Nitriles oxazole synthesis

Oxazole synthesis from benzoin and nitriles or ammonium formate. 

More recently, Williams has described the one pot synthesis of 2-substituted oxazoles 11 by the thermolysis of triazole amides 9 the reaction does not proceed photo-chemically.<92TL1033> Although the reaction does not involve addition to a nitrile, it is an interesting application of a diazo compound since the proposed zwitterionic intermediate 10 is a resonance form of a diazo imine, so formally the reaction may be thought of as a thermal decomposition of a diazo imine (Scheme 6). 

Whatever the exact mechanism, the rhodium(II) catalysed reaction of diazocarbonyl compounds with nitriles is a useful route to oxazoles. A further example from our own laboratory illustrates the use of the reaction in the synthesis of the oxazolylindole alkaloids pimprinine 43a, pimprinethine 43b, and WS-30581A 43c. Diazoacetylindole 42 reacted with simple nitriles in the presence of rhodium(ll) trifluoroacetamide to give the corresponding oxazoles, deprotection of which gave the natural products 43 (Scheme 24).<94S1021>... 

The order of events In this synthesis can be varied - one possibility is to keep the nitrile until after the oxazole has been made. The acid chloride is used for the cyclisation. 

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used l-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1-(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. 

The method described for the preparation of 4-methoxycarbonyl-2-methyl-1,3-oxazole is that of Cornforth, and is widely applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates. The appropriate imidate hydrochloride required for step A is obtained from the reaction of a nitrile with an alcohol in the presence of hydrochloric add (eq. 1 ). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-catalyzed heterocycloaddition of a diazomalonate to a nitrile has been described in Organic Syntheses by Helquist, but appears to be less general than the present route. 

Oxazoles of various substitution patterns are well known heterocycles for which a number of methods of synthesis have been reported.129 Acyl carbenes or functionally equivalent species have been found to undergo cyclization with nitriles to give oxazoles in high yield via nitrile ylide intermediates.130,131 This reaction can be induced to occur under thermal, photolytic, or catalytic conditions.129,132,133 Huisgen and coworkers were the first to study this process in some detail.132 Thermolysis (or copper catalysis) of a mixture of ethyl diazoacetate and benzonitrile resulted in the formation of oxazole 254. The isolation of this product is... 

Several specialized cyclization strategies should not be dismissed. A novel rhodium acetate-mediated cyclization was employed for the first synthesis of 3-methyl-4,6-diphenylfuro[3,4-tf]is-oxazole (9) from the 5-(a-diazobenzyl)isoxazole (185) (Equation (56)). The reactive intermediate is believed to be a carbenoid species <9iCB248i>. Another strategy exploits the reactivity of 4-halo-pyrazol-5-ones (e.g., 186) with stabilized anions (e.g., cyanoacetate esters and nitriles) to afford the 4-cyanofuro[2,3-c]pyrazol-5-ones (187) and 5-aminofuro[2,3-c]pyrazoles (188) (Scheme 30) <84H(22)2523>. Also of interest is the trichloroacetonitrile cyclization of aminopyrazole ketones (189) to the pyrrolo[2,3-c]pyrazoles (190) (Equation (57)) <86S74>. The generality of this cyclization is not known. 

Thermal dehydration of o- (acylamino)phenols is the method of choice for the preparation of benzoxazoles (equation 96) and other annulated oxazoles. 0,iV-Diacyl derivatives of o-aminophenols cyclize at lower temperatures than do the monoacyl compounds. The synthesis is often carried out by heating the aminophenol with the carboxylic acid or a derivative, such as the acid chloride, anhydride, an ester, amide or nitrile. The Beckmann rearrangement of oximes of o-hydroxybenzophenones leads directly to benzoxazoles (equation 97). 

Another synthesis based on the combination of these fragments is the 1,3-dipolar cycloaddition of carbonyl compounds to nitrile ylides. The latter are generated by photolysis of 1-azirines when the irradiation is carried out in the presence of an acyl chloride and triethylamine, oxazoles are formed in moderate yields (equation 121). 

