Isocyanates, addition reaction with carbamates

Impurities in CL have also been destroyed by oxidation with ozone22 followed by distillation. Ozonation treatment of waste CL leaves no ionic impurities. However, the most commonly used oxidizing agents are potassium permanganate, perboric acid, perborate, and potassium bromate. Treatment of CL with these oxidizing agents is carried out in a neutral medium at 40-60°C. Strongly alkaline or acidic conditions accelerate the oxidation of CL to form isocyanates. Hie undesirable oxidation reaction is fast above pH 7 because of the reaction with isocyanate to form carbamic acid salts, which shifts the equilibrium to form additional isocyanate. 

Carbamates (substituted urethanes) are prepared when isocyanates are treated with alcohols. This is an excellent reaction, of wide scope, and gives good yields. Isocyanic acid HNCO gives unsubstituted carbamates. Addition of a second mole of HNCO gives allophanates. 

Monocarbamoylation of diols is generally accomplished only with great difficulty. Reaction of the diol with an alkyl isocyanate is a possibility, but trimerization of the isocyanate frequently occurs [73]. The monocarbamic esters, which have PAF receptor antagonist activity, can be obtained however in acceptable yields via the phase-transfer catalysed in situ formation of the alkyl isocyanate from potassium isocyanate and an alkyl halide, and its subsequent reaction with the diol (see Scheme 3.8 for typical examples) [74], The diols tend to react more rapidly than do simple alcohols and m-diols are more effectively esterified that are /ra/rs-diols. Additionally, the longer the chain length between the hydroxyl centres, the less effective is the reaction. This has led to the reasonable hypothesis that a cyclic H-bonded intermediate between the two hydroxyl groups and the alkyl isocyanate are critical for the preferential and rapid formation of the carbamate. 

There are several types of chiral derivatizing reagents commonly used depending on the functional group involved. For amines, the formation of an amide from reaction with an acyl halide [147,148], chloroformate reaction to form a carbamate [149], and reaction with isocyanate to form the corresponding urea are common reactions [150]. Carboxyl groups can be effectively esterified with chiral alcohols [151-153]. Isocynates have been used as reagents for enantiomer separation of amino acids, iV-methylamino acids, and 3-hydroxy acids [154]. In addition to the above-mentioned reactions, many others have been used in the formation of derivatives for use on a variety of packed and capillary columns. For a more comprehensive list, refer to References 155-159. 

Addition to Other Unsaturated Molecules. When isocyanates are treated with alcohols, substituted methanes or carbamates are prepared (Reaction XIX). 

The relative rates of these reaction sequences were found to depend on the nature of the medium (homogeneous or heterogeneous), rate of addition of water, temperature, reactivity of the amine (formed by the decomposition of the carbamic acid) with the isocyanate, concentration, and other factors. For example, in the reaction with phenyl isocyanate, cold water and heterogeneous medium favored the formation of diaryl urea while with boiling water the main product was aniline. Dilution also favored aniline formation. 

This reaction shows the addition of an active hydrogen compound, HA, across the N=C double bond of an isocyanate. Isocyanates also react with water and the initial product is carbamic acid which is unstable, losing carbon dioxide, and generates an amine that reacts with the excess isocyanate to produce urea as follows ... 

The compound reacts with alcohols, phenols and amines to form products similar to those obtained from the corresponding reaction with COCI [1358]. Depending upon the conditions and stoicheiometry, carbonates and chloroformates [612,1380], carbamates [1380], isocyanates [1184] and ureas [938] can be obtained with diphosgene, in addition to more complicated products such as carbamoyl chlorides, imidic chlorides, carboxylic acid chlorides, isonitriles and IV-carboxy-Q-amino acid anhydrides [1358]. 

The reactions of 2-aminobenzimidazoles have been reviewed <83S86l>. The compounds form Schiffs bases with carbonyl compounds, with isocyanates and isothiocyanates they give ureas and thioureas, they are subject to 1,3-dipolar addition reactions, and to the formation of carbamates on acylation and aroylation. When aminoimidazoles are acylated there is frequently competition between the annular and exocyclic nitrogen (see above). Add chlorides and anhydrides (soft) acylate the amino group chlorocarbonic acid esters (hard) are specific for the heteroatom <84CHE204>. When heated, the A -acyl products isomerize (Scheme 91). 

