Condensations

Condensation reactions are some of the most useful carbon–carbon bond forming methods available. However, many of these reactions require high temperatures and long reaction times. Microwave irradiation has been found to be quite effective in aldol590-601, Knoevenagel136,173,602-624, Pechmann625, Henry626,627, Mannich628-630, and Ugi631 condensations.

Knoevenagel reactions are generally base-catalyzed mixed aldol condensations. This reaction has been used successfully to synthesize coumarin derivatives. These natural products are used extensively in fragrances, pharmaceuticals, and agrochemicals. Scheme 109 shows successful coumarin syntheses from microwave-enhanced reactions of hydroxy-aldehydes, esters, and a basic catalyst, piperidine.605

Scheme 109

Coumarins have also been synthesized by the Pechmann reaction, which involves a condensation of phenols with β-ketonic esters. Conventional Pechmann methods require harsh sulfuric acid conditions for a couple of days, and depending on reactivity of the substrates, high temperatures. Rare aminocoumarins can be synthesized on a graphite/montmorillonite K10 clay support in 5 to 30 minutes with microwave irradiation (Scheme 110).625

Scheme 110

Knoevenagel condensations can also be used in nitroalkene synthesis. Nitroalkenes are important synthetic building blocks to many potential pharmaceuticals. Scheme 111 exhibits a solid-phase approach to substituted nitroalkenes via microwave irradiation.609

Scheme 111

Nitroalkenes can also be synthesized via the Henry condensation, which reacts a carbonyl compound with a nitroalkane under basic conditions. The resulting β-nitro alcohol dehydrates to give the nitroalkene. Classical conditions for the Henry reaction require elevated temperatures, which may not initiate the dehydration. Varma and co-workers have executed very high yielding solvent-free Henry reactions with a catalytic amount of ammonium acetate (Scheme 112).626

Scheme 112

The Mannich condensation is generally a reaction between a carbonyl compound and an iminium ion, which is generated in situ from a secondary amine and formaldehyde. It is mainly used to introduce an α-dialkyl-aminomethyl substituent, and depending on the synthetic goal, it can then be thermally decomposed to α−methylene compounds. Traditional Mannich condensations often require severe reaction conditions. With microwave irradiation, Mannich reactions between o-ethynylphenols, secondary amines, and paraformaldehyde on CuI-doped alumina yield benzo[b]furans (Scheme 113).629

Scheme 113

The Ugi reaction is another one-pot multi-component condensation reaction. There are four components used in this reaction, an amine, an aldehyde/ketone, a carboxylic acid, and an isocyanide. These combine to yield α-acylamino amides. Some Ugi reactions proceed rapidly, but most require 24 hours to several days for successful completion. Solid-phase Ugi condensations were effected in only five minutes in a 2:1 dichloromethane:methanol solvent mixture with microwaves (Scheme 114).631

Scheme 114

Instruments

Discover 2.0

Microwave Synthesizer

136. Villemin, D.; Martin, B. “Dry condensation of creatinine with aldehydes under focused microwave irradiation.” Synth. Commun. 1995, 25, pp. 3135-40.

173. Bogdal, D. “Coumarins - solvent free synthesis by the Knoevenagel condensation under microwave irradiation.” Electronic Conference on Trends in Heterocyclic Chemistry (ECTOC-4: ECHET98) 1998, Article 087 (www.ch.ic.ac.uk/ectoc/).

602. Balalaie, S.; Nemati, N. “One-pot preparation of coumarins by Knoevenagel condensation in solvent-free condition under microwave irradiation.” Heterocycl. Commun. 2001, 7, pp. 67-72.

603. Reddy, G.V.; Maitraie, D.; Narsaiah, B.; Rambabu, Y.; Rao, P.S. “Microwave assisted Knoevenagel condensation: a facile method for the synthesis of chalcones.” Synth. Commun. 2001, 31, pp. 2881-84.

604. Dave, C.G.; Augustine, C. “Microwave assisted Knoevenagel condensation using NaCl and NH4OAc-AcOH system as catalysts under solvent-free conditions.” Indian J. Chem., Sect. B 2000, 39, pp. 403-05.

605. Bogdal, D. “Coumarins - fast synthesis by the Knoevenagel condensation under microwave irradiation.” J. Chem. Res. (S) 1998, pp. 468-69.

606. Kim, S.Y.; Kwon, P.S.; Kwon, T.W.; Chung, S.K.; Chang, Y.T. “Microwave enhanced Knoevenagel condensation of ethyl cyanoacetate with aldehydes.” Synth. Commun. 1997, 27, pp. 533-41.

607. de la Cruz, P.; Diez-Barra, E.; Loupy, A.; Langa, F. “Silica gel catalyzed Knoevenagel condensation in dry media under microwave irradiation.” Tetrahedron Lett. 1996, 37, pp. 1113-16.

608. Peng, Y.Q.; Song, G.H.; Qian, X.H. “Urotropine: an efficient catalyst precursor for the microwave-assisted Knoevenagel reaction.” J. Chem Res. (S) 2001, pp. 188-89.

609. Kuster, G.J.; Scheeren, H.W. “The preparation of resin-bound nitroalkenes and some applications in high pressure promoted cycloadditions.” Tetrahedron Lett. 2000, 41, pp. 515-19.

