1- Benzothiophenes, formation

Thiophenes continue to play a major role in commercial applications as well as basic research. In addition to its aromatic properties that make it a useful replacement for benzene in small molecule syntheses, thiophene is a key element in superconductors, photochemical switches and polymers. The presence of sulfur-containing components (especially thiophene and benzothiophene) in crude petroleum requires development of new catalysts to promote their removal (hydrodesulfurization, HDS) at refineries. Interspersed with these commercial applications, basic research on thiophene has continued to study its role in electrocyclic reactions, newer routes for its formation and substitution and new derivatives of therapeutic potential. New reports of selenophenes and tellurophenes continue to be modest in number. 

In addition, the formation of terminal metabolites may be adverse either for the organism itself, or for other organisms in the ecosystem. Microbial metabolites may also undergo purely chemical reactions to compounds that are terminal products. Examples include the formation of 5-hydroxyquinoline-2-carboxylate from 5-aminonaphthalene-2-sulfonate (Nortemann et al. 1993) or benzo[fc]naphtho[l,2- /]thiophene from benzothiophene (Kropp et al. 1994). Microbial metabolites may be toxic to both the bacteria producing them and to higher organisms. Illustrative examples of toxicity include the following ... 

Table 5 shows HDS product distributions over several catalysts prepared by using the molybdenum-nickel cluster 2. Sulfur content in decane was adjusted to 5.0 wt% in these experiments. MoNi/NaY was found to be more active than MoNi/Al203. It is to be noted that during the high temperature pretreatment the original cluster structure would have been changed. However, the high activity of the MoNi/NaY catalyst for benzothiophene HDS is probably due to the formation of active sites derived from this particular mixed metal cluster. 

Subsequently, Paquette and Johnson used LAH reductions to convert strained thietane or thiolane derivatives to their respective sulphides, generally in good yields. Whitney and Cram described the LAH reduction of a chiral derivative of benzothiophene sulphone, as outlined in equation (24). The authors also noted the formation of hydrogen gas and suggested that their results were consistent with those of Bordwell as outlined in equation (22), namely that reduction takes place by the formation of an aluminium oxide and hydrogen gas. In this case, the reduction clearly cannot involve the formation of an a-sulphonyl carbanion and it is unlikely that any C—S bond cleavage and reformation could have occurred. 

Oxidation of thiophene and its derivatives was studied using hydrogen peroxide (H2O2), t-butyl-hydroperoxide and Ti-Beta redox molecular sieve as selective oxidation catalysts. A new reaction pathway was discovered and investigated using C-13 NMR, GC, GC-MS, HPLC, ion chromatography, and XANES. The thiophene oxidized to thiophene-sesquioxide [3a,4,7,7a-tetrahydro-4,7-epithiobenzo[b]-thiophene 1,1.8-trioxide] and the sesquioxide oxidized mostly to sulfate. 2-Methyl-thiophene and 2,5 dimethylthiophene also oxidized to sulfate and sulfone products. The Benzothiophene oxidation product was sulfone. This proposed new reaction pathway is different from prior literature, which reported the formation of thiophene 1,1-dioxide (sulfone ) as a stable oxidation product... 

The oxidation of thiophene and its derivatives with H202 was studied using a Ti-Beta molecular sieve. The oxidation product is very dependent from the aromaticity of model compounds. The thiophene oxidation product was mostly sulfates and the benzothiophene oxidation product was benzothiophene sulfone. Oxidation of mono and di-alkyl thiophenes also produced sulfates and sulfones. The diffusivity and aromaticity of the relevant sulfur compounds, intermediates and stable product, as well as the proposed new mechanism of oxidation will be discussed. This proposed new reaction pathway is different from current literature, which reports the formation of sulfones as a stable oxidation product. 

Pinney et al. reported the synthesis of benzothiophene CA4 analogs and an example synthesis is given in Scheme 38 [83]. Benzothiophene (145) was produced by reacting aromatic thiol 146 with a-bromoacetophenone 147 to generate the sulfide 148. Compound 148 was then cyclized to the benzothiophene 149 using polyphosphoric acid and heat. Formation of 145 was achieved by Friedel-Crafts aroylation of 149 with the methoxybenzoyl chloride 144. 

Ohta s group investigated the heteroaryl Heck reaction of thiophenes and benzothiophenes with aryl halides [127] and chloropyrazines [128]. Addition of the electrophiles invariably took place at C(2) as exemplified by the formation of arylbenzothiophene 156 from the reaction of benzothiophene and p-bromobenzaldehyde [127]. As expected, the heteroaryl Heck reaction of 2-thienylnitrile, an activated thiophene, with iodobenzene afforded the arylation product 157 [129],... 

