Anhydrides, preparation from

In solutions of acetyl nitrate in acetic anhydride, prepared from purified nitric acid, the 0 -ratio increases slightly with increasing concentrations of acetyl nitrate (table 5.7, expts. 11,13,16). The use of fuming nitric acid in the preparation of the acetyl nitrate considerably accelerates the rates of reaction and also increases the proportion of o-substitution (table 5.7, expts. 12, 15, 18). These effects resemble, but are much stronger than the corresponding effects in nitrations with solutions of nitric acid in acetic acid contaimng dinitrogen tetroxide. 

In an integrated continuous process, cellulose reacts with acetic anhydride prepared from the carbonylation of methyl acetate with carbon monoxide. The acetic acid Hberated reacts further with methanol to give methyl acetate, which is then carbonylated to give additional acetic anhydride (100,101). 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

Alternative methods for the synthesis of peptide aldehydes include reduction of acid halides, phenyl esters, thioesters, and anhydrides prepared from corresponding acids, isoxazolidides, and the hydrolysis of thiazolidine peptides 17,54-56 Enzymes such as thermolysin, subtilisin, and pronase E have proven valuable as effective semisynthetic alternatives 40,57 5 62 ... 

Thiol esters. These esters can be prepared by reaction of mixed anhydrides prepared from this chloride and a carboxylic acid with thiols in the presence of 4-dimethylaminopyridine (equation I). 

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,... 

Peptide synthesis in methanol or ethanol.1 The dimethylphosphinothioic anhydrides prepared from N-protected amino acids with 1 are stable to water or alcohols in the absence of a base, probably because of the P=S bond. As a consequence these active esters can be used for peptide syntheses in methanol or... 

A second procedure consists in heating mixed anhydrides prepared from disubstituted malonic acids and diphenylketene. 

Treatment of the sulfinamide anhydride, prepared from anthranilic acid and thionyl chloride, with carboxamides and thiocarboxamides 1 affords quinazolin-4(3//)-ones 2. Thiocarbox-amides, being much more easily dissolved than carboxamides in nonprotic solvents such as benzene, are more suitable as starting materials. This approach has been used by Kametani et al. in the synthesis of the quinazoline alkaloids glomerine, homoglomerine, chrysoginc, and glycosminine. " ... 

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-... 

Esterification of alcohols is also effected in good yields by using the mixed anhydride prepared from trifluoroacetic anhydride and dialkyl l-(hydroxycarbonyl)methylphosphonate (CH2CI2,... 

Formylation of amines and alcohols. Behai,8 discoverer of the reagent, found that it reacts unidirectionally with simple alcohols to produce alkyl formates free from acetates. Hurd et al. J found that acetic-formic anhydride (prepared from formic acid and ketene) reacts quantitatively with aniline to give formanilide. Another study10 established that acetic-formic anhydride mixes endothermally with 2-nitro-2-methyl-l-propanol, exothermally with 2-nitro-2-methyl-l,3-propanediol, and displays no appreciable temperature effect with either 2-nitro-l-butanol or tris-(hydroxymethyl)-nitromethane. Formic esters are favored by avoiding a high reaction temperature and by not using sulfuric acid as catalyst. The mixed anhydride has been used for the preparation of formyl fluoride.11... 

Phenylhydrazine and pyridine-2,3-dicarboxylic acid anhydride, prepared from the acid in situ, condense in acetic anhydride at 120-130 °C to give 7-phenylpyrido[2,3-[Pg.25]

Additional study of the alkaloidal fractions has given rise to a neutral component, periformyline (XIII) (mp 206°-209° pK a < 4) whose physical properties, formula, UV-, IR-, and mass spectra were suggestive of its structure. The NMR-spectrum in particular showed the formyl hydrogen as a doublet at 8.2 ppm. Its structure was established by the formylation of perivine with the mixed anhydride prepared from acetic anhydride and formic acid (84, 88) (Chart VII). 

At the same time another diketopiperazine, glycyl-l-tyrosine anhydride, was also obtained its nature was established a little later by identification with synthetical glycyl-l-tyrosine anhydride prepared from the ester of chloracetyl tyrosine and ammonia. In one experiment its yield amounted to 4 2 per cent, of the silk-fibroin employed. 

By condensation of sulfinamide anhydride (prepared from anthranilic acid and thionyl chloride) with phenylacetamide or thiophenylacetamide (28,31) according to Scheme 1... 

L-Argininamide hydrochloride allowed to react with the mixed anhydride prepared from N -carbobenzoxy-L-arginine hydrochloride, 1 mole triethylamine, and isobutyl chloroformate in dimethylformamide, and the product isolated as the dihydrochloride Na-carbobenzoxy-L-arginyl-L-argininamide dihydrochloride. Y 71. F. e. R. E. Plapinger et al., J. Org. Ghem. 30, 1781 (1965). 

