4,4-Dimethoxy-2-butanone as 1,3-Dielectrophylic 3-Carbon Building Block: New Route for the Synthesis of Toluene, o-Xylene, Naphthalenes and Pyrimidines

The 4, 4-Dimethoxy-2-butanone 1 (Figure 1) is an interesting three carbon 1, 3-dielectrophilic building block. Which is commercially available and a few of its synthetic applications have been reported in recent years. One of the earliest reactions [1] of 1 is reported to have reacted with hydrazine hydrate to yield the corresponding 3-methylpyrazole in excellent yield. Recently there are a number of patents [2-5] described on the reaction of various phenyl hydrazines with 1 to obtain the corresponding aryl methyl pyrazoles in around 60-68% overall yields. In one of their publications Nielsen et al. [6] have reacted p-methyl benzyl magnesium chloride with 1 to give initially the corresponding carbinol acetal in good yields which on treatment with hydrobromic acid in acetic acid, the corresponding 3, 7-dimethyl naphthalene was formed in 24% yield. Similarly, Butter field and coworkers [7] as a part of their total synthesis of corannulene reacted m-methyl benzyl magnesium chloride with 1, initially to afford the corresponding carbinol which on treatment with acetic acid and 0.8M sulfuric acid at room temperature the corresponding 2, 7-dimethyl naphthalene was formed in 71% yield. Since many years we have been working on α-oxoketenedithioacetal chemistry [8-18] as a useful class of 1, 3-dielectrophylic building blocks for the synthesis of a variety of 5 and 6 membered heterocycles and aromatics. We wanted to extend these ideas to use 4, 4-dimethoxy butanone as a useful 1, 3-dielectrophilic building block and some of these selected reactions are reported in this communication. Results and Discussion


4,4-Dimethoxy-2-butanone as 1,3-Dielectrophylic 3-Carbon Building
The 4, 4-Dimethoxy-2-butanone 1 ( Figure 1) is an interesting three carbon 1, 3-dielectrophilic building block. Which is commercially available and a few of its synthetic applications have been reported in recent years. One of the earliest reactions [1] of 1 is reported to have reacted with hydrazine hydrate to yield the corresponding 3-methylpyrazole in excellent yield. Recently there are a number of patents [2][3][4][5] described on the reaction of various phenyl hydrazines with 1 to obtain the corresponding aryl methyl pyrazoles in around 60-68% overall yields. In one of their publications Nielsen et al. [6] have reacted p-methyl benzyl magnesium chloride with 1 to give initially the corresponding carbinol acetal in good yields which on treatment with hydrobromic acid in acetic acid, the corresponding 3, 7-dimethyl naphthalene was formed in 24% yield. Similarly, Butter field and coworkers [7] as a part of their total synthesis of corannulene reacted m-methyl benzyl magnesium chloride with 1, initially to afford the corresponding carbinol which on treatment with acetic acid and 0.8M sulfuric acid at room temperature the corresponding 2, 7-dimethyl naphthalene was formed in 71% yield. Since many years we have been working on α-oxoketenedithioacetal chemistry [8][9][10][11][12][13][14][15][16][17][18] as a useful class of 1, 3-dielectrophylic building blocks for the synthesis of a variety of 5 and 6 membered heterocycles and aromatics. We wanted to extend these ideas to use 4, 4-dimethoxy butanone as a useful 1, 3-dielectrophilic building block and some of these selected reactions are reported in this communication.

Results and Discussion
To begin with the allyl magnesium bromide [19] 2 was reacted with 1 at room temperature to afford the corresponding carbinol acetal 4 in 90% yields. The acetal was then refluxed with boron trifluoride etherate to afford the corresponding toluene 5 in 63% yield (Scheme 1). Thus, allyl bromide 3 was reacted with 1 in the presence of zinc [20] and saturated ammonium chloride when the carbinol acetal 4 was obtained in 70% yield. The acetal was then refluxed with boron trifluoride etherate as described above to afford the expected toluene 5 (Scheme 1) in 52% yield. The structure of toluene was fully confirmed by its super imposable IR spectra and other analytical data .

