Ring structure thiophene derivatives

Piroxicam (84, Feldene in the US), a non-selective COX inhibitor with both analgesic and antipyretic properties, is one of the most used NSAIDs and serves as prototype of the oxicam family. This drug is utilized to relieve the symptoms of arthritis, menstrual pains or cramps and fever. It is also used in veterinary medicine to treat certain neoplasias expressing COX receptors, such as bladder, colon and prostate cancers. Variation on the structure of piroxicam has produced several other analogues with the benzene ring replaced by a thiophene ring and/or derivatives of the amide moiety, including meloxicam (85, a thiazole amide), isoxicam (86, an isoxazole amide), tenoxicam (87a, a thiophene derivative) and lornoxicam (87b, a chlorothiophene derivative). 

Metal complexes containing q -bonded thiophenes, where the ring formally donates 6 electrons and occupies three coordination sites (Lj-type ligand) are the most numerous and stable of the transition metal-thiophene derivatives, examples being available for Cr, Mn, Re, Fe, Ru, Rh, and Ir. Curiously, the synthesis of the first n-thiophene metal complex, viz. Cr(CO)3(q -T) reported by Fischer as early as 1958 [67] represents still today the only example available for a Group 6 metal it-bonded to thiophene its X-ray structure was solved by Dahl in 1965 albeit with a strong rotational disorder for the... 

In contrast with the triphos-iridium complexes of ring opened thiophenes described above, which are delocalized in nature, these Pt derivatives are better described as localized thiametallacycles, on the basis of NMR data and of the X-ray structure of the BT derivative. On heating these complexes in the presence of excess PEtj the reaction can be reversed this allowed the determination of the corresponding equilibrium constants by use of NMR spectroscopy. The measured values indicate that the thiaplatinacycle derived from BT is about 10 times more stable than those derived from T or DBT, which are in turn, similar to each other. 

Gleiter and coworkers64 have studied a number of planar heteroaromatic systems involving S—N bonds within the ring structure. Thieno[3,4-c]isothiazoleis a nonclassical condensed thiophene, and its triphenyl derivative, triphenylthieno [3,4-c] isothiazole (106), is a 1071 system containing two different masked 1,3-dipolar systems. It was synthesized from 4-phenyl-1,3,2-oxathiazolylium-5-olate (104) and dibenzoylacetylene via the direct precursor isothiazole (105) and its photoelectron spectrum compared with that of the related thieno [3,4-c] thiophene (107)34. The spectrum is characterized by an isolated first band at 6.9 eV which is verified by PPP-CI calculations to involve the 7c( au ) orbital confined to the thienothiophene ring. 

A significant modification of the Bradsher method was introduced recently by Castle to effect homoannulation of structurally appropriate methyl derivatives of condensed thiophenes in four steps (Scheme 28a, where NBS = N-bromosuccinimide DIBAL = diisobutylaluminum hydride).658 106a l26a The main feature is the conversion of a methyl substituent to the—CH=CH— unit of a peri-condensed ring structure. Yields reported for the steps in the transformation 358c -> 76 are 76, 72%, and 32% (last two steps). The intermediate aldehyde 358d undergoes cyclization at C-l. In the same manner, overall yields of 6% for 34a, 9% for 77, and 27% for 79 were obtained. 

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