{ "id": "ep4pz1sqvc", "slug": "hetero-diels-alder-reaction", "title": "Hetero-Diels–Alder reaction", "updated": "2026-10-21", "topic_path": [ { "id": "physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/topics/physical" }, { "id": "physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry" }, { "id": "physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods" }, { "id": "physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-2-to-he", "label": "Titles 2 to He", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-2-to-he" } ], "geo": [ { "id": "geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Non-geographic · 1800 to 1945: Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.t1800", "label": "Non-geographic · 1800 to 1945", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800" }, { "id": "geo.nongeo.t1800.physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical" }, { "id": "geo.nongeo.t1800.physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical.chemistry" }, { "id": "geo.nongeo.t1800.physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical.chemistry.methods" }, { "id": "geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis" }, { "id": "geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1800.physical.chemistry.methods.chemical-synthesis.named-preparative-methods" } ] } ], "excerpt": "The hetero-Diels–Alder reaction is a [4+2] cycloaddition extending the all-carbon Diels–Alder reaction, in which a diene reacts with a heteroatom-containing dienophile to build six-membered heterocycles used in pharmaceutical synthesis.", "snippet": "The hetero-Diels–Alder reaction is a [4+2] cycloaddition extending the all-carbon Diels–Alder reaction, in which a diene reacts with a heteroatom-containing dienophile to build six-membered heterocycles used in pharmaceutical synthesis.", "node": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-2-to-he", "markdown": "# Hetero-Diels–Alder reaction\n\nThe hetero-Diels–Alder (HDA) reaction is a cycloaddition in which a diene reacts with a heteroatom-containing dienophile, or a heteroatom-containing diene reacts with an alkene, to build a six-membered ring containing oxygen, nitrogen, or sulfur. It extends the all-carbon [Diels–Alder reaction](https://www.edgepedia.org/diels-alder-reaction) to heterocycle synthesis and is used to make aza- and oxa-heterocycles bearing multiple stereogenic centers, although it has been much less explored than the parent reaction and dipolar cycloadditions.[1](https://onlinelibrary.wiley.com/doi/10.1002/anie.201404094) A single HDA event can form two new σ bonds, which may include C–heteroatom bonds depending on the diene and dienophile, and up to four adjacent chiral centers at once; by the heteroatom involved, the reaction is classified mainly into oxa-Diels–Alder and aza-Diels–Alder types.[2](https://synbioj.cip.com.cn/EN/10.12211/2096-8280.2023-015) Dienophiles include imines, azenes, carbonyls, thiocarbonyls, and nitroso compounds, while heterodienes include azabutadienes, diazabutadienes, oxabutadienes, thiabutadienes, nitrosoalkenes, and nitroalkenes.[3](https://www.benthamdirect.com/content/journals/coc/10.2174/1385272820666160216000401)\n\n| Key fact | Detail |\n|---|---|\n| Ring formed | Six-membered heterocycle (dihydropyran, piperidine, 1,2-oxazine, dihydropyridinone frameworks) via [4+2] cycloaddition[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) |\n| Stereochemical output | Up to 4 contiguous chiral centers in one step, with moderate to excellent diastereomeric excess and chemical yield[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) |\n| Mechanism | Concerted but asynchronous in most cases; stepwise under Brønsted-acid iminium activation or via Mukaiyama-aldol manifolds[5](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696) |\n| Endo/exo energetics | Nitroso HDA: endo favored by 8.6 kcal/mol; imine HDA: exo-lone-pair favored by 4.3–5.3 kcal/mol, opposite to the all-carbon endo rule[6](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf) |\n| Common