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. 2021 May 5;1(1):11–17. doi: 10.1021/acsorginorgau.1c00006

Enabling Cyclization Strategies through Carbonyl-Ylide-Mediated Synthesis of Malonate Enol Ethers

Júlia Viñas-Lóbez †, Guillaume Levitre †, Adiran de Aguirre †, Céline Besnard ‡, Amalia I Poblador-Bahamonde †, Jérôme Lacour †,*
PMCID: PMC9954264  PMID: 36855638

Abstract

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Malonate enol ethers are afforded in one step by condensation of cyclic ketones with α-diazomalonates under [CpRu(CH3CN)3][BArF] catalysis. The dual reactivity of these 2-vinyloxymalonates can be used to expand the classical range of cyclizations derived from carbonyl ylide intermediates.

Keywords: Carbonyl ylide reactivity, CpRu catalysis, Diazo decomposition, Enol ethers, Malonate

Decompositions of diazo derivatives in the presence of Lewis bases is a recognized strategy to generate ylides efficiently.1−9 With aldehydes and ketones, carbonyl ylides are formed, usually under light irradiation or metal-catalyzed conditions.6,10−26 Traditionally, these reactive intermediates condense to form epoxides or act as 1,3-dipoles in intra- and intermolecular cycloadditions that form five and sometimes larger oxacycles (Scheme 1, top). These (cascade) cyclizations constitute useful and practical synthetic strategies for making (poly)heterocycles.11 Herein, in a new development in the field of carbonyl ylides, we report the general reactivity of ketones 1 and α-diazodiesters 2 to generate 2-vinyloxymalonates 3 (Scheme 1, bottom). The condensation is general and uses principally the complex [CpRu(CH3CN)3][BArF] (BArF: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, [4][BArF]) as the catalyst. Malonate enol ethers 3 of different ring sizes and geometries are obtained (30 examples), often as single regioisomers, and their mechanism of formation is elucidated based on density functional theory (DFT) calculations. In terms of applications, these compounds behave as versatile three- or four-atom building blocks for annulations under Lewis-acid-mediated conditions or visible-light photoredox catalysis. Several fused and spiro-heterocycles were generated to demonstrate the potential of derivatives 3 as synthetic intermediates. This type of reactivity can be used to expand the classical range of cyclizations derived from carbonyl ylide intermediates.

Scheme 1.

Scheme 1

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The direct formation of enol ethers from ketones and diazo reagents has been previously reported in only a few instances (Scheme 2). Jones and collaborators demonstrated that α-diazodiesters react under photoirradiation with cyclopentanone or acetone to generate the corresponding malonate enol ethers (two examples, 18–22%).27 Synthesis of compounds 3 under Cu(II) catalysis has also been reported, with the yields of products being however unknown.28 With monofunctionalized diazoacetates, enol derivatives can be isolated from the reactions with ketones under copper or dirhodium catalysis.29−33 We decided to focus our attention on malonate 3 as diazo reagents substituted with two electron-withdrawing groups (EWGs) such as diazomalonates are among the most stable diazo derivatives34 yet are amenable to decomposition reactions that form very reactive electrophilic carbenes.35

Scheme 2.

Scheme 2

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In the context of acceptor–acceptor diazo reagent decompositions, combinations of CpRu [4] salts and diimine ligands can be used as catalysts, and original reactivities are then afforded for the resulting metal carbenes.36 For instance, α-diazo-β-ketoesters react with aldehydes and ketones but also lactones and cyclic carbonates to yield stable dioxolene adducts exclusively.37,38 With α-diazodiesters 2, such a dioxolene reactivity had not been characterized. We decided to study the reactions of compounds 1 and 2 and harness the potential of either intermediates or products.

Initial experiments were performed by adding dimethyl diazomalonate 2A (3 equiv) to a solution of cyclohexanone 1a (0.3 mmol) in CH2Cl2 in the presence of CuI (10 mol %) (Table 1, entry 1). After 6 h at 100 °C, almost full conversion of ketone 1a was achieved and enol ether 3aA was identified as the major product of a complex crude reaction mixture (1H NMR yield, 27%). With dirhodium catalysts, Rh2(oct)4 and Rh2(TFA)4, enol ether 3aA was formed in 23 and 63% NMR yields, respectively (entries 2 and 3), with the products of double carbene additions being nevertheless observed in the crude mixtures, sometimes as major adducts (eq S1).39 Based on previous studies,36−38,40−42 combinations (1:1) of [CpRu(CH3CN)3][X] or [4][X] salts and 1,10-phenanthroline were tested as decomposition catalysts. Both [4][PF6] and [4][BArF] complexes afforded, under these conditions, 3aA in 41 and 58% yields, respectively (entries 4 and 5);43,44 salt [4][BArF] was preferred for further studies due to its bench stability. With other diimine ligands, significantly lower yields were obtained (45 and 18%, entries 6 and 7). Full conversion of 1a and higher yields of 3aA were achieved in the absence of the phenanthroline ligand (66%, entry 8). Using the tris(benzonitrile)ruthenium(II) complex or increasing sterics and electronics around the cyclopentadienyl ring led to lower yields (entries 9 and 10). Reaction time and stoichiometry were further studied (Tables S1–S3), with 4 h and 1.5 equiv of 2A being optimal to afford 3aA in 65% isolated yield. These conditions (entry 11) were selected for the remainder of the studies.

