Amides 2-acylamino

As many natural and synthetic /3-lactams bear 3-acylamino substituents, the corresponding free amines or protected forms thereof are versatile synthetic intermediates. They may be prepared in several ways, for example by deacylation of the 7-amido group in naturally occurring penicillins by enzymic or chemical means. Chemical degradation usually involves conversion of the amide to a chloroimidate followed by cleavage with aqueous alcohols (75S547 p. 560, 78T1731 p. 1753). 

The trivial name bisnorisopenicillin has been coined for the 6-acylamino-3-thia-l-a2abicyclo[3.2.0]heptane-2-carboxylic acid (85) structural class. While not extensively investigated, an example of this class has been prepared as shown in Scheme 66 (78JMC413). The following features of this sequence are noteworthy (a) the exclusively cis cycloaddition to form intermediate (86) and (b) the use of the 2,4-dimethoxybenzyl amide blocking group. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

The microwave acceleration of Ugi condensations on a sohd support have been utilized in the synthesis of an 18-membered targeted hbrary of a-acylamino amides [60], Irradiation of the four components, immobilizing the amine on TentaGel S RAM, for 3-5 min in a single-mode microwave synthesizer gave the products in moderate to excellent yields and high purity (Scheme 7). 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

Acylamino)-substituted carboxylate esters and amides can be alkylated with good anti-2,4 stereoselectivity using two equivalents of a strong base. The stereoselectivity is independent of the steric bulk of the remainder of the carboxylate structure. Propose a TS that is consistent with these observations. 

Amides of Amino Acids Involving the Amino Group (7V-Acylamino Acids)... 

The first solid-phase application of the Ugi four-component condensation, generating an 18-member acylamino amide library, was presented in 1999 by Nielsen and Hoel [53]. The authors described a library generation utilizing amino-functionalized PEG-polystyrene (Tentagel S RAM) as the solid support (Scheme 7.36). A set of three aldehydes, three carboxylic acids, and two isonitriles was used for the generation of the 18-member library. 

Multicomponent reactions (MCR), in which three or more reactions combine to give a single product, have lately received much attention. The Ugi four-component condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield an ot-acylamino amide, is particularly interesting, because... 

In the third transition state (TS3), the neutral catalyst is recovered by transferring the proton back from the catalyst to the substrate. In other words, the (former) azlactone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer, again an LBHB is formed (N-0 distance 2.479 A, <(0,H,N)=166.2°). In the product complex, the catayst is neutral and the A-acylamino acid ester is bound in its iminol form to the catalyst (Product(iininol)). Finally, an additional 66.6 kJ moF are gained by the subsequent iminol-amide tautomerization (Product(ainide)) (Fig. 1). 

Dialkylquinazolines 825 are available by microwave-assisted amination and ring closure of 2-acylamino phenyl-ketones 824 with ammonium formate <20070L69>. The 2-aminophenyl ketone precursors of the amides 824 are available by a photochemically induced Fries rearrangement of anilides 823, which enables a variety of different alkyl substituents to be incorporated at the 4-position of the quinazoline <20070L69>. 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

There are a number of comprehensive studies reported of the reactions of a particular unsaturated oxazolone with nitrogen nucleophiles. On the other hand, unsaturated 5(4/f)-oxazolones react with a variety of amines to yield acylamino amides with interesting agrochemical properties. ... 

Heterocyclic amines have also been used for aminolysis. Subsequent cyclization of the acylamino amides leads to imidazolones that show a diverse range of biological activities as antibacterial, antifungal, antiviral, antihelmintic, and anti-Parkinsonian agents, as well as central nervous systems (CNS) stimulants. 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

TABLE 7.41. iV-ACYLAMINO ACID AMIDES FROM REDUCTIVE AMINOLYSIS OF UNSATURATED 5(4i7)-OXAZOLONES... 

H-Azirin Elektrophil Reaktionsbe- dingungen d-Acylamino-carbonsaure-amid Ausbeute [%] Schmp. [ C] Lite- Tatur... 

Amides. Metal ions catalyze the hydrolysis of a variety of amides, including acylamino acids, dipeptides and tripeptides, and amino acid amides. In all these compounds it is possible for a metal ion to complex with one or more ligand groups, either amine or carboxylate ion functions, in addition to the amide group. Thus the structural prerequisites for the metal ion catalysis of amide hydrolysis are the same as those for ester hydrolysis. 

Amidation and Amination at an Alkyl Carbon Acylamino-de-hydrogenation... 

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