTQ Orbitrap XL mass spectrometer. The spectra were recorded by infusion into the ESI source using MeOH as the solvent. Chemical shifts (δ) are reported in part per million (ppm) relative to the residual solvent peak. Column chromatography was performed on silica gel (70–230 mesh ASTM) using the reported eluents. Thin layer chromatography (TLC) was carried out on 5 × 20 cm plates with a layer thickness of 0.25 mm (silica gel 60 F254). When necessary they were developed with KMnO₄.

General preparation of hydrazonoyl chlorides (9, 14–17)^11a. The hydrazonoyl chlorides were readily synthesized in two steps:
Preparation of acylhydrazines. To a stirred solution of 2-iodobenzoic acids on a 5 mmol scale in THF (0.2 M, 10 mL) were added EDC HCl (1.05 g, 5.50 mmol, 1.1 eq.), DMAP (0.12 g, 1 mmol, 0.2 eq.), triethylamine (1.40 mL, 10 mmol, 2 eq.) and hydrazine (5 mmol, 1 eq.) at 0 °C. The resulting mixture was allowed to warm to room temperature over 24 h. The crude reaction mixture was washed with HCl 1 M sol. (x2), sat. NaHCO₃ (x2) and brine (x1), evaporated to dryness and used in the next step without further purification.
Preparation of hydrazonoyl chlorides (9, 14–17). The corresponding acylhydrazine (2.50 mmol) was dissolved in CH₃CN (0.5 M, 5 mL) and triphenylphosphine (0.79 g, 3 mmol, 1.2 eq.) and carbon tetrachloride (0.29 mL, 3 mmol, 1.2 eq.) were added. The reaction was stirred at room temperature until all the acylhydrazine was consumed as judged by TLC (typically 8–12 hours). The reaction was concentrated under reduced pressure and purified by column chromatography (n-hexane/EtOAc) and stored below 0 °C.

(Z)-2-Iodo-N′-phenylbenzohydrazonoyl chloride (9). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as a white solid (0.41 g, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (br s, NH), 8.05 (d, J = 7.88 Hz, 1H), 7.64 (br d, 1H), 7.48–7.41 (m, 3H), 7.35–7.33 (m, 2H), 7.14–7.07 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 143.3, 140.5, 139.9, 130.9, 130.7, 129.6, 128.3, 123.0, 121.6, 113.7, 96.8.

(Z)-2-Iodo-N′-(4-methoxyphenyl)benzohydrazonoyl chloride (14). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as a yellowish solid (0.43 g, 44% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.96 Hz, 1H), 7.90 (br s, NH), 7.54 (d, J = 7.72 Hz, 1H), 7.40 (t, J = 7.52 Hz, 1H), 7.15 (d, J = 8.88 Hz, 2H), 7.06 (t, J = 7.52 Hz, 1H), 6.87 (d, J = 8.92 Hz, 1H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 154.7, 140.5, 139.9, 137.2, 130.8, 130.5, 128.2, 122.0, 114.8 (4C), 96.6, 55.7.

(Z)-4-Chloro-2-iodo-N′-phenylbenzohydrazonoyl chloride (15). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as a light yellow solid (0.69 g, 71% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, NH), 7.97 (s, 1H), 7.47 (br d, 1H), 7.39 (br d, AA′XX′, 1H), 7.33–7.29 (m, 2H), 7.22–7.20 (m, 2H), 6.96 (t, J = 7.24 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 142.9, 139.8, 138.2, 135.5, 131.2, 129.4, 128.4, 121.6, 121.5, 113.5, 96.3.

(Z)-N′-(4-Chlorophenyl)-2-iodobenzohydrazonoyl chloride (16). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as a light yellow solid (0.33 g, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (br s, NH), 7. (br d, AA′XX′, 2H), 7.41 (br t, 1H), 7.26 (br d, AA′XX′, 2H), 7.15 (br d, AA′XX′, 2H), 7.08 (br t, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 141.8, 140.4, 139.6, 130.8, 130.7, 129.3, 128.2, 126.1, 123.7, 114.8, 96.5.

