Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Organic Synthesis
  4. Volume 22, Issue 1
  5. Article
Volume 22, Issue 1
  • ISSN: 1570-1794
  • E-ISSN: 1875-6271

Abstract

The [4+2] Diels-Alder cycloaddition has been widely used for the synthesis of six-member scaffolds. In recent years, there have been significant developments in this area, including the discovery and design of novel dienes and dienophiles with improved reactivity and selectivity. These new building blocks can be used to develop diverse molecular structures with functional group compatibility. Additionally, there is the use of catalytic systems and metal-mediated reactions to enable asymmetric [4+2] cycloadditions, resulting in enantiomerically enriched products. Overall, recent studies related to [4+2] Diels-Alder cycloaddition using numerous dienes, dienophiles, and catalysts in different reaction conditions have significantly improved the efficiency, selectivity, and versatility of the reaction, making it an increasingly important tool in the synthesis of complex organic molecules as presented in this review. These advancements offer exciting possibilities for the development of new methods and reagents for the construction of six-membered rings and the synthesis of bioactive compounds.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cos/10.2174/0115701794262102231214074336
2024-01-15
2025-06-20

  • From This Site

    /content/journals/cos/10.2174/0115701794262102231214074336
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. PhillipsA.M.F. Synthetic Approaches to Nonaromatic Nitrogen Heterocycles, 2 Volume Set.John Wiley & Sons202010.1002/9781119708841
     [Google Scholar]
  2. KobayashiS. JørgensenK.A. Cycloaddition reactions in organic synthesis.John Wiley & Sons2002
     [Google Scholar]
  3. AlcaideB. AlmendrosP. Novel cyclization reactions of aminoallenes.Adv. Synth. Catal.201135314-152561257610.1002/adsc.201100160
     [Google Scholar]
  4. HarveyD.F. SiganoD.M. Carbene− alkyne− alkene cyclization reactions.Chem. Rev.199696127128810.1021/cr950010w 11848753
     [Google Scholar]
  5. ZhangM. ZhongZ. LiaoL. ZhangA.Q. Application of a transient directing strategy in cyclization reactions via C–H activation.Org. Chem. Front.20229143882389610.1039/D2QO00765G
     [Google Scholar]
  6. ZhangT. ZhangY. DasS. Deal;Photoredox catalysis for the cycloaddition reactions.ChemCatChem202012246173618510.1002/cctc.202001195
     [Google Scholar]
  7. MinL. HuY.J. FanJ.H. ZhangW. LiC.C. Synthetic applications of type II intramolecular cycloadditions.Chem. Soc. Rev.202049197015704310.1039/D0CS00365D 32869796
     [Google Scholar]
  8. MajiB. Stereoselective haliranium, thiiranium and seleniranium ion‐triggered friedel–crafts‐type alkylations for polyene cyclizations.Adv. Synth. Catal.2019361153453348910.1002/adsc.201900028
     [Google Scholar]
  9. DuretG. Le FoulerV. BisseretP. BizetV. BlanchardN. Diels–Alder and formal Diels–Alder cycloaddition reactions of ynamines and ynamides.Eur. J. Org. Chem.20172017466816683010.1002/ejoc.201700986
     [Google Scholar]
  10. KalníkM. GabkoP. BellaM. KoóšM. The bucherer–bergs multicomponent synthesis of hydantoins—excellence in simplicity.Molecules20212613402410.3390/molecules26134024 34209381
