Isocyano derivatives

The third multicomponent approach to tetrahydrotetrazolo[l,5-zz]pyrazines elaborated by a German team is also reminiscent of the previously discussed two procedures <2004TL3725>. The specific feature of this method is the use of 2-tosyl-oxyethylisocyanide instead the isocyano derivatives described above. This transformation was also carried out in methanolic solution, and simple stirring at room temperature for 24 h led to the tetrahydro products 122 in medium to good yields (42-75%). 

This classification is illustrated in Scheme 330. Imidazole synthesis under this classification consists mainly of two approaches 1,3-dipolar cycloaddition and one-pot addition-cyclization involving isocyano derivatives. 

The pyrrole annulation of 291 with different isocyano derivatives afforded the resin-bound products 292, which were released from the resin with 10% TFA leading to 293 (Scheme 67) <2004JC0142>. 

The O.O -dimethyl-Xanthocillin 28 was prepared from its N, N -diformyl-diamine 27. This was dehydrated by phenyl-sulfonyl-chloride in the presence of pyridine. The procedure was published in Pharmazie [53] in East Germany in 1956, but was not available to Western countries. The method can be used particularly if isocyano-polymers are formed [54]. Two years later, Hertler and Corey [55] reported a similar conversion of a formyla-mino-steroid into its isocyano-derivative. 

Strictly speaking, this reaction does not qualify as either isodesmic or obeying bond additivity because solid AgCN contains both Ag—CN and Ag—NC bonds. However, in that we have already considered isocyano derivatives of silver cyanide, we would nonetheless like to consider this reaction and admit we do not know how to derive the cyanide/isocyanide enthalpy difference. 

The required a-isocyano derivatives (85) of a-amino acids are prepared from the corresponding a-formylamino acids. If (85) is a peptide derivative, no racemization is observed at the a-isocyanoacyl unit. - The preparation of chiral a-isocyanocarboxylate esters, however, is possible with phosgene or... 

A novel method for the reductive deamination of amino-sugars has been published by Barton s group. The process involves sequential iV-formylation, dehydration to the isocyano-derivative, and reduction with tributylstannane. Application of the reaction to l,3,4,6-tetra-C>-acetyl-2-amino-2-deoxy-/3-D-gluco-pyranose afforded 2-deoxy-D-glucose tetra-acetate in 72% yield. 

Monocyclic nitro dromaDcs such as [Pg.336]

The Ugi reaction has been successfully applied to the synthesis of oligopeptide derivatives, c.g.. in the construction of a pure tetra-L-valine derivative69. The 2-methylpropanaldimine 2 of (/7)-l-ferroccnyl-2-rnethylpropylarnine with /V-formyl-L-2-amino-3-methylbulanoic acid (3) as the carboxylic acid component and methyl A/-[(.S)-2-isocyano-3-mcthyl-l -nxo-buLyl -L-2-aiuino-3-inethylbutanoate (4) furnishes the diastereomeric valyl-valyl-valyl-valine derivatives in a ratio (S,S[R],S,S)i(S,R[R],S,S) of 91 9. The stereoselectivity of the process can be enhanced to 98.5 1.5 when two equivalents of tetraethylammonium A -formylvalinate are added. 

Benouazzane, M., Coco, S., Espinet, P. and Marti n-Alvarez, J.M. (1995) Liquid Crystals based on Halogold(I) Complexes with 4-Isocyano-4 -alkoxyphenyl Derivatives. Joumol of Materials Chemistry, 5, 441 5. 

Naturally occurring isocyano compounds are no longer an oddity since their frequent isolation from members of the class of Demospongiae. Their biogenesis has intrigued chemists ever since the first terrestrial isocyano compound (an amino-acid derivative) was described from a micro-organism. All known marine isocyano compounds are terpenoid and their biosynthesis continues to pose an unsolved problem, which is discussed in Chapter 2. 

In those cases where quantities of the test organisms are limited or non-aqueous conditions are preferred, blending of the lyophilized sponge with organic solvents is employed. The latter option is prudent, if one suspects the presence of reactive isocyano and isothiocyano functions. Although these isolation methods may not be unduly harsh, artifacts derived from isonitriles and isothiocyanates may arise. 

Fig. 18 Suggested reaction mechanism for the construction of pyrrolo[3,4-h]pyridme-5-ones (50) from the MCR between isocyano amides, aldehydes, amines, and acryloyl chloride derivatives...

