Isocyanides 5-substituted oxazoles

The van Leusen reaction forms 5-substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (1, TosMIC) with aldehydes in protic solvents at refluxing temperatures. Thus 5-phenyloxazole (2) is prepared in 91% yield by reacting equimolar quantities of TosMIC and benzaldehyde with potassium carbonate in refluxing methanol for 2 hrs. ... 

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. 

Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures. 

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

The reaction of aryl aldehydes with benzotriazol-l-ylmethyl isocyanide (154), obtained in two steps from benzotriazole, formaldehyde and formamide, gives 5-aryl-substituted oxazoles in 35-69% yields (Scheme 71) <89TL6657>. 

Recently, Addie and Taylor extended the synthetic utility of TosMIC by developing conditions to effect desulfonylation of a 5-substituted 4-tosyloxazole 405 (Scheme 1.109, p. 90). Their plan was to generate the dianion of 5-methyl-4-tosyloxazole 402 followed by quenching with an electrophile to produce a 5-substituted-4-tosyloxazole 404. Desulfonylation of 404 would provide a novel entry to 5-substituted oxazoles 405, thereby avoiding the use of toxic methyl isocyanide. In addition, desulfonylation of the 5-substituted 4-tosyloxazoles 406 normally obtained from reaction of TosMIC with an ester, acid chloride, or acid anhydride would further broaden the scope and use of this reaction. 

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. 

KuLkarni and Ganesen " have also demonstrated the synthesis of oxazoles by adapting the procedure reported by Leusen and coworkers.A solid-phase version of /i-tolylsulfo-nylmethyl isocyanide (TosMlC) 60 was prepared from TentaGel-SH (Scheme 12.15). Condensation of the 60 with TBAOH in DME produced aromatic-substituted oxazoles 61 in 25-50% yield. ... 

Among the oxazole syntheses not simply deducible from classical retrosynthesis approaches applying isocyanides as starting materials are of considerable interest [263]. (a) In the van Leusm synthesis, TosMIC reacts with aldehydes under base catalysis (e.g., K2CO3) to give 5-substituted oxazoles 41 ... 

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>. 

Isocyanides are useful reagents for the preparation of oxazoles unsubstituted at C-2. For example, TosMIC was used to generate the oxazole ring in a synthesis of phthoxazolin A 37 <990L1137>. However in the reaction of IV-tosyl aldimines with the isocyanide 38 the oxazoles that were isolated were 2 1 adducts 39 that had been further substituted at C-2 <98T12445>. 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

T10425>. Through a proper use of the Suzuki-Miyamura and van Leusen oxazole synthesis it was possible to synthesize a wide variety of aromatic derivatives substituted with oxazole rings. The strategy was based on the initial synthesis of the aromatic scaffold and the subsequent reaction of the carbonyl functions with toluenesulfonylmethyl isocyanide (TosMIC) as depicted in the following scheme<07S3653>. 

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]. 

Wenkert and co-workers prepared a series of 5-alkenyl-substituted oxazolium salts and investigated their intramolecular Diels-Alder reactions as a means to construct alkaloids (Scheme 1.427). The starting oxazoles 1662a-c, 1663, and 1664 were prepared from an acyclic methyl ester and lithiomethyl isocyanide. Methylation of 1662a-c, 1663, and 1664 with methyl trillate then afforded the corresponding iV-methyloxazolium salt quantitatively. The oxazolium salts 1665, 1666, and 1667 were stable for up to 3 h at 90°C. 

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). 

Isocyanides are very usefiil tools in the synthesis of N-heterocycles such as indoles, imidazoles, tetrazoles, and oxazoles. To form 2,3-disubstituted indoles such as 3-substituted 2-iodo indoles 1518, o-isocyano cinnamates 1517 are important intermediates. They are prepared in high yield (87% for 1517) by dehydration of o-(N-formylarnino)cinnamate 1516 with phosgene [1153, 1166]. 

Formatiort of Isonitriles. The reaction of butyllithium with oxazole leads to the formation of a metallated species that is in equihbrium with a ring opened isocyanide obtained through a-elimination. The a-isocyanoenolate dominates the equilibrium, and it was found that, by warming this species from —78 °C to room temperature in the presence of an acid chloride, the isolation of 2-substituted isocyanoesters is possible in good to excellent yields (eq 13). These compounds were prepared on multi-gram scale and applied in Ugi reactions. Unlike most isonitriles, they do not exhibit a foul odor. 

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