Ring-fused isoxazoles

Ring-fused systems have also been prepared using this bond formation approach. Treat-ent of the /3-aminoketone (281) with lead tetraacetate gave the isoxazole system (282 ... 

A promising combination of sequential multicomponent Ugi reaction and INOC has been carried out for the preparation of fused isoxazoles and isoxazolines (413). The coupling of these two reactions (Scheme 1.38) provide access to the heterocyclic ring systems in two steps, from easily available starting materials (e.g., R = Ph, R/=PhCH2), in moderate to good overall yields (the yields of Ugi reaction products 354 were 50%-70%, those of the INOC products 355 were 27%-64%). 

Gucky et al. prepared oximes 91 by nitrosation of the activated methylene group of 87 using nitrosylsulfuric acid and sodium nitrite in concentrated sulfuric acid (Scheme 68) <2002HC0613>. Oximes 91 were treated with hot POCI3 to induce a five-membered cyclization to provide the fused isoxazole ring in 92. The overall yields for transforming 87 to 92 are shown in Table 5. 

Azole approach. Two main routes lead to fused isoxazoles belonging to this system. Both are adaptations of well-established quinoline syntheses, where the phenyl ring has been replaced by the isoxazole ring. In the first method a carbonyl derivative with at least one hydrogen at an a-carbon atom is condensed with a 4-acyl-5-aminoisoxazole as for the formyl derivative (52) (77H(7)5l) and the ester (53) (77JHC435). In the second method cyclization is effected by means of a carbonyl group which is part of the 5-amino side-chain. 

Photochemically induced rearrangement of the azole ring in the fused isoxazole (231) leads to the corresponding oxazole (232) in low to moderate yields (78CPB2497). 

Fig. 6.20, is followed in situ by reaction with a nitrile oxide to give tricyclic compounds containing a fused isoxazole ring. 

As a result of this first report, a large number of compounds containing an isocyclic or a heterocyclic ring fused tc the steroid skeleton were prepared and tested for androgenic and anabolic activity. Included are steroidal isoxazoles [205], thiazoles [94], pyrroles [206], pyrimidines [207,208], oxazines [209], thiazenone [92], quinoline [107], pyridine [122], and furazane [121], all prepared by the fusion of the heterocyclic ring to ring A. Several bis heterocyclic steroids were also prepared by... 

The nomenclature of benzfused or of any fused system or spiral system follows the Hantszch-Widman system of nomenclature. In these fused systems, the first ring or benzene ring is the base component of the second ring system, isoxazole. Thus the complete name becomes benzisoxazole. The bonds in the base component are labeled as a, b, c, d, e, etc. Atoms in the hetero-ring component are numbered as 1-7 as shown in (2) and (3). Two classes of benzfused systems, that is, 1,2-benzisoxazole (or indoxazene) (2) and 2,1-benzisoxazole (or anthranil) (3) exist. 

A hydroxamoyl chloride reacts with a C—C double bond of a 1,4-quinone in the presence of silver oxide as base and oxidant. The chemistry of heterocyclic quinones has been reviewed [2947, 3650]. Addition of a nitrile oxide (review of reactions [B-43,2115]) across the a,i -double bond of a butenolide leads to a new fused isoxazole ring. Cycloheptatriene undergoes a [6 + 2]n-cycloaddition at the 2,7-positions when it is stirred at room temperature for 4 days with nitrosoben-zene [2875]. 

Compounds in which other heterocyclic rings (pyrazoles, isoxazoles, imidazoles ) are fused to thiopyrans have been described. The interesting thiazolium salts (56) were prepared by allowing the betaines (55) to react with 4-thioxothiazolidin-2-ones. Application of the Fischer indole synthesis and the Friedlander reaction to tetrahydrothiopyran-3-one led to the exported indolo-and quinolino-derivatives. Ring closure of (57) under acidic conditions afforded the rearranged product (58). Syntheses of benzothiopyrano[4,3,2-flfe]-quinazolines (59) from 1-amino-thioxanthones and of their S- and 7V-oxides have been described. ... 

Novel steroids which contain an isoxazole fused ring within the structure have biological activity which is primarily contraceptive (74MI41604, 79MI41607, 79USP4160027) and a variety of other indications (75USP3869467, 75ZOB2090). 

The synthesis of novel heterocycle-fused furo[3,4-d]isoxazoles via ring transformation of 2-isoxazoline-2-oxides by Lewis acids was reported <96H(42)289>. A practical application of the... 

JME696>. Construction of the five-membered ring is also the key step in the synthesis of the pyrazole- and isoxazole-fused pyridopyrimidines 470 (Equation 198) <2004HC089>. 

In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of the isoxazole of the intermediate... 

Japanese researchers varied aryl substituent at C-4 in nitronate (147), LA, and the reaction conditions, they used successfully diastereomerically pure nitronates (147) (Scheme 3.121) for the synthesis of various fused-ring systems, such as benzofuro-[3,2-d]-l,2-oxazines (322), furo-[3,4-d]-isoxazoles (323—326), indolo-[2,3-b]-l-pyrroline 1-oxides (327), 4//-1,2-benzoxazines (328), benzofuro-[2,3-c]-tetrahydropyrans (329), and monocyclic 1,2-oxazines (330). 

The use of allylamine led to isoxazolines instead, whereas starting with y-nitrobu-tanoic acid, the ring that fused to the isoxazole was 7-membered. 

The idea of employing the reaction of a nitroarene or nitroheterocycle with a mtinchnone to synthesize a fused pyrrole ring system has been developed by two groups. Nesi et al. (109) found that mtinchnone 38 reacts with 3-methyl-4-nitroisoxazole (196) and 4-nitro-3-phenylisoxazole (197) to give the corresponding 5//-pyrrolo[3,4-tf]isoxazoles 198 and 199, respectively, in good yield. Presumably loss of carbon dioxide in a retro-Diels-Alder reaction follows loss of nitrous acid. 

Additionally, the same authors have isolated [l,4]diazepino[2,3-f]isoxazoles 27 <2000TL9319> from the same reagents which they suggest proceeds via fused tricyclic compound 26 followed by an electrocyclic ring-opening reaction (Scheme 2), although no yield for the reaction is given in the paper. 

Isoxazolo[5,4-, [l,2,4]triazine-4-ones are prepared by six-membered cyclizations of diazonium salts onto adjacent ester or amide substituents on the isoxazole ring (Section 10.13.9.1.2(i)). [l,2,5]Oxadiazolo[3,4- ]pyrazines (Section 10.13.9.1.2(ii)) and [l,2,5]oxadiazolo[3,4- pyridazines (Section 10.13.9.1.2(iii)) are traditionally accessed by reliable six-membered condensation reactions to give the fused pyrazine and pyridazine rings, respectively. 

The isoxazole annelation reaction2,3 is a general method for fusing a new cyclohexanone ring onto an existing system and is complementary to the well-known Robinson annelation.4 It has several major advantages ... 

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