Quinol-Enedione Rearrangement

doi:10.1021/acs.orglett.5c01266

. 2025 May 9;27(18):4782-4787.

doi: 10.1021/acs.orglett.5c01266. Epub 2025 Apr 30.

Quinol-Enedione Rearrangement

Tomás Vieira de Castro¹, François Richard¹, Steven H Bennett¹, Caspar S Lamborelle¹, Gary S Nichol¹, Rafał Szabla^{2

3}, Andrew L Lawrence¹

Affiliations

¹ EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, U.K.
² Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
³ Department of Physics, Faculty of Science, University of Ostrava, 30. dubna 22, 701 03 Ostrava, Czech Republic.

PMID: 40304360
PMCID: PMC12070464
DOI: 10.1021/acs.orglett.5c01266

Quinol-Enedione Rearrangement

Tomás Vieira de Castro et al. Org Lett. 2025.

. 2025 May 9;27(18):4782-4787.

doi: 10.1021/acs.orglett.5c01266. Epub 2025 Apr 30.

Authors

Tomás Vieira de Castro¹, François Richard¹, Steven H Bennett¹, Caspar S Lamborelle¹, Gary S Nichol¹, Rafał Szabla^{2

3}, Andrew L Lawrence¹

Affiliations

¹ EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, U.K.
² Institute of Advanced Materials, Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
³ Department of Physics, Faculty of Science, University of Ostrava, 30. dubna 22, 701 03 Ostrava, Czech Republic.

PMID: 40304360
PMCID: PMC12070464
DOI: 10.1021/acs.orglett.5c01266

Abstract

The quinol-enedione rearrangement enables the synthesis of 2-cyclohexene-1,4-diones from readily available para-quinol substrates. Building on sporadic early reports of this transformation, we have optimized the reaction conditions and systematically investigated its substrate scope. The utility of Brønsted acid-mediated reaction conditions for a variety of quinol derivatives, including those with substituted and unsubstituted migrating termini, is highlighted. Notably, kinetic selectivity between quinol-enedione and dienone-phenol rearrangements is demonstrated. The synthetic potential of the enedione products is showcased through a range of transformations, leading to the formation of complex polycyclic structures. These findings provide a valuable framework for recognizing and applying the quinol-enedione rearrangement in synthesis, while computational studies offer valuable insights into its mechanistic underpinnings.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Scheme 1. Dienone–Phenol and Quinol–Enedione Rearrangements, Shown Proceeding via Brønsted Acid Catalyzed Mechanisms**

**Scheme 2. Davis’ Seminal Quinol–Enedione Rearrangement and Representative Natural Products That Contain the Enedione Framework**

**Scheme 3. Substrate Scope for the Quinol−Enedione Rearrangement**

**Scheme 4. Investigating Selectivity between Quinol–Enedione and Dienone–Phenol Rearrangements**
1.0 equiv of p-TsOH used.

**Scheme 5. Failed Substrates for the Quinol–Enedione Rearrangement**

**Scheme 6. Derivatization Studies on Model Enedione 2a**
23% yield of the diketone formed from hydrolysis of enol acetate 15 was also isolated.

See this image and copyright information in PMC

Cited by

Total Synthesis of Dactyloquinone A and Spiroetherone A via a Metal-Hydride Hydrogen Atom Transfer (MHAT) Process and a Quinol-Enedione Rearrangement.
Schoenn G, Kouklovsky C, Guillot R, Magauer T, Vincent G. Schoenn G, et al. Angew Chem Int Ed Engl. 2025 Jun 17;64(25):e202505270. doi: 10.1002/anie.202505270. Epub 2025 May 2. Angew Chem Int Ed Engl. 2025. PMID: 40207454 Free PMC article.

