Fused thieno thiophenes

This method has a general character, and was successfully applied to the synthesis of photochrome 166 containing fused thieno[3,2-b]thiophene... 

The present method provides simple and facile access to the variety of furo- 408, benzofuro- 409, thieno- 410, benzothieno- 411, pyrrolo- 412, and indolo- 413 fused [[Pg.45]

Systems outside the scope of this review are, for example (a) those in which no N-doublets contribute to the -system these include thieno-thiophenes 18 and 21 (cf. CKL Section III,H,4 and ref. 34) (b) compounds with sulfur or oxygen at the ring junction, such as trithiapentalenes (22)35 and 6a-thia-l,6-diazapentalenes (23),36 and (c) systems with a third fused heterocyclic ring, e.g., thiazolo 3,2-c]purines (24).37... 

Saito et al. [33] described a new method for the synthesis of heterocycle-fused[c]thiophenes via reaction of aryl heteroaryl thioketones with carbene precursors. Heteroaromatic thioketones A react with carbenoids generated from bis(arylsulfon yl)diazomethanes or phenyliodonium bis(phenylsulfonyl)methylides to give hete-rocycle-fused[c]thiophenes B (Scheme 20). The reaction involves the ring closure of the intermediary thiocarbonyl ylides, followed by restorative aromatization via the elimination of a sulfenic acid. The present method provides simple and facile access to a variety of furo- 118, benzofuro- 119, thieno- 120, benzothieno- 121, pyrrolo-122, and indolo-123 fused [c]thiophenes (Scheme 20). 

Quinolizinium ions fused with thiophene were prepared by cyclo dehydration. A quaternary salt formed by reaction between 2-pyridinecarbalde-hyde and 3-bromomethylthiophene was cyclized with HBr to thieno[3,2-hjquinolizinium salt (270) (72%) (57JA4380). 

The rearrangement of fc-allenyl disulfides provides an interesting route to prepare fused thieno[3,4-c]thiophenes. Thus, Braverman reported that 276 reacted with lithium methoxide to give 280 in 70% yield (Scheme 51) (90T5759). Presumably,... 

The 2-(2-pheriylvinyl) derivative 18 and the thienyl compound 20 cyclize exclusively at the alkene carbon, and at the thiophene ring, to give 3,4-diphenyl-l//-2-benzazepine (19) and 4-phenyl-6-//-thieno[3,2-e]-2-benzazepine (21), respectively.48 A mechanistic rationale for these results has been offered. This method has been extended to the synthesis of 7Z7-pyrido[3,4-t/]-, 7//-pyrido[2,3-t/]- and 77/-pyrido[4,3-r/]benzazepincs and to other thieno- and furo-fused 2-benzazepines.244... 

Pyrrolo[l,2-fl]thieno[2,3-c]pyrazine (186) brominated mainly in the fused pyrrole ring. Only the third bromine atom introduced substituted the thiophene /3-position (86JHC17). 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Three different fused systems have been reported in the literature thieno[3, 2 4,5]thieno[2,3-c]pyridine (f/r-thiophenes), thieno[2, 3 4,5]thieno[2,3-c]pyridine (tram- thiophenes) and thicno[3,2-g]thicno [3,2-d pyridine derivatives. So far, the parent thienothienopyridines have only been prepared via the corresponding pyrylium salts (see below) all others are benzo or extended carbocyclic derivatives, for example, thienothienoquinolines. 

Deuteration in deuteriosulfuric acid of some derivatives of thieno fused diazaborines was studied by NMR spectroscopy. It was found that the pyridinic nitrogen was protonated and that deuteration occurred in the thiophene ring of the protonated molecule. In conformity with the above-mentioned electrophilic substitutions, the thiophenic /3-positions were more reactive than the a-positions. Isosteric thienopyridines showed similar reactivity and it was thus concluded that the systems were related (77JHC893). 

Nucleophilic substitution of (189b) with methoxide ion gave the methoxy substituted compound, which, however, reacted further to give deboronated thiophenes. Copper-promoted nucleophilic substitution of some 4-brominated thieno fused diazaborines can be carried out successfully (equations 13 and 14) <77CS<11)76). 

Diazotization followed by cyclization has been used to prepare fused thiophene derivatives. Thus diazotization of 3-aminothiophene-2-carboxamides in cone. HC1 leads to thieno-1,2,3-triazines (Scheme 122) (75CRV241). A similar reaction was also observed with the 4-carboxamide derivatives. With 2,4-dicarboxamides as substrates the 3-diazo group preferred to cyclize with the 2-carboxamide group. 

A perusal of the / values in Table 1 also shows that/aa is higher in the [3,2-6]-annelated systems than in the corresponding [2,3-6] isomers. For example / , in thieno[3,2-6]thiophene (3) and N-benzylthieno[3,2-6]pyrrole (18) is 1.55 and 1.3 Hz compared to 1.17 and 1.0 Hz for the corresponding [2,3-6 ]- annelated systems (7) and (19). This relatively high value for / - in the [3,2-6]-fused systems is a consequence of the transmission of the spin interactions between the protons through the v- framework rather than the cr-framework. In qualitative terms this means that several resonance structures can be written for such systems wherein electronic perturbations at C-2 are effectively transmitted to C-5 rather than C-6 (Scheme 4). 

A similar abnormal cyclization of 2-pyrrolylthioacetic acid (162) by PPA to the ketone (163) has been reported (Scheme 53) (61JOC2615, 61AK(18)15l). Thus, this Friedel-Crafts approach is not of synthetic value in the [2,3-6]-fused series. The acid-catalyzed cyclization of a 3-thienylthioacetic acid to give a thieno[3,4-6]thiophene was successful, but only if the highly reactive 2-position was blocked. For example, 2,5-dimethyl-3-thienylthioacetic acid (164) was cyclized with anhydrous HF to ketone (165), subsequent reduction of which gave 4,6-dimethylthieno[3,4-6]thiophene (166 Scheme 54) <76AHC(19)123>. 

---