TosMIC isocyanide

After the umpolung of an aldehyde group by conversion to a l,3 dithian-2-ide anion (p. 17) it can be combined with a carbonyl group (D. Seebach, 1969, 1979 B.-T. GrO-bel, 1977 B). Analogous reagents are tosylmethyl isocyanide (TosMIC), which can be applied in the nucleophilic formylation of ketones (O.H. Oldenziel, 1974), and dichloromethyl lithium (G. KObrich, 1969 P. Blumbergs, 1972 H. Taguchi, 1973),... 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

A one-step synthesis o( mtnles from carbonyls by a reductive cyanation with tosylmethyl isocyanide (TosMIC), also synthesis of 1,3-azole or of ketones... 

The van Leusen reaction forms 5-substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (1, TosMIC) with aldehydes in protic solvents at refluxing temperatures. Thus 5-phenyloxazole (2) is prepared in 91% yield by reacting equimolar quantities of TosMIC and benzaldehyde with potassium carbonate in refluxing methanol for 2 hrs. ... 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

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... 

Reaction of pyrrolopyridines 241 with tosylmethyl isocyanide (TosMIC) in the presence of a phase transfer catalyst tetra- -butylammonium iodide (TBAI) provides the tricyclic pyrimidopyrrolopyrimidine derivatives 242 (Equation 30) <20000L3253, 2004JOC4974, 2005JOC4879>. 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

The reaction of the 3-(bromomethyl)pyrazole 276 with various alkyl derivatives of tosylmethyl isocyanide (TosMIC) 277 affords the products 278 (Equation 56) and requires phase-transfer conditions for success <2005JOC4879>. This reaction was also used for the synthesis of ring system 68, but in lower yield (25%). 

Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures. 

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... 

Tipson-Cohen reaction, 30, 2 Tosylhydrazones, 23, 3 39, 1 Tosyhnethyl isocyanide (TosMIC), 57, 3 Transmetallation reactions, 58, 2 Tricar bonyl(r -arene)chromium complexes, 67, 2... 

TosMIC tosylmethyl isocyanide, [(p-toluenesulfonyl)methyl] isocyanide... 

Isocyanides are useful reagents for the preparation of oxazoles unsubstituted at C-2. For example, TosMIC was used to generate the oxazole ring in a synthesis of phthoxazolin A 37 <990L1137>. However in the reaction of IV-tosyl aldimines with the isocyanide 38 the oxazoles that were isolated were 2 1 adducts 39 that had been further substituted at C-2 <98T12445>. 

In Einzelfallen bietet sich die Ugi-Reaktion fur die Synthese bestimmter a-Amino-carbonsauren im Vergleich zu anderen Moglichkeiten als Methode der Wahl an. Beispiele sind die Herstellung von Bis-[l-carboxy-alkyl]-aminen I aus a-Amino-carbonsaure-estern8 [unter Verwendung von 4-Methyl-phenylsulfonylmethyl-isocyanid (TOSMIC)9 als Isonitril-Komponente] und die von 3-(2,5-Cyclohexadienyl)-alanin-methylamid(ll) (37% aus 3-Formylmethyl-l,4-cydohexadien)1. 

Tosylmethyl isocyanide (TosMIC) and its congeners are useful and versatile building blocks for the construction of heterocyclic molecules.5 While TosMIC is available from a variety of commercial sources, substituted TosMIC reagents have suffered from the lack of general and efficient methods for their preparation. ... 

The present procedure provides ready access to a variety of substituted TosMIC reagents, exemplified by a-tosylbenzyl isocyanide (3), by dehydration of the... 

A useful pyrrole synthesis depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,(3-unsaturated ketones or other Michael acceptors (72TL5337) (Scheme 56). 

NMO NMP Nu PPA PCC PDC phen Phth PPE PPTS Red-Al SEM Sia2BH TAS TBAF TBDMS TBDMS-C1 TBHP TCE TCNE TES Tf TFA TFAA THF THP TIPBS-C1 TIPS-C1 TMEDA TMS TMS-C1 TMS-CN Tol TosMIC TPP Tr Ts TTFA TTN N-methylmorpholine N-oxide jV-methyl-2-pyrrolidone nucleophile polyphosphoric acid pyridinium chlorochromate pyridinium dichromate 1,10-phenanthroline phthaloyl polyphosphate ester pyridinium p-toluenesulfonate sodium bis(methoxyethoxy)aluminum dihydride (3-trimethylsilylethoxy methyl disiamylborane tris(diethylamino)sulfonium tetra-n-butylammonium fluoride f-butyldimethylsilyl f-butyldimethylsilyl chloride f-butyl hydroperoxide 2,2,2-trichloroethanol tetracyanoethylene triethylsilyl triflyl (trifluoromethanesulfonyl) trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran tetrahydropyranyl 2,4,6-triisopropylbenzenesulfonyl chloride 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane tetramethylethylenediamine [ 1,2-bis(dimethylamino)ethane] trimethylsilyl trimethylsilyl chloride trimethylsilyl cyanide tolyl tosylmethyl isocyanide meso-tetraphenylporphyrin trityl (triphenylmethyl) tosyl (p-toluenesulfonyl) thallium trifluoroacetate thallium(III) nitrate... 

TosMIC l-(isocyanomethyl)-4-methylben2cne = toeylmethyl isocyanide, TosCHjNC TTN Und v.p.c. thallium(III) trinitrate = TI(N03)3 Undecyl vapor-phase chromatography = GC... 

An alternative way to synthesize imidazoles in a more flexible manner is to use a synthon. An example of such a synthon approach, is the synthesis of imidazoles using tosylmethyl isocyanide (TOSMIC). The original procedure using this synthon gave only moderate overall yields of the substituted imidazoles18, mainly due to the poor yield in the first step (figure 7). 

The utility of TOSMIC in MCR reactions has also received recent interest in the pharmaceutical arena as an approach to the preparation of imidazoles 91. Originally reported by van Leusen in 1977 [76], and involving cycloaddition of tosyl-methyl isocyanides to carbon-nitrogen double bonds, recent elegant work by Sisko et al. has heightened its profile with the description of a one-pot synthesis of imidazole 92, a potent inhibitor of p38 MAP kinase, implicated with the release of the pro-inflammatory cytokine TNF-a (Scheme 11.19) [77]. In this particular example a fluorinated analogue of TOSMIC 90, is employed. 

The TOSMIC anaiog -(tosyl)benzyl isocyanide readily reacts with simple acceptors (ethyl acrylate, acrylonitrile, etc.) to give 4-substituted 2-arylpyrroles. Extension to 2,3-diaryl derivatives by use of styryl acceptors required the use of n-butyllithium as a base. <95SC795>... 

Benzotriazole-l-yl)methyl isocyanide (BetMIC) 813 can be used instead of TosMIC in pyrrole syntheses thus, C-alkylation on the methylene group using /-BuOK and then reaction of the resulting give isocyanide 814 with, -unsaturated ketones, esters, or nitriles produces pyrroles 815 (Scheme 173) <1997H67>. 

T10425>. Through a proper use of the Suzuki-Miyamura and van Leusen oxazole synthesis it was possible to synthesize a wide variety of aromatic derivatives substituted with oxazole rings. The strategy was based on the initial synthesis of the aromatic scaffold and the subsequent reaction of the carbonyl functions with toluenesulfonylmethyl isocyanide (TosMIC) as depicted in the following scheme<07S3653>. 

---