Isonitriles cyclization

Isonitrile cyclization provides a useful alternative method of the Knorr type cyclization for pyrrole synthesis. In 1972, Leusen and coworkers reported pyrrole synthesis based on the reaction of tosylmethyl isocyanide (TosMIC) with electron-deficient alkenes (Eq. 10.12).15... 

Barton-Zard pyrrole synthesis is also applied to synthesis of pyrroles with a variety of substituents. Pyrroles substituted with long alkyl substituents at the 3 and 4 positions,30 pyrroles with P-CF3 (Eq. 10.26),31 3,4-diarypyrroles (Eq. 10.27),32 and pyrrole-2-phophonates (Eq. 10.28)33 are prepared in a similar manner based on isonitrile cyclization. 

Tin-mediated-radical cyclization of isonitriles provides a useful strategy for the preparation of indoles (Fukuyama reaction).90 This radical cyclization is used for synthesis of 6-hydroxy-indole-3-acetic acid, which is the aromatic subunit of Nephilatoxin. The requisite isonitriles are prepared from nitroarenes via amines (Eq. 10.66).91... 

Acetylated Meldrum s acid 172 and a-aminoesters 173 have been used as the building blocks to prepare the substituted imidazoles 174, which are then cyclized to give optically active dihydro products 175 <20030L3907> (Scheme 7). A modified four-component LJgi reaction has been used to prepare dihydro products 177 from the intermediate functionalized imidazole 176, isonitriles, and amines (Equation 24) <2005EJ04670>. 

Ugi reaction of acid 88 with isonitrile 85, isobutyraldehyde and isopropylamine furnished dipeptide 89 in 67% yield. Similar Ugi reactions with other components afforded linear cyclization precursors in yields up to 98%. The final macrocyclization was not straightforward (no similar reactions were described in literature), but after optimization of the reaction conditions (varying base, solvent, concentration and reaction time) cyclopeptide alkaloid analogue 90 was obtained in 96% yield after treatment with K2CO3 and catalytic 18-crown-6 in acetone. 

A similar cyclization can result from lithiation of an isonitrile lithiation of 553 requires two equivalents of LDA and the organolithium 554 can either be trapped with other electrophiles at low temperature or warmed to give an indole 555 (Scheme 219) . It is quite clear that isonitriles activate purely by conjugation, and indeed they promote deprotonation of methyl groups para to an isonitrile just as well as ortho. The ease with which isonitriles can be made from formamides suggests that these methods could be rather more widely used than they are. 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Hulme et al. describes the use of a convertible isonitrile for the generation of a ketopiperazine library (Scheme 12) [32]. Using a mono-A -Boc diamine 68 in the classical Ugi reaction followed by Boc deprotection and base-facilitated cyclization (3 steps, 1 pot) afforded the ketopiperazine 72 in relatively high yields. 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

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... 

A similar approach was recently reported by Hulme and coworkers. They published an Ugi-reaction-based DKP synthesis that does not require special isonitriles but uses simple linear ones like W-butyl isocyanide. The corresponding Amide-Ugi-products usually do not cyclize well, but under microwave conditions, good yields were obtained (Scheme 7) [39]. 

An interesting route to 98 was suggested by Cramer et al. " cyclization of isonitrile 110 could lead to 98 in a rearrangement analogous to the Bergman cyclization. The activation enthalpy for the only slightly exothermic reaction was estimated at 18 kcal/mol. However, this novel access to m-arynes could not be realized experimentally so far. 

Wilkinson (9) isolated the tetrakis(trihalogenophosphine)nickel compounds Ni(PX3)4 (X= F, Cl, Br), and Behrens (10) isolated the triphenylphosphine complex Ni[P(C6H5)3]4 via [Ni(CN)4]4. With iron pentacarbonyl, isonitriles and phosphines yield (11) mono- and disubstituted derivatives, Fe(CO)4L and Fe(CO)3L2, respectively, the latter being the well-known cyclization catalyst of Reppe (7). With the same ligands, carbonyls of the chromium group afforded pentacarbonyl derivatives M(CO)5L. However,... 

The proposed mechanism for formation of 151 is shown in (Scheme 27). Proton abstraction by the hydride base from the activated 2-position of the W-fluoropyridinum triflate yields a highly reactive carbene which undergoes attack by the acetonitrile solvent. The resulting nitrilium ylide eliminates fluoride and subsequently adds the isonitrile with cyclization. Finally, reduction by the hydride reagent and aromatization provide the imidazopyridine 151. The undesired amide 152 is a product of hydrolysis of the intermediate nitrilium compound. 

As an extension of the known radical additions to isonitriles [87], aryl radical cyclizations to /V-acyl cyanamides provide new access to pyrrolo-quinazolines (Scheme 16) [88]. In a tandem process, the iminyl radical 41 resulting from the 5-exo cyclization onto the nitrile was used for a second cyclization step. In this way, the alkaloid luotonin A (42) was synthesized from cyanamide 43 in a single reaction. 

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