Table 1.

a

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entry catalyst (mol %) conv (%) yield (%)
1b CuI (10) 97 27
2 Rh2(oct)4 (1) 99 23
3 Rh2(TFA)4 (1) 92 63
4 [4][PF6]/Phen (2.5) 86 41
5 [4][BArF]/Phen (2.5) 79 58
6 [4][BArF]/BPhen (2.5) 87 45
7 [4][BArF]/diMeObpy (2.5) 45 18
8 [4][BArF] (2.5) 100 66
9 [CpRu(PhCN)3][BArF] (2.5) 100 54
10 [Cp*Ru(CH3CN)3][PF6] (2.5) 100 47
11c [4][BArF] (2.5) 97 67(65)
12 no catalyst, no ligand nr nr
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a

Reaction conditions: 1a (0.3 mmol), 2A (3 equiv), catalyst, CH2Cl2 (0.5 M), 60 °C, 6 h. Yields determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Conversions are based on starting 1a. Yields of isolated products are given in parentheses.

b

Reaction performed at 100 °C.

c

1.5 equiv of 2A and 4 h. Cp = cyclopentadienyl, BPhen = 4,7-diphenyl-1,10-phenanthroline, diMeObpy = 4,4′-dimethoxy-2,2′-bipyridine, Cp* = pentamethylcyclopentadienyl, nr = no reaction.

With the optimized conditions in hand, using 2A as the diazo reagent, the reaction was extended to a variety of ketones, leading to enol ethers 3bA–3wA in yields up to 98% (Scheme 3). Satisfactorily, different ring sizes were amenable (4- to 12-membered cycles, 47–79%), including the transformation of cyclobutanone into the strained cyclobutene analogue 3bA (47%).45 Overall, the best yields were obtained with 4-substituted cyclohexanones as substrates (3fA–3hA, 83–98%).46 Starting from pyranone 2i, enol ether 3iA was formed preferentially, indicating the predominant formation of the carbonyl ylide over the oxonium ylide intermediate. α-Indenone and α-tetralone afforded the corresponding aromatic enol ethers 3jA and 3kA in moderate yields (59–62%).

Scheme 3.

Scheme 3

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Reaction conditions: 1b–1w (0.3 mmol), 2A (1.5 equiv), [4][BArF] (2.5 mol %), CH2Cl2 (0.5 M), 60 °C, 4–24 h.

K2CO3 (1.3 equiv), MeOH/THF (80/20), 25 °C, 1 h. Major regioisomers or geometrical isomers are drawn.

With β-tetralones, moderate to excellent yields were obtained (3lA–3nA, 51–97%) in favor of the conjugated products predominantly (regioisomeric ratio, rr > 19:1). Excellent regioselectivity was also obtained from 1,3-cyclohexanedione, forming only conjugated 3oA (53%, rr > 24:1). A series of α-substituted cyclohexanones was also studied, with some of the reactions requiring longer reaction times for full conversion (6–24 h). With α-methyl and α-phenyl groups, trisubstituted enol ethers 3pA and 3qA were formed preferentially (rr 9:1, 66–74%).47 Such regioselectivity forming the so-called kinetic enol geometry48 was obtained exclusively for bromo derivative 3rA (47%, rr > 24:1), the structure of which being confirmed by X-ray diffraction analysis (Scheme 3). Interestingly, in the solid state and most probably in solution (1H NMR spectroscopy), the bromine atom assumes a pseudoaxial position due to a minimization of the allylic 1,2-strain.49,50 Regioselectivity control was not possible with 3-methylcyclohexanone, menthone, and 2-decalone (cis/trans 1:1) as reactions resulted in inseparable mixtures of regioisomers (3sA–3uA, 69–97%). In the first two cases, a slight preference was noticed for the formation of the less hindered enol ethers (rr up to 3:1). Using acyclic 4-heptanone, the corresponding enol 3vA was prepared in 60% yield, presenting a 5:1 E/Z ratio.45 Finally, acetylated epiandrosterone reacted chemoselectively on the ketone rather than the ester group38 to form 3wA (85%) and without perturbation from the steric hindrance and rigid conformation of the steroid D ring, with the acetate group carried on the A ring being furthermore easily saponified to afford 5 (96%) in the presence of the malonate moiety.51

Then, several diazomalonates were investigated (reactants 2B–2H, Scheme 4). With cyclohexanone 1a as the substrate, yields ranged from 48 to 65% for 3aA to 3aD. With fluorinated 2E and 2F, the presence of the electron-withdrawing side chain(s) was beneficial in relation, probably, with a higher reactivity of the electrophilic carbenes (3aE–3aF, 75–83%). With [4][BArF] as a catalyst, a sensitivity to steric hindrance41 was noticed as diisopropyl product 3aG was isolated in 35% yield only, and enol ether 3aH (tBu) could not be formed. In the latter case, to ensure reactivity, the reaction was performed with Rh2(TFA)4 to afford the targeted enol ether in 42% isolated yield.