A catalytic example of C-S bond breakage in benzothiophene has been reported by Bianchini [47], A catalytic desulfurisation was not yet achieved at the time as this is thermodynamically not feasible at such mild temperatures because of the relative stability of metal sulfides formed. Bianchini used a water-soluble catalyst in a two-phase system of heptane-methanol/water mixtures in which the product 2-ethylthiophenol is extracted into the basic aqueous layer containing NaOH. Figure 2.43 gives the reaction scheme and the catalyst. The 16-electron species Na(sulfos)RhH is suggested to be the catalyst. Note that a hydrodesulfurisation has not yet been achieved in this reaction because a thiol is the product. Under more forcing conditions the formation of H2S has been observed for various systems. 

The 4a,9b double bond in 1,2,3,4-tetrahydrodibenzothiophene 5,5-dioxide (68) and similar compounds, is essentially nonaromatic and in this respect resembles the 2,3 bond in benzo[6]thiophene 1,1-dioxide. Catalytic reduction of 68 results in the formation of l,2,3,4,4a,9b-hexahydrodibenzothiophene 5,5-dioxide (92 /o). Subsequent reduction of the sulfone with LAH yields 1,2,3,4,4a,9b-hexahydrodibenzothiophene (69) as an oil (78 /o). Oxidation of 4-keto-l,2,3,4-tetrahydrodi-benzothiophene (44a) to its sulfone with peracetic acid (63 /o) followed by... 

A limited number of hypervalent iodine-mediated synthesis of thiophenes and benzothiophenes have been reported. An indirect approach for the synthesis of thiophenes involves formation of 1,4-butanediones [85JC-S(CC)420 87JCS(P1)559 88TL3703 89JOC2605], followed by treatment with phosphorus pentasulfide. This approach is especially useful for the synthesis of 3,2 5, 3"-terthiophene (134) starting from 1,4-diketone 65 (85SC789). 

This approach is used for the syntheses of fused heterocycles which have a [l,3]-heteroatom juxtaposition in one of the rings <1996CHEC-II(7)49>. The unambiguous synthesis of tetrahydro-3//-benzothieno[2,3- / imidazole 87, as a target for the potential treatment of anxiety disorders, was accomplished starting from commercially available ethyl 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylate 85 the key formation of the bicyclic heterocycle occurred through a final acid-mediated cyclization of 86 (Scheme 17) <1997SC473>. 

Similar results were achieved over a Rh/alumina monolith catalyst " using catalytic POX for the reforming of a simulated JP-8 military feed containing 500 ppm of sulfur (as benzothiophene or dibenzothiophene). Stable performance for over 500 h with complete conversion of the hydrocarbons to syngas at 1,050°C, 0.5 s contact time, and LHSV of about 0.5 h was reported. At this high temperature, carbon formation was not reported and the sulfur exited as hydrogen sulfide. 

Examples of the formation of sulphur containing heterocycles by similar transformations are quite rare. The palladium catalysed ring closure of S-propargyl-2-iodophenylmercaptane in the presence of formic acid and an amine-base, analogously to phenols and anilines, led to the formation of the partially reduced benzothiophene skeleton, bearing a 3-methylydene function (3.32.),40... 

Unlike in the case of the preparation of indoles and benzofuranes, the synthesis of benzothiophenes from o-ethynyl-thiophenols is not known. A close analogy was reported by Larock, where phenylacetylene was coupled with 2-iodothioanisole. Ring closure of the formed o-ethynyl-sulfide was initiated by the addition of different electrophiles. The reaction led to the formation of the benzothiophene core bearing the electrophile in the... 

The Sonogashira reaction of 2-iodothiophene with 2-methyl-3-butyne-2-ol or trimethylsilylacetylene under phase transfer conditions using sodium hydroxide as base led to the formation of the expected products, which released their end group spontaneously under the applied conditions giving rise to the intermediate formation of 2-ethynylthiophene. This terminal acetylene, in turn, reacted with another molecule of aryl halide, yielding either non symmetrical or symmetrical diarylethynes. When 2-methyl-3-butyn-2-ol was used as acetylene equivalent68 it was possible to introduce a benzothiophene moiety in the second step, while the reaction of 2-iodothiophene and trimethylsilylacetylene led to the formation of l,2-bis(2 -thienyl)acetylene (6.47.),69... 

Ultraviolet photolytic decomposition of benzothiophene (XII) in vacuum results in the formation of XIII and hydrogen, as well as XIV and hydrogen sulfide.95-97... 

Comparison of Rate and Equilibrium Data for the Formation of Some ct-Adducts from Benzothiophene, Thiophene, and Naphthalene Derivatives (Reaction with MeO in MeOH, at 25°C)... 

In describing catalytic activities and selectivities and the inhibition phenomenon, we will use a common format, where possible, which is based on a common reaction pathway scheme as outlined in Scheme 1. In contrast to the simple one- and two-ring sulfur species from which direct sulfur extrusion is rather facile, in the HDS of multiring aromatic sulfur compounds such as dibenzothiophene derivatives, the observed products are often produced via more than one reaction pathway. We will not discuss the pathways that are specific for thiophene and benzothiophene as this is well represented in the literature (7, 5, 8, 9) and, in any event, they are not pertinent to the reaction pathways involved in deep HDS processes whereby all of the highly reactive sulfur compounds have already been completely converted. 

---