Symmetrical carboxylic acid anhydrides

Acyl chlorides are converted in good yield into symmetrical carboxylic acid anhydrides upon treatment with dilute aqueous sodium hydroxide at -I0°C in the presence of a tetra- -butylammonium salt [76, 77]. Yields are considerably lower when Aliquat is used. In a similar manner, chloroformates and ethyl oxalyl chloride are converted into carbonic hemi-ester anhydrides. 

Table 6 Symmetrical Carboxylic Acid Anhydrides from Carboxylic Acids and Reagents (3) and (4)...

A facile one-pot procedure for the s)mthesis of symmetric carboxylic acid anhydrides utilizes tosyl chloride (0.5-0.6 equiv) in K2CO3 media under solvent-free conditions. The desired anhydrides are formed by grinding the reaction mixture for 15 5 min in a mortar. The products were isolated by stirring the reaction mixture with CH2CI2 or CHCI3 followed by filtration and concentration. ... 

Unhindered thiolesters give excellent yields of symmetrical carboxylic acid anhydrides when oxidized with ozone. However, with hindered thiolesters, mixed carboxylic acid-sulphonic acid anhydrides are obtained in good yield. Steroidal alcohols may be converted into the corresponding fluorides, albeit in variable yields, with Et2NSF3. ... 

Generally, phenyl iV-phenylphosphoramidochloridate and other very similar related organophosphorus reagents e.g. phosphorus oxychloride, phenyl dichlorophosphate, diphenylchlorophos-phate and iV,W -bis(2-oxo-3-oxazolinyl)phosphorodiamidic chloride have been utilised in recent years not only to form symmetrical carboxylic acid anhydrides but also in esterification and thiol esterification reactions although phenyl N-phenylphosphoramidochloridate is not so efficient for the latter two reactions compared to its analogs but is probably the best choice for forming the anhydride. ... 

Carboxylic acid anhydrides. Carboxylic acids are converted to the symmetrical anhydride by reaction with 1 and triethylaminc in acetone or methylene chloride at room temperature (equation I). 

Scheme 1 Mixed Carboxylic Acid Anhydrides 1, Mixed Carbonic Acid Anhydrides 2, Symmetrical Anhydrides 3, Al-Carboxyanhydrides 4, iV-Thiocarboxyanhydrides 5, Al-Substituted iV-Carboxyanhydrides 6, and Urethane-Protected Al-Carboxyanhydrides 7...

Iodine triacylates (29) are readily obtained by ozonization of solutions of iodine in aliphatic carboxylic acid anhydrides thermolysis with mercuric oxide affords the symmetrical esters (30) in good yield. Mercuric iodate can perform the same transformation by direct reaction with the anhydride. 

Infrared IR spectroscopy is quite useful in identifying carboxylic acid derivatives The, carbonyl stretching vibration is very strong and its position is sensitive to the nature of IKT the carbonyl group In general electron donation from the substituent decreases the double bond character of the bond between carbon and oxygen and decreases the stretch mg frequency Two distinct absorptions are observed for the symmetric and antisym metric stretching vibrations of the anhydride function... 

The reaction is not suitable for hindered carboxylic acids, since considerable symmetrical anhydride formation (52% with pivalic acid) results. Symmetrical anhydride formation can sometimes be suppressed by the use of stoichiometric quantities of DMAP. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

Unsymmetrical as well as symmetrical anhydrides are often prepared by the treatment of an acyl halide with a carboxylic acid salt. The compound C0CI2 has been used as a catalyst. If a metallic salt is used, Na , K , or Ag are the most common cations, but more often pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. Mixed formic anhydrides are prepared from sodium formate and an aryl halide, by use of a solid-phase copolymer of pyridine-l-oxide. Symmetrical anhydrides can be prepared by reaction of the acyl halide with aqueous NaOH or NaHCOa under phase-transfer conditions, or with sodium bicarbonate with ultrasound. 

