3-Methyl-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)butan-2-ol

Abstract

The reactions of dialkylzinc reagents with ketones are scarcely studied. In this paper, we describe a previously unknown direct alkylation of substituted 2-acetylpyridine with diisopropyl zinc, which gave a corresponding novel alcohol with 82% yield.

1. Introduction

The chemistry of organozinc compounds has become increasingly popular in recent years. As dialkylzinc reagents are less nucleophilic, they are more chemoselective in alkylation reactions compared to lithium and organomagnesium reagents [1]. By using chiral catalysts in the reactions of alkyl zinc reagents with carbonyl compounds, a broad range of optically active alcohols, including alkyl, aryl, vinyl, and alkynyl-substituted compounds, can be prepared [2,3,4,5].

Of particular interest is the Soai autocatalytic amplifying reaction, in which the interaction between diisopropylzinc and pyrimidine aldehyde can result in the spontaneous generation of chiral products from achiral starting compounds [6,7,8,9].

Most of the transformations described in the literature involve the reactions of organozinc reagents with aldehydes. Direct alkylations of ketones without a catalyst are unknown [10]. However, a preliminary transmetalation into copper or palladium organic compounds can solve this problem [11,12]. It is also possible to use the Reformatsky reaction [13].

Here, we report a previously unknown alkylation of 2-acetylpyridine 2 containing TMS-acetylenic substituent with diisopropylzinc. This is the first example of a non-catalytic ketone alkylation with diisopropylzinc. The reaction occurs under mild conditions providing a good yield of a single alkylated product 3.

2. Results and Discussion

Known ketone 2 was obtained via a modified literature procedure [6] from commercially available ketone 1 through the Sonogashira cross-coupling [14] (Scheme 1).

Because it has a six-membered heterocyclic ring in the molecule with a TMS-acetylenic linker in the p-position relative to a carbonyl group, 2-acetylpyridine 2 structurally resembles Soai aldehyde [6,15], and particularly Denmark aldehyde [8], with both demonstrating asymmetric autoamplifying catalysis (Scheme 2 and Scheme 3a,b). We are unaware of any reports on the reactions between diisopropylzinc and compound 2. The reaction of pyridinic ketone and dicyclopentylzinc yielded a reduction product [16] (Scheme 3c).

Ketone 2 is an oily liquid with a characteristic odor, which was isolated by distillation under low pressure. Its structure and composition were confirmed using NMR spectroscopy (Figure S1) and HRMS (Figure S2). The data obtained agree with those published in the literature [17].

The reaction of 2-acetylpyridine 2 with diisopropyl zinc was conducted at room temperature under an argon atmosphere (Scheme 4). After the reaction, alkylation product 3 was isolated as a colorless, oily substance with 82% yield.

In the ¹H NMR spectrum of the isolated compound 3, characteristic signals of the introduced i-Pr fragment were observed: two doublets of methyl groups at 0.64 and 0.96 ppm and a CH septet at 1.95 ppm, and also a singlet of the alcohol OH group at 4.82 ppm (Figure S3). HRMS (Figure S4) and IR (Figure S5) data were in accord with the structure 3.

Attempts to get optically active alcohol 3 by reacting ketone 2 with diisopropylzinc in the presence of a chiral catalyst, (1R,2S)-ephedrine (10 mol%), failed.

3. Materials and Methods

3.1. General Information

The 1-(5-Bromopyridin-2-yl)ethanone (Acros) and diisopropylzinc 1M solution in toluene (Sigma-Aldrich, St. Louis, MO, USA) were used as received without further purification. All reactions were carried out using standard Schlenk techniques under an argon atmosphere in oven-dried glassware with magnetic stirring. All solvents were purified and distilled using standard procedures. Analytical thin-layer chromatography (TLC) was carried out on Merck TLC plates (silica gel 60 F₂₅₄, 0.25 mm) using UV light (254 nm) as the visualizing agent. Flash column chromatography was performed using SepaFlash S-5101-0004 (irregular silica, 40–63 μm 60 Å, 4 g). IR spectra were recorded in the range of 4000–400 cm^–1 (16 scans, with a resolution of 2 cm^–1) using a Bruker (Billerica, MA, USA) ALPHA spectrometer with the thin layer technique. The spectra were analyzed using OPUS software, which was installed on a personal computer. NMR spectra were measured on a Bruker Avance 300 spectrometer at 300.13 MHz (¹H) and 75.47 MHz (¹³C) and a Bruker Avance 500 spectrometer at 500.13 MHz (¹H) and 125.77 MHz (¹³C) at 20 °C in deuterated chloroform. The chemical shifts (δ) are expressed in parts per million (ppm) and are calibrated using residual non-deuterated solvent peak as an internal reference (CDCl₃: δ_H 7.26, δ_C 77.16). All coupling constants (J) are reported in Hertz (Hz), and multiplicities are indicated as follows: s (singlet), d (doublet), sep (septet), and m (multiplet). High-resolution mass spectra (HRMS) were obtained through electrospray ionization (ESI) with positive (+) ion detection on a Bruker micrOTOF–QIII quadrupole time-of-flight mass spectrometer.

