Amides and Carbamates

Amides and carbamates of 2-ami nobenzimidazole have proved of considerable value as anthelminic agents, particularly in veterinary practice. A very considerable number of these agents have been taken to the clinic in the search for commercially exploitable agents. (See the section on Benzimidazoles in Chapter 11 of Volume 2 of this series.) A small number of additional compounds have been prepared in attempts to uncover superior agents. 

The A-(l-alkoxyalkyl)amides and -carbamates are stable compounds, thus allowing reactions under neutral or basic conditions to be carried out elsewhere in the molecule before generation of the A-acyliminium ion with an acidic catalyst. 

The electrochemical oxidation of cyclic and acyclic, V-monosubstitilted and ATY-disubstituted amides and carbamates in a nucleophilic solvent, known as the Ross-Eberson-Ny berg reaction, is a synthetically very useful, clean and efficient method for the introduction of a-oxygen substituents under mild reaction conditions6 1 0. 

Among the agricultural chemicals used for the cultivation of tobacco crops we find several amines, amides and carbamates. These include dimethyldodecylamine acetate (Penar), maleic hydra-zide-diethanolamine (MH-30), and carbaryl (Sevin) as a representative of the methyl urethanes (Figure 3 , 14), It is known that small quantities of these agents are found as residues in harvested tobacco (15). To date, only diethanolamine (DELA), the water-solubilizer for maleic hydrazide in MH-30, has been studied as a possible precursor for nitrosamines in tobacco and in tobacco smoke. In 1976, more than 1,400 metric tons of maleic hydrazide had been used on U.S. tobacco (16), most of which had been applied as the MH-30 formulation with diethanolamine (14,16). 

Lithiation of alkyl groups is also possible and again a combination of donor chelation and polar stabilization of anionic character is required. Amides and carbamates can be lithiated a to the nitrogen. 

These conditions were also successfully applied to arylation of amides and carbamates. 

The reagent is prepared1 by reaction of phosgene with 3,5-dioxo-4-methyl-l,2,4-oxadiazolidine in refluxing toluene (82% yield). It serves as a coupling reagent for esterification and preparation of amides and carbamates. 

The anodic oxidation of amides and carbamates is one of the most general and efficient electrochemical reactions known [115]. The primary intermediate... 

Amide and carbamate bonds. Unprotected peptides can be attached to the surface of liposomes by engaging, for example, their N-terminus into an amide... 

The protonation of more complex molecules containing amide and carbamate elements of structure has also been studied in HSO3F— SbFj—SO2 mixtures by Olah and his collaborators. Thus allo-phanates [124] were found to be protonated in that medium at... 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

Other examples of intramolecularly coordinated (by 0 as well as by N groups) organolithium compounds can be found in Setzer and Schleyer (2) and Seebach (4). Two recent reviews are also pertinent. Klumpp (34) deals with 0- and N-assisted lithiation and carbolithiation of nonaromatic compounds, and Snieckus (34a) deals with directed (by amide and carbamate groups) ortho metalation in polysubstituted aromatics. 

As is true for other classes of aromatic nucleophilic substitution, the halogen displacement can frequently be catalyzed by copper or copper(I) salts. Using sodium hydride as the base and copper(I) iodide as catalyst, a series of o-bromophenylethylamine derivatives, including both amides and carbamates, have been cyclized. Oxidation to the indole can be effected with manganese dioxide (81JCS(P1)290). 

Table 3.15. Nucleophilic cleavage of resin-bound amides and carbamates.

Carbamates can be reduced by lithium aluminum hydride (Entry 3, Table 3.22 [179]) or by Red-Al (Entry 5, Table 10.11). Illustrative examples of the reduction of amides and carbamates on solid phase are listed in Table 10.11. 

Table 10.11. Reduction of support-bound amides and carbamates...

Analytical Properties Separation of diastereomeric amides and carbamates the separation of olefinic geometrical isomers is dependent upon the position of the double bond Reference 29, 30... 

N-Allyl tertiary amides 72 can be lithiated with r-BuLi and, like the secondary amides 54 and 57 they react y to nitrogen to give cis acylenamine products 74, with the intermediate organolithium adopting a structure approximating to 72.152 The stereochemistry of the reactions of lithiated allyl amides and carbamates in the presence of (-)-sparteine53 is discussed further in chapter 6. 

Many studies of separations, primarily by HPLC, have been reported with a view to establishing the mechanisms by which diastereomers separate (56-58). Although substantive criticism has been offered by way of demonstrated exceptions (45, 59), the picture as qualified by Pirkle (57) holds well for simple (otherwise functionally unsubstituted) amides and carbamates. Briefly, solution conformations of amides and carbamates are as shown in Figure 17 the central functional group acts to create a plane, and the asymmetric centers extend alkyl (aryl) residues to either side of that plane. An explanation based on a combination of steric bulk and hydrophobicity has been advanced to explain HPLC elution orders for carbamates. Elution order for GLC is inverted from that of HPLC in all instances studied, the least soluble (faster eluting) diastereomer by GLC is always the cisoid molecule. The notable exceptions are those compounds bearing a CF3 group at R. ... 

Figure 17. Solution conformers of diastereomeric amides and carbamates. Rj and Rt are saturated alkyl groups Rt is longer than R,.

GAS LIQUID CHROMATOGRAPHIC DATA FOR DIASTEREOMERIC AMIDES AND CARBAMATES. 

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