A potential liability associated with such reductive hydroacylations resides in the fact that only one acyl residue of the symmetric anhydride is incorporated into the coupling product. For more precious carboxylic acids, selective acyl transfer from mixed anhydrides is possible. Mixed anhydrides derived from pivalic acid are especially convenient, as they may be isolated chromato-graphically in most cases. In practice, mixed anhydrides of this type enable completely branch-selective hydroacylation with selective delivery of the aromatic and a,()-unsalurated acyl donors (Scheme 19). 

By use of TV-(trifluoroacetyl)- or TV-(trichloroacetyl)-imidazoleare obtained symmetric aliphatic and aromatic anhydrides even from carboxylic acids that do not form insoluble salts in benzene, ether, or THF (Table 13—1). In this case the acid is treated with the imidazolide in a 2 1 molar ratio, and an insoluble imidazolium trifluoro- or tri-chloroacetate is formed. 

In a related study by the same authors, the effect of microwave irradiation on car-bodiimide-mediated esterifications on a solid support was investigated, employing benzoic acid [29]. The carboxylic acid was activated using N,N -diisopropylcarbodi-imide (DIC) through the O-acyl isourea or the symmetrical anhydride protocol (Scheme 7.9). The isourea protocol was carried out in a dichloromethane/N,N-di-methylformamide mixture in sealed vessels, whereas the anhydride reactions were carried out in l-methyl-2-pyrrolidinone (NMP) at atmospheric pressure. 

In a more recent study using dedicated multimode microwave reactors for chemical synthesis, which enable temperature and power control, it was demonstrated that microwave irradiation could be effectively employed to couple aromatic carboxylic acids to polystyrene Wang resin [25], if the symmetrical anhydride procedure was used, and not the three-component O-acylisourea activation method [19]. Almost quantitative loading was achieved in l-methyl-2-pyrrolidone (NMP) at 200 °C within 10 min under... 

Symmetrical acid anhydrides are named by replacing the -acid suffix of the parent carboxylic acids with the word anhydride. Mixed anhydrides that consist of two different acid-derived parts are named using the names of the two individual acids with an alphabetical order. 

A convenient preparation of pyran-4-ones involves heating carboxylic acids or their anhydrides in polyphosphoric acid (67JCS(C)828). Yields are satisfactory, although when the synthesis is applied to a mixture of acids, a mixture of pyranones results. Only symmetrical pyranones (421) are formed, suggesting that the anhydride, rather than the acid, is the precursor of the heterocycle (Scheme 141). 

Tertiary aliphatic alcohol linkers have only occasionally been used in solid-phase organic synthesis [73], This might be because of the vigorous conditions required for their acylation. Esterification of resin-bound linker 4 with /V-Fmoc-prolinc [72,74] could not be achieved with the symmetric anhydride in the presence of DMAP (20 h), but required the use of /V-Fmoc-prolyl chloride (10-40% pyridine in DCM, 25 °C, 10-20 h [72]). A further problem with these linkers is that they can undergo elimination, a side reaction that cannot occur with benzyl or trityl linkers. Hence, for most applications in which a nucleophile-resistant linker for carboxylic acids is needed, 2-chlorotri-tyl- or 4-acyltrityl esters will probably be a better choice than ferf-alkyl esters. 

For the solid-phase synthesis of amides, it makes a significant difference whether the amine or the acid is linked to the support. Resin-bound amines are readily acy-lated by adding first a carboxylic acid and then a carbodiimide (Table 13.3). The acid/ carbodiimide ratio is not critical, because both the O-acylisourea (ratio 1 1) and the symmetric anhydride (ratio 2 1) will lead to N-acylation. It should, however, be borne in mind that the half-lives of O-acylisoureas are shorter than those of anhydrides, and for difficult couplings it might be advantageous to acylate with a symmetric anhydride (two equivalents of acid and one of carbodiimide). 

Triaminophosphonium salts, unlike carbodiimides, only react with carboxylic acids under basic conditions, thereby yielding acyloxyphosphonium salts (Figure 13.5). Depending on the counterion X and on the precise reaction conditions, the acyloxyphosphonium salt can either acylate the amine directly or be transformed into the symmetric anhydride or an active ester [2,82], which then acylates the amine. At low... 

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