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Article Cite This: ACS Omega 2018, 3, 9419−9423
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Synthesis of Highly Functionalized 2‑Pyranone from Silyl Ketene Yuanhui Xiang,† Arnold. L. Rheingold,‡ and Emily B. Pentzer*,† †
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, United States Department of Chemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
‡
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S Supporting Information *
ABSTRACT: We report a highly functionalized 2-pyranone small molecule prepared from tert-butyl diphenyl silyl ketene using an alkoxide catalyst and thermally induced rearrangement. Treatment of the silyl ketene with a substoichiometric amount of alkoxide led to the formation of a trimer which was isolated and fully characterized; heating this trimer in a 1,4dioxane solution induced a thermal rearrangement, yielding the product 2-pyranone. The isolated intermediate and product are characterized by 1D and 2D nuclear magnetic resonance (NMR) spectroscopies, mass spectrometry, and single crystal X-ray diffraction. A mechanism for the thermally induced rearrangement is proposed based on 1H NMR studies, and a rate law is derived from the proposed mechanism with steady-state approximation. This work illustrates a route for the formation of highly functionalized and modifiable 2-pyranone motifs with potential biological activity. The formation of the trimer, and thus the functionalized 2-pyranone, is highly dependent on the silyl substituents and alkoxide counterion and thus indicates the intriguing reactivity of highly functionalized small molecules.
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synthesis of solanopyrones, pheromones, α-chymotrypsins, and other biologically relevant compounds.2 For example, warfarin is a weak inhibitor of HIV protease3 and also interrupts HIV replication,4 whereas arisugacin A has been identified for potential treatment of Alzheimer’s disease and dementia,5 and pentahydro-3-aryl-1-oxopyrano-[4,3-b][1]benzopyrans inhibits tumor growth by up to 100%.6 As such, 2-pyranones and their substituted derivatives are versatile units in the preparation of biologically relevant small molecules. A number of different approaches have been used to synthesize functionalized 2-pyranones. Rossi and co-workers performed the iodolactonization of 5-substituted (Z)-2-en-4ynoic acids to obtain a mixture of 6-substituted 5-iodo-2(2H)pyranone and (E)-5-(1-iodoylidene)-2(5H)-furanone.7 Alternatively, Louie and co-workers reported the synthesis of highly functionalized 2-pyranones by the cycloaddition of tethered alkynes and carbon dioxide using a nickel catalyst (Figure 1B).8 A three-step Baylis−Hillman-based reaction, including lactonization and oxidation, was used by Kim and co-workers to synthesize functionalized 2-pyranones from α,β-unsaturated esters and ketones (Figure 1C).9 More recently, electrocyclization has been exploited as the key step in the synthesis of 2-pyranones, using transition metal complexes based on palladium,10−12 ruthenium,13,14 rhodium,15,16 or gold.17−19 These catalysts coordinate to the two reactive components, alkyne and acrylate derivatives, and facilitate the direct formation of substituted 2-pyranones at elevated temperatures (Figure 1D). Although these approaches provide access to various 2-pyranones functionalized at the α, β, γ, and/or δ
INTRODUCTION 2-Pyranones (Figure 1A) are prevalent moieties in numerous natural products isolated from plants, animals, marine organisms, bacteria, fungi, and insects. These 6-membered lactones exhibit a broad range of biological activities, such as antifungal, antibiotic, cytotoxic, neurotoxic, and phytotoxic properties.1 Typical 2-pyranones such as triacetic acid and tetraacetic acid lactones can be used as precursors for the
Figure 1. (A) 2-Pyranone with positions labeled to describe functionalization; (B) nickel catalyzed route to prepare functionalized 2-pyranones from diyne and CO2;8 (C) Baylis−Hillman based method for the preparation of functionalized 2-pyranones;9 (D) route to 2-pyranone derivative through D−A cyclization catalyzed by a Pd(II) complex;10 (E) work reported herein in which the functionalized 2-pyranone 3 is prepared from a silyl ketene, by way of intermediate 2. © 2018 American Chemical Society
Received: July 3, 2018 Accepted: August 3, 2018 Published: August 17, 2018 9419
DOI: 10.1021/acsomega.8b01531 ACS Omega 2018, 3, 9419−9423
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of 2, which was protonated with a mild acid and isolated. The structure of 2 was verified by 1H, 13C, 29Si, heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond coherence (HMBC), and nuclear Overhauser effect (NOESY) NMR spectroscopies, as well as electrospray ionization mass spectrometry (ESI-MS) and Fourier-transform infrared spectroscopy (FTIR) (Figure S2). Furthermore, the structure was identified by single crystal XRD, as shown in Figure 2A. The
positions, they require metal catalysts and/or multiple steps with low atom efficiency. Herein, we report the synthesis of a highly functionalized 2pyranone bearing three unique silyl groups (compound 3) by a transition metal-free thermal rearrangement approach (Figure 1E). tert-Butyl diphenyl silyl (TBDPS) ketene is treated with an alkoxide, leading to the isolation of a trimer (compound 2), which undergoes a thermal rearrangement upon heating in dioxane. The chemical structures of compounds 2 and 3 are verified by 1H, 13C, 29Si, and 2D nuclear magnetic resonance (NMR) spectroscopies, as well as mass spectrometry and single crystal X-ray diffraction (XRD). Mechanisms are proposed for the conversion of 1 to 2 and 2 to 3, as well as the structures of intermediates and byproduct. Using kinetic data obtained from 1H NMR studies, a rate law is derived from the proposed mechanism with steady-state approximation. This work provides insight into the reactivity of highly functionalized small molecules in the preparation of 2pyranone small molecules with potential applications across a broad range of fields. Variation of reaction conditions, specifically different silyl substituents and alkoxide counterions, led to a complex mixture of products; thus, reactivity is defined by subtle changes in reaction variables.
