Carbamates from alkyl halides

More conveniently, ureas 812 can be synthesized by reaction of amines with carbamate esters 811 prepared from alkyl halides and carbon dioxide in the presence of bases, as described in Section 4.3.2.10 [286]. 

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. 

The preparation of carbonates is mechanistically closely related to the synthesis of carbamates, and similar reagents can be used for this purpose (Table 14.10). Resin-bound alcohols can be directly converted into carbonates by treatment with a chloro-formate (see Experimental Procedure 14.2), in two steps by activation with phosgene or a synthetic equivalent thereof followed by reaction with an alcohol in the presence of a base, or by treatment of a resin-bound alcohol with carbon dioxide and an alkyl halide under basic reaction conditions [125]. Thiocarbonates can be prepared from... 

Despite the great number of metal-carbamates isolated to date, the transfer of a carbamic group from a metal center to an alkylating agent such as an alkyl halide or diatkyl sulfate has been documented in only a few cases [1, 2]. 

Scheme 6.5 Direct synthesis of carbamate esters from primary amines, C02, and alkyl halides in the presence of 18-crown-6-ether.

Inorganic bases have been also employed in this system. When Butcher first used alkali carbonates [50], it was reported that, in DMF and at ambient temperature, the carbamation of primary and secondary aliphatic amines (or also arylamines) with alkyl halides under a C02 atmosphere (0.1 MPa) was effectively promoted by Cs2C03 [50, 51]. The Cs+ cations in the solvent used (DMF) did not form ion pairs with counterions, and favored the formation of naked carbamate anions that were more reactive at the O-ends with alkyl halides. Jung further found that the addition of tetrabutylammonium iodide (TBAI) to the system RR NH/ C02/RX/Cs2C03/DMF promoted the carbamation process with a higher yield and selectivity with respect to N-alkylation [51]. The process has been successfully extended to the synthesis of carbamate functionalities on solid phases. In this case, resin-bound carbamates are readily released from the resin by treatment with LiAlH4 in THF, yielding the respective N-methyl secondary amines [51]. 

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]. 

Synthesis of Carbamates from Amines, CO2 and Alkyl Halides... 

Scheme 5.12 PEG-enhanced synthesis of organic carbamates from amines, C02 and alkyl halides [50]...

An efficient and environmentally benign method for the PEG400-enhanced synthesis of organic carbamates with high chemoselectivity from amines, CO2 and alkyl halides under room temperature and atmospheric pressure utilizing K2CO3 as a base is reported (Scheme 5.12) [50]. PEG probably could serve as both a solvent and PTC, and also activate the carbamic anion so that PEG could depress the alkylation and enhance the selectivity toward the target product. 

Urethanes. Methyl carbamates (1) can be prepared from primary or secondary amines, alkyl halides, and carbon dioxide in a reaction promoted by copper(I) /-butoxide (equation I). The ligand t-butyl isocyanide can be replaced with tri-n-butylphosphine. Copper(I) f-butoxide is more effective than other copper salts. In the case of diethylamine, the intermediates a and b were isolated and b was converted to the methyl carbamate in 86% yield. 

Alkyldithio carbamates are prepared from the acid chloride (EtsN, EtOAc, 0°C) and amino acid, either free or as the O-silyl derivatives (70-88% yield). They may also be prepared by the addition of carbon disulfide to the amine which can then be alkylated with an alkyl halide using CS2CO2 as the base. The A-(i-propyldithio) carbamate has been used in the protection of proline during peptide synthesis. Alkyldithio carbamates can be cleaved with thiols, NaOH, PhsP/TsOH. They are stable to acid. Cleavage rates are a function of the size of the alkyl group as illustrated in the table below. 

Aresta M, Quaranta E (1992) Alkali-metal-assisted transfer of carbamate group from phosphocarbamates to alkyl halides a new easy way to alkali-metal carbamates and to carbamate esters. J Chem Soc Dalton Trans 1893-1898... 

TABLE 5.7 Heterogeneous catalysts for carbamate synthesis from CO, amine and alkyl halide or alcohol. 

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