References

1. Andreocci A. About two new isomers of santonin and santonin acid. Gazz. Chim. Ital. 1893, 23, 468–476.
2. Auwers K. V.; Ziegler K. Hydrocarbons of the Semibenzene Group. Justus Liebigs Ann. Chem. 1921, 425, 217–280. 10.1002/jlac.19214250302. - DOI
3. Clemo G. R.; Haworth R. D.; Walton E. Constitution of santonin. II. Synthesis of racemic desmotroposantonin. J. Chem. Soc. 1930, 1110–1115. 10.1039/JR9300001110. - DOI
4. Wilds A. L.; Djerassi C. Dienone-phenol rearrangement applied to chrysene derivatives. The synthesis of 3-hydroxy-1-methylchrysene and related compounds. J. Am. Chem. Soc. 1946, 68, 1715–1719. 10.1021/ja01213a010. - DOI - PubMed
1. For a useful overview, see: Kurti L.; Czako B.. Dienone–Phenol Rearrangement. In Strategic Applications of Named Reactions in Organic Synthesis; Kurti L., Czako B., Eds.; Elsevier Academic Press, 2005; pp 142–143.
2. For specific examples, see:
3. Hart D. J.; Kim A.; Krishnamurthy R.; Merriman G. H.; Waltos A. M. Synthesis of 6H-dibenzo[b,d]pyran-6-ones via dienone-phenol rearrangements of spiro[2,5-cyclohexadiene-1,1’(3′H)-isobenzofuran]-3′-ones. Tetrahedron 1992, 48, 8179–8188. 10.1016/S0040-4020(01)80487-7. - DOI
4. Parker K. A.; Koh Y. -h. Methodology for the Regiospecific Synthesis of Bis C-Aryl Glycosides. Models for Kidamycins. J. Am. Chem. Soc. 1994, 116, 11149–11150. 10.1021/ja00103a037. - DOI
5. Guo Z.; Schultz A. G. Preparation and Photochemical Rearrangements of 2-Phenyl-2,5-cyclohexadien-1-ones. An Efficient Route to Highly Substituted Phenols. Org. Lett. 2001, 3, 1177–1180. 10.1021/ol015637h. - DOI - PubMed
1. Davis B. R.; Woodgate P. D. Dienone–Phenol Type Rearrangements. Part III. para-Quinols. J. Chem. Soc. C 1968, 0, 712–715. 10.1039/J39680000712. - DOI
1. Burkinshaw G. F.; Davis B. R.; Woodgate P. D.; Hodges R. The Isolation of a Spiran in the Acid-catalysed Rearrangement of a Bicyclic Cyclohexadienone. Chem. Commun. 1968, 528.10.1039/c19680000528. - DOI
2. Burkinshaw G. F.; Davis B. R.; Hutchinson E. G.; Woodgate P. D.; Hodges R. The synthesis and acid-catalysed rearrangements of 4-hydroxycyclohexa-2,5-dienones. J. Chem. Soc. C 1971, 3002–3006. 10.1039/j39710003002. - DOI
3. Berger S.; Henes G.; Rieker A.; et al. Baseninduzierte Acyloin-Umlagerung sterisch gehinderter p-Chinole. Chem. Ber. 1976, 109, 1530–1548. 10.1002/cber.19761090439. - DOI
4. Planas A.; Tomás J.; Bonet J.-J. Spiran isolation in the dienone-phenol rearrangement of steroidal p-quinols. Tetrahedron Lett. 1987, 28, 471–474. 10.1016/S0040-4039(00)95759-9. - DOI
5. Uno H.; Yayama A.; Suzuki H. 1,2-Migration of Perfluoroalkyl Groups in Anionotropic Rearrangement. The Acyloin Rearrangement of 4-Perfluoroalkyl-4-quinols. Chem. Lett. 1991, 20, 1165–1168. 10.1246/cl.1991.1165. - DOI
6. Uno H.; Yayama A.; Suzuki H. Perfluoroalkyl Migration in the Rearrangement of 4-Perfluoroalkyl-4-quinols. Tetrahedron 1992, 48, 8353–8368. 10.1016/S0040-4020(01)86584-4. - DOI
1. Hu P.; Chi H. M.; DeBacker K. C.; Gong X.; Keim J. H.; Hsu I. T.; Snyder S. A. Quaternary-centre-guided synthesis of complex polycyclic terpenes. Nature 2019, 569, 703–707. 10.1038/s41586-019-1179-2. - DOI - PMC - PubMed

LinkOut - more resources

Full Text Sources
- American Chemical Society
- PubMed Central

[1] Andreocci A. About two new isomers of santonin and santonin acid. Gazz. Chim. Ital. 1893, 23, 468–476.

