The carbamates

Once again, it was a natural product which provided the lead to this group of compounds. The natural product was physostigmine (also called eserine) which was 

Working backwards, the positively charged pyrrolidine nitrogen is clearly important since it must bind to the anionic receptor site of the enzyme. 

The benzene ring may be involved in some extra hydrophobic bonding with the receptor site or, alternatively, it may be important in the mechanism of inhibition since it provides a good leaving group. 

The carbamate group is the crucial group responsible for physostigmine s antagonistic properties, and to understand why, we have to look again at the mechanism of hydrolysis at the active site (Fig. 11.49). This time we shall see what happens when physostigmine and not acetylcholine is the substrate for the reaction. 

The first three stages proceed as normal with histidine catalysing the nucleophilic attack of the serine residue on physostigmine (stage 1). The alcohol portion (this time a phenol) is expelled with the aid of acid catalysis from histidine (stage 2), and the phenol leaves the active site to be replaced by a water molecule. 

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The reaction commences at about 120° the carbamic acid formed decomposes immediately into carbon dioxide and ammonia. The latter may form the ammonium salt with unreacted acid the ammonium salt also reacts with urea at temperatures above 120° to yield the amide ... 

Aminopalladation and subsequent carbonylation are also facile reactions. The carbonylation of substituted 3-hydroxy-4-pentenylamine as a carbamate (254) proceeds smoothly via the aminopalladation product 255 in AcOH to give 256[228). The protection of the amino group of the carbamate as tosyl amide is important in the carbonylation of 257 to give 258[229],... 

An intramolecular version offers useful synthetic methods for heterocycles. The total syntheses of a- and 7-lycoranes (373 and 374) have been carried out by applying the intramolecular aminochlorination of the carbamate of 5-(2-aminoethyl)-l,3-cyclohexadiene (372) as a key reaction[312,313]. Interestingly, the 4,6- and 5,7-diene amides 375 and 377 undergo the intramolecular amina-tion twice via x-allylpalladium to form alkaloid skeletons ofpyrrolizidine (376) and indolizidine (378), showing that amide group is reactive[314]. 

Zugravescu et al. (263) showed that ethyl chloroformate reacts on the exocyclic nitrogen of 2-amino-4-methylthiazole to yield the carbamate (101) (Scheme 70) (see also Refs. 264 and 265). With an excess of chloroformate (2 moles for one of the thiazole) under Schotten-Bauman conditions the jV.A -dicarbamate of 2-imino-4-methylthiazoline (102) is obtained (263),... 

The value has been extrapolated because, at temperatures above 170°C, the rate of reaction 2 rapidly iucreases and it is difficult to determine the carbamate vapor pressure owiag to the formation of water and urea and the consequent lowering of the partial pressure of ammonium carbamate. 

The stripper off-gas going to the high pressure carbamate condensers also contains the carbamate recovered in the medium and low pressure recirculation sections. Both of these systems ate similar to those shown in the total-recycle process. 

The Stainicaibon process is described in Figures 3—7. The synthesis section of the plant consists of the reactor, stripper, high pressure carbamate condenser, and a high pressure reactor off-gas scmbber. In order to obtain a maximum urea yield pet pass through the reactor, a pressure of 14 MPa (140 bar) and a 2.95/1 NH —CO2 molar ratio is maintained. The reactor effluent is distributed over the stripper tubes (falling-film type shell and tube exchanger) and contacted by the CO2, countercurrendy. This causes the partial NH pressure to decrease and the carbamate to decompose. 

The urea solution out of the stripper bottom flows to a single-stage low pressure recirculation section (0.4 MPa, 4 bar). The stripper off-gas is sent to the carbamate condenser. 

In this condenser, part of the stripper off-gases are condensed (the heat of condensation is used to generate low pressure steam). The carbamate formed and noncondensed NH and CO2 are put into the reactor bottom and conversion of the carbamate into urea takes place. The reactor is sized to allow enough residence time for the reaction to approach equiUbrium. The heat required for the urea reaction and for heating the solution is suppHed by additional condensation of NH and CO2. The reactor which is lined with 316 L stainless steel, contains sieve trays to provide good contact between the gas and Hquid phases and to prevent back-mixing. The stripper tubes are 25-22-2 stainless steel. Some strippers are still in service after almost 30 years of operation. 

The carbamate solution from the scmbber flows to a high pressure ejector. The NH feed pressure induces enough head to convey the carbamate solution from the scmbber to the carbamate condenser. 

The stream from the reactor consisting of a mixture of urea, unconverted ammonium carbamate, excess water, and NH, is fed into the top of the stripper. The ACES stripper utilizes a ferrite—austenite stainless steel, as do the carbamate condensers. The reactor and scmbber are constmcted with 316 L urea-grade stainless steel. 

Because an excess of ammonia is fed to the reactor, and because the reactions ate reversible, ammonia and carbon dioxide exit the reactor along with the carbamate and urea. Several process variations have been developed to deal with the efficiency of the conversion and with serious corrosion problems. The three main types of ammonia handling ate once through, partial recycle, and total recycle. Urea plants having capacity up to 1800 t/d ate available. Most advances have dealt with reduction of energy requirements in the total recycle process. The economics of urea production ate most strongly influenced by the cost of the taw material ammonia. When the ammonia cost is representative of production cost in a new plant it can amount to more than 50% of urea cost. 