Activation of two Si—Si bonds in bis(disilanyl)alkanes with palladium(O) bis(tert-alkyl isocyanide) induced the formation of the cyclic bis(silyl)palladium(II) bis(terf-alkyl isocyanide) complexes (100) and disilanes described schematically in Scheme 42. These complexes were found to react with phenylacetylene, affording different amounts of five-membered cyclic products and acyclic products which are derived from the insertion of the alkyne into the general intermediate complex 101 (Scheme 42, equation 54). The bis(silanyl)dithiane palladium complex (102) was isolated and characterized in the solid state the two silicon atoms, the two isocyano carbons and the palladium atom are nearly in a plane with a short cross-ring Si—Si distance of 2.613(2) A, suggesting the possibility of covalently bonded two Si—Si atoms in the four-membered ring. Similar reaction with cyclic disilanes afforded oligomers, and cyclic 20-membered compounds have been prepared in the presence of nitriles248,249. 

The possibility of obtaining scaffold diversity by the MCR strategy has been further demonstrated using the M-(cyanomethyl)amide 3CR [60] (discussed earlier) as the primary MCR [103]. By applying the primary a-isocyano amide derivative of 176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles [106, 107] MCRs resulting in various new scaffolds. 

Optically active ferrocenylbisphosphines, (/J)-N,iV-dimethyl-l-[(5)-1, 2-bis(diphenylphosphino)ferrocenyIJethylamine [(/J)-(5)-BPPFA] and its derivatives, are efficient chiral bisphos-phine ligands for rhodium-catalyzed asymmetric hydrogenation, palladium-catalyzed asymmetric allylic substitution reactions, and gold-catalyzed asymmetric aldol-type reactions of a-isocyano carboxylates. ... 

Cyclopropylamine (77) could be oxidized to nitrosocyclopropane (432) by oxygen difluoride or m-chloroperbenzoic acid (equation 106). Azo compounds 433 and 435 were obtained by oxidation of 434 by IF5 (equation 107) or condensation of 77 with a nitroso compound (equation 106). Interconversions of an aminocyclopropane into an isocyano or azido cyclopropane are described, for example, in Refs 105,479-481,515,516 and Refs 89, 461, 517, respectively. For formation of an N-cyclopropyl iminiophos-phorane see Ref. 518. Nitrosation of iV-cyclopropylurea derivatives was usually performed... 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

The peptide-based isocyanides 50a-e were successfully polymerized by Ni(II) catalysts under an inert atmosphere [63-66]. An alanine-derived isocyanide, whose isocyano group was labeled using 13C and 15N, was prepared and successfully polymerized for structure elucidation [67]. Several solvent systems were used in the polymerization of the peptide-based isocyanides, depending upon the solubility of the isocyanides. As mentioned earlier, the use of alcohols as a solvent or co-solvent can accelerate the polymerization. The protective groups on the ester, hydroxy, and imidazole groups were removed after polymerization by treatment with aqueous NaOH to yield poly(isocyanide)s bearing unprotected peptide side chains. 

The thermal iscmierisation in tetradecane of l-isocyano-2-phenylnaphthalenes to benzo[c]phenanthridine is accompanied by the 6-tetradecyl derivative formed by solvent participation. Irradiation of the isocyanide at 300 nm also produces the benz phenanthridine (J.H. Boyer and J.R. Patel. J. chem. Soc. Perkin I, 1979, 1070). 

Intramolecular heterocyclization in polyacrylonitrile 86UK62. a-Isocyano acetates, synthesis of N-heterocycles from 85YGK764. Isonitrosotosyl malonates in synthesis of N-heterocycles 80H(14)1581. Lactams, regioselective formation from bridged bicyclic ketones 81T1283. Malononitrile derivatives, synthesis of N-heterocycles condensed from ... 

Some multicomponent syntheses of trisubstituted oxazoles were described. a-Isocyano-a-alkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T 11317>. 

Multicomponent reactions (MCR) were also highlighted in the literature. The reaction of dimethyl butynedioate 160 and benzyhdenemalononitrile 161 in anhydrous THF with isoquinoline at room temperature gave a mixture of two diastereomers 162 and 163 (2 1) in 81% yield (Scheme 46) <05TL5333>. Isoquinohne was also used in a MCR that included methyl chloroformate and morpholinyl-a-isocyano-P-phenylpropionamide resulting in the synthesis of (l,3-oxazol-2-yl)-l,2-dihydro(iso)quinoline derivatives in moderate yields <05SL532>. 

In the 1960s, a somewhat stable five-membered cyclic a-adduct could also be formed by an isocyano-alkylcarboxylic and a Schiff base. At > 80 °C this a-adduct can be rearranged into a 2,5-piperazinedione derivative. At lower temperatures, a peptide derivative can be formed from this a-adduct, in addition to a secondary amine [8,102]. 

---