Microwave-Assisted Synthesis of Pyrrole-2-Carboxamides

Abstract

A set of ten tricyclic pyrrole-2-carboxamides was synthesized by a Paal-Knorr cyclization under rapid and mild conditions using microwave irradiation. All compounds were also prepared using conventional heating techniques. An efficiency comparison of time, yield and effort clearly proved the microwave technique to be superior.

Key words

heterocycles - library synthesis - microwave irradiation - Paal-Knorr reaction - pyrroles

References

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• Procedure for the Synthesis of Pyrroles 7. To a solution of 20.0 mg (0.0374 mmol) 5 in EtOH (400 µL) in an Emrys Process Vial (0.5-2 mL) was added glacial acetic acid (40 µL) and 3 equiv amine 6. In the case of hydrochloride ammonium salts 1.5 equiv Et₃N were added for each equivalent HCl. The microwave tube was sealed without using an inert gas atmosphere and irradiated in an Emrys Optimizer microwave at 80 °C (IR temperature detection) using an initial power of 150 W (unless otherwise mentioned). If the reaction was performed under conventional heating the same microwave tube was immersed into a preheated oil bath. In both cases the progress of the reaction was followed by TLC. Then the tube was opened and the EtOH was removed in a Radleys GreenHouse Blowdown Evaporator. The crude reaction mixture was purified by column chromatography over silica gel eluting with hexanes-EtOAc.
• 13a

  Reactions at higher temperatures: For reactions in the microwave at 130 °C and 160 °C an initial power of 250 W was necessary.

• 13b

  Reaction under diluted conditions: 20.0 mg (0.0374 mmol) 5 was dissolved in EtOH (1.2 mL) and glacial acetic acid (120 µL) and 10 equiv amine were necessary to drive the reaction to completion.

• 13c

  Aqueous acidic workup: After the reaction was complete EtOAc (10 mL) and 1 M aq HCl (10 mL) was added. The aqueous phase was extracted three times with EtOAc (10 mL), then the combined organic phases were washed with brine and dried over MgSO₄. After evaporation of the solvents, the crude material was purified by column chromatography.

• 13d

  Reaction under inert gas conditions: The microwave tube was flushed with argon prior to irradiation in the microwave.

12

After 10-15 seconds, the desired temperature was reached and only less than 15 W were applied for the rest of the time.

14

Physical Data for rac -(3b R ,4 R ,6a S )-5-Benzoyl-4-(4-fluorobenzyl)-1-(2-methoxyethyl)-2-(pyrrolidine-1-carbonyl)-3b,4,5,6,6a,7-hexahydro-1 H -1,5-diazacyclo-penta[ a ]pentalene-4-carboxylic Acid Methyl Ester (7a).
Mp 95-97 °C. IR: 2949, 2873, 1734, 1640, 1604, 1509, 1446, 1399 cm^-1. ¹H NMR (CDCl₃): δ = 7.43-7.38 (m, 5 H), 7.31 (dd, 2 H, J = 8.4, 5.5 Hz), 7.04 (app. t, 2 H, J = 8.6 Hz), 6.22 (s, 1 H), 4.33 (ddd, 1 H, J = 13.9, 5.6, 4.2 Hz), 4.20 (d, 1 H, J = 13.8 Hz), 4.08 (ddd, 1 H, J = 14.0, 6.0, 4.4 Hz), 3.83 (d, 1 H, J = 7.4 Hz), 3.68-3.55 (m, 9 H), 3.40-3.34 (m, 2 H), 3.24-3.20 (m, 4 H), 2.60 (dd, 1 H, J = 15.3, 7.0 Hz), 2.38-2.29 (m, 1 H), 2.27 (d, 1 H, J = 15.9 Hz), 1.98-1.89 (m, 4 H). ¹³C (CDCl₃): δ = 172.0, 169.8, 161.8, 161.8 (d, J _CF = 243.9 Hz), 141.6, 137.3, 132.6 (d, J _CF = 3.1 Hz), 132.2 (d, J _CF = 7.7 Hz), 129.5, 129.1, 128.3, 126.0, 121.8, 114.9 (d, J _CF = 20.9 Hz), 108.8, 72.9, 72.8, 58.6, 56.2, 52.1, 51.9, 49 (br), 46.9, 46 (br), 45.2, 38.4, 28.6, 27 (br), 24 (br). ¹⁹F NMR (CDCl₃): δ = -116.5 (tt, 1 F, J = 8.5, 5.6 Hz). MS (ESI): m/z (rel. intensity) = 596 (100) [M⁺ + Na], 574 (72) [M⁺ + H], 514 (30). HRMS (ESI): m/z calcd for C₃₃H₃₆N₃O₅FNa: 595.2537; found: 596.2544.