A mild and efficient method for the preparation of 3-(2'-Aminoaryl)pyrazoles from 4-chloroquinolines

SHORT REPORT

A mild and efficient method for the preparation of 3-(2'-Aminoaryl)pyrazoles from 4-chloroquinolines

Julio C. Borges^I; Cesar D. de Oliveira^I; Luiz C. da Silva Pinheiro^I; Roberta K. F. Marra^I; Misbahul Ain Khan^{I, III}; James L. Wardell^II; Solange M. S. V. Wardell^IV; Alice M. R. Bernardino^I,*

^IInstituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, 24020-141 Niterói-RJ, Brazil

^IIChemistry Department, University of Aberdeen, Meston Walk, Old Aberdeen, AB243EU, Scotland

^IIIChemistry Department, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

^IVFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos, 21041-250 Rio de Janeiro-RJ, Brazil

ABSTRACT

We describe a mild and efficient method for the formation of 3-(2'-aminoaryl)pyrazoles in excellent yields from reactions of 4-chloroquinolines with hydrazine. These heterocyclic ring opening reactions occur under much milder conditions then previously described.

Keywords: pyrazoles, 4-chloroquinolines, X-ray diffraction

RESUMO

Um método mais suave e eficiente é descrito para a síntese de 3-(2'-aminoaril)pirazóis, a partir das reações de 4-cloroquinolinas com hidrazina em excelentes rendimentos. Estas reações de abertura de anel heterocíclico ocorrem em condições mais suaves do que as descritas anteriormente.

Introduction

Pyrazoles and their derivatives are widely used as pharmaceutical^1-5 and agrochemical agents⁶ and consequently a large number of synthetic routes to pyrazoles has been reported.^7-13 However, there is still great interest in finding milder and more efficient methods to these valuable compounds. Amino groups undergo various reactions, and as such are excellent and general starting points for the development of chemical libraries.¹⁴ In particular, 3-(2^'-aminoaryl)pyrazoles (1) are useful precursors of more elaborate pyrazolic molecules.¹⁵ A preparation of 3-(2'-aminophenyl)pyrazoles was first described by Alberti¹⁵ from 4-hydroxyquinolines. 4-Chloroquinolines^16,17 on treatment with substituted hydrazines gave 1-substituted-3-(2-aminophenyl)pyrazoles. All these reactions occurred under drastic conditions using autoclave or sealed tubes.^15,16 Later, other workers reported ring opening reactions of 4-hydroxyquinolines¹³ and the preparation of the compound 3-(2'-aminophenyl)pyrazole by the reduction reaction of 3-(2-nitrophenyl)pyrazole.¹⁸

Our research group has developed a route to 3-(2'-aminoaryl)pyrazoles under mild conditions from 4-chloroquinolines (2) and hydrazine in a one-pot process.

Results and Discussion

The 4-chloroquinolines¹⁹ (3) are readily prepared from 4-hydroxyquinolines (2) and can be stored for long periods. The 4-hydroxyquinolines,²⁰ in turn, can be readily made from quinolones via the Gould-Jacobs method.^21,22 Our one- pot synthesis of (1a-i) involves reactions of 4-chloroquinolines with an excess of hydrazine in diethyleneglycol initally at 90-100 ºC for one hour. Substitutions of the chlorine atom in 3 by hydrazine occur in this temperature range to generate intermediate 4-hydrazinoquinolines, which on raising the temperature to 130-140 ºC, react further over a period of six hours to afford the desired products 1a-i, see Scheme 1.

As shown in Table 1, isolated yields range from good to excellent, with electron withdrawing substituents resulting in the higher yields and electron donating substituents resulting in lower yields as expected for a nucleophilic aromatic substitution reaction.

Products were generally identified by ¹H NMR, ¹³C NMR, FT-IR spectroscopies, mass spectrometry and elementary analysis. Specifically, confirmation of the structure of 1a was gained by X-ray diffraction.^23,24 Atom arrangements are shown in Figure 1.

