Ketene, acylating reactions anhydrides from

Acylation. Reaction conditions employed to acylate an aminophenol (using acetic anhydride in alkaU or pyridine, acetyl chloride and pyridine in toluene, or ketene in ethanol) usually lead to involvement of the amino function. If an excess of reagent is used, however, especially with 2-aminophenol, 0,A/-diacylated products are formed. Aminophenol carboxylates (0-acylated aminophenols) normally are prepared by the reduction of the corresponding nitrophenyl carboxylates, which is of particular importance with the 4-aminophenol derivatives. A migration of the acyl group from the O to the N position is known to occur for some 2- and 4-aminophenol acylated products. Whereas ethyl 4-aminophenyl carbonate is relatively stable in dilute acid, the 2-derivative has been shown to rearrange slowly to give ethyl 2-hydroxyphenyl carbamate [35580-89-3] (26). 

But the formation of azlactones as intermediates cannot explain all the observations made in this field. Thus it has been mentioned already that ketene racemizes AT-methyltryptophan. Carter and Stevens (1940) state that certain acyl derivatives of ir-proline and W-methyl-n-phenyl-alanine are rapidly racemized by the action of acetic anhydride in glacial acetic acid. In the same paper it is also reported that the addition of various azlactones to a solution of benzoyl-p-methoxyphenylalanine in acetic acid produces fairly rapid racemization of the acyl derivative. An azlactone can obviously not be formed from a compound such as proline, and there is no evidence that structures such as XLIII exist and even if they exist, there is no apparent reason why they should be so easily racemized. There is a possibility of the transient formation of a dipolar structure such as XLV, which is analogous to the formula proposed for sydnones (Baker and Ollis, 1946). But a more likely explanation is that both ketene and acetic anhydride can form mixed anhydrides with acylamino acids, which can then rearrange to form azlactones and acetic acid. Reference has already been made to the action of ketene on carboxylic acids to produce mixed anhydrides and similar reactions have been observed with acetic anhydride. The marked racemization of such structures is partly explained by the strongly electronegative character of the anhydride group. Such an explanation is supported by the findings... 

The formation of acrylonitriles from the reaction of dihalogenomethylene-phosphoranes with aroyl cyanides has now been extended to include the use of aliphatic acyl cyanides, although the conditions need to be closely defined. Perfluoroisocyanates with diphenylmethylenetriphenylphosphorane give the expected keten-imines (28) or their rearrangement products (29). Formylation of both reactive and stable ylides has been achieved using the mixed anhydride of formic and acetic acids. ... 

Carboxylic acid anhydrides. A soln. of triflic anhydride in ethylene dichloride added dropwise to a soln. of Ph3PO in the same solvent at 0° under N2 after 15 min a soln. of / -toluic acid in ethylene dichloride added followed by EtjN, and stirred for 15 min - p-toluic anhydride. Y 93%. Redox side reactions are avoided, and ketones, esters and ethers unaffected. F.e. inch ketenes, carboxylic acid esters (incl. aryl esters) and amides, amidines from carboxylic acid amides, benzimidazoles, and intramolecular ar. acylation, also using N-diphenylphosphinyl-N -methylpiperazine (without the need for an additional base), s. J.B. Hendrickson, M.S. Hussoin, J. Org. Chem. 54, 1144-9 (1989) alternative prepn. of reagents cf. D. Crich, H. Dyker, Tetrahedron Letters 30, 475-6 (1989). 

Treatment of acyl chlorides with pyridine and trifluoroacetic anhydride (TFAA) was assumed to involve generation of ketenes which can be subjected to electrophiUc attack by TFAA to afford jd-trifluoroacetylacetic acid derivatives 484. Quenching of the reactions with dienophiles resulted in construction of heterocycles 485 that clearly result from cycloaddition reactions of intermediate acylketenes generated by ehmination from 484 (Scheme 155) (1992TL1285, 1995T2573, 1995T2585). 

Trifluoromethylated pyrones can also be prepared from acyl chlorides by reaction with pyridine and trifluoroacetic anhydride followed by capture of the intermediate trifluoroacyl ketene 8 with suitable reagents. Thus, addition of A -cyclohexenyl-morpholine to the intermediate from palmitoyl chloride gave pyrone 9 as the major product, accompanied by amide 10. Ethyl vinyl ether yielded pyrones 11a and 11b (through p-elimination of ethanol) [9] (Scheme 5). 

Diphenylphosphinic mixed anhydrides have been utilized to form peptide bonds. Peptides are easier to isolate by this method than by employing 1,3-Dicyclohexylcarbodiimide. These anhydrides are the method of choice for the formation of amides of 2-alkenoic acids (eq 1 ). Carbodiimide and acyl carbonate methods proved to be inferior. Primary amines result in better yields than secondary amines. This activation protocol can be employed to form thiol esters (eq 2) p-Amino acids are readily converted to p-lactams with chlorodiphenylphosphine oxide (eq 3). Secondary amines work best. This activation protocol has been utilized to convert acids to amines via a Curtius rearrangement. Phenols have been generated from diene acids, presumably via base-induced elimination of diphenylphosphinic acid from the mixed anhydrides to form ketenes which spontaneously cyclize. Acids have been converted to ketones via activation followed by reaction with organometallic reagents (eq 4)."... 

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