Thiophene analogs

A notable exploitation of this reaction has been used for the preparation of potential anticancer agents. In an attempt to control the water solubility of thiophene analogs, a series of sodium salts of 2,5-dicarboethoxy-3,4-dihydroxythiophene have been produced by condensation between thiodiglycolate esters and diethyloxalate. These condensation reactions consistently proceeded in good yield. 

The replacement of a benzene nucleus by a thiophene nucleus in compounds containing other chromophores causes more or less pronounced bathochromic shifts. These effects have been noticed in the thiophene analogs of malachite green (23), in cumulenes such as... 

The spectra and halochromism of thiophene analogs of triphenyl and diphenyl carbinol, " the spectra of anilides of 2- and 3-thenoyl-acetic acid, " and the fluorescence of some thiophene compounds have been investigated. 

One of the most striking differences between benzene and thiophene chemistry is the instability and difficult accessibility of the thiophene analogs of such important, well-known, and easily available compounds as phenol, aniline, and thiophenol. 

The thiophene analog of methadone (253) and isomethadone have been prepared and shown to be active analgesies. Heterocyclic acetamides of the type (254) have been prepared for evaluation of their analgesic and antipyretic activity. - ... 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

Many stilbenelike thiophene compounds have been prepared for a study of estrogenic activity, especially by Buu-Hoi et al. Thiophene derivatives of nonhydroxylated stilbene types showed no significant activitywhereas weak estrogenic activity was found in 5-acetyl-, 5-propionyl-, and 5-benzoyl-2-(-stilbenyl)thiophene. 1-Bromo-l,2-diphenyl-2-(5-bromo-2-thienyl)ethylene (258) was found to inhibit body growth and to produce extensive testicular atropy in male rats. A thiophene analog of estrogenic isoflavones (259)... 

Unlike alk-2-enylbenzonitrile ylides. which on thermolysis yield isolablecyclopropa[c]isoquino-lines, the thiophene analogs 2 and 5, generated from the respective imidoyl chloride, 1 and 4, cyclize directly to thienoazepine 3 and 6, respectively.40... 

Dimethylene-2,3-dihydrothiophene (37, Figure 2.3) is the thiophene analog [38] of o-quinodimethanes and has been used to develop a Diels-Alder-based synthetic approach to benzothiophene derivatives. Generated in situ by treating the trimethylsylyl ammonium derivatives 38 or 39 with Bu4N F , it... 

Despite that the thiophene ring is considered as a bioisoster of the benzene ring, the synthesis and chemistry of thiophene analogs of heterocycles with therapeutic interest remain poorly studied. One of the most recent examples concerns the synthesis of new substituted thioisatoic anhydrides (6 and 7-arylthieno[3,2-d] [1,3]oxazine-2,4-diones), which were prepared on a large scale under microwave irradiation conditions. A small library of thiophene ureidoacids was easily performed using a Normatron microwave reactor (500 W) with high yields and good purity [4,5] (Scheme 4). 

CD and ORD measurements are a useful tool in studying configuration and conformation. The configuration of optically active 4,4 -dicarboxy-2,2, 5,5 -tetramethyl-3,3 -biselenienyl (1, X = Se) relative to its thiophene analog (1, X = S), was determined by reducing both to the corresponding 4,4 -dihydroxymethyl derivatives (2), which could be related to each other by the quasi-racemate method and by circular dichroism studies.15 Compounds 1 have also been related to 3,3, 6,6 -tetramethyl-2,2 -diphenic acid (3), and it was found that the levorotatory form of 1 (X = Se, S) and the dextrorotatory form of 3 have the -configuration.16... 

The condensed isobenzofuran derivative l,3-dimethyl-2,5,7-triphenyl-2/f-furo[3,4-/]isoindoloquinone (64), has been prepared in four steps from a pyrrole derivative143 (Scheme 79) a thiophene analog of64 has been obtained in a similar manner.144 Key intermediates in both types of reactions are condensed rhodacyclopentadienes (cf. 63) which are obtained from appropriate diynes. 

The stability of o-sulfonylbenzonitrile oxides and their thiophene analogs probably depends on electronic factors. The same factors do not prevent dimerization, as can be seen from data concerning several differently substituted nitrile oxides of the thiophene series (103). Sterically stabilized 3-thiophenecarbonitrile oxides 18 (R = R1 = R2 = Me R = R2 = Me, R1 = i -Pr), when boiled in benzene or toluene, isomerized to isocyanates (isolated as ureas on reaction with aniline) while nitrile oxides 18 with electron-withdrawing substituents (R1 and/or R2 = SOiMe, Br) dimerized to form furoxans 19. 

