Tosylmethyl 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),... 

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... 

Van Leusen and Possel described the use of mono-substituted tosylmethyl isocyanides (TosCHRN=C R = alkyl, benzyl, allyl) in the synthesis of 4,5-substituted oxazoles. For example, 4-ethyl-5-phenyloxazole (8) was prepared in 82% yield by refluxing a-tosylpropyl isocyanide (7) and benzaldehyde for 1 hr with 1.5 equivalent of K2CO3 in MeOH. 

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. 

An attractive synthesis of cyclobutanone (253) has been recently described using 1-isocyano-l-tosylcyclobutane(252)(equation 151)144. l-Isocyano-l-tosylcyclobutanes252 can be prepared from (tosylmethyl)isocyanide and alkyl-substituted 1,3-dibromobutanes. This method appears to be superior to previously reported methods for the preparation of cyclobutanone because of high purity and high yields. 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

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%). 

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

In an effort to explore the chemistry of pyrrolodiazines and their quatemized salts (see Section 6.2.2.2), Alvarez-Builla and co-workers prepared a series of pyrrolo[l,2-c]pyrimidines via methodology developed in their laboratory <99JOC7788>. Cyclocondensation of tosylmethyl isocyanide with substituted pyrrole-2-carboxaldehydes 17 produced pyrimidine derivatives 18 sifter removal of the tosyl group. The key to this procedure was the use of tosylmethyl isocyanide, which provided a relatively easily removed tosyl group in comparison to the more problematic decarboxylation of a carboxylic acid functionality. 

Isocyano-l-tosylcyclobutane (20) can be prepared in 71 % yield by intermolecular cyclodialkylation of tosylmethyl isocyanide with 1,3-dibromopropane in the presence of sodium hydride.12 Cyclobutane 20 can also serve as an appropriate precursor of cyclobutanone indeed, smooth acid-catalyzed hydrolysis provides cyclobutanone in 84-88% yield.29... 

Tosylmethyl isocyanide [36635-51-7] M 195.2, m 114-115°. Recrystd from EtOH (charcoal) [Saito and Itano, JCSPT 1 1986. ... 

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. ... 

This reactivity pattern is rather rare but is seen in the condensation of carbon nucleophiles such as nitromethane with arylidene isocyanides (equation 74) (79JHC(S)lll). The isocyanides are obtained by condensing aromatic aldehydes with tosylmethyl isocyanide. 

The [3 + 2] addition of type llbd is a significant method for synthesis of both simple and complex pyrrole derivatives. One manifestation of this pattern is seen in the base-catalyzed condensation of tosylmethyl isocyanide with alkenes having strong electron-accepting substituents. The aromatization by elimination of the arenesulfinic add occurs under the reaction conditions (equation 117) (72TL5337). This reaction can be applied to the synthesis of 2,3,4-trisubstituted pyrroles by using C-alkylated tosylmethyl isocyanides or AT-tosyl-methyl-S- methylthioimidates <77H(7)77, 81JHC1127). 

Sodium hydroxide-Methyltrioctylam-monium chloride, 192 Tosylmethyl isocyanide, 313 Tributyl(iodomethyl)tin, 314 of hydrazones and related compounds 9-Bromo-9-phenylfluorene, 48 Titanium(III) chloride-Diisobutylalu-minum hydride, 303... 

Diketones a-Methylbenzylamine, 185 Methyl vinyl ketone, 193 Tosylmethyl isocyanide, 313 Trityl perchlorate, 339... 

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... 

---