Scheme 4.

Scheme 4

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Reaction conditions: 1a (0.3 mmol), 2A–2H (1.5 equiv), [4][BArF] (2.5 mol %), CH2Cl2 (0.5 M), 60 °C, 4 h.

Reaction time 5 h.

Reaction performed with Rh2(TFA)4 (1 mol %) for 6 h at 60 °C.

In terms of the mechanism, modeled for the reaction of 2A to 3aA, DFT calculations show that the favored pathway starts with the coordination of diazomalonate 2A to [Ru], as defined in Scheme 5, and its subsequent N2 extrusion (TS(a-b), ΔG⧧ = 17.8 kcal·mol–1). This step yields very stable metal-carbene b, lying at −20.2 kcal·mol–1. Intermediate b traps cyclohexanone 1a via TS(b-c), with a relative barrier of 19.7 kcal·mol–1, to achieve the metal-ylide c. This rate-determining step is also endergonic by 14.7 kcal·mol–1. This transformation is fortunately upset by the high concentration of 2A in the media that pushes the process toward the liberation of ylide d and initiates a new catalytic cycle (see Figures S7–S12). Free ylide d then evolves in an exergonic manner to its enol derivative e through a small barrier TS(d-e). For this step d → e, experimental studies with deuterium-labeled substrates demonstrate the intramolecular nature of the hydrogen transfer (see Schemes S2–S3 and Figures S2–S4). Finally, enol e tautomerizes to its diester form, obtaining the final product 3aA.52

Scheme 5. Computed Catalytic Cycle.

Scheme 5

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Gibbs energies are given in kcal·mol–1.

With compounds 3 in hand, we realized that the classical scope of carbonyl ylide cyclizations could be expanded remarkably. In fact, we can rely not only on the three atoms constituting the 1,3-dipole but also on both sp2-carbons of the enol moiety, as well.53 Malonate enol ethers 3 then provide versatile three- or four-atom building blocks for annulation processes. Both malonate and enol functional groups can be manipulated independently and orthogonally but also in synergy to promote diverse ring formations.

Three different types of transformations are presented, two metal-mediated processes and one photoinduced process, that afford a variety of fused and spiro-heterocycles (Scheme 6). All cyclization sequences benefit from the reactivity of the malonate group with alkyl halides (eq 1). In effect, compounds 3aA or 3fA are readily deprotonated in the presence of potassium tert-butoxide, and products of C–C bond formation carrying various functional groups are obtained readily (6a–6d, 60–88%).54

graphic file with name gg1c00006_0001.jpg 1

Scheme 6.

Scheme 6

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Reaction conditions: (a) PtCl2 (5 mol %), dioxane (0.1 M), 60 °C, 16 h; (b) AgOTf (1.0 equiv), 2,6-di-tert-butyl-4-methylpyridine (3.0 equiv), DCM (0.1 M), 25 °C, 2 h; (c) (Ir(ppy)3, 2.5 mol %), blue LEDs irradiation, DIPEA (10 equiv), MeCN (0.1 M), 25 °C, 5 h. SET: single electron transfer. HAT: hydrogen atom transfer.

Then, using propargyl-substituted 6a, a PtCl2-catalyzed (5 mol %) reaction was performed (Scheme 6A).55−61 In the presence of the Lewis acid activating the alkyne (intermediate 7), a 6-exo-dig cyclization occurs, and after proton loss that regenerates the enol, formation of the conjugated chromene 8 is afforded as a single regioisomer (62% yield).62 With 6b and 6c, treatment with AgOTf in the presence of 2,6-di-tert-butyl-4-methylpyridine yielded bicyclic derivatives 10a and 10b in 49 and 55% yields, respectively (Scheme 6B). The reactions proceed most likely via a stabilized allylic cation 9, and after a 6-exo-trig Mukaiyama-type intramolecular alkylation,63−65 proton loss affords the bicyclic enol products 10a and 10b as single regioisomers again. With 6d in hand, a radical cyclization under visible-light photoredox catalysis was considered alternatively (Scheme 6C).66−72 Under blue light-emitting diode (LED) irradiation and using tris[2-phenylpyridinato-C2,N]iridium(III) or Ir(ppy)3 as catalyst,73,74 product 13 was obtained in 67% yield. Compound 6d led to spiro adduct 13 via a 5-exo-trig cyclization, as it is generally observed in radical processes.75,76 A detailed mechanistic proposal is reported in Scheme S1.

