(S)-4-Isopropyl-5,5-diphenyloxazolidin-2-one

Abstract

(S)-4-Isopropyl-5,5-diphenyloxazolidin-2-one has been synthesized for the first time by the enantiospecific oxidative carbonylation of commercially available (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol. The cyclocarbonylation reaction was carried out at 100 °C in 1,2-dimethoxyethane (DME) as the solvent for 15 h, under 20 atm of a 4:1 mixture of CO–air and in the presence of the catalytic system PdI₂/KI (substrate:KI:PdI₂ molar ratio = 100:10:1), to give the oxazolidinone derivative in 81% isolated yield.

1. Introduction

Oxazolidin-2-ones are a very important class of heterocyclic derivatives. Many compounds possessing the oxazolidinone scaffold present important pharmacological activities, antimicrobial activity in particular [1]. Moreover, chiral oxazolidinones are widely used as chiral auxiliaries in organic synthesis [2].

Among the possible synthetic methods for preparing oxazolidin-2-ones from acyclic substrates, the direct metal-catalyzed oxidative carbonylation of β-amino alcohols with CO is one of the most attractive, in consideration of the large availability and inexpensiveness of carbon monoxide and the excellent atom economy of the process, which produces water as the only coproduct, and its enantiospecificity (when starting from enantiopure substrates) [3]. Many oxazolidin-2-one derivatives have been prepared by this approach using different types of catalytic systems [3]. Between them, the PdI₂/KI catalytic system, developed by our research group, has proved valuable for the preparation of a plethora of oxazolidinones starting from the corresponding β-amino alcohols under relatively mild reaction conditions [3,4,5,6].

In this Short Note, we report a further application of our method to the use of sterically demanding (S)-(1) as the starting material, for the first synthesis of (S)-4-isopropyl-5,5-diphenyloxazolidin-2-one (2) by a direct carbonylation approach (Scheme 1). In fact, this derivative, which is a useful chiral auxiliary [7], has been synthesized so far from 1 by alternative methods, which involve the use of activated carbonyl derivatives instead of CO [7,8,9,10,11].

2. Results and Discussion

The enantiospecific cyclocarbonylation of 1 was carried out at 100 °C in 1,2-dimethoxyethane (DME) as the solvent (substrate concentration: 0.5 mmol of 1 per mL of DME), under 20 atm (at 25 °C) of a 4:1 mixture of CO-air, in the presence of catalytic amounts of PdI₂ (1 mol%) in conjunction with KI (10 mol%). After 15 h reaction time, the TLC analysis of the reaction crude showed the complete conversion of the substrate and the formation of a product, which was isolated by crystallization and identified as 2 by full spectroscopic (IR, ¹H-NMR, ¹³C-NMR) and spectrometric (MS) characterization. Oxazolidinone 2 was smoothly formed in an isolated yield as high as 81%, which is a noteworthy result, considering the high steric hindrance present in the substrate. Mechanistically, the formation of 2 can be rationalized as shown in Scheme 2 (anionic iodide ligands are omitted for clarity): nitrogen palladation (with formal elimination of HI) is followed by CO insertion (to give a carbamoylpalladium iodide intermediate) and intramolecular nucleophilic displacement by the hydroxyl group to give 2, Pd(0) and a second mol of HI. Pd(0) is then reoxidized back to PdI₂ by the action of oxygen, in the presence of the HI generated before.

3. Materials and Methods

Solvents and chemicals were reagent grade and used without further purification. Reactions were analyzed by thin layer chromatography (TLC) on silica gel 60 F254 (Merck s.p.a., Vimodrone, Milano, Italy). Starting material 1 was commercially available (Sigma-Aldrich Italia s.r.l., Milano, Italy). Evaporation refers to the removal of solvent under reduced pressure. Melting point is uncorrected. ¹H-NMR and ¹³C-NMR spectra were recorded at 25 °C on a 300 MHz spectrometer (Bruker DPX Avance 300, Bruker Italia s.r.l., Milano, Italy) in DMSO-d₆ solutions with Me₄Si as the internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. IR spectrum was taken with a JASCO FTIR 4200 spectrometer (JASCO Europe s.r.l., Cremella, Italy). Mass spectra were obtained using a Shimadzu QP-2010 GC-MS apparatus (Shimadzu Italia s.r.l., Milano, Italy) at 70 eV ionization voltage. Optical rotation was measured on an Atago Polax-2L polarimeter (Atago Italia s.r.l., Rozzano, Italy).

Synthetic procedure for the preparation of 2. A 250 mL stainless steel autoclave was charged in the presence of air with PdI₂ (7.1 mg, 0.020 mmol), KI (32.5 mg, 0.20 mmol), and a solution of 1 (500.0 mg, 1.96 mmol) in DME (3.9 mL). While stirring, the autoclave was pressurized with CO (16 atm) and air (up to 20 atm) and then heated at 100 °C for 15 h. After cooling, the autoclave was degassed and solvent evaporated. Some of the crude product was already present in the suspension in the reaction mixture. The crude oxazolidin-2-one 2 was purified by the crystallization in CHCl₃/hexane. Yield: 448 mg, 81% based on starting 1. Pure 2 was a white solid, m.p. = 246–247 °C. [α]${}_D^{25}$ (acetone, c = 7.02 × 10⁻³ g∙mL⁻¹) = −253.6 (lit. [12]: [α]${}_D^{25}$ (CHCl₃, c = 2 × 10⁻³ g∙mL⁻¹) = −255.2); IR (KBr): ν = 1767 (s), 1744 (s), 1493 (w), 1450 (m), 1366 (m), 1315 (w), 1250 (m), 1227 (m), 1185 (m), 1042 (m), 1003 (m), 976 (m), 764 (m), 745 (m), 706 (m) cm^–1; ¹H-NMR (300 MHz, DMSO-d₆): δ = 8.14 (s, 1H, NH), 7.68 (d, J = 7.4, 2H, aromatic), 7.47 (d, J = 7.4, 2 H, aromatic), 7.40–7.20 (m, 6H, aromatic), 4.44 (s, CHNH), 1.92–1.75 (m, 1H, CHMe₂), 0.91 (d, J = 6.7, 3 H, CH₃CHCH₃), 0.50 (d, J = 6.7, 3 H, CH₃CHCH₃); ¹³C-NMR (75 MHz, DMSO-d₆): δ = 157.3, 145.2, 139.7, 128.3, 128.0, 127.6, 127.1, 125.4, 125.0, 87.6, 64.1, 29.0, 20.1, 14.4; GC/MS: m/z = 281 (M⁺, 3), 238 (2), 195 (9), 194 (14), 184 (14), 183 (100), 167 (10), 165 (18), 152 (5), 116 (3), 105 (56), 91 (4), 77 (18). The spectroscopic data were in good agreement with those reported [10]. Copies of the IR, ¹H-NMR, ¹³C-NMR, and MS spectra are given in the Supplementary Materials.