     [Google Scholar]
  11. FrontierA.J. HernandezJ.J. New twists in Nazarov cyclization chemistry.Acc. Chem. Res.20205391822183210.1021/acs.accounts.0c00284 32790284
     [Google Scholar]
  12. PulkaK. Pictet-Spengler reactions for the synthesis of pharmaceutically relevant heterocycles.Curr. Opin. Drug Discov. Devel.2010136669684 21061230
     [Google Scholar]
  13. HeraviM.M. RohaniS. ZadsirjanV. ZahediN. Fischer indole synthesis applied to the total synthesis of natural products.RSC Advances2017783528525288710.1039/C7RA10716A
     [Google Scholar]
  14. DielsO. AlderK. Synthesen in der hydroaromatischen Reihe.Justus Liebigs Ann. Chem.192846019812210.1002/jlac.19284600106
     [Google Scholar]
  15. SauerJ. SustmannR. Mechanistic aspects of Diels‐Alder reactions: A critical survey.Angew. Chem. Int. Ed. Engl.1980191077980710.1002/anie.198007791
     [Google Scholar]
  16. ChauhanA.N.S. MaliG. ErandeR.D. Regioselectivity switch towards the development of innovative diels‐alder cycloaddition and productive applications in organic synthesis.Asian J. Org. Chem.2022114e20210079310.1002/ajoc.202100793
     [Google Scholar]
  17. HoukK.N. LiuF. YangZ. SeemanJ.I. Evolution of the diels–alder reaction mechanism since the 1930s: Woodward, houk with woodward, and the influence of computational chemistry on understanding cycloadditions.Angew. Chem. Int. Ed.20216023126601268110.1002/anie.202001654 32662195
     [Google Scholar]
  18. WessigP. MüllerG. The dehydro-diels-alder reaction.Chem. Rev.200810862051206310.1021/cr0783986 18479169
     [Google Scholar]
  19. FernándezI. BickelhauptF.M. Deeper insight into the Diels–Alder reaction through the activation strain model.Chem. Asian J.201611233297330410.1002/asia.201601203 27863108
     [Google Scholar]
  20. NicolaouK.C. SnyderS.A. MontagnonT. VassilikogiannakisG. The Diels--Alder reaction in total synthesis.Angew. Chem. Int. Ed.200241101668169810.1002/1521‑3773(20020517)41:10<1668:AID‑ANIE1668>3.0.CO;2‑Z 19750686
     [Google Scholar]
  21. OliveiraB.L. GuoZ. BernardesG.J.L. Inverse electron demand Diels–Alder reactions in chemical biology.Chem. Soc. Rev.201746164895495010.1039/C7CS00184C 28660957
     [Google Scholar]
  22. HeraviM.M. AhmadiT. GhavidelM. HeidariB. HamidiH. Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products.RSC Advances2015512310199910207510.1039/C5RA17488K
     [Google Scholar]
  23. FringuelliF. PiermattiO. PizzoF. VaccaroL. Recent advances in lewis acid catalyzed diels−alder reactions in aqueous media.Eur. J. Org. Chem.20012001343945510.1002/1099‑0690(200102)2001:3<439:AID‑EJOC439>3.0.CO;2‑B
     [Google Scholar]
  24. ReymondS. CossyJ. Copper-catalyzed diels-alder reactions.Chem. Rev.2008108125359540610.1021/cr078346g 18942879
     [Google Scholar]
  25. HeraviM.M. VavsariV.F. Recent applications of intramolecular Diels–Alder reaction in total synthesis of natural products.RSC Advances2015563508905091210.1039/C5RA08306K
     [Google Scholar]
  26. MassonG. LalliC. BenohoudM. DagoussetG. Catalytic enantioselective [4 + 2]-cycloaddition: A strategy to access aza-hexacycles.Chem. Soc. Rev.201342390292310.1039/C2CS35370A 23172010