In conclusion, we report the effective formation of malonate enol ethers 3 by condensations of ketones with metal carbenes derived from α-diazomalonates and [CpRu(CH3CN)3][BArF] as a catalyst. These 2-vinyloxymalonates 3 are obtained in good to excellent yields (up to 98%), and their mechanism of formation was elucidated based on DFT calculations. Furthermore, they are interesting building blocks for annulation strategies as exemplified by the three transformations selected (Scheme 6). In effect, derivatives 3 predispose reactive enol and malonate functional groups at immediate proximity to enable cyclization strategies that would be difficult to consider otherwise.77

Acknowledgments

We thank the University of Geneva and the Swiss National Science Foundation for financial support (200020-184843 to J.L.). We also acknowledge the contributions of the Sciences Mass Spectrometry (SMS) platform at the Faculty of Sciences, University of Geneva. We also thank Carmine Chiancone for technical support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.1c00006.

  • Synthetic protocols, experimental conditions, full characterizations of new compounds, computational details. Original data related to this publication can be found under DOI: 10.26037/yareta:xt74kr35jrcgblxomojxsmnd3y. It will be preserved for 10 years (PDF)

Author Contributions

§ J.V.-L. and G.L. contributed equally to the work.

The authors declare no competing financial interest.

Supplementary Material

gg1c00006_si_001.pdf (8.7MB, pdf)