Overall the molecules are nearly planar with the angles between the best planes of the two rings in the order of 12º and torsional angles ranging from 0.06 (0.40) to 12.34 (0.45)º. Intramolecular N3X-HAX...N1X (X=A or B) hydrogen bonds help to cement the planar arrangements of the two molecules. Intermolecular N2A-H2A...N3B and N2B-H2B...N3A hydrogen bonds link the two independent molecules, alternatively, into molA...molB...molA chains (Figure 2).

Experimental

Preparation of the compounds 3-(2'-aminoaryl) pyrazoles: 0.8 g (0.004 mol) of the 4-chloroquinolines and 2.0 mL of hydrazine was stirred in 6.0 mL of diethyleneglycol at 90-100 ºC for 1 hour. Later the temperature was raised to 130-140 ºC for 6 hours. Finaly, the mixture was dropped in a beaker with ice and water and the crystals formed were filtered.

3-(2'-Amino-3'-methylphenyl)pyrazole, 1a; R = 3'-CH₃

mp 111 ºC; FT-IR (KBr) n_max/cm^-1: 3400, 3100, 1610, 1485, 765; ¹H NMR (CDCl₃, d in ppm) H4 6.55 (d; 2.4 Hz) H5 7.48 (d; 2.4 Hz); H4' 7.02 (dd; 7.5 and 2.4 Hz); H5' 6.70 (t; 7.5 Hz); H6' 7.35 (dd; 7.8 and 2.1 Hz); NH₂/NH 5.47 (s); CH₃ 2.16 (s). ¹³C NMR (CDCl₃, d in ppm) C3 150.7; C4 103.7; C5 130.5; C1' 123.1; C2' 142.8; C3' 117.4; C4' 126.7; C5' 116.7; C6' 129.8; CH₃ 17.8; MS: m/z 173.0949 (M⁺, 100%). Anal. Calc. for C₁₀H₁₁N₃ (%): C 69.34; H 6.40; N 24.26. Found (%): C 69.16; H 6.21; N 23.98.

3-(2'-Amino-5'-methylphenyl)pyrazole, 1b; R = 5'-CH₃

mp 87 ºC; FT-IR (KBr) n_max / cm^-1: 3400, 3190, 1620, 1590, 1510, 1450, 770; ¹H NMR (CDCl₃, d in ppm) H4 6.61 (s); H5 7.57 (s); H3' 6.69 (d; 8.1 Hz); H4' 6.94 (d; 7.2 Hz); H6' 7.30 (s); CH₃ 2.27 (s); ¹³C NMR (CDCl₃, d in ppm) C3 151.0; C4 103.2; C5 128.8; C1' 116.8; C2' 141.9; C3' 116.6; C4' 129.2; C5' 126.8; C6' 128.7; CH₃ 20.3;MS: m/z 173.0876 (M⁺, 100%). Anal. Calc. for C₁₀H₁₁N₃ (%): C 69.34; H 6.40 N 24.26. Found (%): C 69.23; H 6.55; N 24.01.

3-(2'-Amino-3'-chlorophenyl)pyrazole, 1c; R = 3'-Cl

mp 94 ºC; FT-IR (KBr) n_max / cm^-1: 3420, 3080, 1610, 1585, 1490, 1425, 740; ¹H NMR (CDCl₃, d in ppm) H4 6.67 (d; 2.4 Hz); H5 7.62 (d; 2.4 Hz); H4' 7.24 (dd; 7.8 and 1.5 Hz); H5' 6.68 (t; 7.8 Hz); H6' 7.45 (dd; 1.5 and 7.8 Hz); ¹³C NMR (CDCl₃, d in ppm) C3 151.2; C4 103.5; C5 129.4; C1' 120.0; C2' 141.1; C3' 117.5; C4' 128.4; C5' 117.0; C6' 126.8; MS: m/z 193.0375 (M⁺, 100%). Anal. Calc. for C₉H₈N₃Cl (%): C 55.83; H 4.16; N 21.70. Found (%): C 55.53; H 4.19; N 21.44.

