Isonitriles aldehydes

CH3)3Si)2N]2U(CH2Si((CH3)2)N(Si(CH3)3)) Generally, uranium metaUacycles are quite reactive inserting a host of organics, ie, CO, secondary amines, nitriles, isonitriles, aldehydes, ketones, and alcohols. 

By carrying out the Ugi-reaction with a large number of isonitrils, aldehydes, carboxylic acids, and amines, it was found that formation of different products of the reaction occurred depending on the structure of the amines used. Thus, 3-aminoimidazoles 88 were isolated when aldehyde reacted with isocyanide and heterocyclic aromatic 2-aminoazine as primary amine (Scheme 38). 

In one prominent example such an unexpected reaction product was observed in three research laboratories independently. During attempts to synthesize a library of Ugi-type four-component products using various isonitriles, aldehydes, acids and amines the reaction did not gave the desired Ugi-type four-component reaction product when amino pyridine-like starting materials were used as the amine component. In the case of such 2-amino pyridine-type amines the clean formation of... 

The four component condensation (Ugi reaction) " converts a mixture of substituted amine, isonitrile, aldehyde (or ketone) and carboxylic acid (Scheme 6) to a-acylaminocarboxylic acid amides (pathway a), to diacylamines (pathway b) and to a-aminocarboxylic acid amides (pathway... 

Boc-a-amino acids, isonitriles, aldehydes, prim amines Boc-a-aminoacyl-a-amino acid amides [57]... 

In an alternative synthesis, a two-step sequence involved an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution to provide rapid access to biaryl-ether-containing macrocycles in solution phase and solid phase (Figure 11.34). 55 Using isonitriles, aldehydes, amines, and carboxylic acids as inputs for the Ugi reaction, dipeptides 70 were formed. Upon cyclization of 70 with K2CO3 in DMF, macrocycles 71 with four points of diversity were obtained. Moreover, the presence of the nitro group allowed the introduction of further structural variation. In the solid-phase synthesis, the Ugi condensation used isonitriles attached to a Wang resin. 

Of the four components reacting in the Ugi reaction, the isocyanide and the carboxylic acid have only limited influence on the overall stereoselection. For instance, in the synthesis of 13-demethyldysidenin (R)-l and 13-demethylisodysidenin (S)-l from a chiral aldehyde, chiral carboxylic acid, isonitrile and methylamine79. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

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. 

Other advances over the past few years have been the development of (a) homogeneous hydrogenation catalysts for substrates normally not readily reduced, e.g., aromatics, isonitriles, and nitro compounds, and (b) a number of catalyst systems with unusual selectivity properties, e.g., with the capability of reducing a,/3-unsaturated aldehydes to the corresponding a,/3-unsaturated alcohols (see Sections II,B,2 and VII). 

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

The synthesis of analogous iminoacyl complexes by isonitrile insertion into linear alkyl-zirconocene chlorides is also known. In an overall regiospecific hydrocyanation of alkenes, iminoacyls 21 derived from tBuNC or Me3SiCN (as the Me3SiNC isomer) may be treated with I2 to rapidly generate an imidoyl iodide and subsequently the nitrile 22 (Scheme 3.6) [22], Less hindered iminoacyl complexes (e. g. R = Bu, Cy) may be hydrolyzed to afford aldehydes 23 [23]. 

Isonitrile insertion into zirconacycles to afford iminoacyl complexes 28 is fast, but rearrangement to q2-imine complexes 30 is slow. In the case of tBuNC, the rearrangement does not occur. Amines 32 are formed on protonolysis of the q2-imine complex. The q2-imine complexes 30 readily undergo insertion of Ti-components (alkenes, alkynes, ketones, aldehydes, imines, isocyanates) to provide a wide variety of products 37 via zirconacycles 36. The overall sequence gives a nice demonstration of how a number of compo-... 

