Article | Published:

Dearomative dihydroxylation with arenophiles

Nature Chemistry volume 8, pages 922928 (2016) | Download Citation

  • A Corrigendum to this article was published on 21 October 2016

This article has been updated

Abstract

Aromatic hydrocarbons are some of the most elementary feedstock chemicals, produced annually on a million metric ton scale, and are used in the production of polymers, paints, agrochemicals and pharmaceuticals. Dearomatization reactions convert simple, readily available arenes into more complex molecules with broader potential utility, however, despite substantial progress and achievements in this field, there are relatively few methods for the dearomatization of simple arenes that also selectively introduce functionality. Here we describe a new dearomatization process that involves visible-light activation of small heteroatom-containing organic molecules—arenophiles—that results in their para-cycloaddition with a variety of aromatic compounds. The approach uses N–N-arenophiles to enable dearomative dihydroxylation and diaminodihydroxylation of simple arenes. This strategy provides direct and selective access to highly functionalized cyclohexenes and cyclohexadienes and is orthogonal to existing chemical and biological dearomatization processes. Finally, we demonstrate the synthetic utility of this strategy with the concise synthesis of several biologically active compounds and natural products.

  • Compound

    4-(3,5-bis(trifluoromethyl)phenyl)-1,2,4-triazoline-3,5-dione

  • Compound

    4-methyl-1,2,4-triazoline-3,5-dione

  • Compound

    1,3,4-thiadiazole-2,5-dione

  • Compound

    1,2,4-triazoline-3,5-dione

  • Compound

    4-phenyl-1,2,4-triazoline-3,5-dione

  • Compound

    4,4-dimethyl-3H-pyrazole-3,5(4H)-dione

  • Compound

    benzene

  • Compound

    cumene

  • Compound

    benzyl acetate

  • Compound

    2-phenylpropan-2-yl acetate

  • Compound

    (dimethoxymethyl)benzene

  • Compound

    (1,1-dimethoxyethyl)benzene

  • Compound

    (1-chloro-2-methylpropan-2-yl)benzene

  • Compound

    benzyl chloride

  • Compound

    bromobenzene

  • Compound

    naphthalene

  • Compound

    1-bromonaphthalene

  • Compound

    2-bromonaphthalene

  • Compound

    1-chloronaphthalene

  • Compound

    tert-butyl (4-bromonaphthalen-1-yl)(methyl)carbamate

  • Compound

    1-(1,1-dimethoxyethyl)naphthalene

  • Compound

    1-phenylnaphthalene

  • Compound

    2-(naphthalen-2-yl)pyridine

  • Compound

    phenanthrene

  • Compound

    rac-(5R,8S,11S)-10,11-dihydroxy-2-methyl-5,8-dihydro-1H-5,8-ethano[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

  • Compound

    rac-(3aS,4R,10S)-2-butyl-7-methyl-3a,4,10,10a-tetrahydro-6H-4,10-etheno[1,3,2]dioxaborolo[4,5-d][1,2,4]triazolo[1,2-a]pyridazine-6,8(7H)-dione

  • Compound

    rac-(3aS,4R,10S)-2,2,7-trimethyl-3a,4,10,10a-tetrahydro-6H-4,10-etheno[1,3]dioxolo[4,5-d][1,2,4]triazolo[1,2-a]pyridazine-6,8(7H)-dione

  • Compound

    rac-(3aS,4R,10S)-11-(chloromethyl)-2,2,7-trimethyl-3a,4,10,10a-tetrahydro-6H-4,10-etheno[1,3]dioxolo[4,5-d][1,2,4]triazolo[1,2-a]pyridazine-6,8(7H)-dione

  • Compound

    rac-((3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxol-5-yl)methanol

  • Compound

    rac-2-((3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxol-5-yl)propan-2-ol

  • Compound

    rac-2-((3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxol-5-yl)ethan-1-ol

  • Compound

    rac-2-((3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxol-5-yl)-2-methylpropanoic acid

  • Compound

    rac-(3aR,7aS)-5-bromo-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxole

  • Compound

    rac-N,N'-((3aR,4S,7R,7aS)-5-(benzamidomethyl)-2,2-dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-4,7-diyl)dibenzamide

  • Compound

    rac-N,N'-((3aR,4R,7R,7aS)-5-bromo-2,2-dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-4,7-diyl)dibenzamide

  • Compound

    rac-(5S)-12,13-dihydroxy-2-methyl-5,10-dihydro-1H-5,10-ethano[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione

  • Compound

    rac-(1R,2S,3R,4S)-1,4-diacetamido-1,2,3,4-tetrahydronaphthalene-2,3-diyl diacetate

