Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

Abstract

The esterification and etherification of unhindered, as well as severely hindered, carboxylic acids and phenols with basic amide acetals, such as N,N-dimethylformamide dimethyl acetal, and their side reactions are discussed. Modified procedures are described in which these side reactions are avoided to achieve high or near quantitative yields of the desired corresponding methyl esters or phenol methyl ethers. On the addition of N,N-dimethylform­amide dimethyl acetal, solutions of 4-nitrobenzoic acid in basic solvents, such as tetrahydrofuran or 1,4-dioxane, form precipitates of the corresponding iminium carboxylates, which give near quantitative yields of the desired methyl 4-nitrobenzoate, as well as N,N-dimethylformamide and methanol.

1 Introduction

2 Preparation and Properties of Amide Acetals

3 Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

4 Side Reactions during the Esterifications and Etherifications

4.1 Suppression of the Formation of Quaternary Salts and Other Side Reactions

4.2 Tetrahydrofuran or 1,4-Dioxane as Optimal Reaction Solvents

4.3 Attempted Suppression of Condensation Reactions

5 Concluding Remarks

Key words

phenols - esterification - ethers - amide acetals - carboxylic acids

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91

3β-(4-Nitrophenoxy)-5α-androstan-17-one (82)
To a boiling solution of 3α-hydroxy-5α-androstan-17-one (80) (0.249 g, 1 mmol) in abs benzene (15 mL) was added a third of a suspension of DMF dineopentyl acetal 7d (4.3 mL, 15 mmol) and 4-nitrophenol (81) (2.087 g, 15 mmol) in abs benzene (15 mL). After heating at 80 °C for 24 h, the rest of the suspension was added in small portions over a period of 48 h. The mixture was heated at 80 °C for a further 14 h and then was cooled. Ice (20 g) was added to the mixture, which was then extracted with 2 M NaOH (2 × 35 mL). The extracts were dried (MgSO₄) and benzene was evaporated off to give the crude crystalline product (1.618 g), which on recrystallization (MeOH) gave slightly impure 3β-(4-nitrophenoxy)-5α-androstan-17-one (82) (0.188 g). Filtration of the product in CH₂Cl₂ over a small column of neutral alumina (7.5 g, activity II) and recrystallization of the eluate (MeOH) gave pure 82; mp 214 °C; [α]_D +62.9 (c 1, CHCl₃). The combined mother liquors were column chromatographed [silica gel (70 g), cyclohexane]. Elution [cyclohexane-toluene, 2:3 (200 mL), then 3:7 (400 mL)] afforded homogeneous 5α-androst-2-en-17-one, which was recrystallized (pentane) to give the pure side product. Yield: 0.056 g (24%); mp 106.5-107 °C. Further elution (toluene, 1 L) gave additional pure 82 (0.051 g). Combined yield: 0.239 g (68%).

