Oxazole substitution

It is of interest to note that these were not the first benzoates substituted in the ortho position with a heterocyclic ring to show effects in plants. Invariably, however, in these earlier cases the heterocyclic ring was an aromatic one such as a pyrazole or oxazole substituted with a phenyl group ( -4). 

An oxazole substituted with a complex aminohydantoin side chain is described as a muscle relaxant. Imine formation between glyoxylic acid and aminohydantoin (38-1) results in the imino acid (38-2). Use of that intermediate to acylate the amine on 4-chloro-2 -aminoacetophenone (38-3) leads to the amide (38-4), which now includes a 1,4-dicarbonyl array. Treatment of the keto-amide with phosphorus... 

Oxazoles react with amines to form imidazoles. As more examples have been documented, the critical role that the oxazole substitution pattern plays in the reaction outcome has become apparent. For example, 5-acetyl-2-aminooxazole reacts with amines to give imidazoles as the predominant products <84TL2957>. With the addition of a 4-methyl group, as in 5-acyl-4-methyloxazoles or 5-acetyl-2,4-dimethyloxazole, pyrimidines are formed instead <60CB1998,85IJC(B)535>. The reaction of... 

Oxazoles substituted with a cyano group in the 2-, 4-, and 5-positions are known many of these can be reduced to aldehydes by the Stephen method2 and hydrolyzed by alkali to the related amides and carboxylic acids. 2-Phenyl-5-aminooxazole-4-carbonitrile on treatment with concentrated sulfuric acid forms the crystalline amide (240) further hydrolysis, however, is unsuccessful. The corresponding 4-carboxylic esters are also stable to hydrolysis.389... 

Azides have been used by a number of groups as precursors to oxazoles, and several examples that illustrate the diversity of available oxazole substitution patterns are described. 

There are a variety of other methods available for preparing substituted oxazoles. Some arbitrarily selected examples are discussed in this section. In some cases, these methods are specific for a particular substitution pattern, while others are more general in nature. As before, no attempt has been made to include all possible methods or oxazole-substitution patterns. 

In contrast, bromination of oxazoles with bromine in methanol in the presence of K2CO3 gave rise to nonaromatic addition products as well as ring-opened amides. Hassner and Fischer " conducted a thorough and systematic study of these reaction conditions and found that 4,5- and 2,5-addition products could be isolated. The product distribution depended highly on the nature and pattern of oxazole substitution and the reaction temperature, as shown by the following examples. 

Irradiation of a methanolic solution of an oxazole at —78°C in the presence of O2 and rose bengal produced a 2,5-disubstituted 5-hydroperoxy-4-methoxy-4,5-dihydrooxazole 709 (Scheme 1.197). Here again, the oxazole substitution pattern determined the product distribution. For example, 4,5-diphenyl-2-methyloxazole 231a produced only N, iV-dibenzoyl acetamide 706 (Ri = CH3, R2 = R3 = CeHs). On the other hand, 4-methyl-2-phenyloxazole 701a gave 709 (Ri = CgHs, R2 = CH3, R3 = H), which decomposed on warming to room temperature to yield... 

Synthetic strategies for almost any oxazole-substitution pattern are available from classical methods or have been developed as new methodologies. Oxazoles... 

The first report of a Sonogashira coupling reaction of an oxazole was by Yamanaka in 1987. Oxazoles substituted with bromine at the 4- or 5-positions were coupled with phenylacetylene yielded the alkyne in 83% and 89% yield, respectively. The Sonogashira reaction with 2-halooxazoles was not attempted however, 2-halothiazoles and 2-halo-A -methylimidazoles were subjected to Sonogashira conditions. Yields in both cases were low and not synthetically useful. 

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). 

For isoxazoles the first step is the fission of the weak N—O bond to give the diradical (51) which is in equilibrium with the vinylnitrene (52). Recyclization now gives the substituted 2//-azirine (53) which via the carbonyl-stabilized nitrile ylide (54) can give the oxazole (55). In some cases the 2H-azirine, which is formed both photochemically and thermally, has been isolated in other cases it is transformed quickly into the oxazole (79AHC(2.5)U7). 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Nitration of monocyclic compounds is summarized in Table 4. Substitution occurs in the expected positions. The reaction conditions required are more vigorous than those needed for benzene, but less than those for pyridine. Ring nitration of oxazoles is rare, but (114) has been obtained in this way (74AHC(17)99). 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

Formation of ring-fused systems by this procedure is not as common. If the vicinally substituted hydroxyamino derivative is available, then Pb(OAc)4 treatment will lead to a ring-fused oxazole as in the conversion of (272) into (273) (71JCS(C)1482). In a different approach the CH=N— functional group is generated in situ. The 2-(l-pyrrolidinyl)ethanol... 

Oxazole, 2-dimethylamino-4-phenyl-nitration, 6, 190 Oxazole, 2,5-diphenyl-irradiation, 6, 189 nitration, 6, 190 oxidation, 6, 187 reduction, 6, 194 synthesis, 6, 222 Oxazole, 4,5-diphenyl-mercuration, 6, 190 2-substituted... 

Thieno[3,4-d]oxazole-3a(4H)-carboxylic acid, dihydro-2-methyl-synthesis, 6, 1020 Thieno[2,3-d Joxazoles synthesis, 6, 990 Thieno[3,2-g]pteridine structure, 3, 284 lH-Thieno[3,4-c]pyran-2-ones synthesis, 4, 1032 Thienopyrazines synthesis, 4, 1022-1024 Thieno[2,3-6]pyrazines, 4, 1023 electrophilic substitution, 4, 1024 Thieno[3,4-6]pyrazines, 4, 1024 Thieno[3,4-c]pyrazole, 4,6-dihydro-3-hydroxy-carbamates... 

The aldehyde functionality present in 3-phenyl-2H-azirine-2-carbox-aldehyde reacts selectively with amines and with Qrignard and Wittig reagents to give a variety of substituted azirines. These azirines have been used, in turn, to prepare a wide assortment of heterocyclic rings such as oxazoles, imidazoles, pyrazoles, pyrroles, and benzazepins. ... 

The Cornforth rearrangement involves the thermal interconversion of 4-carbonyl substituted oxazoles, with exchange between the C-C-O side-chain and the C-C-O fragment of the oxazole ring. These reactions generally involve compounds where a heteroatom (-OR, -SR, -Cl) is attached to the 5-position (R2) of the starting oxazole. 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Wipf and Miller have reported side-chain oxidation of 3-hydroxy amides with the Dess-Martin periodinane, followed by immediate cyclodehydration with triphenylphosphine-iodine, which provides a versatile extension of the Robinson-Gabriel method to substituted oxazoles. Application of this method was used to prepare the oxazole fragment 10 in 55% overall yield from 3-hydroxy amide 8. 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

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. 

Thus attack of the TosMlC anion 9 on a carbonyl carbon is followed (or accompanied) by ring closure of the carbonyl oxygen to the electrophilic isocyano carbon to form an oxazoline (12). Loss of p-tolylsulfinic acid provides the 5-substituted oxazole 13. ... 

Workers at SmithKline Beecham extended the synthetic access to interesting mono- and di-substituted oxazoles through an improved procedure for aryl-substituted... 

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