Carbamates from chloroformates

Carbamates derived from chloroformates are used to manufacture pharmaceuticals, including tranquili2ers (58), antihypotensives, and local anesthetics, pesticides, and insecticides (see Carbamic acid). 

Both 3-amino and 5-amino-1,2,4-thiadiazoles form the expected derivatives with isocyanates, carbamates, and chloroformates the products from the reaction with the 5-amino isomer have been claimed as herbicides and bactericides <84CHEC-I(6)463>. 

Optically active dithiocarbamates Co(S2CR2)3 (R = Me, Et, Pr, Bun, Bu1, Bz, Cy, or pip) can be prepared from the potassium dithiocarbamate salts and the optically active K[Co(edta)] or K[Co(pdta)] (pdta = 1,2-propanediaminetetra-acetate).368 The optical inversion of ( + )546-[Co(pyr-dtc)3] (pyr-dtc = NN-dipyrrolidyldithio-carbamate) in chloroform has been studied by loss of optical activity by polarimetry.3 68... 

After separation of compounds (1) and (2), their activity is measured and the mass m can be calculated from eq. (17.20). Homogeneous as well as heterogeneous exchange reactions may be apphed in analytical chemistry. An example is the determination of small amounts of Bi Bi is selectively extracted by diethyldithio-carbamate in chloroform, a known amount of Bil labelled with " Bi is added, after about 30 s Bil4 is extracted into water, and the activities in both phases are measured. In the case of heterogeneous exchange reactions, separation of the components is simple. 

Besides its interest for the synthesis of 1-chloroethyl carbamates from tertiary amines and the N-dealkylation of tertiary amines, this result is also quite unexpected. With most chloroformates other than vinyl chloroformate (VOC-CI), for example EtOCOCI, CI3CH2OCOCI, Ph-CH2OCOCI, the cationic intermediate analogous to (II) fragments to alkyl chloride, carbon dioxide and (I). 

The bis-(A,A -dimethylthiocarbamate) (10.0 g, 0.035 mol) was heated in the bulk at 260°C under nitrogen for 2 h. After cooling, the remaining material was crystallized from chloroform/methanol and further recrystallized from methyl ethyl ketone to afford 8.3 g bis-(A, A -dimethyl-5-carbamate), in a yield of 83%, m.p. 201-203°C. 

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... 

Amino Alcohols. Reaction of chloroformate is much more rapid at the amino group than at the hydroxyl group (4—8). Thus the hydroxy carbamates, which can be cyclized with base to yield 2-oxazoHdones, can be selectively prepared (29). Nonionic detergents may be prepared from poly[(ethylene glycol) bis(chloroformates)] and long-chain tertiary amino alcohols (30). 

The common impurities found in amines are nitro compounds (if prepared by reduction), the corresponding halides (if prepared from them) and the corresponding carbamate salts. Amines are dissolved in aqueous acid, the pH of the solution being at least three units below the pKg value of the base to ensure almost complete formation of the cation. They are extracted with diethyl ether to remove neutral impurities and to decompose the carbamate salts. The solution is then made strongly alkaline and the amines that separate are extracted into a suitable solvent (ether or toluene) or steam distilled. The latter process removes coloured impurities. Note that chloroform cannot be used as a solvent for primary amines because, in the presence of alkali, poisonous carbylamines (isocyanides) are formed. However, chloroform is a useful solvent for the extraction of heterocyclic bases. In this case it has the added advantage that while the extract is being freed from the chloroform most of the moisture is removed with the solvent. 

The following carbamates can be cleaved by photolysis. They can be prepared either from the chloroformate or from the mixed carbonate. 

Indole-2,3-quinodimethanes have also been exploited as the key intermediates in indolo[2,3-a]caibazole synthesis, allowing the preparation of several interesting systems. Thus, when the starting materials 74a-b (obtained from the condensation of protected indole-2-carboxaldehydes with 2-aminostyrene) underwent treatment with methyl chloroformate in hot chlorobenzene, the carbamates 75a-b were obtained, and could subsequently be dehydrogenated into the aromatic compounds 76a-b (Scheme 11). However, all functionalization attempts of the methyl... 

