| 87% |
Stage #1: malonic acid; 4-cyanobenzaldehyde With piperidine; pyridine for 4.5h; Inert atmosphere; Reflux;
Stage #2: With lithium hydroxide monohydrate In tetrahydrofuran; water at 85℃; Inert atmosphere; |
Synthesis of (E)-3-(4-cyanophenyl)acrylic acid 27
A suspension of 4-formylbenzonitrile 25 (0.50 g, 3.8 mmol) and malonic acid 26 (0.79 g, 7.6 mmol) inpyridine (5 mL) was stirred at 45 °C under a N2 atmosphere until a solution was obtained. Piperidine (0.1mL, 0.8 mmol) was then added to the mixture, which was stirred at 85 °C for 30 min. and then at reflux for4 h. The reaction was then cooled to r.t. dissolved in THF (3 mL) and added of LiOH monohydrate (0.4 g,10 mmol) dissolved in water (7 mL). The mixture was stirred at 85 °C overnight, then cooled to r.t. andadded dropwise of 5 N HCl solution while stirring. The precipitate formed was collected by filtration,washed thoroughly with water and dried under vacuum to afford the title compound as a white solid (0.56g, 87%), which was used in the next step without further purification. 1H-NMR (500 MHz, DMSO-d6), δ 12.61 (bs, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.64 ((d, J = 16.1 Hz, 1H), 6.71 ((d, J = 16.1 Hz,1H) ppm. 13C-NMR (125 MHz, DMSO-d6), d: 167.6, 142.3, 139.3, 133.1, 129.3, 123.3, 119.0, 112.5 ppm. |
| 85% |
With piperidine; pyridine at 110℃; |
1 S1.2.1. General Procedure for synthesis of Cinnamic acids (2, 15a to 15s)
General procedure: To a solution of pyridine (3 vol), was added aldehyde (1 mmol) malonic acid (2 mmol)followed by catalytic amount of piperidine (0.1 mmol). The reaction mass was slowly heatedto 110 0C and maintained for 10 - 12 hr at 110 0C. Reaction was monitored by TLC. Reactionmass was cooled to room temperature and quenched into 10 vol of water of pyridine. To thequenched mass was added, NaOH (2 mmol). Reaction mixture was stirred to obtain clearsolution. Then reaction mixture was washed with ethyl acetate (20 vol X 2). Aqueous layerwas then acidified with 50 % sulfuric acid till pH 2.The precipitated solid was filtered andwashed with water (5 vol X 2) followed by pet ether wash 2 vol. The product was suck driedon buchner funnel for 15 min to 60 min. The solid product was dried in oven at 50 to 60 °Covernight. Cinnamic acids were obtained in 80 - 90 % yield. |
| 82% |
With piperidine; pyridine at 23 - 80℃; for 18h; |
|
| 78% |
Stage #1: malonic acid; 4-cyanobenzaldehyde With piperidine; pyridine at 100℃; for 4h;
Stage #2: With hydrogenchloride In water at 20℃; |
4.4. Synthesis of the anilide derivatives 7e-h
General procedure: 3-Cyanobenzaldehyde (11a) or 4-cyanobenzaldehyde (11b) (15 mmol) and malonic acid (30 mmol) were dissolved in pyridine (30 mL). Piperidine (3.0 mmol) was added and the reaction was heated for 4 h at 100 °C. The reaction was cooled to room temperature and 5 M HCl (25 mL) was added slowly. The resulting white precipitate was collected by filtration, washed with water and dried to give (E)-3-cyanocinnamic acid (12a) or (E)-4-cyanocinnamic acid (12b) in yields of 81% and 78%, respectively. |
| 57% |
With piperidine In pyridine at 110℃; for 2h; |
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With piperidine; pyridine |
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Stage #1: malonic acid; 4-cyanobenzaldehyde With piperidine; pyridine
Stage #2: With hydrogenchloride Heating; |
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With pyridine In N,N-dimethyl-formamide at 90℃; |
6.1.1 Substituted cinnamic acids (2)
General procedure: To a solution of the substituted benzaldehyde (50 mmol) and malonic acid (150 mmol) in DMF (30 mL) was added pyridine (50 mmol) and stirred for 3-5 h at 90 °C. After adding water (60 mL), the reaction solution was acidified (pH 1) with concentrated hydrochloric acid and then was cooled to 0 °C. Then the residue was filtered, washed with cold water (2×10mL) and dried in vacuum for 12 h to afford corresponding crude product 2 in yields ranging from 30.2 to 100.0%, which was used directly without further purification. |
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With pyridine for 12h; Reflux; |
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With piperidine; pyridine Reflux; |
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With piperidine; pyridine at 90℃; Inert atmosphere; |
4.2. General procedure for the preparation of trans-Cinnamic acids(2a-p)
General procedure: To a stirred solution of malonic acid (10 mmol) in pyridine(5 mL) and piperidine (3-5 drops) the corresponding aldehydes1a-p (8 mmol) were added. The resulting mixture was stirred at 90°C for 8-12 h. The progress of the reaction was monitored byTLC analyses which indicated the disappearance of the starting material. After the completion of the reactions the reaction mixture were cooled to ambient temperature and the reaction mixture was neutralized with 1N HCl in ice bath resulting a white solid.This soled was filtered and washed three times with cold water.The recrystallization were done from aqueous ethanol (1:1)afforded the product 2a-p. |
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With piperidine; pyridine for 1h; Inert atmosphere; Reflux; |
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