110

Methyl 4-Nitrobenzoate (88)
Using 7a and DCE: To a suspension of 4-nitrobenzoic acid (87) (3.342 g, 20 mmol) in DCE (25 mL) was added a solution of DMF dimethyl acetal 7a (8.2 mL, 62 mmol) in DCE (25 mL) over a period of 5 h at 24 °C with stirring. Stirring was continued for a further 66 h, whereupon a clear yellowish solution resulted. After evaporation at 35 °C/0.5 Torr, the crystalline residue was extracted with boiling Et₂O (3 × 70 mL) resulting in, after further evaporation, crude methyl 4-nitrobenzoate (88). Yield: 3.265 g (90%); mp 92-94 °C. Recrystallization from boiling hexane resulted in pure 88; mp 95-96 °C (Lit. mp 96 °C; see also ref. 108). The crystalline yellowish residue (0.480 g) that remained after the extraction with Et₂O was recrystallized (abs EtOH, 5 mL) to give acidic tetramethylammonium salt 89 (0.063 g); mp 278-281 °C. On acidification of the mother liquor with 1 M H₂SO₄ and extraction with CH₂Cl₂, pure 4-nitrobenzoic acid (87) was recovered; mp 242 °C (see also ref. 20).
Using 13a and DCE: To a suspension of 4-nitrobenzoic acid (87) (2.507 g, 15 mmol) in DCE (40 mL) was added N,N-tetramethylene-formamide dimethyl acetal 13a (4.656 mL, 30 mmol) with stirring at 30 °C. After 4 h at 30 °C, the mixture was stirred with sat. NaHCO₃ soln (20 mL) and then was extracted with Et₂O (3 × 20 mL). After evaporation of the ethereal extract, pure, homogeneous, crystalline methyl 4-nitrobenzoate (88) was obtained. Yield: 2.496 g (92%). The repetition of this experiment over a period of 25 h at 30 °C and workup with NaHCO₃ gave crystalline 88; Yield: 2.712 g (100%) (see also ref. 20)
Using 7a and THF: To a stirred boiling solution of 4-nitro-benzoic acid (87) (0.84 g, 5 mmol) in abs THF (30 mL) in a 100-mL three-necked round-bottom flask, connected to a reflux condenser and an addition funnel and in an oil bath at 80 °C, was added dropwise a solution of DMF dimethyl acetal 7a (1.8 mL, 15 mmol) in abs THF (20 mL), where-upon a colorless precipitate formed. After the addition of about 10 mL (7.5 mmol) of the THF solution of 7a, a clear yellowish solution resulted, indicating the completion of the reaction. Evaporation of the mixture afforded the crude crystalline product (1.33 g), which was dissolved in tert-butyl methyl ether (20 mL) and filtered over a layer of silica gel (18 g) to give crystalline methyl 4-nitrobenzoate (88). Yield: 0.94 g (100%); mp 94-96 °C. Recrystallization (boiling hexane, 40 mL) resulted in the first crop of pure 88 (0.69 g); mp 96 °C. Concentration of the mother liquor afforded another crop of pure 88 (0.16 g). Combined yield: 0.85 g (90%). The remaining hexane mother liquor still contained, according to TLC (hexane-EtOAc, 4:1), methyl 4-nitrobenzoate (88).

115

Dimethyl Fumarate (94) To a stirred boiling solution of fumaric acid (92) (1.16 g, 10 mmol) in abs THF (30 mL) in a 100-mL three-necked round-bottom flask, connected to a reflux condenser and an addition funnel and in an oil bath at 80 °C, was added dropwise a solution of DMF dimethyl acetal 7a (4 mL, 30 mmol) in abs THF (20 mL) over a period of 1 h, whereupon salt 93 formed as a colorless precipitate. Because the solution was still somewhat turbid, additional 7a (1.3 mL, 10 mmol) in abs THF (10 mL) was added over a period of 0.5 h, and the mixture was heated for another 0.5 h and stirred overnight at r.t. for 16 h. The resulting yellowish solution was decanted from a small amount of colorless precipitate (0.03 g), which was washed with tert-butyl methyl ether and the extracts were filtered. On evaporation, the filtrate gave a crude yellowish crystalline substance (1.63 g) that was dissolved in tert-butyl methyl ether (125 mL) and filtered over a layer of silica gel (16 g). The slightly yellowish solution gave, on evaporation, spontaneously crystallizing homogeneous dimethyl fumarate (94). Yield: 1.3 g (93%); mp 99-103 °C; R _f = 0.35 (hexane-EtOAc, 9:1).

119

( E )- and ( Z )-3-(Dimethylamino)acrylonitrile (111) and (112) In a 100-mL three-necked round-bottom flask, connected to a reflux condenser and an addition funnel and in an oil bath at 80 °C, was stirred a solution of cyanoacetic acid (104) (1.70 g, 20 mmol) in 1,4-dioxane (30 mL, previously dried over 4 Å MS). To this solution was added DMF dimethyl acetal 7a (4 mL, 30 mmol) in 1,4-dioxane (20 mL) with vigorous stirring over a period of 1 h. Heating was continued for a further 1 h. After cooling the mixture and evaporating off the solvent, the crude dark oily product (3.16 g) was extracted with tert-butyl methyl ether and the extracts were filtered over a layer of silica gel (ca. 16 g). On evaporation of the yellow filtrate, homogeneous 3-(dimethylamino)acrylonitrile (111/112) was obtained. Yield: 1.92 g (100%); R _f = 0.72 (tert-butyl methyl ether).