(Z)-N′-(4-Cyanophenyl)-2-iodobenzohydrazonoyl chloride (17). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as a light orange solid (0.84 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.44 (br s, NH), 7.98 (br d, 1H), 7.65 (br d, AA′XX′, 2H), 7.59 (br d, 1H), 7.49 (br t, 1H), 7.40 (br d, AA′XX′, 2H), 7.19 (br t, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 148.1, 140.3, 140.2, 134.0, 131.8, 131.0, 129.0, 125.0, 120.0, 114.2, 102.2, 97.5.

General preparation of α-aminocarbonylhydrazones (11, 23–33). The hydrazonoyl chloride (0.5 mmol, 1 eq.), the isocyanide (0.5 mmol, 1 eq.), 2-hydroxymethylbenzoic acid (0.5 mmol, 1 eq.) and TEA (1 mmol, 2 eq.) were one-pot mixed in DCM (0.5 M, 1 mL) and stirred at room temperature under a nitrogen atmosphere overnight. After evaporation of the solvent, the crude material was purified by column chromatography.

(Z)-N-Cyclohexyl-2-(2-iodophenyl)-2-(2-phenylhydrazono)acet-amide (11). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as yellow solid (0.15 g, 66% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.25 (br s, NH), 7.93 (br d, 1H), 7.46–7.45 (m, 2H), 7.29–7.10 (m, 5H), 6.93 (br t, 1H), 5.17 (br d, NH), 3.89–3.82 (m, 1H), 1.94–1.92 (m, 2H), 1.68–1.58 (m, 3H), 1.42–1.33 (m, 2H), 1.16–1.04 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 143.5, 140.7, 140.0, 132.8, 131.8, 130.4, 129.2, 128.9, 121.7, 113.8, 100.6, 48.2, 32.7, 25.4, 24.8. IR (KBr) 3390, 2923, 2846, 1632, 1497, 1171, 760 ν_max/cm⁻¹; mp 121.1–122.3 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₃IN₃O: 448.0886; found: 448.0895 (100%) [M + H]⁺.

(Z)-N-(tert-Butyl)-2-(2-iodophenyl)-2-(2-(4-methoxyphenyl)-hydrazono)acetamide (23). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as sticky reddish solid (0.10 g, 44% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.20 (bs, NH), 7.92 (d, J = 7.96 Hz, 1H), 7.45–7.44 (m, 2H), 7.14 (br d, AA′XX′, 2H), 7.12–7.07 (m, 1H), 6.83 (d, J = 8.92 Hz, 2H), 5.05 (br s, NH), 3.76 (s, 3H), 1.35 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.5, 154.9, 141.2, 139.6, 137.6, 132.3, 131.8, 130.1, 128.9, 115.0, 114.6, 100.7, 55.6, 51.6, 28.6. IR (KBr) 3406, 2956, 1635, 1530, 1500, 1229, 1157 ν_max/cm⁻¹; MS (ESI) m/z (M + H)⁺ calcd for C₁₉H₂₃IN₃O₂: 452.0835; found: 452.0774 (100%) [M + H]⁺.

(Z)-2-(2-Iodophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-N-pentylacetamide (24). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as reddish oil (0.11 g, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.19 (br s, NH), 7.94 (d, J = 7.96 Hz, 1H), 7.47–7.42 (m, 2H), 7.13 (br d, AA′XX′, 2H), 7.11–7.08 (m, 1H), 6.83 (d, J = 8.88 Hz, 2H), 5.27 (br t, NH), 3.76 (s, 3H), 3.26 (q, J = 6.56 Hz, 2H), 1.53–1.46 (m, 2H), 1.33–1.25 (m, 4H), 0.89–0.86 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.7, 155.0, 140.9, 140.0, 139.7, 137.5, 131.7, 130.2, 128.8, 115.0 (2C), 114.6 (2C), 101.0, 55.6, 39.2, 29.1, 29.0, 22.3, 14.0. IR (KBr) 3417, 2950, 2923, 1635, 1506, 1220, 1168, 823 ν_max/cm⁻¹; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₅IN₃O₂: 466.0991; found: 466.0956 (100%) [M + H]⁺.

