Carbamic acids, reaction with phosgene

The y-amino-p-hydroxy acid derived oxazolidinones 55 are prepared from the corresponding N-unprotected y-amino-p-hydroxy ester derivatives by reaction with phosgene,1119,391 carbonyl diimidazole,[41] or benzyl chloroformate.[86] Alternatively, cyclization is obtained from the N-carbamate protected derivatives, i.e. from the TV-isopropenyloxycarbonyl derivatives under heating,[381 or from the TV-Boc or N-Z derivatives under basic conditions. [68 81 87] By analogy, the p,y-diamino acid analogue is converted into the imidazolidinone 57 by treatment of the unprotected compound with phosgene.[83 88]... 

Alcohols and phenols can be attached to support-bound alcohol linkers as carbonates [467,665,666], although few examples of this have been reported. For the preparation of carbonates, the support-bound alcohol needs to be converted into a reactive carbonic acid derivative by reaction with phosgene or a synthetic equivalent thereof, e.g. disuccinimidyl carbonate [665], carbonyl diimidazole [157], or 4-nitrophenyl chloro-formate [467] (see Section 14.7). The best results are usually obtained with support-bound chloroformates. The resulting intermediate is then treated with an alcohol and a base (DIPEA, DMAP, or DBU), which furnishes the unsymmetrical carbonate. Carbonates are generally more resistant towards nucleophilic cleavage than esters, but are less stable than carbamates. Aryl carbonates are easily cleaved by nucleophiles and are therefore of limited utility as linkers for phenols. 

Compared to the reaction with phosgene, better yields are obtained in this reaction when the R substituents are small alkyl groups, such as methyl or ethyl, although in other cases the reaction was found to be better when phosgene was used. Cyclic carbamic acid derivatives 6 have been similarly prepared using phenyl chloro-formate [24] see also Chapter 6. 

Naphthol is mainly used in the manufacture of the insecticide carbaryl (59), l-naphthyl A/-methyicarbamate/ iJ-2j5 - (Sevin) (22), which is produced by the reaction of 1-naphthol with methyl isocyanate. Methyl isocyanate is usually prepared by treating methylamine with phosgene. Methyl isocyanate is a very toxic Hquid, boiling at 38°C, and should not be stored for long periods of time (Bhopal accident, India). India has developed a process for the preparation of aryl esters of A/-alkyl carbamic acids. Thus l-naphthyl methylcarbamate is prepared by refluxing 1-naphthol with ethyl methylcarbamate and POCl in toluene (60). In 1992, carbaryl production totaled > 11.4 x 10 t(35). Rhc ne-Poulenc, at its Institute, W. Va., facihty is the only carbaryl producer in United States. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

First attempts to use the carbonate or the carbamate function for the covalent binding of amino acids and proteins applying the activation of dextran with phosgene showed that this approach is limited due to the fact that it is combined with a number of side reactions (Fig. 51) [355]. 

Carbonate and carbamate derivatives, prepared from the reaction of alcohols and amines with phosgene and /V-hydroxy-2-thiopyridone, provide the corresponding alkoxyl radicals and aminyl radicals respectively, via radical decarboxylation [71-81]. For example, photolytic treatment of carbamate (57) derived from 4-pentenylamine generates the corresponding 4-pentenylaminyl radical, as shown in eq. 8.24. Under neutral conditions in the presence of tert-BuSH, a direct reduction product (A) of 4-pentenylaminyl radical is formed, while, in acidic conditions, cyclized product (C), pyrrolidine, via 5-exo-trig manner from 4-pentenylaminyl radical is formed. Under the latter conditions, the real reactive species is an electrophilic 4-pentenylaminium radical which rapidly cyclized via 5-exo-trig manner. 

Let us now consider to what extent the previous reaction of phosgene with a-amino acid can be applied to (5-amino acids to yield six membered cyclic 0-acyl carbamates. 

Cyclopropanols can be converted to various cyclopropyloxy derivatives (esters, e.g. acetates, ethers, e.g. methyl and ethyl ethers, and acetals, e.g. tetrahydropyran-2-yloxy derivatives) under the appropriate reaction conditions. In most cases the synthesis of cyclopropyl esters by the reaction between a cyclopropanol and an acid chloride (e.g. formation of 1 ) or acetic anhydride (e.g. formation of 2 ) have been reported. The yields were particularly good (84-95%) when acetic anhydride was used, although a drawback of the reaction can be byproduct formation. When a reactive moiety is attached to the cyclopropane ring in addition to the hydroxy group, other reactions can also occur m-l-(aminomethyl)-2,2-dimethyl-3-(2-methylprop-l-enyl)cyclopropanol (3) reacted with phosgene in benzene to give the corresponding carbamate l,l-dimethyl-2-(2-methylprop-l-enyl)-4-oxa-6-azaspiro[2.4]heptan-5-one (4) in 31% yield. ... 