Cyclocondensation of the nitrile 62 with the (/ )-2-methylcysteine building block 5b provides the thiazoline ester 63. After conversion of the ester to the nitrile 64, cyclocondensation with 5b leads to the bis(thiazoline) 65. The subsequent conversion of the ester to the nitrile function (65 66) nearly failed, with 10 % yield. In the last synthetic sequence the bis(thiazo-line) compound 66 is coupled with the oxazole compound 61 to provide the third and last thiazoline ring. Formation of the methylamide is the final step of the thiangazole synthesis of Patten-den. 

Diels-Alder reactions of oxazoles have proven to be quite versatile and continue to attract attention. Oxazoles have traditionally been used as the diene component and react with alkyne dienophiles to give furan products after extrusion of a nitrile molecule via a reverse-cycloaddition process. This method has been used to access highly substituted furans and has been utilized in numerous natural product syntheses. The reaction typically requires the use of high temperatures for efficient conversion. The furan intermediate 67 was obtained by a thermal intermole-cular Diels-Alder reaction between oxazole 66 and an acetylene. Furan 67 was a key intermediate for the synthesis of (—)-teubrevin G (Scheme 10) <2000JA9324>. Similarly, furan 68, obtained from a Diels-Alder reaction between 4-phenyloxazole and an acetylene, served as an intermediate in the total synthesis of the natural product cornexistin (Scheme 10) <20030L89>. 

Kawano Y, Togo H (2009) lodoarene-catalyzed one-pot preparation of 2,4,5-trisubstituted oxazoles from alkyl aryl ketones with mCPBA in nitriles. Tetrahedron 65 6251-6256 Jarikote DV, Siddiqui SA, Rajagopal R, Daniel T, Lahoti RJ, Srinivasan KV (2003) Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Lett 44 1835-1838... 

There has been continued interest in the synthesis of oxazoles from a-diazo carbonyl compounds and nitriles catalyzed by Lewis acids. The BFa-catalyzed reaction of a-diazoacetophenones or methyl p-nitrophenyldiazoacetate with chloroacetonitrile affords 5-aryl-2-chloromethyloxazoles or 2-chloromethyl-5-methoxy-4-(p-nitrophenyl)oxazole, respectively (Equation (19)) <89BCJ618>. The former products react with primary, secondary, and tertiary amines by nucleophilic displacement of the chloride group. Methyl or ethyl isocyanate may be used as the nitrile component to prepare... 

Nagayoshi K. and Sato T. (1983) One-step synthesis of oxazoles from ketones and nitriles using copper(II) trifluoromethanesulfonate as a key reagent Chem Lett. 1355-1356. 

In a related synthesis, acetylenic carbinols (63) have been claimed to condense directly with nitriles in the presence of concentrated sulfuric acid to give substituted oxazoles.133 Intermediates of the type represented by 64 have in fact been prepared independently as their hydrochlorides and are known to give oxazoles on treatment with sulfuric acid.140... 

The starting nitrile may be alkyl, aryl, or even hydrogen cyanide, which leads to the synthesis of oxazole itself180 by hydrolysis and decarboxylation of the oxazole-4-carboxylate (89, R = H). Various exten-... 

The [4+2] cycloaddition is of increasing utility for pyridine synthesis [69]. The pyridine nitrogen is introduced either via the diene component [1- or 2-azadienes, oxazoles (cf. p 131)] or via the dienophile (activated imine or nitrile). 

The synthesis of oxazoles via thermolysis or photolysis of /8-azido or 8,/8-diazido ketones, esters, or nitriles, which can be considered as enaminone derivatives, is well known and has been reviewed in detail (75AGE775). A recent example is the reaction of methyl 3,3-diazido-2-cyanoacrylate 266 with amines to give enaminones 267, which undergo thermolysis or photolysis to give, probably via azirine intermediates, the oxazoles 268 in good yields. Scheme 72 (90CB115). 

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