(Z)-2-(4-Chloro-2-iodophenyl)-N-cyclohexyl-2-(2-phenylhydrazono) acetamide (25). The crude material was purified by column chromatography (n-hexane/EtOAc 30 : 1) to give the product as yellow solid (0.18 g, 74% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.20 (br s, NH), 7.45 (br d, AA′XX′, 1H), 7.37 (br d, AA′XX′, 1H), 7.28–7.24 (m, 2H), 7.17 (br d, AA′XX′, 2H), 6.94 (br t, 1H), 5.07 (br d, NH), 3.88–3.80 (m, 1H), 1.95–1.92 (m, 2H), 1.69–1.59 (m, 3H), 1.42–1.32 (m, 2H), 1.17–1.06 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.3, 143.3, 139.4, 139.0, 135.2, 132.3, 131.5, 129.2, 129.1, 122.0, 113.9, 100.6, 48.2, 32.8, 25.4, 24.8. IR (KBr) 3395, 2928, 2851, 1635, 1495, 1245, 1168, 990, 740 ν_max/cm⁻¹; mp 132.6–133.2 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₂ClIN₃O: 482.0496; found: 482.0482 (100%) [M + H]⁺.

(Z)-N-Benzyl-2-(2-(4-chlorophenyl)hydrazono)-2-(2-iodophenyl)-acetamide (26). The crude material was purified by column chromatography (n-hexane/EtOAc 99 : 1) to give the product as yellowish solid (0.10 g, 41% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.24 (br s, NH), 7.92 (br d, 1H), 7.45–7.10 (m, 12H), 5.63 (br s, NH), 4.50 (d, J = 5.92 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 163.4, 142.15, 140.4, 139.8, 137.3, 132.9, 131.5, 130.5, 129.2, 128.9, 128.7, 126.7, 115.2, 100.6, 43.3. IR (KBr) 3390, 1629, 1533, 1495, 1160, 823, 754 ν_max/cm⁻¹; mp 110.4–111.7 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₁H₁₈ClIN₃O: 490.0183; found: 490.0152 (100%) [M + H]⁺.

(Z)-2-(2-Iodophenyl)-N-(4-methoxyphenyl)-2-(2-phenylhydrazono) acetamide (27). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as yellow solid (0.07 g, 31% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.22 (br s, NH), 7.99 (br d, 1H), 7.57–7.50 (m, 2H), 7.34–7.15 (m, 7H), 6.96 (br t, 1H), 6.88 (br d, AA′XX′, 2H), 6.83 (br s, NH), 3.80 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 157.2, 143.4, 140.5, 139.9, 132.4, 132.0, 130.6, 129.5, 129.1, 123.1, 122.2, 114.3, 114.1, 100.9, 55.5. IR (KBr) 3351, 1601, 1506, 1484, 1234, 1146, 998 ν_max/cm⁻¹; mp 119.3–120.6 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₁H₁₉IN₃O₂: 472.0522; found: 472.0556 (100%) [M + H]⁺.

(Z)-2-(2-(4-Chlorophenyl)hydrazono)-2-(2-iodophenyl)-N-(4-methoxybenzyl)acetamide (28). The crude material was purified by column chromatography (n-hexane/EtOAc 99 : 1) to give the product as white solid (0.11 g, 43% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.24 (br s, NH), 7.91 (br d, 1H), 7.44–7.42 (m, 2H), 7.23–7.10 (m, 7H), 6.85 (br d, AA′XX′, 2H), 5.60–5.57 (m, 1H), 4.42 (br d, 2H), 3.78 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 160.3, 159.1, 142.1, 140.3, 139.8, 132.9, 131.6, 130.5, 129.3, 129.2, 129.1, 128.9, 126.6, 115.1, 114.1, 100.6, 55.3, 42.8. IR (KBr) 3324, 3208, 1626, 1517, 1489, 1242, 1160, 1004, 825 ν_max/cm⁻¹; mp 143.3–144.4 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₂H₂₀ClIN₃O₂: 520.0289; found: 520.0292 (100%) [M + H]⁺.

