Silver-Catalyzed Radical Umpolung Cross-Coupling of Silyl Enol Ethers with Activated Methylene Compounds: Access to Diverse Tricarbonyl Derivatives

Abstract

A silver-catalyzed protocol for the intermolecular radical umpolung cross-coupling protocol of silyl enol ethers with activated methylene compounds is disclosed. The protocol exhibits excellent functional group tolerance, enabling the expedient preparation of a variety of tricarbonyl compounds. Preliminary mechanistic investigations suggest that the reaction proceeds through a process involving free radicals in which silver oxide has a dual role, acting as both a catalyst and a base.

Introduction

Catalytic radical carbon–carbon (C–C) cross-coupling reactions constitute privileged platforms in chemical synthesis, especially for the synthesis of natural products, pharmaceuticals, and materials.^1,2 Although significant progress has been achieved over the past two decades, there is still strong interest in developing novel radical C–C coupling reactions using platform chemicals.

Enolates and β-dicarbonyl compounds are versatile building blocks in organic synthesis, commonly used in cross-coupling reactions.^3,4 Thus far, several notable transformations between these coupling partners have been disclosed, providing access to a wide range of tricarbonyl compounds (Figure 1). Unfortunately, several of the existing protocols suffer from significant drawbacks, including the need for stoichiometric quantities of chemical oxidants, limited functional group tolerance, and a propensity for competitive side reactions or low yields. In 1987, Corey and Chosh reported an innovative approach for accessing 1-alkoxy-1,2-dihydrofurans, involving the intermolecular cross-coupling of enol ethers with β-dicarbonyl compounds.⁵ Later, Parsons and co-workers employed this strategy for achieving alkylation of enol ethers or enol esters with 2-methyl-1,3-dicarbonyl compounds, providing tricarbonyl compounds bearing a quaternary carbon center.⁶ However, these approaches rely on the utilization of superstoichiometric amounts of chemical oxidants, such as manganese(III) acetate, and highly elaborate starting materials to form the intended products. In 2016, Christoffers and co-workers utilized a novel umpolung approach for the oxidative cross-coupling reaction of β-dicarbonyl compounds with enol acetates by employing catalytic amounts of cerium trichloride hydrate as a one-electron oxidant.⁷ In this strategy, although the issues of employing stoichiometric metal-based oxidants were circumvented, a large excess of one of the coupling partners is required, thus significantly reducing the atom economy of the developed protocol. In 2019, Hilt and co-workers demonstrated the electrochemical synthesis of C–C bonds between β-dicarbonyl compounds and an excess of the silyl enol ether coupling partner (5.0 equiv) in the presence of catalytic amounts of manganese salts.⁸ However, the developed methodology is limited to alkyl alkenyl silyl ethers and typically results in moderate yields. In 2015, we disclosed that silver demonstrates remarkable catalytic activity in triggering the free radical coupling between activated methylene compounds and isocyanides.⁹ Furthermore, we recently reported a silver-catalyzed protocol for the controlled intermolecular cross-coupling between various silyl enol ethers that proceeds through a process involving free radicals.^10,11 Inspired by these earlier synthetic protocols, we herein address the limitations of the previously disclosed cross-coupling manifolds involving silyl enol ethers and activated methylene compounds by employing silver catalysis (Figure 1). The developed approach offers a convenient method for the selective synthesis of diverse tricarbonyl scaffolds under mild reaction conditions while utilizing nearly stoichiometric quantities of the two coupling partners.

Figure 1.

Cross-coupling reactions between enolates and β-dicarbonyl compounds.