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Figure 2. Single crystal XRD structures of (A) compound 2 and (B) compound 3. [Si] = SiPh2tBu.
RESULTS AND DISCUSSION TBDPS ketene 1 was prepared from ethyl vinyl ether following an established protocol and purified by distillation.20 The central carbon of silyl ketenes is electron-deficient and is typically attacked by a nucleophile, such as an alcohol or amine, to form an α-silyl ester21 or amide,22 respectively. In an effort to understand the reactivity of silyl ketenes and produce well-defined oligomers,23 we treated 1 with lithium tertbutoxide (LiOtBu). Thus, the reaction of 1 with LiOtBu was expected to proceed by the nucleophilic addition of tBuO− at the central carbon to yield an enolate which could subsequently react with another equivalent of 1. However, isolation of 2 indicated that this reaction did not occur, as no tert-butoxide group was present. A proposed mechanism for the formation of 2 from 1 is shown in Scheme 1. tBuO− likely acted as a base, not a nucleophile, and deprotonated the terminal carbon of 1, yielding an alkynolate which then served as a nucleophile and added to the central carbon of a second equivalent of 1. The resulting enolate then underwent C-alkylation by addition to another equivalent of 1. Subsequent 6-exo-dig cyclization, Brook rearrangement, and ring opening yielded the carboxylate
crystal structure reveals an intramolecular interaction [e.g., hydrogen bond (H-bond)] between the carbonyl oxygen and the hydrogen on the γ-carbon, forming a 6-membered ring and pre-organizing the molecule for subsequent intramolecular reaction (vide infra). Whereas this conformation may also result from a minimization of A1,3-strain, an intramolecular Hbond is reflected in the HSQC NMR spectrum, where a singlet at 6.1 ppm in the 1H NMR spectrum correlates with a peak at 25.3 ppm in the 13C NMR spectrum (Figure S2D). A solution of 2 in dioxane was heated to 70 °C for 12 h, resulting in complete disappearance of 2 and isolation of 3 in >75% yield. The chemical structure of this highly functionalized 2-pyranone was determined by 1H, 13C, 29Si, HSQC, HMBC, and NOESY NMR, as well as ESI-MS and FTIR (Figure S3). The crystal structure shown in Figure 2B reveals that the planar 2-pyranone core bears three distinct TBDPS groups: one TBDPS group attached to the β-position through an oxygen, one TBDPS group directly attached to the γposition of the 2-pyranone core, and one TBDPS group attached through a methylene unit at the δ-position. Thus, not only does the 2-pyranone 3 contain a high degree of functionalization, but it also contains orthogonal silyl functionalities (silyl ether, aryl silane, and alkyl silane). The conversion of 2 to 3 was monitored in situ using 1H NMR (50 °C in dioxane-d8). Figure 3A shows the 1H NMR spectra of the reaction before heating (0 h), after 13 h at 50 °C (∼40% consumption of 2), and after 78 h at 50 °C (>95% of 2). A signature peak of 2 is apparent at 4.50 ppm (black box); full spectra are available in Figure S4. After 13 h, peaks attributed to product 3 are evident at 5.03 and 2.50 ppm (red boxes), as well as two other species assigned as intermediate 6 (peaks at 5.14 and 2.56 ppm, green boxes) and byproduct 10 (peaks at 5.24 and 3.06 ppm, blue boxes). Heating the reaction at 50 °C for a total of 78 h led to the disappearance of all peaks attributed to 2 and 6 and the presence of only product 3 and byproduct 10. Figure 3B shows the proposed structure of intermediate 6 and the HMBC NMR spectrum of the crude
Scheme 1. Proposed Mechanism for the Conversion from 1 to 2
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Figure 3. (A) 1H NMR spectra after heating 2 in dioxane-d8 at 0, 13, and 78 h, with the chemical shifts of starting material 2 (black box), product 3 (red boxes), intermediate 6 (green boxes), and byproduct 10 (blue boxes) identified; (B) 2D HMBC NMR spectrum of compound 2 heated to 50 °C in dioxane after 13 h with the structure intermediate 6 shown and correlations illustrated.
