5-Diethoxymethyl-1,1-diethoxy-5-hydroxyundeca-3,6-diyn-2-one

Abstract

As an extension of our study of the reactivity of derivatives of 3,3,4,4-tetraethoxybut-1-yne, attempts have been made to achieve acid-catalyzed deacetalization of the diethoxymethyl moieties in 5-diethoxymethyl-1,1,2,2-tetraethoxyundeca-3,6-diyn-5-ol. That was not achieved; instead, only deketalization occurred and afforded the title compound, indicating that the triple bond activates the propargylic diethoxy moiety relative to the other acetal groups.

1. Introduction

Since the preparation of 3,3,4,4-tetraethoxybut-1-yne (1) [1], we have studied the chemistry of a range of derivatives of this functionalized alkyne and developed syntheses of groups of compounds, including furans, deoxygenated carbohydrate analogues, triazoles, and a variety of other heterocycles [2,3]. It is indeed significant that not a single successful synthesis involved deacetalization of the diethoxymethyl moiety from 1, and this stimulated us to study the reactivity of chain-elongated derivatives of 1, with at least one additional diethoxymethyl group, under conditions ideal for deacetalization. We started out by exposing 5-diethoxymethyl-1,1,2,2-tetraethoxyundeca-3,6-diyn-5-ol (2) to such reaction conditions, and to our surprise, this compound appeared to give one product only, i.e., the corresponding ketone 5-diethoxymethyl-1,1-diethoxy-5-hydroxyundeca-3,6-diyn-2-one (3). This outcome inspired us to study the reactivity of several analogues of 2, but since these compounds could only be obtained in low to very low yields, the work was terminated. The results from the study of 2 nevertheless deserve publication, and they are reported here.

2. Results and Discussion

Diacetalmonoketal 2 was synthesized from 1,1-diethoxyoct-3-yn-2-one [4], which was prepared in the three different ways summarized in Scheme 1. The starting material in the first preparation was alkyne 1, which afforded 2 in 47% overall yield in a two-step synthesis involving butylation followed by deketalization (Scheme 1, route a). In the two other syntheses, the starting material was 1-hexyne, whose carbon chain could be elongated by attaching the α-ketoacetal functionality to C-1. A number of methods are available for the execution of this transformation, and we applied two, viz. the Dulou method [5] and the much older method developed by Wohl and Lange [6,7]. The former method employed 1,1-diethoxyacetonitrile (DAN) to achieve the chain extension and afforded 1,1-diethoxyoct-3-yn-2-one in 34% yield (Scheme 1, route b). When the latter was utilized and DAN was replaced by 1-(diethoxyacetyl)piperidine (DAP), however, a cleaner and much more efficient reaction took place, and the product was isolated in 78% yield (Scheme 1, route c).

With 1,1-diethoxyoct-3-yn-2-one at hand, the target compound for our investigation, diacetalmonoketal 2, was easily furnished by treating the ynone with the lithium acetylide of 1. Under optimum conditions, 2 was isolated in 65% yield (Scheme 2).

Several attempts were then made to accomplish the deacetalization and deketalization of 2 under conditions known to favor such reactions [8,9,10], with the backdrop that in addition to these reactions, the dipropargylic hydroxyl group might trigger rearrangements and also dehydration that might lead to complex reaction mixtures. It was therefore surprising to observe that when 2 was reacted with water in the presence of a catalytic amount of p-TsOH, only one transformation occurred, viz. deketalization to afford 5-diethoxymethyl-1,1-diethoxy-5-hydroxyundeca-3,6-diyn-2-one (3). At best, 3 was isolated in 60% yield (Scheme 2).

Considering the fact that 1,1-diethoxybut-3-yn-2-one is the only product formed when 1 is exposed to the same hydrolytic conditions as 2, the conversion of the 1,1,2,2-tetraethoxyethyl group in 2 to an α-ketoacetal functionality is not unexpected. The stability of the acetal function has reasonably been ascribed to the electron-withdrawing impact from the ynone moiety [1], which makes protonation of the ethoxy groups just unfavorable enough to prevent deacetalization. An equivalent impact is absent on the diethoxymethyl moiety attached to C-5, but it is apparent that this moiety is stabilized just enough by the collective effect of the inductive influence from the α-hydroxyl group, the impact from the two C-C triple bonds that can both be protonated and form hydrogen bonds, and the steric congestion at C-5. However, to draw a conclusion regarding the interplay between these effects, we must await further studies.

