Danishefsky’s Diene vs Rawal’s Diene in [4+2] Hetero-Diels-Alder Reactions with Aldehydes

Authors

  • Oleksii I. Shamrai Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd, Ukraine
  • Evgenij V. Zarudnitskii Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Ukraine https://orcid.org/0000-0003-2038-4243

DOI:

https://doi.org/10.24959/ophcj.25.324470

Keywords:

Danishefsky’s diene, Rawal’s diene, Diels-Alder reaction, aldehyde, pyran

Abstract

The Diels-Alder reaction remains one of the most versatile and widely employed cycloaddition strategies in synthetic organic chemistry. The development of functionalized dienes, particularly Danishefsky’s diene (DD) and Rawal’s diene (RD), has significantly expanded the synthetic potential of this reaction. A comparative analysis of these two dienes has been performed in this study; in particular their reactivity with aldehyde dienophiles, leading to pyran derivatives – key intermediates in the pharmaceutical synthesis, has been analyzed. The reactivity, scope, and reaction conditions for both dienes have been assessed. Although DD is well studied and widely used in synthetic protocols, RD exhibits higher reactivity, especially under mild thermal conditions, eliminating the need for the Lewis acid catalysis. Experimental results for eight aldehyde substrates have revealed key differences in their efficiency and scalability. The data obtained emphasize the complementary nature of DD and RD in synthetic applications, providing valuable recommendations for optimizing diene selection in complex organic transformations.

Supporting Agency

  • The author received no specific funding for this work.

