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Phenylation of aminoindazole derivatives
⁎Corresponding author at: Laboratoire de Chimie Fine, Université d’Oran, Es-Senia, BP 1523, El Mnaouer, Oran, Algeria. Tel.: +213 662 071 673. miloudi_a@yahoo.fr (Abdellah Miloudi)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
The triphenylbismuth diacetate reacted selectively with different aminoindazole derivatives in presence of copper diacetate to engender a new series of mono phenyl aminoindazole compounds in good to high yields. Moreover, the same reagent with 4-chloro-2-methyl-2H-indazol-7-amine led to a mixture of mono- and N,N-diphenylaminoindazoles. However, its combination with 2H-indazol-4-amine provided only one N,1-diphenylaminoindazole compound.
Keywords
Aminoindazole
Triphenylbismuth diacetate
Copper diacetate
Phenylaminoindazole
Diphenylaminoindazole
1 Introduction
Heterocycles constitute a family of substances particularly important in organic chemistry because of their presence in a large number of natural and synthetic molecules with varied useful properties. They play a major role in many areas of medicine, biology, agronomy, cosmetology, and are endowed with diverse pharmaceutical activities (anti-parasitic, anti-fungal, anti-inflammatory, psychotropic) (Yang and Knochel, 2004; Boyer et al., 2000; Barton et al., 1987; Pinhey et al., 1980). Indeed, many heterocyclic indazole therapeutic effects are reported in the literature. For example, the compound YC-1 (Fig. 1) is an activator of the soluble enzyme guanylyl cyclase (Sopkova-De Oliveria-Santos et al., 2000), whereas Rimonabant (Fig. 2) is an anorectic antiobesity drug that reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients (Scheen et al., 2006).
On the other hand, the N-aryl hetero aromatic molecules are interesting in stereo selective synthesis and challenging because they reveal new pathways to obtain pharmaceutical and agrochemical compounds. In the past few years, considerable importance has been attached to synthetic methods leading to indazole derivatives because of their biological properties (Caron and Vazquez, 1999; Yeu et al., 2001; Sun et al., 1997; Rodgers et al., 1996; Norman et al., 1996; Yoshida et al., 1996; Robertson et al., 1990; Keppler and Hartmann, 1994; Li et al., 2003; Collot et al., 1999; Batt et al., 2000; Cerecetto et al., 2005; Aronov and Murcko, 2004; Chem et al., 2011; Hering et al., 2006; O’Reilly et al., 2001; Ahabchane et al., 2001).
In this paper, we present a simple and efficient synthetic procedure developed to obtain mono and di-N-phenylamino indazole derivatives which were subsequently aryled by means of the diacetate triphenylbismuth/copper diacetate system (Barton et al., 1980; Miloudi et al., 2001, 2004).
2 Results and discussion
Along the course of this arylation synthesis, the amino indazole group was obtained by reduction of the corresponding nitro group with the Pd/H2 catalyst in presence of ethanol. The amino and chloroamino indazole derivatives were obtained in good yields with SnCl2/HCl in a solution of ethanol as products functionalized in different positions (Miloudi et al., 2006).
The derivatives 1–12 were reacted with 1.1 equiv. of triphenylbismuth diacetate in presence of a catalytic quantity of copper diacetate (0.1 equiv) in methylene chloride (5-30 mL) at room temperature. The reaction pathway is summarized in Scheme 1.
The monophenyl compounds 1–9 were obtained with moderate to good yields. The phenylation of the aminoindazoles by the Ph3Bi(OAc)2/Cu(OAc)2 system led to the corresponding monophenylated products with yields varying from 62% to 97%. The lowest yield of 49% was in each case achieved with 4-aminophenyl-7-chloro-2-methylindazolic 4 (Table 1).
