Isoxazolo pyridin-7-ones

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. 

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). 

Substitution of one of the Cl-bonds in the isoxazolo[4,3-c]pyridine 113 with a variety of nucleophiles has been reported by Ponticelli and co-workers (Equation 23 Table 21) <2003S2518>. 

Synthesis of pyridine jV-oxides has been reported by a direct cyclization in a [3+2+1] annulation reaction (Equation 156) <20010L209>. A one-step synthesis of fused isoxazolo[4,5-/(]pyridine Ar-oxides was reported. Deoxygenation to the pyridine was achieved using PCI3 (Scheme 102) <2003IJB1742>. 

The isoxazole-to-oxazole rearrangement has been also used in the synthesis of benzocondensed derivatives. The irradiation of benzisoxazoles 81 in water (high-pressure Hg lamp) produces almost quantitative yields of the corresponding ben-zoxazoles 82 (Scheme 12.24) [53]. Benzoxazolin-2-ones 83 are similarly obtained [54], Furthermore, oxazolo[5,4-b]pyridines 84 and oxazolo[5,4-b]quinoline 85 are obtained by preparative-scale photolysis in ether with a high-pressure Hg lamp of the corresponding isoxazolo[5,4-b]pyridines or isoxazolo[5,4-b]quinoline, respectively (Scheme 12.24) [55]. 

Isoxazolo[2,3-a]pyridin-7-ones were prepared by domino metathesis of the strained nitroso Diels-Alder adduct 87 and a terminal alkene in the presence of a catalytic amount of second generation Grubbs carbene or Hoveyda-Grabbs carbene complex. For example, 88 was obtained as the major product along with minor amounts of 89 starting from 87 and but-3-en-l-ol <07OL1485>. 

A novel domino metathesis reaction of nitroso Diels-Alder cycloadduct 152 has been developed by Calvet et al. <07OL1485>. This reaction uses favorable thermodynamics to rearrange a strained unsaturated bicycle to access a rare lactam-containing scaffold, isoxazolo[2,3-a]pyridine-7-ones 153. 

Tu and co-workers [74] have synthesized a series of new polycyclic-fused isoxazolo[5,4-h]pyridines 25-29 by a one-pot tandem reaction under microwave... 

New pyrazolopyridine derivatives have been synthesized <03SC253>, <03BMCL3367>, <03J1C311>. An elegant one-step synthesis of 5,6-disubstituted isoxazolo[4,5-fc]pyridine N-oxides has been carried out <03SC3077>. 

A novel rearrangement of suitably 2-substituted side-chain perhy-dro-isoxazolo[2,3-a]pyridines has been shown to afford indolizine and quinolizine derivatives (86TL1727). Thus, 2-spirocyclopropylperhydro-isoxazolo[2,3-a]pyridine (61), obtained as a mixture with the 3-spiro isomer from the reaction between 3,4,5,6-tetrahydropyridine-l-oxide and methylene cyclopropane, undergoes thermal rearrangement (400°C, 0.2 mmHg) to the quinolizidin-2-one (62). 

Isoxazolo[2,3- ]pyridin-2-one derivatives such as 568 were prepared by intramolecular oximino malonate HDA reactions. These compounds underwent aromatization to substituted pyridines under mild basic conditions (Scheme 139) <20000L4007>. 

The electrophilic substitution in position 4 of the isoxazole ring is widespread for 3-AI and 5-AI however, the electrophilic substitution in position 3 or 5 of 4-AI has not been observed (Section III.A). Theoretically, one should expect the formation of isoxazolo[3,4-Z>]pyridines 20 and isoxazolo[5,4-Z>]pyridines 21 from 3-AI and 5-AI, correspondingly. A synthesis of isoxazolo[4,3-Z>]pyridines 22 or isoxazolo[4,5-Z>]pyridines 23 from 4-AI, with the substitution of hydrogen, seems impracticable (Scheme 11). 

One synthesis of isoxazolo[5,4-Z>]pyrimidines from 4-unsubtituted 5-AI has been reported (Section III.C.2). As discussed above for isoxazolo[3,4-Z>]pyridines, the reaction of 3-amino-5-methylisoxazole with carbamate 44 does not produce isoxazolo [3,4-7>]pyrimidines, isoxazolo[2,3-a] 1.3.5-triazines 45 being formed as the only products. Meanwhile, the condensation of 5-amino-3-methylisoxazole with the same carbamate yielded isoxazolo[5,4-Z>]pyrimidine 46 (04KGS496) (Scheme 20). 

Heating isoxazolo[3,4-h]pyridines together with primary amines has been reported to produce 3-substituted pyrido[2,3-d]pyrimidin-4 3/f)-ones.307... 

A -Unsaturated lactone, 2-hexenolide, enters as a dipolarophile 1,3-dipolar cycloaddition reaction with A -piperideine giving a new heterocyclic system, l/f-oxepino[3 4 4,5]isoxazolo-[2,3-fl]pyridin-1-one (Equation (7)) <90MRC947>. 

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