Letter pubs.acs.org/OrgLett
Synthesis of Spiro Ketals, Orthoesters, and Orthocarbonates by CpRu-Catalyzed Decomposition of α‑Diazo-β-ketoesters Cecilia Tortoreto,† Thierry Achard,† Léo Egger,† Laure Guénée,‡ and Jérôme Lacour*,† †
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland Laboratory of Crystallography, University of Geneva, Quai Ernest Ansermet 24, CH-1211 Geneva 4, Switzerland
‡
S Supporting Information *
ABSTRACT: Reactions of α-diazo-β-ketoesters with cyclic ketones, lactones, and carbonates are reported. Thanks to the combined use of salt [CpRu(CH3CN)3][BArF] and 1,10phenanthroline as catalyst for the diazo decomposition, effective and practical syntheses of spiro bicyclic ketals, orthoesters, and orthocarbonates are afforded.
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[BArF] 7a (Cp = C5H5, BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate)6 and 1,10-phenanthroline (phen)7 as diazo decomposition catalyst.8 A mild counterion effect9 is also reported as 7a is shown to be more reactive than classical [CpRu(CH3CN)3][PF6] 7b;10 the increased reactivity of 7a allowing in general a use of a 1:1 stoichiometry between diazo reagents and reactive carbonyl groups in these intermolecular condensations. Recently, in the context of syn-stereoselective epoxide openings, it was shown that [CpRu(CH3CN)3][BArF] 7a efficiently catalyzes the decomposition of α-diazo-β-ketoesters and promotes condensation reactions of the generated carbenes with oxirane substrates.6,11 This salt leads to higher substrate conversion, reaction selectivity, and catalyst turnovers than 7b.12 It was then logical to test the combination of 7a and phen in other condensation reactions, and that of reactive carbonyl groups in particular. First, the catalytic combination of 7a and phen was tested with cyclohexanone 8a. α-Diazo-β-ketoesters 3a to 3f were used as substrates in a 1:1 stoichiometry, and positive results were obtained in these initial experiments (Scheme 2). In practice, diazo 3a to 3f (1 equiv) were added to solutions of 8a (1 equiv) in CH2Cl2 together with [CpRu(CH3CN)3][BArF] 7a and phen (2.5 mol % each). After 3 h at 60 °C, full conversions were usually achieved; the conversions being determined by 1H NMR spectroscopy (400 MHz, crude mixtures).13 With bulkier tBu ester 3d, a prolonged reaction time of 4.5 h was necessary to afford full decomposition of the diazo reagent. Spiroketal adducts 4a to 4d were isolated in moderate to good yields (55−79%, Scheme 2). For the formation of 4a, it was shown that the reaction is easily scaled up to a 1 g scale (see Supporting Information). With a linear propyl chain α to the carbonyl group (3e), similar reactivity and yields were obtained (4e, 85%), while, with a phenyl substituent, the reaction was slower and a lower yield of ketal was achieved (4f, 15%).14 With these reactions and
lectrophilic metal carbenes are known to react with nucleophilic carbonyl groups and form carbonyl ylides.1 These reactive intermediates, metal-free 1 or metal-bound 2 (Scheme 1), behave as 1,3-dipoles and are known to react in [3 + Scheme 1. Selective Formation of Spiro Ketals, Orthoesters, and Orthocarbonates
2]-dipolar cycloadditions to yield oxygenated 5-membered heterocycles (Scheme 1, route a).2 Alternatively, carbonyl ylides 1 or 2 may condense to form epoxides and dioxolenes (routes b and c). While these intramolecular reactions occur with carbonyl ylides derived from aldehydes and ketones,2b,c,3 they are unknown with ylides made by additions of esters and carbonates.1a,4,5 Herein, in a general development, reactions of α-diazo-β-ketoesters 3 with cyclic ketones are reported but also with lactones and cyclic carbonates. Effective and reliable syntheses of spiro ketals 4, orthoesters 5, and orthocarbonates 6 are afforded thanks to the combined use of [CpRu(CH3CN)3]© XXXX American Chemical Society
Received: November 25, 2015
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DOI: 10.1021/acs.orglett.5b03380 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
selectivity was confirmed with estrone 8m (Scheme 4) for which an excellent yield of product 4m was obtained (90%) albeit
Scheme 2. Spiro Ketal Synthesis: Initial Experiments
Scheme 4. Reactivity with Estrone
as a 1:1 mixture of diastereoisomers.15 This result shows that the dioxolene reactivity is general, even in the case of rigid sterically encumbered substrates. Treating cyclohexane-1,4-dione 8n with two equivalents of 3a afforded products of double cycloadditions and a 1:1 mixture of trans-4n and cis-4n′ was also obtained (Scheme 5). It was again conditions in hand, a comparison of the reactivity of BArF 7a and PF6 7b complexes was performed. The results are reported in Table S1 (Supporting Information). The difference is moderate for most substrates but strong in case of a steric hindrance, i.e., for 4d. As a rule, an increased reactivity is observed for the BArF complex 7a, which was kept for further experiments. Cyclic saturated and unsaturated ketones 8g to 8l were then used to afford spiro dioxolenes 4g to 4l as only products in yields up to 83% (Scheme 3). Epoxides were never observed in the
Scheme 5. Bis Spiro Ketal Synthesisa
Scheme 3. Spiro Ketal Synthesis: Extension
a Reaction conditions: 3a (2.0 equiv), 7a and phen (2.5 mol % each), 60 °C, CH2Cl2, 3 h, c = 0.5 M. OLEX views of the crystal structure of 4n and 4n′. Thermal ellipsoids are drawn at 50% probability.
