Amide acetals, reactions

Conversion of Acid Anhydrides into Amides Acetic anhydride is also commonly used to prepare iV-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts rather than the less nucleophilic -OH group. 

A. Claisen Rerrangements of Ketene Aminats and Imidates. A reaction that is related to the orthoester Claisen rearrangement utilizes an amide acetal, such as dimethylacetamide dimethyl acetal, in the exchange reaction with allylic alcohols.257 The products are y, 8-unsaturated amides. The stereochemistry of the reaction is analogous to the other variants of the Claisen rearrangement.258... 

Potassium acetate, reaction with N,N-dichlorocyclohexylamine, 46,17 Potassium amide, 48, 41 Potassium / butoxide, 46, 33 alcohol-free, reaction with bromo-benzene, 46, 89... 

An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes, and are frequently so much faster that it is possible to observe those types of reaction involved in enzyme catalysis. Thus groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolysing aliphatic esters and amides. Bimolecular reactions in water between acetic acid or imidazole and substrates such as ethyl acetate and simple amides are frequently too slow to... 

Bonds typically hydrolyzed include carboxylic and phosphoric esters, amides, acetals, amidines, as well as metal ion complexes. (When a nucleophilic substitution reaction uses the solvent as the nucleophile, the reaction is often referred to as solvolysis.)... 

Radical mechanisms were suggested at the time, but it should be noted that lead(IV) acetate can bring about the amide-isocyanate reaction,105 so that the reactions may, in fact, be ionic. 

Although complexes with these ligands are common in palladium(II) chemistry, their occurrence is more scarce in platinum(II) compounds. Nevertheless these complexes can be prepared, examples being platinum(II) complexes of the optically active quadridentate Schiff base of salicylaldehyde and (R)-l, 2-diamines.1212 An alternative synthesis involves formation of the Schiff base by reaction of a complexed amino ligand on platinum(II) with amide acetates (equation 372).1213... 

In the synthesis of specially substituted methylene diphosphines, made from secondary phosphines and carbonyl derivatives (7), a carbenium ion adjacent to trivalent phosphorus as the transition state has been discussed. The transfer of this reaction principle to primary phosphines and suitable carbonyl compound revealed a further pathway to derivatives of dicoordinated phosphorus (8). Aromatic phosphines react with carboxylic acid amide acetals under elimination of alcohol giving dialkylamino-alkylidene phosphines (Scheme 5). A modification of the synthesis... 

Amino acids exhibit chemical reactions that are typical of both amines and carboxylic acids. For example, the acid can be converted to an ester by the Fischer method. This reaction requires the use of an excess of acid because one equivalent is needed to react with the amino group of the product. As another example, the amine can be converted to an amide by reaction with acetic anhydride. Additional examples are provided by the reactions that are used in the preparation of peptides from amino acids described in Section 26.7 ... 

A drawback of all of these methods is that they produce racemic amino acids. If the product is to be used in place of a natural amino acid, it must first be resolved. This can be accomplished by the traditional method of preparing and separating diastereomeric salts. Alternatively, nature s help can be enlisted through the use of enzymes. In one method the racemic amino acid is converted to its amide by reaction with acetic anhydride. The racemic amide is then treated with a deacylase enzyme. This enzyme catalyzes the hydrolysis of the amide back to the amino acid. However, the enzyme reacts only with the amide of the naturally occurring L-amino acid. The L-amino acid is easily separated from the unhydrolyzed D-amide. The following equation illustrates the use of this process to resolve methionine ... 

The synthesis of 1,3-dithiolanes (284) which contain a 2-dimethylamino group results from the reaction of ethanedithiol with amide acetals of type (283) (69BSF332). 

Bicyclic amide acetals have synthetic utility, as illustrated by the catalytic reduction of (84 R1 = H, R2 = Pr") leading to amino alcohols (85) reaction of (84 R1 = OH, R2 = H) with formic acid involves double ring fission to give (86) (71S16,78MI43600). 

Reactions of nitriles with nucleophilic reagents normally require catalysis by acids or bases. Heating iminodiethanols with aliphatic nitriles in the presence of catalytic amounts of sodium alkoxide leads to oxazolo[2,3-6Joxazoles ( bicyclic amide acetals ), in a single process via oxazolidine intermediates (equation 18) (73AG(E)1055>. 

Finally, the [3,3]-sigma tropic rearrangement can be carried out by heat as part of the same step or as a separate step depending on the compounds. This is a very flexible reaction sequence and can be used for aldehydes (as shown above), ketones, esters, or amides. In each case acetal-like compounds are used—acetals themselves for aldehydes and ketones orthoesters and orthoamides for the other two (though the orthoamides are often called amide acetals ). 

The reaction of propargyl alcohols with an amide acetal affords enamine products512. 

The addition of a base to an acetylenic ester or ketone provides another method of preparation of enaminones594,595. A convenient one-pot synthesis of enaminones from trimethylsilylethynyl ketones and amines was described596. The reaction of activated methylene compounds, such as cycloalkanones, MeCOPh and PhCH2COOMe, with amide acetals gave high yields of enaminones597 (equation 39). 

A powerful oxidizer. Explosive reaction with acetaldehyde, acetic acid + heat, acetic anhydride + heat, benzaldehyde, benzene, benzylthylaniUne, butyraldehyde, 1,3-dimethylhexahydropyrimidone, diethyl ether, ethylacetate, isopropylacetate, methyl dioxane, pelargonic acid, pentyl acetate, phosphoms + heat, propionaldehyde, and other organic materials or solvents. Forms a friction- and heat-sensitive explosive mixture with potassium hexacyanoferrate. Ignites on contact with alcohols, acetic anhydride + tetrahydronaphthalene, acetone, butanol, chromium(II) sulfide, cyclohexanol, dimethyl formamide, ethanol, ethylene glycol, methanol, 2-propanol, pyridine. Violent reaction with acetic anhydride + 3-methylphenol (above 75°C), acetylene, bromine pentafluoride, glycerol, hexamethylphosphoramide, peroxyformic acid, selenium, sodium amide. Incandescent reaction with alkali metals (e.g., sodium, potassium), ammonia, arsenic, butyric acid (above 100°C), chlorine trifluoride, hydrogen sulfide + heat, sodium + heat, and sulfur. Incompatible with N,N-dimethylformamide. 

Anode acetals. Carboxamides (1) arc alkylated in high yield (95 100%) by triethyloxonium fluoroborate to give the corresponding carbonium iluoroborates (2). As a rule, the reaction of (2) with sodium ethoxide at 0° aifords an amide acetal (3). 

Yields are in the range 50-70%. The reaction of (3) with nucleophiles at 80 results in elimination of ethanol and formation of an aminomethylene compound. Thus the amide acetal (4) reacts with nilromelhane to give (5) in 60% yield. 

The imidatc (27) reacts at 100°C with excess triethyl orthoformate to give 4,5-dicyano-l-ethylimidazole after vacuum distillation. The reaction becomes economically competitive with other reactions which alkylate 4,5-dicyanoimidazole since the 1-alkyl-4,5-dicyanoimidazoles can be made in one-pot reactions merely by heating DAMN at 100°C with excess ortho ester. No co-solvent is necessary. Presumably, (27) forms first, then 4,5-dicyanoimidazole, then the 1-alkyl derivative, with the anion of 4,5-dicyanoimidazole probably being the reactive species. Imidazole itself is not N-alkylatcd by ortho esters instead it induces alkoxidc displacement to give amide acetals [34]. 

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