Rearrangement mixed anhydride

With higher aliphatic acids, RCOOH, keten yields first a mixed anhydride CH3COOCOR, which can be distilled under reduced pressure by slow distillation at atmospheric pressure the mixed anhydride undergoes rearrangement into the anhydride of the higher fatty acid and acetic acid, for example ... 

The rearrangement is self-cataly2ed by the organosulfonic acid that is already present or acid from hydrolysis of the mixed anhydride product. If the... 

Smith and Stirton applied this mechanism to the sulfonation of long-chain fatty acid esters [31]. Instead of forming the well-defined mixed anhydride during the reaction of fatty acids with S03, the acid esters form a complex less defined in structure and composition. In this complex the a-hydrogen is activated, so that a second molecule of S03 can react. These two addition steps are fast. The final step is again a slow rearrangement of the intermediate with a loss of one molecule of S03. 

In the first step an S03 molecule is inserted into the ester binding and a mixed anhydride of the sulfuric acid (I) is formed. The anhydride is in a very fast equilibrium with its cyclic enol form (II), whose double bonding is attacked by a second molecule of sulfur trioxide in a fast electrophilic addition (III and IV). In the second slower step, the a-sulfonated anhydride is rearranged into the ester sulfonate and releases one molecule of S03, which in turn sulfonates a new molecule of the fatty acid ester. The real sulfonation agent of the acid ester is not the sulfur trioxide but the initially formed sulfonated anhydride. In their detailed analysis of the different steps and intermediates of the sulfonation reaction, Schmid et al. showed that the mechanism presented by Smith and Stirton [31] is the correct one. 

The Arndt-Eistert reaction (Scheme 2.1) which involves the Wolff rearrangement of diazoketones 13 (prepared from the corresponding commercially available N-protected-a-amino acids 12 by reaction of their mixed anhydrides with diazomethane a cautionary note is warranted here the generation and handling of diazomethane require special precautions) has been used extensively by Seebach and coworkers for the preparation of N-protected /9 -amino acids 14 and /9 -amino acid esters 15 and 16. 

Section A of Scheme 10.15 contains a number of examples of Curtius rearrangements. Entry 1 is an example carried out in a nonnucleophilic solvent, permitting isolation of the isocyanate. Entries 2 and 3 involve isolation of the amine after hydrolysis of the isocyanate. In Entry 2, the dihydrazide intermediate is isolated as a solid and diazotized in aqueous solution, from which the amine is isolated as the dihydrochloride. Entry 3 is an example of the mixed anhydride procedure (see p. 948). The first stage of the reaction is carried out in acetone and the thermolysis of the acyl azide is done in refluxing toluene. The crude isocyanate is then hydrolyzed in acidic water. Entry 4 is a reaction that demonstrates the retention of configuration during rearrangement. 

The reaction starts with the formation of a mixed anhydride and an acetate on treatment with an excess of acetic anhydride at 80 °C. There follows a Dieckmann condensation to give 2-590 and an intramolecular rearrangement/Michael addi-hon/retro Michael addition to afford the desired tetracyclic compound 2-592 via 2-591 in an overall yield of remarkable 92%. 

The suitably protected amino acid is activated as the mixed anhydride and treated with diazomethane to produce the corresponding diazo ketone. Rearrangement in the presence of water furnishes the p-amino acid. Diazomethane contains varying amounts of water, which is able to hydrolyze the activated amino acid. This leads to subsequent methylation by diazomethane to form the methyl ester as a side product. This cannot easily be removed from the diazo ketone, but can be separated during work-up of the homologated amino acids. 

The presence of the fluoromethyl thioester group in fluticasone (30-4) requires that the carboxyl group in (29-1) first be converted to a thioacid. This conversion can be accomplished most conveniently by taking advantage of the rearrangement of a mixed anhydride of (30-1) with a carbonylthione. That transient anhydride... 

Thioamide formation benzodiazepinone, 505 heteiodiazepinone, 621 phosphorus pentasulf ide, 323, 600 Thioazole formation, nitrile addition, 301 Thiocarbamate formation, 588 phenol, 95 rearrangement, 517 Thioenol ether formation, 185, 517 addition-elimination, 554 Thioester formation, mixed anhydride, 184 Thioether formation, 241, 300, 413, 416 alkylation, 586, 588 aromatic displacement, 416 Thiohydantoin formation, 293 Thiol interchange, benzothiazole formation, 422... 

Curtius rearrangement of the acyl azide of Ac-Phe-OH 31, at rt in dilute HC1, provided Ac-Phe-NH2-HC1 32 in up to 65% yield. Coupling of Z-Phe-OH with 32 using the mixed anhydride method afforded Ac-Pheip[NHCO]Phe-Z 33 as a single diastereomer in 55% yield. Reaction of 33 after hydrogenation with HCOCH(iPr)C02Me provides 34. Compound 34 was hydrogenated to afford the reduced-retro pseudotripeptide 35 in 65% yield for the two steps. 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

The reduction of a-amino mixed anhydrides with lithium tri-/ert-butoxyaluminum hydride in THF at —70 °C is a very efficient method for synthesis of amino aldehydes (Table 9). 551 Three approaches were taken for the reduction of a-amino mixed anhydrides. 55 The first approach reduced Boc-Ala-OC02Et with lithium tri-terf-butoxyaluminum hydride was unsuccessful due to intramolecular rearrangements that gave Boc-Ala-OEt in addition to the Boc-Ala-H. The second approach involved reduction of diphenylacetic anhydride derivatives, which were prepared from Boc amino acids and diphenyl ketene, gave a diphenylacetic acid byproduct that was very difficult to remove unless the aldehyde was converted into its semicarbazone and separated chromatographically yields were 51-69%. The last and... 

Methyl 2,3,5-tri-Q-acetyl a and p-D-ribofuranoside, 86 Michael reaction, 221-242 Mixed anhydride, 353 Molecular graphic techniques, 353 Molecular rearrangements, 183-190 ( )-Monomorine, 213 Monothioacetal, 21 Morphinans, 356-357... 

Fig. 14.44. A one-pot diastereoselective degradation of a carboxylic acid to a Boc-protected amine via a Curtius rearrangement Boc refers to tert-butoxylcarbonyl. The mixed anhydride B is formed by a condensation of the phosphorus ) reagent with the carboxyl group. The anhydride B acylates the concomitantly generated azide ion forming the acyl azide A. A Curtius degradation converts A to C, and the latter reacts subse-guently with tert-butanol to the Boc-protected amine.

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