catalysts | Lewis acids (ZnCl2, TiCl4, SnCl4, rare-earth triflates), Jacobsen Cr(III)-salen, chiral phosphoric acids, NHCs, Fe(III)/N,N′-dioxide complexes[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) |\n| Main variants | Oxo-Diels–Alder, aza-Diels–Alder (Povarov), nitroso HDA, inverse-electron-demand HDA, domino Knoevenagel–HDA, intramolecular HDA[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) |\n| Biocatalysis | Enzyme-catalyzed HDA steps are known in natural product biosynthesis; Abx(−)F performs a dual-oxa HDA in anthrabenzoxocinone biosynthesis[8](https://www.nature.com/articles/s41557-025-01804-0) |\n\n## How it works\n\nThe reaction is a pericyclic [4+2] cycloaddition whose orbital demand depends on the partners. In the normal-electron-demand case, an electron-rich diene reacts with an electron-poor dienophile; in the inverse-electron-demand case, the interaction is between the LUMO of an electron-poor hetero diene and the HOMO of the dienophile. Asymmetric catalytic versions follow three activation strategies: LUMO-lowering, HOMO-raising, and dual activation.[5](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696)\n\nConcerted but asynchronous describes most HDA transition states. Computational studies (STO-3G, MP2/6-31G*, B3LYP/6-31G*) of 1-aza- and 2-aza-butadiene reactions with ethylene indicate distinctly concerted but asynchronous reactions,[9](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380) and Houk's pioneering computations showed the intermolecular nitroso HDA proceeds concertedly through an asynchronous transition state.[6](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf) The reaction becomes stepwise under strong polarization of one partner: for formaldiminium, generated under Brønsted-acid activation, the transition structure shows forming-bond lengths of 1.919 and 3.058 Å, indicating a highly asynchronous transition state rather than, by itself, a stepwise mechanism.[9](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380)\n\nRegioselectivity follows substituent position on the diene: for 1-substituted dienes the proximal isomer is strongly preferred, while for 2-substituted dienes the distal isomer is slightly preferred, with substituents and conditions both playing a role.[6](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf) For 1-oxa-1,3-butadienes, four transition states (endo/exo orientation crossed with E/Z oxadiene configuration) govern diastereoselectivity: cis-adducts arise from endo-E or exo-Z orientations, and trans-adducts from exo-E or endo-Z.[7](https://link.springer.com/article/10.1007/s41061-016-0026-2)\n\nEndo/exo selectivity inverts with the heteroatom. In the nitroso reaction, the endo transition state lies 8.6 kcal/mol below the exo for HNO with butadiene, an effect attributed to the exo lone pair effect.[6](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf) For imines the preference reverses: the nitrogen lone pair exo transition state of formaldimine with butadiene is 4.3–5.3 kcal/mol more stable than the endo orientation.[9](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380) Across these cases, HDA reactions generally proceed with high regio- and diastereoselectivity, generating up to 4 contiguous chiral centers in a single step.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k)\n\n## How it is done\n\nThe choice of dienophile and catalyst defines the experiment. Imine dienophiles generally need activation, for example electron-withdrawing carbonyl or sulfonyl groups on nitrogen, or use with activated dienes; imines bearing electron-withdrawing N-substituents are the most reactive because the reaction involves the imine LUMO.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) Simple Lewis acids such as ZnCl2, TiCl4, SnCl4, EtAlCl2, Me2AlCl, LiClO4, Mg(ClO4)2, Eu(fod)3, and Yb(fod)3 accelerate HDA reactions and influence endo/exo stereoselectivity;[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) the rare-earth triflates Yb(OTf)3, Sc(OTf)3, and In(OTf)3 tolerate small amounts of water.