Universal isocyanide

Cyclohexen-l-yl isocyanide 1 known as Armstrong convertible isocyanide has also been called universal isocyanide . It was prepared in 1963 by Ugi and Rose-ndahl [5] to be used as a synthetic equivalent of the unknown hydrogen isocyanide . The Ugi-4CR between 1, cyclohexanone N-benzylimine 2, and formic acid afforded N-cyclohexen-l-yl amide 3, which was cleaved in acidic medium to afford the primary a-acylamino amide 4 rather than the N-substituted amides usually obtained by the Ugi-4CR (Scheme 2.1). 

Keating and Armstrong [17,18] have developed a solution-phase Ugi four-component reaction (Fig. 4) which utilises a universal isocyanide. The a-acylamino amides can be... 

A very versatile application of the Ugi reaction has been reported by Keating and Armstrong [42]. They use cyclohexenyl isonitrile (1) as a universal isocyanide in an Ugi four-component condensation. The other components are varied. The reaction products, 2-acylamino-alkanoic acid amides of generic structure 2, can undergo a number of further reactions leading in parts to new types of structures and increased diversity (Scheme 3.4). If a resin with free alcoholic groups is used the acylaminoacyl moiety can be bound to the solid phase before it is subjected to further modifications (resin capture). 

The Ugi reaction is also limited in its postcondensation modification. Commercially available isocyanides introduce a secondary amide functionality into the reaction that can be difficult to hydrolyze in the absence of harsh conditions, which represents a problem for highly functionalized compounds. Thus, in recent years, there has been a growing interest among researchers to develop convertible isocyanides (CICs), or isocyanides with an easily removable protecting group (PG). These CICs (at times referred to as universal isocyanides ) eliminate the need to... 

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... 

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 use of resin-bound convertible isocyanides such as the universal Rink isocyanide-resin [18], the safety-catch linker isocyanide-resin [8b, 19] the cyclo-hexenyl isocyanide-resin [8b], and the carbonate convertible isocyanide-resin [20] has found interesting applications in solid-phase Ugi-4CR and post-condensation transformations [21] (Scheme 2.9). 

Universal Rink Isocyanide-resin Safety Catch Linker Isocyanide-resin... 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

An especially effective and fruitful way to synthesize novel scaffolds is by isocyanide-based MCRs (IMCRs). They mostly rely on the classical reactions of the pioneers of this chemistry, Passerini and Ugi (Figure 3.1). Passerini was born in 1891 in Scandicci and was a Professor of Chemistry in Italy, from 1930 to 1932 at the University of Siena and from 1932 at the University of Florence. He died in 1962. Ivar Ugi was bom in 1930 in Estonia. After being Forschungsdirektor of the Zentrallabor in Leverkusen at BAYER , he accepted a chair as full professor at the USC in Los Angeles from 1967 to 1970. From there he moved to the Technische Universitat Miinchen in 1970, where he held the prestigious Emil Fischer chair until 2001. 

See, for example, R. N. Porter and L. M. Raff, Qassical trajectory methods in molecular collisions, in Dynamics of Molecular Collisions, Part B, p. 1, and P. J. Kuntz, Features of potential energy surfaces and their effect on collisions, in Dynamics of Molecular Collisions, Part B, p. 53, W. H. Miller, ed.. Plenum, New York 1976 S. A. Jayich, A. Study of the Collisional Energy Transfer of Methyl Isocyanide with Monatomic and Diatomic Collision Partners, Ph.D. Thesis, University of California, Irving, Calif., 1975. 

So far, our laboratories have primarily focused on the development, testing, and implementation of ccCA, but early success has been obtained in utilizing ccCA to solve chemical problems. For instance, a prototype version of ccCA was used by our group in collaboration with the experimental group of Professor T. Brent Gunnoe (then of North Carolina State University) to compute bond-dissociation enthalpies (BDEs) of ethylene, formaldehyde, methylene imine, carbodiimide, isocyanide, and their hydrogenated counterparts in order to probe useful correlations between the free BDEs of these model substrates and the proclivity of their insertion into the Ru(II)-phenyl bond of a catalyst-active species [108]. The BDEs of these small model systems provided a useful diagnostic to explain the thermochemical preferences of certain types of bond insertions. 

Professor of Chemistry, University of Cincinnati, Ohio Poly(a-phenylethyl isocyanide)... 

Ulrich Schollkopf (1927-1998) and Rolf Schroder of the University of Gottingen first reported the preparation of 4,5-disubstituted oxazoles (3) from the condensation of a-metalated alkyl isocyanides and a range of acid chlorides, esters, and amides in 1971. 

C. M. Bastos, "Coupling Reactions of Alkylidyne Ligands with Carbonyl, Isocyanide, and Alkylidyne Ligands on Tungsten", Ph. D. Thesis. State University of New York at Stony Brook, 1991. 

T MOELLER Arizona State University Carbonyls, Cyanides, Isocyanides and Nitrosyls W P GRIFFITH Imperial College of Science Technology London... 

Removal of Ru residue at the end of the reaction is always an issue. Professor Grubbs has decribed (Organic Lett. 2007, 9, 1955) a PEG-based catalyst that is easy to separate from the metathesis products. Alternatively, Steven T. Diver of the University at Buffalo has shown (Organic Lett. 2007, 9, 1203) that workup of the reaction mixture from G1 or G2 with a polar isocyanide led to products having less than 5 ppm Ru. 

Universal Rink Resin CIC Chen and coworkers utilized Hofheinz-Isenring s CIC concept and developed universal rink resin isocyanide Izi [110]. 

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