Conversion of amines into substituted amides

Transamidation has often been used also as a convenient method of converting urea into N- or N,N -substituted ureas and hydrazides. The amine and urea are melted together1150 or heated together for some time in glacial acetic acid.1151 The reaction temperature and the proportions of the reactants determine whether the monosubstituted or symmetrically disubstituted urea is produced, but mixtures of the two are frequently formed. Amide hydrochlorides can also be used, being boiled with the urea in aqueous solution a well-known example is the conversion of urea into methylurea by 3 hours boiling with methylamine hydrochloride, which is a step in the preparation of 1-methyl-l-nitrosourea.1152... 

Conversion of Acid Anhydrides into Amides Acetic anhydride is also commonly used to prepare iV-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts rather than the less nucleophilic -OH group. 

A potential versatile route into a-amino acids and their derivatives is via a combination of (i) nitrile hydratase/amidase-mediated conversion of substituted malo-nonitriles to the corresponding amide/acid followed by (ii) stereospecific Hofmann rearrangement of the amide group to the corresponding amine. Using a series of a,a-disubstituted malononitriles 14, cyanocarboxamides 15 and bis-carboxamides 16, the substrate specificity of the nitrile hydratase and amidase from Rhodococcus rhodochrous IF015564 was initially examined (Scheme 2.7). The amidase hydrolyzed the diamide 16 to produce (R)-17 with 95% conversion and 98%e.e. Amide 17 was then chemically converted to a precursor of (S)-a-methyldopa. It was found... 

The procedure for synthesizing sulfanilamide (a sulfa drug) is a multistep procedure as illustrated in Figure 13-50. The first step also works if you substitute an acyl chloride for the acid anhydride. The conversion of the amine to an amide converts the strong activator into a medium activator, limiting multiple attacks. The last step converts the amide back into an... 

Platinum-catalyzed hydrolytic amidation of unactivated nitriles was reported by Cobley and coauthors. The platinum(ii) complex, [(Me2PO- H- PMe2)PtH (PMe2OH)], efficiently catalyzes the direct conversion of unactivated nitriles into N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Isolated yields vary from 51 to 89% [25]. 

On the other hand, LDA metalation of 3-bromopyridine (42) at -70°C yields, after hydrolysis, a mixture of 3- and 4-substituted products (43 and 44) in addition to starting material 42 (Scheme 14) (82T3035). A potential explanation for these results involves the formation of 3,4-pyridyne, which undergoes nonregioselective attack by amine or lithio amide to give 43 and 44. An alternative rationalization is the isomerization of 42 into the 4-isomer 45 under the metalation conditions (see Section II,B,4), followed by the conversion of either isomer into the radical anions 46 which, via the caged radical pairs 47, is converted into 43 and 44 (Radical Anion-Radical Pair = RARP pathway). 

The direct conversion of a carboxylic acid to an amide with NH3 or an amine is very difficult, even though a more reactive acyl compound is being transformed into a less reactive one. The problem is that carboxylic acids are strong organic acids and NH3 and amines are bases, so they undergo an acid-base reaction to form an ammonium sait before any nucleophilic substitution occurs. 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

Intramolecular nucleophilic photosubshtutions have also been reported. The most commonly found example is the photo-Smiles rearrangement, which is the conversion of aryl-co-aminoalkylethers into the corresponding substituted anilines upon irradiahon [10, 97, 98]. Recently, the photochemistry of (Z)-N-acyldehy-droarylalaninamides in methanol in the presence of a base, such as DBU or triethylamine (TEA), has been reported and found to produce substituted dihydroquinolinones in high yields (Scheme 14.20) [99-101]. The reaction is initiated by ET from the amine to the excited state of the amide. Competitive side reactions were also observed, thereby lowering the yields of the cyclized products. 

Making the activating group larger in size increases the proportion of para-over ortho- substitution (as steric hindrance minimises ortho- attack). For example, conversion of an amine (-NH2) into a bulkier amide (-NHCOR) leads to selective para-substitution and the amide is described as a blocking... 

Conversion of an amine into a substituted amide is a convenient and widely used method for the protection of amino groups. Monoacylation of a primary amine often affords sufficient protection, i.e., against oxidation, alkylation, etc., and more complete protection is obtained by forming cyclic diacyl derivatives. Acyclic diacylamines easily revert to mono-acylamines and have only been used under very mild conditions [20]. Of the simple acylamines in common use the stability increases in the order formyl < acetyl < benzoyl and many more complex acyl groups have been evaluated in order to adjust the stability of the derivatives for various purposes. 

Proton removal adjacent to a heteroatom is further facilitated if the lithium can be internally coordinated to proximate electron donors, such as the carbonyl oxygen, permitting the formation of dipole-stabilized carbanions. Thus lithiations of various amides, thioamides, imides, esters, Boc derivatives of cyclic amines (pyrrolidines, piperidines, and hexahydroaze-pines), thioesters, )V,iV-dialkylthiocarbamates, and various formamidine derivatives are achieved conveniently using s-BuLi (eqs i3 i7) 32,43b.44.47a,48a Subsequent addition of electrophiles followed by hydrolytic removal of the activating carbonyl, carbamoyl, or formamidine moiety provides a valuable synthetic route to a variety of a-substituted amines, alcohols, and thiols. Successful alkylation of the dipole-stabilized car-banions may require the conversion of the initial lithio carban-ions into their organocuprate derivatives, e.g. by the addition of n-PrC=CCu. ... 

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