3-Methyl-2-((methylthio)methyl)but-2-enal

Abstract

During the Swern oxidation of 3-methylbut-3-en-1-ol, an unexpected C-C bond formation product, 3-methyl-2-(methylthio)but-2-enal, was obtained. Its structure was characterized using ¹H-NMR, ¹³C-NMR, and HRMS. Based on the classical Swern oxidation mechanism and the unique structural features of the substrate, we propose a plausible reaction pathway. This discovery not only provides insights into the selection of oxidation conditions for 1, 1-disubstituted homoallylic alcohols with analogous structures but also offers a viable synthetic route for the preparation of compounds containing the 3-methyl-2-(methylthio)but-2-enal motif.

1. Introduction

Swern oxidation represents a widely utilized oxidation methodology in organic synthesis, primarily employed for the conversion of primary and secondary alcohols to their corresponding aldehydes and ketones under exceptionally mild conditions. This reaction protocol is characteristically conducted at low temperature through sequential activation of DMSO with oxalyl chloride, followed by alcohol activation and subsequent quenching with organic bases. Historically, the conceptual foundation originated from Kornblum and co-workers’ seminal work on DMSO-mediated oxidations [1]. Subsequently, Pfitzner and Moffatt achieved significant advancement by developing an alternative activation system employing DCC and phosphoric acid [2]. Ultimately, Swern and co-workers systematically optimized the reaction conditions, conclusively establishing oxalyl chloride as the most efficient activating reagent [3,4,5,6]. This critical optimization led to the development of the contemporary Swern oxidation protocol, which has gained predominant acceptance in synthetic chemistry due to its operational simplicity, excellent functional group tolerance, and minimized side reactions characteristic of classical oxidation methods.

However, in practical implementations of Swern-type oxidations, a certain amount of methylthio-methylated byproduct has been empirically correlated with multiple reaction parameters [7]. During the final step of synthesizing the potential antidiabetic agent PNU-91325 (2) (oxidation of a pyridinol 1 to ketone 2), the use of TEA led to the presence of 10–25% impurity 2′ in the product (Figure 1A) [8]. This issue persisted even when replacing TEA with DIPEA, suggesting that the observed impurity likely originated from nucleophilic attack of imide species on the reactive sulfonium intermediate, thereby introducing a sulfur-containing side chain at the nitrogen atom of the imide group.

In contrast, during the practical synthesis of the CCR5 antagonist RO5114436 (Figure 1B) [9], when oxidation of alcohol 3 was performed under Parikh–Doering conditions, the resulting sulfide byproduct 4′ was formed through a Pummerer rearrangement after the generation of a sulfur ylide via the action of triethylamine on the hydroxyl-activated species.

2. Results and Discussion

During the Swern oxidation of 3-methylbut-3-en-1-ol (5), an unexpected C-C bond formation product, 3-methyl-2-(methylthio)but-2-enal (6), was obtained in 11% yield. According to previous studies [4], considering the presence of chlorosulfonium salts in the Swern oxidation system and the homoallylic alcohol structure of the substrate, we propose that compound 5 was initially oxidized to intermediate Int-1 under oxidative conditions, followed by deprotonation at the α-position of the aldehyde by triethylamine to yield Int-2. Concurrently, as the temperature increased, the residual dimethylchlorosulfonium salt in the system underwent Pummerer rearrangement to generate chlorodimethyl sulfide. Subsequently, Int-2 participated in an S_N2 reaction with chlorodimethyl sulfide to form a C-C bond. Finally, under basic conditions, the double bond isomerized to the conjugated position, yielding the α,β-unsaturated aldehyde 6 (Figure 2).

3. Materials and Methods

All reagents and chemicals were obtained from commercial sources, Energy Chemical^® (Anqing, China). Further purifications and drying via standard methods were used when necessary. Except as indicated otherwise, reactions were magnetically stirred and monitored via thin-layer chromatography (TLC) using Silica Gel 60 F254 plates (Merck^®, Darmstadt, Germany) and visualized via fluorescence quenching under UV light. In addition, compounds on the TLC plate were visualized with a spray of 5% w/v phosphomolybdic acid (PMA) in ethanol and with subsequent heating. Chromatographic purification of products (flash chromatography) was performed on Silica Gel 60 (230–400 mesh) (Merck^®, Darmstadt, Germany). All evaporation of organic solvents was carried out with a rotary evaporator. Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated. ¹H NMR and ¹³C NMR spectra were recorded on a 400 M instrument as stated. Chemical shifts for ¹H NMR and ¹³C NMR spectra were reported in ppm (δ) (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad signal) and were referenced to either TMS (δ_H = 0.00 ppm, δ_C = 0.0 ppm) or residual undeuterated solvent as an internal standard (CDCl₃: δ_H = 7.26 ppm, δ_C = 77.0 ppm). High-resolution mass spectra (HRMS) were recorded on aOrbitrap Exploris 120 mass spectrometer (Thermo Fisher Scientific^®, Vernon Hills, IL, USA) using an electrospray ionization (ESI) technique.

Synthesis

At −78 °C, oxalyl chloride (7.4 mL, 87 mmol) was dissolved in 500 mL of dry dichloromethane, followed by the slow dropwise addition of DMSO (12.4 mL, 174 mmol). The reaction was allowed to proceed for 15 min until no gas evolution was observed. 3-Methylbut-3-en-1-ol (5.9 mL, 58 mmol) was dissolved in 80 mL of dry dichloromethane and added dropwise to the system via a constant-pressure dropping funnel. After reacting at −78 °C for 45 min, triethylamine (40.0 mL, 290 mmol) was added to quench the reaction. The mixture was then warmed to room temperature and stirred overnight, followed by the addition of 150 mL of water. The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and subjected to flash column chromatography on silica gel, using petroleum ether–ethyl acetate (v/v = 50:1) as the eluent, yielding 920 mg of an orange–red oily liquid (6, 11% yield) and 3.80 g of an light yellow oily liquid (3-methylbut-3-enal, 78% yield).

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 3.39 (s, 2H), 2.23 (s, 3H), 2.06 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 189.7, 157.9, 134.0, 27.6, 23.7, 19.6, 16.0. R_f = 0.72 (PE/EtOAc = 10:1, PMA). Electrospray ionization (ESI) m/z calculated for [M + H]⁺ C₇H₁₃OS⁺ = 145.0682 found 145.0687.