3. Conclusions

The title compound has been obtained pure in 30% overall yield from 1-hexyne via the intermediates 1,1-diethoxyoct-3-yn-2-one and 5-(diethoxymethyl)-1,1,2,2-tetraethoxyundeca-3,6-diyn-5-ol.

4. Materials and Methods

4.1. General Considerations

The chemicals were obtained from commercial suppliers and used without further purification. Anhydrous THF was prepared by using an MB-SPS-800 solvent-purification system. All reactions carried out under anhydrous conditions were performed in oven-dried (150 °C) glassware under nitrogen using the syringe–septum cap technique. Thin-layer chromatography (TLC) was performed using pre-coated aluminum TLC plates (Alugram, 0.20 mm Silica Gel 60 F₂₅₄) and eluting with mixtures of hexanes and ethyl acetate. Visualization of the chromatograms was carried out with phosphomolybdic acid (NH₄)₄MoO₄·4H₂O) in ethanol or ninhydrin stains. Flash-column chromatography (FC) was performed manually using silica gel from Fluka Analytical (230–400 mesh) and eluting with a mixture of hexanes and ethyl acetate. NMR spectra were recorded on a Bruker Biospin AV500 instrument (500 MHz for ¹H, 125 MHz for ¹³C) in CDCl₃ as solvent, using the solvent peaks as references in both ¹H- and ¹³C-NMR spectra (7.26 and 77.16 ppm, respectively). The chemical shifts are reported in ppm, the coupling constants (J) in Hz, and the multiplicity is given as s (singlet), d (doublet), t (triplet), and m (multiplet). Infrared (IR) spectra were recorded on a Nicolet Protege 460 FT-IR spectrophotometer with an attenuated total reflectance (ATR) unit attached. Samples were analyzed neat on a ZnSe crystal, and absorption peaks are reported in wavenumbers (cm⁻¹). High-resolution mass spectra (HRMS) were obtained on a JEOL AccuTOF T100GC mass spectrometer operated in ESI or APCI in positive mode. NMR and IR spectra and accurate-mass recordings are shown in the Supplementary Material.

4.2. Preparation of 1,1-Diethoxyoct-3-yn-2-one

4.2.1. From 3,3,4,4-Tetraethoxybut-1-yne (1)

An oven-dried, two-necked, round-bottomed flask, equipped with a magnetic stirrer, a condenser, and a septum, was flushed with N₂ and charged with anhydrous THF (20 mL) and alkyne 1 (1.25 g, 5.43 mmol). The resulting solution was cooled to −78 °C (acetone/dry ice), and a 2.5 M solution of BuLi in hexane (2.4 mL, 6.0 mmol) was added with a syringe over 5 min, producing a faint yellow solution. After stirring for 10 min, the reaction mixture was allowed to reach 0 °C (ice/water), and butyl iodide (1.10 g, 5.97 mmol) was added dropwise. As the ice melted, the reaction was allowed to stir for 20 h, followed by the dropwise addition of a saturated aq solution of NH₄Cl (30 mL), and extraction with DCM (3 × 30 mL) took place. The combined organic extracts were dried (MgSO₄) and concentrated in vacuo on a rotary evaporator. The resulting residue was purified by FC (9:1 hexanes/ethyl acetate) and afforded 0.85 g (55%) of essentially pure 1,1,2,2-tetraethoxyoct-3-yne as an oil.

¹H NMR (CDCl₃, 500 MHz): δ 4.35 (s, 1H), 3.83–3.66 (m, 4H), 2.27 (t, J = 7.1 Hz, 3H), 1.56–1.38 (m, 4H), 1.24 (t, J = 7.1 Hz, 6H), 1.21 (t, J = 7.1 Hz, 6H), 0.90 (t, J = 7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 104.3, 98.9, 88.3, 74.9, 64.9, 59.6, 30.7, 22.1, 18.7, 15.6, 15.4, 13.7. IR (neat) ν_max: 2974, 2931, 2874, 2242, 1444, 1388, 1370, 1327, 1252, 1114, 1072, 1015, 878, 803, 741. HRMS (APCI+/TOF): calcd for C₁₆H₃₀O₄Na [M+Na⁺] 309.20418, found 309.20399.

