2-substituted benzothiophenes

Synthesis of benzothiophenes can also be accomplished by an acid-promoted intramolecular cyclization reaction. The 3-substituted thiophene undergoes a rearrangement under acidic conditions to produce 2-substituted benzothiophenes. ... 

As discussed in Section III, when the sulfur content is lowered from 0.20 to 0.05%, the chemistry of HDS of gas oils is essentially the chemistry of alkyl-substituted dibenzothiophenes. Though gas oils initially contain mostly alkyl-substituted benzothiophenes, these are completely removed by the time 0.20% S is achieved. Thus, this review will deal predominantly with the reaction pathways involved in the HDS of alkyl-substituted dibenzothiophenes. There are many excellent reviews on reaction pathways of the more reactive sulfur species such as thiophenes and benzothiophenes (2, 5, 8, 23, 24), and the reader is referred to those reviews for information on the reaction pathways and mechanisms of HDS for the more reactive... 

Reactivities of Methyl-Substituted Benzothiophenes (25) (C0M0/AI2O3, 40Cf C, 1 atm)... 

As mentioned earlier, the MOPAC-PM3 calculations also helped to determine the importance of bond order in the hydrogenative route to desulfurization. Figure 28 shows the calculated bond orders of all bonds in a wide variety of thiophenes, benzothiophenes, and dibenzothiophenes (38). These values were correlated with the rates of desulfurization of sterically hindered alkyl-substituted benzothiophenes and alkyl-substituted 1,1 -diox-... 

Fig. 30. Relative hydrogenation reactivity of methyl-substituted benzothiophenes and methyl-substituted l,T-dioxodibenzothiophenes versus their C2-C3 bond order. (O) Benzothiophenes (5) BT (7) 2-methyl-BT (8) 3-methyl-BT (9) 2,3-dimethyl-BT. ( ) 1,1-Dioxoben-zothiophenes (BT02) (11) BTO2 (29) 2-methyl-BT02 (30) 3 methyl-BT02 (31) 2,8-di-methyl-BT02. Reprinted with permission from Ref. 38, Ma et al. (1995). Copyright 1995 American Chemical Society.

Phenyl vinyl sulfides cyclize to substituted benzothiophenes on photolysis. They also rearrange during photolysis to give rearranged benzothiophenes (46). The rearrangement reaction and the elimination of hydrogen (presumably to give the benzothiophene molecule ion) are both prominent processes in the mass spectra of the aryl vinyl sulfides.88)... 

The presence at the ortho position of an aldehyde function has been used for the synthesis of substituted benzothiophenes (Scheme 26) [68,69]. 

Thiophenes are common pyrolysis products of the Murchison macromolecular material and thiophene, methylthiophene, dimethylthiophene, and benzothiophene have been detected in this way (Biemann, 1974 Holtzer and Oro, 1977 Sephton et al, 1998). Sodium dichromate oxidation has revealed the presence of substituted benzothiophene and dibenzothiophene moieties... 

This methodology was also applied to 2-aryl-3-substituted benzothiophenes 271 and 273 bearing either a nitrogen at the 3-position or a phenolic oxygen to give benzothiophenes 272 and 274 in good yields [178d]. 

Of particular current interest is the fact that the most abundant residual sulfur compounds in diesel fuels are found in the form of alkyl-substituted benzothiophenes and dibenzothiophenes, 4-methyldibcnzothiophene and 4,6-dimethyldibcnz.othiophcnc being the prototypes of the most difficult compounds to degrade. The removal of these very stable molecules through what has come to be known as deep desulfurization in order to meet the severe new standards for sulfur contents in fuels is certainly a most difficult task and a satisfactory solution for this problem has not yet been found [14-16, 19, 20]. 

Lithio-benzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. ° Direct deprotonation of benzothiophenes follows the usual pattern for flve-membered heterocycles and takes place adjacent to the heteroatom,"" and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen the sequence below shows how this can be utilised to develop substituted benzothiophenes. 2-Lithiated reagents react with electrophiles for example with p-toluenesulfonyl cyanide, 2-cyano derivatives are produced and similarly, 2-trimethylstannylbenzofuran and -benzothiophene and benzofuran-2- and benzothiophene-2-boronic acids can be prepared. 

Photochemistry. The photochemical reaction of benzisothiazoles (46 R = H) with DMAD gives a mixture of [48 Z (30%), E (50%)] and the substituted benzothiophen (47) (Scheme 5). 5-Chlorobenzisothiazole behaves similarly. A mechanism involving initial cleavage of the thiazole ring to a diradical has... 

Hydrodesulfurisation of benzothiophenes is conveniently achieved using Raney nickel," and before the advent of modern spectroscopic methods was utilised in the determination of structure of substituted benzothiophenes by conversion to a recognisable derivative. 

The Friedel-Crafts acylation reaction at the C3 position of a substituted benzothiophene was shown to be a key C-C bond forming step in the synthesis of raloxifene, as first reported in 1984 and illustrated below. ... 

A modification of the Fiesselman synthesis was used to produce a 5-substituted benzothiophene from the corresponding benzaldehyde derivative as illustrated below. This methodology was also employed in the synthesis and study of zileuton analogues as anti-inflammatory and anti-nocieptive agents." ... 

Route 1 involves an initial migratory arylzincation pathtvay that is followed by a copper-mediated reaction with elemental sulfur, with accompanying C-S cyclization to afford a substituted benzothiophene in a one-pot reaction. Alternatively, in route 2, the zinc intermediate is first trapped by iodine, and subsequent copper-catalyst allows C-S/C-Se bond formation followed by cyclization in the presence of elemental sulfur or selenium to afford the corresponding benzochalcogenophene. A modular two-step synthesis of dithieno[3,2-l) 2, 3 -d]thiophene derivatives by C-S cross-coupling and oxidative dehydro C-H coupHng was also described in the year 2014 (14OL4086). 

New alkylselenyl-substituted benzothiophene-based solution-processable 2D n-conjugated polymers were synthesized (14SEM136). A typical synthesis is shown below. 

The electronic effects ofmeta- and para-substituents located in the phenyl ring have been studied for aryl-substituted benzothiophenes (Scheme 36(a)). 

In a somewhat different approach, TIPS was used to protect the C-2 carbon of benzothiophene by treatment with LDA followed by TIPSCl (eq 17). Subsequent metalation with BuLi in hexane/TMEDA produced the desired 7-lithio-2-triisopropylsilyl-benzothiophene which reacted with a Boc-protected piperidone to afford the 7-substituted benzothiophene. The TIPS group was removed by treatment with TEA in CH2CI2. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

Benzothiophenes are biologically important molecules that exhibit anti allergenic, and ocular hypotensive properties, and prevent osteoporosis. Kim and coworkers have shown that BE3 OEt2 is efficient in mediating the Eriedel-Craft type cyclization of 2-arylthio-ketones (43) at ambient temperature to give the 3-aryl-substituted benzothiophenes (44) in good yields (Equation 29) [31]. 

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