Carbamates from alcohols

The effects of catalysts on the yields and rates of formation of carbamates from alcohols and urea are shown in Table II. The catalytic effectiveness of BF3 has also been reported [13]. 

Catalytic Effect on the Yields and Rates of Formation of Carbamates from Alcohols and Urea... 

The hydroxy groups in natural products like, for example, the macrolide antibiotics erythromycin, 1"1 and desmycosin, 2001 2011 as well as the 3-(hydroxymethyl)-2- or 3-cephems 2021 and derivatives of the amino sugar garamin 2031 have been converted into the carbamate function with CDI and amines. In the case of aminoglycoside antibiotics of the sisomicin series, thiocarbamates or dithiocarbamates have been prepared from alcohols or thiols using ImCSIm and amines.12041... 

Experiments.—Being a primary hydrazide (of carbamic acid), semicarbazide reduces ammoniacal silver solutions and Fehling s solution. It reacts readily with aldehydes and ketones with the elimination of water and formation of semicarbazones, which, since they are more easily hydrolysed than are phenylhydrazones and oximes, are to be preferred to the latter for purposes of separation and purification of carbonyl compounds. Shake an aqueous solution of the hydrochloride (prepared as described above) with a few drops of benzaldehyde, isolate the semicarbazone and purify it by recrystallisation from alcohol. Melting point 214° decomp. Benzaldehyde semicarbazone is decomposed into its constituents by gentle warming with concentrated hydrochloric acid. 

Klan et al. proposed that both alcohols and amines are initially released as carbonates and carbamates from 44 these undergo thermal decarboxylation to release CO2 and form their respective alcohols and amines.Furthermore, the chemical yields of the protected amine were reduced since they were involved in electron transfer reactions that decomposed 44. 

Surprisingly it was reported that when potassium cyanate is substituted for sodium cyanate the yields of carbamates are reduced to less than 5 %. The reason for this drastic effect is not known at this time. In addition, the use of other alkali or alkaline metal cyanates in this reaction has not been investigated. The Loev [28] procedure appears applicable to the synthesis of carbamates from primary, secondary, and tertiary alcohols (2 hr reaction time affords 60-90% yields), cyclic and acyclic 1,3-diols, phenols, oximes, ald-oximes, and ketoximes, and primary, secondary, and tertiary mercaptans. Carbamates could not be obtained from diphenylethylcarbinol (dehydrated to 1,1-diphenylethylene) or trichloro- and trifluoromethylcarbinols. 

Aliphatic carbamates (readily available from alcohols and sodium cyanate)313 have also been submitted to fluorodediazoniation16,90 314 to give alkyl fluoroformates 890 which are useful tools in peptide synthesis and also valuable precursors of alkyl fluorides.315... 

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

Carbamates have mainly been used in solid-phase synthesis as linkers and protective groups for amines (see Sections 3.6.2 and 10.1.10.1). Carbamates are generally prepared by treating amines with aryl carbonates or chloroformates, which can be prepared from alcohols and phosgene or synthetic equivalents thereof. The alternative route, in which carbamates, isocyanates, or carbamoyl chlorides are reacted with alcohols, is less widely used, but can also lead to satisfactory results on insoluble supports (Tables 14.7 and 14.8). 

Table 14.7. Preparation of carbamates from support-bound alcohols or alkoxycarbonylating reagents.

Enantiomerically pure aminoalcohols, which are readily available by reduction of a-amino acids, can be converted into alkoxycarbonylating reagents suitable for the solid-phase synthesis of oligocarbamates (Figure 16.26). Particularly convenient alkoxycarbonylating reagents are 4-nitrophenyl carbonates, which can be prepared from alcohols and 4-nitrophenyl chloroformate, and which react smoothly with aliphatic primary or secondary amines to yield the corresponding carbamates. 

With respect to the synthesis from amines, C02 and alkyl halides, the synthesis of carbamates from amines, C02 and alcohols (Equation 6.10) is not only a phosgene-free, but also a halogen-free process. Moreover, water forms as the only reaction coproduct. Whilst these features make the route very attractive from the point of view of environmental sustainability, unfortunately the reaction suffers from both thermodynamic and kinetics limitations. Kinetic impediments make necessary the use of a suitable catalyst which, moreover, must be water-tolerant in order to avoid deactivation by cogenerated H20. Several strategies have been explored to overcome these restraints, based mainly on the use of alcohols in a dehydrated form (for instance, as ortho esters or ortho carbonates) [63], or on the use of dehydrating agents [64, 65]. 

