Polar Diels-Alder Reactions Under Microwave Irradiation Employing Different Heterocyclic Compounds as Electrophiles

Author(s): Pedro M.E. Mancini , Carla M. Ormachea , María N. Kneeteman* .

Journal Name: Mini-Reviews in Organic Chemistry

Volume 16 , Issue 6 , 2019

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Graphical Abstract:


During the last twenty years, our research group has been working with aromatic nitrosubstituted compounds acting as electrophiles in Polar Diels-Alder (P-DA) reactions with different dienes of diverse nucleophilicity. In this type of reaction, after the cycloaddition reaction, the nitrated compounds obtained as the [4+2] cycloadducts suffer cis-extrusion with the loss of nitrous acid and a subsequent aromatization. In this form, the reaction results are irreversible. On the other hand, the microwave-assisted controlled heating become a powerful tool in organic synthesis as it makes the reaction mixture undergo heating by a combination of thermal effects, dipolar polarization and ionic conduction. As the Diels-Alder (D-A) reaction is one of the most important process in organic synthesis, the microwave (MW) irradiation was applied instead of conventional heating, and this resulted in better yields and shorter reaction times. Several substituted heterocyclic compounds were used as electrophiles and different dienes as nucleophiles. Two experimental situations are involved: one in the presence of Protic Ionic Liquids (PILs) as solvent and the other under solvent-free conditions. The analysis is based on experimental data and theoretical calculations.

Keywords: Diels-Alder, microwave irradiation, nitro-heterocycles, ionic liquids, solvent-free conditions, DFT.

