Isocyanides 5- 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. 

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. 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

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>. 

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

Bossio R, Marcaccini S, Pepino R (1991) Synthesis of isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann Chem 1107-1108... 

For arylsulfonyl methyl isocyanides (3), [3 + 2] cycloadditions with aldehydes yielding 4,5-disubstituted oxazoles (N) have been reported [115]. The cycloaddition takes place in the same manner as with the use of isocyano esters (A, = H) ... 

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>. 

C==0, C=N, C=S, C=C, and N=N containing substrates. Thus oxazoles imidazoles, thiazoles, pyrroles, and 1,2,4-triazoles have been prepared, respectively. Furthermore, jj-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones into cyanides and in a two-step synthesis of a-hydroxyaldehydes from ketones. ... 

Reaction with lactones.1 Under controlled conditions and in DMF as solvent lilhiomethyl isocyanide reacts with lactones to form alcoholic oxazoles (equation I). 

The use of an a-isocyanoacetamide instead of an a-isocyanoacetate is essential in order to obtain oxazoles when the latter compounds are employed, other condensations (Knoevenagel, Mannich), affording imidazolines or amidines, will take place [88]. This reaction has been explored for the preparation of a series of 2-imidazolines employing isocyanoacetates [91]. The reaction worked smoothly to give compounds 105a,b (Scheme 1.36) with the trans isomer prevailing, provided that a racemic isocyanide with an acidic a-proton and a sterically undemanding amine are used. 

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). 

The reactivity of halogen atoms in position 2 of oxazoles is considerably enhanced by quaternization. This is best illustrated by the synthetic utility of the salt (141) which, like other Ar-alkyl-2-halogeno-azolium and -azinium salts, effects a number of condensation reactions but it far surpasses these other salts in activity (79AG(E)707). Thus it activates carboxylic acids and it dehydrates formamides to isocyanides (Scheme 6). Amides are similarly converted into cyanides, ketones (RCH2COAr) into alkynes (RC=CAr), and cyanohydrins (RCH(OH)CN) are transformed into the corresponding chloro compounds <79CL1117>. 

Oxazoles with a free 2-position are metallated thereat by n-butyllithium, while 2,4,5-trimethyloxazole forms the anion (142) (81JOC1410). In the presence of a carboxyl or methoxycarbonyl group at C(4) the metallation is directed to the 5-position, even in the absence of a 2-substituent, to give, for example, the lithio compounds (143) and (144) (81TL3163). 2-Lithiooxazoles can equilibrate with open-chain isocyanides and the diphenyl compound has been trapped as a mixture of cis- and /rans-trimethylsilyl ethers (equation 9). 

The tosyl compound reacts with aldehydes in the presence of potassium carbonate to yield 5-alkyl- or 5-aryl-oxazoles, the intermediate dihydrooxazoles (which can be isolated) eliminating toluene-p-sulfinic acid (Scheme 30). Use of acyl chlorides in place of aldehydes leads to 4-tosyloxazoles (288). Furthermore, alkylation of tosylmethyl isocyanide with an alkyl halide RfX, followed by treatment with an aldehyde R2CHO, yields a 4,5-disubstituted oxazole (289). A related reaction is that of A-tosylmethyl-iV -tritylcarbodiimide with aromatic aldehydes under phase-transfer catalysis to yield 2-tritylaminooxazoles which are readily converted into 2-amino-5-aryloxazoles (equation 117) (81JOC2069). 

When jV-protected indole-3-carboxaldehydes were allowed to react with tosylmethyl isocyanide, 3-(oxazol-5-yl)-indoles were obtained in satisfactory yields and applied to the synthesis of novel indole-based IMPDH inhibitors <02BMCL3305>. In the same context, a modified approach to 2-(JV-aryl)oxazoles employing an iminophosphorane/ isothiocyanate-mediated methodology and its application to the synthesis of the potent IMPDH inhibitor BMS-337197, was reported <020L2091>. 

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>. 

A whole set of related powerful isocyanide-based MCRs has been developed by Zhu s research group. By varying the structures of the starting materials and slightly changing the reaction conditions, the group was able to produce different hetereocyclic scaffolds selectively. For example, heating a methanolic mixture of an aldehyde, an amine and an isocyanoacetamide 9-80 allowed the clean formation of 5-amino-oxazoles 9-82 (Scheme 9.16) [56]. It can be assumed that, in the formation of the products 9-82, the imines 9-79 as well as the adducts 9-81 act as intermediates. 

Keywords Isocyanide Macrocycle Macrocyclization Macrocylopeptide Multicomponent reaction Multicomponent reaction Oxazole Passerin-3CR Staudinger reaction Ugi 4CR... 

Recently, our group also contributed to CBD as a tool for DOS. By judicious selection of the reaction conditions, the 3CR between ot-acidic isocyanides 145 (isocyano amides and isocyano esters " ), carbonyl components 6 and primary amines 146 could be directed towards either 2//-2-imidazolines 150 or trisubsti-tuted oxazoles 152 (Scheme 13) [98]. 

Scheme 13 Directing the MCR of a-acidic isocyanides, carbonyl components and primary amines towards 2//-2-imidazolines 150 and trisubstituted oxazoles 152 and their proposed mechanisms...

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]. 

A polymer-supported TosMIC reagent 196 has been developed in which the isocyanide is attached to a ringopening metathesis polymer (ROMP gel) (Scheme 57). The use of this reagent significantly simplified the purification of the oxazole products <20010L271>. 

Chiral isocyanides such as 198 have also been used for the synthesis of chiral 4,5-disubstituted oxazoles such as 199, which are potentially useful in fluorescence-detected circular dichroism for on-column capillary electrophoresis (Equation 12) <1996JOC8750>. 

Tosylmethyl isocyanide (TsMIC) (120) is an easily prepared sulfone with a wide repertoire of useful reactions thus, TsMIC may be converted to ketones (121), alkanes (122) and alicyclic ketones (123) and (124), as shown in Scheme 52. The alicyclic compounds formed may be either small rings, e.g. cyclobutanone (123), or medium-sized rings like the 10-membered compound (124). In these reactions, the utility of TsMIC (120) is dependent on the good leaving group capacities of the tosyl and isonitrile moieties. The reagent (120) can also be used to synthesise heterocycles, e.g. oxazoles (125) (Scheme 53). 

OXAZOLES Copper(I) oxide. Lithio-methyl isocyanide. 

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