Short Communication
Progress in Petrochemical Science

C CRIMSON PUBLISHERS
Wings to the Research Scheme 1: Synthesis of toluene from method 1 and method 2.
We next extended this reaction for the synthesis of p-xylene (Scheme 2) by reacting crotyl zinc bromide [21] and it was reasoned that the organo zinc bromide prepared from crotyl bromide would react with 1b in 1,2 addition mode to yield the corresponding carbinol acetal 8, which on acid assisted cyclization would give p-xylene 9 (path a). However, the anion reacted from its third carbon with 1b to yield the different carbinol acetal 10 which on cyclization the corresponding o-xylene 11 (path b) was obtained in 32% yield (Scheme 2).  In the next experiment, benzyl magnesium chloride [22] 12 was reacted with 1 to afford the corresponding carbinol acetal 13 in high yield. It was then cyclized in the presence of boron trifluoride etherate, the corresponding 2-methyl naphthalene 14 (Scheme 3) was obtained in 53% yield.

General instructions
All the reagents and solvents used were purchased from commercial suppliers (Aldrich, TCI and SD fine chemicals) and used without further purification. 1H and 13C NMR spectra were recorded on 400MHz and 500MHz spectrophotometer using CDCl 3 as the solvent. Chemical shift values are reported in ppm taking tetramethylsilane as the internal standard, and J values are given in hertz. HRMS data were acquired on a time of flight (TOF) mass spectrometer (Waters Q-TOF Premier-HAB213). IR spectra of all the compounds were obtained by PerkinElmer Spectrum version 10.3.06 IR spectrometer. Reactions were monitored by thin layer chromatography (TLC) using precoated silica gel plates, visualized by UV light. Melting points were determined using Thiele tube apparatus and are uncorrected.
argon, allyl magnesium bromide 2 (22.7ml) was slowly added to 1 (3g, 22.7mmol) at 0 °C and the reaction mixture was stirred at that temperature for 45min. (TLC). The reaction mixture was treated with saturated ammonium chloride solution (10ml) followed by extraction with ether which was dried, and the solvent was removed under reduced pressure to afford the corresponding carbinol 4 (3.53g, 20.28mmol) in 90% yield. The carbinol acetal was then refluxed with boron trifluoride etherate (6.18g, 50.65mmol) for 30minutes (TLC). The reaction mixture was poured into saturated NaHCO3 solution and extracted with ether (30ml), washed (H 2 O), dried (Na 2 SO 4 ) and evaporated to yield the crude toluene 5 which was purified through vacuum distillation to give pure toluene in 63% yield;

Procedure for the synthesis of 2-Methylnaphthalene 14:
In a neat reaction under argon, benzyl magnesium bromide (22.7ml) 12 was slowly added to 1 (3g, 22.7 mmol) at 0 °C and the reaction mixture was stirred at that temperature for 45min. The reaction mixture was treated with saturated ammonium chloride solution (10ml) followed by extraction with ether which was dried and the solvent was removed under reduced pressure to afford the corresponding carbinol acetal (4.58g, 20.45mmol) 13 in 90% yield. The carbinol acetal was then refluxed with boron trifluoride etherate (6.23g, 51.1mmol) for 30minutes. The reaction mixture was poured into saturated NaHCO 3 solution and extracted with ether (30ml), washed (H 2 O), dried (Na 2 SO 4 ) and evaporated to yield the crude naphthalene which was purified through silica gel column eluting with petroleum ether to afford the desired 2-methylnaphthalene 14 (1.15g, 9.84mmol) in toluene (5ml) was added drop wise and continued stirring for 15minutes. The butanone 1 (1g, 7.57mmol) in toluene (5ml) was then added slowly and the reaction mixture was stirred at room temperature for 6h (TLC). It was then poured into saturated ammonium chloride solution and extracted with ethyl acetate (30X2). The combined organic extracts was washed with water, dried (Na 2 SO 4 ) and evaporated to yield crude 1, 4-additionelimination adduct 16 Procedure for the synthesis of 2-Amino-4-methylpyrimidine 18: A mixture of sodium ethoxide (2.06g, 30.3mmol) and guanidine nitrate (1.38g, 11.3mmol) in ethanol was stirred for 20minutes. Then a solution of butanone 1 (1g, 7.57mmol) was added and the reaction mixture was refluxed for 6h (TLC). The solvent was removed under reduced pressure and the reaction mixture was treated with water and extracted with ethyl acetate, washed (H 2 O), dried (Na 2 SO 4 ) and the solvent was removed under vacuum to get the crude pyrimidine 18 which was passed over silica gel column eluting with petroleum ether and ethyl acetate (94:6) to yield the colorless crystalline needles in 66% yield.