(Z)-N-(tert-Butyl)-2-(2-(4-cyanophenyl)hydrazono)-2-(2-iodo-phenyl)acetamide (29). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as white solid (0.11 g, 47% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.45 (br s, NH), 7.94 (br d, 1H), 7.53–7.41 (m, 4H), 7.21–7.16 (m, 3H), 5.18 (br s, NH), 1.35 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 162.7, 147.0, 140.2, 139.7, 136.7, 133.5, 131.5, 130.8, 129.0, 119.7, 113.8, 103.5, 99.6, 52.1, 28.4. IR (KBr) 3390, 3164, 2961, 2214, 1637, 1508, 1149, 990 ν_max/cm⁻¹; mp 167.8–168.8 °C; MS (ESI) m/z (M + H)⁺ calcd for C₁₉H₂₀IN₄O: 447.0682; found: 447.0646 (100%) [M + H]⁺.

(Z)-2-(2-(4-Cyanophenyl)hydrazono)-2-(2-iodophenyl)-N-pentyl-acetamide (30). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as yellowish solid (0.12 g, 52% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.43 (br s, NH), 7.96 (br d, 1H), 7.54–7.41 (m, 4H), 7.22–7.15 (m, 3H), 5.42 (br s, NH), 3.30–3.25 (m, 1H), 1.55–1.48 (m, 2H), 1.33–1.25 (m, 4H), 0.88 (br t, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 146.9, 139.9, 139.8, 135.9, 133.6, 131.4, 130.8, 129.0, 119.7, 113.9, 103.8, 99.9, 39.5, 29.1, 28.8, 22.3, 13.9. IR (KBr) 3329, 2923, 2214, 1646, 1508, 1149, 828 ν_max/cm⁻¹; mp 91.0–92.4 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₂IN₄O: 461.0838; found: 461.0852 (100%) [M + H]⁺.

(Z)-2-(2-(4-Cyanophenyl)hydrazono)-2-(2-iodophenyl)-N-(4-methoxyphenyl)acetamide (31). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as reddish solid (0.08 g, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.40 (br s, NH), 8.00 (br d, 1H), 7.56–7.54 (m, 5H), 7.34–7.21 (m, 4H), 6.92 (br s, NH), 6.89 (br s, AA′XX′, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 161.2, 157.6, 146.7, 140.0, 139.7, 135.7, 133.6, 131.8, 131.1, 129.2, 128.9, 123.1, 119.6, 114.3, 114.1, 104.2, 100.0, 55.5. IR (KBr) 3395, 2208, 1607, 1506, 1229, 1141, 825 ν_max/cm⁻¹; mp 111.2–112.3 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₂H₁₈IN₄O₂: 497.0474; found: 497.0482 (100%) [M + H]⁺.

(Z)-N-(tert-Butyl)-2-(2-(4-chlorophenyl)hydrazono)-2-(2-iodo-phenyl)acetamide (32). The crude material was purified by column chromatography (n-hexane/EtOAc 97 : 3) to give the product as yellow solid (0.11 g, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.26 (br s, NH), 7.93 (br d, 1H), 7.46–7.42 (m, 2H), 7.22–7.10 (m, 5H), 5.11 (br s, NH), 1.35 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 163.2, 142.3, 140.8, 139.7, 134.0, 131.7, 130.4, 129.1, 128.9, 126.2, 114.9, 100.2, 51.8, 28.5. IR (KBr) 3406, 2956, 1643, 1489, 1231, 1157, 987, 823 ν_max/cm⁻¹; mp 139.4–140.6 °C; MS (ESI) m/z (M + H)⁺ calcd for C₁₈H₂₀ClIN₃O: 456.0340; found: 456.0304 (100%) [M + H]⁺.

