2.4- dimethyl substituted oxazoles

Mechanistically, the authors studied these reactions using H NMR, since the intermediates were unstable and difficult to isolate. They concluded that ring-opened products (e.g., 600 and 601) predominated for 2-aryloxazoles. 3-OxazoUnes 602 were the predominant product versus 2-oxazolines 603 for a 4-phenyl- or 2,4-dimethyl-substituted oxazole. Selected examples of oxazoUnes and ring-opened amides are shown in Table 1.43. 

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. ... 

Substituted oxazoles heated with DMAD in toluene in the presence of hydroquinone gave474 the furans 12 in up to 90% yield. Dimethyl acetylenedicarboxylate reacts similarly with other oxazoles,476 whereas MP gives mixtures of the possible isomeric furans.476 Addition of DMAD to the oxazole 13 in boiling ether gave 14 with retention of the nitrile fragment.474... 

Various preparation methods have been described. Wiley (1945, 1947) converted a-amino acids to acetdmido ketones by reaction with acetic anhydride in pyridine and obtained 2,5-dimethyl-4-substituted oxazoles after dehydration of the enol form of the intermediate. Theilig (1953) applied the reaction of a-bromoketones with the appropriate amides. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

A study of the influence of the proton donor hydroquinone on the polarographic reduction of a series of phenyl- and naphthyl-substituted oxazoles in dimethyl formamide suggest that they are reduced at high proton donor to compound ratios.2 5 The polarographic behavior of 2,5-diphenyloxazole hydrobromide in DMF has also been studied.2 6... 

Fig. 2. Plots of pXa values for 4-methyl-(A) and 2,4-dimethyl-5-substituted oxazoles (B) against the Hammett (meta)-a constants. [Reproduced with permission from D. J. Brown and P. B. Ghosh, J. Chem. Soc. B, 270 (1969).]...

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

Nucleophilic substitution reactions can be carried out on poly(methyl methacrylate) with heterocyclic organolithium reagents. " The reactions are conducted in homogeneous solutions in tetrahydrofuran or in benzene combined with hexamethylphosphoramide. Copolymers will form with tautomeric keto-j5-heterocyclic structures. The following heterocyclic reagents are useful 2-picolinyllithium, [(4,4-dimethyl-2-oxazole-2-yl)methyl]lithium, quinaldinyllithium, and [2-thiazole-2-yl-methyl]lithium. 

Interestingly, deprotonation of the 3-oxo-pyrrolo[l,2-f]oxazole 277 with r-BuLi at —78°C took place at the C-5 position. Addition of an electrophile provided the substituted products 278 in good yields. Stannyl and silyl chlorides, dimethyl sulfate, ketones, and benzaldehyde were successfully used as electrophiles. A significant feature of this lithiation-substitution reaction is the generally high Ar-diastereoselectivity only single diastereomers of products were isolated (Scheme 41) <2001JA315>. 

Lewis acid SnCLj-assisted reaction between the l,3-thiazole-5-thione 434 and /ra r-2,3-dimethyloxirane led to the m 4,5-dimethyl-l,3-oxathiolane 435 The same Lewis acid enabled a second addition of /ra/ -2,3-dimcthyloxirane onto the C—N bond of the 1,3-thiazole ting of 434, leading to the formation of the tetrahydro-2//-thiazolo[2,3- ]-oxazole adduct 436 (Equation 200) <2000HCA3163>. Condensation of 2,4-dinitroimidazole, 8-bromotheophylline, and 8-bromoadenine with substituted methyloxiranes involved sequential A -alkylation-r/wo-substitution and furnished a series of 2,3-dihydro-imidazo[2,l- ]oxazole derivatives 437, 438, and 439 (Equations 201-203) <2000CCC1126, 2000EJ03489, 2005TL3561, 2004JHC51>. 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

Substituted binaphthyl compounds can be synthesized in high optical yields using nucleophilic aromatic substitution reactions in which the chiral leaving groups are alkoxy moieties derived from naturally occurring alcohols28-29. For example, the condensation of 2-(l-alkoxynaphth-2-yl)-4.5-dihydro-4,4-dimethyl-l,3-oxazole with 1-naphthyllithium or 2-methoxy-l-naphthyl 2-magnesium bromide leads to (ft)- or (.S)-(l,T-binaphthyl-2-yl)-4,5-dihydro-4,4-dimethyl-l,3-oxazole derivatives. 

Dimethyl diazomalonate undergoes reaction with nitriles in the presence of rhodium(II) acetate to give 2-substituted-4-carbomethoxy-l,3-oxazoles (255). The reaction proceeds with a wide range of nitriles,133-139 although cyclopropanation is a competing process in the case of unsaturated nitriles.129... 

Dilithiated amides, derived from JV-phenyl- or /V-methylacetamide and n-BuLi, react with 3-cyanopyridine, 3-(l,3-oxazol-2-in-2-yl)pyridine, or 3-(4,4-dimethyl-l,3-oxazol-2-in-2-yl)pyridine to give mainly 6-substituted dihydropyridines, which can be aromatized (KMnO4, acetone) to 3,6-disub-stituted pyridines (85H57). 

The photoisomerizations of this type appear to be quite general, but the yield of the oxazoles varies considerably. Thus ultraviolet irradiation of 3,5-dimethylisoxazoIe in methanol gives an 80% yield of 2,5-dimethyl-oxazole.176 1,2-Benzisoxazoles (112) similarly rearrange to benzoxazoles together with some substituted o-hydroxybenzonitriles as by-products.176... 

As in the case of oxazoles, the pyridine-like N-atom makes electrophilic substitution reactions more difficult. Thus thiazole does not react with halogens. Donor substituents enhance the reactivity, e.g. 2-methylthiazole reacts with bromine to give 5-bromo-2-methylthiazole. Thiazole cannot be nitrated. 4-Methylthiazole reacts slowly to yield the 5-nitro compound, 5-methylthiazole even more slowly to give the 4-nitro compound, but 2,4-dimethylthiazole reacts fastest producing 2,4-dimethyl-5-nitrothiazole. Sulfonation of thiazole demands the action of oleum at 250°C in the presence of mercury(II) acetate, and occurs at the 5-position. Acetoxymercuration of thiazole with mercury(II) acetate in acetic acid/water proceeds stepwise by way of the 5-acetoxymercury compound and the 4,5-disubstituted product to 2,4,5-tris(acetoxymercury)thiazole. 

TABLE 1.78. 2-ACYL-1-METHYI 5-SUBSTITUTED PYRROLE-3.4-DICARBOXYLIC ACID DIMETHYL ESTERS FROM 2,5-DISUBSTITUTED OXAZOLES, METHYLTRIFLATE,... 

---