Preparation of methyl 3,4-dioxopentanoate-4-ethylenedithioacetal; monoprotected 3,4-dioxo-ester

Carlos Afonso ([email protected]),
A contribution from the Carlos A. M. Afonso, C. D. Maycock Group, New University of Lisbon, Portugal

Chemicals Used
Sodium (Merck), methyl pyruvate (Aldrich), anhydrous methyl acetate (distilled from P₂O₅), 1,2-ethanedithiol (Merck), boron trifluoride diethyl etherate (Aldrich, fresh distilled), anhydrous dichloromethane (distilled from P₂O₅), anhydrous methanol (distilled from Mg), trimethyl orthoformate (Merck), p-toluenesulfonic acid (Merck). Methyl 2,2-dimethoxypropanoate was prepared by slow distillation (40-50 ^oC, 7 h, 6-7 mL) of a reflux solution (70 ^oC) of methyl 2-oxo-propanoate (10.0 g, 97.95 mmol), trimethyl orthoformate (11.8 mL, 1.1 eq), anhydrous methanol (14.7 mL) and p-toluenesulfonic acid (0.24 g, 1.3 mol%) followed by distillation (78-80 ^oC/water aspirator pump) giving 10.96 g (75 %) of the product as a clear liquid.

Procedure
To a stirred solution of methyl 2,2-dimethoxypropanoate (10.89 g, 73.5 mmol), methyl acetate (10.8 mL, 136.0 mmol) and anhydrous methanol (0.1 mL) was added sodium pieces (< 5 mm, 2.1 g, 90.5 mmol) and the mixture was stirred at 60 ^oC for 16 h (orange solution). More methyl acetate (10.8 mL, 136.0 mmol) and sodium sodium pieces (< 5 mm, 2.1 g, 90.5 mmol) were added and stirring continued for a further 8 h. The reaction mixture was allowed to cool, ice added (40 g), acidified with hydrochloric acid 12 M (final pH of 6) and was extracted with diethyl ether (4 x 60 mL). The combined organic phase was dried (MgSO₄), evaporated under vacumm and distilled (62-66 ^oC/0.3 mmHg) giving methyl 4,4-dimethoxy-3-oxopentanoate (7.98 g, 57 %) as a clear liquid. The above methyl ester (6.41 g, 33.7 mmol) was added to a stirred cold (ice bath) solution of anhydrous dichloromethane (20 mL) under an argon atmosphere, followed by the dropwise addition (2 h) of a solution of boron trifluoride diethyl etherate (3.4 mL, 33.7 mmol) and 1,2-ethanedithiol (2.83 mL, 33.7 mmol) in anhydrous dichloromethane (14 mL) and stirring was continued for a further 1h. Aqueous saturated NaHCO₃ (20 mL), was added followed by extration with dichloromethane (3 x 30 mL). The combined organic phases were dried (MgSO₄), evaporated under vacuum and purified by flash chromatography (SiO₂, eluent: petroleum ether 40/60 : ethyl acetate from 1:0 to 6:4) to give the title compound (5.57 g, 75 %), as colorless liquid, Rf = 0.50 (CHCl₃).

Author's Comments
The first step has been carried out several times on scales of 60 to 70 mmol. In case of the second step none of the isomeric methyl 3,4-dioxopentanoate-3-ethylenedithioacetal was detected by 1H NMR from the crude reaction mixture. The two step procedure was applied to the preparation of ethyl 3,4-dioxopentanoate-4-ethylenedithioacetal (first step 50 %, second step 74%). The second step was also applied to the preparation of monodithioacetals from different 1,2-dicarbonyl compounds (7 examples). Due to the strong smell of thiols is strongly recommended to use a very well ventilated fumehood.

Data
1H NMR (60 MHz, CCl₄), (aprox. of 4% of the enol form) d: 1.82 (3H, s, C-5 Me), 1.94 (s, C-5 Me of the enol), 3.35 (s, S(CH₂)₂S of the enol), 3.45 (s, S(CH₂)₂S), 3.70 (2H, s, C-2 CH₂), 3.80 (3H, s, CO₂CH₃), 5.60 (s, C(2)H of the enol); IR (film): 2960, 2940, 2850, 1745, 1710, 1620, 1440, 1405, 1375, 1320, 1265, 1205, 1140, 1100, 1075, 1040, 1000, 955, 850 cm^-1; MS (EI, m/e): 220 (M+), 189, 177, 147, 145, 133, 128; Acc. Mass. (EI) calcd for C₈H₁₂O₃S₂: 220.0227; observed: 220.0236.

Lead Reference
Afonso, C. A. M.; Barros, M. T.; Godinho, L. S.; Maycock, C. D. Synthesis 1991, 575.

Other References
The first step was based on original similar reported conditions: Bettesti, P.; Battesti, O.; Sélim, M. Bull. Soc. Chim. Fr. 1974, 2214. For the second step see also: Theodora W. Greene, Peter G. m. Wuts, Protective Groups in Organic Synthesis, third edition, John Wiley & Sons, 1999, pp 333-336.

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