(Z)-2-(2-(4-Chlorophenyl)hydrazono)-N-cyclohexyl-2-(2-iodo-phenyl)acetamide (33). The crude material was purified by column chromatography (n-hexane/EtOAc 97 : 3) to give the product as orange solid (0.08 g, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 13.25 (br s, NH), 7.93 (br d, 1H), 7.46–7.41 (m, 2H), 7.20 (br d, AA′XX′, 2H), 7.14–7.09 (m, 4H), 5.16 (br d, NH), 3.87–3.79 (m, 1H), 1.92–1.89 (m, 2H), 1.67–1.63 (m, 3H), 1.38–1.31 (m, 2H), 1.12–1.05 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.5, 142.2, 140.5, 139.7, 133.5, 131.7, 130.4, 129.2, 128.9, 126.3, 114.9, 100.4, 48.2, 32.7, 25.4, 24.7. IR (KBr) 3390, 2923, 2846, 1635, 1492, 1160, 993 ν_max/cm⁻¹; mp 134.8–135.4 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₂ClIN₃O: 482.0496; found: 482.0472 (100%) [M + H]⁺.

General preparation of N-arylindazole-3-carboxamides (12, 34–44). The α-aminocarbonylhydrazone (0.1 mmol, 1 equiv.) is dissolved in dry 1,4-dioxan (0.3 M) and cesium carbonate (0.1 mmol, 1 equiv.), tri-o-tolylphosphine (0.01 mmol, 0.1 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.007 mmol, 0.07 equiv.) were added. The reaction mixture was stirred at reflux temperature overnight, evaporated and purified by chromatographic column (n-hexane/ethyl acetate).

N-Cyclohexyl-1-phenyl-1H-indazole-3-carboxamide (12). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as yellow solid (0.03 g, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 8.12 Hz, 1H), 7.73–7.66 (m, 3H), 7.58–7.54 (m, 2H), 7.46–7.40 (m, 2H), 7.35–7.32 (m, 1H), 7.04 (br d, NH), 4.10–4.00 (m, 1H), 2.08–2.03 (m, 2H), 1.80–1.64 (m, 3H), 1.50–1.20 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 140.4, 139.7, 139.5, 129.6 (2C), 127.6 (2C), 123.9, 123.4 (2C), 123.3, 123.2, 110.4, 48.0, 33.3 (2C), 25.6, 25.0 (2C). IR (KBr) 2923, 2851, 1662, 1555, 1363, 1245, 1171, 1056 ν_max/cm⁻¹; mp 104.3–105.5 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₂N₃O: 320.1763; found: 320.1730 (100%) [M + H]⁺.

N-(tert-Butyl)-1-(4-methoxyphenyl)-1H-indazole-3-carboxamide (34). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as reddish oil (0.03 g, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J = 8.08 Hz, 1H), 7.60–7.56 (m, 3H), 7.42 (br t, 1H), 7.31 (br t, 1H), 7.08–7.04 (m, 3H), 3.89 (s, 3H), 1.53 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 162.0, 159.0, 140.7, 139.6, 132.4, 127.4, 125.2 (2C), 123.4, 123.3, 123.0, 114.7 (2C), 110.3, 55.7, 51.3, 29.1. IR (KBr) 3406, 2956, 1668, 1533, 1508, 1196, 1028, 751 ν_max/cm⁻¹; MS (ESI) m/z (M + H)⁺ calcd for C₁₉H₂₂N₃O₂: 324.1712; found: 324.1728 (100%) [M + H]⁺.

