Pyrrolo isoxazoles

AH-Pyrrolo[3,4-c]isoxazole, 3-amino-biological activity, 6, 1024 4H-Pyrrolo[3,4- c]isoxazole-5(6/7)-carboxylic acid, 3-amino-ethyl ester... 

A one-pot synthesis of 3-methyl-5-aryl-4//-pyrrolo[2,3-<7]isoxazoles was performed in high yields by Sharpless epoxidation of 4-amino-3-methyl-5-styrylisoxazoles <06TL4957>. 1,2,4,5-Tetrazines were condensed with isoxazolylcyclobutanones in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7-dihydro-5//-[l,2]diazocin-4-ones <06JOC2480>. 

In CHEC-II(1996) <1996CHEC-II(8)48>, it was reported that pyrrolo[l,2-A isoxazoles are not known, but many examples of 3a,4,5,6-tetrahydro and perhydro pyrrolo[l,2-A]isoxazoles have been described. 

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. 

Table 11 FVrrolo[2,3-c]isoxazoles (X=0), pyrrolo[2,3-c]isothiazoles (X = S), 2/-/-pyrrolo[2,3-c]pyrazoles (X = NH)...

Direct alkylation has been reported for thieno[3,2-c]isoxazole (4) and 5-phenylfuro(pyrrolo or thieno)[3,2-rf]isothiazoles (14)-(16) to afford the hydrolytically sensitive jV-methylisothiazolium salts (31) (Equation (6)) <85KGS223> and N-alkylisoxazolium salt (32) (Equation (7)) <76CS165>. In contrast, thieno[2,3-c]isothiazole (17) is a weak base and does not react with alkyl halides <82AJC385>. 

Several specialized cyclization strategies should not be dismissed. A novel rhodium acetate-mediated cyclization was employed for the first synthesis of 3-methyl-4,6-diphenylfuro[3,4-tf]is-oxazole (9) from the 5-(a-diazobenzyl)isoxazole (185) (Equation (56)). The reactive intermediate is believed to be a carbenoid species <9iCB248i>. Another strategy exploits the reactivity of 4-halo-pyrazol-5-ones (e.g., 186) with stabilized anions (e.g., cyanoacetate esters and nitriles) to afford the 4-cyanofuro[2,3-c]pyrazol-5-ones (187) and 5-aminofuro[2,3-c]pyrazoles (188) (Scheme 30) <84H(22)2523>. Also of interest is the trichloroacetonitrile cyclization of aminopyrazole ketones (189) to the pyrrolo[2,3-c]pyrazoles (190) (Equation (57)) <86S74>. The generality of this cyclization is not known. 

Further functionality (i.e., 4-oxo) has been introduced by the cyclization of a-allyloxy-carbonylnitrones, which have traditionally been problematic to obtain. Tamura and co-workers have reported that simple alkoxycarbonylnitrones (e.g., (243)) undergo transesterification and cyclization with various allylic alcohols in the presence of titanium isopropoxide (Scheme 43) <95T107, 95T119). Alternatively, allyl a-oximinocarboxylates (246) are converted in situ to nitrones (247) and further cyclized to the bicyclic heterocycles (248) (Scheme 44) <91T4495>. Tetrahydro-1 //-pyrrolo[3,4-c]isoxazoles (250) have been prepared by the condensation of C-acylnitrones with allyl amines <78AJC2013> further reduction of the bicycles (250) with sodium borohydride affords the 3-oxa-2,7-diazabicyclo[3.3.0]octane (251) (Scheme 45). 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

The use of nitro aromatics as dipolarophiles in cycloaddition reactions has shown great utility in heterocyclic synthesis. The reaction of 3-substituted-4-nitroisoxazoles (299) with trisubstituted oxazolium 5-oxides (300) affords an intermediate adduct (301) which eliminates carbon dioxide and nitrous acid to afford 3,4,6-trisubstituted pyrrolo[3,4-r/]isoxazoles (302) (Scheme 56) <93G633>. 

Similar reactions have been carried out with variously substituted pyrroline 1-oxides, imidazole 1-oxides, isoxazoline N-oxides (nitronic esters) and 3,4-diazacyclopentadienone AT-oxides in combination with a large variety of alkenic and alkynic dipolarophiles, aryl isocyanates, aryl isothiocyanates and N- sulfinylamines, leading to pyrrolidinoisoxazoles, pyrrolo[l,2-6][l,2,4]oxadiazoles, pyrrolo[2,l-d][l,2,3,5]oxathiadiazoles, isoxazolo[2,3-b ]isoxazoles and isoxazolo[l, 2-6 ]pyrazoles. 

The condensation of ethyl 3-cyano-4-hydroxy-3-pyrroline-l-carboxylate with hydroxyl-amine followed by base treatment of the resulting oxime gives ethyl 3-amino-4H-pyrrolo[3,4-c]isoxazole-5(6F7)-carboxylate (equation 50) (68JMC453). Arylidenehippuric... 

Isosorbide is a diuretic the dinitrate is a vasodilator. Hexahydrofuro[3,2-6 ]pyrrole derivatives are useful as bronchodilators and thrombocyte aggregation inhibitors. 3-Amino-4//-pyrrolo[3,4-c]isoxazoles produce hypotension. 3,4,5,6-Tetrahydro-2H-cycIopen-tathiazol-2-one is an effective analgesic. 

Cyclohepta[4,5)pyrrolo[l,2-fl]imidazoles, 2-aryl-, halogenation. 59, 283 Cyclohepta[4,5)pyrrolo[3,2-e][l,2,4]triazine, 3-chloro- 10-(4-chlorobutyD-5,6,7,8,9,10-hexahydro-, 59, 50 3//-Cyclohept(e]isoxazoles, 3a,4,5,6,7,8-hexahydro-, 60, 311-3 Cyclohex-2-en-l-ones, 2- and 3-bromo-, regioselectivity of nitrile oxide cycloaddition, 60, 304 Cyclols, piperazine-2,5-dione-related, 57, 211-7... 

Sharpless oxidation of the oxazole 52 provides an intermediate epoxide, which is attacked by the neighboring amino group, eventually leading to the pyrrolo[2,3-r/ isoxazole 53 (Equation 12). Variation of the aryl substituent provided access to a set of related derivatives in excellent yields <2006TL4957>. 

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