Carboxylic esters isocyanides

The unusually high observed initial intrinsic viscosity was at first thought to be due to molecular aggregation of polymer chains, made possible by presumed interaction of the carboxyl ester groups. Molecular association is known in many polymeric systems, but in those cases the association process is also apparent in osmometric data. No evidence of association is observed in the osmometric data of poly[(a-carboxymethyl)ethyl isocyanide]. Moreover, it would be expected that, if molecular association would have taken place, different values of [>7] would have been observed upon changing of solvents. Such change is not observed upon addition of triethyl amine (i.e. 10% volume) to 1,2-dichloroethane, or by solvent change to p-dioxane. 

Occasionally it is also suitable to have an isocyanide 13e whose product 18n contains a -CO-NH-R group that can be converted into a derivative 31C with the group -CO-Y, which can correspond to a carboxylic acid (Y = OH), a carboxylic ester (Y = OR with an alkyl group), or an amide (Y = NH2) (Scheme 4.20). 

Besides the formation of oxazole derivatives, Schollkopf and the others have successfully extended the a-alkali metalated isocyanides to the formation of the chain-extended primary amines, 2-oxazolines, 2-thiazoline-4-carboxylic esters," 2-imidazolines, 2-pyrrolines and pyrroles, thiazoles, 2-imidazolin-5-ones," 2-imidazolinones," etc. For example, a simple reaction between lithiomethyl isocyanide with two equivalents of piperonal followed by acetylation of the intermediate with acetic anhydride affords the corresponding oxazoline. ... 

Passerini Carbonyl compounds + carboxylic acid + isocyanide Amino esters... 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

The convertible isocyanide also enables transformation of the secondary amide in the Ugi product to a carboxylic acid, ester, or thioester, which is thus amenable to further functionalization. The aforementioned templates are all readily accessible via manufacture in 96-well plates using 96-well plate liquid handlers. The initial condensations are optimal with excess aldehyde (2 equiv.), which can be subsequently removed via a simple scavenging and filtration step with PS-TsNHNH2.18 Several universal resin-bound isocyanides have also been developed to exploit UDC methodology for the generation of the above heterocyclic products. 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

Finally, other reactions can be performed directly using water as a solvent. Ugi s four components reaction, for example, provides an expedient access to peptidic scaffolds starting from an isocyanide, an amine, an aldehyde and a carboxylic acid. However, in competition to Ugi s reaction, Passerini ester formation often pollutes the reaction mixture and it is of great interest to perform this type of highly complex transformation in supported versions. Indeed, when an ammonium chloride supported aldehyde, similar to those used in Grieco s multicomponent reactions, are dissolved in water in the presence of an amine, the imine formation occurs within 15 min and isocyanide and acid can subsequently be added to the mixture. After 24 h at room temperature, amides were isolated in high yield with no other purification than washing with diethyl ether [135] (Fig. 44). 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

Two different reaction pathways have been h5q>othesized for the Passerini reaction the first one is supposed to be ionic (Fig. 5.1) the second one, concerted (Fig. 5.2). In polar solvents such as methanol or water, the reaction proceeds hy protonation of the carbonyl followed by nucleophilic addition of the isocyanide to produce the nitrilium ion, 3 (below). Addition of a carboxylate gives the intermediate, 4. Acyl group transfer and amide tautomerization yield the desired ester, 5. 

NH, mercaptans, sulfides, unsaturated hydrocarbons, amines, isocyanides, pyrazines, ketones, esters, aldehydes, carboxylic acids, furanones, lactones, ionones, Ru" ... 

The preceding survey of the recent developments in the synthesis of CICs and their application in small molecules and bioactive natural products reflects an active current interest in this highly versatile class of useful reagents. From a practical point of view, CICs have revolutionized the application of IMCRs, in particular that of U-4CR, due to their mild removal conditions that are compatible with many commonly used functional handles and their odorless, fragrant-like smell. Post-Ugi modification using CICs provides a method of transforming Af-terminal secondary amides into carboxylic acids, esters, thioesters, ketones, aldehydes, and alcohols for further chemical diversification and thus helped remedy the lack of commercial isocyanide inputs. 

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