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,Ndimethylformamide and methanol.

Microwave‐Assisted [3+2] Cycloaddition and Suzuki–Miyaura Cross‐Coupling for a Concise Access to Polyaromatic Scaffolds

“…Based on our previous one‐pot cyclization of anthranilic acid and various aminonicotinic acid isomers into quinazolin‐4(3 H )‐ones and pyridopyrimidin‐4(3 H )‐ones, respectively,4 we wished to use amines bearing a propargyl moiety. Microwave irradiation of anthranilic acid ( 1a ) or 2‐aminonicotinic acid ( 2 ) in the presence of N , N ‐dimethylformamide dimethyl acetal (DMFDMA)7 in DMF followed by irradiation with propargylamine in acetic acid gave the expected 3‐(prop‐2‐ynyl)quinazolin‐4(3 H )‐one ( 3 ) and 3‐(prop‐2‐ynyl)pyrido[2,3‐ d ]pyrimidin‐4(3 H )‐one ( 4 ) in excellent overall yields (Scheme ).…”

SNAAP Sulfonimidate Alkylating Agent for Acids, Alcohols, and Phenols

“…They concluded that: 'O-alkyl sulphonimidates are unlikely to be synthesized by direct O-substitution. ' We have successfully accomplished the preparation of ethyl N-tert-butyl-4-nitrobenzenesulfonimidate (1) (Equation 1) by silver oxide mediated O-ethylation of Ntert-butyl-4-nitrobenzenesulfonamide (2). The best method we developed is a one-pot procedure involving anhydrous silver(I) oxide, iodoethane, and a sterically hindered sulfonamide, such as 2, in anhydrous, refluxing dichloromethane.…”

“…There are a variety of methods for direct alkylation of carboxylic acids at oxygen, but many have limitations because of toxicity, thermal instability, reactivity with moisture in air, multiple components, severe conditions, or extended reaction times. A recent review by Vorbruggen 2 focused on the alkylation of carboxylic acids and phenols with amide acetals. He noted that classical procedures involving sterically hindered tetrahedral intermediates limit the scope of those procedures.…”

“…Additionally, some direct alkylation methods, such as the toxic and explosive diazoalkanes, 3,4 also undergo side reactions with aldehydes, ketones and α,β-unsaturated carbonyl compounds. 5 Amide acetals are effective alkylating agents for many carboxylic acids and some acidic phenols, 2 but they are sensitive to water, alcohols, and amines, and easily condense with active methylene groups. Yoshino et al 6 reported an improved esterification procedure for various carboxylic and phosphonic acids and other protic compounds with excess trialkyl orthoacetates in ionic liquids at 80°C.…”

Mild Esterification of Carboxylic Acids via Continuous Flow Diazotization of Amines

“…The esterification of carboxylic acids with alcohols is typically achieved under acid catalysis . For more challenging sterically hindered or highly functionalized substrates (namely with acid sensitive functionality), the activation of the acid or the alcohol is often necessary. , An alternative strategy for the synthesis of methyl esters applies diazomethane as the methylating reagent . Under these mild reaction conditions, highly functionalized carboxylic acids are cleanly esterified in excellent yields.…”