AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES

Amine oxides, anhydrous, SO, 55, 58 Amines, protecting group for, 50,12 AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES 1-PHENYLCYCLOPENTYL-AMINE,51,4S... 

AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES ... 

Alenylacetylenes, 50,101 Aluminum chloride, with ethylene and p-methoxyphenylacetyl chloride to give 6-methoxy-/3-tetralone, 51,109 with propylene and acetyl chloride to give 4-chloropentan-2-one, 51,116 Amine oxides, anhydrous, 50, 55, 58 Amines, protecting group for, 50,12 AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES 1-PHENYLCYCLOPENTYLAMINE,... 

Phenylcyclopentylamine has also been prepared from 1-phenylcyclopentanecarboxylic acid by means of the Hofmann degradation of the intermediate amide4 6 and from the intermediate carboxylic acid chloride by the Curtius reaction.6 In the method described, using the mixed carboxylic-carbonic anhydride,7 improved yields of the amine are obtained. 

The reaction is usually carried out with one equivalent of a tertiary base (EtsN or N-methylmorpholine) in dichloromethane. As a rule, the activation time is not high (from 25 min to 2 h), though this process occurs at a low temperature (—15°C—0°C). Generally, the duration of the second step is 12 h and the yields of the pure amides 109—119 are 53—88%. The mixed ethyl carbonic anhydrides can also be generated by the reaction of carboxylic acids with EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) in the presence of the amines (99). This approach allows amides 121 and 122 to be obtained in high yields (Scheme 24.14, Table 24.5) (74). 

All anhydrides derived from an amino acid, other than a symmetrical anhydride, are mixed anhydrides . However, in the field of peptide chemistry, the term mixed anhydride is commonly used to refer to anhydrides derived from an amino acid and either a carboxylic acid 1 or a carbonic acid 2 (Scheme 1). Other mixed anhydrides will be addressed separately. The use of mixed anhydrides 1 and 2 for peptide synthesis encompasses two distinct reaction steps, as outlined in Scheme 2. The first step is the formation of the mixed anhydride, the activation step, which is the reaction of an amino acid derivative 8 with an acid chloride 9, in the presence of a tertiary amine, in an inert solvent to give the mixed anhydride 10. The second step is the condensation of the mixed anhydride 10 with the amine of an amino acid derivative 11 to give peptide product 12 and the carboxylic acid 13. 

The mechanism of CDI-mediated acylation of amines is well understood. The first step involves a partial protonation of the basic imidazole-nitrogen, protonated A-acetylimidazole has a p a of 3.6,f l leading to an activated species which is then attacked by the carboxylate. The resulting mixed anhydride extrudes carbon dioxide giving rise to A-acylimidazole which on treatment with an amine compound leads to the desired anoide (Scheme 1). An important advantage of this method over the carbodiimide method is that the byproducts carbon dioxide and imidazole are readily and quantitatively separated from the reaction product by simple washing procedures. 

A resin with mixed carbonic-carboxylic anhydride function has been prepared and used as acylating reagent [144], Thus, the supported chloroformate 140 was obtained by reaction of hydroxymethylated polystyrene with phosgene in benzene (Scheme 7.43). Further treatment with benzoic acid in the presence of triethyl-amine in benzene gave rise to the supported mixed anhydride 141. This polymer has been used in the benzoylation of several amines, although variable amounts of benzoic acid from attack to the internal carbonyl were obtained when using aromatic amines. 

Unsymmetric anhydrides that react selectively on one side are useful. Although formic anhydride is unstable above 10°C, acetic formic anhydride can be prepared by stirring sodium formate with acetyl chloride in ether (64% yield, bp 27-28°C) [22]. It is useful for the formylation of alcohols and amines. A stable solid formylating agent is the mixed anhydride prepared in 89% yield from p-methoxybenzoyl chloride and sodium formate catalyzed by a polymeric pyridine oxide [23]. Ethyl chlorofor-mate gives mixed anhydrides with various carboxylic acids which are then susceptible to nucleophilic substitution at the carboxylic carbonyl carbon. 

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