Oxazole-4-carboxylates, preparation

Wood and Ganem" described a more direct approach for deprotonation of a 2-methyl group (Scheme 1.304). They prepared 2-methyl-5-(trimethylsilyl)-4-oxazole carboxylic acid 1201 in which the 5-position was blocked. Dianion formation, followed by quenching with an electrophile, afforded 1202 in excellent yield. In one example investigated, desUylation with cesium fluoride was quantitative. This methodology was developed to complement their convergent strategy to 1182. 

Oxazoles are prepared from tryptophan loaded Wang resin 53 (Scheme 9.7) The deprotected N-terminal was condensed with carboxylic acids 54 or carboxylic acid anhydrides 55 to give Af-acetyltryptophans 56. The key step involved oxidation of 56 with 2 equiv of DDQ (dichlorodicyanoquinone) in THF H20 (9 1) at room temperature for 15 min, producing the key intermediate 57. Compound 57 underwent cyclocondensation in the presence of triethylamine, CCLj, and triphenylphosphine in acetonitrile at room temperature for 2h to afford the oxazole 58. After cleavage from the resin with 20% TFA in DCM, esterification was carried out using TMS diazomethane to give the final product 59. 

Oxazoles, prepared from carboxylic acids (benzoin, DCC NH4OAC, AcOH, BOSS % yield), have been used as carboxylic acid protective groups in a variety of synthetic applications. They are readily cleaved by singlet oxygen followed by hydrolysis (ROH, TsOH, benzene or K2CO3, MeOH ). 

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>. 

In the second method, oxazoles 150 have been prepared in good yields by HTIB-induced ring closure of enamine carboxylic acids 149 [91JCR(S)302]. 

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. 

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). 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

Fused ring oxazoles lead, in apolar solvents, to products which derive from cleavage at the 2-3 and 4-5 positions of the endoperoxides to cyano-anhydrides 81 followed by hydrolysis or CO loss. This sequence has been efficiently used to prepare oo-cyano carboxylic acids 82 (Sch. 47) [78],... 

For the preparation of 70-72 Koyama etal. (28) employed the 5-3 -(indolyl)-oxazole 88 obtained from ethylindole-3-carboxylate (87) and isocyanomethyl lithium. The oxazole 88 was refluxed in acetic anhydride—acetic acid or propionic anhydride-propionic acid to afford pimprinine (70) and pimprinethine (71) in 13 and 19% yield, respectively. Hydrolysis of these reaction mixtures and that produced with phenylacetic acid anhydride-phenylacetic acid gave high yields (84-92%) of the 3-acylamidoindoles 79-81, which could be smoothly cyclized with phosphorus oxychloride to the natural products 70-72 (28). 

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). 

C—C—O—C+N. The formation of oxazoles from a-acyloxy ketones and ammonium salts was discovered in 1937 when it was found that treatment of benzoin benzoate with ammonium acetate in hot acetic acid gave triphenyloxazole in excellent yield. It has been shown that the reaction proceeds by way of intermediate enamines (equation 113). The synthesis is quite general and it is only.limited by the difficulty of obtaining the starting keto esters, particularly formates. The latter are probably intermediates in the preparation of cycloalkenooxazoles from acyloins and formamide in hot sulfuric acid (equation 114). Another variation is to heat a mixture of an a-bromo ketone, the sodium salt of a carboxylic acid and ammonium acetate in acetic acid (equation 115). 

The zinc chloride assisted cyclo-condensation of ethyl 3-acetyl-l,3-oxazolidine-4-carboxylates proceeds at 180 °C to give derivatives of pyrrolo[l,2-c]oxazole (Scheme 1) (X = O) pyrrolo[l,2-c]thiazoles (X=S) were prepared similarly (81BCJ1844). 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

The use of a-ketol esters with formamide has been reported by Novelli and de Santis72 for the synthesis of oxazoles and imidazoles. It appears that in this case the reaction proceeds through reaction of the oxazole with formamide. The a-ketol esters are prepared by treating the corresponding a-bromoketones with the potassium salt of the appropriate carboxylic acid. 

The 2-aryloxazoles have also been synthesized under microwave activation by the direct Stille and Suzuki cross-coupling reactions of 1,3-oxazoline (OXT) [17]. Nolt et al. [18] utilized the microwave-assisted Cornforth rearrangements for the preparation of substituted 5-amino-oxazole-4-carboxylate (v). 

Carbenoid insertions. The species generated from decomposition of diazo compounds in the presence of rhodium carboxylates are capable of inserting into various X-H bonds. Thus, N-C bond formation has been exploited for the preparation of precursors of indoles, oxazoles, and peptides. ... 

Disubstituted oxazole 26 was prepared from 2-chlorooxazole-4-ethylcarboxylate via the Suzuki coupling with phenylboronic acid [26]. The carboxylic functionality at C(4) of 26 could then be exploited by a variety of synthetic transformations. 

A series of 2-aryloxazoloquinolones 32 having high affinity for the GABA receptor were prepared via a Pd-catalyzed intramolecular diaryl coupling of ethyl 5-bromo-2-phenyl-oxazole-4-carboxylate with 2-aminophenylboronic acid followed by cyclization [37]. This one-pot intramolecular Suzuki reaction was followed by cyclization to afford a tricyclic compound 32. 

---