Oxazole and Thiazole Derivatives

9-dione (207) was obtained from 2-acylamino-3-alkylamino-1,4-naphthoquinone in the presence of concentrated sulfuric acid (69T2427). Similarly, derivatives of 208 were obtained from 2,5-bis(acetylamino)-3,6-dihydroxy- 

4-benzoquinones and acyl halide or anhydride (64ZOB3037). The five-membered ring is easily cleaved in warm dilute acid or base (64ZOB3037). 

The extended quinone 212 was obtained from 2-amino-3-mercapto-1,4-naphthoquinone, prepared in situ, and formaldehyde, with dehydrogenation taking place simultaneously (50JCS680). All attempts to reduce the quinone were unsuccessful. 

The 6-hydroxy-5-n-undecyl derivative of 210 (UHDBT) is a structural analog of ubiquinone. It inhibits the oxidation of succinate and NADH (78MI2 85MI3), blocks the respiratory chain in membranes from Pseudomonas cichorii or Pseudomonas aptata (85MI4), and increases the activity of cytochrome c, about 2-fold (86MI5). It also inhibits the conversion of p-hydroxybenzoic acid (77BBR1536). 

Only a few oxazoloquinones are known. 2-Methylnaphtho[2,3-d]oxazole-4,9-dione (207) was obtained from 2-acylamino-3-alkylamino-l,4-naphtho-quinone in the presence of concentrated sulfuric acid (69T2427). Similarly, derivatives of 208 were obtained from 2,5-bis(acetylamino)-3,6-dihydroxy-1,4-benzoquinones and acyl halide or anhydride (64ZOB3037). The five-membered ring is easily cleaved in warm dilute acid or base (64ZOB3037). 

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Anthraquinoneazoles. In contrast to the older yellow Algol dyes, which contain two thiazole rings (e g., 2,2-bisanthra [2,1 d thiazole-6,11-quinonyl), the red to blue oxazoles and thiazoles derived from l-aminoanthraquinone-2-carboxylic acid and 3-amino-2-hydroxy- or -mercaptoanthraquinones exhibit good lightfastness. The good fastness to atmospheric conditions and chlorine of the blue deriv-... 

Ill was prepared by condensation of ethylbromopyruvate with thioamide 110. Utilizing these oxazole and thiazole derivatives, sequential couplings of 109 and 111 and then 112 and 113 with EDCI-N-hydroxybenzotriazole (HOBt) (EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in basic medium afforded the linear precursor 114. Deprotection followed by macrolactamization with FDPP/DIPEA afforded dendroamide A 106 in 91% yield. 

Reaction of the diphosphine ligand R2P(CH2)2PR2 (R = benzothiazolyl) (L) with [RhCl(PPh3)3] gives the exclusively P-coordinated product [RhCl(PPh3)(L)] (88JOM(338)C31, 92JCS(D)241), which is perhaps a common feature of the P-substituted derivatives of oxazole and thiazole. 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Davies et al. describe the preparation of both oxazole- and thiazole-containing derivatives of combretastatin. By formation of the ketoamide intermediate 60, in a 54% yield (Scheme 14), both classes of compounds may be obtained by altering the last step of the reaction [58]. To produce the oxazole 61 a cyclo-dehydration reaction was performed using triphenylphosphine-iodine-triethylamine, and the thiazole compound 62 was formed by thiona-tion using Lawesson s reagent, with an excellent yield (94%). 

The carbonylation of imidazole derivatives with several olefins takes place in high yields with the aid of an Ru3(CO)i2 catalyst.112,112a The carbonylation occurs exclusively at the a-position to the sp2 nitrogen (Equation (85)). A wide range of olefins can be utilized in this reaction, and a variety of functional groups are compatible under the reaction conditions. The (/i-H)triruthenium clusters such as 12 are proposed as a key species in this carbonylation reaction. Other five-membered A-heteroaromatic compounds, such as pyrazoles, oxazoles, and thiazoles, can be used for the carbonylation reactions, where the carbonylation takes place at the a-C-H bond to the sp2 nitrogen. 

The chemistry of the thiazoles does, of course, bear some similarity to that of the oxazoles. Metallated thiazoles and thiazole derivatives have found use, for example, both as carbonyl equivalents and masked acetaldehyde enolates. Additionally, as will be exemplified below, thiazole derivatives have served as catalysts for benzoin-type condensations, and they have provided access to a unique class of activated acid derivatives. 

Dihydroimidazoles, -oxazoles, and -thiazoles 463, and their benzo derivatives 464, are all very easily aromatized (e.g., 464 465), and syntheses which might be expected to yield such dihydro compounds often afford the corresponding aromatic products. Among reagents which can be used for aromatization of 4,5-dihydropyrazoles are chloranil in... 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

Few reliable methods relative to the preparation of oxazole and thiazole systems have been reported. Generally, the 2-substituted products are prepared through the use of selenoamide derivatives. The synthesis of 2-unsubstituted selenazoles is made more difficult by the instability of the product. For example, the parent compound has never been isolated. The simplest 2-unsubstituted selenazole that has been reported is 4-methylselenazole <79HC(34)217>. 

C.i.d. Heck Reaction. 7r-Deflcient chloropyrazines can be Heck-coupled into 1,3-azoles (Scheme 50). It will be recalled that the same methodology was used to couple into the TT-excessive furan, thiophene, and pyrrole heterocycles and their benzo derivatives (vide supra). The Heck reaction in oxazole and thiazole proceeds in a regiospeciflc manner. The new carbon-carbon bond is formed in the 5-position 117 next to the ether heteroatom as commonly observed in vinyl ethers and strongly favored in furan and thiophene. In benzoxazole and benzothiazole the only vacant position is between the two heteroatoms, and the Heck coupling results in substitution into the 2-position 118. " ... 

Among systems with two and more various heteroatoms in the ring, thiazole, oxazole, and their derivatives attract attention because of the interesting physicochemical properties and significant biological activity... 

Scheme 36 Tautomerization of oxazole and thiazole to the corresponding carbene derivatives at a Mn(l) fragment.

Pivalic acid displayed superior reactivity conqtared with other acidic additives (AcOH, EtC02H, and l-AdC02H). Installing electron-donating substituents onto the naphthyl moiety hampered reactivity due to decreasing N-H acidity, disfavoring cyclometalation. Benzofuran, oxazoles, and thiazoles could be effectively coupled with 1-napthylamine derivatives, and heteroary-lated pyrene systems were accessible however, benzylamine derivatives were incompatible. 

Scheme 15 shows the synthesis of an oxazole 63a and thiazole 63b derivative, accomplished by Yokooji et al. [59]. They employed arylation using tertiary phosphines and bromobenzene with CS2CO3 in xylene to form these compounds. 

Heterocyclic ring systems are also used to connect two anthraquinone groups. Typical examples include Cl Vat Red 10 (6.106), which is an oxazole derivative obtained from 2-amino-3-hydroxyanthraquinone and the appropriate acyl chloride, the similar thiazole derivative Cl Vat Blue 31 (6.107) and the oxadiazole derivative Cl Vat Blue 64 (6.108). 

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