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References

  1. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe. Justus Liebigs Annalen der Chemie 1928, 460 (1), 98 – 122. https://doi.org/10.1002/jlac.19284600106.
  2. Oppolzer, W. In Comprehensive Organic Synthesis; Pergamon Press: New York, 1991; Vol. 5.
  3. Rana, A.; Mishra, A.; Awasthi, S. K. Recent advancements in the chemistry of Diels–Alder reaction for total synthesis of natural products: a comprehensive review (2020–2023). RSC Adv. 2025, 15 (6), 4496 – 4525. https://doi.org/10.1039/D4RA07989B.
    | |
  4. Li, J. J., Diels–Alder Reaction. In Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications, Springer International Publishing: Cham, 2021; pp 166 – 175. https://doi.org/10.1007/978-3-030-50865-4_45.
  5. Boger, D. L. Diels-Alder reactions of heterocyclic aza dienes. Scope and applications. Chem. Rev. 1986, 86 (5), 781 – 793. https://doi.org/10.1021/cr00075a004.
    |
  6. Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley: New York, 1990.
  7. Petrzilka, M.; Grayson, J. I. Preparation and Diels-Alder Reactions of Hetero-Substituted 1,3-Dienes. Synthesis 1981, 1981 (10), 753 – 786. https://doi.org/10.1055/s-1981-29592.
    |
  8. Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry; Verlag Chemie: Weinheim, 1970
  9. Herndon, W. C. Theory of cycloaddition reactions. Chem. Rev. 1972, 72 (2), 157 – 179. https://doi.org/10.1021/cr60276a003.
    |
  10. Johnson, J. R.; Jobling, W. H.; Bodamer, G. W. Studies of 1,3-Dienes. The Mercuration of 1,3-Butadiene and Synthesis of 2,3-Dialkoxy-1,3-butadienes. J. Am. Chem. Soc. 1941, 63 (1), 131 – 135. https://doi.org/10.1021/ja01846a031.
  11. Fiesselmann, H. Diensynthesen mit Oxyprenen, I. Mitteil.: Über 4-Methoxy-, 4-Äthoxy- und 4-Methoxy-1-methyl-Δ3-tetrahydrobenzaldehyd. Berichte der deutschen chemischen Gesellschaft (A and B Series) 1942, 75 (7), 881 – 891. https://doi.org/10.1002/cber.19420750720.
  12. Flaig, W. Einige neue Umwandlungen des Crotonaldehyds. Justus Liebigs Annalen der Chemie 1950, 568 (1), 1 – 33. https://doi.org/10.1002/jlac.19505680102.
  13. McElvain, S. M.; Morris, L. R. Ketene Acetals. XXVIII. The Dehalogenation of α,α-Dibromoacetals. Isopropenylketene Diethylacetal. J. Am. Chem. Soc. 1952, 74 (10), 2657 – 2662. https://doi.org/10.1021/ja01130a056.
  14. Shavrygina, O. A.; Makin, S. M. Khim. Farm. Zh. 1969, 3, 17.
  15. Danishefsky, S.; Kitahara, T. Useful diene for the Diels-Alder reaction. J. Am. Chem. Soc. 1974, 96 (25), 7807 – 7808. https://doi.org/10.1021/ja00832a031.
    |
  16. Jung, M. E.; McCombs, C. A. 2-Trimethylsilyloxy-1,3-butadiene, a new reactive diene. Preparation and reactions. Tetrahedron Lett. 1976, 17 (34), 2935 – 2938. https://doi.org/10.1016/S0040-4039(01)85493-9.
    |
  17. Danishefsky, S.; Singh, R. K.; Gammill, R. B. Diels-Alder reactions of 1,1-dimethoxy-3-trimethylsilyloxy-1,3-butadiene. J. Org. Chem. 1978, 43 (2), 379 – 380. https://doi.org/10.1021/jo00396a060.
    |
  18. Taheri kal Koshvandi, A.; Heravi, M. M. Applications of Danishefsky’s dienes in asymmetric Oxo-Diels-Alder reactions. Tetrahedron: Asymmetry 2017, 28 (11), 1506 – 1556. https://doi.org/10.1016/j.tetasy.2017.10.030.
    |
  19. Kal-Koshvandi, A. T.; Heravi, M. M. Applications of Dainshefsky’s Dienes in the Asymmetric synthesis of Aza-Diels-Alder Reaction. The Chemical Record 2019, 19 (2 – 3), 550 – 600. https://doi.org/10.1002/tcr.201800066.
    | |
  20. Langenbeck, W.; Gödde, O.; Weschky, L.; Schaller, R. Über Diënsynthesen mit Derivaten des 1-Amino-butadiens-(1.3). Berichte der deutschen chemischen Gesellschaft (A and B Series) 1942, 75 (3), 232 – 236. https://doi.org/10.1002/cber.19420750305.
  21. Overman, L. E.; Jessup, P. J. Synthetic applications of N-acylamino-1,3-dienes. An efficient stereospecific total synthesis of dl-pumiliotoxin C, and a general entry to cis-decahydroquinoline alkaloids. J. Am. Chem. Soc. 1978, 100 (16), 5179 – 5185. https://doi.org/10.1021/ja00484a046.
    |
  22. Krohn, K. Chiral 2-Amino-1, 3-butadienes: New Reagents for Asymmetric Cycloadditions. Angew. Chem., Int. Ed. Engl. 1993, 32 (11), 1582 – 1584. https://doi.org/10.1002/anie.199315821.
    |
