Tosylmethyl isocyanide , pyrrole

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. 

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... 

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. 

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). 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

The stabilised anion of tosylmethyl isocyanide (TosMIC) (or of benzotriazol-l-ylmethyl isocyanide -BetMlC ") adds in Michael fashion to unsaturated ketones and esters, with subsequent closure onto isocyanide carbon, generating the ring. Proton transfer, then elimination of toluenesulfinate generates a 3//-pyrrole that tautomerises to an aromatic pyrrole that is unsubstituted at both a-positions. Addition of the TosMIC anion to unsaturated nitro-compounds gives rise to 2,5-unsubstituted-3-nitropyrroles. ... 

Diaza-compounds. Phenacyl bromide reacts with 2-aminopyridine 1-oxide to yield 2-phenylimidazo[l,2-a]pyridin-3-ol (769) another derivative of this ring system, compound (771), is produced by the action of diphenylketen on the sulphilimide (770), dimethyl sulphide being eliminated.(6-Methyl-2-pyri-dyl)acetyl azide (772) forms the dihydroimidazo[3,4-a]pyridinone (773) on heating." Whereas l-methylpyrrole-2-aldehyde and other heterocyclic aldehydes react with tosylmethyl isocyanide to give oxazoles, e.g. (774), pyrrole-2-aldehyde affords the 6-azaindolizine (775). The action of potassium amide on the derivative (776) of 3-bromopyridine furnishes the pyrrolo[3,4-c]pyridine (777) by cyclization of an intermediate pyridyne." ... 

Anions of isocyanides, especially tosylmethyl isocyanide (TsMIC) and esters of isocyanoacetic acid, form pyrroles by addition to electrophilic alkenes and alkynes. For example, addition of TsMIC to acrylate esters in the presence of NaH is followed by cyclization at the isocyanide carbon leading to an intermediate which can aromatize by loss of sulfinate (Scheme 76) <80Mi 203-01 >. 

Tosylmethyl isocyanide (TosMIC) was employed in a key step for the synthesis of bicyclic heterocycles from L-glutamic acid <01H(55)2099>, while benzyl isocyanoacetate was utilized for reaction with a-acetoxynitro compound 41 to yield the pyrrole 42, an intermediate in the synthesis of (+)-deoxypyrro oline, a putative cross-link of bone collagen <01JOC11>. 

This reaction is similar to the Leusen Pyrrole Condensation, based on the reaction of tosylmethyl isocyanide and electron-deficient alkenes (a toluenesulfinate anion is eliminated). The most important advantage of this reaction is that of-free pyrroles can be obtained directly. 

Gribble and Pelkey adapted the Barton-Zard pyrrole synthesis [84] to 3-nitroindoles and ethyl isocyanoacetate (and tosylmethyl isocyanide) to give 2,4-dihydropyrrolo [3,4-T [indoles (Scheme 15, equation 1) [85, 86], In complementary work, Gribble and cowoikers synthesized pyrrolo[3,4-fc]indoles from the 1,3-dipolar cycloaddition of 2- and 3-nitroindoles with miinchnones (1,3-oxazo-lium-5 elates) (eqnations 2, 3) [87, 88]. The mesoionic miinchnones were generated in situ from the appropriate Af-benzyl-Af-acylamino acids. Gribble and Kishbaugh... 

The first report was made by Saikachi et al. [98] in 1979. They reacted dimethyl acetylenedicar-boxylate and methyl propiolate with /j-tosylmethyl isocyanide in the presence of DBU to give the corresponding pyrroles in low yields (7% and 12%, respectively). 

Alditol-l-yl substituted pyrroles or pyrazoles (e.g. 88 and 89) were obtained by addition to per-<7-acetylated 1,2-dideoxy-l-nitro-D- a/acm- and D-manno-l-hep-tenitols of the sodium salt of tosylmethyl isocyanide or the zwitterionic diaryl nitrile imines (e.g. PhC=N -N Ph), respectively. A general one-pot synthesis of alditol-l-yl substituted imidazoles (e.g. 90) involved reaction of aldoses with... 

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