DL-Phenylalanine heated with tri-n-butyltin oxide in toluene, the water removed azeotropically with most of the toluene, cooled to 0, added with exclusion of moisture to a cold toluene soln. of a mixed anhydride prepared from carbo-benzoxyglycine and ethyl chloroformate (s. Synth. Meth. 7, 447), stirred 0.5 hr. at —5° and 3 hrs. at room temp., water added, stirred 10 min., 1 N NaOH-soln. added, and stirred another 10 min. -> N-carbobenzoxyglycyl-DL-phenylalanine. Y Sl%.—The trialkyltin group can be easily attached, and easily removed by dil. acid or base. No racemization occurred during Ibe prepn. of tri-n-butyltin L-leucinate. F. e. and limitation s. M. Frankel et al., J. Org. Chem. 30, 1596 (1965). 

Clajenine [3820-67-5], analgesic, anti-infiammatoty, 125. Isatoic anhydride, prepared from o-aminobenzoic add 122 and phosgene, has been used as a starting material in the synthesis of Glafenine [94, 95],... 

A soln. of 0-benzyl phosphorous 0,0-diphenyl phosphoric anhydride prepared from monobenzyl phosphite, diphenyl phosphorochloridate, and dry pyridine in benzene added to 0-isopropylideneglycerol and 2,6-lutidine, stirred 1 hr. under anhydrous conditions 1,2-isopropylideneglyceryl benzyl phosphite. Y 79%. D. M. Brown and P. R. Hammond, Soc. 1960, 4229. 

The mixed anhydride prepared from 3.2 g (10 mmoles) of Z-Gly-Leu-OH, 1.1 ml (10 mmoles) of iV-methylmorpholine and 1.34 ml (10 mmoles) of iso butyl chloroformate in 60 ml of anhydrous tetrahydrofuran at —10° to —15° is allowed to react with L-phenylalanine chloromethyl ketone hydrobromide and 1.3 ml of fV-methylmorpholine for 1.25 hr while the reaction mixture is allowed to warm to room temperature under anhydrous conditions. Work-up of the reaction mixture involves evaporation of tetrahydrofuran, extraction of the residue into ethyl acetate, washing with citric acid and sodium bicarbonate solutions, drying over magnesium sulfate, and evaporation. The product is recrystallized from ethyl acetate-cyclohexane to yield 3.41 g (68%) of product with m.p. 140.5°-143°. 

Thioesters.—Mixed anhydrides prepared from 2,4,6-trichlorobenzyl chloride and a carboxylic acid react with various thiols in the presence of 4-dimethyl-aminopyridine to give thioesters in 78—86% isolated yield.Somewhat less impressive yields were obtained in a few of the cases studied when l-fluoro-2,4,6-trinitrobenzene was used to couple the acid and the thiol.Treatment of 1-acylimidazoles with thiols in the presence of a catalytic amount of Mg(OEt)2 furnishes thioesters in good yields. Diphenyl-2-oxo-3-oxazolinylphosphonate brings about effective reaction between acids and thiols. Thiolacetates are efficiently prepared using the reaction of an alcohol with triphenylphosphine and di-isopropyl azodicarboxylate in the presence of thiolacetic acid/ A synthesis of some amino-acid derivatives containing the thioester functional group is achieved by the reaction of a vinyloxyborane with a Schiffs base (Scheme 56). ... 

B. From Mixed Anhydrides Prepared from Malonic Adds and Diphenylkdene... 

Mixed anhydrides prepared from carboxylic acids and alkyl chlorocarbonates are of paricular value for the preparation of amides of sensitive acids such as A -acylated amino acids. The reaction of cyclic dianhydrides with amines yields imides. If diamines are used with dianhydrides, polyimide resins are produced. 

Direct conversion of the enamine (A) to the a-dicarbonyl compound (B) could also be accomplished in a single step by alkylation with the mixed anhydride prepared from pyruvic acid and ethyl chloroformate, cf., E. W. Colvin, J. Martin, W. Parker, R. A. Raphael, B. Shroot and M. Doyle, J. Chem. Soc. Perkin 1, 860 (1972). 

The structure of batrachotoxin was confirmed by a partial synthesis from batrachotoxinin A. This proved feasible using a mixed anhydride prepared from 2,4-dimethylpyrrole-3-carboxylic acid and ethyl chlorofor-mate (Scheme I). A variety of analogs of batrachotoxin were prepared in a similar manner. These compounds are documented in Table 4. A dihydro-batrachotoxin was prepared by sodium borohydride reduction (Scheme II) and apparently is subject to allylic rearrangement to other dihydroproducts 251). 

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