Thiophenes 2,3,5-trisubstituted

The precursor 3 served as a starting material for a series of trisubstituted thiophenes in a study towards progesterone receptor modulators, giving for example the product 4 upon reaction with an appropriate bromoketone. The fact that rather complex thiophene derivatives could be prepared in a straightforward manner compensates for the low overall yields <06JHC1391>. 

A tandem palladium catalyzed multi-component approach has been devised providing direct access to for instance trisubstituted thiophenes from the simple starting material 3-iodothiophene 41. In a representative experiment, the substrate 41 was converted to the product 42 by treatment with ethyl acrylate and iodobutane in the presence of a catalytic system consisting of Pd(OAc)2, tri(2-furyl)phosphine (TFP), norbomene, and a base. A mechanistic rationale accounting for this outcome was also proposed <06OL3939>. 

In addition, 1,4-diketones react efficiently with Lawesson s reagent under similar reaction conditions to give trisubstituted thiophene derivatives. The scope of this reaction is depicted in Table 7. 

A three-component procedure for preparation of trisubstituted thiophenes involving the 5-aryldihydrothiophen-2-ones 49, pyrrolidine, and aldehydes has been developed, leading for example to the series 50 in moderate yields. A corresponding series of reactions involving piperidine gave similar products, albeit in lower yields <07TL6133>. 

The NMR spectrum of thiophene (in acetone-,76) shows the C-2 and C-3 carbons at 125.6 and 127.3 ppm, respectively <1965JA5333, 1975CS76>. The larger value of the C-H coupling constants for the 2-position as compared to the 3-position (185 vs. 168 Hz) is helpful in the structure elucidation of trisubstituted derivatives. 

LR-mediated cyclization of 1,4-carbonyl compounds 589 under MW irradiation affords the corresponding thiophenes 590 (Equation 27) <2001JOC7925>. 2,3,5-Trisubstituted thiophenes 592 are prepared from 591 in a similar way <2005EJO5277>. 

The Pauson Khand reaction is compatible with a wide variety of functionalities, such as ethers, alcohols, tertiary amines, thioethers, ketones, ketals, esters, tertiary amides, carbamates, and benzene, furan, and thiophen rings. Disubstituted alkynes, alkenes with bulky allylic substituents, and trisubstituted alkenes frequently afford reduced yields of products. Because of the reduced ability of sterically hindered alkenes to coordinate and undergo insertion, insertion of one or more molecules of alkyne occurs instead. 

A [3,3] Claisen rearrangement of thiomorpholides has been reported to produce 2,3,5-trisubstituted thiophenes 11 <03XL6253>. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

Table 30 Formation of 2,3,5-Trisubstituted Thiophenes (260) from Ketone Enolates and 3-Thiazolines (257) ...

The trisubstituted thiophenes 21 were accessed by treatment of the intermediates 22 with ethyl 2-diazo-3-trimethylsilyloxy-3-butenoate 23 in the presence of Hg(OAc)2. The products 21 subsequently served as precursors for some thieno[3,2-6]pyridine derivatives <03JOC4867>. 

Dihydrothienocoumarins that have analgesic activity without anti-inflammatory activity have been synthesized. Compounds of type (154), with antibacterial, antifungal, and other activities, have been synthesized. Some NN N"-trisubstituted guanidines that contain thiophen rings and have anti-inflammatory properties have been synthesized. " Nitrosation of methapyrilene in vitro has been studied. 

Treatment of crude akynylalkanols (92), which are obtainable from (91) and 1-alkynylmagnesium halides, with hot aqueous acid provides a convenient synthesis of 3,5-di- and 2,3,5-trisubstituted (five-, six-, and seven-membered ring-fused) thiophenes (93) (Scheme 25) <89S2io>. Starting materials (91) are easily synthesized from a-halo ketones in high yields. The reaction may involve electrophilic attack of vinyl cation, produced by protonation of the triple bond, on the sulfur. 

The C3 position understandably undergoes carboxylation when both the C2 and C5 positions are substituted, albeit with diminished yields in comparison to the reaction at the C2 position. For example, the palladium(II)-catalyzed reaction of the 2,5-dichlorothiophene under thermal conditions gave the corresponding 2,3,5-trisubstituted thiophene with 1.6% yield. ... 

Dimethylsulphonium methylide reacts with trimethyl- or triphenyl--cyclopropenium salts to provide trisubstituted thiophenes [53] ... 

Thus, we decided to return to the concept of the original synthesis and couple the vinyl iodide 16 and thiophene boronic acid 17 to arrive to the same intermediate trisubstituted alcohol 18. 

Trisubstituted oxadiazoboroles 152 were synthesized in 28—85% yields using the cyclocondensation reactions of thiophene, furan, or pyridine... 

The poly(3-hexylthiophene) exhibited a distinct peak at 820 cm due to the out-of-plane vibration of the 2,3,5-trisubstituted thiophene. In the visible spectra, the polymer showed an absorption peak at 505 nm with two shoulders at 550 and 600 nm. The absorption edge was 650 nm. The was 4.5 x [O with a poly-dispersity index of 5.5. The iodine-doped film showed a conductivity of 200 S cm at a stretching ratio of 5. 

For the synthesis of potential glycogen synthase kinase 3>p (GSK-3 ) inhibitors, C-5 acylated 2,3,4-trisubstituted thiophenes were obtained by chloroacetylation in the presence of AICI3 in CS2. The same conditions were applied to acylate C-3 of... 

Trisubstituted thiophene 138 was synthesized in good yields using a tandem Michael addition and intramolecular Knoevenagel condensation strategy starting... 

G.G. Mandawad, B.S. Dawane, S.D. Beedkar, C.N. Khobragade, O.S. Yemul, Trisubstituted thiophene analogues of l-thiazolyl-2-pyrazoline, superoxidase inhibitors and free radical scavengers, Bioorg. Med. Chem. 21 (2013) 365-372. 

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