1-(4-Methoxyphenyl)-N-pentyl-1H-indazole-3-carboxamide (35). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as an off-white solid (0.03 g, 92% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J = 8.12 Hz, 1H), 7.59–7.56 (m, 3H), 7.41 (br t, 1H), 7.31 (br t, 1H), 7.14 (br t, NH), 7.06 (br d, AA′XX′, 2H), 3.87 (s, 3H), 3.52–3.47 (m, 2H), 1.66–1.61 (m, 2H), 1.39–1.35 (m, 4H), 0.92–0.88 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.5, 159.1, 140.6, 139.0, 132.5, 127.4, 125.1 (2C), 123.5, 123.2, 123.1, 114.7 (2C), 110.3, 55.6, 39.1, 29.5, 29.2, 22.4, 14.0. IR (KBr) 3291, 2956, 1640, 1544, 1245, 1201, 1026 ν_max/cm⁻¹; mp 58.7–59.8 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₄N₃O₂: 338.1869; found: 338.1843 (100%) [M + H]⁺.

6-Chloro-N-cyclohexyl-1-phenyl-1H-indazole-3-carboxamide (36). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as an off-white solid (0.03 mg, 98% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 8.60 Hz, 1H), 7.69–7.67 (m, 3H), 7.60–7.57 (m, 2H), 7.48–7.44 (m, 1H), 7.30 (d, J = 8.64 Hz, 1H), 6.99 (br d, NH), 4.08–4.00 (m, 1H), 2.08–2.05 (m, 2H), 1.80–1.66 (m, 4H), 1.49–1.17 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 140.7, 139.8, 139.0, 134.2, 129.7 (2C), 128.0, 124.4 (2C), 123.5 (2C), 122.2, 110.2, 48.0, 33.2 (2C), 25.6, 25.0 (2C). IR (KBr) 3324, 2934, 2851, 1637, 1536, 1495, 1251, 751 ν_max/cm⁻¹; mp 146.1–147.2 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₁ClN₃O: 354.1373; found: 354.1349 (100%) [M + H]⁺.

N-Benzyl-1-(4-chlorophenyl)-1H-indazole-3-carboxamide (37). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as white solid (0.03 g, 92% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 8.12 Hz, 1H), 7.68–7.65 (m, 3H), 7.53–7.29 (m, 10H), 4.73 (br d, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.1, 140.2, 139.5, 138.2, 138.0, 133.2, 129.7 (2C), 128.7 (2C), 128.0, 127.9 (2C), 127.5, 124.4 (2C), 124.0, 123.6, 123.3, 110.3, 43.1. IR (KBr) 3302, 1648, 1539, 1492, 1196, 1086, 976 ν_max/cm⁻¹; mp 101.3–102.6 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₁H₁₇ClN₃O: 362.1060; found: 362.1030 (100%) [M + H]⁺.

N-(4-Methoxyphenyl)-1-phenyl-1H-indazole-3-carboxamide (38). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as red solid (0.03 g, 75% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.88 (br s, NH), 8.53 (d, J = 7.00 Hz, 1H), 7.73–7.66 (m, 5H), 7.57–7.54 (m, 2H), 7.46–7.41 (m, 2H), 7.34 (br t, 1H), 6.91 (d, J = 8.68 Hz, 2H), 3.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 160.1, 156.3, 140.5, 139.4, 139.3, 131.0, 129.6, 127.8 (2C), 123.9, 123.5, 123.4, 123.2, 121.5, 114.2, 110.6, 55.5. IR (KBr) 3318, 2956, 1668, 1530, 1240, 1020, 823 ν_max/cm⁻¹; mp 116.6–117.3 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₁H₁₈N₃O₂: 344.1399; found: 344.1407 (100%) [M + H]⁺.

1-(4-Chlorophenyl)-N-(4-methoxybenzyl)-1H-indazole-3-carboxamide (39). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as orange solid (0.03 g, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (br d, 1H), 7.64–7.61 (m, 3H), 7.49–7.46 (m, 4H), 7.37–7.31 (m, 3H), 6.86 (br d, AA′XX′, 2H), 4.64 (br d, 2H), 3.77 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.0, 159.0, 140.2, 139.7, 138.0, 133.1, 130.4, 129.7, 129.3, 128.0, 124.3, 124.0, 123.5, 123.4, 114.1, 110.3, 55.3, 42.6. IR (KBr) 3313, 1646, 1541, 1492, 1086, 828 ν_max/cm⁻¹; mp 135.0–136.1 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₂H₁₉ClN₃O₂: 392.1166; found: 392.1133 (100%) [M + H]⁺.