References

  1. Phelps R.; Orr-Ewing A. J. Direct Observation of Ylide and Enol Intermediates Formed in Competition with Wolff Rearrangement of Photoexcited Ethyl Diazoacetoacetate. J. Am. Chem. Soc. 2020, 142 (17), 7836–7844. 10.1021/jacs.0c00752. [DOI] [PubMed] [Google Scholar]
  2. Neuhaus J. D.; Oost R.; Merad J.; Maulide N. Sulfur-Based Ylides in Transition-Metal-Catalysed Processes. Top. Curr. Chem. 2018, 376 (3), 376. 10.1007/s41061-018-0193-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hock K. J.; Koenigs R. M. Enantioselective [2,3]-Sigmatropic Rearrangements: Metal-Bound or Free Ylides as Reaction Intermediates?. Angew. Chem., Int. Ed. 2017, 56 (44), 13566–13568. 10.1002/anie.201707092. [DOI] [PubMed] [Google Scholar]
  4. Deng Y.; Qiu H.; Srinivas H. D.; Doyle M. P. Chiral Dirhodium(II) Catalysts for Selective Metal Carbene Reactions. Curr. Org. Chem. 2015, 20 (1), 61–81. 10.2174/1385272819666150714182732. [DOI] [Google Scholar]
  5. Murphy G. K.; West F. G.. Oxonium Ylide Rearrangements in Synthesis; John Wiley & Sons, Inc., 2015; pp 497–538. [Google Scholar]
  6. Hodgson D. M.; Labande A. H.; Muthusamy S.. Cycloadditions of Carbonyl Ylides Derived from Diazocarbonyl Compounds Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; Vol. 80, pp 133–496. [Google Scholar]
  7. Sheng Z.; Zhang Z.; Chu C.; Zhang Y.; Wang J. Transition metal-catalyzed [2,3]-sigmatropic rearrangements of ylides: An update of the most recent advances. Tetrahedron 2017, 73 (29), 4011–4022. 10.1016/j.tet.2016.11.045. [DOI] [Google Scholar]
  8. Bach R.; Harthong S.; Lacour J.. Nitrogen- and Sulfur-Based Stevens and Related Rearrangements; Elsevier B.V., 2014; pp 992–1037. [Google Scholar]
  9. Clark J. S.Nitrogen, Oxygen and Sulfur Ylides: An Overview; Oxford University Press, 2002; pp 1–113. [Google Scholar]
  10. Loui H. J.; Suneja A.; Schneider C. Cooperative Rh/Chiral Phosphoric Acid Catalysis toward the Highly Stereoselective (3 + 3)-Cycloannulation of Carbonyl Ylides and Indolyl-2-methides. Org. Lett. 2021, 23, 2578. 10.1021/acs.orglett.1c00489. [DOI] [PubMed] [Google Scholar]
  11. Padwa A. Use of oxygenated 1,3-dipoles for the synthesis of nitrogen containing heterocycles. ARKIVOC (Gainesville, FL, U. S.) 2021, 2021 (5), 24–40. 10.24820/ark.5550190.p011.381. [DOI] [Google Scholar]
  12. Wang Q.; May J. A. Formation of β-Oxo-N-vinylimidates via Intermolecular Ester Incorporation in Huisgen Cyclization/Carbene Cascade Reactions. Org. Lett. 2020, 22 (24), 9579–9584. 10.1021/acs.orglett.0c03619. [DOI] [PubMed] [Google Scholar]
  13. Wang Z.; Martin S. F. Total Syntheses of (±)-Melicolones A and B. Org. Lett. 2020, 22 (22), 9071–9074. 10.1021/acs.orglett.0c03454. [DOI] [PubMed] [Google Scholar]
  14. Klein I. M.; Husic C. C.; Kovács D. P.; Choquette N. J.; Robb M. J. Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry. J. Am. Chem. Soc. 2020, 142 (38), 16364–16381. 10.1021/jacs.0c06868. [DOI] [PubMed] [Google Scholar]
  15. Suneja A.; Loui H. J.; Schneider C. Cooperative Catalysis for the Highly Diastereo- and Enantioselective [4 + 3]-Cycloannulation of ortho-Quinone Methides and Carbonyl Ylides. Angew. Chem., Int. Ed. 2020, 59 (14), 5536–5540. 10.1002/anie.201913603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bakthadoss M.; Agarwal V. Rhodium-Catalyzed Diastereoselective [3 + 2] Cycloaddition of Carbonyl Ylide: An Access to the Core Ring System of Cordigol and Lophirone H. J. Org. Chem. 2020, 85 (23), 15221–15231. 10.1021/acs.joc.0c02073. [DOI] [PubMed] [Google Scholar]
  17. Petzold M.; Jones P. G.; Werz D. B. (3 + 3)-Annulation of Carbonyl Ylides with Donor-Acceptor Cyclopropanes: Synergistic Dirhodium(II) and Lewis Acid Catalysis. Angew. Chem., Int. Ed. 2019, 58 (19), 6225–6229. 10.1002/anie.201814409. [DOI] [PubMed] [Google Scholar]
  18. Yadagiri D.; Chaitanya M.; Reddy A. C. S.; Anbarasan P. Rhodium Catalyzed Synthesis of Benzopyrans via Transannulation of N-Sulfonyl-1,2,3-triazoles with 2-Hydroxybenzyl Alcohols. Org. Lett. 2018, 20 (13), 3762–3765. 10.1021/acs.orglett.8b01338. [DOI] [PubMed] [Google Scholar]
  19. Fu L.; Hoang K.; Tortoreto C.; Liu W.; Davies H. M. L. Formation of Tertiary Alcohols from the Rhodium-Catalyzed Reactions of Donor/Acceptor Carbenes with Esters. Org. Lett. 2018, 20 (8), 2399–2402. 10.1021/acs.orglett.8b00739. [DOI] [PubMed] [Google Scholar]
