N-Alkyl carbamate

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. 

Calderazzo has reported the synthesis of isocyanates from metal N-alkyl carbamates and acyl or aroyl chlorides (Scheme 6.27), used in this context as oxygen... 

Palmitate Cinnamate Glycinate N-Alkyl carbamate Chloramphenicol esters devoid of bitter taste... 

Polycyclic aromatic hydrocarbons Carbamic acid esters and N-alkylated carbamates-urethan... 

Figure 42 Gastric and intestinal absorption rate constants log k Bs of homologous n-alkyl carbamates R —OCONH2 (R = methyl to n-octyl eqs. 166 and 167) (reproduced from Figure 14 of ref. [442] with permission from Editio Cantor Verlag GmbH, Aulendorf, Germany).

N-Unsubstituted carbamates can also be prepared by this route using cyanic acid, although reaction of the carbamate with a second molecule of cyanic acid may then occur. Alkylation [445] of these carbamates with alkenes in the presence of boron trifluoride yields N-alkyl carbamates. 

Catalytic Carbonylation with CO The oxidative carbonylation of amine to produce N-alkyl carbamate or N,N -disubstituted urea followed by thermal decomposition is a potential route for the non-phosgene synthesis of isocyanate. Scheme 2.23. 

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 ... 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-43), but the cyanate ion practically always gives exclusive N-alkylation. ° Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNN02) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(N02)CN. ° When alkyl halides are treated with NCO in the presence of ethanol, carbamates can be prepared directly (see 16-7). ° Acyl halides give the corresponding acyl isocyanates and isothiocyanates. For the formation of isocyanides, see 10-111. 

Under certain conditions, amides can add directly to alkenes to form N-alkylated amides. 3-Pentenamide was cyclized to 5-methyl-2-pyrrolidinone by treatment with trifluorosulfonic acid. Acylbydrazine derivatives also cyclized in the presence of hypervalent iodine reagents to give lactams. When a carbamate was treated with Bu3SnH, and AIBN, addition to an alkene led to a bicyclic lactam. 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

The first reported synthesis of hydroxyurea (24) consists of the condensation of hy-droxylamine with potassium cyanate (Scheme 7.14) [87]. Condensation of hydroxy-lamine with ethyl carbamate also gives pure hydroxyurea in good yield after recrystallization (Scheme 7.14) [88]. Nitrogen-15 labeled hydroxyurea provides a useful tool for studying the NO-producing reactions of hydroxyurea and can be prepared by the condensation of N-15 labeled hydroxylamine with either potassium cyanate or trimethylsilyl isocyanate followed by silyl group removal (Scheme 7.14) [89, 90]. Addition of hydroxylamine to alkyl or aryl isocyanates yields alkyl or aryl N-hydroxyureas (Scheme 7.14) [91, 92]. The condensation of amines with aromatic N-hydroxy carbamates also produces N-substituted N-hydroxyureas (Scheme 7.14) [93]. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

The chelate formation in lithium complexes 17 or 20 contributes to stabilization. Enhancement of kinetic acidity arises from the formation of pre-complexes 16 and 19, respectively. Here, already a dipole is induced and, in addition, proton exchange can proceed intramolecularly via a five- or six-membered ring. Despite these favourable features, the acidity of alkyl carbamates 15 is lower than those of the 1-proton in butane n-BuLi does not lead to deprotonation. In order to suppress carbonyl attack, a branched amino residue NR2 such as diisopropylamino (in Cb) or 2,2,4,4-tetramethyl-l,3-oxazolidin-3-yl (in Cby) is essential. A study on the carbenoid nature of compounds 17 was undertaken by Boche and coworkers. ... 

Contrary to Uthiated alkyl carbamates, which hold a pyramidalized sp -hybridized carb-anionic centre and thus generally react with electrophiles under retention of configuration (see Section n.B.l), lithiated ( )-allyl carbamates 310 have a high tendency for antarafa-cial reactions, which seem to be enforced by the bulky sparteine as the lithium ligand (equation 79). Fortunately, in these reactions, the Af,Af-diisopropylcarbamoyloxy group prefers the ewdo-position to lead to the a-product 311 (inversion) and to the y-product (Z)-312 [sometimes besides small amounts of (E)-ent-312)]. 

There are a few reports on the amination of a-metallated carbonyl compounds with 0-(arenesulfonyl)hydroxylamine-type reagents. However, in recent years there has been substantial progress in Af-(alkoxycarbonyl) 0-(arenesulfonyl)hydroxylamine [alkyl N-(arenesulfonyloxy)carbamate]-type reagents for the amination of enolates and eniminates. 

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