N-(tert-Butyl)-1-(4-cyanophenyl)-1H-indazole-3-carboxamide (40). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as yellowish solid (0.02 g, 65% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (br d, 1H), 6.91 (br d, AA′XX′, 2H), 7.84 (br d, AA′XX′, 2H), 7.73 (br d, 1H), 7.49 (br t, 1H), 7.35 (br t, 1H), 6.99 (br s, NH), 1.53 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 161.3, 143.0, 141.7, 140.0, 133.6, 128.5, 124.4, 123.9 (2C), 122.7, 118.2, 110.3, 110.3, 51.5, 29.0. IR (KBr) 3340, 2967, 2230, 1651, 1541, 1363, 850 ν_max/cm⁻¹; mp 131.7–133.0 °C; MS (ESI) m/z (M + H)⁺ calcd for C₁₉H₁₉N₄O: 319.1559; found: 319.1525 (100%) [M + H]⁺.

1-(4-Cyanophenyl)-N-pentyl-1H-indazole-3-carboxamide (41). The crude material was purified by column chromatography (n-hexane/EtOAc 95 : 5) to give the product as light pink solid (0.02 g, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (br d, 1H), 7.91 (br d, AA′XX′, 2H), 7.84 (br d, AA′XX′, 2H), 7.75 (br d, 1H), 7.51 (br t, 1H), 7.37 (br t, 1H), 7.12 (br t, NH), 3.53–3.48 (m, 2H), 1.76–1.65 (m, 2H), 1.39–1.38 (m, 4H), 0.92–0.89 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 143.1, 141.1, 140.0, 133.6, 128.5, 124.5, 124.0, 123.8, 122.7, 118.2, 110.4, 110.3, 39.2, 29.5, 29.1, 22.4, 14.0. IR (KBr) 3285, 2934, 2225, 1646, 1555, 1421, 1179, 842 ν_max/cm⁻¹; mp 144.2–145.5 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₁N₄O: 333.1715; found: 333.1728 (100%) [M + H]⁺.

1-(4-Cyanophenyl)-N-(4-methoxyphenyl)-1H-indazole-3-carboxamide (42). The crude material was purified by column chromatography (n-hexane/EtOAc 9 : 1) to give the product as pink solid (0.02 g, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.78 (br s, NH), 8.56 (br d, 1H), 7.96 (br d, AA′XX′, 2H), 7.88 (br d, AA′XX′, 2H), 7.78 (br d, 1H), 7.66 (br d, AA′XX′, 2H), 7.56 (br t, 1H), 7.43 (br t, 1H), 6.93 (br d, AA′XX′, 2H), 3.82 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.5, 156.5, 142.9, 141.0, 140.2, 133.7, 130.6, 128.7, 124.5, 124.3, 123.8, 122.9, 121.6, 118.1, 114.3, 110.7, 110.4, 55.5. IR (KBr) 3302, 2225, 1648, 1599, 1506, 1237, 1168, 836 ν_max/cm⁻¹; mp 191.5–192.4 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₂H₁₇N₄O₂: 369.1352; found: 369.1341 (100%) [M + H]⁺.

