Isonitrile with aldehyde

Imidazo[l,2-fl]pyridines are formed upon treatment of isonitriles with aldehydes and 2-aminopyridines (Entry 14, Table 15.14). 2-Aminoazines other than 2-aminopyr-idine can also be used in this multicomponent reaction, yielding the corresponding fused imidazoles [179-183]. 

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 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. 

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

Passerini, M., Formation of a-hydroxycarboxamides on treatment of an isonitrile with a carboxylic acid and an aldehyde or ketone, Gazz. Chim. Ital, 1921, 51, 126. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

Ketenimine complexes can serve as three-atom components in [3 + 2] cycloadditions. The reaction of the tungsten complex (378) with cyclohexyl isonitrile and phenyl isocyanate produces the heterocyclic carbene complex (379), which is the result of the in situ trapping of a ketenimine complex with the isocyanate. Complexes of the type (379) can be oxidatively cleaved to give the previously inaccessible 5-ethoxyhydantoins. [3 + 2] Cycloadditions of this type have also been carried out with aldehydes. 

Oxazoles. Oxazoles are formed using this building block on reaction with aldehydes and acid chlorides. The isonitrile is prepared from the corresponding formamide by dehydration with POClj-EtjN. 

Ionic hquid-bound pyrrolo-[l,2-fl]-benzimidazoles have been synthesized by Sun et al. by reacting IL-supported 2-(cyanomethyl)benzimidazole with aldehydes and isonitriles under microwave irradiation at high temperature [95], After precipitation and cleavage from the IL support, the desired products could be obtained in good yields and moderate to high purity without chromatographic purification. 

A novel strategy for the synthesis of pyridines from aldehyde, enam-ide, and isonitrile was described by Wang and coworkers in 2013 [122], The reaction works under mild reaction conditions and good to excellent yields can be achieved. Mechanistically, this cascade reaction consisted by Zn(OTf)2-promoted [1 + 5] cycloaddition of isonitrile with A-formylmethyl-substituted enamide, facile aerobic oxidative aromatization and intermolecular acyl transfer from the pyridinium nitrogen to the 5-hydroxy oxygen, and finally acylation of the 4-amino group by an external acyl chloride efficiently afforded 2-substituted 4-acylamino-5-acyloxypyridines. 

These multicomponent reactions are novel. Multicomponent reactions of aldehydes and isonitriles with amino acids have been described in the literature [42], but the utilization of the carbonyl function of carbohydrates instead of aldehydes has not been reported previously. 

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. 

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]. 

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>. 

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