Nitration of furans

Furans can be nitrated with a mixture of fuming nitric acid and acetic anhydride at low temperature. The initial products from the nitration of furan-2-carbaldehyde and its diacetate are (525), (526), (527) and (528), indicating that both 1,4- and 1,2-addition to the diene system may occur (76KGS601) (see Section 3.11.2.2.3). Analogous products are obtained from the nitration of furan-2-carboxylate (75KGS883). Carboxylic acid groups are often replaced thus 5-bromofuran-2-carboxylic acid on nitration yields 5-bromo-2-nitrofuran, which may be readily converted to 5-iodo-2-nitrofuran and 2,5-dinitrofuran (61ZOB263). 

The nitration of furan by nitric acid in organic solvents takes a peculiar course. It has been known for a long time114-116 that the nitration of furan in acetic acid proceeds through the formation of a... 

Whilst the mechanism shown above applies to pyrrole and thiophene, the nitration of furan with acetyl nitrate gives the 2,5-addition product 2.32, arising from attack of acetate ion on the intermediate cation 2.31. Treatment of 2.32 with pyridine eliminates the elements of acetic acid producing nitrofuran 2.33. 

Nitration of furan with nitronium tetrafluoroborate produces nitrofuran 2.33 directly. Contrast this result to the two stage reaction necessary with acetyl nitrate, page 16. Explain these observations. 

A mixture of 2-t-butylfuran and 2,5-di-t-butylfuran is obtained by the action of t-butyl chloride on furan in the presence of mesitylene nolybdenum tricarbonyl." The intermediate in the nitration of furan-2-aldehyde in acetic anhydride has been identified as compound (26). Treatment of 5-bromo-2-furoic acid with sulphur tetrafluoride in hydrogen fluoride yields the dihydrofuran (27). Bromo-furans are converted into aryl-furans by crosscoupling with aryl Grignard reagents in the presence of nickel(II)-phosphine complexes. 2-Furoic acid is lithiated at position 5, 3-furoic acid at C-2. 2-Methylfuran yields the 5-methylthio-derivative by lithiation and subsequent treatment with dimethyl disulphide. The corresponding phenylthio-compound (28) has been converted into a series of 4-substituted 2-methyl-furans (29 R = alkyl, MeaSi, CO2H, or RCHOH) by the sequence bromi-nation, lithiation, treatment with the appropriate electrophile, and, finally, desulphurization with Raney nickel. 2-Lithiofuran reacts with copper(II)... 

Olah and Kuhn reported that thiophene forms nitrothiophene in 91% yield on nitration with NOJBFJ [17], while the nitration of furan results in a 14% yield of nitrofuran. 3-Nitro-6-phenyl-2-pyridone has been obtained in 40% yield by the nitration of 6-phenyl-2-pyridone with NO2 BF4 [75],... 

Nitration of furan rings is accomplished by treatment of furan with concentrated nitric acid and sulfuric acid. This protocol was employed by Fathali and co-workers in their concise synthesis of the antibacterial nitrofurazone. Treatment of 2-furaldehyde with nitric acid, followed by treatment with acetic anhydride, gave the corresponding 5-nitrofurfuraldiacetate. Reaction of 5-nitrofurfuraldiacetate with semi-... 

An alternative route to 5-nitro-2-furancarboxaldehyde requires nitration of 2-furancarboxaldehyde oxime [1121 -47-7] with mixed acid to give the nitrated oxime [555-15-7] and concomitant hydrolysis (22). Furthermore, 2-furan-carboxaldehyde derivatives with the R-substituent in place have been nitrated to the desired product (23). 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Nitration of furfuryl alcohol (2-furylmethanol) in acetic anhydride yields the nitro-nitrate 57 which possesses both a reactive methylene group able to undergo aldol reactions, etc., and also a nitrate ion leaving group for nucleophilic substitutions.137 Detailed studies of the nitration disclose various products resulting from the addition of one or even two acetic acid residues to the furan nucleus in competition with the nitrations.138,139... 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

Changes in intramolecular selectivity in the bromination and nitration of alkyl-benzenes in acidic media have been attributed to changes in medium polarity or changes in electrophile solvation. Mass spectrometric studies of the first stage in the gas-phase reactions of halobenzenes, furan, thiophene and pyrrole with alkyl cations have been rationalized in terms of co-existing a- and tt-complexes. The extent of... 

There are examples of ipso attack during the nitration of pyrroles, furans and thiophenes and in the corresponding benzo-fused systems. Reactions resulting in nitro-dealkylation, nitrodeacylation, nitro-decarboxylation and nitro-dehalogenation are to be found in the monograph reactivity chapters of CHEC. Treatment of the 3-azophenylindole (64) with nitric acid in acetic acid at room temperature gives 80% of the 3-nitroindole (65) (81JCS(P2)628). 

Nitration of benzo[6]furan may be achieved with nitric acid in acetic acid and affords the 2-nitro compound, although nitrogen dioxide in benzene is reported to give the 3-nitro compound. 2-Phenylbenzo[6]furan with nitric acid in acetic acid yields the 3- and 6-nitro compounds. Treatment of 2-bromobenzo[6]furan with nitric acid and sodium nitrite yields 2-nitrobenzo[6]furan. The only electrophilic substitution reported with a benzo[c]furan is nitration of 1,3-diphenylbenzo[c ]furan with sodium nitrate and sulfuric acid, and this occurs on a phenyl group. 

The nitration of phenylfurans takes place in the furan ring very readily. The nitration of methyl 3,4-diphenylfuran-2-carboxylate using nitric acid acetic anhydride at low temperatures (-40 to 20°C) gives products due to nitration in the furan ring (20) and (21), up to 40% of (20) and 20% of (21) being obtained. With the addition of concentrated sulfuric acid to the nitrating mixture, compounds (22) and (23) (approx. 30 and 10%, respectively) are obtained and none of the products (20) and (21) (81CPB635). 

Afterward, analogous intermediates have been isolated by several authors in the nitration of other furan derivatives bearing electron-withdrawing substituents.119 120 Michels and Hayes119 studied the kinetics of the conversion of the addition intermediate into the final nitro-substituted derivative by the action of several bases. 

The orientation of the substitution in mixed systems containing two different rings. For instance, the higher reactivity of furan with respect to thiophene was deduced from the orientation in the nitration of 2-furyl-2-thienylketone (13)176 and in the acetylation of 2-furyl-2-thienylmethane177 (14). 

Furan and pyrrole are not stable to mineral acids, but acetyl nitrate can be used for the nitration of all three heterocycles. 

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