Isocyanides a-metalated

Oxazoline and thiazoline derivatives metalated at the 2-position can also be prepared by the combination of acyclic precursors, namely by the reaction of a-metalated isocyanides with ketones or thioketones (Scheme 141) [76LA183 77AG(E)339 79PAC1347]. Although this route is normally used to produce 2-unsubstituted derivatives via protonation, there is presumably no reason why other electrophiles could not also be utilized instead. 

A new synthesis of 4-cyanothiazole derivatives via a-metallated isocyanides and thionoesters have been reported by Hartman and Wein-stock (Scheme 144) (812), with R2 = H, Me, n-CsH7, Ph, PhCHj. 4-Cyanothiazole (in 50% yield) was also formed by condensing thio-fonnamide with Q2C=C(NH2)CN (803). 

For a review on a-metallated isocyanides see U Schollkopf, Angew Chem Int Ed Engl, 16, 339 (1977)... 

As a result of this convenient method of synthesizing isocyanides, their chemistry has flourished vigorously in the past 30 years. Isocyanides are no longer an exotic class of compounds they are now routinely used as reagents by organic chemists. The preparative methods based on a-metallated isocyanides and the Ugi reactionare amongst the most important contributions of modem isocyanide chemistry to organic synthesis. 

Treatment of 1,2-di-t-butyldiaziridinone (458) with a-metallated isocyanides (459) at room temperature gives 5-substituted l,2-di-t-butyl-l,2-dihydro-6-hydroxy-l,2,4-triazines (460) (Equation (63)) <83S477>. 

In the Schollkopf synthesis, a-metalated isocyanides 13 (from isocyanides and /z-butyllithium) react with acid chlorides to give 4,5-disubstituted oxazoles 14 via C-acylation and electrophilic C-O bond formation. 

The 2,5 -isomer (67) has not been reported, but the 2 -phenyl and 2 -heteroaryl derivatives have been synthesized by multistep procedures (86KGS826). Neither the parent 4,4 isomer (68) nor simple substituted derivatives have been reported. However, both the 4,5 and 5,5 isomers, 69 and 70, have been synthesized via the Schollkopf procedure that involves the acylation of a-metallated isocyanides. Thus, as shown in Scheme 26,... 

Isocyanides react readily with organometallic reagents if the isocyanide possesses an a-hydrogen atom, then this will be abstracted to give an a-metalated isocyanide. If not, then a-addition to the isocyanide yields a metalloaldimine. Both reactions are valuable in synthetic studies. 

Six articles cover general aspects of heterocyclic chemistry 1,3-dipolar cycloreversions, syntheses with arylnitrenes and a-metallated isocyanides, and photo-oxygenation of nitrogen heterocycles,while others deal with more specialized subjects, i.e. preparation and use of halogeno-lactones, aspects of the chemistry of furan, 1-hydroxy-indoles, ring-opening of azoles by the action of amines, " the use of 2-chlorobenzoxazolium (1) and other heterocyclic onium salts for dehydration and condensation reactions," the synthesis of monosub-stituted tetrathiafulvalenes (2), cycloadditions of azoles containing three heteroatoms,sydnone imines (3), the conversion of acyl-benzofuroxans into nitro-indazoles (cf. p. 199), and advances in the chemistry of pyrrolizidine " and indolizine." ... 

Oxazoles.—Formation. ci)-Diazoacetophenone reacts with benzonitrile in the presence of trifluoromethanesulphonic acid to give 2,5-diphenyloxazole (514). Bi-, ter-, and quater-oxazoles have been synthesized from a-metallated isocyanides thus lithiobenzyl isocyanide (PhCHLiNC) and dimethyl oxazole-3,4-dicarboxylate afford compound (515). Stable methylene-oxazolines (516 R = Me or Ph) are obtained by heating the iminesHN=C(Ph)OCHRC=CH. The fluorinated oxazoline (518) results from the action of benzonitrile on the oxiran (517), and also from the reaction of bis(trifluoromethyl)carbene with the benzoylimine (CF3)2C=NCOPh/ Treatment of 2-acylamino-l-aryl-alkan-l-ols (519) under the conditions of the Pictet-Gams reaction, i.e. with phosphorus pentoxide in boiling toluene or xylene, results in cis- and trans-2-oxazolines (520), rather than isoquinolines, as claimed previously. The spiro-oxazolines (521 R = Me or Ph) are formed when the lithiated di-isocyanide CN—CH2CH2CHLi—NC is treated with acetone or benzophenone, respec-tively. ... 

This reaction was first reported by Schollkopf and Schroder in 1971 It is the formation of a 2-unsubstituted oxazole derivative by the condensation of an a-metalated isocyanide with an acylating reagent. Therefore, this reaction is known as the Schollkopf oxazole synthesis or Schollkopf reaction. ... 

Substituted glycines (171) have been prepared by Michael addition of Grignard reagents to 2-isocyanoacrylate esters (170), and the a-metallated isocyanide species (172) is found to react with simple Schiff s bases to give 2-imidazolines which on... 

Recent applications of a-metallated isocyanides in organic synthesis have been reviewed. ... 

U. Schollkopf, Recent Applications of a-Metalated Isocyanides in Organic Synthesis , Angew. Chem. Internat. Edn., 1977,16, 339. 

Choice of base can play a crucial role in the success of the Schdllkopf reaction, as the reactivity of a-metalated isocyanides varies as a function of the metal counterion. For example, although lithium ethyl isocyanoacetate (8) condenses readily with a wide range of acid chlorides, lithio-8 fails to react with less reactive ester electrophiles and affords only isocyanide dimerization products. Likewise, only a-metalated alkyl isocyanides lacking electron-withdrawing groups at the a-position are sufficiently nucleophilic to react with amide electrophiles in the Schdllkopf reaction. ... 

A full paper detailing the preparation and chemical properties of diphenylthiiren 1-oxide has appeared.The reactions of thiiren 1,1-dioxides with a-metallated isocyanides and lithium azide have been reported. The latter leads to a new heterocyclic system (69). Dimethyl- and diphenyl-thiiren 1,1-dioxides are reported to react with the 1,3-dipoles (70) and (71) to give (72) or (73) respectively. In the case of (71) and diphenylthiiren 1,1-dioxide, (74) is also formed. The Diels-Alder reaction with a diene-amine, but not the structure of the product, is mentioned in the same report. 

Larionov OV, de Meijere A (2005) Versatile direct synthesis of ohgosubstituted pyrroles by cycloaddition of a-metalated isocyanides to acetylenes. Angew Chem Int Ed 44 5664-5667... 

Miscellaneous.—A new pyridine synthesis has been reported that involves the addition of 2 moles of a nitrile (RCN) to a dianion, and then ring closure (Scheme 7)/ a-Metallated isocyanides also provide routes to nitrogen heterocycles, as shown in Scheme 8/ ... 

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