  20. Fegheh-Hassanpour Y.; Arif T.; Sintim H. O.; Al Mamari H. H.; Hodgson D. M. Synthesis of (−)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition-Rearrangement and Cross-electrophile Coupling. Org. Lett. 2017, 19 (13), 3540–3543. 10.1021/acs.orglett.7b01513. [DOI] [PubMed] [Google Scholar]
  21. Padwa A. Use of rhodium carbenoid intermediates for dipolar cycloaddition chemistry. Prog. Heterocycl. Chem. 2017, 29, 45–64. 10.1016/B978-0-08-102310-5.00002-3. [DOI] [Google Scholar]
  22. Deng Y.; Pei C.; Arman H.; Dong K.; Xu X.; Doyle M. P. Syntheses of Tetrahydropyridazine and Tetrahydro-1,2-diazepine Scaffolds through Cycloaddition Reactions of Azoalkenes with Enol Diazoacetates. Org. Lett. 2016, 18 (22), 5884–5887. 10.1021/acs.orglett.6b02965. [DOI] [PubMed] [Google Scholar]
  23. Padwa A. Cycloaddition chemistry of carbonyl ylides for alkaloid synthesis. Russ. Chem. Bull. 2016, 65 (9), 2183–2194. 10.1007/s11172-016-1566-x. [DOI] [Google Scholar]
  24. Nakhla M. C.; Lee C.-W.; Wood J. L. Chemoselective Intramolecular Carbonyl Ylide Formation through Electronically Differentiated Malonate Diesters. Org. Lett. 2015, 17 (23), 5760–5763. 10.1021/acs.orglett.5b02847. [DOI] [PubMed] [Google Scholar]
  25. Navickas V.; Ushakov D. B.; Maier M. E.; Ströbele M.; Meyer H. J. Synthesis of the Guaianolide Ring System via Cycloaddition of a Bicyclic Carbonyl Ylide with Allyl Propiolate. Org. Lett. 2010, 12 (15), 3418–3421. 10.1021/ol1012185. [DOI] [PubMed] [Google Scholar]
  26. Selden D. A.; Hodgson D. M.. Aldehyde and Ketone Functions Further Substituted on Oxygen; Elsevier Ltd., 2005; pp 309–353. [Google Scholar]
  27. L’Esperance R. P.; Ford T. M.; Jones M. Reaction of dicarbomethoxycarbene with acetaldehyde and simple ketones. J. Am. Chem. Soc. 1988, 110 (1), 209–213. 10.1021/ja00209a034. [DOI] [Google Scholar]
  28. Talinli E. N.; Anaç O.; Kumbaracı I. V. Competing Formations of Oxonium and Carbonyl Ylides with Carbonylcarbenes. Helv. Chim. Acta 2003, 86 (8), 2779–2783. 10.1002/hlca.200390227. [DOI] [Google Scholar]
  29. Kharasch M. S.; Rudy T.; Nudenberg W.; Büchi G. Reactions of diazoacetates and diazoketones. I. Reaction of ethyl diazoacetate with cyclohexanone and with acetone. J. Org. Chem. 1953, 18 (8), 1030–1044. 10.1021/jo50014a018. [DOI] [Google Scholar]
  30. Landgrebe J. A.; Iranmanesh H. Regiospecificity of enol ether formation in the catalyzed decomposition of ethyl diazoacetate in the presence of unsymmetrical ketones. J. Org. Chem. 1978, 43 (6), 1244–1245. 10.1021/jo00400a049. [DOI] [Google Scholar]
  31. Lottes A. C.; Landgrebe J. A.; Larsen K. Regio- and diastereoselectivity of enol ether formation by 1,4-sigmatropic shifts of hydrogen in carbonyl ylides. Tetrahedron Lett. 1989, 30 (31), 4089–4092. 10.1016/S0040-4039(00)99329-8. [DOI] [Google Scholar]
  32. Lottes A. C.; Landgrebe J. A.; Larsen K. Catalyst dependent mechanistic paths in the reactions of ethyl diazoacetate with β-keto esters. Tetrahedron Lett. 1989, 30 (31), 4093–4096. 10.1016/S0040-4039(00)99330-4. [DOI] [Google Scholar]
  33. Busch-Petersen J.; Corey E. J. A Rhodium(II) Catalytic Approach to the Synthesis of Ethers of a Minor Component in a Tautomeric Set. Org. Lett. 2000, 2 (11), 1641–1643. 10.1021/ol005964+. [DOI] [PubMed] [Google Scholar]
  34. Green S. P.; Wheelhouse K. M.; Payne A. D.; Hallett J. P.; Miller P. W.; Bull J. A. Thermal Stability and Explosive Hazard Assessment of Diazo Compounds and Diazo Transfer Reagents. Org. Process Res. Dev. 2020, 24 (1), 67–84. 10.1021/acs.oprd.9b00422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Doyle M. P. Catalytic methods for metal carbene transformations. Chem. Rev. 1986, 86 (5), 919–939. 10.1021/cr00075a013. [DOI] [PubMed] [Google Scholar]
  36. Tortoreto C.; Achard T.; Austeri M.; Zeghida W.; Lacour J. Original reactivity of 3-diazo---ketoesters catalyzed by CpRu complexes. Chimia 2014, 68 (4), 243–247. 10.2533/chimia.2014.243. [DOI] [PubMed] [Google Scholar]
  37. Austeri M.; Rix D.; Zeghida W.; Lacour J. CpRu-Catalyzed O-H Insertion and Condensation Reactions of alpha- Diazocarbonyl Compounds. Org. Lett. 2011, 13, 1394–1397. 10.1021/ol2000815. [DOI] [PubMed] [Google Scholar]
  38. Tortoreto C.; Achard T.; Egger L.; Guénée L.; Lacour J. Synthesis of spiro ketals, orthoesters and orthocarbonates by CpRu-catalyzed decomposition of b-diazo---ketoesters. Org. Lett. 2016, 18 (2), 240–243. 10.1021/acs.orglett.5b03380. [DOI] [PubMed] [Google Scholar]