     [Google Scholar]
  27. JasińskiR. On the question of stepwise [4+ 2] cycloaddition reactions and their stereochemical aspects.Symmetry20211310191110.3390/sym13101911
     [Google Scholar]
  28. LichmanB.R. O’ConnorS.E. KriesH. Biocatalytic strategies towards [4+ 2] cycloadditions.Chemistry201925286864687710.1002/chem.201805412 30664302
     [Google Scholar]
  29. YamamotoK. NagaeH. TsurugiH. MashimaK. Mechanistic understanding of alkyne cyclotrimerization on mononuclear and dinuclear scaffolds: [4 + 2] cycloaddition of the third alkyne onto metallacyclopentadienes and dimetallacyclopentadienes.Dalton Trans.20164543170721708110.1039/C6DT03389J 27730228
     [Google Scholar]
  30. MoschonaF. SavvopoulouI. TsitopoulouM. TatarakiD. RassiasG. Epoxide syntheses and ring-opening reactions in drug development.Catalysts20201010111710.3390/catal10101117
     [Google Scholar]
  31. GawrońskiJ. Asymmetric syntheses and transformations--tools for chirality multiplication in drug synthesis.Acta Pol. Pharm.2006635333351 17357583
     [Google Scholar]
  32. JuhlM. TannerD. Recent applications of intramolecular Diels–Alder reactions to natural product synthesis.Chem. Soc. Rev.200938112983299210.1039/b816703f 19847335
     [Google Scholar]
  33. RammohanA. KrinochkinA.P. KhasanovA.F. KopchukD.S. ZyryanovG.V. Sustainable solvent-free diels–alder approaches in the development of constructive heterocycles and functionalized materials: A review.Top. Curr. Chem.202238054310.1007/s41061‑022‑00398‑2 35951264
     [Google Scholar]
  34. SoaresM.I.L. CardosoA.L. Pinho e MeloT.M.V.D. Diels–Alder cycloaddition reactions in sustainable media.Molecules2022274130410.3390/molecules27041304 35209094
     [Google Scholar]
  35. YangB. GaoS. Recent advances in the application of Diels–Alder reactions involving o -quinodimethanes, aza- o -quinone methides and o -quinone methides in natural product total synthesis.Chem. Soc. Rev.201847217926795310.1039/C8CS00274F 29993045
     [Google Scholar]
  36. LiJ. YuB. LuZ. Chiral imidazoline ligands and their applications in METAL‐CATALYZED asymmetric synthesis†.Chin. J. Chem.202139248851410.1002/cjoc.202000486
     [Google Scholar]
  37. LiM. Iron (III) catalyzed asymmetric Diels-Alder reaction-Iron (II) catalyzed thia-Michael addition and aldehyde allylation reactions.Université Laval2019
     [Google Scholar]
  38. ZhangY. WeiY. ShiM. A silver-catalyzed domino inverse electron-demand oxo-Diels–Alder reaction of 3-cyclopropylideneprop-2-en-1-ones with 2,3-dioxopyrrolidines via cyclobutane-fused furan.Chem. Commun.202157293599360210.1039/D1CC00707F 33710234
     [Google Scholar]
  39. YangY. ZhangX. ZhongL.P. LanJ. LiX. LiC.C. ChungL.W. Unusual KIE and dynamics effects in the Fe-catalyzed hetero-Diels-Alder reaction of unactivated aldehydes and dienes.Nat. Commun.2020111185010.1038/s41467‑020‑15599‑w 32296076
     [Google Scholar]
  40. BeeckS. WegnerH.A. Mechanistic studies on the bidentate lewis acid catalyzed domino inverse electron‐demand diels‐alder/thiol transfer reaction.Eur. J. Org. Chem.2023268e20220128910.1002/ejoc.202201289
     [Google Scholar]