[9](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380)\n\n**Asymmetric catalysis** spans metal and organocatalyst platforms. Yamamoto's chiral (acyloxy)borane (CAB) catalysts gave early enantioselective aldehyde HDA reactions.[10](https://doi.org/10.1021/jo00033a005) Jacobsen's chromium(III)-salen complexes catalyze additions to aliphatic, vinylic, and aromatic aldehydes in 65–98% yield and 85:15–96:4 er, with mechanistic studies supporting a synchronous HDA pathway.[11](https://chemistry.illinois.edu/system/files/inline-files/05CovellChem535Abstract.pdf) A chiral silicon Lewis acid promotes formal aza-Diels–Alder reactions of acylhydrazones at ambient temperature: pivaloyl hydrazone with 2,3-dimethyl-1,3-butadiene in CH2Cl2 gave the tetrahydropyridine in 91% yield and 85% ee, improved by recrystallization to 70% yield and 98% ee.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC2918383/) Organocatalytic options include chiral phosphoric acids for tetrahydroquinolines, [N-heterocyclic carbene catalysis](https://www.edgepedia.org/n-heterocyclic-carbene-catalysis) for dihydropyridinones, and squaramide or thiourea bifunctional catalysts.[5](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696) A 2024 chiral N,N′-dioxide/Fe(III) complex catalyzes inverse-electron-demand HDA of dioxopyrrolidines with simple olefins to bicyclic dihydropyrans in up to 99% yield, 99:1 dr, and 99% ee under mild conditions.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC10966964/)\n\n**Conditions vary widely.** A Povarov-type HDA toward luotonin A used 10 mol% Dy(OTf)3 in CH3CN with a relatively long reaction time to give 51% yield after purification.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) Modern process alternatives include solid-phase, aqueous, and microwave-assisted protocols for nitrogen heterocycles.[14](https://www.eurekaselect.com/article/83512)\n\n## Origin\n\nThe parent Diels–Alder reaction was reported by [Otto Diels](https://www.edgepedia.org/otto-diels) and [Kurt Alder](https://www.edgepedia.org/kurt-alder) in \"Synthesen in der hydroaromatischen Reihe\" (Justus Liebigs Annalen der Chemie, 1928);[15](https://doi.org/10.1002/jlac.19284600106) the 1950 [Nobel Prize in Chemistry](https://www.edgepedia.org/nobel-prize-in-chemistry) recognized this work, and Lewis acid catalysis was later shown to accelerate the parent reaction.[16](https://pubs.rsc.org/en/content/articlehtml/2025/ra/d4ra07989b) The most comprehensive early review of HDA chemistry is the 1997 Topics in Current Chemistry survey by Lutz F. Tietze and Georg Kettschau.[17](https://doi.org/10.1007/bfb0119240)\n\nThe 1982 Tetrahedron Letters paper \"On the lewis acid catalyzed cyclocondensation of imines with a siloxydiene\" by James F. Kerwin and Samuel Danishefsky extended [Lewis acid catalysis](https://www.edgepedia.org/lewis-acid-catalysis) within the HDA reaction family.[18](https://doi.org/10.1016/s0040-4039%2800%2987694-7) Aza Diels–Alder reactions in aqueous solution with simple iminium salts generated under Mannich conditions were reported by Scott D. Larsen and Paul A. Grieco in 1985 ([Journal of the American Chemical Society](https://www.edgepedia.org/journal-of-the-american-chemical-society)).[19](https://doi.org/10.1021/ja00292a057) Later milestones include the CAB-catalyzed asymmetric HDA of Gao and colleagues (1992, [The Journal of Organic Chemistry](https://www.edgepedia.org/the-journal-of-organic-chemistry)),[10](https://doi.org/10.1021/jo00033a005) Waldmann's 1994 review of asymmetric HDA in Synthesis,[20](https://doi.org/10.1055/s-1994-25519) the first highly enantioselective catalytic HDA of ketones by Mogens Johannsen and Sulan Yao (1997, Chemical Communications),[21](https://doi.org/10.1039/a706463b) bis(oxazoline) copper(II)-catalyzed enantioselective dihydropyran synthesis by Evans, Johnson, and Olhava (2000, Journal of the American Chemical Society),[22](https://doi.org/10.1021/ja992175i) the highly enantioselective inverse-electron-demand HDA of α,β-unsaturated aldehydes by Gademann, Chavez, and Jacobsen (2002), and the first organocatalytic enantioselective inverse-electron-demand HDA by Karsten Juhl and Karl Anker Jørgensen (2003, Angewandte Chemie International Edition).