Mancini, P.M.; Ormachea, C.M.; Della Rosa, C.D.; Kneeteman, M.N.; Suarez, A.; Domingo, L.R. Ionic liquids and microwave irradiation as synergistic combination for polar Diels-Alder reactions using properly substituted heterocycles as dienophiles. A DFT study related. Tetrahedron Lett., 2012, 53(48), 6508-6511.
Kneeteman, M.N.; López Baena, A.F.; Della Rosa, C.; Mancini, P.M. Polar Diels-Alder reactions using heterocycles as electrophiles. Influence of microwave irradiation. IRJPAC, 2015, 8(4), 229-235.
Della Rosa, C.; Mancini, P.M.; Kneeteman, M.N.; López Baena, A.F.; Suligoy, M.; Domingo, L.R. Polar Diels-Alder reactions using electrophilic nitrobenzothiophenes. A combined experimental and DFT study. J. Mol. Struct., 2015, 1079, 47-53.
Mancini, P.M.; Kneeteman, M.N.; Cainelli, M.; Ormachea, C.M. Cycloaddition reactions assisted by microwave irradiation: Protic ionic liquids vs. solvent-free conditions. Curr. Microw. Chem., 2017, 4, 1-10.
Mancini, P.M.; Kneeteman, M.N.; Cainelli, M.; Ormachea, C.M. Domingo, L.R. Nitropyrroles, Diels-Alder reactions assisted by microwave irradiation and solvent effect. An experimental and theoretical study. J. Mol. Struct., 2017, 1147, 155-160.
Biolatto, B.; Kneeteman, M.; Mancini, P.M. Diels-Alder reactions of N-tosyl-3-nitroindole and dienamides: Synthesis of intermediates of Aspidospermine alkaloids. Tetrahedron Lett., 1999, 40, 3343-3346.
Paredes, E.; Biolatto, B.; Kneeteman, M.; Mancini, P.M. 1-Nitro-naphthalene as a dienophile in Diels-Alder reactions. Molecules, 2000, 5, 403-404.
Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P.M. Reactions of 1-tosyl-3-substituted indoles with conjugated dienes under thermal and/or high-pressure conditions. J. Org. Chem., 2001, 66, 3906-3912.
Della Rosa, C.D.; Ormachea, C.M.; Sonzogni, A.S.; Kneeteman, M.N.; Domingo, L.R.; Mancini, P.M. Polar Diels-Alder reactions developed in a protic ionic liquid: 3-Nitroindole as dienophile. Theoretical studies using DFT methods. Lett. Org. Chem., 2012, 9, 691-695.
Ormachea, C.; López Baena, A.F. Della Rosa, C.; Kneeteman, M.N.; Mancini, P.M. N-tosyl-nitropyrroles as dienophiles in polar cycloaddition reactions developed in protic ionic liquids. J. Chem. Chem. Eng., 2012, 6, 661-667.
Della Rosa, C.; Kneeteman, M.; Mancini, P.M. Comparison of the reactivity between 2- and 3-Nitropyrroles in cycloaddition reactions. A simple indole synthesis. Tetrahedron Lett., 2007, 48, 1435-1438.
Della Rosa, C.; Ormachea, C.M.; Kneeteman, M.; Adam, C.; Mancini, P.M. Diels-Alder reactions of N-tosylpyrroles developed in protic ionic liquids. Theoretical studies using DFT methods. Tetrahedron Lett., 2011, 52, 6754-6757.
Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave-assisted organic synthesis. A review. Tetrahedron, 2001, 57, 9225-9283.
Buffler, C.R. Microwave Cooking and Processing: Engineering Fundamentals for the Food Scientist; Van Nostrand Reinhold: New York, 1993.
Gabriel, C.; Gabriel, S.; Grant, E.; Halstead, B.; Michael, D.; Mingos, P. Dielectric parameters relevant to microwave dielectric heating. Chem. Soc. Rev., 1998, 27, 213-224.
Galema, S.A. Microwave chemistry. Chem. Soc. Rev., 1997, 26, 233-238.
Seddon, K.R. Ionic liquids for clean technology. J. Chem. Biotechnol, 1997, 68, 351-356.
Seddon, K.R. Room temperature ionic liquids: Neoteric solvents for clean catalysis. Kinet. Catal. Engl. Transl., 1996, 37, 693-697.
Walden, P. Molecular weights and electrical conductivity of several fused salts. Bull. Acad. Imp. Sci. Saint Petersburg, 1914, 1800, 405-422.
Carruthers, W. Cycloaddition reactions in organic synthesis. Tetrahedron Organic Chemistry Series; Baldwin, J.E. & Magnus, P.D; Pergamon Press: Oxford, 1990.
Diels, O.; Alder, K. Synthesen in der hydro-aromatischen Reihe, II. Mitteilung: Über Cantharidin. Chem. Ber., 1929, 62, 554-652.
Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe. XII. Mitteilung. (“Dien-Synthesen” sauerstoffhaltiger Heteroringe. 2 Dien-Synthesen des Furans.). Liebigs Ann. Chem., 1931, 490, 243-257.
Reinhoudt, D.N.; Kouwenhoven, C.G.; Volger, H.C.; Wynberg, H.; Helder, R. [2+2] cycloaddition of substituted thiophenes to acetylenes. Tetrahedron Lett., 1974, 13(52), 5265-5376.
Hurd, C.D.; Juel, L.H. The reaction of aromatic nitro compounds with polynuclear hydrocarbons at elevated temperatures. J. Am. Chem. Soc., 1955, 77, 601-606.
Wenkert, E.; Piettre, S.R. Reaction of alpha- and beta-acylated furans with conjugated dienes. J. Org. Chem., 1988, 53, 5850-5853.
Wenkert, E.; Moeller, P.; Piettre, S.R. Five-membered aromatic heterocycles as dienophiles in Diels-Alder reactions. Furan, pyrrole, and indole. J. Am. Chem. Soc., 1988, 110, 7188-7194.
Paredes, E.; Biolatto, B.; Kneeteman, M.; Mancini, P.M. One-step synthesis of 2,9-disubstituted phenantrenes via Diels-Alder reactions using 1,4-disubstituted naphthalenes as dienophiles. Tetrahedron Lett., 2002, 43, 4601-4603.
Paredes, E.; Kneeteman, M.; Gonzalez-Sierra, M.; Mancini, P.M. Reactivity of 1-nitronaphthalene and 1,3-dinitronaphthalene with conjugated dienes. An easy access to N-naphthylpyrroles. Tetrahedron Lett., 2003, 44, 2943-2945.