The Groebke-type multi-component reaction between 3-amino-l,2,4-triazole, aromatic aldehydes and benzylic isonitriles afforded iV-alkylidene-4//-imidazo[l,2-A [l,2,4]triazol-6-amines in moderate to good yields <2006TL6891>. 

A highly efficient access to diversely substituted indolizines using a new three-component condensation of activated methylene compounds, aldehydes, and isonitriles is described <2006QSAR504>. 

Reduced 5-oxo derivatives of ring system 68 have been prepared by reaction between an iV)./V-nitroketene acetal and cr-chloroisocyanates <2007S835>. Attempts to form examples of ring system 68 using the three-component coupling method referred to above result in zero or very low yields however by pre-forming an imine intermediate from the aminoheterocycle and the aldehyde, which is then reacted with the isonitrile component, satisfactory yields can be obtained <2007TL2213>. 

Isonitrile complexes, having a similar electronic structure to carbonyl complexes, can also react with nucleophiles. Amino-substituted carbene complexes can be prepared in this way (Figure 2.6) [109-112]. Complexes of acceptor-substituted isonitriles can undergo 1,3-dipolar cycloaddition reactions with aldehydes, electron-poor olefins [113], isocyanates [114,115], carbon disulfide [115], etc., to yield heterocycloalkylidene complexes (Figure 2.6). 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

The following compounds are unaffected by bis(p-methoxyphenyl) telluroxide dithi-olanes, enamines, aldehydes, ketones, alcohols, pyrroles, indoles, amino acids, aromatic amines, monohydroxyarenes, esters, hindered thiocarbonates, isonitriles, oximes, arylhy-drazones, sulphides, and selenides. ... 

Perhaps the most useful and most widely employed multicomponent reaction in this context is the Ugi four-component reaction (U4CR and variations, Fig. 11), where an isonitrile, an aldehyde, an amine, and a carboxylic acid react to form a single product [65, 66]. The principal product is a dipeptide or dipeptide derivative and a high degree of diversity can be introduced by substituents (each of the four components can be varied), subsequent reactions, or by other reaction paths, which can lead to a vast varia-... 

The linear macrocycle precursor 84 is formed in one step by Ugi reaction between tyrosamine-derived isonitrile 85, a-methylene acids 86, and simple aldehydes and amines (route A). This synthesis plan combines the generation of significant molecular complexity with a short synthetic sequence and several possibilities for variation. 

The four components required for the key Ugi reaction are simple aldehydes and amines such as isopropylamine and isobutyraldehyde, isonitrile 85 and a-(bromomethyl)acrylic acid and derivatives (86). Isonitrile 85 was synthesized from tyrosamine in three straightforward steps [94]. 

The steroid may be bifunctionalized with any of the functional groups participating in the Ugi reaction, i.e., isonitrile, amine, aldehyde (ketone), and carboxylic acid, and having two different functionalities on one steroid building block even increases the possibilities. 

In addition, we should note that data of H, NMR spectroscopy, mass-spectra, and elemental analysis given in [138] did not contradict the structure of compound 98, being regioisomer of 97. The similar situation had already been shown in the synthesis of 3-aminoimidazo[l,2-a]pyrimidines [139]. Mandair et al. carried out the model MCRs of 2-aminopyrimidine with several aldehydes and isonitrile components in the methanol under the ambient temperamre with the various catalysts. As a result, 3-aminoimidazo[l,2-a]pyrimidine and position isomeric 2-aminoimidazo[l,2-a]pyrimidines were isolated from the reaction mixture in different ratio (Scheme 45). The stmctures of the isomers obtained in this case were confirmed by the X-ray diffraction analysis, as well as the structures of the side-products isolated. 

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

In 2009, the MCR between o-phenylenediamines (13), aldehydes, and TosMIC (8a) which yields 2,6,7-trisubstituted quinozalines (14) has been described [135]. The mechanism probably proceeds via the initial attack of deprotonated TosMIC at the in situ-generated imine affording intermediate 16 (Fig. 8). Apparently, attack of the secondary amine in 16 at the terminal isonitrile C-atom that yields the... 

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