Thiophene, 3-chloro-, synthesis

Benzo[b]thiophene-2-carbonyl chloride, 3-chloro-synthesis, 4, 870, 889... 

Thiophene, bromotetrahydromethyl-pyrolysis, 3, 902 Thiophene, 5-t-butyl-2-methyl-dealkylation, 4, 800 Thiophene, chloro-polymerization, 4, 758 reaction with n-butyllithium, 4, 831 synthesis, 4, 835, 882, 933 Thiophene, 2-chloromercurio-reactions... 

Benzo[6]thiophene-2-carboxylic acid, 5-chloro-synthesis, 4, 933... 

Benzo[i]thiophene, 6-/-butyl-3-methyl-synthesis, 4, 880 Benzo[6]thiophene, 2-chloro-... 

Benzo[b]thiophene, 3-chloro-2-phenyl-synthesis, 4, 116 Benzo[6]thiophene, 2-cyano-synthesis, 4, 921 Benzo[6]thiophene, 3-cyano-synthesis, 4, 922... 

Phenanthro[l,2-d][l,2,3]selenadiazole, 10,11 dihydro- H NMR, 6, 348 synthesis, 6, 353 Phenanthro[b]thiophenes synthesis, 4, 914 Phenanthro[4,5-bcd]thiophenes synthesis, 4, 883, 907, 914 Phenanthro[9,10-ej[l, 2,4]triazines synthesis, 3, 434 Phenarsazin synthesis, 1, 561 Phenazine dyes, 3, 196-197 nitration, 3, 177 UV Spectra, 2, 127 Phenazine, 3-amino-2-hydroxy-in colour photography, 1, 374 Phenazine, 1-chloro-nucleophilic substitution, 3, 164-165 5-oxide... 

Dichlorothiophene can also be used for the synthesis of 3-substituted thiophenes, since it can be smoothly acylated and chloro-methylated in the 3-position, and the halogens can then be readily removed at the appropriate stage. 3-Thenylsuccinic acid (28) has thus been obtained by treating 2,6-dichloro-3-thenylsuccinic acid with sodium amalgam. 2-Bromo-3-thenylbromide can be utilized in a similar way. ... 

There have been a number of different synthetic approaches to substituted PTV derivatives proposed in the last decade. Almost all focus on the aromatic ring as the site for substitution. Some effort has been made to apply the traditional base-catalyzed dehydrohalogenation route to PTV and its substituted analogs. The methodology, however, is not as successful for PTV as it is for PPV and its derivatives because of the great tendency for the poly(u-chloro thiophene) precursor spontaneously to eliminate at room temperature. Swager and co-workers attempted this route to synthesize a PTV derivative substituted with a crown ether with potential applications as a sensory material (Scheme 1-26) [123]. The synthesis employs a Fager condensation [124] in its initial step to yield diol 78. Treatment with a ditosylate yields a crown ether-functionalized thiophene diester 79. This may be elaborated to dichloride 81, but pure material could not be isolated and the dichloride monomer had to be polymerized in situ. The polymer isolated... 

Typical examples are the formation of 3-chloro-2-phenylbenzo[b]-thiophene (21) in near quantitative yield from diphenylacetylene at room temperature,27 and the synthesis of the dichlorothianonane (22) from 1,5-cyclooctadiene.28... 

Representative of recent applications of the reaction to the synthesis of heterocycles are the photodehydrochlorination of chlorobenzo[b]thiophen (347) to give the fused pyrimidone 348,287 the photoelimination of HI from iodobenzene derivatives 349 to give the benzazepines 350,288 and the synthesis of the medium ring aza-heterocycle 351 by irradiation of the chloro precursor 352.289 Included among the many other examples of... 

A tremendous amount of work has been reported on the synthesis of arylthiophenes and heteroarylthiophenes utilizing the Stille reaction approach. In one case, 2-tributylstannylthiophene was coupled with p-acetoxyphenyl iodide to give thienylphenol 114 after hydrolysis [93]. In another, the union of 2-tributylstannylbenzo[fc]thiophene and p-acetyliodobenzene provided arylbenzothiophene 115 using inexpensive Pd/C as a heterogeneous catalyst, Cul as a co-catalyst, and AsPh3 as a soft ligand [94], Moreover, Kennedy et al. coupled 2-tributylstannylthiophene and 2-chloro-4-bromobenzylphosphonate (116) to make heterobiaryl... 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

Substituted 3-hydroxythiophenes are convenient starting-points for the synthesis of the thieno[3,2-Mthiophene system. Shvedov et obtained 50% of 3-chloro-3-ethoxycarbonyl-5-methylthiophene-2-aldehyde (110) from 3-ethoxycarbonyl-4-hydroxy-2-methylthiophene (109) by Vilsmeier formylation at 100°. Reaction with thioglycolic ter formed 3-ethoxycarbonyl-5-methoxycarbonyl-2-methylthieno[3,2-6]-thiophene (111) [. (36)]. 

Methods of synthesis of 3-chloro- and 3,4-dichloro-thiophenes have usually involved tedious procedures in which tri- and tetra-chloro derivatives are dechlorinated by reductive or other methods. Gthanolic potassium hydroxide converted 2,3,4,5-tetrachlorothiophene into a 50 50 mixture of 2,4- and 3,4-dichlorothiophenes direct heating of the same tetrachloro substrate gave a mixture of 2,3- and 2,4-dichloro isomers (48JA1158). 3,4,5-Trichlorothiophene was readily prepared by the reaction of 1,1,2,3-tetrachloro-l,3-butadiene with sulfur (82JOU348). 

Nucleophilic substitution procedures are also of use of the synthesis of j3-chlorinated thiophenes. Copper(I) chloride converted 3-bromothio-phene into its chloro analogue. Such reactions are best carried out in an... 

Tetrahydrobenzo[6]thiophen-4-one (103) may be prepared from y-(2-thienyl)butyric acid by cyclization with phosphoric acid854 or by Friedel-Crafts cyclization of the corresponding acid chloride.194, 355.358 j s 5-methyl,357 2-ethyl,194 2-isopropyl,358 2- and 3-tert-butyl,359 2,3-dimethyl,360 2-ethyl-3-methyl,360 and 2-bromo 354 derivatives and diethyl 4,5,6,7-tetrahydrobenzo[6]thiophene-4,5-di-carboxylate861 may be prepared similarly. 4,5,6,7-Tetrahydrobenzo-[6]thiophen-7-one (104)357 362,863 and its 5- and 6-methyl 357 and 2-chloro 362 derivatives are obtained from the appropriately substituted y-(3-thienyl)butyric acid, A recent patent 364 describes the vapor phase cyclization of y-(2-thienyl)butyric acid to 103. Ketones (103 and 104) are useful intermediates for the synthesis of 4- and 7-substituted benzo[6]thiophenes, respectively their reactions are discussed in Section VI, B, 4. 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

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