Introduction {#sec1}
============

2-Pyranones ([Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}A) 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.^[@ref1]^ Typical 2-pyranones such as triacetic acid and tetraacetic acid lactones can be used as precursors for the synthesis of solanopyrones, pheromones, α-chymotrypsins, and other biologically relevant compounds.^[@ref2]^ For example, warfarin is a weak inhibitor of HIV protease^[@ref3]^ and also interrupts HIV replication,^[@ref4]^ whereas arisugacin A has been identified for potential treatment of Alzheimer's disease and dementia,^[@ref5]^ and pentahydro-3-aryl-1-oxopyrano-\[4,3-*b*\]\[1\]benzopyrans inhibits tumor growth by up to 100%.^[@ref6]^ As such, 2-pyranones and their substituted derivatives are versatile units in the preparation of biologically relevant small molecules.

![(A) 2-Pyranone with positions labeled to describe functionalization; (B) nickel catalyzed route to prepare functionalized 2-pyranones from diyne and CO~2~;^[@ref8]^ (C) Baylis--Hillman based method for the preparation of functionalized 2-pyranones;^[@ref9]^ (D) route to 2-pyranone derivative through D--A cyclization catalyzed by a Pd(II) complex;^[@ref10]^ (E) work reported herein in which the functionalized 2-pyranone **3** is prepared from a silyl ketene, by way of intermediate **2**.](ao-2018-01531h_0001){#fig1}

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-4-ynoic acids to obtain a mixture of 6-substituted 5-iodo-2(2*H*)-pyranone and (*E*)-5-(1-iodoylidene)-2(5*H*)-furanone.^[@ref7]^ 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 [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}B).^[@ref8]^ 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 [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}C).^[@ref9]^ More recently, electrocyclization has been exploited as the key step in the synthesis of 2-pyranones, using transition metal complexes based on palladium,^[@ref10]−[@ref12]^ ruthenium,^[@ref13],[@ref14]^ rhodium,^[@ref15],[@ref16]^ or gold.^[@ref17]−[@ref19]^ 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 [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}D). Although these approaches provide access to various 2-pyranones functionalized at the α, β, γ, and/or δ positions, they require metal catalysts and/or multiple steps with low atom efficiency.

Herein, we report the synthesis of a highly functionalized 2-pyranone bearing three unique silyl groups (compound **3**) by a transition metal-free thermal rearrangement approach ([Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}E). *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 ^1^H, ^13^C, ^29^Si, 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 ^1^H 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 2-pyranone 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.

Results and Discussion {#sec2}
======================

TBDPS ketene **1** was prepared from ethyl vinyl ether following an established protocol and purified by distillation.^[@ref20]^ 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 ester^[@ref21]^ or amide,^[@ref22]^ respectively. In an effort to understand the reactivity of silyl ketenes and produce well-defined oligomers,^[@ref23]^ we treated **1** with lithium *tert*-butoxide (LiO^*t*^Bu). Thus, the reaction of **1** with LiO^*t*^Bu was expected to proceed by the nucleophilic addition of ^*t*^BuO^--^ 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](#sch1){ref-type="scheme"}](#sch1){ref-type="scheme"}. ^*t*^BuO^--^ 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 of **2**, which was protonated with a mild acid and isolated. The structure of **2** was verified by ^1^H, ^13^C, ^29^Si, 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](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf)). Furthermore, the structure was identified by single crystal XRD, as shown in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}A. The 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 H-bond is reflected in the HSQC NMR spectrum, where a singlet at 6.1 ppm in the ^1^H NMR spectrum correlates with a peak at 25.3 ppm in the ^13^C NMR spectrum ([Figure S2D](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf)).

![Single crystal XRD structures of (A) compound **2** and (B) compound **3**. \[Si\] = SiPh~2~^*t*^Bu.](ao-2018-01531h_0002){#fig2}

![Proposed Mechanism for the Conversion from **1** to **2**](ao-2018-01531h_0005){#sch1}

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 ^1^H, ^13^C, ^29^Si, HSQC, HMBC, and NOESY NMR, as well as ESI-MS and FTIR ([Figure S3](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf)). The crystal structure shown in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}B 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 γ-position 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 ^1^H NMR (50 °C in dioxane-*d*~8~). [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}A shows the ^1^H 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](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf). 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 [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}B shows the proposed structure of intermediate **6** and the HMBC NMR spectrum of the crude mixture after 13 h. Three-bond correlations from proton ① to carbon C~c~, proton ② to carbon C~c~, and proton ② to carbon C~g~ were observed, as well as ②--C~b~, ①--C~a~ and ①--C~d~ 2-bond couplings. Weak symmetrical peaks from protons ① and ② are 1-bond coupling: ①--C~e~ and ②--C~f~. The chemical structure of byproduct **10** is confirmed by ^1^H, ^13^C, ^29^Si, HSQC, and HMBC NMR, NOESY NMR, FTIR, and ESI-MS of the isolated compound ([Figure S5](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf)).

![(A) ^1^H NMR spectra after heating **2** in dioxane-*d*~8~ 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.](ao-2018-01531h_0003){#fig3}

Integration of ^1^H 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](#fig4){ref-type="fig"}](#fig4){ref-type="fig"}). The concentration of **2** was 0.17 M at 0 h, and 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 (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.

![Plot of the concentration of starting material **2** (black squares), product **3** (red triangles), intermediate **6** (green circles), byproduct **10** (blue inverted triangles), and **3** + **6** (purple diamond) against time. Solid lines are kinetic data derived from steady state approximations.](ao-2018-01531h_0004){#fig4}

On the basis of the ^1^H NMR studies, a mechanism is proposed for the thermal rearrangement of **2** to **3** and **10**, as shown in [Scheme [2](#sch2){ref-type="scheme"}](#sch2){ref-type="scheme"}. In the formation of product **3**, a 1,5-hydride shift from carbon to oxygen first occurred to yield **4**, as pre-organized by the conformation of **2**, established by ^1^H 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 1,5-silyl shift yielded **8**, replacing the carbon--silicon bond with the more stable oxygen--silicon bond (i.e., an intramolecular Brook rearrangement).^[@ref24]^ Further tautomerization and Brook rearrangement then produced byproduct **10**, fully characterized in [Figure S5](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf). Using this proposed mechanism, the rate law for the reaction was derived with steady state approximations;^[@ref25],[@ref26]^ the concentration of **2**, **10**, and combined concentration of **3** and **6** ([Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}B, purple trace) gave good agreement and the lines fits shown in [Figure [4](#fig4){ref-type="fig"}](#fig4){ref-type="fig"}, with *R* values of 0.99, 0.99, and 0.96, respectively (see [Appendix S3](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf) for details).

![Proposed Mechanism for the Conversion of **2** to **3** and **10**\
\[Si\] = SiPh~2~^*t*^Bu](ao-2018-01531h_0006){#sch2}

Conclusions {#sec3}
===========

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 an unidentifiable mixture of compounds is obtained under other conditions (solvents, alkoxide counterion, silyl substituents, see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf) 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](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf)). 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 2-pyranone scaffold of interest for various biologically active targets.

The Supporting Information is available free of charge on the [ACS Publications website](http://pubs.acs.org) at DOI: [10.1021/acsomega.8b01531](http://pubs.acs.org/doi/abs/10.1021/acsomega.8b01531).Synthetic details, characterization spectra, and crystallographic data ([PDF](http://pubs.acs.org/doi/suppl/10.1021/acsomega.8b01531/suppl_file/ao8b01531_si_001.pdf))

Supplementary Material
======================

###### 

ao8b01531_si_001.pdf

The authors declare no competing financial interest.

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.
