Carbamates from isocyanates

The reverse reaction is the one usually employed -for the synthesis o-f carbamates -from isocyanates obtained by phosgenation o-f the amines. 

Table 14.8. Preparation of carbamates from support-bound amines or isocyanates.

In a similar approach, Pimmg and Chen [3] prepared an indexed library of 54 carbamates from a set of nine alcohols and nine isocyanates. The library was prepared as 15 sublibraries in which each of the alcohols and isocyanates was reacted with an equimolar mixture of the other reactants. The product mixtures were tested as inhibitors of acetylcholinesterase and their activities were used as indices to the rows and columns of a two-dimensional matrix reflecting the activities of individual products. An identical approach was used by the same authors in the preparation of a library of 72 tetrahydro-acridines by the condensation of 12 cyclohexanones with six cyanoanilines in 18 sublibraries [4]. 

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]. 

Apart from the preceding processes, the hydroxy group in hydroxyalkyl-phosphonic or -phosphinic esters has been acylated straightforwardly or by carboxylic acids in the presence of dicyclohexylcarbodiimide " , a procedure also particularly useful for the N-acylation of aminoalkylphosphonic acids for the purpose of enantiomer analysis, phos-phitylated ", phosphorylated and replaced by halogen (Chapter 3, Section II.C. 1). Carbamates have been prepared from isocyanates or isothiocyanates " and hemiacetals formed in reactions with trichloroacetaldehyde the acetal 200 was prepared from ben-zaldehyde and the bis(a-hydroxybenzyl)phosphinic acid. Cyclic boron diesters have also been prepared. ... 

The free acids are not known although their formation from isocyanic or isothiocyanic acid and one mole of a hydrogen halide can be visualized. While the esters of isocyanic acid, the isocyanates III, add one mole of hydrogen halide to afford the corresponding carbamic acid chlorides (IV), methyl isothiocyanate (V) adds hydrogen bromide to form a mixture of two isomers, to which 1-bromothioformidic acid structures VI and VII have been assigned ( ). 

A significant advance in the resolution of asymmetric alcohols has been the formation of carbamates from the reaction with a chiral isocyanate. Isocyanates are highly reactive and are widely used for the derivatization of hydroxyl and amine functional groups. Alcohols react relatively slowly and require heating for several hours, whereas phenols react rapidly, even at room temperature. Reagents used have included (R(-P)/S(—) phenylethyl isocyanate (15) and R(-p)/S( —)- -( -naphthyl)ethyl isocyanate (16) the diastereomeric carbamates are stable and no evidence for racemization has been recorded. The individual enantiomers can be recovered by refluxing the dias-tereomeric carbamates... 

Formation of diastereomeric carbamates from chiral isocyanates... 

A urethane (also called a carbamate) is a functional group that is simultaneously an ester and an amide at a single carbonyl group. Urethanes are commonly prepared from isocyanates and alcohols. 

Polyurethanes (qv) are polymers containing urethane (—NH—COO—) linkages carbamate is a synonym for urethane. Urethanes are usually formed by reaction of an alcohol with an isocyanate, but they can also be made by other methods. Commonly, urethanes made by a nonisocyanate route are called carbamates. To add to the confusing terminology, the terms urethane snApolyurethane are applied to almost any binder derived from isocyanates even though only part, if any, of the reaction products are urethanes. The article on polyurethanes discusses s5mthesis and sources of various polyisocyanates. 

A method for the preparation of halosilyl carbamates and isocyanate involves direct synthesis from amines via halosilyl carbamate intermediates [277]. A primary amine is converted to its carbamic acid salt, which is then treated with a silane containing > 2 halogen atoms bonded to Si. Gentle heating of the resulting halosilyl carbamate gives the isocyanate. In an alternative (exchange) procedure, the carbamic acid salt is treated with any halosilane to form a silyl carbamate, which is trans-silylated. 

Carbamates are generally prepared from isocyanates or chloroformates (see Scheme 4.2). Since isocyanates and chloroformates are usually prepared with phosgene, the corresponding synthetic routes are subject to the relevant safety considerations regarding the phosgene source (for a safe phosgene source, see Chapter 7). Moreover, the handling of several lower alkyl isocyanates is associated with a similar hazard level (toxicity), and therefore the search for a less hazardous procedure has been intense. 

Carbonic add diesters are very attractive reagents and of great economic interest because they represent safe, nonenvironmentally acceptable alternatives to phosgene for carbonylation and carboxylation reactions. For example, methoxycarboxylation with dimethyl carbonate offers an eco-friendly alternative route for the production of carbamates and isocyanates, which are valuable precursors of ureas (see Sections 4.3.1 and 4.3.2) [781, 782]. The method is comparable, from an environmental point of view, with the transition metal catalyzed carbonylation of nitro compounds and amines with CO. 

D-Glucose reacted with dodecyl chloroformate in DMF in the presence of sodium carbonate to produce a mixture of carbonates which was separated into mono-, di-, and tri-carbonates by t.l.c. on silica gel. Sucrose monoesters have been prepared in 44—85% yield from sucrose and 1-alkoxyethyl isocyanates in DMF containing triethylamine. The syntheses and properties of sucrose A (aryloxyalkaneacyl)-carbamates from sucrose and the corresponding isocyanate have been reported. As part of a study of the behaviour of the... 