One transformation that is closely related to the synthesis of carbamate esters from alcohols, amines and C02, is the formation of cyclic urethanes, such as oxazolidin-2-ones, by reaction of C02 with 1,2-amino alcohols or their formally dehydrated derivatives, aziridines. 

Scheme 6.12 Proposed mechanism for the synthesis of cyclic carbamates from amino alcohols and C02, using P(lll) reagents and haloalkanes.

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]. 

Examples of gold-catalyzed carbonylation of amines and olefins exist related to the activation of carbonyl. The first case involves the formation of carbamates from anilines and CO in the presence of alcohols or the production of acetamides from aliphatic amines. In these examples, Au(I) (usually [AuCl(PPh3)]) catalysts are preferred. For the carbonylation of olefins, gold(I) carbonyls are prepared in situ in sulfiu ic acid media to afford carboxyhc acids. ... 

Nonracemic NEA is equally useful in preparing diastereomeric carbamates. Typically, the carbamates are derived from alcohols and (R)-(+)-naphthylethyl isocyanate, which is conveniently prepared from (R)-(+)-NEA (see (R)-1-(1-Naphthyl)ethyl Isocyanate). However, the diastereomeric carbamates may also be... 

Liquid-liquid extraction of EC from alcoholic beverages and wines can be performed using dichloromethane after saturation of the sample with NaCl (Conacher et al., 1987 Daudt et al., 1992), or extraction with diethyl ether after adjusting the sample to pH 9 using n-butyl carbamate or cyclopentyl carbamate as an internal standard (Fauhl and Wittkowski, 1992 Ferreira and Fernandes, 1992). 

SCHEME 6.15 Direct synthesis of carbamates from C02, amines, and alcohols. 

Alternatively, Schultz and coworkers [59] have proposed an approach related to that of Burgess which utilizes azido 4-nitrophenyl carbamates 98 as activated monomers. Carbamates 98 were prepared in four steps from alcohol 95. Mesylation of 95 followed by azide displacement afforded the A-Boc-protected azide in high yield (80-90%). Boc deprotection and treatment of the resulting free amine with / -nitrophenyl chloroformate in the presence of pyridine in THF provided 98 (50-90% for the two steps). Solid-phase urea bond formation was performed on a Rink amide resin by coupling 98 (5 equiv.) in CH2CI2 in the presence of DIEA (7 equiv.) for 4 h at room temperature. Support-bound azide 99 was reduced in less than 2 h using... 

An efficient method for the synthesis of 1,3-disubstituted ureas and carbamates from carboxamides by using iodosylbenzene as the oxidant in the presence of amines or alcohols has been described [505]. For example, carbamates 408 have been prepared by this procedure in high yields (Scheme 3.164). Various symmetric and asymmetric ureas and ureidopeptides can also be prepared in good yields by this method [505]. 

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... 

Chromatography Gas chromatographic analysis of the diastereomeric carbamates from linalool was carried out on a DB-1 column at temperatures between 150 and 200 °C [30] R(-F )-phenylethylcarbamates of several simple secondary alcohols were separated on a Carbowax 20M column [32]. 

The newest variation of the HR is an electrochemical method e.g., 46- 48, which does not appear to have been explored beyond its discoverers/ " The method is particularly useful for the synthesis of alkyl carbamates from primary alcohols containing sensitive functional groups since this electrochemical HR operates under neutral conditions. Some of the alkyl carbamates prepared using this HR are shown (202-205). The yields of the same methyl carbamates are uniformly higher with this electrochemical HR than with the classical bromine and sodium methoxide HR. Furthermore, little or no urea products are formed in the electrochemical HR. ... 

The reverse reaction is the one usually employed in the synthesis of carbamates from isocyanates obtained by phosgenation of the amines. Ureas can be intermediately converted to the corresponding carbamates by reaction with an alcohol or directly thermolysed (see Chapter 3). 

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