Nitro compounds, thiophene derivatives

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Bromination (Br2) of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords either a 2-bromo or a 5-bromo derivative, depending on whether the reaction is carried out at 0° in ether,445,446 or at—5 to 0°in 50% aqueous acetic acid.354 The 5-bromo derivative condenses with morpholine or potassium phthalimide to give 140a or 140b, respectively.445, 446 Hydrazinolysis of 140b fails to give any of the 5-amino derivative.445,446 On nitration, the 2-bromo derivative affords the 3-nitro compound or 141 (R = N02), depending on the reaction conditions.354 With sodium azide in PPA the 2-bromo and 2-bromo-3-... 

Aminobenzo[6]thiophene and its simple ring-substituted derivatives are most conveniently obtained by reduction of the corresponding nitro compound with tin and hydrochloric acid,883,334,544,545 iron and hydrochloric acid,555 ferrous sulfate and ammonia,185,330 333 334,497 sodium borohydride and palladized charcoal,337 cata-lytically,152, 422,488,543 or, preferably, with Raney nickel and hydrazine hydrate.152,298,338,497,556 Several 5-aminobenzo-[6]thiophenes may also be made by cyclization reactions (Section IV, D).239,330,331 333,494... 

Dimethoxy- and 5,6-methylenedioxybenzo[6]thiophene undergo bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation in the 2-position (see Section VI, A).189 With nitric acid, however, 5,6-methylenedioxybenzo[6]thiophene affords an unidentified mononitro derivative, which is not the 2-nitro compound.548... 

Thiophene possesses the characteristics of aromatic compounds it is converted into nitro compounds by nitric acid, into halogen derivatives by bromine and chlorine, into sulphonic acids by... 

The 5-acetyl derivative of (538) has been converted into the 5-NHj, 5-CO2H, and 5-CH2C02H compounds. From the amino-compound the 5-bromo-derivative was obtained upon diazotization, which upon treatment with potassium amide in liquid ammonia gave a mixture of the 4-amino-(major) and 5-amino-isomers. The compound (538) was converted into the iST-oxide, which upon nitration in sulphuric acid gave 4-nitrothieno-[2,3-Z>]pyridine 7-oxide. Nitration in acetic acid, on the other hand, gave the isomeric 5-nitro-derivative. Several reactions were carried out with these nitro-compounds. In a manner similar to that described for (538) and (539), the compounds (542)—(544) were prepared from 3-aminobenzo[6]-thiophen, 2-aminothieno[2,3- ]thiophen, and 5-aminobenzo[6]thiophen... 

Mechanistic studies supported the evidence that arylcopper compounds are intermediates in the synthesis of biaryls [60, 61]. This observation smoothed the way for the efficient synthesis of unsymmetric biaryls in a two-step procedure consisting, first, in the preparation of an, e.g. thienylcopper derivative followed by the treatment with different aryl halides. 2-Thienylcopper 42, for example, is prepared from the corresponding Li—Ti—H 9 or Grignard derivative and a copper(I)halide and is then reacted with iodo- or bromoarenes in pyridine or quinoline. By this procedure e.g. H-T2-H 2 is formed in 42% yield by the reaction of Cu-Ti-H 42 and 2-iodothiophene 8 [61] [Eq. (14)]. Analogously, 2-(/i-nitro-phenyl)thiophene is obtained in 70% when Cu—Ti—H 42 is treated with />-iodo-nitrobenzene. Note that the formation of undesired symmetric biaryl products is avoided [60, 61, 63]. 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

Mercury(II) acetate tends to mercurate all the free nuclear positions in pyrrole, furan and thiophene to give derivatives of type (74). The acetoxymercuration of thiophene has been estimated to proceed ca. 10 times faster than that of benzene. Mercuration of rings with deactivating substituents such as ethoxycarbonyl and nitro is still possible with this reagent, as shown by the formation of compounds (75) and (76). Mercury(II) chloride is a milder mercurating agent, as illustrated by the chloromercuration of thiophene to give either the 2- or 2,5-disubstituted product (Scheme 25). 

Direct nitration of dibenzothiophene occurs in the 2-position, while prior oxidation of the sulfur atom to either the sulfoxide or sulfone causes nitration to be directed to the 3-position. These two reactions form the starting point for the synthesis of most of the known derivatives of dibenzothiophene, which normally proceed via the derived amines. This has now been further illustrated by the synthesis of both 1-nitro- and 4-nitrodibenzothiophene from iV -derivatives of 2- and 3-aminodibenzo-thiophene, respectively, as described below. The synthesis of these two compounds thus completes the series of mononitrodibenzothiophenes. Unfortunately hopes of s3mthesizing nitrodibenzothiophenes via the chlorocyclohexanone route have been almost certainly ruled out by the failure to produce 2-nitrodibenzothiophene by this route (Section IV, A). 

Two substrates of special interest are 2-(2-hydroxyethoxy)-3-nitro-thiophene and its 3-(2-hydroxyethoxy)-2-nitro isomer. Both compounds form Meisenheimer-type spiro adducts, 135 and 136, by ring closure at the 2-and 3-positions, respectively.177 Intramolecular cyclization brings in an extra driving force for the formation of the adduct, which is also observed in the trinitrobenzene series.31 This would account for the structure of adduct 136, which exceptionally bears the sp3-hybridized carbon on a ft position. No other examples of such a structure from 5-membered heteroaromatic substrates is known even for transient species, except for benzoannelated derivatives (see Section III,A,3). 

---