Isocyanide addition, amide

Another electrophile that can interact with the isocyanide-derived amide is an aldehyde. However, an additional carbonyl function cannot be introduced as such into one of the components without interfering with the Ugi process. Thus it is better used in masked form as an acetal (Fig. 9). Starting from amine 49 a series of oxopiperazines 51 has been prepared, also on solid phase [66],... 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

Although the mechanism of this process was not studied, a plausible mechanistic hypothesis is invoked by the authors (Scheme 8.4). On the latter, the nitrophenol 16 is assumed to act as acid surrogate activating the aldehyde to promote the further isocyanide addition. The resulting nitrilium 17 is trapped by the nucleophilic phenoxide generating imidate intermediate 18, which undergoes a final Smiles rearrangement [15,16] to provide the more stable a-aryloxy amide 15 (Scheme 8.4). 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

The mechanistic analogy to the Streckcr synthesis becomes obvious in the addition of the isocyanide to the imine to produce the a-amino nitrilium intermediate. Since all four components are involved in this step, it might be expected that every chiral component (chiral groups R1, R2, R3, R4) contributes to diastereofacial differentiation in the nucleophilic attack on the imine. However, in peptide syntheses by four-component condensation5, the chiral isocyanide or a chiral carboxylic acid component has only limited influence on the diastereoselectivity of the a-amino amide formation5. 

The use of the triphenylphosphine-carbon tetrachloride adduct for dehydration reactions appears to be a very simple way of synthesizing nitriles from amides, carbodi-imides from ureas, and isocyanides from monosubstituted formamides. All of these reactions involve the simultaneous addition of triphenylphosphine, carbon tetrachloride, and tri-ethylamine to the compound to be dehydrated. The elimination of the elements of water is stepwise. An adduct, e.g. (46), is first formed, chloroform being eliminated, which decomposes to produce hydrogen chloride and the dehydrated product. 

Addition of excess /-butyl isocyanide, CO2, or CyNCO resulted in the formation of five-membered ring chelate compounds 107, the metal-bound imino acid 108, and the metal-bound imino amide 109, respectively, as shown in Scheme 47.170... 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

In a three-component synthesis the amide (86-1) obtained from the ester (85-5) and benzyl isocyanide is reacted with the piperdone (86-2). The product from this transform consists of the addition product (86-3) where amide nitrogen in (86-1) as well as the carbon from the isocyanide have added to the carbonyl group on the piperidine. Treatment of the adduct (86-3) with a strong acid hydrolyzes the urethane function on the fert-butyloxycarbonic protecting group, leaving behind the primary... 

The UDC concept can be further extended by application of ethyl glyoxylate (a convertible aldehyde ). Simple reaction of 48 in the Ugi MCR with /V-Boc anthranilic acids, /V-Boc-rt-amino acids, mono-A-Boc diamines, and niono-A-Boc phenylenediamines, followed by acid treatment and in some cases proton scavenging, affords 1,4-benzodiazepines 49, diketopiperazines 50, ketopiperazines 51, and dihydroquinoxalinones 52, respectively.25 Note that products differ from those obtained from convertible isocyanides in that they contain an additional exocyclic amide... 

Boron—nitrogen coordination polymers, with ferrocene, 6, 208 Boron nucleophiles, in conjugate additions asymmetric 1,4-additions, 10, 388 mechanisms, 10, 384 to nitroolehns, 10, 388 to a,/3-unsaturated amides, 10, 386 to a,/3-unsaturated esters, 10, 386 to a,/3-unsaturated ketones, 10, 384 Boron-silicon bonds, addition to alkenes, 10, 760 to alkynes, 10, 758 to allenes, 10, 760 to carbenoids, 10, 766 to 1,3-dienes, 10, 762 to isocyanides, 10, 765... 

A useful preparation of A-acylureas initiated by the addition of A-halo amides to isocyanides was described (equation 35)53. / -Keto-a-(phenylthio)alkyl p-tolyl sulfones in... 

Peptides. In the presence of an aliphatic isocyanide, amino acids and amines condense to form amides. Yields are increased by addition of ZnCl, CH2CI2 is preferable to alcoholic solvents. Yields of dipeptides range from 25 to 90%. ... 

The a-amidoalkylation reaction, which involves the addition of carbon nucleophiles (primarily aromatic rings, alkenes, cyanides, isocyanides, alkynes, organometallic and active methylene-containing compounds) to substituted amides (89) where X is a leaving group (Scheme 17), has been extensively re-viewed. A variety of organometallic condensations have since been reported which extend the scope of this reaction. The reactive intermediates in these reactions are considered to be N-acylimines (88) or N-acyliminium salts (SKI). Direct displacement of the a-haloalkylamide precursors (89 X = halogen) cannot in certain cases be discounted. 

Multicomponent condensations such as the Ugi reaction [44] and the Big-inelli condensation [45] are especially useful for the creation of diverse chemical libraries on the solid phase. Four-component condensations have been reviewed by Mjalli and Toyonaga [46] for the synthesis on the solid phase of small-ring heterocycles [47]. For example, the one-pot condensation of an amine (derived from amino acids) and an aldehyde, followed by the addition of an isocyanide and a carboxylic acid, provides a dipeptidomimetic iV-alky 1-A-acyl- a-amino amide 10 that can serve as a useful starting point for the synthesis of imidazoles 11 and pyrroles 12, which are pharmaceutically useful compounds (Fig. 4). 

Arylimines can be obtained by the addition of N-silylated amides to aryl-lithium compounds (Scheme 200) 44 the imines may be isolated or reduced in situ to amines, or hydrolysed to carbonyl compounds. a-Ketodicarboxylic acid chloride imine chlorides, which readily undergo cyclization to N-heterocycles, have been prepared by -addition of dicarboxylic acid chlorides to isocyanides (Scheme 201).444 Two new formimidoylamino-substituted carbapenems (4) have been prepared by a route involving a hetero Diels-Alder reaction (Scheme 4).14... 

Condensation reactions are one of the most frequently used approaches to prepare pyridinones. A novel synthesis of pyridine-2(l//)-thiones has been described using arylmethylenecyanothioacetamides and dimedone <97T 17441, 97JCR(S)200>. A Ugi four-component condensation reaction between cinnamaldehyde, benzoylformic acid, an isocyanide and an amine affords an amide intermediate that upon addition of base cyclizes to the 1,6-... 

Direct evidence for the presence of nitrile groups in the residue of a PAM sample heated to 250 °C and held for 1.5 hours is obtained by FT-IR, which shows the characteristic nitrile (C N) absorption at 2239 cm h The spectrum also shows the presence of isocyanide groups (2168 cm" ) as well as either inorganic cyanide or diazo (2052 cm" ). In addition one can see evidence of amide groups (3340, 3211, 1686 and 1620 cm" ) and imide groups (C=0 absorption above 1700 cm" ). 

Isocyanides are also utilized for the synthesis of amides,amines,bicyclic compounds, ring compounds of the size Cn-Ci5, formamides, heterocyclic compounds, serines, products of Michael addition,saturated and unsaturated cyclic derivatives of olefins, and heterobicyclic compounds. 

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