One patent reported a catalytic system composed of a palladium compound e.g. PdCl2Py2), VOCI3, FeCl2Py2, quinoline and POCI3. Instead of an alcohol, phenol was used, to yield (from DNT) diphenyl toluendicarbamate [100]. The experimental conditions are quite drastic (190 °C, 240-260 Kg/cm CO), but their need is probably connected with the use of phenol instead of an alcohol, since the former is usually much less efficient than the last in these reactions. The use of phenol appears to be prompted by an easier decomposition of the corresponding carbamates to isocyanates. Indeed essentially the same catalytic system and under almost the same conditions was reported by some of the same... 

Fig. 6.9 Energy profile for the synthesis of DMC from methanol and CO2 under DCC catalysis lower part) at 330 K. Increasing the temperature above 340 K the selectivity of the process is decreased as new compounds (carbamates and isocyanates) are formed upper part). Reprinted with permission from [74]. Copyright (2014) Springer...

Spry (1974, 1975b, 1977), at Lilly, prepared various C-3 N-acy derivatives including amides (190), ureas (191), carbamates (189), and thio-carbamates from the C-3 isocyanates (188). These cephalosporins, as indicated in Table XVIII, display gram-positive activity comparable to... 

Finally, a few references have appeared in which bidentate compounds have been cyclized using well understood chemistry to produce some novel heterocycles. There are numerous examples of 5- and 6-membered diazaphos-phorus heterocycles but there are far fewer with smaller or larger rings. Dichlorophosphinyl carbamates, prepared from isocyanates, have been cyclized with diamines to afford the novel benzodiazaphosphepin system (395). Oxadiazepins (396) have been prepared by reaction of the amino-oximes with formaldehyde and 1,3,4,6-thiatriazepins (397) were obtained by Moss and Taylor using cyclic thioureas. 

Carbamic Acids. The esters of carbamic add or substituted carbamic acids (urethans) do not react readily with hydrazine, but the corresponding carbamyl chlorides do. The semicarbazide or substituted semi-carbazides that result yield carbamyl azides with nitrous acid. Most carbamyl azides are prepared more conveniently from the carbamyl chlorides and sodium azide. Monosubstituted carbamyl azides can also be synthesized from isocyanates and hydrazoic acid. -... 

Jiao and co-workers reported in 2014 a simple and practical catalytic methodology for the direct formation and application of isocyanates for the synthesis of carbamates [48]. This chemistry provides an efficient and practical approach to synthesize carbamates from simple organic azides, CO atmosphere and alcohols. The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. Moreover, simple examples of modilication of bioactive molecules and constmction of macrocycles were achieved through this protocol. By utilizing this protocol, the marketed dmgs Chlorzoxazone (a centrally acting muscle relaxant) and Chlorpropham (an important herbicide and sprout suppressant) were easily prepared from simple and readily available aromatic azides, CO, and alcohols in high yields (Scheme 5.17). The mechanism is proposed... 

Kim JG, Jang DO (2009) Indium-catalyzed reaction for the synthesis of caibamates and carbonates selective protection of amino groups. Tetrahedron Lett 50(22) 2688-2692 Paul F (2000) Catalytic synthesis of isocyanates or carbamates from nitroaromatics using group viii transition metal catalysts. Coord Chem Rev 203(l) 269-323 Dieck HA, Laine RM, Heck RE (1975) Low-pressure, palladium-catalyzed iV4V -diarylurea synthesis from nitro compounds, amines, and carbon monoxide. J Org Chem 40(19) 2819-2822... 

Breitler S, Oldenhuis NJ, Fors BP, Buchwald SL (2011) Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions. Org Lett 13(12) 3262-3265 Hooker JM, Reibel AT, Hill SM, Schueller MJ, Fowler JS (2009) One-Pot, Direct Incorporation of [ C]C02 into Carbamates. Angew Chem Int Ed 48(I9) 3482-3485 Peterson SL, Stucka SM, Dinsmore CJ (2010) Parallel synthesis of ureas and carbamates from amines and CO2 under mild conditions. Org Lett 12(6) 1340-1343 Wei Y, Liu J, Lin S, Ding H, Liang F, Zhao B (2010) Acetoacetanilides as masked isocyanates facile and efficient synthesis of unsymmetrically substituted ureas. Org Lett 12 (19) 4220 223... 

The release of carbamates from carbamate linkers has been shown by Buchstaller [195] who pubhshed a synthesis for oxazolidinones 217 on sobd supports (Scheme 32). Starting from Wang resin which is reacted with isocyanates 213, Buchstaller formed the reactive hydroxyl group via addition of pyrrolidine to an epoxide 215 former introduced via N-alkylation of the core structure 214 on bead. Nucleophilic ring opening results in the formation of an amino alcohol intermediate that cyclizes spontaneously and gives free oxazolidinones 217 in an overall 71% to quantitative yield in three steps. 

Alkyl carbamates (urethanes) ate formed from reaction of alcohols with isocyanic acid or urea (see Urettpane polymers). 

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