Methylation of halothiophenes 86 and 88 was accomplished via the Stille reaction with tetramethyltin to give methylated thieno[3,2- >]pyran 87 [74] and thienyldeoxyuridine 89 [75], respectively. Analogously, the coupling of an allyl chloride, chloromethylcephem 90 and 2-tri-n-butylstannylthiophene furnished 91, an intermediate for a C(3) thiophene analog of cephalosporin [76]. 

In order to investigate the antitubercular activity of thiophene analogs, thiosemicarbazones were synthesized 12). It was found that the addition of a small amount of acetic acid facilitated the reaction between thiosemicarbazide and the thiophene carbonyl compound and that the reaction was essentially completed in one half to one hour. The activities of these semicarbazones, however, were not recorded. 

Buu-Hoi, No. Ph., Ng. Hoan and D. Lavit Thiophene Derivatives of Potential Biological Interest. Part. I. Thiophene Analogs of Stilbene and Related Compounds. J. chem. Soc. 1950, 21304. 

Part II. Thiophene Analogs of Marphanil Marphenide . J. chem. Soc. 1952, 165. 

The reactions of the thiophene derivatives in both forward and reverse directions are characterized by lower enthalpies and entropies of activation than the reactions of the selenophene analogs. In the forward reactions, enthalpy and entropy changes compensate nearly exactly and result in slightly greater rates of adduct formation for the selenophene derivatives despite the higher enthalpies of activation. The higher entropies of activation for the selenophene derivatives have been attributed to less solvated transition states as compared to the reactions of the thiophene analogs (Table XXVIII). 

As expected by thiophene analogy, irradiation of 2-phenylselenophene (50) yields 3-phenylselenophene (51). The enyne (52) and elemental selenium are also formed irradiation of 2-phenyltellurophene yields solely the enyne (52) and tellurium (81T3627,76JOM(108)183>. 

The pKa values for the four readily available thienopyridines (258-261) have been determined (Table 9). As can be seen from these data, the isoquinoline analogs are stronger bases than the quinoline analogs the same is true for isoquinoline and quinoline. The UV data of the benzo[6]thiophene analogs (258-261) (Table 10) show a considerable similarity to that of quinoline (258, 261) and isoquinoline (259,260). As expected, the spectra of thieno-[3,4-6]- and -[3,4-c]-pyridine differ from the parent compounds the colors of (262) and (263) are probably due to their long-wavelength maxima. 

Benzo[6]thienylketones are reduced by lithium aluminum hydride to secondary alcohols.465, 526 The carbinol bases of a series of benzo-[6]thiophene analogs of malachite green have been prepared.621... 

Benzo[6]thiophene-2,3-dicarboxylic anhydride reacts with phenol and resorcinol, respectively, to yield the benzo[ >]thiophene analogs of phenolphthalein and fluorescein.625... 

This synthetic procedure was used to synthesize thiophene analogs of PDE-I and PDE-II such as 196, compounds able to inhibit cyclic adenosine-3, 5 -monophosphate phosphodiesterase (86JCS(CC)826). In this case, the photochemical reaction by using Pd on carbon methodology gave the product in 64% yield. 

Thiophene analogs of higher polynuclear aromatic systems are readily available by oxidative photocyclization, as illustrated by the conversion of the following olefins to heterohelicenes (Scheme 21) (68JA5339 70JA6664 ... 

Conducting charge-transfer salts based on thiophene analogs of tetra-cyanoquinodimethane 91CSR355. 

Thiophene analogs of tetracyanoquinodimethane as new organic metals 92MI23. 

The harmala alkaloids harmaline (368 X = NH) and harmine (369 X = NH) are active reversible inhibitors of monoamine oxidase (MAO). Benzo[Z> ]thiophene analogs of harmaline (368 X = S) and harmine (369 X = S), when tested in vitro as inhibitors of rat liver MAO, showed that (368 X = S) was 50 times more potent than harmaline, but (369 X = NH or S) were equivalent in potency. The replacement of the indolic nitrogen by sulfur greatly increased the lipid solubility of the molecule, which was reflected in the physiological disposition of the two analogs. 

In the past several years a number of reports have appeared describing cardiovascular and diuretic effects associated with benzo[Z>]thiophene derivatives. Among these was the study of the benzo[ ]thiophene analog (371) of the/3-adrenergic blocking agent propanolol, which is the a-naphthol ether. The compounds showed comparable activity, showing that benzo[ ]thiophene may function as a bioisostere of naphthalene also. 

---