The carbamates, derived from the reaction of 8-aminoquinoline with phenyl or ethyl chloroformate, upon reduction with NaBH4 gave the... 

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

Alternatively, two phosgene equivalents were studied, methyl chloroformate and p-nitrophenyl chloroformate. When methyl chloroformate was used for the end game, N-carbamate 54 was obtained smoothly but subsequent cyclization to ben-zoxazinone 1 was sluggish. Furthermore, removal of the unreacted intermediate methyl carbamate 54 from Efavirenz was not trivial, thus we did not pursue this method. On the other hand, reaction of 53 and p-nitrophenyl chloroformate initially provided the corresponding p-nitrophenyl carbamate 55 under mild basic conditions (KHC03). Carbamate 55 was smoothly cyclized to 1 upon increasing... 

A number of other symmetric dichalogeno carbamates have been employed in, for example, the deposition of ZnS by a dip-dry method186 from a chloroform solution containing an equimolar mixture of [Zn(S2CNBu2)2] and the thiolate compound [EtZn(SPr )]. Pyrolysis was carried out at 300 °C under N2 and the polycrystalline (cubic phase) films were free from oxide contamination. 

B) Benzyl Carbamate.—A measured aliquot (suitably 10 cc.) of the solution of benzyl chloroformate, prepared as described above, is added slowly and with vigorous stirring to five volumes of cold concentrated ammonium hydroxide (sp. gr. 0.90), and the reaction mixture is allowed to stand at room temperature for thirty minutes. The precipitate is filtered with suction, washed with cold water, and dried in a vacuum desiccator. The yield of practically pure benzyl carbamate, melting at 85-86°, is 7.0-7.2 g. (91-94 per cent of the theoretical amount based on the benzyl alcohol used in. 4). Pure benzyl carbamate melting at 87° is obtained by recrystallizing the slightly impure material from two volumes of toluene. 

Bilikova and Kuthan [87] developed a gas chromatographic method for the determination of submicrogram concentrations of Carbofuran (2,3-dihydro-2, 2,-dimethylbenzofuran-7-yl-methyl carbamate) in soils. Soil samples are mixed with methanol-water (80 20) and water samples are extracted with chloroform. After separation of the chloroform, and weak alkaline hydrolysis, derivatization is performed with l-fluoro-2,4-dinitrobenzene. The ester produced is isolated from benzene and cleaned up with acetone. The acetone extract is used to determine Carbofuran by gas chromatography with a nitrogen-specific detector. 

Symmetrical and unsymmetrical carbonates have also been obtained from the reaction of chloroformates with alcohols under soliddiquid conditions [55], and the reaction of carbamoyl fluorides with alcohols produces alkyl carbamates [58]. r-Butyloxycarbonylation of alcohols and phenols is effected by trans-esterification of di-r-butyl carbonate under basic phase-transfer catalysed conditions [59]. Yields tend to be high for the reaction with the phenols (>85%), but only moderate with the alcohols (30-81%). 

Al-(Alkoxycarbonyl) 0-(arenesulfonyl)hydroxylamines [alkyl Af-(arenesulfonyloxy) carbamates] 3i-o can be easily obtained by sulfonylation of commercially available iV-(alkoxycarbonyl)hydroxylamines (alkyl V-hydroxy carbamates). Af-(Alkoxycarbonyl) hydroxylamines can be also prepared from hydroxylamine and alkyl chloroformate . ... 

Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). lodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative... 

The original synthesis of duloxetine (3) is relatively straightforward, involving a four-step sequence from readily available 2-acetylthiophene 30 (Scheme 14.7). Understandably, the main synthetic challenge stems from the presence of a chiral center, because duloxetine (3) is marketed as the (5)-enantiomer as shown. Thus, a Mannich reaction between 30 and dimethylamine generated ketone amine 31, which was then reduced to provide intermediate racemic alcohol amine 32. The desired optically active (5)-alcohol 32a was accessed via resolution of racemate 32 with (5)-(+)-mandelic acid, which provided the necessary substrate for etherihcation with 1-fluoronaphthalene to afford optically active amine 33. Finally, A -demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the intermediate carbamate with zinc powder and formic acid led to the desired target duloxetine (3). 

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