  41. LuoN. WangS. ZhangY. XinJ. WangC. DBU-promoted cascade selective nucleophilic addition/C–C bond cleavage/hetero-diels–alder reactions of 2-amino-4 h -chromen-4-ones with β-nitrostyrenes and/or aryl aldehydes: Access to 5 H -Chromeno[2,3- b]pyridin-5-ones.J. Org. Chem.20208521142191422810.1021/acs.joc.0c01993 33118353
     [Google Scholar]
  42. LiX. KongX. YangS. MengM. ZhanX. ZengM. FangX. Bifunctional thiourea-catalyzed asymmetric inverse-electron-demand diels–alder reaction of allyl ketones and vinyl 1,2-diketones via dienolate intermediate.Org. Lett.20192171979198310.1021/acs.orglett.9b00035 30865466
     [Google Scholar]
  43. QinJ. ZhangY. LiuC. ZhouJ. ZhanR. ChenW. HuangH. Asymmetric inverse-electron-demand Diels–Alder reaction of β, γ-unsaturated amides through dienolate catalysis.Org. Lett.201921187337734110.1021/acs.orglett.9b02629 31465234
     [Google Scholar]
  44. ChithannaS. YangD.Y. Intramolecular diels–alder cycloaddition of furan-derived β-enamino diketones: An entry to diastereoselective synthesis of polycyclic pyrano[3,2- c]quinolin-5-one Derivatives.J. Org. Chem.20228785178518710.1021/acs.joc.1c03163 35380043
     [Google Scholar]
  45. ShenL.W. ZhangY.P. YouY. ZhaoJ.Q. WangZ.H. YuanW.C. Inverse electron-demand aza-Diels–Alder reaction of α, β-unsaturated thioesters with in situ-generated 1, 2-diaza-1, 3-dienes for the synthesis of 1, 3, 4-thiadiazines.J. Org. Chem.20228764232424010.1021/acs.joc.1c03072 35212520
     [Google Scholar]
  46. WangZ. YamazakiS. MikataY. ObaM. TakashimaH. MorimotoT. OgawaA. Intramolecular diels–alder reactions of α-bromostyrene-functionalized unsaturated carboxamides.J. Org. Chem.20228716111481116410.1021/acs.joc.2c01417 35944162
     [Google Scholar]
  47. YuanC. WangJ. WangG. SunS. WangJ. Assembly of dihydropyridazines via [4+2] cycloaddition of in situ generated azoalkenes.Asian J. Org. Chem.2023122e20220067110.1002/ajoc.202200671
     [Google Scholar]
  48. PanL.N. WangQ. SunJ. YanC-G. Intramolecular diels‐alder reaction of styrene with phenoxy‐acrylate for construction of functionalized naphthalenes.Asian J. Org. Chem.202110102591259510.1002/ajoc.202100401
     [Google Scholar]
  49. MiaoY.H. HuaY.Z. GaoH.J. MoN.N. WangM.C. MeiG.J. Catalytic asymmetric inverse-electron-demand aza-Diels–Alder reaction of 1,3-diazadienes with 3-vinylindoles.Chem. Commun.202258547515751810.1039/D2CC02458F 35687078
     [Google Scholar]
  50. KoayW.L. MeiG.J. LuY. Facile access to benzofuran-fused tetrahydropyridines via catalytic asymmetric [4 + 2] cycloaddition of aurone-derived 1-azadienes with 3-vinylindoles.Org. Chem. Front.20218596897410.1039/D0QO01236J
     [Google Scholar]
  51. KikuchiJ. YeH. TeradaM. Chiral phosphoric acid catalyzed enantioselective [4+ 2] cycloaddition reaction of α-fluorostyrenes with imines.Org. Lett.202022228957896110.1021/acs.orglett.0c03360 33136411
     [Google Scholar]
  52. SiX.G. ZhangZ.M. ZhengC.G. LiZ.T. CaiQ. Enantioselective synthesis of cis ‐decalin derivatives by the inverse‐electron‐demand diels–alder reaction of 2‐pyrones.Angew. Chem. Int. Ed.20205942184121841710.1002/anie.202006841 32662155
     [Google Scholar]
