Isoxazolo pyridine

Isoxazoio[4,3-c]pyridine, 3-amino-4,5,6,7-tetrahydro-appiications, 6, 634 Isoxazolo[4,3-c]pyridine, tetrahydro-synthesis, 6, 633-634 Isoxazoio[4,5-h]pyridine synthesis, 6, 626 Isoxazoio[4,5-c]pyridine synthesis... 

Isoxazolo[5,4-h]pyridine applications, 6, 634 photochemical rearrangement, 6, 662 synthesis... 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

Isoxazolo[2,3-4]pyridines 44, isothiazolo[2,3-4]pyridines 46, and their fully saturated derivatives 45 and 47 (Scheme 16) were discussed in CHEC(1984) <1984CHEC(6)613> and CHEC-II(1996) <1996CHEC-II(8)249>. Very little information was available on the isothiazolo[2,3- ]pyridine ring system while most of the informations given on the oxygenated parent, isoxazolo[2,3- ]pyridines, concerned the fully saturated system. Careful examination of the literature clearly shows that the situation did not change much almost no references have been reported on isothiazolo[2,3- ]pyridines and most of the work done in the last decade concerns the synthesis and reactivity of hexahydro-isoxazolo[2,3- ] pyridines 45. Therefore, this chapter will briefly describe the new reactions of fully conjugated systems and will focus on the partially/completely saturated derivatives. 

NMR data for new compounds are routinely reported. The hexahydro-isoxazolo[2,3- ]pyridine ring system 48 can exist as a mixture of three conformers 48-trans, 48-cm-A, and 48-cis-B (Scheme 17). While the two conformers possessing a as ring junction 48-m-A and 48-m-B are interconverted by chair inversion, conversion of the cis-conformer 48-cis-h to 48-trans requires inversion of the nitrogen. The presence of the adjacent oxygen slows down... 

In contrast to the conjugated system, the reactivity of hexahydro-isoxazolo[2,3-tf] pyridines has been the subject of considerably more attention, which can most certainly be attributed to its greater synthetic potential, as demonstrated by the synthesis of many complex natural products. However, most of the reactions reported since 1996 have been known for many years and the last decade was in fact characterized by their use in syntheses or optimization. After a brief survey of the thermal reactions, procedures involving the reductive cleavage of the N-O bond will be detailed. 

Interestingly, both the amino and the hydroxy groups can participate in another reaction with a suitable reacting group present in the molecule as shown with the two examples in Scheme 23 <1998T11581>. Finally, it should be mentioned that this N-0 bond reduction is also efficient starting from quaternary ammonium derivatives of hexahydro-isoxazolo[2,3- ]pyridines <1999JOC1932>. 

Representative examples illustrating these concepts and general rules as well as giving an overview of all different dipolarophiles engaged in the formation of hexahydro-isoxazolo[2,3- ]pyridines are collected in Table 6. 

Various chiral dipolarophiles have been used in the asymmetric synthesis of hexahydro-isoxazolo[2,3- ]pyridines. Examples include // / -2-methylcnc-l, 3-dithiolane 1,3-dioxide 83 <1998JOC3481>, chiral vinyl sulfoxide 85 <1997TA109>, or chiral dioxolanes <2001TA1747> (Scheme 27). 

On the nitrone side, high levels of selectivities have been reached using camphorsultam-derived nitrone 87 since hexahydro-isoxazolo[2,3- ]pyridine 88 en route to (—)-histrionicotoxin was obtained as a single regio- and diaster-eoisomer <1999JA4900> (Scheme 28). A polyhydroxylated hexahydro-isoxazolo[2,3- ]pyridine could also be obtained starting from a nitrone derived from a C2-symmetric piperidine <2002TL9357>. 

If nitrones have been widely used as 1,3-dipoles in the synthesis of hexahydro-isoxazolo[2,3- ]pyridines, the use of nitroacetates such as 92 in the cycloaddition sequence allows for an efficient access to hexahydro-isoxazolo[2,3-tf] pyridin-7-ones such as 93 after spontaneous dehydration (Scheme 30) <2000JOC499>. 

An efficient preparation of hexahydro-isoxazolo[2,3- ]pyridin-2-ones relies on the anionic addition of nucleophiles at the electrophilic carbon of the nitrone followed by cyclization of the resulting Ar-oxide. As shown by results collected in Scheme 31, various nucleophiles can be engaged in the reaction and include enolates 95 <20020L3119> or 98 <2000BML1811>, silyl acetals 101 <2003TL2817>, or ynolates 103 <20020L3119> (Scheme 31). 

Few isoxazolo[2,3- ]pyridines have found important applications in the field of chemistry and/or medicinal chemistry. Natural products of the nareline family such as nareline methyl ester 105 <1997P1303> or 10,11-dimethoxy-nareline 106 <2004JNP547> have been isolated (Scheme 32). 

To carry out MCRs of aminoazoles with aldehydes and cyclic CH-acids, the methods of green chemistry were also applied. For example, treatments of 3-methylisoxazol-5-amine and aromatic aldehydes with 1,3-cyclohexanedione, dimedone, 1,3-indanedione, or titronic acid were proceeded in water under micro-wave irradiation at 120°C [100] (Scheme 31). As a result, clean, efficient, and convenient procedures for the generation of polycyclic-fused isoxazolo[5,4-b] pyridines 71 were developed. An interesting fact is that, in the case of 1,3-cyclohexanedione, dihydropyridine s were obtained while in aU other cases only hetero-aromatized derivatives were isolated. No reason for this experimental fact was discussed in the article. 

---