(green circles). In the first 16 h of the reaction, the concentration of product 3 and byproduct 10 increased at similar rates, but then diverged (red triangles and blue inverted triangles for 3 and 10, respectively), when the concentration of 10 plateaued and the concentration of 3 continued to increase. On the basis of the 1H NMR studies, a mechanism is proposed for the thermal rearrangement of 2 to 3 and 10, as shown in Scheme 2. In the formation of product 3, a 1,5hydride shift from carbon to oxygen first occurred to yield 4, as pre-organized by the conformation of 2, established by 1H NMR and XRD (vide supra). Compound 4 then underwent a 6-exo-dig cyclization, followed by proton transfer to form the 6-membered ring 5. Tautomerization of 5 yielded 6, the intermediate identified by NMR spectroscopy; proton transfer readily transformed 6 to product 3. Alternatively, byproduct 10 was obtained upon rotation of 2 to access 7; a subsequent 1,5silyl shift yielded 8, replacing the carbon−silicon bond with the more stable oxygen−silicon bond (i.e., an intramolecular Brook rearrangement).24 Further tautomerization and Brook rearrangement then produced byproduct 10, fully characterized in Figure S5. Using this proposed mechanism, the rate law for the reaction was derived with steady state approximations;25,26 the concentration of 2, 10, and combined concentration of 3 and 6 (Figure 3B, purple trace) gave good agreement and the lines fits shown in Figure 4, with R values of 0.99, 0.99, and 0.96, respectively (see Appendix S3 for details).
mixture after 13 h. Three-bond correlations from proton ① to carbon Cc, proton ② to carbon Cc, and proton ② to carbon Cg were observed, as well as ②−Cb, ①−Ca and ①−Cd 2-bond couplings. Weak symmetrical peaks from protons ① and ② are 1-bond coupling: ①−Ce and ②−Cf. The chemical structure of byproduct 10 is confirmed by 1H, 13C, 29Si, HSQC, and HMBC NMR, NOESY NMR, FTIR, and ESI-MS of the isolated compound (Figure S5). Integration of 1H NMR spectra over the course of the reaction for the conversion of 2 to 3 was used to observe the evolution of intermediate 6, byproduct 10, and product 3 (Figure 4). The concentration of 2 was 0.17 M at 0 h, and
Figure 4. Plot of the concentration of starting squares), product 3 (red triangles), intermediate byproduct 10 (blue inverted triangles), and 3 + 6 against time. Solid lines are kinetic data derived approximations.
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CONCLUSIONS In summary, we have reported the synthesis of a highly functionalized 2-pyranone small molecule using silyl ketene as a starting material, alkoxide catalyst, and a thermally driven rearrangement. The starting material, intermediate, product, and byproduct were thoroughly characterized by various techniques, including 1D and 2D NMR spectroscopies, mass spectrometry, and single crystal XRD. Mechanisms are proposed for conversion of silyl ketene 1 to intermediate trimer 2 and for transformation of intermediate 2 to product 3, as well as byproduct 10. Central to this process are the identities of the silyl substituents, counterion, and solvent, as
material 2 (black 6 (green circles), (purple diamond) from steady state
upon reaction, this concentration decreased (black squares) and the concentration of intermediate 6, product 3, and byproduct 10 all increased (green circles, red triangles, and blue inverted triangles, respectively). The concentration of 6 increased for the first 32 h, reaching a maximum concentration of 0.06 M and then decreased until 6 was no longer observed 9421
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Scheme 2. Proposed Mechanism for the Conversion of 2 to 3 and 10a
a
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an unidentifiable mixture of compounds is obtained under other conditions (solvents, alkoxide counterion, silyl substituents, see Supporting Information for details). The kinetic profile of the thermally induced transformation was evaluated using steady state approximations, supporting the proposed mechanism. The 2-pyranone 3 is highly functionalized with reactive handles that present opportunities for further modification; for example, the silyl ether can be easily converted to an alcohol by treatment with a base, and the alpha position can be brominated by treatment with bromine (see Figures S7 and S8). Ongoing work focuses on further establishing how to exploit the many unique moieties for further modification of compound 3. This work gives insight into the small molecule reactivity and provides access to a 2pyranone scaffold of interest for various biologically active targets.
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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/acsomega.8b01531. Synthetic details, characterization spectra, and crystallo-
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graphic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Emily B. Pentzer: 0000-0001-6187-6135 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS E.B.P. and Y.X. thanks the American Chemical Society Petroleum Research Fund Doctoral New Investigator Program (ACS PRF #55563-DNI7) and CWRU College of Arts and Sciences for financial support and NSF MRI-1334048 for NMR instrumentation.
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