Acid anhydrides amide synthesis

Ketone Synthesis. In the Friedel-Crafts ketone synthesis, an acyl group is iatroduced iato the aromatic nucleus by an acylating agent such as an acyl haUde, acid anhydride, ester, or the acid itself. Ketenes, amides, and nittiles also may be used aluminum chloride and boron ttitiuotide are the most common catalysts (see Ketones). 

Oxidation is the first step for producing molecules with a very wide range of functional groups because oxygenated compounds are precursors to many other products. For example, alcohols may be converted to ethers, esters, alkenes, and, via nucleophilic substitution, to halogenated or amine products. Ketones and aldehydes may be used in condensation reactions to form new C-C double bonds, epoxides may be ring opened to form diols and polymers, and, finally, carboxylic acids are routinely converted to esters, amides, acid chlorides and acid anhydrides. Oxidation reactions are some of the largest scale industrial processes in synthetic chemistry, and the production of alcohols, ketones, aldehydes, epoxides and carboxylic acids is performed on a mammoth scale. For example, world production of ethylene oxide is estimated at 58 million tonnes, 2 million tonnes of adipic acid are made, mainly as a precursor in the synthesis of nylons, and 8 million tonnes of terephthalic acid are produced each year, mainly for the production of polyethylene terephthalate) [1]. 

The adducts (94) of triphenylphosphine and alkylphenyl-AT-p-tosylsulphilimines also act as dehydrating agents, and have been employed in the synthesis of acid anhydrides, esters, and amides.90-91... 

In Chapter 9 you see the basic structure of each of the carboxylic acids and Ccirboxylic acid derivatives. In this chapter we focus on the carboxylic acids and related compounds, such as esters, acyl chlorides, and acid anhydrides, and we also include some information on amides (see Chapter 13 for an additional examination of cimides). Before you can get into synthesis and reactions, though, you need to understand the structure and nomenclature of these compounds. 

Preparation of oxazole Cyclocondensation of amides, through dehydration, leads to the formation of corresponding oxazoles. This synthesis is known as Robinson-Gabriel synthesis. A number of acids or acid anhydrides, e.g. phosphoric acid, phosphorus oxychloride, phosgene and thionyl chloride, can bring about this dehydration. 

If benzyl carbamate is used as the amide component in the reaction with a-oxo acids 23 then the Na-benzyloxycarbonyl-DHA 24 is obtained directly (Scheme 8). Shin and et al.[77 84l widely exploited the above method in the synthesis of various a, 3-didehydropeptides (Table 3). In presence of 3 M thionyl chloride and acetyl chloride, 24 gave the A-carboxy-DHA anhydride ANCA 25, which could be conveniently converted into dehydropeptides.[77 84 Compared with the common saturated A-carboxy-a-amino acid anhydrides (NCAs), ANCAs were found to be stable at room temperature for several months. 

The T2 linker has recently been shown to be a versatile backbone amide anchor. Immobilized disubstituted triazenes were acylated with carboxylic acid anhydrides or chlorides to give amide derivatives. These amides were cleaved under very mild conditions using trimethyl chlorosilane. This sequence thus employs the T2 system as backbone amine linker and was demonstrated in the automated library synthesis of substituted amide derivatives.54... 

In one example sequence the technology has been used to synthesize a variety of amides from amines and acid anhydrides. It is currently also being used to optimize reactions through the variations of auxiliaries and solvents and might become an interesting and more direct alternative to solid-phase synthesis. 

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary. The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configuration shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to the appropriate enolate is a widely used method for producing the enantiomers of a-alkyl substituted carboxylic acids...

Amides can also be synthesised from acid anhydrides and esters but in general these reactions offer no advantage over acid chlorides because acid anhydrides and esters are less reactive. Moreover, with acid anhydrides, half of the parent carboxylic acid is lost as the leaving group. Thus, acid anhydrides are only used for the synthesis of amides if the acid anhydride is cheap and freely available (e.g. acetic anhydride). 

Asymmetric synthesis of ketones and acids A new synthesis of chiral ketones and acids starts with the reaction of an anhydride or an acid chloride with either I-or li-ephedrin to form a chiral N,N-disubstituted amide (1) in almost quantitative yield. The amide (1) is then alkylated via the anion to give 2, which contains three asymmetric centers. Acid hydrolysis of 2 gives a carboxylic acid (3) with an optical yield of 75% (two examples). Cleavage of 2 with methyllithium gives a methyl ketone (4), in optical yields of 45-75%. 

For an excellent review of this field up to 1966, see Hamilton-Miller [93], The different amide derivatives (68) of penicillin were investigated in the very early period. Their syntheses started from penicillanic acid anhydride, but later different mixed anhydrides were applied for this purpose [94-98]. Moreover, other procedures described in peptide chemistry are also useful, e.g. the DCC method [99], or synthesis through active esters [100],... 

Two methods for the first synthesis of partial amides (257), (258) and a partial amide ester (259) of etidronate have been developed (Figure 48). The preparation of 1,1-bisphosphonates from tris(trimethylsilyl)phosphite (260) and acid anhydrides (261) has been described. This synthesis allows a... 

Adducts (6) and (7) from amides and chlorophosphoric acid aiyl esters or dichlorophosphoric acid aryl esters respectively are well known. - The adducts are formed in a 1 1 ratio. They have been applied to the synthesis of mixed anhydrides from diarylphosphoric acids and carboxylic acids, as well as mixed substituted esters of pyrophosphoric acid. The adduct formation between primary or secondary carboxamides and dichlorophosphates has been used to prepare nitriles and isonitriles respectively. The adduct from DMF and phenyldichlorophosphate is a useful reagent for the preparation of carboxylic acid esters from the corresponding acids and alcohols, 3-lactams from imines and carboxylic acids," carboxylic acid anhydrides, carboxylic acid esters and thiol esters. Adducts of amides with ester amides or diamides of chlorophosphoric acid have been studied. ... 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Use Preparation of substituted amines and amides, acid anhydrides, esterification of alcohols, synthesis of other organic compounds. 

Cramer, R, Preparation of esters, amides, and phosphoric acid anhydrides, Angew. Chem.. 72. 236, 1960. Allen, J.E, and Johnson, O.H.. The synthesis of monovinyl esters of phosphorus(V) acids. J. Am. Chem. Soc., 77, 2871, 1955. 

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