  • Compound

    rac-2,2,2-trichloroethyl (4S,7R,7aS)-2,2-dimethyl-3a,4,7,7a-tetrahydro-4,7-(epoxyimino)benzo[d][1,3]dioxole-8-carboxylate

  • Compound

    conduramine A

  • Compound

    rac-(3aS,4R,5R,7aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxole-4,5-diol

  • Compound

    MK7607

  • Compound

    rac-(3aS,4R,5S,7aR)-6-bromo-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxole-4,5-diol

  • Compound

    7-methyl-3-methyleneoct-6-en-1-yne

  • Compound

    3-O-desmethyl-phomentrioloxin

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Change history

  • 22 September 2016

    In the version of this Article originally published, in the Figure 2 caption, the HOMO–LUMO gap of the arene, rather than the arenophile, was described as the first requirement for arenophile reactivity. Furthermore, in the caption for Table 3, an oversight resulted in the inclusion of p-TsNH2 as the additive, however, the additive used in this reaction was citric acid (0.5 equiv.); and 2.0 equivalents of NMO were used. This has been corrected in the online versions of this Article.

References

  1. 1.

    & Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).

  2. 2.

    , & Transition-metal-mediated dearomatization reactions. Chem. Rev. 100, 2917–2940 (2000).

  3. 3.

    , , , & Nucleophilic dearomatizing (DNAr) reactions of aromatic C,H-systems. A mature paradigm in organic synthesis. Chem. Rev. 107, 1580–1691 (2007).

  4. 4.

    , & Hypervalent iodine-mediated phenol dearomatization in natural product synthesis. Tetrahedron 66, 2235–2261 (2010).

  5. 5.

    , & Catalytic asymmetric dearomatization reactions. Angew. Chem. Int. Ed. 51, 12662–12686 (2012).

  6. 6.

    & Convergent synthesis of (±)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (±)-morphine. J. Am. Chem. Soc. 114, 9688–9689 (1992).

  7. 7.

    & Short chemoenzymatic total synthesis of ent-hydromorphone: an oxidative dearomatization/intramolecular [4+2] cycloaddition/amination sequence. Angew. Chem. Int. Ed. 53, 4355–4358 (2014).

  8. 8.

    et al. Gram-scale enantioselective formal synthesis of morphine through an orthopara oxidative phenolic coupling strategy. Angew. Chem. Int. Ed. 53, 13498–13501 (2014).

  9. 9.

    , , , & A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308, 395–398 (2005).

  10. 10.

    , , & New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester. J. Org. Chem. 73, 4895–4902 (2008).

  11. 11.

    , & A concise and flexible synthesis of the potent anti-influenza agents Tamiflu and Tamiphosphor. Angew. Chem. Int. Ed. 47, 5788–5791 (2008).

  12. 12.

    , , & Symmetry-based design for the chemoenzymatic synthesis of oseltamivir (Tamiflu) from ethyl benzoate. Angew. Chem. Int. Ed. 48, 4229–4231 (2009).

  13. 13.

    & The Birch reduction of aromatic compounds. Org. React. 42, 1–334 (1992).

  14. 14.

    & Oxidation of phenolic compounds with organohypervalent iodine reagents. Org. React. 57, 327–415 (2001).

  15. 15.

    The meta photocycloaddition of arenes to alkenes. Chem. Rev. 93, 615–669 (1993).

  16. 16.

    & Dearomatization via η6-arene complexes. Top. Organomet. Chem. 7, 71–94 (2004).

  17. 17.

    & A new generation of π-basic dearomatization agents. Organometallics 24, 1786–1798 (2005).

  18. 18.

    , & Synthetic applications of the dearomatization agent pentaammineosmium(II). Tetrahedron 57, 8203–8225 (2001).

  19. 19.

    , , , & Stereoselective umpolung tandem addition of heteroatoms to phenol. J. Am. Chem. Soc. 130, 6906–6907 (2008).

  20. 20.

    , & Stereochemical observations on the bromate induced monobromopentahydroxylation of benzene by catalytic photoinduced charge-transfer osmylation. A concise synthesis of (±)-pinitol. Chem. Commun. 1283–1284 (1997).

  21. 21.

    Microbial arene oxidations. Org. React. 63, 117–264 (2004).

  22. 22.

    & Arene cis-dihydrodiol formation: from biology to application. Org. Biomol. Chem. 4, 181–192 (2006).

  23. 23.

    Photoadditions of aromatic compounds. Chem. Rev. 87, 811–860 (1987).

  24. 24.

    & The arene–alkene photocycloaddition. Beilstein J. Org. Chem. 7, 525–542 (2011).

  25. 25.

    et al. Arene–alkene cycloadditions and organic synthesis. Pure Appl. Chem. 62, 1597–1602 (2009).