Results and Discussion

At the onset of our investigations, silyl enol ether 1a and ethyl acetoacetate (2a) were used as model substrates for the optimization of the oxidative cross-coupling platform (see Table 1). To our delight, conducting the reaction in MeCN at ambient temperature and under an argon atmosphere in the presence of AgF (20 mol %) and bromobenzene (2 equiv) yielded the desired tricarbonyl compound 3a in 33% isolated yield after 6 h (Table 1, entry 1). Encouraged by these results, we proceeded to conduct a comprehensive examination of additional silver-based precursors encompassing Ag₂O, Ag₂CO₃, AgOTf, AgBF₄, and AgOAc. This demonstrated that the reactivity of Ag₂O was superior to those of the other silver salts (Table 1, entries 2–6, respectively). Other metal-based precursors, including CuI and Pd(OAc)₂, did not afford any detectable amounts of product 3a (Table 1, entries 7 and 8, respectively). Subsequently, the yield of cross-coupling product 3a was significantly enhanced to 53% by substituting MeCN as the solvent with 1,4-dioxane (Table 1, entry 9). Conversely, the application of nonane or polar solvents, such as DMF, toluene, and DCE, had an adverse impact on the reaction (Table 1, entries 10–12, respectively). However, when EtOH was used as a protic solvent, the corresponding ketone was exclusively produced from the silyl enol ether (Table 1, entry 13). Control experiments validate that molecular oxygen is essential for the reaction, increasing the yield to 83% (Table 1, entry 14). Reducing the catalyst loading from 30 to 20 and 10 mol % significantly impacts the reaction outcomes; a catalyst loading of 20 mol % is adequate for the transformation (Table 1, entries 15 and 16, respectively). According to our prior experience and the control experiments, we concluded that bromobenzene does not have a substantial impact on the developed reaction (Table 1, entries 17 and 18). Additionally, a significant quantity of cross-coupling product 3a can also be produced. The optimal reaction conditions are highlighted in entry 18 of Table 1.

Table 1. Optimization of the Reaction Conditions^a,^b.

entry	[M]	solvent	yield (%)b
1	AgF	MeCN	33
2	Ag2O	MeCN	48
3	Ag2CO3	MeCN	46
4	AgOTf	MeCN	0
5	AgBF4	MeCN	0
6	AgOAc	MeCN	26
7	CuI	MeCN	0
8	Pd(OAc)2	MeCN	0
9	Ag2O	1,4-dioxane	53
10	Ag2O	DMF	42
11	Ag2O	toluene	47
12	Ag2O	DCE	31
13	Ag2O	EtOH	0
14c	Ag2O	1,4-dioxane	83
15c,d	Ag2O	1,4-dioxane	86
16c,e	Ag2O	1,4-dioxane	57
17c,f	Ag2O	1,4-dioxane	82
18c,d,f	Ag2O	1,4-dioxane	85

^aReactions were carried out with 1a (1.0 mmol), 2a (0.5 mmol), a catalyst (30 mol %), and PhBr (1.0 mmol) in a solvent (2.0 mL) at ambient temperature under argon for 6 h.

^bIsolated yields of 3a after purification by column chromatography.

^cReactions under air.

^dWith 20 mol % catalyst.

^eWith 10 mol % catalyst.

^fReaction in the absence of PhBr.

Upon identifying the optimal reaction conditions for the developed transformation (Table 1, entry 18), we commenced our investigations by examining whether the protocol could be applied to various coupling partners (Scheme 1). A collection of differently functionalized silyl enol ethers 1 participated in the cross-coupling reaction with activated methylene compounds 2, resulting in the formation of the corresponding products 3 in good to excellent yields (Scheme 1). For example, aryl-based silyl enol ether motifs containing electron-donating or electron-withdrawing moieties exhibited good tolerance, resulting in the formation of the corresponding products 3b–3q in high yields. Gratifyingly, the successful utilization of heteroaryl silyl ethers and aromatic ring silyl ethers, such as 2-naphthyl and 2-furyl, resulted in the generation of the corresponding adducts 3r and 3s, demonstrating the compatibility of the established protocol. Additionally, other activated methylene compounds, such as dimethyl/diethyl malonate, 2,2-dimethyl-1,3-dioxane-4,6-dione, and malononitrile, were also suitable coupling partners, providing the corresponding products 3t–3y in yields ranging from 82% to 93%. Gratifyingly, subjecting alkyl-based silyl enol ethers to ethyl (4-methoxybenzoyl)acetate afforded the desired products 3z and 3aa in 76% and 85% yields, respectively. Unfortunately, 2-methyl-1,3-dicarbonyl compounds, which would allow the formation of tricarbonyl compounds (3ab) featuring a quaternary carbon center, are not tolerated by the protocol. To further explore the synthetic utility of the developed protocol, the applicability of the silver-catalyzed approach was highlighted by conducting the reaction at a 5 mmol scale with 1a and 2a, thus leading to the successful synthesis of product 3a (1.01 g, 73%) in a straightforward fashion (see Scheme 1). The conceived protocol successfully provides expedient access to highly decorated tricarbonyl derivatives, which can be used for further diverse synthetic manipulations. For example, tricarbonyl compound 3a was employed as an entry to tetracarbonyl compound 4 and elaborate thiophene 5 upon reaction of 3a with 4-methoxystyrene and diphosphorus pentasulfide, respectively (see Scheme 1).^12,13

Scheme 1. Silver-Catalyzed Synthesis of Tricarbonyl Derivatives,

All reactions were carried out with 1a (1.0 mmol), 2a (0.5 mmol), and Ag₂O (20 mol %) in 1,4-dioxane (2.0 mL) at room temperature under air for 6 h.