[23](https://doi.org/10.1002/anie.200250652) Tietze, Schneider, and Grote reported stereodivergent HDA reactions of chiral 1-oxa-1,3-butadienes through a Lewis-acid-induced conformational switch (1996, Chemistry – A European Journal).[24](https://doi.org/10.1002/chem.19960020205) A catalytic enantioselective nitroso Diels–Alder reaction was reported by Biplab Maji and Hisashi Yamamoto in 2015 (Journal of the American Chemical Society).[25](https://doi.org/10.1021/jacs.5b11273)\n\n## Variants\n\n**Oxo-Diels–Alder** reactions use aldehyde (carbonyl) dienophiles, classically with Danishefsky's siloxydiene, to give dihydropyranones. **Aza-Diels–Alder** reactions use imine dienophiles, and the Povarov reaction is the prominent aniline/aldehyde/imine-based member of this family.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) **Nitroso HDA** combines nitroso dienophiles with dienes to form the 3,6-dihydro-2H-1,2-oxazine scaffold.[6](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf)\n\n**Inverse-electron-demand HDA** of 1-oxa-1,3-butadienes with electron-rich alkenes gives an enantioselective approach to chiral dihydropyrans.[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) The **domino Knoevenagel–HDA** sequence generates the 1-oxa-1,3-butadiene in situ from an aldehyde and a 1,3-dicarbonyl compound, allowing two or more rings to form in one operation, and is described as one of the most powerful synthetic routes to heterocycles and natural products.[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) **Intramolecular HDA** constructs two or more rings simultaneously in a single step, avoiding sequential chemical conversions.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) The heterodiene/heterodienophile scope continues to widen: ketenimines were evaluated as aza-dienophiles in a 2025 study by DeAngelis, Goyal, Liss, and colleagues,[26](https://doi.org/10.1021/jacs.4c17174) and hetero-Diels–Alder reactions of (isobenzo)furans were reviewed by DeAngelis and Newton in 2025.[27](https://doi.org/10.1039/d5ob00050e)\n\n## Applications\n\nHDA products are heterocyclic building blocks of direct pharmaceutical relevance. Inverse-electron-demand HDA of α,β-unsaturated carbonyl compounds with electron-rich alkenes gives chiral dihydropyrans, precursors for carbohydrate derivative synthesis;[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) NHC-catalyzed aza-HDA gives dihydropyridinones, chiral phosphoric acid catalysis gives tetrahydroquinolines,[5](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696) and chiral silicon Lewis acid catalysis gives tetrahydropyridines.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC2918383/)\n\n**Total synthesis** uses HDA as a key step for targets including luotonin A (Povarov reaction, 51% yield),[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) (−)-epibatidine via an N-acylnitroso HDA with an 8-arylmenthol chiral auxiliary, and phyllanthine via a Yb(OTf)3-catalyzed HDA of an imine with Danishefsky's diene.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k) Inverse-electron-demand HDA has served as a key step toward luotonin A, leporin A, and goniotriol.[5](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696) A 2023 total synthesis of guajavadimer A used a Lewis acid-catalyzed cascade double HDA.[28](https://doi.org/10.1021/acs.orglett.3c02522) The reaction's bond-forming economy and high regio- and stereoselectivities make it an efficient route to polycyclic nitrogen compounds compared with other heterocyclizations.[14](https://www.eurekaselect.com/article/83512)\n\n**Biocatalysis** has become the most visible recent direction. A 2024 review of enzyme-catalyzed HDA reactions in natural product biosynthesis, focused mainly on pyridine and indole alkaloid pathways, presents them as green, mild alternatives to Lewis acid, metal-ion, and organocatalytic HDA, while noting that known HDA enzymes have narrow substrate spectra, poorly characterized mechanisms, and rather poor stereoselectivity.