N-(tert-Butyl)-1-(4-chlorophenyl)-1H-indazole-3-carboxamide (43). The crude material was purified by column chromatography (n-hexane/EtOAc 98 : 2) to give the product as yellow solid (0.02 g, 59% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (br d, 1H), 7.67–7.61 (m, 3H), 7.52 (br d, AA′XX′, 2H), 7.45 (br t, 1H), 7.33 (br t, 1H), 7.01 (br s, NH), 1.53 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 161.7, 140.5, 140.3, 138.0, 133.1, 129.7, 127.9, 124.5, 123.8, 123.6, 123.4, 110.1, 51.3, 29.1. IR (KBr) 3401, 3060, 2961, 1662, 1530, 1497, 1193, 1091 ν_max/cm⁻¹; mp 47.1–48.7 °C; MS (ESI) m/z (M + H)⁺ calcd for C₁₈H₁₉ClN₃O: 328.1217; found: 328.1224 (100%) [M + H]⁺.

1-(4-Chlorophenyl)-N-cyclohexyl-1H-indazole-3-carboxamide (44). The crude material was purified by column chromatography (n-hexane/EtOAc 98 : 2) to give the product as yellow solid (0.03 g, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (br d, 1H), 7.67 (br d, AA′XX′, 2H), 7.63 (br d, 1H), 7.52 (br d, AA′XX′, 2H), 7.45 (br t, 1H), 7.34 (br t, 1H), 7.00 (br s, NH), 4.10–4.01 (m, 1H), 2.08–2.03 (m, 2H), 1.83–1.76 (m, 3H), 1.49–1.20 (m, 5H). ¹³C NMR (100 MHz, CDCl₃) δ 161.3, 140.2, 140.0, 138.0, 133.1, 129.7, 127.9, 124.4, 124.0, 123.5, 123.4, 110.1, 48.0, 33.3, 25.6, 25.0. IR (KBr) 3401, 2923, 2846, 1657, 1528, 1492, 1196, 1086, 831 ν_max/cm⁻¹; mp 58.9–60.8 °C; MS (ESI) m/z (M + H)⁺ calcd for C₂₀H₂₁ClN₃O: 354.1373; found: 354.1384 (100%) [M + H]⁺.

General preparation of N-arylindazole-3-carbonitriles (45). N-Benzyl-1-(4-chlorophenyl)-1H-indazole-3-carboxamide 37 (0.07 mmol, 1 equiv.) is dissolved in phosphorous oxychloride (0.03 M) stirred at 150 °C for 4 hours. The reaction mixture is cooled at room temperature and poured into ice/ammonium hydroxide. The product is then extracted with ethyl acetate (x3); the organic phase is washed with brine, dried over Na₂SO₄ and evaporated. The product is then purified by chromatographic column (n-hexane/ethyl acetate).

1-(4-Chlorophenyl)-1H-indazole-3-carbonitrile (45). The crude material was purified by column chromatography (n-hexane/EtOAc 98 : 2) to give the product as yellowish solid (0.02 g, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.93 (br d, 1H), 7.75 (br d, 1H), 7.68 (br d, AA′XX′, 2H), 7.57–7.55 (m, 3H), 7.44 (br t, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 130.0, 137.4, 134.3, 130.0, 128.9, 126.1, 124.6, 124.4, 120.6, 120.1, 113.1, 111.2. IR (KBr) 2236, 1495, 1355, 1218, 1089, 834 ν_max/cm⁻¹; mp 164.4–165.6 °C; MS (ESI) m/z (M + H)⁺ calcd for C₁₄H₉ClN₃: 254.0485; found: 254.0467 (100%) [M + H]⁺.

Acknowledgements

Financial support from Università del Piemonte Orientale, Novara, and Università degli Studi di Napoli “Federico II” is acknowledged. This research was funded by Regione Campania under POR Campania FESR 2007-2013-O.O.2.1 (FarmaBioNet, CUP B25C13000230007).

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17. The conversion to carbonitrile has been successfully accomplished with high yield also with the para-methoxy analog of benzyl amide 37: however, as the synthesis of compound “a” needs para-methoxy-benzylisocyanide in place of the commercially available benzyl isocyanide used for benzyl amide 37, and the yields of the conversion of both the benzyl amides are the same (96%), we reasoned that the best way to get such a carbonitrile was by using the commercially available benzyl isocyanide.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra01442a

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