Isocyanides, addition onto

HX=H20, HiSe, H2S2O3, HN3, H2NCN, HOCN, HSCN, RCO2H, RCOSH, ROCO2H, etc.) form the ions 8 and 9, which subsequently undergo an a-addition onto the unique divalent carbon of the isocyanide 10 (Scheme 2). The a-substituted adduct 13 then rearranges into its final product.t 1 Since 1962 this reaction has been called the Ugi four-component reaction (U-4CR).P 1 The U-4CR can formally be considered as the union of the HO-3CR and the P-3CR. Both of these three-component reactions have in common that they use carbonyl compounds and acids as reactants. 

Chemical reactions are in principle equilibria between one or two educts and products. In practice, the preferred preparative reactions proceed irreversibly. Syntheses of products from three or more educts are usually sequences of preparative steps, where after each reaction step its intermediate or hnal product must be isolated and purihed while the yield decreases. Exceptions can be the reactions of three components on solid surfaces and also some MCRs with a-additions of intermediate cations and anions onto the isocyanides. 

In 1993 the first MCR composed of seven educts was introduced, and it was soon recognized that such higher MCRs are usually unions of the U-4CR and additional reactions. In the first 7-CR, the intermediate 63 was formed by an A-4CR and underwent with the equilibrating product 67 the a-addition of the cations and ions onto the isocyanide 27. Finally, this a-adduct, 69, rearranges into the final product, 71 (Scheme 1.17). 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

It is no wonder therefore that very few investigations were made on the reactivity of isocyanides. However, in 1910 Oliveri-Mandala and Alagna [40] discovered the formation of the N-substituted tetrazoles by the a-additions of hydrazoic acid onto the isocyanides and the subsequent rearrangements into their final products. 

The chemistry of even higher MCRs began when the concept of unions was fully realized [2], and when it was shown that higher unions of one-pot reactions can succeed if their last procedures are MCRs of type II. The first 7CRs were accomplished in 1993 [116, 117]. In Britain [118] and the USA [119], it was soon recognized that such MCRs were the start of a new era of MCR chemistry and their libraries. The first 7CR took place via the a-addition of 69b and 6b onto 13c, forming 70. This corresponds to the isocyanide 13c a-adduct 3h of 4a + 8 and the intermediate A-4CR product 68a of Id, 2a, 66b and 68 rearranges into 70, as its last event, just like an U-4CR (Scheme 4.32). 

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. ... 

Oxidative addition of the silicon-silicon bond of l,l,2,2-tetramethyl-l,2-disilacy-clopentane 2 onto bis(tert-butyl isocyanide)palladium(O) occurred instantaneously to give a six-membered cyclic bis(organosilyl)bis(tert-butyl isocyanide)palladium(II) complex 3a (Scheme... 

Some interesting multicomponent syntheses of simple furan derivatives in water have been disclosed. For instance, Yadav reported the preparation of highly functionalized 2-aminofuran derivatives 26 in water via the coupling of aldehydes with dimethyl acetylenedicaiboxylate and cyclohexyl isocyanide [20]. This transformation presumably starts by the initial Michael addition of the isocyanide onto the acetylenedicaiboxylate diester, generating the 1,3-dipole 27, whose subsequent [3+2] cycloaddition to the aldehyde carbonyl followed by tautomerization leads to the observed product (Scheme 1.14). 

In 2009, de Meijere s group reported on the formal cycloaddition of a-metallated methyl isocyanides onto the triple bond of electron-deficient acetylenes, giving oligosubstituted pyrroles. The reaction showed broad scope (24 examples, 25-97% yield). In addition, a related novel Cu(l)-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides was reported (11 examples, 5-88% yield) [99,100]. 

The first step of this method involves a Knoevenagel-type condensation of TosMIC to provide intermediate 36a [28], It is noteworthy that the conditions used helped (a) cope with the lower activity of the 17-oxo group of 35 and (b) avoid elimination of sulfinic acid. The second step involves the condensation of 36a with formaldehyde (9c) to form intermediate 38, which then undergoes an internal nucleophilic attack onto the isocyanide carbon to generate the oxazoline intmnediate 39. Addition of 10 equivalents of MeOH to the phase transfer catalyst directly generates oxazoline 41 via the elimination of tosyl sulfonic acid from 40. Acid-catalyzed hydrolysis provides the target compound 37 (Scheme 7.8). 

Scheme 1-152. Addition of jec-butyllithium onto a sterically hindered isocyanide followed by carboxylation and hydrolysis of the intermediate 209.

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