  53. VarletT. GelisC. RetailleauP. BernadatG. NeuvilleL. MassonG. Enantioselective redox‐divergent chiral phosphoric acid catalyzed quinone Diels–Alder reactions.Angew. Chem. Int. Ed.202059228491849610.1002/anie.202000838 32112662
     [Google Scholar]
  54. ZhuX.Q. WangQ. ZhuJ. Organocatalytic enantioselective diels–alder reaction of 2‐trifluoroacetamido‐1,3‐dienes with α,β‐unsaturated ketones.Angew. Chem. Int. Ed.2023621e20221492510.1002/anie.202214925 36347807
     [Google Scholar]
  55. MendozaS.D. RombolaM. TaoY. ZuendS.J. GötzR. McLaughlinM.J. ReismanS.E. Expanding the chiral monoterpene pool: Enantioselective diels–alder reactions of α-acyloxy enones.Org. Lett.202224213802380610.1021/acs.orglett.2c01343 35594569
     [Google Scholar]
  56. NgamnithipornA. ChuentragoolP. PloypradithP. RuchirawatS. Syntheses of 3-aryl tetrahydroisoquinolines via an intermolecular [4 + 2] cycloaddition of sultines with imines.Org. Lett.202224234192419610.1021/acs.orglett.2c01437 35639829
     [Google Scholar]
  57. YangX.X. ZhaoX-L. OuyangQ. DuW. ChenY-C. Palladium-catalysed diastereodivergent inverse-electron-demand oxa-Diels–Alder reactions of in situ formed cyclopentadienones via ligand-control.Org. Chem. Front.2022951364136910.1039/D1QO01876K
     [Google Scholar]
  58. ShcherbakovN.V. Dar’inD.V. KukushkinV.Y. DubovtsevA.Y. Hetero-tetradehydro-diels–alder cycloaddition of enynamides and cyanamides: Gold-catalyzed generation of diversely substituted 2,6-diaminopyridines.J. Org. Chem.202186107218722810.1021/acs.joc.1c00558 33961747
     [Google Scholar]
  59. StefaniakM. BudaS. MlynarskiJ. Asymmetric hetero‐diels‐alder reaction of trans ‐1‐methoxy‐3‐trimethylsilyloxy‐buta‐1,3‐diene catalyzed by zinc complexes.Eur. J. Org. Chem.20202020335388539310.1002/ejoc.202000822
     [Google Scholar]
  60. XuW.L. HuW. ZhaoW.M. WangM. ChenJ. ZhouL. Copper(I)/DDQ-mediated double-dehydrogenative diels–alder reaction of aryl butenes with 1,4-diketones and indolones.Org. Lett.202022187169717410.1021/acs.orglett.0c02486 32902298
     [Google Scholar]
  61. GiofrèS. KellerM. Lo PrestiL. BeccalliE.M. MolteniL. Switchable oxidative reactions of N -allyl-2-Aminophenols: Palladium-catalyzed alkoxyacyloxylation vs an intramolecular diels–alder reaction.Org. Lett.202123207698770210.1021/acs.orglett.1c02539 34570517
     [Google Scholar]
  62. YesilcimenA. JiangN.C. GottliebF.H. WasaM. Enantioselective organocopper-catalyzed hetero diels–alder reaction through in situ oxidation of ethers into enol ethers.J. Am. Chem. Soc.2022144146173617910.1021/jacs.2c01656 35380438
     [Google Scholar]
  63. MasudaK. AgalaveS.G. ChenW. OnozawaS. ShimadaS. SatoK. KobayashiS. Continuous‐flow diels‐alder reactions of unactivated dienes over zeolitic catalysts.Asian J. Org. Chem.2023121e20220038210.1002/ajoc.202200382
     [Google Scholar]
  64. KamoS. KurosawaH. MatsuzawaA. SugitaK. Total synthesis of (−)-Lamellodysidine a via an intramolecular diels–alder reaction.Org. Lett.202224392192310.1021/acs.orglett.1c04289 35019657
     [Google Scholar]
  65. MarzabadiC.H. KeltyS.P. AltamuraA. Inverse-electron demand Diels Alder Reactions between glycals and tetrazines.Carbohydr. Res.202251910862310.1016/j.carres.2022.108623 35738050
     [Google Scholar]
