Thiophenes nitro-, nucleophilic substitution

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-... 

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... 

Selected substituted thiophene derivatives may also react with nucleophiles. Primary and secondary amines react with 2-bromo-3-substituted-5-nitrothiophenes to produce 11 <95T5403>. Vicarious nucleophilic substitution of hydrogen (VNS) works generally for both 2-nitro- and 3-... 

Nucleophilic substitution is a relatively rare reaction with pyrrole, thiophene, or furan and requires an activating group such as nitro, carbonyl, or sulfonyl, just as it does with benzene (Chapter 23). Here is an intramolecular example used to make the painkiller ketorolac. 

Selenophene compounds are also more reactive in nucleophilic substitutions. Thus, 3-nitro- and 5-nitro-2-bromoselenophenes90 react with piperidine faster than do the corresponding thiophenes.91 The effect of electron-accepting substituents on the nucleophilic substitution of bromine located at the 2-position of 3,5-disubstituted selenophenes has been studied, as also has the applicability of the Hammett equation to this piperidino-debromination.92... 

In direct contrast with electron-deficient heterocycles like pyridines and the diazines, the five-membered systems do not undergo nucleophilic substitutions, except in simations (especially in furan and thiophene chemistry) where halide is situated ortho or para to a nitro group. In the maifipulation of the five-membered heterocycles, extensive use has been made of the various paUadium(0)-catalysed couplings regimes, as illustrated with one example (see 4.2 for a detailed discussion). 

The photonucleophilic substitution of five-membered heteroaromatic nitrocompounds has been investigated with the nucleophiles CN-, CNO, OMe-, and water.108 Both 2-nitrofuran and the thiophen undergo smooth substitution of the nitro-group, but 2-nitropyrrole is stable to light. Such substitution reactions may be of synthetic importance as the 2-nitro-compounds are readily available. Light-induced nitro-group replacement has also been observed for 8-nitro-quinoline, which in the presence of a hydrogen donor yields 8-hydroxyquinoline.109 In carbon tetrachloride solution the keto-oxime (52) is reported to be formed. 

Substituted nitrothiophenes serve as precursors for a variety of condensed thiophenes. The synthesis of thienopyrroles has been reviewed <85S143>. Treatment of (2-nitro-3-thienyl)methyl phenyl sulfone (497) with diethyl maleate in the presence of K2CO3 and 18-crown-6 gave the thienopyridine A -oxide (498) in 38% yield <92acs689>. The reaction apparently proceeds by Michael addition, followed by elimination of phenylsulfinate and cyclization. The starting material can be prepared by vicarious nucleophilic substitution discussed earlier. 

Vicarious nucleophilic substitution (VNS) of hydrogen has successfully installed a-functionalized carbon side chains on nitroindoles [1], One of the earliest examples of this was the alkylation of 5- and 6-nitroindoles (35 and 37) at the 4 and 7 positions, respectively [23]. Makosza and coworkers applied this chemistry to other nitro heteroaromatics, such as thiophene, furan, and pyrrole [24],... 

Although nucleophilic substitution of 3-halo-1,2,5-thiadiazoles is known, the symmetry of the heterocyclic nucleus prevents the detection of the aryne 567 by cine-substitution in the absence of isotopic labeling. An attempt to trap this species with anthracene (147) from the aprotic diazotization " of the amino acid 568 gave, instead of the heterotriptycene 569, a mixture of 9-nitro- (341) and 9-thiocyanoanthracene (570). The former compound is also observed in a similar reaction in the thiophene series (Section III.3.A.d) and could arise by direct nitration of anthracene with nitrous acid " present in the alkyl nitrite. 

Direct nucleophilic substitution on a thiophene ring is rather limited. It proceeds only with highly reactive substrates - thiophenes possessing strong electron-withdrawing groups like nitro - or with highly reactive nucleophiles. 

Nice examples of nucleophilic substitution on a thiophene ring are represented by nucleophilic substitutions of 5-acetyl-2-chloro-3-nitrothiophene (Scheme 103) [164], The acetyl group, as a second electron-withdrawing group, in addition to the nitro group, was necessary to support successful nucleophilic substitution. Various nucleophiles were effective, including aliphatic and aromatic V-nucleophiles, aliphatic 0-nucleophiles as well as aliphatic S-nucleophiles (Scheme 103) [164],... 

Another mechanism of nucleophilic substitution which is relevant to thiophenes is oxidative nucleophilic substitution of hydrogen (ONSH). An example is the reaction of 2-nitrothiophene with the carbanion originating from diphenylacetonitrile. This carbanion forms On-adducts only at a position para to a nitro group for steric reasons. Thus, after addition of an oxidant KMn04, the final product is 83 (Scheme 116) [173]. 

Nucleophilic Substitutions.— The rates of nucleophilic substitution of bromine in 3-bromo>2-nitrothiophen with o-, m-, and p-substituted thiophenoxide ions in methanol are faster than those of 2-bromo-3-nitro-thiophen with the same nucleophiles." Somewhat unexpectedly, 2,3-di-bromo-4-methyl-5-nitrothiophen reacts faster with nucleophiles such as piperidine and phenylthiolate at position 2 than does 2,3-dibromo-S-nitro-thiophen." 4-Cyano-2-nitrothiophen reacts with sodium methoxide in methanol to give the Meisenheimer adduct (107), whereas 2-cyano-4-nitro-thiophen gives the sodium salt of the carboxyimidate (108), from which methyl 4-nitrothiophen-2-carboxyiimdate can be isolated upon acidification."" If, however, 2-cyano-4-nitrothiophCT is treated with sodium methoxide in [ He]DMSO, formation of the Meisenheimer complex (109) is... 

Nucleophilic Substitution, Metallation, and Halogen-Metal Exchange.—Direct nucleophilic displacement of the 7-chloro-group of 7-chloro-3-methyl-benzo[b]thiophen has been achieved. 3-Bromobenzo[b]thiophen was reduced to the 3-deuterio-derivative by the reaction with sodium borodeuteride and palladium chloride. Meisenheimer complexes were formed in the reaction of methoxide ion with 2-methoxy-3-nitro- and 3-methoxy-2-nitrobenzo[b]thiophen. Rate and equilibrium data were determined in methanol at 25 C. On treatment of 2-bromobenzo[b]thiophen with potassium amide in liquid ammonia, bromine migration to the adjacent carbon atom was observed. Considerable evidence for the occurrence of an intermolecular transbromination was obtained. The reaction of 3-bromo-benzo[b]thiophen with piperidine has been reinvestigated and found to give primarily the normal, but also some of the cine-substitution product, which is the only product obtained in the reaction of 2-bromobenzo[b]thiophen. Possible mechanisms for some of these reacticms are suggested. 

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). 

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>. 

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