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.
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.
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.
Diels-Alder Reactions of 1-Alkoxy-1-amino-1,3-butadienes: Direct Synthesis of 6-Substituted and 6,6-Disubstituted 2-Cyclohexenones and 6-Substituted 5,6-Dihydropyran-2-ones
P. K. Elkin, N. D. Durfee, V. H. Rawal, Org. Lett., 2021, 23, 5288-5293.
The hetero Diels-Alder reaction of 1-amino-3-siloxy-1,3-butadiene with a range of unactivated carbonyl compounds and imines proceeds in good yields readily under remarkably mild conditions at room temperature and in the absence of Lewis acid catalysts. The cycloadducts can be converted directly to the corresponding dihydro-4-pyrones and dihydro-4-pyridones.
Y. Huang, V. H. Rawal, Org. Lett., 2000, 2, 3321-3323.
[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.
FeCl3 as an Ion-Pairing Lewis Acid Catalyst. Formation of Highly Lewis Acidic FeCl2+ and Thermodynamically Stable FeCl4- To Catalyze the Aza-Diels-Alder Reaction with High Turnover Frequency
R. Tomifuji, J. Maeda, T. Takahashi, T. Kurahashi, S. Matsubara, Org. Lett., 2018, 20, 7474-7477.
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.
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.
An Inverse Electron Demand Azo-Diels-Alder Reaction of o-Quinone Methides and Imino Ethers: Synthesis of Benzocondensed 1,3-Oxazines
D. V. Osipov, V. A. Osyanin, G. D. Khaysanova, E. R. Masterova, P. E. Krasnikov, Y. N. Klimochkin, J. Org. Chem., 2018, 83, 4775-4785.
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