Furan, hydroxylation

NitrofuraZone. 2-[5-Nitro-2-furanyl)methylene]hydrazinecarboximide, the first nitrofiiran to be employed clinically, is prepared from 5-nitro-2-furancarboxaldehyde and semicarbazide (19). This product has seen clinical use topically as an antibacterial, for systemic appHcation for bacterial infections in poultry and swine, and also has been employed as a food additive. In rats, nitrofurazone is hydroxylated at the 4 position of the furan moiety (27). The involvement of nitrenium ions has also been postulated in the mechanism of action of nitrofurazone (38). 

In rats, the oxidative and reductive metaboHsm products have been identified as the 4-hydroxylated furan and [(3-cyano-l-oxopropyl)methyleneamino]-2-4-imidazohdinedione, respectively (27,42). In addition, the ease of electron transfer as a mechanism of activity with nitrofurantoin and nitrofurazone has been studied (43). 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Heterocyclic compounds carrying hydroxyl groups may be compared with phenols. Thomson has reviewed the tautomeric behavior of phenols often both tautomeric forms of polycyclic compounds such as naphthols can be isolated. Early work on hydroxy-thiophenes and -furans was also reviewed by Thomsond but until recently their chemistry has been in a somewhat confused state. A pattern is now beginning to emerge, at least for the a-substituted compounds, which appear to exist as A -oxo derivatives and to attain equilibrium slowly with the corresponding A -oxo forms. For the a-hydroxy compounds, the equilibrium generally favors the A -oxo form. 

The construction of the five contiguous stereocenters required for a synthesis of compound 3 is now complete you will note that all of the substituents in compound 5 are positioned correctly with respect to the carbon backbone. From intermediate 5, the completion of the synthesis of the left-wing sector 3 requires only a few functional group manipulations. Selective protection of the primary hydroxyl group in 5 as the corresponding methoxymethyl (MOM) ether, followed by benzylation of the remaining secondary hydroxyl, provides intermediate 30 in 68 % overall yield. It was anticipated all along that the furan nucleus could serve as a stable substi-... 

The spontaneous polymerization of furan adsorbed on carbon black with or without SnCl4 vapours35 has been explained by a similar cationic mechanism. Also, the polymerization of gaseous furan on liquid acidic surfaces35 has the same origin, but in these systems the polymers suffer an acid-catalyzed hydrolysis of their tetrahydrofuran rings which produces a considerable proportion of hydroxyl and carbonyl groups. 

The use of the hydroxyl groups of poly(vinylalcohol) as reactive sites for the preparation of various unconventional polymers is well known and indeed the very synthesis of poly(vinylalcohol) is based on a similar but reverse reaction. This general principle has been applied successfully to the synthesis of some vinyl-type furanic polymers, which cannot be made by classical routes. 

The potential of these transformations has not been fully exploited. The method is certainly valuable both for the purpose of studying the structure of furan polymers which might be of interest but cannot be prepared easily by conventional techniques and for preparing polymers in which a certain proportion of the hydroxyl groups of poly(vinylalcohol) are substituted with a furan moiety which gives the new product some special property. 

Analysis and purification of the product solution is best accomplished by gas chromatography. The submitters used a 500 cm. by 0.6 cm. aluminum or polyethylene column packed with 21% oxydipropionitrile on Chromosorb P with column, injector and detector operated at 25° and a flow rate of 50 ml./minute. Under these conditions the retention times of bicyclopentene and cyclopentadiene were 3 and 5 minutes, respectively, beyond that of the coinjected air. Since bioyclo-pentene is extremely labile with respect to acid catalysis any contact with water, hydroxylic solvents, and nonprotic acids should be avoided (Note 11). Bicyclopentene stored at —78° in anhydrous tetrahydro-furan is stable indefinitely. 

The reverse reaction (that is, the oxidation of a vinyl radical by Fe to the corresponding vinyl cation) may be involved in the reaction of the dimethyl ester of acetylenedicarboxyUc acid 261 with Fenton s reagent [Fe —H2O2, (217)] (216). When 261 was treated with Fe —H2O2 and the reaction mixture was extracted with ether, a small amount of furan 262 was isolated. A possible mechanism (216) for its formation may be addition of hydroxyl radical to the triple bond of 261, followed by addition of the intermediate vinyl radical to a second molecule of 261 and oxidation of the resulting radical with Fe to the corresponding vinyl cation, followed by cyclization to 262, as shown in Scheme XX. 

Whereas the degradation of the carboxylates of the monocyclic furan, thiophene, and pyrrole is initiated by hydroxylation, degradation of their benzo analogs is generally carried out by dioxygenation. The degradation of the analogs dibenzofuran and dibenzo-[l,4]-dioxin is discussed in Part 2 of this chapter. 

Anodic hydroxylation/methoxylation of furans has an exact chemical counterpart in the well-known bromine/methanol reaction, and the choice of method is not always easily made. One can compare the two methods particularly easily in syntheses of the flavoring component, the pyrone maltol 121, from the furan 122 since one group used the electrolytic method299 and another the chemical method.300... 

Hydroxymethyl-4,8-dimethylfuro[2,3-/z]chromen-2-one was realized in an efficient manner via a Claisen rearrangement of 4-(hydroxybut-2-ynyloxy)-4-methylchromen-2-one as depicted in the following scheme. Other examples with substitution of hydroxyl and with other substituents, such as chloro, amino, acetoxy were also reported <06JHC763>. A new approach for the synthesis of oxygenated benzo[fe]furans was developed via epoxidation and cyclization of 2 -hydroxystilbene <06T4214>. 

Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brpnsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated a-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2-dihydrobenzo /j]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. 

Substrates in which the furan was tethered at C-3 have also been examined107. These cases typically possessed ring-oxygenation at C-4, and the nature of this substituent proved to be important (Scheme 50). Examples with a free hydroxyl or a methyl ether at this position led to low yields of cycloadducts 221-224 and substantial amounts of polar by-products, possibly via competing solvent trapping pathways which ultimately lead to... 

The synthetic approach to the benzo[fo]furan is similar to that of the thiophenes described in Scheme 39. The synthetic approach was described by Flynn et al. [73], and an example synthesis is given in Scheme 40. The appropriate iodophenol 104 is coupled to the aryl alkyne 111. The intermediate 155 is subsequently cyclized in the presence of an appropriately substituted aryl iodide, e.g., 107 under an atmosphere of carbon monoxide gas, to give the benzo[fr]furan chalcone derivative 156. Deprotection of the hydroxyl produces the target compound 157. 

Titanium silicate molecular sieves not only catalyze the oxidation of C=C double bonds but can be successfully employed for the oxidative cleavage of carbon-nitrogen double bonds as well. Tosylhydrazones and imines are oxidized to their corresponding carbonyl compounds (243) (Scheme 19). Similarly, oximes can be cleaved to their corresponding carbonyl compounds (165). The conversion of cyclic dienes into hydroxyl ketones or lactones is a novel reaction reported by Kumar et al. (165) (Scheme 20). Thus, when cyclopentadienes, 1,3-cyclohexadiene, or furan is treated with aqueous H202 in acetone at reflux temperatures for 6 h in the presence of TS-1, the corresponding hydroxyl ketone or lactone is obtained in moderate to good yields (208). 

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