Isoxazoles as Substrates

Although not widely used, at least three procedures have been employed to convert isoxazoles into pyrazines, as illustrated in the following examples  

3-Phenyl-5-isoxazolol (53) gave 2,5-diphenylpyrazine (54) (hv, MeOH, 5°C, 7 h 67% oxidation during work up).449 

4-(C-Acetylformamido)-4-isopropyl-3-methyl-4,5-dihydro-5-isoxazolone (55) gave 6-isopropyl-3,5-dimethyl-2 (1 //)-pyrazinone (56) [Lindlar catalyst (Pd/CaC03/trace Pb), H2, EtOH, 20°C, 10 h 90%] also several homologues likewise and in comparable yields.227 

4-Amino-4,5-dihydro-3 (2//)-isoxazolone (57) gave 3,6-bis(aminooxymethyl)-3,6-dihydro-2,5 (1H, All )-pyrazinedione (58) (AcOH—EtOH, reflux, 45 min  

Primary Syntheses from Other Heterocyclic Systems 

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In the photochemical isomerization of isoxazoles, we have evidence for the presence of the azirine as the intermediate of this reaction. The azirine is stable and it is the actual first photoproduct of the reaction, as in the reaction of r-butylfuran derivatives. The fact that it is able to interconvert both photochemically and thermally into the oxazole could be an accident. In the case of 3,5-diphenylisoxazole, the cleavage of the O—N bond should be nearly concerted with N—C4 bond formation (8IBCJ1293) nevertheless, the formation of the biradical intermediate cannot be excluded. The results of calculations are in agreement with the formation of the azirine [9911(50)1115]. The excited singlet state can convert into a Dewar isomer or into the triplet state. The conversion into the triplet state is favored, allowing the formation of the biradical intermediate. The same results [99H(50)1115] were obtained using as substrate 3-phenyl-5-methylisoxazole (68ACR353) and... 

Synthetic thiazolium salts (86c), developed by Stetter and his co-workers and similar to thiamine itself (Stetter 1976), have been successfully used by Suzuki et al. for a diastereoselective intramolecular crossed aldehyde-ketone benzoin reaction in the course of an elegant synthesis of preanthraquinones (Hachisu et al. 2003). By using the highly functionalized isoxazole 104 as substrate, the tetracyclic a-hydroxy ketone 105 was obtained by base-promoted cyclocondensation in good yield. The high diastereoselectivity was induced by pre-existing stereocenters in the substrates (Scheme 28). 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Only a few 1NOC reactions have been run on alkynyl substrates.5152 The reactions do proceed well, as for example, cyclization of the alkynyl nitrile oxide (108), derived in situ from the corresponding oxime.51 The oxime itself was formed in situ by reaction of an a-bromosilyloxime with propargyl alcohol, presumably via a vinylnitroso intermediate (Scheme 32). The alkynyl acylnitrile oxide (109) also cy-clized to afford a bicyclic isoxazole.52... 

Nitrile oxides display three types of reactivity (apart from isomerization and deoxygenation) 1,3-cycloaddition, 1,3-addition, and dimerization to furoxans. The first can give isoxazolines and isoxazoles directly. The second can give isoxazolines and isoxazoles indirectly. The third (which may be regarded as a carbenoid reaction,62 but see also Lo Vecchio et al.63) is an undesirable side reaction as far as the synthesis of isoxazoles is concerned. Thus, although many methods for generating nitrile oxides are available, and in some cases they may be isolated and used, methods capable of generating them in the presence of the substrate are preferred. 

It should be noted that it is in many cases conceivable that isoxazoles and isoxazolines are formed from chloroximes without the intermediacy of a nitrile oxide. This route could occur if the substrate acted as a nucleophile to give an intermediate, such as the alkynyloxime (25) from an acetylide, which can cyclize to the isoxazole (26). In this case, by trapping with nonnucleo-philic alkenes, the reaction has been shown to involve a nitrile oxide.60,71 However, experiments on reactions of chloroximes with other nucleophiles suggest that a nitrile oxide is not invariably involved.72,73... 

The general route for the reactions leading to isoxazoles is shown in Scheme 2. A variation, using enolate ions as the substrate, is illustrated by the example shown in Scheme 3.101 As indicated, the isoxazole could be formed by cyclodehydration of an open-chain intermediate such as 35. 

A series of iridium-based complexes formed in situ have been used to mediate ort o-exchange of hydrogen with deuterium in model substrates such as 3-phenyl-5-acetylisoxazole <2003T3349>. 4,5-Diarylisoxazoles were exploited in the synthesis of phenanthro[9,10- isoxazoles. For instance, compound 242 was prepared by... 

A procedure by using enamino ester and alkynone as the substrates was developed as well [2]. 2,3,4,6-Tetrasubstituted pyridines were prepared in a single step. Various acids, such as acetic acid, Amberlyst 15 ion exchange resin, zinc(II) bromide or ytterbium(III) triflate, can be applied as promoter for the cycUzation step of the Michael addition adduct. 4-(3-Oxoalkyl)isoxazoles found could be applied as starting material for pyridine synthesis as well [3],... 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

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