Heterocyclics benzoxazoles

Direct Arylation of Benzoxazoles and Related Heterocycles. Benzoxazole 3 was functionalized with a variety of arenes and heteroarenes in the presence of catal)4ic amounts of [Pd(phen)2](PFe)2 (eq 3). In particular, heteroaryl iodides provided excellent yields of the comesponding products. The reaction... 

Heterocycle = quinoxaline, imidazole, oxadiazole, benzoxazole, benzimidazole... 

In contrast with the hitherto described silylation-aminations of six-membered heterocycles, silylation-amination of five-membered hydroxy-N-heterocycles such as benzoxazol-2-one 289 with excess benzylamine and HMDS 2, to give 2-benzyla-minobenzoxazole, fails, because of the equilibrium between 2-trimethylsilyloxy-... 

The Boger group [64-66] has extensively studied the use of a-ketoheterocycles as FAAH inhibitors. In their initial studies, a range of a-ketoheterocycles based on oleic acid was synthesised. A range of five- and six-membered monocyclic heterocycles and three bicyclic heterocycles (benzothiazole, benzimidazole and benzoxazole) was examined. Although many of the compounds tested were found to inhibit FAAH activity with micromolar affinities, the best results were obtained with heterocycles that incorporated a weakly basic nitrogen a - to the heterocycle (Table 6.5) [64]. 

Roger and co-workers [68] have recently extended their studies to encompass heterocyclic sulfoxides and sulfones. In general, these compounds were less potent (up to 1,000 fold) than their a-keto heterocycle congeners. The best results were obtained with the benzoxazole sulfoxide (50) with a K of 2.6/iM. 

Indolines, benzoxazole, and benzothiazole are possible as 2-methylene heterocycles. The number of known spirooxazine derivatives is much less than for the spiropyrans. This may be partly due to lack of many substituted o-nitrosonaphthols and partly due to lack of sufficient stability of spiro-oxazines. The structures of parent spirooxazines and the Xmax of their photomerocyanine forms are listed in Table 5. The Xmax of the colored forms of compounds 41-43 are not described in the literature. 

Cu-catalyzed domino reactions have been used for the synthesis of carbocycles, as well as for heterocycles such as indoles, benzoxazoles, and quinoxalines. A very useful process is also the combination of the formation of allyl vinyl ethers, followed by a Claisen rearrangement. 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

Synthetic use can be made of the potent electrophilic properties of ADC compounds by transforming the initial adducts into heterocyclic products. For example, reaction of DEAZD with enamine 92 gives the substitution product 93 in quantitative yield. Further treatment of this initial adduct with acid, followed by base hydrolysis leads to benzoxazol-2-ones. The dimethyl substituted enamine (92, R = Me) gives the rare, but isolable 6//-benzoxazol-2-one ring system (Scheme 13).147... 

A wide variety of different classes of fluorescent molecules has been investigated in the peroxyoxalate chemiluminescent systems. Among those screened were fluorescent dyes such as rhodamines and fluoresceins, heterocyclic compounds such as benzoxazoles and benzothiazoles, and a number of polycyclic aromatic hydrocarbons such as anthracenes, tetracenes, and perylenes. The polycyclic aromatic hydrocarbons and some of their amino derivatives appear to be the best acceptors as they combine high fluorescence efficiency with high excitation efficiency in the chemiluminescent reaction [28],... 

In addition to palladium catalysts, Co(OAc)2 shows a catalytic activity for the arylation of heterocycles, including thiazole, oxazole, imidazole, benzothiazole, benzoxazole, and benzimidazole.78 As shown in Scheme 6, the catalytic system Co(OAc)2/9/Cs2C03 gives G5 phenylated thiazole, while the bimetallic system Co(OAc)2/CuI/9/Cs2C03 furnishes the G2 phenylated thiazole. The rhodium-catalyzed reaction of heterocycles such as benzimidazoles, benzoxazole, dihydroquinazoline, and oxazoline provides the arylation product with the aid of [RhCl(coe)]2/PCy3 catalyst.79 The intermediacy of an isolable A-heterocyle carbene complex is proposed. 

Heterocyclic compounds Heterocyclic C=N systems, such as benzoxazole and related thia-zoles, react with complex 2b to yield the ring-expanded adducts, e. g. complexes 90 and 91, by formal C-X (X = O, S) bond cleavage and coupling with the alkyne. In the case of benzisoxazole, the alkyne is not coupled but eliminated, and ring-enlargement of the ben-zisoxazole leads to the N-bridged dimer 92 [48]. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

This lead has been pursued extensively at Wyeth-Ayerst, resulting in several additional series of active compounds (reviewed in [340]). Activity was retained by replacement of the quinoline by other benzo-fused heterocycles such as benzothiazole and A -methylbenzimidazole, but the benzoxazoles were inactive no correlation was seen between in vitro and in vivo activities... 

One of the earliest uses for rhodium(II)-catalyzed dipoles was demonstrated in Davies furan synthesis [22]. Isomiinchnones were also shown to produce substituted furans [115]. Additional furan syntheses have been described using silylacetates [116], unsaturated esters [117], and fluoroalkyl diazo acetates [118]. The synthesis of furofuranones and indenofuranones 35 from a-diazo ketones having pendant alkynes has also been reported (Eq. 6) [119]. Other fused heterocyclic systems include furo[3,4-c]furans [120, 121] furo[2,3-b]furans [122] as well as thiobenzofurans [123], and benzoxazoles[124] have also been synthesized with this methodology. 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

It was also demonstrated, that under similar coupling conditions related heterocycles, such as benzoxazoles and benzothiazoles react with a similar efficiency (6.82.), The coupling of piperidine with the above compound gave the 2-piperidino heterocycles in 66% and 78% yield, while the benzimidazole derivative gave 71%. 12... 

Benzoxazoles, as in (99), are prepared by condensation of two molecules of an o-aminophenol with a dicarboxylic acid such as terephthalic acid, or by condensation of the o-aminophenol with a dialdehyde such as terephthalaldehyde followed by oxidation of the Schiff base (50JCS1722). Pendant heterocycles, such as benzotriazoles, are also commonly incorporated. 

In the presence of air or oxygen, it has been shown15 that />-tolyl-substituted heterocycles in DMF with potassium hydroxide are oxidized to symmetrical stilbenes. Thus, for example, 2-(/ -tolyl)benzoxazole yields 4,4 -bis(benzoxazol-2-yl)stilbene (14). Similar reactions have also been carried out with p-tolyl-substituted benzotriazoles, oxazoles, 1,3,4-thiadiazoles, 1,2,4-and 1,3,5-triazines, and quinazolines. 

This surprising reactivity of extremely weakly acidic methyl groups has resulted in extending the Anil Synthesis to a number of heterocyclic systems in which activation in the sense of the benzoxazole group would not be expected. 

TABLE VIII Heterocyclic Styryl Derivatives of Benzoxazoles and Benzisoxazoles1... 

Methyl-substituted thiophenes are also capable of reaction with benzalaniline, provided that the 5-position carries a carbo- or heterocyclic aromatic group, as, for example, 2-(benzoxazol-2-yl)-5-methyl-thiophene (109), which yields the styryl derivative 110.11 The isomeric compound 111 may be obtained analogously from 2-(/ -tolyl)benzox-azole and Schiff s base from 2-formylthiophene and p-chloroaniline. 

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