[2](https://synbioj.cip.com.cn/EN/10.12211/2096-8280.2023-015) These efforts build on earlier enzymatic [4+2] chemistry, including the spinosyn A cyclase (2011),[29](https://doi.org/10.1038/nature09981) SAM-dependent enzymatic pericyclic reactions (2017),[30](https://doi.org/10.1038/nature23882) and the inverse-electron-demand Diels–Alderase in ilicicolin H biosynthesis (2019).[31](https://doi.org/10.1021/jacs.9b02204) In 2025, Abx(−)F, a bifunctional vicinal oxygen chelate (VOC)-like protein, was reported to catalyze dehydration and dual-oxa HDA reactions to form the oxygen-bridged tricyclic acetal of (−)-anthrabenzoxocinone; isotope assays and DFT calculations support a dehydration-coordinated concerted HDA mechanism, with Asp17 acting as the general base that forms an o-quinone methide intermediate.[8](https://www.nature.com/articles/s41557-025-01804-0)\n\n**New catalysis** includes a 2024 palladium-catalyzed three-component reaction that generates ortho-quinodimethane dienes in situ for trapping by N-sulfonylaldimines, giving tetrahydrocarboline indole alkaloids in 44–68% isolated yields with excellent diastereoselectivity,[32](https://www.nature.com/articles/s41467-024-55190-1) and copper-catalyzed dehydrogenative oxidation paired with HDA for dihydropyran synthesis (2024).[33](https://doi.org/10.1002/ajoc.202400118) A 2025 review covering 2020–2023 presents total syntheses of approximately 80 natural products using Diels–Alder reactions, including hetero-Diels–Alder and inverse-electron-demand variants.[16](https://pubs.rsc.org/en/content/articlehtml/2025/ra/d4ra07989b)\n\n## Limitations and alternatives\n\n**Reactivity is the main constraint.** Unactivated α,β-unsaturated carbonyl 1-oxa-1,3-butadienes have low HDA reactivity and require high temperature or high pressure; even with enol ether dienophiles, high temperature is needed and diastereoselectivity remains low.[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) Electron-withdrawing groups at the 3-position lower the diene LUMO and enhance reactivity, with cyano and trifluoromethyl groups having the highest influence.[7](https://link.springer.com/article/10.1007/s41061-016-0026-2) On the imine side, simple 1-azadienes suffer from competitive self-condensation, dimerization, imine addition, and imine tautomerization.[9](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380) Endo/exo and facial selectivity can flip with the catalyst, solvent, or stoichiometry, so conditions must be optimized per substrate.[4](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k)\n\n Within the HDA family itself, the practical alternatives are process-based: solid-phase, catalytic, aqueous, and microwave-assisted protocols.[14](https://www.eurekaselect.com/article/83512)\n\n## References\n\n1. [The Asymmetric Hetero-Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds (Angew. Chem. Int. Ed., 2014)](https://onlinelibrary.wiley.com/doi/10.1002/anie.201404094)\n2. [Enzyme-catalyzed Hetero-Diels-Alder reactions (Synthetic Biology Journal, 2024)](https://synbioj.cip.com.cn/EN/10.12211/2096-8280.2023-015)\n3. [Recent Contributions to Hetero Diels-Alder Reactions (Current Organic Chemistry, 2016)](https://www.benthamdirect.com/content/journals/coc/10.2174/1385272820666160216000401)\n4. [Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products (Heravi et al., RSC Advances 2015)](https://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra17488k)\n5. [Organocatalytic Strategies for the Development of the Enantioselective Inverse-electron-demand Hetero-Diels-Alder Reaction (Chem. Eur. J., 2021)](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202101696)\n6. [Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes (Beilstein J. Org. Chem., 2016)](https://beilstein-journals.org/bjoc/content/pdf/1860-5397-12-184.pdf)\n7. [Recent