Auwers K. V.; Ziegler K. Hydrocarbons of the Semibenzene Group. Justus Liebigs Ann. Chem. 1921, 425, 217–280. 10.1002/jlac.19214250302. - DOI

Clemo G. R.; Haworth R. D.; Walton E. Constitution of santonin. II. Synthesis of racemic desmotroposantonin. J. Chem. Soc. 1930, 1110–1115. 10.1039/JR9300001110. - DOI

Wilds A. L.; Djerassi C. Dienone-phenol rearrangement applied to chrysene derivatives. The synthesis of 3-hydroxy-1-methylchrysene and related compounds. J. Am. Chem. Soc. 1946, 68, 1715–1719. 10.1021/ja01213a010. - DOI - PubMed

[2] Andreocci A. About two new isomers of santonin and santonin acid. Gazz. Chim. Ital. 1893, 23, 468–476.

[3] Auwers K. V.; Ziegler K. Hydrocarbons of the Semibenzene Group. Justus Liebigs Ann. Chem. 1921, 425, 217–280. 10.1002/jlac.19214250302. - DOI

[4] Clemo G. R.; Haworth R. D.; Walton E. Constitution of santonin. II. Synthesis of racemic desmotroposantonin. J. Chem. Soc. 1930, 1110–1115. 10.1039/JR9300001110. - DOI

[5] Wilds A. L.; Djerassi C. Dienone-phenol rearrangement applied to chrysene derivatives. The synthesis of 3-hydroxy-1-methylchrysene and related compounds. J. Am. Chem. Soc. 1946, 68, 1715–1719. 10.1021/ja01213a010. - DOI - PubMed

[6] For a useful overview, see: Kurti L.; Czako B.. Dienone–Phenol Rearrangement. In Strategic Applications of Named Reactions in Organic Synthesis; Kurti L., Czako B., Eds.; Elsevier Academic Press, 2005; pp 142–143.

For specific examples, see:

Hart D. J.; Kim A.; Krishnamurthy R.; Merriman G. H.; Waltos A. M. Synthesis of 6H-dibenzo[b,d]pyran-6-ones via dienone-phenol rearrangements of spiro[2,5-cyclohexadiene-1,1’(3′H)-isobenzofuran]-3′-ones. Tetrahedron 1992, 48, 8179–8188. 10.1016/S0040-4020(01)80487-7. - DOI

Parker K. A.; Koh Y. -h. Methodology for the Regiospecific Synthesis of Bis C-Aryl Glycosides. Models for Kidamycins. J. Am. Chem. Soc. 1994, 116, 11149–11150. 10.1021/ja00103a037. - DOI

Guo Z.; Schultz A. G. Preparation and Photochemical Rearrangements of 2-Phenyl-2,5-cyclohexadien-1-ones. An Efficient Route to Highly Substituted Phenols. Org. Lett. 2001, 3, 1177–1180. 10.1021/ol015637h. - DOI - PubMed

[7] For a useful overview, see: Kurti L.; Czako B.. Dienone–Phenol Rearrangement. In Strategic Applications of Named Reactions in Organic Synthesis; Kurti L., Czako B., Eds.; Elsevier Academic Press, 2005; pp 142–143.

[8] For specific examples, see:

[9] Hart D. J.; Kim A.; Krishnamurthy R.; Merriman G. H.; Waltos A. M. Synthesis of 6H-dibenzo[b,d]pyran-6-ones via dienone-phenol rearrangements of spiro[2,5-cyclohexadiene-1,1’(3′H)-isobenzofuran]-3′-ones. Tetrahedron 1992, 48, 8179–8188. 10.1016/S0040-4020(01)80487-7. - DOI

[10] Parker K. A.; Koh Y. -h. Methodology for the Regiospecific Synthesis of Bis C-Aryl Glycosides. Models for Kidamycins. J. Am. Chem. Soc. 1994, 116, 11149–11150. 10.1021/ja00103a037. - DOI

[11] Guo Z.; Schultz A. G. Preparation and Photochemical Rearrangements of 2-Phenyl-2,5-cyclohexadien-1-ones. An Efficient Route to Highly Substituted Phenols. Org. Lett. 2001, 3, 1177–1180. 10.1021/ol015637h. - DOI - PubMed

[12] Davis B. R.; Woodgate P. D. Dienone–Phenol Type Rearrangements. Part III. para-Quinols. J. Chem. Soc. C 1968, 0, 712–715. 10.1039/J39680000712. - DOI

[13] Davis B. R.; Woodgate P. D. Dienone–Phenol Type Rearrangements. Part III. para-Quinols. J. Chem. Soc. C 1968, 0, 712–715. 10.1039/J39680000712. - DOI