| Entry | Product | NH2 | NCH3 | X | Yield (%) |
|---|---|---|---|---|---|
| 1 | 1a | 4-NH2 | 1-CH3 | 7-H | 62 |
| 2 | 2a | 4-NH2 | 1-CH3 | 7-Cl | 72 |
| 3 | 3a | 4-NH2 | 2-CH3 | 7-H | 97 |
| 4 | 4a | 4-NH2 | 2-CH3 | 7-Cl | 49 |
| 5 | 5a | 5-NH2 | 1-CH3 | 4-H | 84 |
| 6 | 6a | 5-NH2 | 1-CH3 | 4-Cl | 88 |
| 7 | 7a | 5-NH2 | 2-CH3 | 4-H | 79 |
| 8 | 8a | 6-NH2 | 1-CH3 | 7-H | 74 |
| 9 | 9a | 6-NH2 | 2-CH3 | 7-H | 66 |
| 10 | 10a | 7-NH2 | 1-CH3 | 4-H | 85 |
| 11 | 11a | 7-NH2 | 1-CH3 | 4-Cl | 85 |
| 12 | 12a | 7-NH2 | 2-CH3 | 4-H | 70 |
It should be noted that the phenylation of the 7-amino-4-chloro-2-methylindazole 13 by the same system led to a mixture of mono and diphenylated compounds 13a and 13b, respectively (Scheme 2). The latter products were isolated by silica gel chromatography with a yield of 28% and 22%, respectively.
Moreover, the reaction of 4-aminoindazole 14 with triphenylbismuth diacetate led to 4-phenylamino-1-phenylindazole 14a diphenylation product with a 23% yield (Scheme 3).
The phenylation was done at two sites: the N-1 nitrogen of the azolic cycle and the amine related to C-4 of the indazole group.
3 Experimental section
3.1 Measurements
Melting points were determined by the Büchi Melting Point apparatus and were not corrected. The 1H and 13C NMR spectra were measured on a Bruker Avance 300 spectrometer operating at 300 MHz. Chemical shifts were recorded as units relative to DMSO-d6 or CDCl3 as the solvent unless otherwise stated, with J values in Hertz. Combustion analyses were performed in the “Laboratoire de Microanalyse du centre National de la Recherche Scientifique”, Vernaison (France). Chromatography separations were achieved on silica gel (Merck).
3.2 General procedure of N-phenylamin-indazole derivative preparation
A mixture of the appropriate amino indazole (1 equiv.), triphenylbismuth diacetate (1.1 equiv.) and copper diacetate (0.1 equiv.) in dichloromethane solution of variable volume according to the substrate was stirred at room temperature during 5 h, unless otherwise stated. After filtration of the solution, the solvent was distilled under reduced pressure to afford oil which was then purified by chromatography on silica gel with ether/pentane (1:1) eluent to supply N-phenylation products (Barton et al., 1978).
All the following compounds were obtained using the general preparation procedure described above.
3.2.1 1-Methyl-N-phenyl-1H-indazol-4-amine (1a)
Yield 62%, m.p. 102 °C. 1H NMR (CDCl3): ppm 7.95 (s, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.21 (d, J = 8.2, 1H), 7.04 (t, J = 7.4, 1H), 6.90 (d, J = 7.5, 1H), 6.85 (s, 1H), 4.02 (s, 3H).
13C NMR (CDCl3): ppm 142.19, 141.34, 137.01, 130.22, 129.11, 127.40, 121.73, 119.21, 116.12, 104.75, 100.91, 35.40.
3.2.2 7-Chloro-1-methyl-N-phenyl-1H-indazol-4-amine (2a)
Yield 72%, m.p. 85 °C. 1H NMR (CDCl3): ppm 8.15 (s, 1H), 7.53 (t, J = 7.8, 2H), 7.37 (d, J = 8.1, 1H), 7.36 (d, J = 8.1, 2H), 7.25 (t, J = 7.4, 2H), 6.98 (d, J = 8.1, 1H), 6.65 (s, 1H), 4.56 (s, 3H). 13C NMR (CDCl3): ppm 141.76, 136.87, 135.97, 130.22, 129.18, 128.01, 121.98, 119.24, 118.61, 105.42, 100.60, 38.58.
3.2.3 2-Methyl-N-phenyl-2H-indazol-4-amine (3a)
Yield 97%, m.p. 193 °C. 1H NMR (DMSO-d6): ppm 8.49 (s, 1H), 8.16 (s, 1H), 7.29 (d, J = 8.1, 2H), 7.27 (t, J = 8.3, 2H), 7.20 (s, 1H), 7.04 (t, J = 7.4, 1H), 6.91 (t, J = 6.80, 1H), 6.89 (d, J = 8.30, 1H), 6.83 (d, J = 7.30, 1H), 3.98 (s, 3H). 13C NMR (CDCl3): ppm 141.72, 141.44, 136.25, 130.16, 128.83, 127.57, 121.53, 118.93, 116.22, 104.57, 100.71, 35.13.
