N- alkyl amides

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

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. 

O-Protonated cations of eimides in concentrated and anhydrous acids are now well characterized by nmr spectroscopy. O-Protonated cations of N,N-dimethyl amides are most easily observed, even in 72% perchloric acid which has a water activity of about 10 , because for tertiary amides the N-protonated forms is relatively less stabilized by hydration (Liler, 1972a). O-Protonated cations of N-alkyl amides show considerable exchange of NH-protons with the solvent in 72% perchloric acid owing to the intervention of the N-protonated form. For primary amides (acetamide), however, O-protonated cations are not observable in that solvent (Liler, 1972b),... 

Conformational equilibria, which are slow on the NMR chemical shift timescale, exhibit a doubled signal set. These slow interconversions are observed when two amide bond retainers are significantly populated, e.g. for N-alkylated amide bonds such as Xaa-Pro bonds. The barriers in these equilibria are in the order of 18 kcal-mol-1, leading to signal coalescence at 80-120 °C. 47 It is difficult to analyze each conformation in such equilibria in detail because frequently, but not always, even in cyclic peptides the peptide bond interconversion... 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

N-nitroso-N-alkylureas N-nitroso-N-alkylcarbamates N-nitroso-N-alkyl amides... 

The occurrence of the ds-isomer in a tertiary amide bond. 19-21 N-Alkylated amides normally exhibit a mixture of cisltrans-isomers that equilibrate in the order of seconds (AG+ 18-20 kcal-mol-1). The situation is shifted from a pure trans configuration in a secondary (—NHCO—) peptide bond to an equilibrium of both isomers of similar energy upon N-alkylation the percentage of ds-isomer depends upon both the solvent and the sequence. The ds-peptide bond 22-27 is observed between the N-alkylated and the preceding residues in the chain. It is evident that Xaa-Pro peptides will behave similarly. 

Amides, N-alkyl amides, lactams, hydantoins have been identified in both Murchison and Yamoto-791198 meteorites [63,65], confirming preliminary results from Cooper and Cronin [66]. The only peptides identified until now are diglycine and diketopiperazine (cyclic diglycine). Since only N1-unsubstituted hydantoins have been detected, this provides a good argument for the involvement of the Biicherer-Bergs reaction in their formation (cf. Sect. 2.1.4). 

This is a new reaction for the preparation of N-alkyl amides. Nitriles and various substituted cyano compounds are treated with active olefins in the presence of sulfuric acid. Reaction occurs at room temperature in glacial acetic acid or dibutyl ether solution. The use of hydrogen cyanide in the reaction leads to the formation of N-alkylformamides. /-Butyl alcohol and sodium cyanide are used in place of the olefin and hydrogen cyanide in the preparation of N-/-butylfotmamide (50%). The reaction has been extended to the synthesis of N-alkyl diamides from dinitriles and olefins or alcohols. ... 

The initial compounds prepared were the 2-(substituted)phen-oxynicotinic acids (I, Figure 1). These (substituted)2-phenoxy-nicotinic acids were devoid of herbicidal activity at our 4 lb/acre screening rate. In order to change the polarity of the products, these nicotinic acids were converted to N-alkyl amides by merely heating them with alkyl isocyanates in the absence of a solvent (II, Figure 1). 

Fig. 9.8. Histograms of C(0)-N-C(a)-C(/ff) torsion angles r (absolute values) in N-alkyl amides derived from (a) tertiary C(a) and (b) primary C a) amines. Of the three values for the tertiary case, the one closest to 60° was chosen...

Most simple derivatives of amino acids (e.g., alkyl hydroxyproline, N-alkyl amides) and isosteric replacements for amide bonds are not included in this review because these modifications are often encountered along the path leading to more significantly nonpeptidic structures. An exception to this rule is made, however, when a particular study is the only example from a given... 

All primary amides display the amide I band, usually between 1715 and 1675 cm" in solution and around 1650cm" in the solid state. For n-alkyl amides CH3(CH2) C0NH2 (where n = 1 to 10) the band is observed at 1679 cm" in dilute... 

The solid phase synthesis of peptidyl amides and peptidyl N-alkyl amides is centred around two main strategies ... 

Significant amounts of the amine ester and amide ester are also formed by secondary reactions on the alcoholic functional group. Reaction of alkanolamines with esters at 110°C results in the N-alkyl amides [2] ... 

Arylmethylamines can be oxidized to the corresponding arylamides by formation of a Schiff base with 2,6-di-t-butylbenzoquinone and base-catalysed oxygenation. Allenic alcohols are oxidized to allenic amides by nickel peroxide at -20 °C in ethereal ammonia. N-Alkyl-amides can be prepared from aldehydes in a four-step procedure consisting of imine formation and subsequent reactions with N-chlorosuccinimide, potassium cyanide, and finally alcoholic HCl. ... 

Sodium superoxide in DMSO is a useful reagent for converting nitriles into amides. Isolated yields are above 70% for this reaction, which was unexpected as nitriles are inert to Na02 in other solvents. The mechanism is not completely understood. The Ritter-type synthesis of N-alkyl-amides from nitriles and alcohols can be improved by the addition of metal carbonyls to help stabilize the intermediate carbonium ions, and an alternative approach is to treat a nitrile with an alkyl halide and nitrosonium hexafluorophosphate. ... 

Chanl995 Chan, W.C. and Mellor, S.L., Reductive Alkylation of 9-Amino-xanthen-3-yloxymethylpoly(styrene) a Novel Procedure for the Synthesis of Peptidyl N-Alkyl Amides by Fmoc/But Chemistry, J. Chem. Soc., Chem. Commun., (1995) 1475-1477. 

In order to develop an enzymatic method to S5mthesize D-alanine N-alkyl amide, which is found in the structure of an artificial sweetener, alitame (L-a-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanine amide), we screened microorganisms for an enzyme that catalyzes o-stereospecific amino acid amide hydrolysis [1]. 

This disappointing result is unfortunately quite neral. Secondary amines react with crown ether acid chlorides to give N-alkyl amides, but the slower reaction with crown ether anhydrides results in much poorer yields and significant competing epimerization via deprotonation-ieprotonation at the carbon adjacent to the carboxylic acid. The monoamide-triadd (above R-H) can be prepared from the corresponding primary amino-alcohol. The more reactive amine steers the dominant reaction towards amide formation without epimerization. 

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