Schollkopfs isocyanides

The synthesis of tetrazolopiperazines 191 was achieved by Bienayme et al. via Ugi reaction of primary amines 192, aldehydes 193, hydrazoic acid 194, and Schollkopf isocyanide 195 [57]. This transformation was used to prepare large arrays of drug-like molecules (Scheme 34). Overall yields for this highly efficient process were fair to good. 

Taking advantage of the multifunctionalities and ready accessibility of methyl (2)-3-(dimethylamino)-2-isocyanoacrylate (Schollkopfs isocyanide) (53), Bienayme and Bouzid developed a four-component synthesis of bicyclic tetrazole 54 (Scheme 5.16) [34]. Simply stirring a methanolic solution of an aldehyde, an amine, 53, and TMSN3 afforded 54 in good to excellent yield. Trapping the nitrilium 55 by azide afforded the intermediate 56, which was subsequently cyclized to furnish the tetrazole 57. A sequence of intramolecular Michael addition followed by (3-elimina-tion of dimethylamine then provided the final product 54. The intermediate tetrazole 57 could be isolated and was found to cyclize to the bicyclic tetrazole 11 in essentially quantitative yield under the reaction conditions. 

In 1979, Schollkopf et al. " formed a-isocyano- 3-dimethylamino-acryl methyl esters 86, and Bienayme prepared many similar isocyanides,which can undergo a variety of heterocycles, forming reactions like the synthesis of 88 from 84-87 (Scheme 1.20). 

SchOllkopf et al. reacted lithiated isocyanides with epoxides to obtain 3-hydroxyalkyl isocyanides. The reaction was also performed with cyclohexene oxide, and the hydroxyisocyanate formed was cyclized to oxazines with copper(I) oxide, resulting in a diastereomeric mixture of 174 and 175 (76LA2105 86AG755). Irradiation of aliphatic dieneamides yielded a variety of dihydrooxazines of type 167 (88T1959). 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

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

Recently, we found that thioacids work in Ugi s MCR forming monothiobisamides.Together with Schollkopf s isocyanide, this resulted in a new thiazole synthesis. For that particular substitution pattern of thiazoles it seems to be the most versatile synthesis so far known [129], First experiments show that oxazoles and imidazoles are also accessible [128]. 

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,... 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Vedejs and Barda adapted Schollkopf s methodology " and prepared an indole-oxazole C-D-E model fragment, which was subsequently incorporated into a more advanced C-D-E-G-1 fragment. 4-Benzyloxyindole was converted to 1496 in four steps and excellent overall yield (Scheme 1.383, p. 337). Treatment of 1496 with lithiomethyl isocyanide produced a 2 1 mixture of the acylisocyanide (not shown) and 1497. Reaction of this mixture with PPTS cleanly provided the C-D-E model fragment, 1497. The triflate 1497a was then prepared in three straightforward steps. 

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. ... 

Besides the formation of oxazole derivatives, Schollkopf and the others have successfully extended the a-alkali metalated isocyanides to the formation of the chain-extended primary amines, 2-oxazolines, 2-thiazoline-4-carboxylic esters," 2-imidazolines, 2-pyrrolines and pyrroles, thiazoles, 2-imidazolin-5-ones," 2-imidazolinones," etc. For example, a simple reaction between lithiomethyl isocyanide with two equivalents of piperonal followed by acetylation of the intermediate with acetic anhydride affords the corresponding oxazoline. ... 

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

Unsaturated isocyanides, too, have been the focus of considerable attention. Vinyl isocyanides have been prepared either by Cu20-catalysed isomerisation of allylic analogues or by the Schollkopf method of reacting aldehydes with situ metallated methyl isocyanide followed by dehydration of the adducts.The... 

The Schollkopf oxazole synthesis, also known as the Schollkopf reaction, is the base-promoted condensation of an alkyl isocyanide (1) and an acylating agent (2) to produce an oxazole substituted at either (or both) the 4- or 5-position (3). 

Ulrich Schollkopf (1927-1998) and Rolf Schroder of the University of Gottingen first reported the preparation of 4,5-disubstituted oxazoles (3) from the condensation of a-metalated alkyl isocyanides and a range of acid chlorides, esters, and amides in 1971. 

Subsequent research has expanded the range isocyanides, bases, and acylating agents compatible with this transformation and has led to considerable use of the Schollkopf reaction in both the academic and industrial synthetic communities vide infra). 

In 1982, Hamada and Shioiri reported that carboxylic acids could be directly employed as acyl donors in the Schollkopf reaction via in situ activation (presumably via a mixed anhydride or azidocarbonyl species) using diphenyl phosphorazidate (DPPA). Thus reaction of a mixture of carboxylic acid, isocyanide, DPP A, and potassium carbonate in DMF afforded the anticipated oxazole product in good yield cf, 14 + 15 —> 16). Notably, this reaction was compatible with iV-protected a-amino acid starting materials and proceeded with minimal epimerization. Although diethyl phosphorocyanidate (DEPC) has found similar use in... 

Carbon disulfide and isothiocyanates have also proven suitable electrophiles for the preparation of thiazoles via the Schollkopf reaction. Isocyanides bearing electron-withdrawing a-substituents are insufficiently nucleophilic to react with nitriles to afford the eorresponding imidazoles, however iV-alkyl 4-tosylimidazoles are accessible through the sodium hydride-mediated condensation of toluenesulfonylmethyl isocyanide and imidoyl chlorides. Furthermore, the more electron-rich -tolylthiomethyl isocyanide reacts smoothly with carbodiimides and nitriles to afford the corresponding imidazoles. ... 

In related studies on the transformations of tosylmethyl isocyanide (24 TosMIC), van Leusen and co-workers found that the based-mediated condensation of 24 and a range of aldehydes yielded the corresponding 5-substituted oxazoles (c/, 28). This methodology thus provided an alternative to the Schollkopf reaction in the preparation of these compounds, and has subsequently become known as the van Leusen oxazole synthesis. 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

In a variation of the Wittig reaction, the a-metallized retinyl isocyanide (98) was reacted with retinaldehyde (2) to give P-carotene via an unstable oxazoline intermediate (Schollkopf, 1977). 

Based on the Schollkopf synthesis, a fiiUy automatized continuous-flow synthesis has been developed [264], in which EWG-substituted methyl isocyanides are reacted with... 

Notably, when arylmethylisocyanides are reacted with acid chlorides in the presence of 2,6-lutidine as a base, 2,5-disubstituted oxazoles are formed instead of the 4,5-disubstituted oxazoles obtained when using SchOllkopf conditions (nBuLi). This effect is believed to be due to primary acylation of the isocyanide functionality [265]. 

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