Advances in Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes (Topics in Current Chemistry, 2016)](https://link.springer.com/article/10.1007/s41061-016-0026-2)\n8. [An enzymatic dual-oxa Diels–Alder reaction constructs the oxygen-bridged tricyclic acetal unit of (–)-anthrabenzoxocinone (Nature Chemistry, 2025)](https://www.nature.com/articles/s41557-025-01804-0)\n9. [Tetrahedron report number 575: Recent developments in imino Diels–Alder reactions (Tetrahedron)](https://www.sciencedirect.com/science/article/abs/pii/S0040402001004380)\n10. [Qingzhi Gao and colleagues (1992). Asymmetric hetero Diels-Alder reaction catalyzed by stable and easily prepared chiral (acyloxy)borane (CAB) catalysts. The Journal of Organic Chemistry.](https://doi.org/10.1021/jo00033a005)\n11. [Catalytic, Enantioselective Hetero-Diels-Alder Reactions of Aldehydes (literature review, U. Illinois Chem 535, 2006)](https://chemistry.illinois.edu/system/files/inline-files/05CovellChem535Abstract.pdf)\n12. [Enantioselective (Formal) Aza-Diels-Alder Reactions with Non-Danishefsky-Type Dienes (primary research paper)](https://pmc.ncbi.nlm.nih.gov/articles/PMC2918383/)\n13. [Iron(III)-catalyzed asymmetric inverse-electron-demand hetero-Diels–Alder reaction of dioxopyrrolidines with simple olefins (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10966964/)\n14. [Hetero-Diels-Alder Reactions in the Synthesis of Biologically Active Nitrogen Compounds: A Review](https://www.eurekaselect.com/article/83512)\n15. [Otto Diels, Kurt Alder (1928). Synthesen in der hydroaromatischen Reihe. Justus Liebig s Annalen der Chemie.](https://doi.org/10.1002/jlac.19284600106)\n16. [Recent advancements in the chemistry of Diels–Alder reaction for total synthesis of natural products: a comprehensive review (2020–2023) (RSC Advances, 2025)](https://pubs.rsc.org/en/content/articlehtml/2025/ra/d4ra07989b)\n17. [Lutz F. Tietze, Georg Kettschau (1997). Hetero Diels-Alder reactions in organic chemistry. Topics in current chemistry.](https://doi.org/10.1007/bfb0119240)\n18. [On the lewis acid catalyzed cyclocondensation of imines with a siloxydiene (Tetrahedron Letters, 1982)](https://doi.org/10.1016/s0040-4039%2800%2987694-7)\n19. [Scott D. Larsen, Paul A. Grieco (1985). Aza Diels-Alder reactions in aqueous solution: cyclocondensation of dienes with simple iminium salts generated under Mannich conditions. Journal of the American Chemical Society.](https://doi.org/10.1021/ja00292a057)\n20. [Herbert Waldmann (1994). Asymmetric Hetero Diels-Alder Reactions. Synthesis.](https://doi.org/10.1055/s-1994-25519)\n21. [Mogens Johannsen, Sulan Yao (1997). 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Asian Journal of Organic Chemistry.](https://doi.org/10.1002/ajoc.202400118)\n\n---\n*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Chemical principles and methods › Chemical synthesis › Named synthetic methods › Titles 2 to He*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026; Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/hetero-diels-alder-reaction", "markdown_url": "https://www.edgepedia.org/hetero-diels-alder-reaction.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Hetero-Diels–Alder reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/hetero-diels-alder-reaction. Edgepedia Community License 1.0.", "credit_md": "\"[Hetero-Diels–Alder reaction](https://www.edgepedia.org/hetero-diels-alder-reaction)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/hetero-diels-alder-reaction](https://www.edgepedia.org/hetero-diels-alder-reaction). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Hetero-Diels–Alder reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/hetero-diels-alder-reaction. Edgepedia Community License 1.0.", "speakable": "The hetero-Diels–Alder reaction is a cycloaddition extending the all-carbon Diels–Alder reaction, in which a diene reacts with a heteroatom-containing dienophile to build six-membered heterocycles used in pharmaceutical synthesis." }