A round-bottomed flask, fitted with a condenser and magnetic stirrer, was charged with 1,1,2,2-tetraethoxyoct-3-yne (0.85 g, 3.0 mmol), p-TsOH (0.01 g, 0.06 mmol), acetone (6 mL), and water (2 mL) and stirred under reflux for 20 h. After cooling, filtration, and concentration on a rotary evaporator, brine (5 mL) was added. The product was extracted with diethyl ether (3 × 10 mL), and the combined organic phases were washed with a saturated solution of NaHCO₃ and dried (MgSO₄). Filtration and concentration in vacuo gave a residue, from which 0.53 g (85%) of 1,1-diethoxyoct-3-yn-2-one was isolated by FC (4:1 hexanes/ethyl acetate) as a clear, yellowish oil.

The spectroscopic data were in accordance with those reported in the literature [4].

4.2.2. From 1-Hexyne by the Dulou Method

An oven-dried, two-necked, round-bottomed flask, equipped with a magnetic stirrer, a condenser, and a septum, was flushed with N₂ and charged with 1-hexyne (3.23 g, 25.0 mmol) and anhydrous diethyl ether (100 mL). The resulting solution was cooled to 0 °C (water/ice) and BuLi (2.5 M solution in hexane) (10 mL, 25.0 mmol) was added over 5 min. The mixture was stirred for 15 min before diethoxyacetonitrile (2.05 g, 25.0 mmol) was added in one batch. The stirring continued at bath temperature for 1 h, water (100 mL) was added dropwise, and the hydrolysate was then stirred for 60 min. The product was isolated by extraction with diethyl ether (2 × 100 mL) in a separatory funnel; the combined organic extracts were dried (MgSO₄) and then concentrated in vacuo. From the resulting orange crude product, 1.78 g (34%) of essentially pure 1,1-diethoxyoct-3-yn-2-one was isolated by FC (9:1 hexanes/ethyl acetate) as a yellowish oil.

The spectroscopic data were in accordance with the literature [4].

4.2.3. From 1-Hexyne by the Wohl–Lang Method

An oven-dried, two-neck, round-bottomed flask, equipped with a magnetic stirrer, a condenser, and a septum, was flushed with N₂ and charged with anhydrous THF (12 mL) and 1-hexyne (0.33 g, 4.0 mmol). A 2.5 M hexane solution of EtMgBr (1.6 mL, 4.0 mmol) was then added dropwise and the resulting mixture was heated to 58 °C and left stirring for 1.5 h. 1-(Diethoxyacetyl)piperidine (0.87 g, 4.0 mmol) was then added neat and the mixture was stirred for 20 h. The reaction was quenched by a dropwise addition of 0.5 M H₂SO₄ (10 mL) and stirred for 1 h before being worked up by extraction with diethyl ether (2 × 10 mL). The combined organic extracts were dried (MgSO₄), filtered, and concentrated in vacuo on a rotary evaporator. TLC analysis of the residue revealed two products that were isolated by FC (4:1 hexanes/ethyl acetate) and gave 1,1-diethoxyoct-3-yn-2-one (0.66 g, 78%) and 7-(diethoxymethyl)trideca-5,8-diyn-7-ol (0.025 g, 4%) as a clear oil and a yellowish oil, respectively.

The spectroscopic data for 1,1-diethoxyoct-3-yn-2-one were in accordance with the literature [4].

The data for 7-(diethoxymethyl)trideca-5,8-diyn-7-ol were the following: ¹H NMR (CDCl₃, 500 MHz): δ 4.44 (s, 1H), 3.93–3.87 (m, 2H), 3.78–3.72 (m, 2H), 2.91 (s, 1H), 2.26 (t, J = 7.2 Hz, 4H), 1.55–1.49 (m, 4H), 1.46–1.38 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H), 0.90 (t, J = 7.2 Hz, 6H). ¹³C NMR (CDCl₃, 125 MHz): δ 105.6, 85.2, 78.3, 66.3, 65.8, 30.5, 22.1, 18.7, 15.4, 13.8. IR (neat): ν_max 3486, 2957, 2931, 2872, 2240, 1466, 1370, 1325, 1116, 1065, 1009, 913, 816, 741, 603, 550. HRMS (ESI+/TOF): calcd for C₁₈H₃₀O₃Na [M+Na⁺] 317.20926, found 317.20942.

