Thiophene, nitro-substituted

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

Many examples of VNS of hydrogen in nitro-substituted benzenes, pyridines, thiophenes, and other five- and six-membered heterocycles can be found in [213]. 

Nitronium triflate (Tf0N02) which is readily generated in dichloromethane from tetramethylammonium nitrate (McqN NOa") and triflic anhydride, can be used as a nitrating agent. Its application for the nitration of methyl thiophene-2-carboxylate afforded 5-nitro- and 4-nitro-substituted isomeric products in 91% combined yield (Scheme 89) [137]. 

Nitration of benzo[6]thiophene (HNOs/AcOH) yields mainly the 3-nitro derivative. Under these conditions the /3 to a ratio of substitution is approximately 5 1, which is... 

Thiophene, 3-nitro-4-(phenylsulfonyl)-cine substitution, 4, 817, 825 Thiophene, oxo-synthesis, 4, 125... 

Finally, certain 3-substituted compounds can be prepared by utilizing the - meta) directing powet (cf. Section IV,B) of some groups in the 2-position which afterward can be removed. 3-Nitrothiophene is prepared by nitration of 2-thiophenesulfonyl chloride and by removal of the sulfonic acid group of the 4-nitro-2-sulfonyl chloride formed with superheated steam. Another approach to 3-nitrothio-phene is to nitrate 2-cyanothiophene, separate the 4-nitro-2-cyano-thiophene from the 5-isomer, hydrolyze, and decarboxylate. A final method of preparation of 3-nitrothiophene is by simultaneous de-bromination and decarboxylation of 5-bromo-4-nitro-2-thiophene-carboxylic acid obtained through the nitration of methyl 5-bromo-2-thiophenecarboxylate. 

From resonance structure (12) it is obvious that a —I—M-substit-uent strongly deactivates the 2-position toward electrophilic substitution, and one would thus expect that monosubstitution occurs exclusively in the 5-position. This has also been found to be the case in the chlorination, bromination, and nitration of 3-thiophenecarboxylic acid. Upon chlorination and bromination a second halogen could be introduced in the 2-position, although further nitration of 5-nitro-3-thiopheneearboxylic acid could not be achieved. Similarly, 3-thiophene aldehyde has been nitrated to 5-nitro-3-thiophene aldehyde, and it is further claimed that 5-bromo-3-thiopheneboronic acid is obtained upon bromination of 3-thiopheneboronic acid. ... 

The position of substitution in disubstituted thiophenes can, in most cases, easily be deduced from the directing effect of each substituent. Thus with a - -M-substituent in the 2-position and a —M-substituent in the 5-position, both substituents direct the entering group to the 3-position as is exemplified by the nitration of methyl 2-bromo-5-thiophenecarboxylate to methyl 2-bromo-3-nitro-5-thio-phenecarboxylate (109) or in the chlororaethylation of methyl 2-methyl-5-thiophenecarboxylate to methyl 2-methyl-3-chloromethyl-5-thiophenecarboxylate (110). °... 

Radicaloid substitution has not been extensively studied in the thiophene series. Molecular orbital calculations indicate that substitution should occur in the a-position. This has been found to be the case in the Gomberg-Bachmann coupling of diazohydroxides with thiophenes which has been used for the preparation of 2-(o-nitro-phenyl) thiophene, 2-(p-toluyl) thiophene, " " and 2-(p-chloro-phenyl)thiophene. " Coupling in the /8-position has been used for the preparation of 1,3-dimethyl-4,5-benzisothionaphthene (148) from 2-amino-tt-(2,5-dimethyl-3-thienyl)cinnamic acid (149). A recent investigation describes the homolytic phenylation of 2- and 3-phenyl-... 

Nucleophilic substitution has been used for the preparation of many thiophenes. For instance, 2-phenylthio-3,4-dinitro-5-piperidino-thiophene (155) has been prepared " through stepwise reaction of (150) with different nucleophiles. Nitrothienols and derivatives of them have been obtained from halogenated nitrothiophenes. " Allyl ethers have been prepared by the reaction of 5-chJoro-4-nitro-2-acetylthiophene, 3-nitro-2-chlorothiophene, and 2-nitro-3-bromothio-... 