3-(2'-Amino-5'-chlorophenyl)pyrazole, 1d; R = 5'-Cl

mp 58 ºC; FT-IR (KBr) n_max / cm^-1: 3400, 3050, 1611, 1487, 765; ¹H NMR (CDCl₃, d in ppm) H4 6.63 (d; 2.4 Hz); H5 7.60 (d; 2.4 Hz); H3' 6.68 (d; 8.7 Hz); H4' 7.05 (dd; 8.4 and 2.4 Hz); H6' 7.48 (d; 2.4 Hz); ¹³C NMR (CDCl₃, d in ppm) C3 150.3; C4 103.3; C5 129.6; C1' 117.7; C2' 143.1; C3' 117.5; C4' 128.2; C5' 121.9; 127.8; MS: m/z 193.0396 (M⁺, 100%). Anal. Calc. for C₉H₈ClN₃ (%): C 55.83; H 4.16; N 21.70. Found (%): C 55.66; H 4.29; N 21.79.

3-(2'-Amino-3'-fluorophenyl)pyrazole, 1e; R = 3'-F

mp 87 ºC; FT-IR (KBr) n_max / cm^-1: 3420, 3160, 1615, 1470, 1245, 755; ¹H NMR (CDCl₃, d in ppm) H4 6.65 (d; 2.1 Hz); H5 7.60 (d; 2.1 Hz); H4' 6.91-6.99 (m); H5' 6.67 (t; 8.4 Hz); H6' 7.31 (7.8 Hz); NH₂/NH 5.47 (s); ¹³C NMR (CDCl₃, d in ppm) C3 150.8; C4 103.6; C5 129.5; C1' 118.4; C2' 133.3 (d; 13.6 Hz); C3' 152.1 (d; 236.6 Hz); C4' 113.7 (d; 18.4 Hz); C5' 116.4 (d; 7.8 Hz); C6' 123.3; MS: m/z 177.0623 (M⁺, 100%). Anal. Calc. for C₉H₈FN₃ (%): C 61.01; H 4.55; N 23.72. Found (%): C 61.15; H 4.58; N 23.81.

3-(2'-Amino-5'-fluorophenyl)pyrazole, 1f; R = 5'-F

mp 92 ºC; FT-IR (KBr) n_max / cm^-1: 3400, 3040, 1610, 1467, 810, 725; ¹H NMR (CDCl₃, d in ppm) H4 6.61 (d; 2.4 Hz); H5 7.60 (d; 2.4 Hz); H3' 6.70 (m); H4' 6.80 (m); H6' 7.20 (m); ¹³C NMR (CDCl₃, d in ppm) C3 150.3; C4 103.4; C5 129.7; C1' 117.5; C2' 140.2; C3' 117.5 (d; 8.5 Hz); C4' 114.2 (d; 23.6 Hz); C5' 155.6 (d; 233,2 Hz); C6' 115.1 (d; 22.6 Hz); MS: m/z 177.0678 (M⁺, 100%). Anal. Calc. for C₉H₈FN₃ (%): C 61.01; H 4.55; N 23.72. Found (%): C 61.09; H 4.58; N 23.77.

3-(2'-Amino-5'-bromophenyl)pyrazole, 1g; R = 5'-Br

mp 83 ºC; FT-IR (KBr) n_max / cm^-1: 3400, 3000, 1610, 1462, 735; ¹H NMR (CDCl₃, d in ppm) H4 6.64 (s); H5 7.60 (s); H3' 6.64 (d; 7.5 Hz); H4' 7.18 (dd; 8.4 and 2.1 Hz); H6' 7.65 (d; 2,1 Hz); ¹³C NMR (CDCl₃, d in ppm) C3 150.7; C4 103.7; C5 128.8; C1' 109.4; C2' 143.9; C3' 118.8; C4' 131.1; C5' 118.8; C6' 131.0; MS: m/z 238.0811 (M⁺, 100%). Anal. Calc. for C₉H₈BrN₃ (%): C 45.40; H 3.39; N 17.65. Found (%): C 45.37; H 3.36; N 17.61.