4.3. Preparation of 5-(Diethoxymethyl)-1,1,2,2-tetraethoxyundeca-3,6-diyn-5-ol (2)

An oven-dried, two-necked, 25 mL round-bottomed flask, equipped with a magnetic stirrer, a condenser, and a septum, was flushed with N₂ and charged with 3,3,4,4-tetraethoxybut-1-yne (1) (0.124 g, 0.54 mmol) and anhydrous diethyl ether (7 mL). The resulting mixture was cooled to 0 °C (water/ice) before BuLi (0.22 mL, 2.5 M, 0.55 mmol) was added dropwise over 5 min. After stirring for 15 min, 1,1-diethoxyoct-3-yn-2-one (0.115 g, 0.54 mmol) was dissolved in 1 mL anhydrous diethyl ether and added dropwise to the mixture over 5 min. As the ice melted, the reaction was allowed to reach rt and kept stirring for 22 h. The reaction was then quenched with a saturated solution of NH₄Cl, and the hydrolysate was stirred for 1 h before being worked up by extraction with DCM (3 × 10 mL). The combined organic fractions were dried (MgSO₄), filtered, and concentrated in vacuo on a rotary evaporator to give a residue, from which the title compound (0.155 g, 65%) was isolated as a clear oil by FC (7:3 hexanes/ethyl acetate).

The spectroscopic data for 2 were the following: ¹H NMR (CDCl₃, 500 MHz): δ 4.49 (s, 1H), 4.38 (s, 1H), 3.90–3.67 (m, 12H), 3.06 (s, 1H), 2.23 (t, J = 7.0 Hz, 2H), 1.52–1.37 (m, 4H), 1.26–1.19 (m, 18H), 0.90 (t, J = 7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 105.0, 104.3, 98.7, 85.8, 78.4, 66.3, 65.6, 65.4, 64.7, 60.45, 30.5, 22.0, 18.6, 15.6, 15.5, 15.4, 13.7. IR (neat): ν_max 3426, 2974, 2930, 2898, 2873, 2244, 1444, 1370, 1327, 1246, 1112, 1067, 1017, 913, 803, 731, 541. HRMS (APCI+/TOF): calcd for C₂₄H₄₂O₇Na [M+Na⁺] 465.28282, found 465.28261.

4.4. Preparation of 5-(Diethoxymethyl)-1,1-diethoxy-5-hydroxyundeca-3,6-diyn-2-one (3)

A 10 mL flask containing diynol 2 (0.065 g, 0.15 mmol), p-TsOH (0.005 g, 0.03 mmol), acetone (3 mL), and water (1 mL) was refluxed for 20 h before being worked up in the usual way with brine (5 mL) and DCM (3 × 10 mL). The combined organic fractions were dried (MgSO₄), filtered, and concentrated in vacuo on a rotary evaporator to give a residue, from which the title compound (0.033 g, 60%) was isolated as a clear yellowish oil by FC (7:3 hexanes/ethyl acetate).

The spectroscopic data for 3 were the following: ¹H NMR (CDCl₃, 500 MHz): δ 4.79 (s, 1H), 4.52 (s, 1H), 3.90–3.61 (m, 8H), 3.14 (s, 1H), 2.24 (t, J = 7.0 Hz, 2H), 1.53–1.48 (m, 2H), 1.44–1.37 (m, 2H), 1.28–1.25 (m, 12H), 0.90 (t, J = 7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 182.5, 104.8, 101.4, 92.5, 87.4, 80.3, 75.9, 66.6, 65.7, 63.1, 30.3, 29.8, 22.0, 18.6, 15.3, 15.2, 13.7. IR (neat): ν_max 3446, 2976, 2959, 2929, 2873, 2219, 1691, 1445, 1371, 1319, 1246, 1106, 1063, 913, 837, 731, 649, 615, 563. HRMS (ESI+/TOF): calcd for C₂₀H₃₂O₆Na [M+Na⁺] 391.20966, found 391.20929.