3.2.4 7-Chloro-2-methyl-N- phenyl-2H-indazol-4-amine (4a)
Yield 49%, m.p. 98 °C. 1H NMR (CDCl3): ppm 7.70 (s, 1H), 7.25 (t, J = 8.5, 2H), 7.13 (d, J = 7.7, 1H), 7.03 (dd, J = 8.5, J = 1.2, 2H), 6.95 (t, J = 7.3, 2H), 6.64 (d, J = 7.9, 1H), 4.09 (s, 3H). 13C NMR (CDCl3): ppm 146.95, 142.33, 135.15, 129.22, 126.11, 123, 88, 121.68, 118.87, 117.33, 113.32, 106.33, 40.39.
3.2.5 1-Methyl-N-phenyl-1H-indazol-5- amine (5a)
Yield 84%, m.p. 150 °C. 1H NMR (DMSO-d6) ppm 8.01 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.0, 1H), 7.40 (s, 1H), 7.20 (d, J = 9.0, 1H), 7.17 (t, J = 6.0, 2H), 7.00 (d, J = 9.0, 2H), 6.74 (t, J = 9.0, 1H), 4.00 (s, 3H). 13C NMR (DMSO-d6): ppm 145.59, 136.90, 136.55, 131.77, 129.59, 124.58, 121.91, 119.02, 115.64, 110.76, 108.78, 35.82.
3.2.6 4-Chloro-1-methyl-N-phenyl-1H-indazol-5-amine (6a)
Yield 88%, m.p. 107 °C. 1H NMR (DMSO-d6): ppm 7.99 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.9, 1H), 7.37 (d, J = 8.9, 1H), 7.15 (t, J = 7.5, 2H), 6.80 (d, J = 8.5, 2H), 6.73 (t, J = 7.9, 1H), 4.05 (s, 3H). 13C NMR (CDCl3): ppm 149.50, 137.41, 132.36, 130.13, 129.00, 124.15, 123.41, 118.85, 116.39, 115.01, 109.49, 35.78.
3.2.7 2-Methyl-N-phenyl-2H-indazol-5-amine (7a)
Yield 79%, m.p. 144 °C. 1H NMR (DMSO-d6): ppm 8.06 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 7.26 (d, J = 9.0, 1H), 7.19 (t, J = 7.6, 2H), 7.03 (d, J = 9.0, 1H), 7.02 (d, J = 7.4, 2H), 6.74 (t, J = 7.4, 1H), 4.09 (s, 3H). 13C NMR (DMSO-d6): ppm 145.10, 144.78, 136.55, 129.04, 122.28, 118.64, 117.63(2C), 115.65, 112.84, 103.87, 39.76.
3.2.8 1-Methyl-N-phenyl-1H-indazol-6-amine (8a)
Yield 74%, m.p. 143 °C. 1H NMR (DMSO-d6): ppm 8.37 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.27 (t, J = 7.7, 1H), 7.18 (d, J = 7.7, 1H), 7.12 (s, 1H), 6.88 (d, J = 8.6, 1H), 6.87 (t, J = 7.7, 1H), 3.90 (s, 3H). 13C NMR (DMSO-d6): ppm 143.10, 142.42, 140.97, 132.18, 129.31, 121.44, 120.16, 118.12, 117.35, 114.28, 92.97, 35.12. Anal. calcd for C14H13N3. C: 75.34, H: 5.83, N: 18.83. Found. C: 75.14, H: 5.96, N: 18.65.
3.2.9 2-Methyl-N-phenyl-2H-indazol-6-amine (9a)
Yield 66%, m.p. 144 °C. 1H NMR (DMSO-d6): ppm 8.15 (s, 1H), 8.13 (s, 1H), 7.54 (d, J = 8.9, 1H), 7.23 (t, J = 7.5, 2H), 7.11 (s, 1H), 7.09 (d, J = 7.5, 2H), 6.81 (d, J = 7.4, 1H), 6.80 (t, J = 7.3, 1H), 4.04 (s, 3H). 13C NMR (DMSO-d6): ppm 149.26, 143.72, 140.66, 129.13, 124.25, 120.94, 119.50, 117.19, 117.06, 116.76, 98.27, 39.50. Anal. calcd for C14H13N3. C: 75.34, H: 5.83, N: 18.83. Found. C: 75.21, H: 5.98, N: 18.95.