3-(2'-Amino-3'-methoxyphenyl)pyrazole, 1h; R = 3'-OCH₃

mp 111 ºC; FT-IR (KBr) n_max / cm^-1: 3410, 3100, 2980, 1590, 1495, 1220, 725; ¹H NMR (CDCl₃, d in ppm) H4 6.59 (d; 2.3 Hz); H5 7.53 (d; 2.3 Hz); OCH₃ 3.88 (s); NH₂/NH 6.41 (s). ¹³C NMR (CDCl₃, d in ppm) C3 150.8; C4 103.5; C5 130.2; C1' 120.6; C2' 147.7; C3' 116.6; C4' 135.0; C5' 116.4; C6' 135.1; OCH₃ 55.7; MS: m/z 189.2120 (M⁺, 100%). Anal. Calc. for C₁₀H₁₁N₃O (%): C 63.48; H 5.86; N 22.21. Found (%): C 63.21; H 6.02; N 22.48.

3-(2'-Amino-4'-methoxyphenyl)pyrazole, 1i; R = 4'-OCH₃

mp 82 ºC; FT-IR (KBr) n_max / cm^-1: 3410, 3090, 1610, 1510, 1210, 830, 770; ¹H NMR (CDCl₃, d in ppm) H4 6.45 (d; 2.3 Hz); H5 7.43 (d; 2.3 Hz); OCH₃ 3.70 (s); NH₂/NH 6.39 (s). ¹³C NMR (CDCl₃, d in ppm) C3 150.7; C4 103.4; C5 129.9; C1' 115.2; C2' 145.6; C3' 117.6; C4' 129.6; C5' 134.1; C6' 116.0; OCH₃ 55.0; MS: m/z 189.2145 (M⁺, 100%). Anal. Calc. for C₁₀H₁₁N₃O (%): C 63.48; H 5.86; N 22.21. Found (%): C 63.46; H 5.87; N 22.35.

Conclusions

In conclusion we would like to reiterate that the method is a simple and efficient one, not requiring special equipment or harsh conditions. The respectable yields in these reactions also make it a viable method for the synthesis of 3-(2-amino-aryl/hetaryl)pyrazoles. Following this procedure, eight new compounds (1a-f, 1h-i) were thus prepared.

Acknowledgments

We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal Docente (CAPES) and the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) for the financial support. We also thank the EPSRC X-ray crystallographic services based at the University of Southampton, England for the data collection.

23. Crystal data: C₁₀H₁₁N₃, colourless, M = 173.22, T = 120 (2)K, monoclinic, space group c2, a = 25.9750(3), b =9.5820(6), c = 7.8299(7)Å, b = 107.541(3)º, V =1858.2(2) ų, Z = 8, D_x = 1.238 gcm^-3, monochromated Mo-Ka radiation, l = 0.71073 Å, µ = 0.078 mm^-1.

24. Data collection. The unit cell and intensity data were collected on a Bruker-Nonius diffractometer. 5454 reflections were collected, of which 2925 [R(int) = 0.0489]were independent reflections, with the 2q range for data collection of 2.28 to 24.99º.

25. Structure Solution and Refinement: Structure solution and refinement were achieved using SHELX97 and SHELXL97. Full matrix least squares on F² of data converged to R1=0.0437, wR2=0.0841 [I>2sI]. Atomic coordinates, bond lengths, angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Center, deposition number CCDC 635098.

