Hydrolysis of Carbamates and Amides

Early attempts to prepare 4(5)-aminoimidazole (25 R = H) from the carbamates (34 R = Me, Et) [obtained from the hydrazide (35) using the Curtius method] by either acid- or base-catalyzed hydrolysis resulted in failure (30JCS268). 

However, in a later study, Cohen and Kirk described a successful hydrolysis of the f-butyl derivative (34 R = rBu) using tetrafluoro-boric acid (73JA4619, 73JOC3647). The resulting 4(5)-aminoimidazole (25 R = H) was diazotized in situ, and the solution irradiated to give 4-fluoroimidazole (yield 41%). This carbamate (34 R=fBu) was also hy- 

Hunter and Nelson (41 Mil) attempted the preparation of 4(5)-aminoimidazole (25 R = H) from its acetyl derivative (28 R = H, R1 = Me), which they obtained by reduction of 4(5)-nitroimidazole (27 R = H) with tin(II) chloride in acetic anhydride. The authors noted that hydrolysis of compound (28 R = H, R = Me) with aqueous acids resulted in fission of the imidazole ring and formation of acetic acid, formic acid, ammonia, and glycine. Base hydrolysis gave similar results (41 Mil), although a trace of 4(5)-aminoimidazole (25 R = H) was detected. 

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Four approaches to the synthesis of 4(5)-aminoimidazoles (25) have been described and are summarized in Scheme 1. These are (a) reduction of 4(5)-nitroimidazoles (27), (b) hydrolysis of carbamates and amides (28),... 

While ester, carbonate, carbamate and anilide hydrolyses have been catalysed effectively by antibodies, the difficult tasks of hydrolysis of an aliphatic amide or a urea remain largely unsolved. Much of this problem hinges on the fact that breakdown of a TF is the rate-determining step, as established by much... 

Carbamate and amide groups have been found to be stable under these coupling conditions73. In the presence of TiCLt or SnCLt, chiral a-keto amides 36 react with allyl-silane to produce, after hydrolysis, optically active tertiary alcohols 37 with extremely high optical selectivity (equation 23)74. The addition reaction appears to occur from the Si face of the carbonyl group. In a similar manner, a high degree of stereoselectivity is obtained from the reactions of A-Boc-a-amino aldehydes 38 with 2-substituted allylsilanes (equation 24)75. 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

An early variation of the classic HR is the use of lead tetraacetate (LTA) to accomplish the rearrangement of primary amides to carbamates via the intermediacy of isocyanates. Discovered independently by Beckwith and Baumgarten, the reaction is proposed to involve nitrene 6 leading to isocyanate 2 (Scheme 1). Thus, in the presence of LTA, cyclohexyl amide (16) is converted to methyl carbamate 17, phthalamide (18) forms dioxoquinazoline 19, and amide ester 20 yields amino acid 22 after hydrolysis of carbamate 21 with retention of configuration. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

Enzymatic Method. L-Amino acids can be produced by the enzymatic hydrolysis of chemically synthesized DL-amino acids or derivatives such as esters, hydantoins, carbamates, amides, and acylates (24). The enzyme which hydrolyzes the L-isomer specifically has been found in microbial sources. The resulting L-amino acid is isolated through routine chemical or physical processes. The D-isomer which remains unchanged is racemized chemically or enzymatically and the process is recycled. Conversely, enzymes which act specifically on D-isomers have been found. Thus various D-amino acids have been... 

Carbamates are formed from an amine with a wide variety of reagents, the chlo-roformate being the most common amides are formed from the acid chloride. n-Alkyl carbamates are cleaved by acid-catalyzed hydrolysis A-alkylamides are cleaved by acidic or basic hydrolysis at reflux and by ammonolysis, conditions that cleave peptide bonds. 

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

Illustrative Example 13.5 Calculating Hydrolysis Reaction Times as a Function of Temperature and pH Carboxylic Acid Amides Carbamates... 

Enzymatic Hydrolysis Reactions of Esters. Xenobiotic compounds containing esters or other acid derivatives in their structures (e.g., amides, carbamates, ureas, etc., see Table 17.3) are often readily hydrolyzed by microorganisms. To understand how enzymatic steps can be used to transform these substances, it is instructive to consider the hydrolases (i.e., enzymes that catalyze hydrolysis reactions) used by organisms to split naturally occurring analogs (e.g., fatty acid esters in lipids or amides in proteins). The same chemical processes, and possibly even some of the same enzymes themselves, are involved in the hydrolysis of xenobiotic substrates. 

Huang, C. H., Hydrolysis of Amide, Carbamate, Hydrazide, and Sulfonylurea Agrochemicals, Ph.D. thesis, Johns Hopkins University, Baltimore, MD, 1997. 

This chapter deals with the kinetics and mechanisms of the hydrolysis of carboxylic acid derivatives of general formula RCOX. These include carboxylic acid halides, amides, and anhydrides with small sections on carboxylic acid cyanides etc. Many recent developments in this field have been made with acid derivatives in which R is not an aliphatic or aromatic group, for example, carbamic acid derivatives, and these are reported where relevant, as are reactions such as ethanolysis, aminolysis, etc. where they throw light on the mechanisms of hydrolysis. 

The enantiomerically pure oxazolidinone derivative 7 (Scheme 4),14,20 was converted into the metathesis precursor 6 by a sequence of carbamate hydrolysis, amide alkylation and protection of the secondary alcohol as the TBDMS ether in a 95% overall yield. Subsequent [Ru-1] catalysed ROM-RCM converted 6 into the desired dihydropyrrole 5. 

Much of the a-deprotonation chemistry of the amides is mirrored by hindered thioamides, imides, ureas, carbamates and phosphonamides,28 and the important asymmetric versions of these reactions are discussed in chapters 5 and 6. Difficulties removing the heavily substituted groups required for protection of the carbonyl group in these compounds have been overcome in such cases as the urea 75, which is resistant to strong base, but which undergoes acid-catalysed hydrolysis and retro-Michael reaction to reveal the simpler derivative 76.54... 

MO-Acetals are extremely sensitive to hydrolysis and therefore seldom used to protect simple amines, but their stability is significantly enhanced if the nitrogen atom is embedded in a functional group wherein the basicity of the nitrogen is diminished by delocalisation as in amides, carbamates and aromatic heterocycles. Our discussion of MO-acetals as M-protecting groups can be divided into... 

Hydrolysis is an important route of metabolism for esters, amides, carbamates, and acyl hydrazines. Aspirin is rapidly converted to salicylic acid this may be further metabolised to gentisic acid (5-hydroxysalicylic acid), conjugated with glucuronic acid or glycine, or excreted unchanged. 

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