Neste patented an industrial route to a cellulose carbamate pulp (90) which was stable enough to be shipped into rayon plants for dissolution as if it were xanthate. The carbamate solution could be spun into sulfuric acid or sodium carbonate solutions, to give fibers which when completely regenerated had similar properties to viscose rayon. When incompletely regenerated they were sufficientiy self-bonding for use in papermaking. The process was said to be cheaper than the viscose route and to have a lower environmental impact (91). It has not been commercialized, so no confirmation of its potential is yet available. 

Phenylcarbamates. Phenylcarbamate herbicides represent one of two subgroups of carbamate herbicides, the phenylcarbamates and the thiocarbamates (299). Both groups are prone to volatilization losses the thiocarbamates are particularly susceptible and should be sod-incorporated immediately after apphcation (2). The carbamate herbicides are used, in general, for the selective pre-emergence control of grass and broadleaved weeds (299). Exceptions would include barban, desmedipham, and phenmedipham which are appHed post-emergence. 

Carbamate Insecticides. These are stmcturaUy optimi2ed derivatives of the unique plant alkaloid physostigmine [57-47-6] a cholinergic dmg isolated in 1864 from Phjsostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The A/,A/-dimethylcarbamates of heterocycHc enols (36) and the Ai-methylcarbamates of a variety of substituted phenols (35) with a wide range of insecticidal activity were described in 1954 (35). The latter are the most widely used carbamate insecticides, and the A/-methylcatbamates of oximes have subsequentiy been found to be effective systemic insecticides. 

Industrially, polyurethane flexible foam manufacturers combine a version of the carbamate-forming reaction and the amine—isocyanate reaction to provide both density reduction and elastic modulus increases. The overall scheme involves the reaction of one mole of water with one mole of isocyanate to produce a carbamic acid intermediate. The carbamic acid intermediate spontaneously loses carbon dioxide to yield a primary amine which reacts with a second mole of isocyanate to yield a substituted urea. 

The first synthetic pyrogaHol plant using hydrolysis of chlorinated cyclohexanol (2,2,6,6-tetrachlorocyclohexanone) was built by BFC Chemicals, Inc. (Muskegon, Michigan) and has been producing pyrogaHol for the carbamate insecticide Beniocarb since 1982 (8,19). SocifitH Fransaise Hoechst offers pyrogaHol for sale in the United States (American Hoechst Corp.), and Japan is also a source of this chemical. 

Up until 1986 the major use for 2-j -butylphenol was in the production of the herbicide, 2-j -butyl-4,6-dinitrophenol [88-85-7] which was used as a pre- and postemergent herbicide and as a defoHant for potatoes (30). The EPA banned its use in October 1986 based on a European study which showed that workers who came in contact with 2-j -butyl-4,6-dinitrophenol experienced an abnormally high rate of reproduction problems. Erance and the Netherlands followed with a ban in 1991. A significant volume of 2-j -butyl-4,6-dinitrophenol is used worldwide as a polymerization inhibitor in the production of styrene where it is added to the reboiler of the styrene distillation tower to prevent the formation of polystyrene (31). OSBP is used in the Par East as the carbamate derivative, 2-j -butylphenyl-Ai-methylcarbamate [3766-81-2] (BPMC) (32). BPMC is an insecticide used against leaf hoppers which affect the rice fields. 

Because of environmental concerns about 2-j -butylphenol-based derivatives, the market growth is expected to be negative in the future, with the exception of possible significant growth in the use of the carbamate insecticide (see Table 3). 

Multifunctional Hydroxy, Mercapto, and Amino Compounds. These are used to cross-link halogenated polymers. Depending on the labihty of the halogen, the cross-linking agents can be capped to reduce reactivity or used in combination with accelerators to increase the rate of reaction. Benzoyl capping is common with hydroxy and mercapto compounds forming the carbamate by reaction with one equivalent of carbon dioxide is used with diamines. 

A series of carbamates have been prepared that are cleaved by liberation of a phenol, which, when treated with base, cleaves the carbamate by quinone methide formation through a 1,6-elimination. ... 

Simple amides that are difficult to cleave can first be converted to a BOC derivative by an exchange process that relies on the reduced electrophilicity of the carbamate as well as its increased steric bulk. °... 

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 main difference between tlie various urea syntliesis processes are in tlie metliods used to handle tlie converter effluent, to decompose the carbamate and carbonate, to recover tlie urea, and to recover tlie mireacted aimnonia and carbon dioxide for recycle with a nia. inium recovery of heat. The amiutil production rate is approximately 4.5 million metric tons. End use is... 

The Bnpeoc group was developed as a base-labile protective group for solid-phase peptide synthesis. The carbamate is formed from the O-succinimide (DMF, 10% Na2C03 or 5% NaHC03) and is cleaved using DBN, DBU, DBU/AcOH, or piperidine. ... 

The carbamate, prepared from the 4-nitrophenyl carbonate, is cleaved by reduction with dithiothreitol (DTT) and TEA to give the aniline, which triggers fragmentation, releasing the amine. ... 

Benzyl groups, as well as other alkyl groups, can be converted to various carbamates as a variation of the von Braun reaction.The carbamates can then be cleaved by conditions that are outlined in the section on carbamates. 

The carbamate (28) reacts with hydrazine hydrate to yield 3-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4(l, 3 I)-dione (29). ... 

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... 

Reaction of the glycol, 70, affords an oxazolidinone rather than the expected carbamate (71) on fusion with urea. It has been postulated that the urea is in fact the first product formed. This compound then undergoes 0 to N migration with loss of carbon dioxide reaction of the amino alcohol with the isocyanic acid known to result from thermal decomposition of urea affords the observed product, mephenoxolone (74) this compound shows activity quite similar to that of the carbamate. An analogous reaction on the glyceryl ether, 75, affords metaxa-lone (76). 

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