With mixed carboxylic-carbonic anhydrides

Sodium, with l-bromo-3-chloro-cyclobutane to give bicyclo [l.l.O]butane, 51, 55 Sodium amalgam, 50, 50, 51 Sodium amide, with 2,4-pentane-dione and diphenyliodonium chloride to give l-phenyl-2, 4-pentanedione, 51, 128 Sodium azide, 50, 107 with mixed carboxylic-carbonic anhydrides, 51, 49 Sodium borohydride, reduction of erythro-3-methanesulfony-loxy-2-butyl cyclobutanecar-boxylate, 51, 12 reduction of 2-(1-phenylcyclo-pentyl)-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine to 2-(1-phenylcyclopentyl)-4,4, 6-trimethyltetrahydro-l,3-oxazine, 51, 25 Sodium cyanoborohydride, used... 

Phenylcyclopentanecarboxylic acid, with ethyl chlorocar-bonate to give mixed carboxylic-carbonic anhydride, 51, 48... 

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,... 

The usual procedure of preparing acid azides, which involves treating an acid chloride with sodium azide,8,9 suffers from the disadvantage that it is often difficult to obtain pure acid chlorides in good yields from acids which either decompose or undergo isomerization in the presence of mineral acids.7 Synthesis of the azide by way of the ester and hydrazide10 has been used to circumvent this difficulty but is much less convenient. The present procedure permits ready formation of acid azides in excellent yields from mixed carboxylic-carbonic anhydrides and sodium azide under very mild conditions. 

The simple method for the preparation of dialkyl. . 1-aminoalkanephosphonates discovered in our laboratory — enabled us to solve that problem.Phosphonopeptides 2. were prepared by condensation of N-blocked amino acids with dialkyl 1-aminoalkanephosphonates by means of dicyclohexylcarbodiimide ( DCC ) method,or preferably using the mixed carboxylic-carbonic anhydride ( MCA ) method. 

Mixed carboxylic-carbonic anhydrides decompose in the presence of DMAP to give esters and carbon dioxide under mild conditions [Scheme 6,51], In the case of benzyl esters, the mixed car boxy lic-car bon ic anhydrides can be generated by reaction of the carboxylic acid with benzyl chloroformate in the presence of triethylamine (1.1 equiv) and DMAP (0.1 equiv)126 or more conveniently by reaction of the carboxylic acid with dibenzyl dicarbonate (dibenzyl pyrocarbo-nate) in THF or ferf-butyl alcohol in the presence of DMAP (0.1 equiv).127 The reactions generally work well except for hindered carboxylic acids. The method can also be used to make methyl, ethyl, ferf-butyl and ally esters. Carboxylic acids react with 2 equivalents of benzyl 2,2t2-trichloroacetimidate12s in the presence of a catalytic amount of boron trifluoride etherate to give the benzyl ester in modest to good yield,12g... 

One of the most convenient esterification methods developed earlier was based on the decarboxylation of unstable mixed carboxylic-carbonic anhydrides prepared by reaction of chloroformates with carboxylic acids (Ref. 38) according to scheme 43. 

The reaction of chloroformate (I) with acrylic acid followed by the decarboxylation of the unstable mixed carboxylic-carbonic anhydride formed, gives the 2-oxo-1,3-dioxolan-4-yl methyl acrylate in good yield (Ref. 51). The reaction of (I) with 2-hydroxyethyl acrylate in the presence of a base affords a new acrylic monomer, SNPE code number CL 1042, in excellent yield (Ref. 51) [5cheme 52]. 

Phosgenation of a-hydroxy acids affords cyclic mixed carboxylic-carbonic anhydrides which can be used as activated form of acid function in reaction with amines to afford amides as illustrated by the example given in scheme 182 (Ref. 235). 

The acyl azides required for Curtius rearrangement can be prepared under mild conditions via mixed carboxylic-carbonic anhydrides. The original 1961 report detailed preparation of racemic c/5-2-phenylcyclopropylamine. Treatment of carboxylic acid 58 with ethyl chloroformate and base in aqueous acetone provided the mixed anhydride, which was treated in situ with sodium azide. The crude acyl azide was isolated by extractive workup and underwent Curtius rearrangement, followed by acid hydrolysis. After raising the pH, the free base 59 was obtained in good overall yield. 

C amandole [42540-40-9], antibiotic, 58. A key intermediate, the qfdic mixed carboxylic-carbonic anhydride 56, prepared by phosgenation of mandelic acid 55, is used as an activated form of acid function in reaction with an amine to afford the active antibiotic [46]. 

Carboxylic acids can be activated in situ as mixed anhydrides B (Figure 6.14) that are mixed anhydrides of a carboxylic acid and a carbonic acid half ester. As can be seen from Table 6.1, in anhydrides of this type the C=0 double bond of the carboxylic acid moiety is stabilized less by resonance than the C=0 double bond of the carbonic acid moiety. Therefore, a nucleophile chemoselectively reacts with the carboxyl carbon of the carboxylic and not the carbonic acid ester moiety. 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

Where acid chlorides are difficult to obtain, Weinstock s method of using mixed carboxylic-carbonic acid anhydrides can be helpful. The acid to be converted into its azide is treated with ethyl chlorofor-mate and base, the ethyl carbonate moiety is then displaced by azide ion. The method has been used in the penicillin field . It is not general, however when the alkanoyl part of the mixed anhydride is sterically hindered, the azide ion displaces it instead of the carbonate moiety, and ethyl azidoformate is produced Cyclic anhydrides can be opened by azide ion, to give the salts of omega-azidocarbonyl acids, such as Na+ "OOCCHaCHaCONa . 

Another synthetic approach to acyl azides was reported by Weinstock one decade earlier. In this methodology, acyl azides are prepared via carboxylic-carbonic anhydrides. Generally, carboxylic acids are treated with ethyl chloroformate, generating mixed anhydrides which are trapped in situ by sodium azide. This sinple strategy was applied recently in the synthesis of ( )-spisulosine fScheme 4.21 After only 5 min in the presence of ethyl chloroformate, the appropriate carboxylic acid 58 was next treated with sodium azide. The intermediate ene-isocyanate 59 was obtained after heating, and this latter is finally hydrolyzed by water. The corresponding methyl ketone 60 was isolated in 40% overall yield. 

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). 

Scheme 24.14 The Generation of Mixed Ethyl Carbonic Anhydrides by the Reaction of Carboxylic Acids and Tbeir Subsequent Interaction with N-(silyl)methylamines.

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

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