  39. For details on the product of double carbene addition, see eq S1 in the Supporting Information.
  40. Tortoreto C.; Achard T.; Zeghida W.; Austeri M.; Guénée L.; Lacour J. Enol-Acetal Synthesis via Carbenoid C-H Insertions into Tetrahydrofurans Catalyzed by CpRu Complexes. Angew. Chem., Int. Ed. 2012, 51, 5847–5851. 10.1002/anie.201201541. [DOI] [PubMed] [Google Scholar]
  41. Achard T.; Tortoreto C.; Poblador-Bahamonde A. I.; Guénée L.; Bürgi T.; Lacour J. CpRu-catalyzed carbene insertions into epoxides: 1,4-dioxene synthesis via SN1-like chemistry with retention of configuration. Angew. Chem., Int. Ed. 2014, 53 (24), 6140–6144. 10.1002/anie.201402994. [DOI] [PubMed] [Google Scholar]
  42. Egger L.; Guénée L.; Bürgi T.; Lacour J. Regioselective and Enantiospecific Synthesis of Dioxepines by CpRu-Catalyzed Condensations of Diazocarbonyls and Oxetanes. Adv. Synth. Catal. 2017, 359 (17), 2918–2923. 10.1002/adsc.201700638. [DOI] [Google Scholar]
  43. Kündig E. P.; Monnier F. R. Efficient synthesis of tris(acetonitrile)-(eta(5)-cyclopentadienyl)ruthenium(II) hexafluorophosphate via ruthenocene. Adv. Synth. Catal. 2004, 346 (8), 901–904. 10.1002/adsc.200404124. [DOI] [Google Scholar]
  44. Achard T.; Egger L.; Tortoreto C.; Guenée L.; Lacour J. Preparation and structural characterization of [CpRu(1,10-phenanthroline)(CH3CN)][X] and precursor complexes (X= PF6, BArF, TRISPHAT-N). Helv. Chim. Acta 2020, 103, e2000190 10.1002/hlca.202000190. [DOI] [Google Scholar]
  45. For 3eA and 3vA, two geometrical isomers are formally possible. Herein, the compounds are represented as their most stable (E)-3eA and (Z)-3vA geometries. See Figure S1 and related explanations.
  46. The substituents probably induce small but significant changes to the preferred chair conformation of the substrates that favor the (preferentially axial) proton loss and hence the enol formation.
  47. This regioselectivity corresponds, by analogy with base-mediated reactions, to the malonate functionalization of the kinetic rather than the thermodynamic enolates.
  48. Mekelburger H. B.; Wilcox C. S.. 2.06 Formation of Enolates. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel P., Ed.; Elsevier: Amsterdam, 2014; pp 243–272. [Google Scholar]
  49. Johnson F. Allylic strain in six-membered rings. Chem. Rev. 1968, 68 (4), 375–413. 10.1021/cr60254a001. [DOI] [Google Scholar]
  50. Hoffmann R. W. Allylic 1,3-strain as a controlling factor in stereoselective transformations. Chem. Rev. 1989, 89 (8), 1841–1860. 10.1021/cr00098a009. [DOI] [Google Scholar]
  51. With unprotected epiandrosterone, O–H insertion was observed instead. With cyclohexenone as substrate, cyclopropanation occurred preferentially instead of the enol ether formation.
  52. Complete computational details for this transformation together with the full analysis of ylide reactivity and the possible involvement of the Ru catalyst are provided in the Supporting Information. A particular attention is given to the formation of cyclic dioxolene intermediates that behaves as a resting state for the reaction (Figure S10).
  53. Lempenauer L.; Lemière G.; Duñach E. Cyclisation Reactions Involving Alkyl Enol Ethers. Adv. Synth. Catal. 2019, 361 (23), 5284–5304. 10.1002/adsc.201900478. [DOI] [Google Scholar]
  54. In these experiments, we could not find evidence for I-elimination processes, which would have formed potassium enolates and carbenoid intermediates.
  55. Oliveira B. L.; Stenton B. J.; Unnikrishnan V. B.; de Almeida C. R.; Conde J.; Negrao M.; Schneider F. S. S.; Cordeiro C.; Ferreira M. G.; Caramori G. F.; Domingos J. B.; Fior R.; Bernardes G. J. L. Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation. J. Am. Chem. Soc. 2020, 142 (24), 10869–10880. 10.1021/jacs.0c01622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Fürstner A. Gold and platinum catalysis—a convenient tool for generating molecular complexity. Chem. Soc. Rev. 2009, 38 (11), 3208–3221. 10.1039/b816696j. [DOI] [PubMed] [Google Scholar]
  57. Zhang L.; Sun J.; Kozmin S. A. Gold and platinum catalysis of enyne cycloisomerization. Adv. Synth. Catal. 2006, 348 (16–17), 2271–2296. 10.1002/adsc.200600368. [DOI] [Google Scholar]
  58. Harrak Y.; Blaszykowski C.; Bernard M.; Cariou K.; Mainetti E.; Mouries V.; Dhimane A.-L.; Fensterbank L.; Malacria M. PtCl2-catalyzed cycloisomerizations of 5-en-1-yn-3-ol systems. J. Am. Chem. Soc. 2004, 126 (28), 8656–8657. 10.1021/ja0474695. [DOI] [PubMed] [Google Scholar]