possible to separate the adducts by chromatography (37 and 34% yield, respectively). The trans and cis configurations and the solid-state conformations were established by X-ray diffraction analyses.17 A mechanistic rationale, consistent with the experimental results, is proposed in Scheme 6. Complex 7a reacts with phen to generate [CpRu(phen)(CH3CN)][BArF], which, upon dissociation of acetonitrile, forms the 16-electron catalytically active species A. The diazo moiety reacts with A to afford metal carbene intermediate B by nitrogen extrusion. At this stage, a nucleophilic attack of the cyclic ketone occurs to form the carbonyl ylide intermediate C. Subsequent ring closure affords the desired products of condensation (C → D). The spiro products are then released and the catalytic cycle continues. Based on this proposal, the reactivity of lactones and cyclic carbonates with carbene intermediates of type B was envisaged. Saturated and unsaturated lactones 9a to 9f (Scheme 7) were first tested under previously developed conditions (3 h reaction time, 1 equiv of 3a). A lower reactivity was immediately noticed as conversions of only 60% were observed. To obtain the corresponding orthoesters 5a to 5f in moderate to good yields (57−82%), it was necessary to increase both reaction time (up to 24 h) and stoichiometry (3a, 3 equiv). As before, with unsaturated lactones 9d and 9e, evidence of competing
crude reaction mixtures nor cyclopropanes in the reactions of unsaturated substrates 8j and 8k.15 Increasing the ring size, from four to seven, improved the stability of the corresponding ketals. In fact, products 4 are quite sensitive to acidic conditions decomposing upon standing over silica gel and after a few hours in CDCl3. Although unlikely, the possibility to perform this reaction stereoselectively was examined with 4-tBu-cyclohexanone 8l (Scheme 3). As expected, a 1:1 mixture of diastereomers was afforded.16 The isomers of 4l displayed a rather large difference in retardation factors (0.57 and 0.43, TLC silica gel, pentane/ether 9:1) and could be separated on column chromatography (40 and 41%, respectively). This lack of B
DOI: 10.1021/acs.orglett.5b03380 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 8. Orthocarbonate Synthesisa
Scheme 6. Mechanistic Rational
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Only one diastereoisomer isolated.
Gutmann’s scale of solvent Lewis basicity indicates that ketones, esters, and (to a lesser degree) carbonates present similar Donor Numbers (15−18 kcal·mol−1).19 It is therefore more likely that lactones and cyclic carbonates are less nucleophilic than ketones for the trapping of the electrophilic carbene (step B → C, Scheme 6). In conclusion, using a combination of [CpRu(CH3CN)3][BArF] 7a and 1,10-phenanthroline, it was found that α-diazo-βketoesters 3 react with a large range of cyclic carbonyl moieties. The reaction conditions are mild and spiro ketals, orthoesters, and orthocarbonates are generated selectively. Due to a general acid sensitivity of the products, care must be taken during their purification, and moderate to good yields are obtained (up to 90%). Interestingly, these reactions seem to be the first examples of intermolecular condensations of metal carbenes with esters and carbonates leading afterward to an intramolecular ring closure. In terms of potential application, a use of compounds 4, 5, and 6 can be furthermore foreseen in protecting group strategies as masked forms of cyclic ketones, esters, and carbonates.
Scheme 7. Orthoester Synthesis
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03380. Experimental procedures and full spectroscopic data (PDF) Crystallographic information (CIF)
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cyclopropanation or epoxide formations could not be found. Also, using coumarin 9f, a complete formation of desired product was monitored but trioxospiro 5f decomposed partially during the chromatography (SiO2 or Al2O3) to be afforded in only 64% yield.18 Reactions with cyclic carbonates 10a to 10c to form corresponding adducts 6a to 6c were even slower (Scheme 8). Three days were necessary to ensure complete conversion. In the case of orthocarbonates 6a and 6b, the isolation was complicated by their sensitivity (yields up to 36% only). In the case of 6b, a 1:1 mixture of diastereoisomer was observed by 1H NMR analysis, and only one diastereoisomer could be isolated (27%). Using 6membered ring 10c, product 6c was however obtained in good yield (72%). This lower reactivity of lactones 9 and cyclic carbonates 10 is not trivially explained. One rationalization could have been a stronger complexation of catalyst [CpRu(phen)][BArF] A with compounds 9 or 10, which would have slowed the release of A and hence the catalytic cycle. However, a comparative analysis of
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the University of Geneva and the Swiss National Science Foundation for financial support. We acknowledge the contributions of the Sciences Mass Spectrometry (SMS) platform at the Faculty of Sciences, University of Geneva.
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REFERENCES
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DOI: 10.1021/acs.orglett.5b03380 Org. Lett. XXXX, XXX, XXX−XXX
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(13) Crude mixtures in these reactions contain only starting materials and products 4, 5, or 6 providing trivial NMR spectra with welldistinguished signals and excellent baselines. (14) The lower reactivity of diazo benzoylacetonates is common in this type of reactions. See refs 8o and 11. (15) Wang, H. B.; Guptill, D. M.; Varela-Alvarez, A.; Musaev, D. G.; Davies, H. M. L. Chem. Sci. 2013, 4, 2844−2850. (16) The diastereomeric ratio was determined by 1H NMR spectroscopy (400 MHz). (17) CCDC 1438101−1438102 contain the supplementary crystallographic data for this paper. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (18) Using 5-bromofuran-2(5H)-one and 3,4-dibromofuran-2(5H)one, no reactivity was detected. (19) The analysis is reported in the supporting information and the values are based on Cataldo, F. Eur. Chem. Bull. 2015, 4, 92−97 and references therein.
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DOI: 10.1021/acs.orglett.5b03380 Org. Lett. XXXX, XXX, XXX−XXX