Melles and Backer " found, from a study of the oxidation of substituted thiophenes with perbenzoic or peracetic acid, that sulfones could be obtained from polysubstituted methyl- and phenyl-thiophenes and that the presence of electron-attracting groups, such as nitro, hindered the oxidation. Oxidation of thiophene - led to a product which was formed through a Diels-Alder reaction between the intermediate thiophene sulfoxide (211) and thiophene sulfone (212) and for which two alternative structures, (213) or (214), were suggested. Similar sesquioxides were also obtained from 2- and 3-methylthiophene and 3-phenylthiophene. The structures were not proved. Bailey and Cummins synthesized thiophene-1,1-dioxide... 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

Such nucleophilic displacements are likely to be addition-elimination reactions, whether or not radical anions are also interposed as intermediates. The addition of methoxide ion to 2-nitrofuran in methanol or dimethyl sulfoxide affords a deep red salt of the anion 69 PMR shows the 5-proton has the greatest upfield shift, the 3- and 4-protons remaining vinylic in type.18 7 The similar additions in the thiophene series are less complete, presumably because oxygen is relatively electronegative and the furan aromaticity relatively low. Additional electronegative substituents increase the rate of addition and a second nitro group makes it necessary to use stopped flow techniques of rate measurement.141 In contrast, one acyl group (benzoyl or carboxy) does not stabilize an addition product and seldom promotes nucleophilic substitution by weaker nucleophiles such as ammonia. Whereas... 

Chakrabarti and coworkers at Eli Lilly in the United Kingdom have reported the initial discovery and synthesis of olanzapine (Schemes 5 and,6). The thiophene 22 was synthesized by adding a DMF solution of malononitrile to a mixture of sulfur, propionaldehyde and triethylamine in DMF. The anion of amino thiophene 22 underwent a nucleophilic aromatic substitution with 2-fluoronitrobenzene to provide 23. The nitro group was reduced with stannous chloride and the resulting anihne cyclized with the cyano group to form amidine 24. Finally, a mixture of N-methylpiperazine and 24 were refluxed in DMSO/toluene to afford olanzapine (2). 

Alternatively, substituting malononitrile with methyl cyanoacetate in the thiophene forming reaction gave 25 with a carbo methoxy group at the 3 position of the thiophene (Scheme 6). Compound 25 was reacted with 2-fluoronitrobenzene as in Scheme 5 to form 26 and hydrogenation of the nitro group provided 27. The crude... 

Cine substitution has also been observed in the reaction of the 3-nitro-4-sulfone (423) with thiophenoxide <76JCS(P1)2264). A mixture of products (424) and (425) is formed, but the major one is (425) where the N02 has been displaced. Preliminary studies have shown that here the mechanism may also be similar to the one described above for the dinitro-thiophene reaction (78JCS(P1)1140). 

The activated halogenothiophene is more reactive than a similarly activated halogeno-benzene. A quantitative study of the rate of piperidino-debromination of six isomeric bromonitrothiophenes reveals that these substrates react considerably faster than the corresponding bromonitrobenzenes. As in electrophilic substitution, the 2,3-, 2,4- and 2,5-relationships have been equated to ortho, meta and para substitution in benzene derivatives. Although there is some validity in this, a few inexplicable results have been encountered in the above study thus 2-bromo-4-nitrothiophene reacts much faster than either 2-bromo-3-nitro- or 2-bromo-5-nitro-thiophene (64AHC(3)285>. 

Benzo[6 jthiophenes with nitro groups at the 4-, 5-, 6- or 7-positions may be synthesized by ring closure reactions of appropriately substituted benzene derivatives. Nitration of 5-acetaminobenzo[6]thiophene gives the 4-nitro derivative, which can be hydrolyzed and deaminated to yield 4-nitrobenzo[6]thiophene (equation 44). 5-Nitrobenzo[6]thiophene is conveniently available by decarboxylation of 5-nitrobenzo[6]thiophene-2-carboxylic acid, which in turn is available by a Perkin reaction of 4-nitro-2-formylphenylthioglycoIic ester (equation 45 Section 3.15.2.3). The 7-nitro isomer may be obtained similarly. 

A variety of substituted 3-aminobenzo[6]thiophenes have been obtained by ring closure reactions of nitriles (equation 57). Various o -cyanophenylthioacetyl derivatives, when treated with base, yield the 3-amino derivatives (Section 3.15.2.2.3). The benzonitriles may be obtained by displacement of the o-nitro group from o -nitrobenzonitriles (74JOC3440). 2-Arylthio-l-chloroenamines are cyclized to 3 -dialkylaminobenzo[6]thiophenes in the presence of Lewis acid catalysts (equation 58). The 1 -chloroenamines may be prepared from t-amides or ynamines <8lH(15)l 179>. 

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