610. Mitra, A.K.; De, A.; Karchaudhuri, N. “Solvent-free microwave enhanced Knoevenagel condensation of ethyl cyanoacetate with aldehydes.” Synth. Commun. 1999, 29, pp. 2731-39.

611. Abdallah-El Ayoubi, S.; Texier-Boullet, F.; Hamelin, J. “Minute synthesis of electrophilic alkenes under microwave irradiation.” Synthesis 1994, 3, pp. 258-60.

612. Sabitha, G.; Reddy, B.V.S.; Babu, S.R.; Yadav, J.S. “LiCl catalyzed Knoevenagel condensation: comparative study of conventional method vs. microwave irradiation.” Chem. Lett. 1998, pp. 773-74.

613. Balalaie, S.; Nemati, N. “Ammonium acetate-basic alumina catalyzed Knoevenagel condensation under microwave irradiation under solvent-free condition.” Synth. Commun. 2000, 30, pp. 869-75.

614. Kwon, P.S.; Kim, Y.M.; Kang, C.J.; Kwon, T.W.; Chung, S.K.; Chang, Y.T. “Microwave enhanced Knoevenagel condensation of malonic acid on basic alumina.” Synth. Commun. 1997, 27, pp. 4091-100.

615. Abdallah-El Ayoubi, S.; Texier-Boullet, F. “Clay-mediated synthesis of gem-bis(alkoxycarbonyl)alkenes under microwave irradiation.” J. Chem. Res. (S) 1995, pp. 208-09.

616. Kim, J.K.; Kwon, P.S.; Kwon, T.W.; Chung, S.K.; Lee, J.W. “Application of microwave irradiation techniques for the Knoevenagel condensation.” Synth. Commun. 1996, 26, pp. 535-42.

617. Gasparova, R.; Lacova, M. “Study of microwave irradiation effect on condensation of 6-R-3-formylchromones with active methylene compounds.” Collect. Czech. Chem. Commun. 1995, 60, pp. 1178-85.

618. Kumar, H.M.S.; Reddy, B.V.S.; Anjaneyulu, S.; Yadav, J.S. “Non solvent reaction: ammonium acetate catalyzed highly convenient preparation of trans-cinnamic acids.” Synth. Commun. 1998, 28, pp. 3811-15.

619. Mitra, A.K.; De, A.; Karchaudhuri, N. “Application of microwave irradiation techniques to the syntheses of cinnamic acids by Doebner condensation.” Synth. Commun. 1999, 29, pp. 573-81.

620. Kumar, H.M.S.; Reddy, B.V.S.; Reddy, E.J.; Yadav, J.S. “SiO2 catalyzed expedient synthesis of (E)-3-alkenoic acids in dry media.” Tetrahedron Lett. 1999, 40, pp. 2401-04.

621. Villemin, D. Martin, B. “Clay catalysis: an easy synthesis of 5-nitrofuraldehyde and 5-nitrofurfurylidene derivatives under microwave irradiation.” J. Chem. Res. (S) 1994, pp. 146-47.

622. Villemin, D. Martin, B. “Potassium fluoride on alumina: dry synthesis of 3-arylidene-1,3-dihydro-indol-2-one under microwave irradiation.” Synth. Commun. 1998, 28, pp. 3201-08.

623. Villemin, D.; Martin, B.; Bar, N. “Application of microwave in organic synthesis. Dry synthesis of 2-arylmethylene-3(2)-naphthofuranones.” Molecules 1998, 3, pp. 88-93.

624. Villemin, D.; Martin, B.; Khalid, M. “Dry reaction on KF-alumina: synthesis of 4-arylidene-1,3-(2H,4H)-isoquinolinediones.” Synth. Commun. 1998, 28, pp. 3195-200.

625. Frere, S.; Thiery, V.; Besson, T. “Microwave acceleration of the Pechmann reaction on graphite/montmorillonite K-10: application to the preparation of 4-substituted-7-amino-coumarins.” Tetrahedron Lett. 2001, 42, pp. 2791-94 and Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5) 2001, E0015 (www.mdpi.net).

626. Varma, R.S.; Dahiya, R.; Kumar, S. “Microwave-assisted Henry reactions: solventless synthesis of conjugated nitroalkenes.” Tetrahedron Lett. 1997, 38, pp. 5131-34.

627. Kumar, H.M.S.; Reddy, B.V.S.; Yadav, J.S. “SiO2 catalyzed Henry reaction: microwave assisted preparation of 2-nitroalkanols in dry media.” Chem. Lett. 1998, pp. 637-38.

628. Kabalka, G.W.; Wang, L.; Pagni, R.M. “A microwave-enhanced, solventless Mannich condensation on CuI-doped alumina.” Synlett. 2001, pp. 676-78.

629. Kabalka, G.W.; Wang, L.; Pagni, R.M. “A novel route to 2-(dialkylaminomethyl) benzo[b]furans via a microwave-enhanced, solventless Mannich condensation-cyclization on cuprous iodide doped alumina.” Tetrahedron Lett. 2001, 42, pp. 6049-51.

630. Gadhwal, S.; Baruah, M.; Prajapati, D.; Sandhu, J.S. “Microwave-assisted regioselective synthesis of β-amino ketones via the Mannich reaction.” Synlett. 2000, 3, pp. 341-42.

631. Hoel, A.M.L.; Nielsen, J. “Microwave-assisted solid-phase Ugi four-component condensations.” Tetrahedron Lett. 1999, 40, pp. 3941-44.