3.2.10 1-Methyl-N-phenyl-1H-indazol-7-amine (10a)
Yield 85%, m.p. 130 °C. 1H NMR (DMSO-d6): ppm 8.07 (s, 1H), 7.78 (d, J = 7.7, 2H), 7.57 (d, J = 8.7, 2H), 7.21 (t, J = 7.8, 2H), 7.13 (d, J = 7.8, 1H), 6.88 (t, J = 8.0, 1H), 6.75 (t, J = 7.4, 1H), 4.00 (s, 3H). 13C NMR (DMSO-d6): ppm 147.50, 137.47, 135.20, 129.40, 124.25, 122.43, 122.20, 121.44, 121.25, 120.46, 115.15, 38.25.
3.2.11 4-Chloro-1-methyl-N-phenyl-1H-indazol-7-amine (11a)
Yield 85%, m.p. 80 °C. 1H NMR (DMSO-d6): ppm 8.06 (s, 1H), 7.15 (t, J = 7.4, 2H), 7.12 (d, J = 5.3, 1H), 7.08 (d, J = 8.0, 1H), 6.77 (d, J = 7.8, 2H), 6.73 (t, J = 7.4, 1H), 4.10 (s, 3H). 13C NMR (DMSO-d6): ppm 147.04, 145.56, 136.88, 129.44, 124.80, 124.71, 122.06, 121.00, 120.99, 120.27, 115.15, 38.25.
3.2.12 2-Methyl-N-phenyl-2H-indazol-7-amine (12a)
Yield 70%, m.p. 128–130 °C. 1H NMR (DMSO-d6): ppm 8.40 (s, 1H), 7.54 (d, J = 8.0, 1H), 7.16–7.20 (m, 5H), 7.04 (d, J = 7.8, 1H), 6.85 (t, J = 8.3, 1H), 4.12 (s, 3H). 13C NMR (DMSO-d6): ppm 147.04, 145.21, 136.88, 129.32, 124.80, 122.59, 122.40, 122.06, 121.00, 120.66, 119.04, 40.02.
3.2.13 4-Chloro-2-methyl-N-phenyl-2H-indazol-7-amine (13a) and (13b)
Yield of 13a is 28%, m.p. 125 °C. 1H NMR (DMSO-d6): ppm 8.43 (s, 1H), 7.20 (t, J = 7.6, 2H), 7.04 (d, J = 7.8, 1H), 6.91 (t, J = 7.9, 1H), 6.94 (d, J = 7.2, 2H), 6.85 (d, J = 7.7, 1H), 4.03 (s, 3H). 13C NMR (DMSO-d6): ppm 147.35, 145.01, 134.98, 129.08, 124.81, 123.43, 123.00, 122.36, 122.20, 120.46, 120.27, 40.35; and yield of 13b is 22%, m.p. 130 °C. 1H NMR (DMSO-d6): ppm 8.43 (s, 1H), 7.70 (d, J = 8.9, 2H), 7.39 (t, J = 8.9, 2H), 7.22 (t, J = 7.9, 1H), 7.19 (d, J = 7.6, 2H), 7.04 (d, J = 7.8, 1H), 6.94 (t, J = 7.9, 4H), 6.85 (d, J = 7.7, 1H), 4.03 (s, 3H). 13C NMR (DMSO-d6): ppm 150.71, 147.52, 145.18, 135.17, 129.62, 129.25, 125.90, 125.00, 123.57, 123.25, 122.55, 122.35, 121.99, 121.18, 120.62, 40.51.
3.2.14 N,1-Diphenyl-1H-indazol-4-amine (14a)
Yield 23%, m.p. 170 °C. 1H NMR (DMSO-d6): ppm 8.48 (s, 1H), 7.76 (d, J = 7.9, 2H), 7.59 (t, J = 7.2, 2H), 7.40 (t, J = 7.0, 2H), 7.33 (d, J = 8.3, 2H), 7.29 (d, J = 8.1, 1H), 7.27 (d, J = 8.3, 1H), 7.24 (t, J = 8.3, 1H), 6.97 (t, J = 7.0, 1H), 6.92 (t, J = 8.3, 1H). 13C NMR (DMSO-d6): ppm 142.49, 140.11, 139.96, 137.93, 134.22, 129.77, 129.61, 129.39, 126.59, 122.31, 121.49, 119.29, 116.99, 104.29, 101.27.
4 Conclusion
We may conclude that pentavalent triphenylbismuth diacetate appears to be a promising reagent for a novel source of C-N bond formation with high efficiency on the primary amines of indazole derivatives to provide the mono- and/or diphenylated compounds with good yields. Moreover, it should be noted that the efficiency of this arylating agent is improved by the presence of the copper diacetate catalyst.
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