2-Aryl-substituted benzo thiophenes

Methyl- and 2-aryl-substituted benzo[fc]thiophenes (26) can be synthesized starting from o-toluenethiol in three steps, which involves the intramolecular addition of thiols, produced by acid hydrolysis, to the carbonyl group followed by dehydration as the final step (Scheme 3) (91JHC173). 

In 1949, Werner187 announced the synthesis of several 3-alkyl- and 2,3-dialkylbenzo[6]thiophenes by the cyclodehydration of (arylthio)-acetones with phosphorus pentoxide or zinc chloride [Eq. (5)]. The reaction has since been widely used to synthesize alkyl- and aryl-substituted benzo[6]thiophenes (Table IV). Cyclodehydration proceeds most conveniently with PPA,297 298 but concentrated sulfuric acid,299,300 hydrofluoric acid, 299 aluminum chloride in benzene301 or chlorobenzene,302 zinc chloride and hydrochloric acid,303 a melt of aluminum and sodium chlorides,304 and phosphorus pentoxide in boiling o-dichlorobenzene 305 have been less widely used. 

A synthesis of 2-alkyl- or 2-aryl-substituted benzo[Z>]thiophens consists of the cyclization of an aryl thioether with an acetonyl or phenacyl group in the or/Ao-position (315) with 48% hydrobromic acid. In order to obtain (315 R = Ph), 2-methylthiobenzyl cyanide is treated with phenyl-magnesium bromide. The reaction of or//to-methylthiostyrene derivatives, especially cinnamic acids (316), with sulphuryl chloride followed by pyridine, probably gives the benzo[6]thiophens (318) via the sulphenyl chloride (317). ... 

When benzyl halides, benzylidene halides, benzotrichloride, or aryl-substituted haloethanes are heated with sulfur, complex mixtures containing thiophenes, benzo[6]thiophenes, and other condensed... 

A general route to l,3-diaryl-benzo[c]thiophenes starts with the synthesis of an aryl-substituted phthalide, reaction of this with an aryl (heteroaryl) Grignard reagent, then thionation using Lawesson s reagent. ... 

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[d]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2 -bithiophenes have been 5,5 -diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>. 

An alternative approach to benzo[Z ]thiophene derivatives includes treatment of an aryl-substituted ketene dithioacetal monoxide 188 with trifluoromethanesulfonic anhydride [99] (TfjO) in the presence of K2CO3 in toluene at 25 °C, followed by addition of ethanolamine to the reaction mixture, provided benzo[fc]thiophenes, including 3-trifluoromethylbenzo[Z ]thiophene 189, in good yields. The cyclization proceeded through formation of reactive sulfonium electrophile [1(X)]. The synthesis of the starting material 188 was also facile and scalable, starting from aryl ketone 186 and formaldehyde dimethyl dithioacetal S-oxide (FAMSO) [101]. 

A series of 3-cyano-substituted benzo[fo]thiophenes has been shown to undergo Heck-type coupling, at C2, with various aryl halides (eq 87). ... 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

The synthetic approach to the benzo[fo]furan is similar to that of the thiophenes described in Scheme 39. The synthetic approach was described by Flynn et al. [73], and an example synthesis is given in Scheme 40. The appropriate iodophenol 104 is coupled to the aryl alkyne 111. The intermediate 155 is subsequently cyclized in the presence of an appropriately substituted aryl iodide, e.g., 107 under an atmosphere of carbon monoxide gas, to give the benzo[fr]furan chalcone derivative 156. Deprotection of the hydroxyl produces the target compound 157. 

The possibility of optical isomerism arising from restricted rotation (atropisomerism) about the 2,2 -bond in 3-substituted 2-(2-naphthyl)-benzo[6]thiophenes has been recognized by Lamberton and McGrail.54 Schuetz and Ciporin164 have interpreted the UV spectra of six 3-aryl-benzo[6]thiophenes according to a theory of steric hindrance to free rotation about the pivot bond of the two aromatic rings, but the results are now invalid, since some of the 3-arylbenzo[6]thiophenes used in this study have been shown to be the corresponding 2-isomers (see Section IV, C). No attempt appears to have been made to resolve compounds of this type. 

In the following sections we have attempted to classify the methods available for the synthesis of benzo[6]thiophenes. (Arylthio)acetalde-hyde dialky] acetals, (arylthio)acetones, aryl phenacyl sulfides, and S-arylthioglycolic acids are the most common starting materials. A number of the syntheses, which we have included in Section IV, A, may become general methods in the future, e.g., cyclohexanone and a number of substituted cyclohexanones have been used recently as starting materials. 

The 2,3-double bond in benzo[6]thiophene-1,1-dioxides undergoes addition reactions with nucleophiles in a manner comparable to that of other a,/9-unsaturated sulfones no aromatic properties are detectable in this way for the thiophene ring.718-723 For example, thiophenol and p-thiocresol give the adducts (340 R = H or Me) in the presence of base.723 However, if the aryl mercaptan and the sulfone are heated together, a radical reaction occurs to give the corresponding 2-substituted compound.723 In contrast to the behavior of aryl mercap-... 

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