Oxazole-4-carboxylates, arylation

The synthesis of 86 commenced with oxazole carboxylic acid 87. Base-catalyzed lithiation and coupling with isatin 88 followed by methyl ester formation and Boc deprotection provided tertiary alcohol 89. A second coupling of the amine 89 with carboxylic acid 90 followed by chlorination afforded chloride 91. Treatment of 91 with TBAF gave a 1 1 mixture of O-aryl ether 92 (CIO) in excellent yield. Refluxing 92 in chloroform resulted in the formation of 93 (70%, with 30% of the isomer), which was subjected to a three-step reaction sequence to furnish intermediate 86 (Scheme 16). 

The effect of the halogen of the aryl halide was also carefully studied using bromobenzene and chlorobenzene as the electrophile. When the arylation was performed on ethyl 4-oxazole carboxylate using di-tert-butyl(methyl)phosphine as the Ugand and cesium carbonate as the base, the product of C5 arylation B was obtained when bromobenzene was used as the electrophile. Conversely, the product of C2 arylation A was formed if chlorobenzene was employed (eq 16). Similar results were obtained for the arylation of tert-butyl 4-thiazole carboxylate when mbidium carbonate was used as the base (eq 16). Again, it should be noted that the regioselectivity is highly dependent on the choice of the base and the phosphine. 

The coupling of various oxazoles with aryl iodides proceeds under Irgandless conditions, employing Pd(OAc)2 as the catalyst and Cul as the additive (eq 166). In case of the oxazole, it was necessary to use the aryl iodide as the limiting reagent to obtain synthetically useful yields (23 versus 74%). Moreover, two complementary C-2 C-5 arylations were developed for oxazoles. On the one hand, it was demonstrated that in nonpolar solvents, such as toluene, in the presence of a phosphine, such as RuPhos, selectivities >100 1 were obtained for arylation at the C-2 position (eq 167). On the other hand, polar solvents and hindered phosphines led to predominantly C-5 arylation (eq 167). It was hypothesized that, for the C-5 arylation, a CMD-type mechanism is operative, while a deprotonation pathway is the more likely explanation for the C-2 arylation. A general, paUadium-catalyzed, sequential arylation of ethyl oxazole-4-carboxylates at the C-2 and C-5 positions with a variety of aryl halides has also been reported. 

The effect of the halogen on the aryl halide was also investigated using bromo- and chlorobenzene as the electrophile. Using cesium carbonate as the base and tri-(cr(-butylphosphine as the ligand, the arylation of ethyl 4-oxazole carboxylate with bromobenzene proceeded mainly at the C5 position, affording product B (eq 21). However, when chlorobenzene was used, the C2 aryloxazole A was obtained as the major product. Similar results were obtained... 

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>. 

The condensation of furo[3,2- ]pyrrole-type aldehydes 8g and 265-267 with hippuric acid was carried out in dry acetic anhydride catalyzed by potassium acetate as is shown in Scheme 26. The product methyl and ethyl 2-[( )-(5-oxo-2-phenyl-l,3-oxazol-5(4//)-ylidene)methyl]furo[3,2- ]pyrrol-5-carboxylates 268a-d were obtained. The course of the reaction was compared with the reaction of 5-arylated furan-2-carbaldehydes with hippuric acid. It was found that the carbonyl group attached at G-2 of the fused system 8 is less reactive than the carbonyl group in 5-arylated furan-2-carbaldehydes in this reaction <2004MOL11>. The configuration of the carbon-carbon double bond was determined using two-dimensional (2-D) NMR spectroscopic measurements and confirmed the (E) configuration of the products. 

The oxazoles and their derivatives have played a variety of fascinating roles in the preparation of new molecular systems. Much of this chemistry stems from their ability to serve as diene components (azabutadiene equivalents) in reactions with a variety of dienophilic agents, to undergo nuclear metallation, to activate attached aryl or alkyl groups to deprotonation (thus functioning as masked aldehydes, ketones or carboxylic acid groups), and to serve as useful electrophiles on conversion to AT-alkylated salts. 

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). 

Bis(trifluoromethyl)oxazol-5(2//)-ones are carbonyl-group protected, carboxyl-group activated, a-oxoacid derivatives that undergo reaction with benzene-1,2-diamine to yield quinoxa-lin-2(1 7)-one or its 3-alkyl- or 3-aryl-substituted derivatives. ... 

Oxazoles can react at the C-4 position with aromatic aldehyde electrophiles under Friedel-Crafts conditions when the C-5 position is substituted with an alkoxy group. This feature has been exploited in a chiral Lewis acid-catalyzed formal [3-1-2] cycloaddition of aromatic aldehydes and 2-aryl-5-methoxyoxazoles 45 to generate enantiomerically enriched 2-oxazoline-4-carboxylates 46 (Scheme 4) <2001AGE1884>. These products can serve as masked /3-hydroxy a-amino acids, which are useful synthetic intermediates and have been found in peptide-based natural... 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

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-... 

Infrared absorption spectral data for several oxazole derivatives,86 90 including alkyl-98 186 and aryl-263 264 substituted oxazoles, 2-amino- and substituted-amino derivatives109 112 136, 5-amino179 198-201 and 5-alkoxy-oxazoles,66 carboxylic acids,112 147 esters,126 179 184 carboxamides,199 200 4-acetyloxazoles,147 halogenoalkyl oxazoles,91 oxazolines,262 and benzoxazoles262 have been reported. 

Oxazoles and 4,5-dihydrooxazoles can be transformed into quinolines. For instance, 5-(o-acylamino-aryl)oxazole-4-carboxylic esters 104, made from benzoxazinones 103 and isocyanoacetic ester, are converted into 3-aminO 4-hydroxy-2-quinolones 105 in an acid medium [109]. 

Heating aryl azides in a mixture of a carboxylic acid and polyphosphoric acid affords a useful, fairly general method of fusing an oxazole ring to aromatics and heterocycles.The method suffers from the limitation that bicyclic azides in which the azido substituent is a- to the ring junction give 0-diacetyl derivatives of the 1,4-aminohydroxy compound as, for example, the formation of 98 from a-naphthyl azide ... 

Pd(ll)-mediated direct arylation (with aryl halides) in the 2-position of oxazole-4-carboxylate 10 has been efficiently achieved to give the products 11, which allow a second arylation in the 5-position affording the diarylated 4-carboxylates 12 [256] ... 

In addition, oxazole-4-carboxylate 10 can be subjected to direct Pd-catalyzed alkenylation, benzylation, and alkylation in the 2-position [257]. Recently, direct 2-C-H-functionaUzation (alkylation and arylation) has been reported for oxazoles (as well as thiazoles and benzazoles) with free 2-position utihzing chelated Ni/Cu-catalysts derived from 2,2 -bis(dimethylamino)diphenylamine [258] or chelated Cu/Pd-complexes derived from Xantphos ]259] in the presence of a base. 

The decarboxylative arylation of thiazole- and oxazole-5-carboxylic acids with aryl halides occurs in the presence of a Pd/Ag system (Scheme 4.46) [51]. The azole-azole coupling also proceeds through decarboxylation and C-H bond cleavage (Scheme 4.47) [52]. 

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