Carboxylic acid anhydrides: aliphatic synthesis

Acetonitrile, 407 Acetophenone, 725,729,730 phenylhydrazone, 852 p-Acetotoluidide, 593, 605 Acetoxime, 343 Acetylacetone, 861, 862, 863 Acetylation, reductive, 749 Thiele, 749 Acetyl chloride, 367 2-Acetylcyciohexanone, 862, 864 Acetylene, 245, 897 reactions of, 245, 246 Acetylenic compounds, synthesis of, 467-469, 895-902 Acetylglycine, 909 Acetylmethylurea, 968, 969 Acetylsalicylio acid, 996 Acetyl-o-toluidide, 578 2-Acetylthiophene, 837 Acid anhydrides of aliphatic carboxylic acids, 371... 

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. 

An acyl transfer agent which can be used for the synthesis of acid anhydrides is obtained from the reaction of an acid chloride with 4-benzylpyridine (equation 24). In this way benzoic acid anhydride and cinnamic acid anhydride were obtained in 72% and 57% yields, respectively. As the intermediate, 1-acyl-4-benzylidene-l,4-dihydropyridines, can be isolated, Ais procedure should be well suited for the preparation of mixed anhydrides. Mixed aromatic and aliphatic anhydrides can be prepared with 2-ben-zoylthio-l-methylpyridinium chloride and salts of carboxylic acids. These reactions are carried out in aqueous solution. Iliey make use of the high reactivity of esters of thiocarboxylic esters towards nucleophiles. The mixed anhydrides of benzoic acid with 3-phenylpropanoic acid, phenoxyacetic acid, isobu-tyric acid, p-toluic acid and cinnamic acid were formed in 82, 79,61,91 and 66% yields, respectively. 

Related condensations involving the replacement of the anhydride component with succinic acid (Fit-tig synthesis)27 or with malonic acid (Knoevenagel condensation, see Volume 2, Chapter 1.11) provide complementary preparative methods which are useful for both aromatic and aliphatic systems. The Fittig extension of the Peikin transformation involves heating an aliphatic or aromatic aldehyde with sodium succinate and acetic anhydride to give the condensation products (17), which lose carbon dioxide to afford p.y-unsaturated carboxylic acids (18), accompanied by small amounts of the corresponding y-buty-rolactones (19 Scheme 7).27... 

This reaction was initially reported by Granacher in 1922. It is the preparation of thionic acid by the treatment of Aldol Condensation product from an aldehyde and rhodanine with a base (e.g., NaOH). Therefore, this reaction is known as the Granacher synthesis or Granacher reaction." The prepared thionic acid in this reaction can be further converted into a variety of derivatives under different conditions. For example, it can be transformed into a-thiol acid under a basic sodium amalgam reduction, whereas aliphatic acid is formed under an acidic zinc amalgam reduction. In addition, when the thionic acid is treated with ammonia, a-keto acid is generated, and the thionic acid can be converted into af-carboxyl oxime in reaction with hydroxylamine, from which either cy-amino acid or aliphatic nitrile forms via the treatment of sodium amalgam reduction or acetic anhydride, respectively. 

Moreover, they are versatile building blocks for the synthesis of functionalized naphthalenes, anthracenes, and naphthacene natural products [8]. Recently, Rh-catalyzed C-H activation followed by nucleophilic addition to aldehydes emerged as a powerful alternative to access phthalides. In 2012, Li and coworkers developed a novel Rh(III)-catalyzed synthesis of three substituted phthalides from benzoic acids and aldehydes through carboxylate-directed ortho-C-H functionalization and subsequent intramolecular cyclization (Scheme 6.2a) [9]. In 2013, GooCen and coworkers described the straightforward synthesis of S-alkylidenephthalides from benzoic acids and aliphatic acids or anhydrides in the presence of [Rh(cod)Cl]2 and CsF (Scheme 6.2b) [10]. 

The synthesis of 2-benzenesulfonylpyridazin-3(2//)-ones has been discussed in Section 8.01.5.5.4. They can be used to prepare A -alkylbenzenesulfonamides via reaction with aliphatic amines <2002JHC203>. 4,5-Dichloro-2-[(4-nitrophenyl)sulfonyl]pyridazin-3(27/)-one proved to be useful for the preparation of carboxylic anhydrides from the corresponding acids in the presence of base in THF or CH2CI2 <2003S1517>. 

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