  26. 26.

    & Para photoaddition of N-methyltriazolinedione to benzene. Synthesis of energy-rich azo compounds comprising benzene + nitrogen. J. Am. Chem. Soc. 111, 9247–9249 (1989).

  27. 27.

    & Comparison of DFT methods for molecular orbital Eigenvalue calculations. J. Phys. Chem. A 111, 1554–1561 (2007).

  28. 28.

    et al. The osmium-catalyzed asymmetric dihydroxylation: a new ligand class and a process improvement. J. Org. Chem. 57, 2768–2771 (1992).

  29. 29.

    , , & Dihydroxylation of polyenes using Narasaka's modification of the Upjohn procedure. J. Org. Chem. 63, 7322–7327 (1998).

  30. 30.

    & Application of radical cation spin density maps toward the prediction of photochemical reactivity between N-methyl-1,2,4-triazoline-3,5-dione and substituted benzenes. J. Org. Chem. 78, 4697–4707 (2013).

  31. 31.

    The retro-Diels–Alder reaction. Part II. Dienophiles with one or more heteroatoms. Org. React. 53, 223–629 (1998).

  32. 32.

    et al. Hyperaromatic stabilization of arenium ions: a remarkable cis stereoselectivity of nucleophilic trapping of β-hydroxyarenium ions by water. J. Am. Chem. Soc. 133, 19718–19728 (2011).

  33. 33.

    , , , & Intramolecular electron transfer between doubly six σ-bond-linked trialkyldiazenium cation and diazenyl radical units. J. Am. Chem. Soc. 119, 6873–6882 (1997).

  34. 34.

    & Enantioselective hydrogenation of the C=N group: a catalytic asymmetric reductive amination procedure. J. Am. Chem. Soc. 114, 6266–6267 (1992).

  35. 35.

    & Photochemical cycloaddition of N-methyltriazolinedione to naphthalene. J. Am. Chem. Soc. 106, 5368–5370 (1984).

  36. 36.

    & Photochemical Diels–Alder addition of N-methyltriazolinedione to phenanthrene. Tetrahedron Lett. 29, 5509–5512 (1988).

  37. 37.

    & A photochemical Diels–Alder reaction of N-methyltriazolinedione. J. Photochem. 28, 205–214 (1985).

  38. 38.

    & Further studies of the thermal and photochemical Diels−Alder reactions of N-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with naphthalene and some substituted naphthalenes. J. Org. Chem. 65, 2863–2869 (2000).

  39. 39.

    in Advances in Physical Organic Chemistry Vol. 4 (ed. Gold, V.) 31–71 (Academic Press, 1966).

  40. 40.

    , & Conduritols and related compounds. Tetrahedron 46, 3715–3742 (1990).

  41. 41.

    , & Copper-catalyzed aerobic oxidation of hydroxamic acids leads to a mild and versatile acylnitroso ene reaction. J. Am. Chem. Soc. 133, 10430–10433 (2011).

  42. 42.

    et al. Novel herbicidal MK7607 and its manufacture with Curvularia. Japan Kokai Tokkyo Koho, Japanese Patent 06306000 (1994).

  43. 43.

    et al. Phomentrioloxin, a fungal phytotoxin with potential herbicidal activity, and its derivatives: a structure–activity relationship study. J. Agric. Food Chem. 61, 9645–9649 (2013).

  44. 44.

    , & Chemoenzymatic total synthesis of the phytotoxic geranylcyclohexentriol (−)-phomentrioloxin. J. Nat. Prod. 76, 1514–1518 (2013).

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Acknowledgements

The authors acknowledge the University of Illinois for generous support of this work. E.H.S. is a Springborn Graduate Fellow and J.P. is a Fellow of the German Research Foundation (DFG). We thank S. E. Denmark and P. J. Hergenrother (University of Illinois) for critical proofreading of this manuscript. We dedicate this article to K. C. Nicolaou on the occasion of his 70th birthday.

Author information

Author notes

    • Emma H. Southgate
    •  & Jola Pospech

    These authors contributed equally to this work

Affiliations

  1. Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA

    • Emma H. Southgate
    • , Jola Pospech
    • , Junkai Fu
    • , Daniel R. Holycross
    •  & David Sarlah

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Contributions

E.H.S., J.P., J.F. and D.R.H. conducted the experiments, analysed the data and prepared the Supplementary Information. E.H.S., J.P. and D.S. conceived and designed the project, analysed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Sarlah.

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    Crystallographic data for compound 5a

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    Crystallographic data for compound 8a

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    Crystallographic data for compound Ac-9a

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DOI

https://doi.org/10.1038/nchem.2594

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