Domingo, L.R.; Aurell, M.J.; Kneeteman, M.N.; Mancini, P.M. Mechanistic details of the domino reaction of nitronaphthalenes with the electron-rich dienes. A DFT study. J. Mol. Struct., 2008, 853, 68-76.
Della Rosa, C.; Paredes, E.; Kneeteman, M.; Mancini, P.M. Behaviour of thiophenes substituted with electron-withdrawing groups in cycloaddition reactions. Lett. Org. Chem., 2004, 1, 369-371.
Della Rosa, C.; Kneeteman, M.; Mancini, P.M. 2-Nitrofurans as dienophiles in Diels-Alder reactions. Tetrahedron Lett., 2005, 46, 8711-8714.
Della Rosa, C.; Kneeteman, M.; Mancini, P.M. Behaviour of selenophenes substituted with electron-withdrawing groups in polar Diels-Alder reactions. Tetrahedron Lett., 2007, 48, 7075-7078.
Paredes, E.; Brasca, R.; Kneeteman, M.; Mancini, P.M. A novel application of the Diels-Alder reaction: Nitronaphthalenes as normal electron demand dienophiles. Tetrahedron, 2007, 63, 3790-3799.
Brasca, R.; Della Rosa, C.; Kneeteman, M.; Mancini, P.M. Five-membered aromatic heterocycles in Diels-Alder cycloaddition reactions: Theoretical studies as a complement of the experimental researches. Lett. Org. Chem., 2011, 8, 82-87.
Cook, M.J.; Cracknell, S.J. The Diels-Alder reaction of 2,5-dialkylfurans and fumaronitrile revisited. Tetrahedron, 1994, 50, 12125-12132.
Cainelli, M.; Ormachea, C.M.; Kneeteman, M.N.; Mancini, P.M. A theoretical study of the Diels-Alder reaction between 3-nitrofuran and different dienes developed in ionic liquids. IRJPAC, 2016, 12(2), 1-10.
Bini, R.; Chiappe, C.; Mestre, V.L.; Pomelli, C.S.; Welton, T.A. Rationalization of the solvent effect on the Diels-Alder reaction in ionic liquids using multiparameter linear solvation energy relationships. Org. Biomol. Chem., 2008, 6(14), 2522-2529.
Adam, C.; Fortunato, G.; Mancini, P.M. Nucleophilicity and acid catalyst behavior of a protic ionic liquids in a molecular reaction media. Part 1. J. Phys. Org. Chem., 2009, 22, 460-465.
Gordon, C.M.; Holbrey, J.D.; Kennedy, A.R.; Seddon, K.R. Ionic liquid crystals: Hexafluorophosphate salts. J. Mater. Chem., 1998, 8, 2627-2636.
Earle, M.J.; Katdare, S.P.; Seddon, K.R. Paradigm confirmed: The first use of ionic liquids to dramatically influence the outcome of chemical reactions. Org. Lett., 2004, 6, 707-710.
Brasca, R.; Kneeteman, M.; Mancini, P.M.; Fabian, W.M.F. Comprehensive DFT study on site-, regio-, and stereoselectivity of Diels-Alder reactions leading to 5-hydroxybenzofurans. Eur. J. Org. Chem., 2011, 721-729.
Parr, R.G.; Pearson, R.G. Absolute hardness: Companion parameter to absolute electronegativity. J. Am. Chem. Soc., 1983, 105, 7512-7516.
Parr, R.G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989.
Domingo, L.R.; Chamorro, E.; Pérez, P. Understanding the reactivity of captodative ethylenes in polar cycloaddition reactions. A theoretical study. J. Org. Chem., 2008, 73, 4615-4624.
Domingo, L.R.; Pérez, P. The nucleophilicity N index in organic chemistry. Org. Biomol. Chem., 2011, 9, 7168-7175.
Kohn, W.; Sham, L.J. Self-consistent equations including exchange and correlation effects. Phys. Rev., 1965, 140, 1133-1138.
Domingo, L.R.; Emamian, S.R. Understanding the mechanisms of [3+2] cycloaddition reactions. The pseudoradical versus the zwitterionic mechanism. Tetrahedron, 2014, 70, 1267-1273.
Domingo, L.R.; Aurell, M.J.; Perez, P.; Contreras, R. Quantitative characterization of the local electrophilicity of organic molecules. Understanding the regioselectivity on Diels-Alder reactions. J. Phys. Chem. A, 2002, 106, 6871-6875.
Pérez, P.; Domingo, L.R.; Duque-Noreña, M.; Chamorro, E. A condensed-to-atom nucleophilicity index. An application to the director effects on the electrophilic aromatic substitutions. J. Mol. Struct., 2009, 895, 86-93.
Contreras, R.; Fuentealba, P.; Galván, M.; Pérez, P. A direct evaluation of regional Fukui functions in molecules. Chem. Phys. Lett., 1999, 304, 405-413.
Lopez Baena, A.F. Polar Diels-Alder reactions using aromatic azaheterocycles as electrophiles. An experimental study about the influence of microwave radiation and ionic liquids as solvents in these reactions., Ph.D. Thesis, National University of Litoral, March. 2015.
Brasca, R.; Kneeteman, M.N.; Mancini, P.M.; Fabian, W. Diels-Alder reactions for the rational design of benzo[b]thiophenes: DFT-based guidelines for synthetic chemists. J. Mol. Struct., 2012, 1010, 158-168.
Gaussian09, Revision A.01; Gaussian, Inc., Wallingford CT, 2009.
Becke, A.D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 1993, 98, 5648-5652.
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B, 1988, 37, 785-789.
Hehre, W.J.; Radom, L.; Schleyer, P.V.R.; Pople, J.A. Ab initio Molecular Orbital Theory; Wiley: New York, 1986.
Schlegel, H.B. Optimization of equilibrium geometries and transition structures. J. Comput. Chem., 1982, 3, 214-218.
Schlegel, H.B. Modern Electronic Structure Theory, Yarkony, D.R Ed., World Scientific Publishing: Singapore. 1994.

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Year: 2019
Page: [527 - 543]
Pages: 17
DOI: 10.2174/1570193X15666180608083925
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