3-Chloro-4-fluoro-N-{[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol- 4-yl]methyl}aniline

Abstract

A direct reductive amination of 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 2 with 3-chloro-4-flouroaniline using NaBH₄/I₂ as a reducing agent is described. The reaction was carried out in MeOH under neutral conditions at room temperature to give the secondary amine, 3-chloro-4-fluoro-N-{[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]methyl}aniline (3).

1. Introduction

The direct reductive amination of aldehydes and ketones with a metal hydride reagent is one of the most useful methods for the synthesis of secondary and tertiary amines [1,2,3,4]. Secondary amines and their derivatives constitute many biologically active molecules and are important intermediates in the synthesis of active pharmaceutical ingredients, dyes, and fine chemicals [5,6,7]. In continuation of our interest in the synthesis of heteroaryl amines [8], we report herein the reductive amination of 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 2 with 3-chloro-4-flouroaniline using NaBH₄/I₂ as reducing agent.

2. Result and Discussions

In the present study, a synthesis of 3-chloro-4-fluoro-N-{[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]methyl}aniline (3) is reported from 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 2 and 3-chloro-4-fluoroaniline via direct reductive amination using NaBH₄/I₂ as a reducing agent. The functional group transformation of compound 2 into 3 was established on the basis of IR, ¹H and ¹³C NMR and mass spectral data. In the ¹H NMR spectrum of compound 2, the aldehydic proton signal at 9.95 ppm disappeared and a new signal of –CH₂NH- arose in the spectrum of compound 3 due to reductive amination. It appears at 4.17 ppm as a doublet which suggests coupling with the NH proton (J = 4.8 Hz). Moreover, in the ¹³C NMR spectrum the aldehydic carbon of compound 2 after transforming into the secondary amine showed a new carbon signal at 39.92 ppm. The complete spectral details of compound 2 and 3 are disclosed in the experimental part. The values are in complete agreement with the structure assigned.

Scheme 1. Synthetic route to the title compound 3.

Scheme 1. Synthetic route to the title compound 3.

3. Experimental

The starting material 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 2 was synthesized based on a literature method [9].

2.1. 3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 2

1-(1-(4-methoxyphenyl)ethylidene)-2-phenylhydrazine 1 (3.6 g, 0.015 mol) was added to a cold (4–6 °C) solution of DMF (25 mL), then POCl₃ (5 mL) was added and the resulting mixture was stirred at 50–60 °C for 6 h. The mixture was poured into ice-cold water. A saturated solution of sodium bicarbonate was added to neutralize the mixture, the solid precipitate was filtered, washed with water, dried and recrystallized from ethanol.

Yield, 70%; m.p. 130 ^oC; creamy white crystalline solid.

IR (KBr) cm^-1: 1603 (C=N), 1522 (C=C), 1053 (C-N), 1710 (C=O).

¹H NMR (300 MHz, DMSO-d₆): δ 3.81 (s, 3H, OCH₃), 7.03–7.06 (m, 2H, Ar-H), 7.45–7.48 (m, 1H, Ar-H), 7.53–7.56 (m, 2H, Ar-H), 7.88 (d, 2H, Ar-H, J = 8.9 Hz), 7.96 (d, 2H, Ar-H, J = 7.8 Hz), 9.28 (s, 1H, pyrazole-H-5), 9.95 (s, 1H, CHO).

¹³C NMR (75 MHz, DMSO-d₆) δ; 56.09 (OCH₃), 119.07, 125.86, 126.36, 127.62, 127.98, 128.67, 129.17, 131.07, 134.58, 139.49, 146.08, 151.88. 176.98 (CHO).

Anal. Calcd for C₁₇H₁₄N₂O₂: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.69; H, 5.03; N, 10.12.

2.2. 3-Chloro-4-fluoro-N-{[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]methyl}aniline 3

To a solution of 3-(4-methoxyphenyl)-1-phenyl-pyrazole-4-carboxaldehyde (0.278 g, 0.001 mol) in 10 mL of methanol, 3-chloro-4-flouroaniline (0.145 g, 0.001 mol) and iodine (0.051 g, 0.002 mol) were added with stirring at room temperature. To the stirred solution, sodium borohydride (0.055 g, 0.015 mol) was added slowly. Stirring was continued for 2 h. The precipitate formed was filtered, washed with water, dried and recrystallized from ethanol. The progress of reaction and purity of the compound was checked by TLC, using benzene:acetone (9:1) as mobile phase.

Yield, 73%; m.p. 117 ^oC; white-fluffy solid.

IR (KBr) cm^-1: 1610 (C=N), 1536 (C=C), 993 (C-N).

¹H NMR (300 MHz, DMSO-d₆): δ 3.77 (s, 3H, OCH₃), 4.17 (d, 2H, CH₂, J = 4.8 Hz), 6.17 (t, 1H, NH, J = 4.5 Hz), 6.60–6.63 (m, 1H, Ar-H), 6.75–6.78 (m, 1H, Ar-H), 6.99–7.15 (m, 3H, Ar-H), 7.29 (t, 1H, Ar-H, J = 7.2 Hz), 7.49 (t, 2H, Ar-H, J = 7.9 Hz), 7.72 (d, 2H, Ar-H, J = 8.7 Hz), 7.85 (d, 2H, Ar-H, J = 7.8 Hz), 8.54 (s, 1H, pyrazole H-5).

¹³C NMR (75 MHz, DMSO-d₆) δ; 39.92 (CH₂), 56.33 (OCH₃), 113.86, 115.42, 118.52, 126.38, 127.69, 127.93, 129.34, 130.13, 137.50, 139.73, 144.25, 150.96, 154.47, 157.63.

FAB-MS m/z: 408 (M+1).

Anal. Calcd for C₂₃H₁₉ClFN₃O: C, 67.73; H, 4.70; N, 10.30. Found: C, 68.08; H, 4.73; N, 10.35.