  23. Enders, D.; Meyer, O.; Raabe, G. Diastereo- and Enantioselective Synthesis of 4-Nitrocyclohexanones by [4+2] Cycloaddition of a Chiral 2-Aminobutadiene to Nitroalkenes. Synthesis 1992, 1992 (12), 1242 – 1244. https://doi.org/10.1055/s-1992-26349.
    |
  24. Smith, A. B., III; Wexler, B. A.; Tu, C. Y.; Konopelski, J. P. Stereoelectronic effects in the cationic rearrangements of [4.3.2]propellanes. J. Am. Chem. Soc. 1985, 107 (5), 1308 – 1320. https://doi.org/10.1021/ja00291a034.
    |
  25. Ludwig, C.; Wistrand, L.-G. Regioselective Cycloadditions of 1-Acylamino Dienes. Synthesis of Hydrogenated Quinolines. Acta Chem. Scand. 1989, 43, 676. https://doi.org/10.3891/acta.chem.scand.43-0676.
  26. Kozmin, S. A.; Rawal, V. H. Preparation and Diels−Alder Reactivity of 1-Amino-3-siloxy-1,3-butadienes. J. Org. Chem. 1997, 62 (16), 5252 – 5253. https://doi.org/10.1021/jo970438q.
    |
  27. Kozmin, S. A.; Janey, J. M.; Rawal, V. H. 1-Amino-3-siloxy-1,3-butadienes: Highly Reactive Dienes for the Diels−Alder Reaction. J. Org. Chem. 1999, 64 (9), 3039 – 3052. https://doi.org/10.1021/jo981563k.
    | |
  28. Kozmin, S. A.; Green, M. T.; Rawal, V. H. On the Reactivity of 1-Amino-3-siloxy-1,3-dienes: Kinetics Investigation and Theoretical Interpretation. J. Org. Chem. 1999, 64 (21), 8045 – 8047. https://doi.org/10.1021/jo990923g.
    |
  29. Gagnon, A.; Danishefsky, S. J. Evaluation of Diene Hierarchies for Diels–Alder Reactions En Route to Xestocyclamine A: Elaboration of an Ansa Bridge by B-Alkyl Suzuki Macrocyclization. Angew. Chem. Int. Ed. 2002, 41 (9), 1581 – 1584. https://doi.org/10.1002/1521-3773(20020503)41:9%3C1581::AID-ANIE1581%3E3.0.CO;2-F.
    | |
  30. Anderson, K. R.; Atkinson, S. L. G.; Fujiwara, T.; Giles, M. E.; Matsumoto, T.; Merifield, E.; Singleton, J. T.; Saito, T.; Sotoguchi, T.; Tornos, J. A.; Way, E. L. Routes for the Synthesis of (2S)-2-Methyltetrahydropyran-4-one from Simple Optically Pure Building Blocks. Org. Process Res. Dev. 2010, 14 (1), 58 – 71. https://doi.org/10.1021/op900163a.
    |
  31. Young, I. S.; Haley, M. W.; Tam, A.; Tymonko, S. A.; Xu, Z.; Hanson, R. L.; Goswami, A. A Scalable Synthesis of (R,R)-2,6-Dimethyldihydro-2H-pyran-4(3H)-one. Org. Process Res. Dev. 2015, 19 (10), 1360 – 1368. https://doi.org/10.1021/op500135x.
    |
  32. Burns, M.; Bi, W.; Kim, H.; Lall, M. S.; Li, C.; O’Neill, B. T. Ketoreductase/Transaminase, One-Pot, Multikilogram Biocatalytic Cascade Reaction. Org. Process Res. Dev. 2021, 25 (4), 941 – 946. https://doi.org/10.1021/acs.oprd.0c00557.
    |
  33. Danishefsky, S.; Kerwin, J. F., Jr. A simple synthesis of dl-chalcose. J. Org. Chem. 1982, 47 (8), 1597 – 1598. https://doi.org/10.1021/jo00347a053.
    |
  34. Shamrai, O.; Iermolenko, I.; Ostapchuk, E.; Leha, D.; Zarudnitskii, E.; Ryabukhin, S.; Volochnyuk, D. Shackles Off: A Kilo Scale Synthesis of Rawal’s Diene. ChemRxiv 2025. https://doi.org/10.26434/chemrxiv-2025-rzg0w.
    |
  35. Kuklish, S. L.; Antonysamy, S.; Bhattachar, S. N.; Chandrasekhar, S.; Fisher, M. J.; Fretland, A. J.; Gooding, K.; Harvey, A.; Hughes, N. E.; Luz, J. G.; Manninen, P. R.; McGee, J. E.; Navarro, A.; Norman, B. H.; Partridge, K. M.; Quimby, S. J.; Schiffler, M. A.; Sloan, A. V.; Warshawsky, A. M.; York, J. S.; Yu, X.-P. Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorg. Med. Chem. Lett. 2016, 26 (19), 4824 – 4828. https://doi.org/10.1016/j.bmcl.2016.08.023.
    | |
  36. Barcelos, R. C.; Pastre, J. C.; Caixeta, V.; Vendramini-Costa, D. B.; de Carvalho, J. E.; Pilli, R. A. Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells. Bioorg. Med. Chem. 2012, 20 (11), 3635 – 3651. https://doi.org/10.1016/j.bmc.2012.03.059.
    | |
  37. Edwards, H.J.; Goggins, S.; Frost, C.G. Trans-Selective Rhodium Catalysed Conjugate Addition of Organoboron Reagents to Dihydropyranones. Molecules 2015, 20, 6153 – 6166. https://doi.org/10.3390/molecules20046153.
    | |

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Published

2025-05-05

How to Cite

(1)
Shamrai, O. I.; Zarudnitskii, E. V. Danishefsky’s Diene Vs Rawal’s Diene in [4+2] Hetero-Diels-Alder Reactions With Aldehydes. J. Org. Pharm. Chem. 2025, 23, 22-29.

Issue

Vol. 23 No. 1 (2025)

Section

Original Researches

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