[14] Burkinshaw G. F.; Davis B. R.; Woodgate P. D.; Hodges R. The Isolation of a Spiran in the Acid-catalysed Rearrangement of a Bicyclic Cyclohexadienone. Chem. Commun. 1968, 528.10.1039/c19680000528. - DOI

Burkinshaw G. F.; Davis B. R.; Hutchinson E. G.; Woodgate P. D.; Hodges R. The synthesis and acid-catalysed rearrangements of 4-hydroxycyclohexa-2,5-dienones. J. Chem. Soc. C 1971, 3002–3006. 10.1039/j39710003002. - DOI

Berger S.; Henes G.; Rieker A.; et al. Baseninduzierte Acyloin-Umlagerung sterisch gehinderter p-Chinole. Chem. Ber. 1976, 109, 1530–1548. 10.1002/cber.19761090439. - DOI

Planas A.; Tomás J.; Bonet J.-J. Spiran isolation in the dienone-phenol rearrangement of steroidal p-quinols. Tetrahedron Lett. 1987, 28, 471–474. 10.1016/S0040-4039(00)95759-9. - DOI

Uno H.; Yayama A.; Suzuki H. 1,2-Migration of Perfluoroalkyl Groups in Anionotropic Rearrangement. The Acyloin Rearrangement of 4-Perfluoroalkyl-4-quinols. Chem. Lett. 1991, 20, 1165–1168. 10.1246/cl.1991.1165. - DOI

Uno H.; Yayama A.; Suzuki H. Perfluoroalkyl Migration in the Rearrangement of 4-Perfluoroalkyl-4-quinols. Tetrahedron 1992, 48, 8353–8368. 10.1016/S0040-4020(01)86584-4. - DOI

[15] Burkinshaw G. F.; Davis B. R.; Woodgate P. D.; Hodges R. The Isolation of a Spiran in the Acid-catalysed Rearrangement of a Bicyclic Cyclohexadienone. Chem. Commun. 1968, 528.10.1039/c19680000528. - DOI

[16] Burkinshaw G. F.; Davis B. R.; Hutchinson E. G.; Woodgate P. D.; Hodges R. The synthesis and acid-catalysed rearrangements of 4-hydroxycyclohexa-2,5-dienones. J. Chem. Soc. C 1971, 3002–3006. 10.1039/j39710003002. - DOI

[17] Berger S.; Henes G.; Rieker A.; et al. Baseninduzierte Acyloin-Umlagerung sterisch gehinderter p-Chinole. Chem. Ber. 1976, 109, 1530–1548. 10.1002/cber.19761090439. - DOI

[18] Planas A.; Tomás J.; Bonet J.-J. Spiran isolation in the dienone-phenol rearrangement of steroidal p-quinols. Tetrahedron Lett. 1987, 28, 471–474. 10.1016/S0040-4039(00)95759-9. - DOI

[19] Uno H.; Yayama A.; Suzuki H. 1,2-Migration of Perfluoroalkyl Groups in Anionotropic Rearrangement. The Acyloin Rearrangement of 4-Perfluoroalkyl-4-quinols. Chem. Lett. 1991, 20, 1165–1168. 10.1246/cl.1991.1165. - DOI

[20] Uno H.; Yayama A.; Suzuki H. Perfluoroalkyl Migration in the Rearrangement of 4-Perfluoroalkyl-4-quinols. Tetrahedron 1992, 48, 8353–8368. 10.1016/S0040-4020(01)86584-4. - DOI

[21] Hu P.; Chi H. M.; DeBacker K. C.; Gong X.; Keim J. H.; Hsu I. T.; Snyder S. A. Quaternary-centre-guided synthesis of complex polycyclic terpenes. Nature 2019, 569, 703–707. 10.1038/s41586-019-1179-2. - DOI - PMC - PubMed

[22] Hu P.; Chi H. M.; DeBacker K. C.; Gong X.; Keim J. H.; Hsu I. T.; Snyder S. A. Quaternary-centre-guided synthesis of complex polycyclic terpenes. Nature 2019, 569, 703–707. 10.1038/s41586-019-1179-2. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Quinol-Enedione Rearrangement

Affiliations

Quinol-Enedione Rearrangement

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Related information

LinkOut - more resources

Full Text Sources