Isocyanates are very reactive toward compounds containing labile hydrogen atoms, forming addition compounds with the hydrogen donors. One such reaction, with hydroxyl-bearing compounds to form carbamates, or urethanes,... 

The process from the FMC company involves as the pivotal step an intramolecular stereoselective [2 + 1 [-cycloaddition. In a Prins reaction [94] of chloral and isobutene, followed by an isomerisation, a racemic, trichloromethyl-substituted aUyl alcohol is obtained. Reaction with the isocyanate from (R)-naphthylethyl-amine enables separation ofthe diastereomers by crystallisation. The carbamate is cleaved by trichlorosilane/triethylamine, thus permitting the recycling of the chiral auxiliary. The optically pure (R)-aUyl alcohol is reacted with diketene, to produce the / -keto-ester. After diazo transfer and basic cleavage, the diazoacetate is obtained catalysed by a copper salt, this is converted in a [2 + 1 ]-cyclo-addition into a bicyclic lactone. The Boord reaction (discovered by Cecil E. Boord in 1930) [95] finally gives (IR)-cis-permethric acid. [96]... 

Independent conHimation of the plausibility of this reaction was demonstrated by the addition of an equal molar amount of the dianim of o-sulfobenzoic acid to the anhydride giving the same linear benzoic anhydride. This result points out that attack of the caiboxylate is competitive with carbamate attack on the cyclic anhydride. The generation of linear anhydride does not appear to affect the production of isocyanate. 

Isocyanates react with water (Scheme 1) at a rate similar to their rate of reaction with a secondary alcohol, provided that both the isocyanate and water are soluble in the reaction medium. The initial addition product, a carbamic acid (3), is generally unstable and loses carbon dioxide, generating an amine which rapidly reacts with additional isocyanate to produce a urea (4). Kinetic studies of the isocyanate-water reaction indicate that the overall reaction sequence may be more complicated than that presented in Scheme 1. A more detailed discussion of this can be found in the literature. ... 

Activation of the carboxylic acid as the acyl chloride permits direct reaction with azide anion to form the acyl azide substrates for Curtius rearrangement. Sodium azide is commonly used, and the reaction has been used on the process chemistry scale for the synthesis of benzyl-A-vinyl carbamate. Acryloyl chloride was combined with sodium azide in a biphasic system with phase-transfer catalysis (PTC), providing acyl azide 25. Upon heating, Curtius rearrangement provided vinyl isocyanate, which was distilled directly into benzyl alcohol containing phenothiazine (27) to inhibit polymerization of 26 and triethylamine to catalyze addition of the alcohol to the isocyanate. The vinyl carbamate product 28 was isolated by crystallization. As the autiior clearly pointed out, preparation and reaction of acyl azides, particularly on large scales, require appropriate safety precautions. 

Typical procedure. Dehydration of carbamate anions with POCI3 [286] The amine (5 mmol), base/NH2 (15 mmol), and biphenyl (154 mg internal standard) were dissolved in acetonitrile (25 mL) and CO2 (1 atm) was passed in for up to 1 h. POCI3 (1 equiv./NH2) was diluted vith acetonitrile (25 mL) and both solutions were cooled to 0 °C prior to addition of the carbamate solution to the POCI3. The progress of the reaction was monitored by GC analysis until no more isocyanate was produced. Isolated yields, i.e. following an aqueous acid extraction to remove the phosphorus salts and purification by distillation, are reported in Table 4.19. Virtually identical yields were obtained by using 1 equiv. of PCI3/NH2 under the same conditions. 

Carbamates are usually prepared by the addition of an alcohol to an isocyanate. The reaction of isocyanates with alcohols is fast and quantitative (indeed, it is used to characterize alcohols). The reaction with phenols is slower, but can be catalyzed by tertiary amines. 

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