Received: May 21, 2007

Web Release Date: November 30, 2007

• 1. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungust, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S.; J. Med. Chem 2001, 44, 566.
• 2. Abdon, I. M.; Saleh, A. M.; Zodhi, H. F.; Molecules 2004, 9, 109.
• 3. Wong, P. C.; Pinto, D. J. P.; Knabb, R. M.; Cardiovasc. Drug. Rev 2002, 20, 137.
• 4. Straub, A.; Stasch, J.; Alonso-Alija, C.; Benet-Buchholz, J.; Ducke, B.; Feurer, A.; Furstner, C.; Bioorg. Med. Chem. 2001, 11, 781.
• 5. Balbi, A.; Anzaldi, M.; Mazzei, M.; Miele, M.; Bertolotto, M.; Ottonellob, L.; Dallegrib, F.; Bioorg. Med. Chem. 2006, 14, 5152.
• 6. Ge, M.; Cline, E.; Yang, L.; Tetrahedron Lett. 2006, 47, 5797.
• 7. Sakya, S. M.; Rast, B.; Tetrahedron Lett. 2003, 44, 7629.
• 8. Martins, M. A. P.; Cunico, W.; Siqueira, G. M. ; Leidens, V. L.; Zanatta, N.; Bonacorso, H. G.; Flores, A. F. C.; J. Braz. Chem. Soc. 2005, 16, 275.
• 9. Bonacorso, H. G.; Oliveira, M. R.; Costa, M. P.; Silva, L. B.; Zanatta, N.; Martins, M. A. B.; Flores, A. F. C.; J. Braz. Chem. Soc. 2005, 16, 868.
• 10. Martins, M. A. B.; Beck, P.; Machado, P.; Brondani, S.; Moura, S.; Zanatta, N.; Bonacorso, H. G. B.; Flores, A. F. C.; J. Braz. Chem. Soc. 2006, 17, 408.
• 11. Selvis, S.; Perumal, P. T.; J. Heterocycl. Chem. 2002, 39, 1129.
• 12. Atlan, V.; Buron, C.; Kaim, L. E.; Synlett 2000, 489.
• 13. McQuaid, A. L.; Smith, E. C. R.; South, K. K.; Mitch, C. H.; Schoepp, D. D.; True, R. A.; Calligaro, D. O.; O'Malley, P. J.; Lodge, D.; Ornstein, P. L.; J. Med. Chem 1992, 35, 3319.
• 14. Qu, G.; Han, S.; Zhang, Z.; Geng, M.; Xue, F.; J. Braz. Chem. Soc. 2006, 17, 915.
• 15. Alberti, C.; Gazz. Chem. Ital. 1957, 87, 772.
• 16. Bowie, R. A.; Wright, B.; J. Chem. Soc. Perkin Trans. 1 1972, 1109.
• 17. McQuaid, A. L.; Mitch, C. H.; Ornstein, P. L.; Schoepp, D. D.; Smith, E. C. R.; US Pat. 5,153,196, 1992
• 18. Player, M. R.; Baindur, N.; Brandt, B.; Chadha, N.; Patch, R. J.; Asgari, D.; Georgiadis, T.; US Pat. 2005113566, 2005
• 19. Schaefer, J. P.; Kulkarni, K. S.; Costin, R.; Higgins, J.; Honig, L. M.; J. Heterocycl. Chem. 1970, 7, 607.
• 20. Augui, H; Komatsu, T.; Nakagome, T.; J. Heterocycl. Chem. 1975, 12, 557.
• 21. Price, C. C.; Roberts, R. M.; J. Am. Chem. Soc. 1946, 68, 1204.
• 22. Walsh, C. T.; Wright, T.; Chem. Rev 2005, 105, 562.
• 26. Sheldrick, G.M.; SHELXS97 and SHELXL97, University of Göttingen: Germany, 1997.

Publication Dates

• Publication in this collection
  12 Feb 2008
• Date of issue
  2007

History

• Accepted
  30 Nov 2007
• Received
  21 May 2007