Alkyl carbonic acid mixed anhydrides

In order to keep side reactions at a minimum alkyl-carbonic acid mixed anhydrides are prepared and used for acylation in the cold. Nevertheless, both reactions require a very short time. The byproducts of coupling, CO2 and an alcohol (R OH), do not interfere with the isolation of the desired peptide. These features readily explain the popularity of the approach, but the principal advantage of alkylcarbonic acid mixed anhydrides lies in the fact that they give rise to only small amounts of the undesired second acylation product, a urethane ... 

A mixed anhydride of an alkyl carbonic acid is formed. This technique minimizes racemization of the chiral a C. 

FIGURE 7.6 Decomposition of a mixed anhydride (A) to the 2-alkoxy-5(4//)-oxazolone and the alkyl carbonate.9 The latter is in equilibrium with the anion whose reaction (B) with a second molecule of anhydride produces pyrocarbonate and the acid anion whose reaction (C) with a third molecule produces the symmetrical anhydride. The oxazolone eventually reacts with the alcohol to give the ester. (D) Acyloxonium ions formed by reaction of the anhydride with dimethylformamide and tetrahydrofuran. 

The mercapto group of 9-mercapto-4//-pyrido[ 1,2-a]pyrimidin-4-ones 513 was alkylated with (het)aralkyl bromides and chlorides in the presence of potassium carbonate in dimethylformamide at ambient temperature for several hours. It also was acylated with carboxyl chlorides in the presence of potassium carbonate in acetone at room temperature or with mixed anhydride, prepared from aryl carboxylic acid and ethyl chloroformate,... 

All other carboxylic acid derivatives in Table 6.1, in which the leaving group is bound to the carboxyl carbon through an O atom, are increasingly better acylating agents than carboxylic acid alkyl esters (entry 3) in the order carboxylic acid phenyl ester (entry 4) < acyl isourea (entry 7) < mixed carboxylic acid/carbonic acid anhydride (entry 8) < carboxylic acid anhydride (entry 9) < mixed carboxylic acid anhydride (entry 10). 

Cellulose can be esterifled with almost any organic acid [81,82,84], Whereas this is possible in principle with both alkyl chlorides and carboxylic anhydrides, commercial practice has focused on the anhydride option. Although many esters have been described in the literature, industrially manufactured organic esters are prepared only with aliphatic fatty acids with between 2 and 4 carbon atoms in length (i. e., acetates to butyrates, CA to CB). Exceptions are some mixed esters with phthalic acid, which are used for enteric coatings in pharmaceutical applications and a novel carboxymethyl cellulose acetate butyrate (CMCAB), which is used in water-borne coatings applications [81,84],... 

Replacement of side chain carbon C21 by thioester sulfur retains corticoid activity and at the same time provides a function that is destroyed by serum enzymes. The synthesis starts with the potent antiallergic agent flumethasone (32-1). Reaction of that steroid with periodic acid cleaves the terminal bond in the hydroxyacetone side chain to give the hydroxyl acid 32-2 (Scheme 7.32). Steric hindrance around the acid invoke the need for extra activation of that function. Reaction of 32-2 with diphenyl chlorophosphate thus provides the mixed anhydride 32-3. This intermediate is not isolated but reacted in situ with AA -thioformamido chloride. The transient new mixed anhydride, 32.4, then undergoes an internal O to S rearrangement to give the acyl thioacid 32-5. Saponification with sodium hydroxide affords the corresponding thioacid. Alkylation of that intermediate with fluoromethyl bromide then yields the fluoromethyl thioester fluticasone (32-6). 

A carbonyl group is a carbon double-bonded to an oxygen an acyl group is a carbonyl group attached to an alkyl or aryl group. Acyl halides, acid anhydrides, esters, and amides are called carboxylic acid derivatives because they differ from a carboxylic acid only in the nature of the group that has replaced the OH group of the carboxylic acid. Cyclic esters are called lactones cyclic amides are lactams. There are symmetrical anhydrides and mixed anhydrides. 

Mixed anhydride method, a procedure of peptide coupling using reactive species resulting from the carboxylic moiety of a N-acylated amino acid and alkyl chlorocar-bonates (alkyl chloroformates), especially isobutyl chlorocarbonate (isobutyl chloro-formate), that readily reacts with an amino component. The nucleophilic amino component attacks the carboxy group of the amino acid component, with formation of the desired peptide derivative and release of the unstable isobutyl carbonic acid which immediately decomposes into carbon dioxide and isobutanol [J. Meienhofer, in The Peptides Analysis, Synthesis, Biology,... 

An established method for the activation of carboxylic groups, particularly those of N-protected amino acids or peptides, is to form mixed anhydrides with alkyl chloroformates or dialkyl dicarbonates such as B0C2O. Acyl carbonates can also be essential intermediates in the reactions of anhydrides with carbonates. 

A very mild esterification method involves reaction of mixed carboxylic-carbonic anhydrides derived from carboxylic acids and alkyl chloroformates in the presence of a catalytic amount of DMAP. ... 

Mixed carboxylic-carbonic anhydrides, prepared from carboxylic acids and alkyl chloioformates in the presence of base, are easily converted to acyl azides by the action of sodium azide. Since the reaction sequence from carboxylic acids to acyl azides proceeds under mild conditions, it has a broad applica-... 

The use of polymer-bound triphenylphosphine has also been described in combination with carbon tetrachloride for the condensation of carboxyhc acids with primary amines to give amides via the corresponding in situ formed mixed phosphinic anhydride, and for the conversion of aliphatic alcohols to the corresponding alkyl chlorides [38]. 

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