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Alder-Ene Reaction
1,3-dipolar cycloaddition
Synthesis of cyclohexenes

Diels-Alder Reaction

The [4+2]-cycloaddition of a conjugated diene and a dienophile (an alkene or alkyne), an electrocyclic reaction that involves the 4 π-electrons of the diene and 2 π-electrons of the dienophile. The driving force of the reaction is the formation of new σ-bonds, which are energetically more stable than the π-bonds.

In the case of an alkynyl dienophile, the initial adduct can still react as a dienophile if not too sterically hindered. In addition, either the diene or the dienophile can be substituted with cumulated double bonds, such as substituted allenes.

With its broad scope and simplicity of operation, the Diels-Alder is the most powerful synthetic method for unsaturated six-membered rings.

A variant is the hetero-Diels-Alder, in which either the diene or the dienophile contains a heteroatom, most often nitrogen or oxygen. This alternative constitutes a powerful synthesis of six-membered ring heterocycles.

Mechanism of the Diels-Alder Reaction

Overlap of the molecular orbitals (MOs) is required:

Overlap between the highest occupied MO of the diene (HOMO) and the lowest unoccupied MO of the dienophile (LUMO) is thermally allowed in the Diels Alder Reaction, provided the orbitals are of similar energy. The reaction is facilitated by electron-withdrawing groups on the dienophile, since this will lower the energy of the LUMO. Good dienophiles often bear one or two of the following substituents: CHO, COR, COOR, CN, C=C, Ph, or halogen. The diene component should be as electron-rich as possible.

There are “inverse demand” Diels Alder Reactions that involve the overlap of the HOMO of the dienophile with the unoccupied MO of the diene. This alternative scenario for the reaction is favored by electron-donating groups on the dienophile and an electron-poor diene.

The reaction is diastereoselective.

Cyclic dienes give stereoisomeric products. The endo product is usually favored by kinetic control due to secondary orbital interactions.

Recent Literature

Chiral Oxazaborolidine-Aluminum Bromide Complexes Are Unusually Powerful and Effective Catalysts for Enantioselective Diels-Alder Reactions
D. Liu, E. Canales, E. J. Corey, J. Am. Chem. Soc., 2007, 129, 1498-1499.

Regioselective and Asymmetric Diels-Alder Reaction of 1- and 2-Substituted Cyclopentadienes Catalyzed by a Brønsted Acid Activated Chiral Oxazaborolidine
J. N. Payette, H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 9536-9537.

Diarylprolinol Silyl Ether as Catalyst of an exo-Selective, Enantioselective Diels-Alder Reaction
H. Gotoh, Y. Hayashi, Org. Lett., 2007, 9, 2859-2862.

Asymmetric Diels-Alder Reactions of α,β-Unsaturated Aldehydes Catalyzed by a Diarylprolinol Silyl Ether Salt in the Presence of Water
Y. Hayashi, S. Samanta, H. Gotoh, H. Ishikawa, Angew. Chem. Int. Ed., 2008, 47, 6634-6637.

Catalytic Enantioselective Diels-Alder Reaction via a Chiral Indium(III) Complex
Y.-Chua Teo, T.-P. Loh, Org. Lett., 2005, 7, 2539-2541.

Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction
D. Nakashima, H. Yamamoto, J. Am. Chem. Soc., 2006, 128, 9626-9627.

A Mild and Efficient Asymmetric Hetero-Diels-Alder Reaction of the Brassard Diene with Aldehydes
Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng, Eur. J. Org. Chem., 2005, 3542-3552.

DIANANE-Cr(III)-salen Complexes as Highly Enantioselective Catalysts for Hetero-Diels-Alder Reactions of Aldehydes with Dienes
A. Berkessel, N. Vogl, Eur. J. Org. Chem., 2006, 5029-5035.

Highly Selective Diels-Alder Reactions of Directly Connected Enyne Dienophiles
M. Dai, D. Sarlah, M. Yu, S. J. Danishefsky, G. O. Jones, K. N. Houk, J. Am. Chem. Soc., 2007, 129, 645-657.

[AlCl3 + 2THF]: A New and Efficient Catalytic System for Diels-Alder Cycloaddition of α,β-Unsaturated Carbonyl Compounds under Solvent-Free Conditions
F. Fringuelli, R. Girotti, F. Pizzo, L. Vaccaro, Org. Lett., 2006, 8, 2487-2489.

Strong Counteranion Effects on the Catalytic Activity of Cationic Silicon Lewis Acids in Mukaiyama Aldol and Diels-Alder Reactions
L.-B. Han, C.-Q. Zhao, J. Org. Chem., 2005, 70, 10121-10123.

Regioselective Synthesis of C-3-Functionalized Quinolines via Hetero-Diels-Alder Cycloaddition of Azadienes with Terminal Alkynes
R. K. Saunthwal, M. Patel, A. K. Verma, J. Org. Chem., 2016, 81, 6563-6572.

2-[(Trimethylsilyl)methyl]benzyl Methanesulfonates: Useful Precursors for the Generation of o-Quinodimethanes
H. Shirakawa, H. Sano, Synthesis, 2014, 46, 1788-1792.

Reaction of Aldehydes/Ketones with Electron-Deficient 1,3,5-Triazines Leading to Functionalized Pyrimidines as Diels-Alder/Retro-Diels-Alder Reaction Products: Reaction Development and Mechanistic Studies
K. Yang, Q. Dang, P.-J. Cai, Y. Gao, Z.-X. Yu, X. Bai, J. Org. Chem., 2017, 82, 2336-2344.

Synthesis of Dihydronaphthalenes via Aryne Diels-Alder Reactions: Scope and Diastereoselectivity
C. Dockendorff, S. Sahli, M. Olsen, L. Milhau, M. Lautens, J. Am. Chem. Soc., 2005, 127, 15028-15029.

Imidazolinium salts as catalysts for the aza-Diels-Alder reaction
V. Jurcik, R. Wilhelm, Org. Biomol. Chem., 2005, 3, 239-244.

Catalytic Asymmetric Inverse-Electron-Demand Diels-Alder Reaction of N-Sulfonyl-1-Aza-1,3-Dienes
J. Esquivias, R. G. Arrays, J. C. Carretero, J. Am. Chem. Soc., 2007, 129, 1480-1481.

Chiral Brønsted Acid-Catalyzed Inverse Electron-Demand Aza Diels-Alder Reaction
T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc., 2006, 128, 13070-13071.

Regioselective Cobalt-Catalyzed Diels-Alder Reaction towards 1,3-Disubstituted and 1,2,3-Trisubstituted Benzene Derivatives
G. Hilt, M. Danz, Synthesis, 2008, 2257-2263.

Halocycloalkenones as Diels-Alder Dienophiles. Applications to Generating Useful Structural Patterns
A. G. Ross, S. D. Townsend, S. J. Danishefsky, J. Org. Chem., 2013, 78, 204-210.

Organic Chemistry Highlights

Selected Articles

The Intramolecular Diels-Alder Reaction in Natural Product Synthesis
Advances in the Diels-Alder Reaction: Synthesis of (±)-Lycoridine and of Dolabellatrienone
New Dienes and Dienophiles for Intermolecular and Intramolecular Diels-Alder Cycloadditions
Asymmetric Hetero-Diels-Alder Reactions