Yields are of isolated products after purification by column chromatography.

To gain insight into the operating mechanism, radical inhibitor (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) was added to the reaction mixture. TEMPO was shown to effectively suppress the silver-mediated cross-coupling reaction between silyl enol ethers 1a and 2b. Instead, adduct 6 could be isolated in 67% yield, indicating that the reaction proceeds through a free radical pathway.^14,15 On the basis of the experimental results and literature precedent,^3,9,16,17,18 a plausible mechanism for the cross-coupling reaction is proposed (Scheme 2). Initially, deprotonation and one-electron oxidation of activated methylene substrate 2 by Ag^I result in the formation of α-carbonyl radical A. The oxidizing behavior of silver can be explained by the frequently observed silver mirror during the reactions. Then, α-carbonyl radical A undergoes radical addition to silyl enol ether 1 to form carbon-centered radical B, which participates in a second single-electron transfer (SET) event to furnish cross-coupling product 3 along with regeneration of Ag^I upon reoxidation by O₂,¹⁹ thereby closing the catalytic cycle. In the envisioned mechanism, Ag₂O has a dual role and functions as both a base and a catalyst.

Scheme 2. Radical Trapping Experiments and Mechanistic Hypothesis.

Conclusions

In conclusion, we devised a silver-catalyzed intermolecular cross-coupling reaction between silyl enol ethers and activated methylene compounds. The protocol demonstrates excellent functional group tolerance, enabling expedient access to a variety of synthetically valuable tricarbonyl derivatives. Preliminary mechanistic investigations suggest that the reaction proceeds through a free radical-based pathway. The disclosed method offers a versatile framework for the oxidative formation of carbon–carbon bonds from simple starting materials.

Experimental Section

General Information

All reagents were purchased from commercial sources and used without treatment, unless otherwise indicated. The products were purified by column chromatography over silica gel. ¹H nuclear magnetic resonance (NMR) and ¹³C NMR spectra were recorded at 25 °C on a Varian spectrometer at 400 and 101 MHz, respectively, with TMS as the internal standard. Mass spectra were recorded on a BRUKER AutoflexIII Smartbeam MS spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker microTof instrument using ESI-TOF. Infrared spectroscopy was performed on a ThermoFisher Scientific Nicolet iS10 FTIR spectrometer.

General Procedure for the Preparation of Silyl Enol Ethers²⁰

NaI (1.4 mmol, 1.4 equiv) was placed in a tube and dried under vacuum using a heat gun. Upon being cooled to room temperature, the tube was filled with argon. Then, dry CH₃CN (1.0 mL), ketone (1.0 mmol, 1.0 equiv), and Et₃N (1.5 mmol, 1.5 equiv) were successively added. The mixture was cooled with an ice/water bath, and TMSCl (1.3 mmol, 1.3 equiv) was added at 0 °C. The cooling bath was removed, and the mixture was stirred at room temperature for 12 h. Then, the volatile components were evaporated under a vacuum. The solid residue was washed with petroleum ether (3 × 15 mL), and the petroleum ether layers were decanted and filtered through a cotton plug. The combined filtrates were concentrated on a rotary evaporator, furnishing the silyl enol ether, which was used without further purification.

General Procedure for the Preparation of Products 3

To a 10 mL Schlenk tube equipped with a magnetic stir bar were added silyl enol ether 1 (1 mmol, 2.0 equiv), compound 2 (0.5 mmol, 1.0 equiv), Ag₂O (0.1 mmol, 0.2 equiv), and 1,4-dioxane (2.0 mL). The reaction mixture was stirred at room temperature in air for ∼6 h. The resulting mixture was concentrated, and the residue was taken up in ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. Purification of the crude product by column chromatography (silica gel; petroleum ether/ethyl acetate) afforded product 3.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c00310.

• Experimental procedures, characterization data, and copies of NMR spectra for all obtained products (PDF)

• FAIR data, including the primary NMR FID files, for compounds 3a–3z, 3aa, and 4–6 (ZIP)

Author Contributions

^∥ T.L. and Q.Y. contributed equally to this work.

The authors declare no competing financial interest.