Further Information
Literature
Related Reactions
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.
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.
Enantioselective Synthesis of Dihydropyrans. Catalysis of Hetero Diels-Alder
Reactions by Bis(oxazoline) Copper(II) Complexes
D. A. Evans, J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc., 2000,
122, 1635-1649.
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.
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.
Balancing Activity and Stability in Halogen-Bonding Catalysis:
Iodopyridinium-Catalyzed One-Pot Synthesis of 2,3-Dihydropyridinones
Y. Li, Y. Ge, R. Sun, X. Yang, S. Huang, H. Dong, Y. Liu, H. Xue, X. Ma, F.
Fu, Z. Chen, J. Org. Chem., 2023, 88,
11069-11082.
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.
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 Pyridazine Derivatives via Aza-Diels-Alder Reactions of
1,2,3-Triazine Derivatives and 1-Propynylamines
T. Kodama, I. Sasaki, H. Sugimura, J. Org. Chem., 2021, 86,
8926-8932.
Inverse Electron Demand Diels-Alder-Type Heterocycle Syntheses with
1,2,3-Triazine 1-Oxides: Expanded Versatility
S. Biswas, L. De Angelis, G. Rivera, H. Arman, M. P. Doyle, Org. Lett., 2023, 25,
1104-1108.
Synthetic Route to Phenyl Diazenes and Pyridazinium Salts from
Phenylazosulfonates
S. Gradl, J. Köckenberger, J. Oppl, M. Schiller, M. R. Heinrich, J. Org. Chem., 2021, 86,
6228-6238.
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.
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.
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.
Organocatalyzed Synthesis of Highly Functionalized Phthalimides via
Diels-Alder Reaction Employing Two Dienophiles
M. S. Akhthar, Y. R. Lee, J. Org. Chem., 2020, 85,
15129-15138.
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.
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