Anhydride acetic, reaction with amine

The use of activated anthranihc acid derivatives facUitates the preparation of the amides in those cases where the amines are either umeactive or difficult to obtain. Thus, reaction of (87-1) with phosgene gives the reactive the isatoic anhydride (89-1). Condensation of that with ortho-toluidine leads to the acylation product (89-2) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (89-3) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (89-4) [99]. 

Acetic anhydride, electrostatic potential map of, 791 reaction with alcohols, 807 reaction with amines, 807 reaction with monosaccharides, 988... 

The efficient At-nitration of secondary amines has been achieved by transfer nitration with 4-chloro-5-methoxy-2-nitropyridazin-3-one, a reagent prepared from the nitration of the parent 4-chloro-5-methoxypyridazin-3-one with copper nitrate trihydrate in acetic anhydride. Reactions have been conducted in methylene chloride, ethyl acetate, acetonitrile and diethyl ether where yields of secondary nitramine are generally high. Homopiperazine is selectively nitrated to At-nitrohomopiperazine or At, At -dinitrohomopiperazine depending on the reaction stoichiometry. At-Nitration of primary amines or aromatic secondary amines is not achievable with this reagent. 

Padwa et al. (75) found that the unsymmetrical miinchnone 137, which was generated from A-acetyl-7/-benzylglycine (136) and refluxing acetic anhydride, reacts with methyl propiolate to give an 8 1 mixture of pyrroles 138 and 139. The same product ratio is obtained from the reaction of methyl propiolate and the azomethine ylide derived from 7/-benzyl-A(-(a-cyanoethyl)-A(-[(trimethylsilyl)-methyl] amine. 

Triethylamine (bp 89°) is another commonly used tertiary amine and is considerably more basic than pyridine. Along with all other aliphatic amines, it may be dried by heating to reflux with and distilling from barium oxide. Secondary amines are common impurities in tertiaiy amines and may be removed by heating the amine with a small amount of acetic anhydride. If the amine has a boiling point considerably different from that of acetic anhydride (bp 140°), it may be distilled directly from the reaction mixture. Otherwise, the reaction mixture should be shaken with 20 per cent potassium hydroxide solution, dried over potassium hydroxide, and distilled from barium oxide. 

With the platinum-metal catalysts, this reaction can be suppressed by conducting the hydrogenation in acid solution or in acetic anhydride, which removes the amine from the equilibrium as its salt or as its acetate. For reactions with Raney nickel, where acid cannot be used, secondary amine formation is prevented by addition of ammonia. Hydrogenation of nitriles containing other functional groups may lead to cyclic compounds. For example, indoUzidine and quinoUzidine derivatives have been obtained in certain cases (7.21). 

Acid anhydrides also react with alcohols, in the presence of amine bases, to give esters. The reaction is essentially the same as that for acid chlorides, and triethylamine is commonly added as a base. This is most useful when symmetrical anhydrides such as acetic anhydride are used. Heating acetic anhydride and isopropanol to reflux gives an 80% yield of isopropyl acetate (19 in Section 20.2). When fert-butyl alcohol 59 is heated with acetic anhydride, ester 62 is formed, along with acetic acid. Mixed anhydrides are expected to give a mixture of all possible ester products, so this reaction is done most often with symmetrical anhydrides such as acetic (ethanoic) anhydride or propanoic anhydride. When acetic anhydride reacts with methanol, for example, the products are methyl acetate and acetic acid. Formation of esters by reaction of an alcohol and an anhydride will be used only when a symmetrical anhydride can be used as a starting material. 

Routine syntheses of glycosyl isothiocyanates, involving reaction of the corresponding hexopyranosyl bromides with potassium thiocyanate, and then-subsequent conversion to thiourea and thiosemicarbazide derivatives on reaction with amines and hydrazine, respectively, have been reported. Partially protected -D-galactopyranosylamine derivatives, e g. (25) and (26), have been obtained by reaction of the corresponding galactosyl isothiocyanate with a-aminoaceto-phenones and a-aminoacetone, respectively. In acetic anhydride, the thiourea (25) qrclised to compound (27). ... 

Titration in acetic acid, with and without chemical reaction (148) The total amine oxide and tertiary amine content of the product may be determined by direct potentiomet-ric titration with perchloric acid in acetic acid solvent. Another portion of the sample is reacted for 10 min with acetic anhydride, converting tertiary amine oxide to an amide and an aldehyde. The reaction product is titrated with perchloric acid in 2 1 acetic acid/acetic anhydride. Under these conditions, only tertiary amine is titrated. 

Although the acetylation of alcohols and amines by acetic anhydride is almost invariably carried out under anhydrous conditions owing to the ready hydrolysis of the anhydride, it has been shown by Chattaway (1931) that phenols, when dissolved in aqueous sodium hydroxide solution and shaken with acetic anhydride, undergo rapid and almost quantitative acetylation if ice is present to keep the temperature low throughout the reaction. The success of this method is due primarily to the acidic nature of the phenols, which enables them to form soluble sodium derivatives, capable of reacting with the acetic... 

In general, however, the diacetyl derivatives are unstable in the presence of water, undergoing hydrolysis to the mono-acetyl compound, so that when they (or a mixture of mono- and di-acetyl derivatives) are crystallised from an aqueous solvent, e.g., dilute alcohol, only the mono-acetyl derivative is obtained. A further disadvantage of the use of acetic anhydride in the absence of a solvent is that all the impm-ities in the amine are generally present in the reaction product. Heavily substituted amines, t.g., 2 4 6-tribromoaniline, react extremely slowly with acetic anhydride, but in the presence of a few drops of concentrated sulphuric acid as catalyst acetylation occurs rapidly, for example ... 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Reaction with ammonia and amines (Section 20 14) Acid an hydrides react with ammonia and amines to form amides Two molar equivalents of amine are required In the example shown only one acyl group of acetic anhydride becomes incor porated into the amide the other becomes the acyl group of the amine salt of acetic acid... 

Acylation. Aliphatic amine oxides react with acylating agents such as acetic anhydride and acetyl chloride to form either A[,A/-diaLkylamides and aldehyde (34), the Polonovski reaction, or an ester, depending upon the polarity of the solvent used (35,36). Along with a polar mechanism (37), a metal-complex-induced mechanism involving a free-radical intermediate has been proposed. 

Acylation. Aromatic amines react with acids, acid chlorides, anhydrides, and esters to form amides. In general, acid chlorides give the best yield of the pure product. The reaction with acetic, propionic, butanoic, or benzoic acid can be catalyzed with phosphoms oxychloride or trichloride. 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

Other Rea.ctlons, The anhydride of neopentanoic acid, neopentanoyl anhydride [1538-75-6] can be made by the reaction of neopentanoic acid with acetic anhydride (25). The reaction of neopentanoic acid with acetone using various catalysts, such as titanium dioxide (26) or 2irconium oxide (27), gives 3,3-dimethyl-2-butanone [75-97-8] commonly referred to as pinacolone. Other routes to pinacolone include the reaction of pivaloyl chloride [3282-30-2] with Grignard reagents (28) and the condensation of neopentanoic acid with acetic acid using a rare-earth oxide catalyst (29). Amides of neopentanoic acid can be prepared direcdy from the acid, from the acid chloride, or from esters, using primary or secondary amines. 

The simplest method for acetamide preparation involves reaction of the amine with acetic anhydride or acetyl chloride with or without added base. Some other methods are listed below. 

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