Thionyl chloride amide synthesis

A classical procedure for the synthesis of the A-(1-chloroalkyl)amides1 or carbamates68 involves substitution of the hydroxy group in stable A-( 1-hydroxyalkyl)amides (or carbamates) by a halogen function with reagents such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, etc. In certain cases merely heating in concentrated hydrochloric or hydrobromic acid suffices1. 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

In one synthesis of this drug, L-proline (11-2) is acylated with the acid chloride (11-1) obtained from the addition of hydrogen chloride to the double bond in methacrylic acid followed by reaction with thionyl chloride to give amide (11-3) as a mixture of diastereomers. The pure 2S isomer is then isolated from the mixture by fractionation as the dicyclohexylamine salt. Treatment of that compound with ammonium hydrosulfide leads to the displacement of chlorine by a thiol group and the formation of captopril (11-4) [13]. 

Preparation of oxazole Cyclocondensation of amides, through dehydration, leads to the formation of corresponding oxazoles. This synthesis is known as Robinson-Gabriel synthesis. A number of acids or acid anhydrides, e.g. phosphoric acid, phosphorus oxychloride, phosgene and thionyl chloride, can bring about this dehydration. 

In a detailed study on phosphonate diester and phosphonamidate synthesis, Hirschmann, Smith, and co-workers reported that pyrophosphonate anhydrides may be produced as side products during conversion of phosphonate monoesters into phosphonochloridates. 72 They recommended adding the phosphonate monoester to a solution of the chlorinating agent (thionyl chloride or oxalyl chloride) to minimize formation of the less reactive anhydrides. They also found that addition of tertiary amines (e.g., TEA) to the phosphonochloridates, prior to addition of the alcohol or amine component, results in formation of a phospho-nyltrialkylammonium salt that is more reactive than the corresponding phosphonochloridate and leads to better yields of the phosphonate esters and amides. 

If benzyl carbamate is used as the amide component in the reaction with a-oxo acids 23 then the Na-benzyloxycarbonyl-DHA 24 is obtained directly (Scheme 8). Shin and et al.[77 84l widely exploited the above method in the synthesis of various a, 3-didehydropeptides (Table 3). In presence of 3 M thionyl chloride and acetyl chloride, 24 gave the A-carboxy-DHA anhydride ANCA 25, which could be conveniently converted into dehydropeptides.[77 84 Compared with the common saturated A-carboxy-a-amino acid anhydrides (NCAs), ANCAs were found to be stable at room temperature for several months. 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

A key step in the synthesis of the /3-lactamase inhibitor cilastatin (Bayer, Leverkusen, Germany) is the preparation of (S)-2,2-dimethylcyclopropane carboxamide. The chemically synthesized corresponding nitrile, l-cyano-2,2-dimethylcyclopropane, is hydrolyzed by a highly active but enanhounspecific nitrile hydratase to the racemic carboxamides. An amidase from Comomonas acidovorans overexpressed in E. coli selectively hydrolyzes the undesired (R)-isomer to the acid. The remaining (S) enantiomer is obtained with > 99% e.e. and 48% conversion (the resulting E value thus exceeds 100). The (R)-acid is recycled by chemical amidation with thionyl chloride and ammonia. The process has been developed by Lonza (Visp, Switzerland) and runs on a 15 m3 scale (Rasor, 2001). 

Nitriles can be prepared by the SN2 reaction of a cyanide ion with a primary alkyl halide. However, this limits the nitriles that can be synthesised to those having the following general formula RCH2CN. A more general synthesis of nitriles involves the dehydration of primary-amides with reagents such as thionyl chloride or phosphorus pentoxide ... 

From a.-Amino Acid Amides and Amidines a-Amino acid amides, which fall into the amine-imine class according to the general model (beginning of Section II,B), are converted to 3-alkyl-4-hydroxy-l,2,5-thiadiazoles by reaction with sulfur mono-chloride, thionyl chloride, or thionyl aniline. A large number of -amino acid amides were employed in the synthesis (see Table I)... 

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

Aromatic nitriles are also prepared by heating amides with phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, and ammonium sulfamate. In addition, the action of a double salt of aluminum and sodium chlorides, NaCl- AlClj, gives excellent yields of nitriles from both aliphatic and aromatic amides. Heating an amide with phthalic anhydride causes dehydration. A novel synthesis consists in treating a mixture of an aromatic acid and p-toluene-sulfonamide with phosphorus pentachloride the yields of nitriles range from 63% to 79%. ... 

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. " ... 

Further work has also been carried out on the synthesis and biological evaluation of novel amidate prodrugs of PMEA and PMPA. To synthesise (22a-i), PMPA and PMEA were converted under mild conditions into their corresponding dichloridate using thionyl chloride and pyridine. The desired compounds were obtained only when the addition of the phenols and the amino acid methyl esters in the presence of triethylamine were performed in that order. ... 

When imidazole-4,5-dicarboxylic acid is heated with acetic anhydride, the bis-azolide (146) which is formed readily hydrolyzes in water to give the monocarboxylic acid. This is a novel method of removing one carboxyl group <82JHC253>, which has been modified to broaden its applicability to the synthesis of mono- and diesters and -amides. Replacement of the acetic anhydride by thionyl chloride forms the related azolide (147) which forms the unstable carboxylic analogue which reacts with nucleophiles such as alcohols and amines (Scheme 81) <84SC251,85JHC413>. 

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