Indoles isocyanides

A new stereocontrolled synthetic route to the potent proteasome inhibitor omuralide 46 has been developed from methyl pyroglutamate <07JOC10108>. The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids has culminated in the formal total synthesis of omuralide featuring a stereocontrolled Ugi reaction <07OL3631>. A novel enantioselective total synthesis of 20S proteasome inhibitor salinosporamide A 47 included, as a key feature, an intramolecular aldol cyclization <07OL2289>. A concise total synthesis of ( )-salinosporamide A, ( )-cinnabaramide A, and derivatives via a bis-cyclization process has been documented <07OL2143>. The... 

The reaction of propiophenone with thionyl chloride in pyridine provides 3,4-diben-zoylthiophene (79H(l2)46i). The boron trifluoride catalyzed reaction of benzophenone with f-butyl isocyanide gives an indole derivative (Scheme 84b) (67TL3881). Another... 

Ethyl indole-2-carboxylate, 43,40 Ethyl isocyanide, 41, 15 N-Ethyi-N-methylaniline, 43,47 Ethyl o-nitrophenylpyruvate, potassium salt of, 43, 40... 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

Indoles were synthesized by the intramolecular functionalization of a benzylic C-H bond. Hence, the reaction of 2,6-xylyl isocyanide with a ruthenium complex led to 7-methylindole (Equation (36)). 

The 2,3-substituted indols are formed via a palladium-catalyzed coupling reaction of aryl halide, o-alkenylphenyl isocyanide, and amine (Equation (122)).481 Oxidative addition of an aryl halide, insertion of both the isonitrile and alkene moieties of o-alkenylphenyl isocyanide, and 1,3-hydrogen migration may form a 7r-allylpalladium species, which is then attacked by an amine to afford an indol. 

Marcaccini S, Pepino R, Marcos CF, Polo C, Torroba T (2000) Studies on isocyanides and related compounds. Synthesis of furan derivatives and their transformation into indole derivatives. J Heterocycl Chem 37 1501-1503... 

Indole derivatives such as dihydroindolone are scaffolds of potentially biological interest. Thus, the development of such functionalized skeletons has been approached by a MCR involving cyclic 1,3-diketones, cyclohexyl isocyanide, aromatic aldehydes, and ammonium acetate in the presence of catalytic amount of KHSO4 in refluxing acetonitrile (Scheme 30) [117]. hi this strategy, the imine derived from the Knoevenagel adduct reacts with cyclohexyl isocyanide to give the... 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

A number of indoles of type 315 have been made (80TL281 83JOC3639) by stirring f-butyl and some other isocyanides in benzene or acetonitrile with various arylnitropropenes (314), and the reaction is thought to proceed as indicated. 5-,6-, and 7-Substituted and benzole]- and -[g]-l-hydroxyindoles have also been obtained yields varied from 15-87%. 

Indole Iodide Isocyanide Isoquinoline (dihydro) (tetrahydro) Isoquinolinone Isoxazole P-Keto ester Ketone... 

Another type of unique coupling reaction was reported by Jones and coworkers [87]. The low-valent ruthenium phosphine complexRuH2(dmpe)2 catalyzed intramolecular insertion of isocyanide into the benzyl C-H bond of 2,6-xy-lylisonitrile under thermal conditions (Eq. 59). Their finding provided a new route to the synthesis of indoles. 

An interesting catalytic indole synthesis was realized by the benzilic C-H bond activation on 2,6-xylyl isocyanide (Eq. 38) [93]. A coordinatively unsaturated... 

When jV-protected indole-3-carboxaldehydes were allowed to react with tosylmethyl isocyanide, 3-(oxazol-5-yl)-indoles were obtained in satisfactory yields and applied to the synthesis of novel indole-based IMPDH inhibitors <02BMCL3305>. In the same context, a modified approach to 2-(JV-aryl)oxazoles employing an iminophosphorane/ isothiocyanate-mediated methodology and its application to the synthesis of the potent IMPDH inhibitor BMS-337197, was reported <020L2091>. 

Formotoluide can be prepared by heating a mixture of 856 g. (8 moles) of o-toluidine and 403 g. (8.4 moles) of 90 per cent formic acid on a steam bath for about three hours and allowing the reaction mixture to stand overnight. The mixture is fractionated under reduced pressure there is obtained 920-963 g. (85-89 per cent of the theoretical amount) of o-formotoluide, b.p. 173-5°/25 mm., m.p. 55-58°. This product is a pale yellow solid which contains traces of toluidine and possesses an odor indicating the presence of traces of an isocyanide. However the material is sufficiently pure for conversion to indole. By use of 99 per cent formic acid, a quantitative yield may be obtained. If a purer product is desired, the original reaction mixture is mixed... 

Alternative approaches to indole construction that rely on radical cyclization have been reported by Bowman and co-workers who used aniline derived imidoyl selanides 95 as radical precursors <07T191>. The Ogawa group has also reported the photoinduced thiotelluration of isocyanides, e.g., 97 to 98 <07TL5953>. 

A tactic for the synthesis of C3 imines has been developed by the Chatani group that involves Lewis acid-promoted insertion of isocyanides into indole C-H <07OL3351>. In a... 

Several protocols using multi-component reactions to prepare multisubstituted furans were reported. One procedure was that using acetylenedicarboxylate, isocyanides, triphenylphosphine and an aromatic carboxylic acid <07SL1610>. The others include the reaction of acetylenedicarboxylate, isocyanides and nicotinic acid <07S2637>, of dibenzoylacetylene, amines and diketene <07T8083>, of alkyl isocyanides, aromatic aldehydes and 3-cyanoacetyl indoles <07TL8987>, and of naphthoquinone, isocyanides and aldehydes <07T10269>. 

Alkyl isocyanides undergo a smooth reaction with isopropylidene Meldrum s acid 396 in the presence of pyrrole or indole to produce 1-alkyl-3,3-dimethyl-4-(l//-pyrrole-2-carbonyl)-pyrrolidine-2,5-diones 400 (Scheme 86) or 1-alkyl-4-(lf/-indole-3-carbonyl)-3,3-dimethyl-pyrrolidine-2,5-diones 401 (Equation 94) in good yields <2004S0989>. 

The reaction starts from [4+1] cycloaddition of the isocyanide to the electron-deficient heterodiene moiety of acid 396 to form intermediate iminolactone 397 that loses acetone to give acyl ketene 398 which then reacts with pyrrole at the ketene carbonyl to form the second acyl ketene 399 (Scheme 86). Ring closure of this ketene leads to the final product 400. Similar reaction conditions as described above, were employed for indole and 2-methylindole (Equation 94). 

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