Catalysis by 4-dialkylaminopyridines

Representative experimental procedures are given for the most important types of reactions catalyzed by 4-dimethylaminopyridine (DMAP).


Introduction
The treatment of substrates such as alcohols, phenols and amines with acetic anhydride (or acetyl chloride) in the presence of pyridine has provided a general acetylation method since the turn of the 20th century. However, this approach often proves to be unsatisfactory for the acetylation of deactivated substrates. It was not until the late 1960's that certain 4-dialkylaminopyridines were found (independently by two research groups) 1 to be much superior to pyridine as catalysts for difficult acetylations or acylations, in general. 4-Dialkylaminopyridines were soon found to have general applicability for catalysis of a wide variety of reactions. 4-dimethylaminopyridine's (DMAP) wide applicability has been frequently reviewed since the first review appeared in 1978. 2 The accelerating pace of reported applications for DMAP and the availability of DMAP in commercial quantities, at modest prices, has continued to stimulate great interest in its use as a catalyst in the fields of organic, polymer, analytical and biochemistry. Today there are thousands of examples of the use of DMAP in far ranging fields of chemistry in both patents and the research literature. Many full-scale production processes utilizing DMAP have been and are being operated. Several pharmaceutical and agricultural products that rely on DMAP's superior catalytic properties in their synthetic sequences have been produced for years. Since 1976 more than 11,000 US patents have been granted which mention DMAP or dimethylaminopyridine.
Reactions that have been published in the literature using DMAP fall into, but are not limited to, the following types of reactions: Acylation; Acetylation; Alkylation; Benzoylation; Bischler-Naperalski cyclization, Carbonylation; Carbo-diimidation; Cyclization; Dehydration; Esterificaton; Indole Synthesis; Nucleophilic Substitution; Rearrangement; Silylation; The following is a collection of samples of reactions with reaction conditions from the literature in which DMAP has been used effectively to improve, and in some cases make possible, transformations in organic chemistry. It is our hope that collecting these procedures and presenting them in this easily accessible format will make your job easier and more effective as you search for ways to synthesize new products or for ways to improve existing processes.
2. The reaction mixture slightly exotherms and stirring is continued for a further 15 min. 3. The reaction mixture is quenched by the addition of 0.1% sodium hydroxide solution (100 mL) followed by ether (100 mL). The layers are separated and the organic layer washed with 0.1% sodium hydroxide solution (50 mL) followed by brine. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 1ethenyl)heptanyl 3-ketobutanoate (11.3 g, 94%) as a pale yellow oil. Further purification can be accomplished by distillation (b.p. 113-114°C at 1.4 mm) to afford a colorless oil.
2. The reaction mixture is stirred for a further 30 min.
2. The mixture is allowed to stand at room temperature for 17 h.
3. The reaction mixture is worked-up by initially adding water, followed by sodium carbonate until carbon dioxide evolution ceases and the aqueous layer remains basic. The organic layer is extracted with chloroform, dried over anhydrous sodium carbonate, and the solvent removed to give the crude product. Distillation at atmospheric pressure (b.p. 176°C) affords 1-methylcyclohexyl acetate (13.7 g, 88% yield). (1.98 g, 73%, m.p. 101°C).
2. An exothermic reaction ensues, and after 2 h, addition of methanol and evaporation of the solvents gives an oily residue. (1) 2. The reaction mixture is stirred at ambient temperature for 4 h.
3. The precipitated salts are filtered off, the solution concentrated, the residue purified by filtration through a short column of silica gel (eluent dichloromethane) followed by evaporation of the solvent to afford the thiol ester (184 mg, 95%). 3 The crude salt (5.5 g, 78%) is suspended in water and acidified with citric acid (10 g).
2 The reaction mixture is extracted with methylene chloride and washed successively with sodium bicarbonate and brine. Chromatography of the crude product (ether-methylene chloride (3:1) eluent) gave 82% yield of pure 2a as a yellow oil.