“One-Pot” Synthesis of 4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic Acids via a MeONa/LiCl-Mediated Sterically Hindered Claisen Condensation–Knorr Reaction–Hydrolysis Sequence

Abstract

A “one-pot” synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylic acids was first reported in moderate to good yields. This concise procedure, featuring efficiency and green chemistry, was composed of MeONa/LiCl-mediated sterically hindered Claisen condensation, Knorr reaction and hydrolysis.

Key words

MeONa/LiCl - sterically hindered Claisen condensation - Knorr reaction - 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylic acids - “one-pot” synthesis

• References and Notes


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• 11 Typical “one-pot” procedure for 4: An oven-dried vial was charged with LiCl (0.53 g, 12.5 mmol) and MeONa (0.41 g, 7.5 mmol) in anhydrous THF (15 mL). The mixture was stirred and heated at reflux for 3 h and then cooled to 0 °C, and alkylphenone 1 (5.0 mmol) and diethyl oxalate (0.95 g, 6.5 mmol) were added. The resulting mixture was stirred at r.t. for 3 h and then concentrated to remove THF. Anhydrous EtOH (15 mL), TFA (1.14 g, 10.0 mmol) and arylhydrazine hydrochloride 3 (5.0 mmol) were added at r.t., and the mixture was heated to reflux for 12 h. A solution of NaOH (0.8 g, 20.0 mmol) in H₂O (2 mL) was then added to the reaction solution, which was stirred and heated to reflux for a further 4 h. The solution was then concentrated in vacuo to remove EtOH, affording a residue, to which was added H₂O (15 mL), CH₂Cl₂ (15 mL), and 10% HCl (ca. 10 mL) until pH 3–4 to make the solution partition into organic and aqueous layers. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic phase was washed with H₂O (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by recrystallization (petroleum ether–EtOAc, 5:1 v/v; 6 mL) to give the corresponding product 4. Representative compound 4aa: yellow solid; Yield: 1.01 g (73%); mp 158–160 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.37 (m, 3 H), 7.37–7.25 (m, 5 H), 7.25–7.15 (m, 2 H), 2.38 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 165.4, 142.8, 141.2, 139.4, 130.1 (2C), 129.3, 128.9 (2C), 128.7, 128.6 (2C), 128.1, 125.2 (2C), 120.3, 9.6; HRMS (ESI): m/z [M – H⁺] calcd for C₁₇H₁₃N₂O₂: 277.0977; found: 277.0974.
• 12 When the mixture of LiCl and MeONa was used directly, the SHCC of 1a with diethyl oxalate gave unsatisfactory results.