  66. MerkulovaE.A. KolobovA.V. LyssenkoK.A. NenajdenkoV.G. Diene-transmissive hetero-Diels–Alder reaction of distyryl thioketone.Mendeleev Commun.202232338438510.1016/j.mencom.2022.05.031
     [Google Scholar]
  67. NoualiF. SousaJ.L.C. AlbuquerqueH.M.T. MendesR.F. PazF.A.A. SaherL. KibouZ. Choukchou-BrahamN. TalhiO. SilvaA.M.S. Microwave-assisted synthesis of 4,6-disubstituted isoindoline-1,3-diones by Diels-Alder reactions.J. Mol. Struct.2023127513460810.1016/j.molstruc.2022.134608
     [Google Scholar]
  68. SchwingerD.P. PeschelM.T. JaschkeC. JandlC. de Vivie-RiedleR. BachT. Diels–alder reaction of photochemically generated (E)-Cyclohept-2-enones: Diene scope, reaction pathway, and synthetic application.J. Org. Chem.20228774838485110.1021/acs.joc.2c00186 35315664
     [Google Scholar]
  69. XieF. LiX. XuL. MaJ. SunL. ZhangB. LinB. ChengM. LiuY. Diels‐alder cycloaddition of azepino[4,5‐ b]indoles towards hydrocarbazole derivatives and related heterocycles.Adv. Synth. Catal.2022364487388910.1002/adsc.202101401
     [Google Scholar]
  70. JessenB.M. TaarningE. MadsenR. Synthesis, stability, and diels‐alder reactions of methyl 2‐oxobut‐3‐enoate.Eur. J. Org. Chem.20212021294049405310.1002/ejoc.202100370
     [Google Scholar]
  71. de la Rosa-BarralesA. Alvano Pérez-BautistaJ. Cruz-GregorioS. Luisa Meza-LeónR. QuinteroL. Cortezano-ArellanoO. Sartillo-PiscilF. Chiron approach and the [4 + 2] Diels-Alder cycloaddition of 2-pyrones for the synthesis of cis-(-)-aminoindan-2-ol.Results in Chemistry2021310017410.1016/j.rechem.2021.100174
     [Google Scholar]
  72. CraigD. SpreadburyS.R.J. WhiteA.J.P. Synthesis and hetero-Diels–Alder reactions of enantiomerically pure dihydro-1 H -azepines.Chem. Commun.202056689803980610.1039/D0CC04413J 32705107
     [Google Scholar]
  73. ManikandanP. KarunakaranJ. VarathanE. SchreckenbachG. MohanakrishnanA.K. Diels–Alder reaction of tetraarylcyclopentadienones with benzo[ b]thiophene S, S -dioxides: An unprecedented de-oxygenation vs. sulfur dioxide extrusion.Chem. Commun. 20205697153171532010.1039/D0CC05842D 33179634
     [Google Scholar]
  74. SinghV. VermaR.S. KhatanaA.K. TiwariB. Construction of phenanthrenes and chrysenes from β-bromovinylarenes via aryne diels–alder reaction/aromatization.J. Org. Chem.20198421141611416710.1021/acs.joc.9b01644 31552743
     [Google Scholar]
  75. LvW.X. LiZ. LinE. LiJ.L. TanD.H. CaiY.H. LiQ. WangH. Regio‐ and diastereoselective synthesis of cyclohexadienylborons via an intermolecular diels–alder reaction of alkenyl MIDA boronates with 2‐pyrones.Chemistry201925164058406110.1002/chem.201900011 30697832
     [Google Scholar]
/content/journals/cos/10.2174/0115701794262102231214074336
Loading
A Brief Review on Recent Developments in Diels-alder Reactions
Curr. Org. Synth. 22, 2 (2025); https://doi.org/10.2174/0115701794262102231214074336
/content/journals/cos/10.2174/0115701794262102231214074336
/content/journals/cos/10.2174/0115701794262102231214074336
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): [4+2] Diels-Alder cycloaddition; asymmetric synthesis; catalytic systems; diene; dienophile; intramolecular cycloaddition

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test