A further variant can be used with strongly basic aliphatic amines and has proved especially valuable for diamines whose hydrochlorides do not react with phosgene first, dry carbon dioxide is led into a solution of the amine in a solvent suitable for the phosgene reaction, this giving a carbamic acid salt ... 

By analogy with the general synthesis of imidoyl chlorides it can be expected that carbamates and thiocarbamates undergo reaction with a variety of acid halides to afford 1-haloformimidates and 1-halothio-formimidates, respectively. For example, carbamates have been reacted with carbonyl chloride ( ), pyrocatecholphosphorus trichloride ( ), and phosphorus pentachloride ( ), and isocyanates were obtained. In view of the catalytic effect of N,N-dimethylformamide in the phosgenation of carbamates to isocyanates, the intermediacy of 1-chloroformimidates X is anticipated ( ). 

A simpler non-phosgene process for the manufacture of isocyanates involves the reaction of amines with carbon dioxide (CO2) in the presence of an aprotic organic solvent and a nitrogenous base. The corresponding ammonium carbamate is treated with an electrophilic dehydrating agent [198, 282, 283]. This concept has been applied to the synthesis of several aromatic and ahphatic isocyanates. The process relies on the facile formation of amine<arbon dioxide salts using acid halides such as phosphoryl chloride and thionyl chloride [284, 285]. 

From a practical point of view, isocyanates, together with carbamates and ureas (Chapter 3), are the most important organic products discussed in this book. Their synthesis from nitroarenes has indeed been the subject of many patents. There are also limited examples of aliphatic isocyanates obtained by this route. Organic mono- and diisocyanates may be prepared in a continues liquid phase method by treating the appropriate amine with phosgene. However, the reaction is rather complex [6] and, besides the use of the dangerous phosgene, the formation of the corrosive hydrochloric acid creates several problems. Aliphatic isocyanates can also be obtained from olefins with isocyanate ion in the presence of a salt of a coordination compound of palladium or platinum [7], from olefins with isocyanic acid in the vapour phase over Pt/ALOs [8], and from formamides, by oxidation over a silver catalyst [9]. Apparently only the last reaction seems to have some potential practical applications [10]. 

This reaction forms the basis of a method for the quantitative determination of methyl chloroformate which consists essentially in treating the substance to be tested with aniline solution and titrating the hydrochloric acid formed. In this case it is not possible to determine the carbamic ester formed gravimetrically (as in the phosgene estimation), for it is very soluble in water. ... 

The developed solid-phase approach started with the preparation of immobilised ureas 114 obtained via acylation of amino acids linked to acid-labile Sasrin resin 104 with ortho-methoxycarbonyl aryl isocyanates or activated para-nitrophenyl carbamates 113. Alternatively, ureas of type 114 could also be generated by reaction of anthranilic esters 115 with immobilised amino acid-derived isocyanates (easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of a base such as 2,6-lutidine) or activated carbamates 116 (Scheme 4.1.23). 

Carbonates can be described as diester derivatives of carbonic acid, formed by condensation with hydroxyl compounds. However, carbo q lic acids do not possess the necessaiy reactivity to synthesize such products. Therefore bifunctional reactive molecules such as phosgene or carbonyldiimidazoles like N,N -carbonyldiimidazole (CDI) and disuccinimidyl carbonate (DSC) are commonly used (Scheme 1.13). These compounds readily react with nucleophiles to form stable conjugates. They react with hydro)q l-containing molecules to form the amino-reactive carbonate or carbamate intermediates. These intermediates react in a subsequent step with primaiy amines to form stable carbamate bonds (aliphatic urethanes). The reaction is usually carried out in alkaline media (pH 7-9) and in the absence of competing amino and... 

A large-scale cyclization reaction of carbamates with functionalized butenoates, starting from carbamates prepared without phosgene, for the efEdent preparation of 3-(substituted phenyl)-5-isopropylidene-l,3-oxazolidine-2,4-dione derivatives (azaladones) having potent herbicidal adivity, has been described in a patent application [240]. By reacting an N-(substituted phenyl)carbamate 312 with a 2-hydroxy-3-alkenoic acid ester (for example, ethyl 2-hydroxy-3-methyl-3-butenoate) or a 3-alkoxy-2-hydroxyalkanoic add ester, at 210 °C for 15 h, azaladone 313 was formed in 71.5% yield. 

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