Trisubstituted oxazoles

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

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). 

A microwave-assisted one-pot approach towards 2,4,5-trisubstituted oxazoles employed a hypervalent iodine (III) catalyst to bring about the reaction of ketones, 1,3-diketones and /3-keto-carboxylic acid derivatives with amides [75]. Microwave dielectric heating was also successfully utilized in a solid-supported, solvent-free synthesis of 2-phenyl-oxazol-5-ones (azlac-tones) [76] as well as in a solution phase synthesis of isomeric 2-phenyl-oxazol-4-ones (oxalactims) [77]. 

Liu et al. [16] synthesized twenty novel 2,4,5-trisubstituted oxazole derivatives (iv) containing heterocycle moiety and evaluated them for their antiproliferative activity. They showed that the microwave irradiation promoted the rapid 0,N-acylation-cyclodehydration cascade reaction of oximes and acid chlorides. 

The readily available ethyl 2-chlorooxazole-4-carboxylate proved to be a versatile scaffold for the synthesis of 2,4-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles. 

Kawano Y, Togo H (2009) lodoarene-catalyzed one-pot preparation of 2,4,5-trisubstituted oxazoles from alkyl aryl ketones with mCPBA in nitriles. Tetrahedron 65 6251-6256 Jarikote DV, Siddiqui SA, Rajagopal R, Daniel T, Lahoti RJ, Srinivasan KV (2003) Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Lett 44 1835-1838... 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

Alkoxybenzenes and -naphthalenes when treated at elevated temperatures with acylated a-amino acids in the presence of polyphosphoric acid react to give 2,4,5-trisubstituted oxazoles.69 A typical reaction is illustrated in Eq. (3). 

Hoefle and Steglich164 have recently found that thermolysis of 2,4-disubstituted 4-acyl-2-oxazoline-5-ones and 2,4-disubstituted 2-acyl-3-oxazolin-5-ones gives 2,4,5-trisubstituted oxazoles (93 and 94, respectively), with elimination of carbon dioxide. In the latter case, the substituents at C-2 and C-4 were interchanged. 

TABLE 1.6. 2,4-DISUBSTITUTED- 2,5-DISUBSTITUTED- AND 2,4,5-TRISUBSTITUTED-OXAZOLES FROM REARRANGEMENT OF 2-ACYLISOXAZOL-5-ONES ... 

Tobinaga and co-workers prepared a series of 2,4,5-trisubstituted oxazoles... 

TABLE 1 18. 2.4,5-TRISUBSTITUTED OXAZOLES FROM OXIDATION OF KETONES WITH IRON(III) solvates of NITRILES" ... 

Nilsson and Hacksell isolated 2,5-dimethyl-4-phenyloxazole 245 (Ri = CH3, R2 = CeHs) as the only product from methylation of N-(l-phenyl-2-propynyl)acet-amide 244 (Ri = CH3, R2 = CeHs). The authors found that propargyl amides could be cyclized to 2,5-disubstituted and 2,4,5-trisubstituted oxazoles (Scheme 1.67). Thus a propargyl alcohol 243 was converted to the corresponding amide 244 in... 

Eguchi and co-workers ° developed a general synthesis of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles from an intramolecular Aza-Wittig reaction of (Z)-p-(acyloxy)vinyl azides (Scheme 1.74). An a-bromoketone 277 was converted to an a-azidoketone 278, which was O-acylated at 78°C to give, exclusively, a (Z)-p-(acyloxy)vinyl azide 279. This was attributed to intramolecular chelation of lithium by the enol oxygen and the a-nitrogen atom of the azide. 

Treatment of 279 with triethylphosphite produced an intermediate iminophos-phorane that then cyclized to a 2,5-disubstituted or 2,4,5-trisubstituted oxazole 226 in good to excellent yield. The authors found triethylphosphite was more effective than tributylphosphine or triphenylphosphine in the Staudinger reaction. This... 

TABLE 1.22. 2,5-DISUBSnTUTED- AND 2,4,5-TRISUBSTITUTED-OXAZOLES FROM INTRAMOLECULAR AZA-WITTIG REACTION OF (Z)-P-(ACYLOXY)VINYL AZIDES"... 

Kaufmann and co-workersexplored several complementary methods to prepare 2,5-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles as flash-lamp pumped laser dyes (Scheme 1.122). Prolonged reflux of 440 with POCI3 effected cyclodehydration to 5-(4-methoxyphenyl)-2-(4-pyridyl)oxazole 441 in modest... 

TABLE 1.36. 2,5-DISUBSTITUTED 4-OXAZOLECARBOXYLIC ACID ESTERS, 2,4,5-TRISUBSTITUTED OXAZOLES, AND 2,4 -BIS-OXAZOLES FROM DESS-MARTIN PERIODINANE OXIDATION AND (CeHslsP/yiCzHjlsN CYCLIZATION-... 

TABLE 1.37. 2-SUBSTITUTED 2,5-DISUBSTITUTED AND 2,4,5-TRISUBSTITUTED OXAZOLES VIA MICROWAVE-ACCELERATED CYCLODEHYDRATION OF 2-ACYLAMINO KETONES OXAZOLES USING BURGESS REAGENT"... 

Previously, these authors reported a general synthesis of 2,4,5-trisubstituted oxazoles 561 from 558 (Scheme 1.153). Addition of an alkyUithium reagent to 558 generated a lithium p-bis(trimethylsilyl)amino enolate 559 that was acylated in situ to produce a p-(acyloxy)-A,A-bis-(trimethylsilyl) enamine 560. Cyclization of 560 to 561 was accomplished using FVP or TMSOTf. 

Tsveniashvili and co-workers acquired polarographic data for series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles and investigated the effects of substituents on the electrochemical reduction potential. They explained their results by two one-electron reversible steps to produce a dianion, which was then protonated. Rogers and co-workers described anion-pi radicals formed during electrochemical reduction of fused oxazoles, e.g., 2-phenylbenzox-azole. 

Vedejs and Grissom" described the synthesis and reactions of azomethine ylides generated from 4-oxazolines. They found that alkylation of a 2,5-disubsti-tuted or a 2,4,5-trisubstituted oxazole 15 gave an A -alkyloxazolium salt, which was... 

Kim and co-workers prepared a series of 2,4,5-trisubstituted oxazoles 1614 in low to good yields from desoxybenzoins 1613 and nitriles (Scheme 1.411). This Ritter-like reaction works best in the presence of a 1 1 mixture of trifluoromethane-sulfonic acid-sulfuric acid. Trifluoromethanesulfonic acid or sulfuric acid alone is ineffective. Fuming sulfuric acid gave < 10% of an oxazole. The authors proposed that sulfuric acid acts as an oxidant, analogous to Tl(OTf)3 or Cu(OTf)2. ... 

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