3.2. Chemical Synthesis

1-(5-((Trimethylsilyl)ethynyl)pyridin-2-yl)ethanone (2) was obtained using a modification of a published procedure [6]. A 100-mL Schlenk tube was charged with a magnetic stirrer, CuI (91 mg, 0.48 mmol, 0.048 eq), tetrakis(triphenylphosphine)palladium(0) (208 mg, 0.18 mmol, 0.018 eq), and ketone 1 (2.0 g, 10 mmol, 1.0 eq), sealed with a septum, and filled with argon through three vacuum-argon cycles. A quantity of 25 mL of THF and 10 mL of diisopropylamine were added to the flask via cannula. The yellowish turbid mixture was stirred vigorously and cooled in an ice bath. A trimethylsilylacetylene solution (1.57 mL, 110 mmol, 1.1 eq) in 3 mL of THF was added dropwise via syringe over a period of 30 min. After 30 min, the ice bath was removed, and the reaction mixture was stirred under argon overnight. The reaction mixture was diluted with 50 mL of THF and filtered under argon through a silica gel column. The eluate was concentrated to produce a black solid, which was then further purified by distillation in a vacuum (127 °C, 0.3 mm Hg) to obtain a brown oil with 84% (1.82 g) yield. R_f 0.78 (ethyl acetate—hexane, 1:1); ¹H NMR (CDCl₃, 300 MHz, ppm) δ 8.72–8.66 (1H, m, X-part of ABX-system, Py-H), 7.96 (1H, m, B-part of ABX-system, Py-H, J_AB = 8.1 Hz, J_BX = 0.4 Hz), 7.84 (1H, m, A-part of ABX-system, Py-H, J_AB = 8.1 Hz, J_AX = 2.0 Hz), 2.70 (3H, s, CH₃), 0.27 (9H, s, TMS); ¹³C{¹H} NMR (CDCl₃, 125 MHz, ppm) δ 199.52 (C=O), 151.83, 139.72, 131.72, 123.90, 120.95 (C_Py), 101.80, 101.11 (C≡), 25.93 (CH₃), –0.15 (CH₃(TMS)); HRMS (ESI) m/z 218.1004 (calcd for C₁₂H₁₆NOSi [M + H]⁺ 218.0996). The spectral characteristics are consistent with the literature data.

In order to 3-Methyl-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)butan-2-ol (3), a 25-mL Schlenk tube equipped with a magnetic stirrer and septum was charged with ketone 2 (55 mg, 0.25 mmol, 1.0 eq) and filled with argon through three vacuum-argon cycles. Then, 5 mL of toluene were added, and the mixture was stirred until all the ketone was dissolved. Diisopropyl zinc (1M, 0.75 mL, 3.0 eq) was added dropwise at ambient temperature. The reaction mixture was stirred overnight and was then quenched with an aqueous HCl solution (0.1 M, 10 mL). After stirring for 5 min, the reaction mixture was neutralized with a saturated solution of NaHCO₃ (10 mL). The organic phase was separated, and the yellow aqueous layer was extracted with CHCl₃ (3 × 10 mL). The solvent from the combined organic layers was removed in vacuo to provide a brown oily liquid, which was purified by column chromatography (SepaBean machine U100, silica gel, 4 g, 10 mL/min, hexane, product eluates after 1.5 CVs) to afford compound 3 with 82% (53 mg) yield. Colorless oil; R_f 0.72 (ethyl acetate—hexane, 1:1); ¹H NMR (CDCl₃, 300 MHz, ppm) δ 8.59–8.56 (1H, m, X-part of ABX-system, Py-H), 7.76–7.70 (1H, m, B-part of ABX-system, Py-H, J_AB = 8.1 Hz, J_BX = 0.9 Hz), 7.26–7.22 (1H, m, A-part of ABX-system, Py-H, J_AB = 8.1 Hz, J_AX = 2.1 Hz), 4.82 (1H, s, OH), 1.95 (1H, sep, J = 6.8 Hz, CH(iPr)), 1.47 (3H, s, CH₃), 0.96 (3H, d, J = 6.8 Hz, CH₃(iPr)), 0.64 (3H, d, J = 6.8 Hz, CH₃(iPr)), 0.26 (9H, TMS); ¹³C{¹H} NMR (CDCl₃, 75 MHz, ppm) δ 164.79, 150.23, 139.63, 119.10, 118.40 (C_Py), 101.51, 98.07 (C≡), 75.93 (C–OH), 38.67 (CH(iPr)), 26.17 (CH₃), 17.31, 17.03 (CH₃(i-Pr)), –0.03 (CH₃(TMS)); IR ν_max 3428 (OH), 2965 (C–H), 2163 (C≡C), 1593 (C=C), 1251 (Si–CH₃) cm⁻¹; HRMS (ESI) m/z 262.1631 (calcd for C₁₅H₂₄NOSi [M + H]⁺ 262.1622).

4. Conclusions

As a result of the reaction between 2-acetylpyridine 2 and diisopropylzinc in the absence of any catalysts, a new alcohol 3 was synthesized and characterized. This is a product of direct noncatalytic alkylation; it is the first example of a ketone being alkylated with diisopropylzinc without the use of a catalyst. This discovery expands the understanding of the chemistry of acetylpyridines and demonstrates the potential for noncatalytic alkylation of these compounds.