  59. Méndez M.; Munoz M. P.; Nevado C.; Cardenas D. J.; Echavarren A. M. Cyclizations of enynes catalyzed by PtCl2 or other transition metal chlorides: Divergent reaction pathways. J. Am. Chem. Soc. 2001, 123 (43), 10511–10520. 10.1021/ja0112184. [DOI] [PubMed] [Google Scholar]
  60. Fürstner A.; Stelzer F.; Szillat H. Platinum-catalyzed cycloisomerization reactions of enynes. J. Am. Chem. Soc. 2001, 123 (48), 11863–11869. 10.1021/ja0109343. [DOI] [PubMed] [Google Scholar]
  61. Chatani N.; Furukawa N.; Sakurai H.; Murai S. PtCl2-catalyzed conversion of 1, 6-and 1, 7-enynes to 1-vinylcycloalkenes. Anomalous bond connection in skeletal reorganization of enynes. Organometallics 1996, 15 (3), 901–903. 10.1021/om950832j. [DOI] [Google Scholar]
  62. Unlike the reactions of TIPS enol ethers, which generate the “kinetic” trisubstituted enols after proton loss, see; Magnus P.; Mugrage B. New trialkylsilyl enol ether chemistry. Regiospecific and stereospecific sequential electrophilic addition. J. Am. Chem. Soc. 1990, 112 (1), 462–464. 10.1021/ja00157a079. [DOI] [Google Scholar]; Reactions of 6a–6c form the tetrasubstituted enol derivatives.
  63. Mukaiyama T.; Banno K.; Narasaka K. New cross-aldol reactions. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride. J. Am. Chem. Soc. 1974, 96 (24), 7503–7509. 10.1021/ja00831a019. [DOI] [Google Scholar]
  64. Kim D. Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene. Synlett 2013, 25 (01), 33–57. 10.1055/s-0033-1340050. [DOI] [Google Scholar]
  65. Miesch L.; Welsch T.; Rietsch V.; Miesch M. Intramolecular Alkynylogous Mukaiyama Aldol Reaction Starting from Bicyclic Alkanones Tethered to Alkynyl Esters: Formal Total Synthesis of (±)-Hamigeran B. Chem. - Eur. J. 2009, 15 (17), 4394–4401. 10.1002/chem.200802309. [DOI] [PubMed] [Google Scholar]
  66. Marzo L.; Pagire S. K.; Reiser O.; König B. Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis?. Angew. Chem., Int. Ed. 2018, 57 (32), 10034–10072. 10.1002/anie.201709766. [DOI] [PubMed] [Google Scholar]
  67. Douglas J. J.; Sevrin M. J.; Stephenson C. R. J. Visible Light Photocatalysis: Applications and New Disconnections in the Synthesis of Pharmaceutical Agents. Org. Process Res. Dev. 2016, 20 (7), 1134–1147. 10.1021/acs.oprd.6b00125. [DOI] [Google Scholar]
  68. Romero N. A.; Nicewicz D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116 (17), 10075–10166. 10.1021/acs.chemrev.6b00057. [DOI] [PubMed] [Google Scholar]
  69. Shaw M. H.; Twilton J.; MacMillan D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81 (16), 6898–6926. 10.1021/acs.joc.6b01449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Yoon T. P. Visible Light Photocatalysis: The Development of Photocatalytic Radical Ion Cycloadditions. ACS Catal. 2013, 3 (5), 895–902. 10.1021/cs400088e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Prier C. K.; Rankic D. A.; MacMillan D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113 (7), 5322–5363. 10.1021/cr300503r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Zeitler K. Photoredox Catalysis with Visible Light. Angew. Chem., Int. Ed. 2009, 48 (52), 9785–9789. 10.1002/anie.200904056. [DOI] [PubMed] [Google Scholar]
  73. King K. A.; Spellane P. J.; Watts R. J. Excited-state properties of a triply ortho-metalated iridium(III) complex. J. Am. Chem. Soc. 1985, 107 (5), 1431–1432. 10.1021/ja00291a064. [DOI] [Google Scholar]
  74. Sun J.; Wu W.; Zhao J. Long-Lived Room-Temperature Deep-Red-Emissive Intraligand Triplet Excited State of Naphthalimide in Cyclometalated IrIII Complexes and its Application in Triplet-Triplet Annihilation-Based Upconversion. Chem. - Eur. J. 2012, 18 (26), 8100–8112. 10.1002/chem.201200224. [DOI] [PubMed] [Google Scholar]
  75. Loertscher B. M.; Castle S. L.. 4.13 Radical Cyclizations and Sequential Radical Reactions. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel P., Ed.; Elsevier: Amsterdam, 2014; pp 742–809. [Google Scholar]
  76. McCourt R.; Scanlan E. M. 5-exo versus 6-endo Thiyl-Radical Cyclizations in Organic Synthesis. Helv. Chim. Acta 2019, 102 (11), e1900162 10.1002/hlca.201900162. [DOI] [Google Scholar]
  77. Bicyclic products 8, 10a, 10b, and 13 present core structures found in natural products such as pestaloficiol G and rotalin A (Figure S2).

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