Aldehydes 2-acylamino

Azlactones (anhydrides of a-acylamino acids) are formed by the condensation of aromatic aldehydes with acyl derivatives of glycine in the presence of acetic anhydride and anhydrous sodium acetate. Thus beiizaldehyde and acetyl-... 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

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 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... 

Dipolar cycloaddition of diazomethane to aldehydes can successfully be used for the preparation of tetrahy-drooxadiazole derivatives. Photochemical interconversion of 3-acylamino-l,2,5-oxadiazole derivatives leads to 1,3,4-oxadiazoles, though the method suffers from lack of selectivity. Many reports concentrate only on the synthesis and applications of new 1,3,4-oxadiazoles substituted with a wide variety of groups without introducing much of new chemistry. 

A diastereoselective synthesis of /3-(iV-acylamino)aldehydes was accomplished via ruthenium-catalyzed isomerization of 0-vinyl-iV,0-acetals followed by rearrangement in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (Scheme 36).63... 

Scheme 1 a Amidocarbonylation of aldehydes b Applications of N-acylamino acids... 

The two-step activation of oxazolidinones is depicted in Fig. 8.26. Hydrolysis yields an A-(l -hydroxy alkyl) derivative, which breaks down to liberate the peptide or A-acylamino acid (Fig. 8.26, Reactions a and b). Since oxazolidinones are prepared by the condensation of a peptide and an aldehyde (Fig. 8.26, Reaction c), the reverse reaction (i. e., one-step activation) cannot be excluded. Examples of this type of prodrug are provided by a series of oxazolidinones of the general structure 8.190 (R = PhCH20 R = H, Me, i-Pr, or PhCH2 R" = H, Me, or Ph Fig. 8.26) [248]. In phosphate buf-... 

Erlenmeyer synthesis org chem Preparation of cyclic ethers by the condensation of an aldehyde with an a-acylamino acid in the presence of acetic anhydride and sodium acetate. 3r-l3n,mT-3r sin-th3-s3s erucic acid org chem C22H42O2 A monoethenoid acid that is the cis isomer of bras-sidic acid and makes up 40 to 50% of the total fatty acid in rapeseed, wallflower seed, and mustard seed crystallizes as needles from alcohol solution, insoluble in water, soluble in ethanol and methanol. o rus ik as ad erythrite See erythritol. er o.thrTt ... 

There are many reports describing the preparation of various butyrolac-tones from AAs. When r-butyl 2-dibenzylaminoacetate in the form of its Li-enolate was treated with (5)-0-benzyllactic aldehyde, a mixture of four diastereoisomeric hydroxy-AAs was obtained. After separation and further treatment, three lactones were obtained (Scheme 17) (87T2317). Similar compounds were obtained from a-acylamino-y-keto acids after cycliza-tion (75CC905). 

The first procedure to prepare unsaturated 5(4//)-oxazolones was the Erlenmeyer synthesis" " that was described more than one hundred years ago and is still used extensively with some variations in the experimental conditions. In general, the reaction employs an acylamino acid, for example, A-acetyl- or A-benzoylglycine are the most common, and a carbonyl compound, usually an aldehyde, in the presence of a cyclodehydrating agent such as acetic anhydride (Scheme 7.114). Hundreds of unsaturated oxazolones 363 have been obtained via this procedure and these compounds are valuable intermediates for the synthesis of many interesting organic compounds. 

The hydrolysis and alcoholysis reactions have been extended to the heterocyclic series. A systematic study has been published of the hydrolysis of unsaturated oxazolones derived from a selection of heterocyclic aldehydes. A detailed study of the synthesis and stereospecific hydrolysis and methanolysis of the (Z) and ( ) isomers of 2-methyl (or phenyl)-4-(thienylmethylene)-5(4F/)-oxazo-lones 435 and 437 has also been described (Scheme 7.144). The synthesis of 2-acylamino-3-(indol-3-yl or carbazol-3-yl)acryhc acid derivatives as potential antifertility agents via oxazolone hydrolysis has also been published. ... 

In the heterocyclic series, racemic 3-(fur-2-yl)alanine has been prepared from furfural using this approach. In addition, (3-(pyrid-3-yl)alanine, ° p-(quinol-3-yl)alanine, ° a p-(benzofuranyl)alanine derivative, 2-amino-3-(2,2 -bipyridi-nyl)propanoic acid, and some interesting derivatives of histidines—in particular 1-alkylhistidines with amphiphilic properties have all been synthesized using this methodology. The complete reaction sequence starting from an aldehyde and an A-acylamino acid derivative is shown in Scheme 7.150. 

A convenient synthesis of a-acylamino aldehydes (541) has, for example, been developed which is based on the transformation of the a-acylamino acid (540) into its acylimidazolide with carbonyldiimidazole (79CC79). Diisobutylaluminum hydride reduction of the imi-dazolide then affords the aldehyde, generally in high optical purity (equation 6). 

Few solid-phase syntheses of oxazoles have been reported (Table 15.17). The most general strategy is the dehydration of a-(acylamino) ketones (Entry 2, Table 15.17) or 2-(acylamino)phenols (Entry 1, Table 15.17). Oxazolidin-2-ones have been prepared by intramolecular nucleophilic cleavage of carbamates from insoluble supports (Entries 5 and 6, Table 15.17). Resin-bound 2-aminoethanols, which are accessible by nucleophilic ring-opening of oxiranes with amines, undergo cyclocondensation with aldehydes to yield oxazolidines [220,221]. These compounds are unstable towards acids, and can be released from the support only under neutral or basic reaction conditions. 

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. 

A set of three aldehydes, three carboxylic acids and two isonitriles (Fig. 7.11) was used for the generation of the 18-member acylamino amide library. 

The presence of electron-withdrawing substituents at C(4) facilitates reactions with nucleophiles, which may well be initiated by attack at C(5). Thus oxazole-4-aldehydes undergo ring-fission on treatment with aqueous alkali to form (acylamino)malondialdehydes (equation 3), and 2-pentyloxazole-4-carboxylic acid yields 2-pentylimidazole, with concomitant decarboxylation, when heated with ammonia at 150 °C. An example of a more complex ring transformation is the formation of 3-aminopyridines (131) by the action of malononitrile on 4-acetyloxazoles under alkaline conditions (equation 4). 

An extension of the Erlenmeyer synthesis is the condensation of acylamino acids with triethyl orthoformate which leads to the ethoxymethylene derivatives (297). These can be hydrolyzed to the corresponding enols, which in turn can be converted into chloromethylene compounds, e.g. (298). The lability of the chlorine atom in this compound (see arrows) can be put to good account reaction with organometallic compounds or with benzene and its derivatives under Friedel-Crafts conditions yields unsaturated lactones (298 aryl or heteroaryl in place of Cl). The method is especially valuable in cases where the aldehyde is not readily available. 

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