Condensed furoxans

Benzofuroxans (2), benzodifuroxan (37), and benzotrifuroxan (38) are systems that have long been known [6-8,10,11]. Early studies showed that 37 is a potent in vivo and in vitro vasodilator, as are its furazanobenzofuroxan and thiazolobenzofuroxan analogues [26]. Structural comparison between 37 and the extended glyceryl trinitrate (GTN) conformation has shown a close similarity in the relative position between 1 and 3 positioned NO2 moieties in GTN and the 0-N+-0 substructures in the furoxan 

7-Dimethyl-l,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (41) is also an old product [7,11, 31] that has recently been found to react with GSH to give S-nitrosogluta-thione, NO and HNO [32]. It stimulates partially purified rat lung soluble guanylate cyclase, but not the heme-deficient enzyme. The activation is inhibited by ODQ. The product also displays significant vasodilator activity on rat thoracic aorta rings at nanomolar concentrations. Finally, [l,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide derivatives (42, R,Ri=CH3,H) release NO, detected as nitrite, in the presence of thiols. A mechanism for this release has been proposed [33]. 

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A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

OOOKGSlOO) (Scheme 134). Triazolylfurazans 207 were also prepared by condensation of azidofurazans with active methylene compounds in the presence of MgCOs (99MI1). A variety of azidofurazans and -furoxans reacted similarly to form the corresponding triazole derivatives. 

The of study furoxanes, for example, condensed 2,1,5-oxadiazole A-oxides, also involves consideration of the oxadiazole nucleus. Thus, a series of 6,... 

There is no doubt that the classes of furoxan derivatives most extensively studied for their NO-dependent activities are the furoxans condensed to the benzene ring and to heterocyclic systems, the furoxan sulfones, the cyano substituted furoxans and the furoxancarboxamides. 

The condensation reactions of diacylfurazans and furoxans also provide a convenient means of constructing fused heterocyclic systems incorporating the 1,2,5-oxadiazole unit. Representative examples include the conversion of diaroylfuroxans into furoxano[3,4-r/]pyradizines (61) using hydrazine <92JHC87>, and the formation of furazano[3,4-c]pyridines (62) with primary amines and DBU <79S687>. 

The usual method of synthesis of this system is by condensation of a diketone with 3,4-diamino-oxadiazoles (151). The alternative use of butyllithium followed by a bis-chlorooxime leads to the formation of the derivative (152) <91JHC1677> which can be cyclized to a bis(oxadiazolo)pyrazine (Equation (20)). Tetrahydro derivatives are formed from the bis-oximes (153) which give either the furoxan derivatives (155) (70-98%) by oxidation with potassium ferricyanide or the oxadiazoles (154) (55-70%) on heating (Scheme 14) <85JOC5l23>. 

The reactions of the homocyclic ring of benzofuroxans, which are described in detail in Section 4.22.3.3, provide access to numerous derivatives. Nucleophilic displacement of halides is facile when activating nitro groups are present, allowing alkoxy, aryloxy, thio and amino groups to be introduced. Electrophilic substitutions, e.g. nitration, are also valuable. Further transformations may also be performed on benzo-ring substituents. Such modifications include acetoxy to hydroxy acetamido to amino and acyl halides to esters and amides. Some reactions of the substituents of monocyclic furoxans allow hetero-substituted analogues of benzofuroxans to be prepared. For example, pyridazinofuroxans are formed by condensation of diacylfuroxans with hydrazine. 

Nitriles and dinitriles are also valuable intermediates, and their preparation by phosphite deoxygenation of furoxans (Section V,D,3) opens further routes via these compounds. It has been suggested512 that methyl groups may be modified, by alkylation, condensation, etc., before deoxygenation ... 

Superelectrophilic properties of nitroarenes are retained when mie of the furoxan rings in NBDF is replaced with electron-deficient isoxazole [124] or pyridine fragments [125]. As in case of NBDF, the reactions of these fused nitroarenes with ethyl vinyl ether were found to lead to the correspruiding benzoxazine N-oxides 143 and 144 condensed with heterocyclic rings (Scheme 72). 

Thermally decomposed TATB condensed phase products have been isolated by repeated thin layer chromatography (TLC) elution, and chemical ionization mass spectrometry (CIMS) analysis reveals at least three furoxan products formed by the loss of H2 and cyclization of adjacent amino and nitro groups (Figure 11). 3 This must involve N—H bond rupture and is consistent with it being the same... 

Nitromethyl ketones react with p-toluenesulfonic acid (PTSA) in refluxing toluene to give the corresponding furo-xans in 97% yield [20]. When refluxed several hours in xylene or mesitylene in the presence of dipolarophiles and catalytic PTSA, not only activated nitro compounds but also phenylnitromethane and 1-nitropropane afforded the expected isoxazole derivatives, as a result of nitrile oxide cycloadditions [21]. Microwave irradiation in the presence of catalytic PTSA has been successfully applied to condensations between methyl nitroacetate and dipolarophiles [22]. Nitroacetic esters have been converted into the corresponding furoxans with cold sulfuric acid [23], while phenylnitromethane and phenylacetylene in ethereal boron trifluoride etherate are reported to give 3,5-diphenylisoxazole [24]. 

A further specific behavior of bases in chloroform marks a difference between the two model nitro compounds the nitroketone, unlike the nitroacetate, with some bases undergoes dehydration prior to cycloaddition, at least in part. This is indicated by the production of the corresponding furoxan as an intermediate of consecutive transformation products (see Section 8.2.5). With other bases (e.g., imidazole and its derivatives) condensation is the sole observed reaction, even for the nitroketone. 

In base catalyzed condensations of active nitro compounds with dipolarophiles in chloroform, furoxans are observed in general as minor by-products, with the noticeable exception of a-nitroketones. The base screening on the model reaction between benzoylnitromethane and styrene in chloroform has shown that, depending on the base employed, the yield of the condensation product is found to be close or considerably lower than the overall conversion of flie dipolarophUe. The missing product corresponds to the furoxan 3 (R = PhCO), which however cannot be detected because it reacts with the dipolarophUe to afford the... 

Condensations of nitroacetone with styrene or norbomene permitted the detection of minor amounts of the corresponding furoxan, besides the expected isoxazoUnes [62]. 

The competition between condensation and conjugate addition, observed with electron-poor dipolarophiles, suggests cycloaddition of nitronic acid to dipolarophile to be the next step toward condensation. Direct dehydration to nitrile oxides possibly gives a partial contribution to the process since minor amounts of furoxans have been detected in some cases. When condensation competes with conjugate addition. 

Competition between addition and condensation has been already discussed. Since furoxans are often (not always) detected beside condensation products, formation of... 

Addition of Cu salts to the base allows nitroalkanes to undergo condensations with dipolarophiles it is reasonable to relate this catalytic effect to the known existence of complexes with nitronates [92]. Formation of such complexes might affect conversion of nitro compound into a species prone to cycloaddition and possibly catalyzes cycloaddition. Dehydration to nitrile oxide must be considered, too. In fact, furoxans can be detected in the presence of dipolarophile, while in their absence furoxans can be prepared, at least from nitroacetates or other activated nitro compounds [83]. The Mn nitronate from ethyl nitroacetate has been reported to generate the corresponding nitrile oxide [81]. 

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