A-Acylamino amides

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 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). 

They produced an 18-member library of a-acylamino amides, in acceptable to high yields and purity, from a variety of isocyanides, aldehydes and carboxylic acids by using an amino-functionalised TentaGel resin (TentaGel S RAM). The developed procedure represents a rapid and efficient way of synthesising a-acylamino amides, simplifying the tedious purifications, which can usually accompany multi-component reactions. 

Cyclohexen-l-yl isocyanide 1 known as Armstrong convertible isocyanide has also been called universal isocyanide . It was prepared in 1963 by Ugi and Rose-ndahl [5] to be used as a synthetic equivalent of the unknown hydrogen isocyanide . The Ugi-4CR between 1, cyclohexanone N-benzylimine 2, and formic acid afforded N-cyclohexen-l-yl amide 3, which was cleaved in acidic medium to afford the primary a-acylamino amide 4 rather than the N-substituted amides usually obtained by the Ugi-4CR (Scheme 2.1). 

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

Keating and Armstrong [17,18] have developed a solution-phase Ugi four-component reaction (Fig. 4) which utilises a universal isocyanide. The a-acylamino amides can be... 

Title Compounds of the A-Acylamino Amide Family, Compositions Comprising Same, and Uses... 

A one-pot 4-component Ugi reaction and Pd-catalyzed intramolecular Heck reaction was developed for the synthesis of two types of isoquinoline scaffolds illustrated in Scheme 37. In this approach an amine, an aldehyde, a carboxylic acid, and an isocyanide react to provide a diversity of a-acylamino amides 81 and 82 which undergo a Pd-catalyzed intramolecular Heck and double bond isomerization reaction to generate the isoquinoline products 83 and 84... 

Ugi four-component coupling reaction, in which an amine, aldehyde or ketone, carboxylic acid and isocyanide react to yield an a-acylamino amide, was performed by Nielsen et al. on a solid polymer support under microwave irradiation... 

The mixture of aldehydes, carboxylic acids, and isocyanides in a methylene dichloride (DCM) and methanol solution together with amine-bound resins were irradiated (5 min) in a single-mode reactor (Microwell 10) in 10-ml Teflon screw-capped vials to give 18 a-acylamino amides in 24-96% yield (Fig. 37). Usually, un-... 

Because of the inherently low reactivity of most components, a very large number of other functional groups are tolerated in the reaction. Functionalities that are not compatible within the Passerini reaction include those that are reactive toward activated or unhindered aldehydes or ketones under the mildly acidic conditions, lest such reactivity be competitive with the slow Passerini reaction. As a direct consequence, unprotected primary or secondary amines are not compatible because of the facility by which they form imines and iminiums by acid-catalyzed condensation. Iminiums, themselves are susceptible to nucleophilic attack by isonitriles and the formation of a-acylamino amides by this process is called the Ugi reaction (see chapter 3.6). In reactions where the Ugi and Passerini reactions are possible competitive processes the Ugi products are generally favored to the detriment of any Passerini products. ... 

The classical Ugi four-component reaction (U-4CR) originally described by Ugi et al. [1] consists in the reaction of a primary amine, a carbonyl compound (aldehyde or ketone), an isocyanide, and a carboxylic acid to afford a-acylamino amides 36 (Scheme 7.14) [31, 32], Rapidly, other components or adducts were found to give the Ugi-4CR—that is, ammonia, hydroxylamine, or hydrazine as amine component or thiosulfates [33], thiocarboxylic acids [34], isothiocyanic acids [35], hydrazoic acid [36], or carbonic acid monoesters... 

Asym. synthesis of a-acylamino amides, models of peptides has been achieved with high stereoselectivity by a 4-component reaction A new alternating liquid-solid phase procedure improves the selectivity of the synthesis of peptides, producing them with less contamination The substitution of the nitrosamino part of a nitrosamidine group by various nucleophiles has produced a number of unusual 2-substituted benzodiazepines... 

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