Thiophenes arylations

Alkanes and cycloalkanes. Obviously a variety of acyclic and cyclic hydrocarbon structures can be synthesized from the appropriate alkyl- or aryl-thiophenes (Scheme 46). The reaction is especially useful for the construction of macrocycles (Scheme 47). One of the most interesting applications of this reaction is in the synthesis of the chiral hydrocarbon butylethylmethylpropylmethane (210) (80JOC2754). The chiral acid (209) was the precursor, in which the thiophene was the potential n-butyl group. Raney nickel desulfurization, followed by standard manipulations to convert the acetic acid unit into an ethyl group, gave the hydrocarbon (210) (Scheme 48) this had [a]578 = -0.198°. It was established that... 

Aroyl ketene A, 3 -acetals 330 undergo deprotonation in the presence of LDA to generate stabilized carbanion 331 which undergoes a cyclization to afford the corresponding 2-amino-4-aryl thiophenes 332 (Scheme 56) <1996SC4157>. 

Treatment of 1,4-dicarbonyl compounds 565 with P2SS leads to mercaptothienoindoles 566 <1998JOC2909>. The role of red phosphorus in the synthesis of 3-aryl thiophene 568 from disodium 2-arylsuccinate 567 using P4S10 has been discussed (Scheme 89) <1995SC235>. 

Volhard-Erdmann cyclization. Synthesis of alkyl and aryl thiophenes by cyclization of disodium succinate or other 1,4-difunctional compounds (y-oxo acids, 1,4-diketones, chloroacetyl-substituted esters) with phosphorus heptasulfide. 

Linker 88 has been successfully employed in the synthesis of a small hbrary of benzopyranones, of which the individual compounds were obtained in high yields and purities [101]. A further application of the linker has been in the synthesis of oligo(3-aryl-thiophenes) [102]. 

Aryl radicals generated by a variety of methods,the most effective of which are aprotic diazotisation and photolysis of iodo-arenes (particularly iodo-hetarenes ° ), attack to produce 2-aryl-thiophenes. However, this has been superseded as a route to aryl-thiophenes by palladium-catalysed coupling. Radicals generated in various ways have been utilised in elaborating thiophenes and in ring-closing reactions examples are shown below. ° ° ... 

The classic photochemical reaction involving thiophenes is the isomerisation of 2-aryl-thiophenes to 3-aryl-thiophenes the aromatic substituent remains attached to the same carbon and the net effect involves interchange of C-2 and C-3, with C-4 and C-5 remaining in the same relative positions scrambling of deuterium labelling is, however, observed, complicating interpretation of the detailed mechaifism. 

The reactions of a-halo-substituted fluorine-containing furans with nucleophilic reagents ° ° are the most studied reactions proceeding with participation of halogen atoms. A fluorine atom in 2-fluoro-3-trifluoromethyl-5-aryl-furans 224 is replaced smoothly by various nucleophiles.The similar reactions were reported for 2-fluoro-3 -trifluoromethyl-5 -aryl-thiophenes. ... 

The Gewald aminothiophene synthesis was employed in the generation of 2-amino-3-(3,4,5-trimethoxybenzoyl)-5-aryl thiophenes as derivatives of the anti-tubulin agent combretastatin A." Condensation of 2,5-dihydroxy-1,4-dithiane with 3-oxo-3-(3,4,5-trimethoxyphenyl)-propionitrile and elemental sulfur in the presence of triethylamine afforded the thiophene product in 74% yield. Further synthetic steps yielded an antitubulin agent that not only inhibited tubulin polymerization but also showed anti-proliferation activity against both L1210 and K562 cancer cell lines. 

Further investigation of anti-tubulin agents by Romagnoli et al. led to the development of a modified Fiesselmann thiophene synthesis to produce 3-amino-2-(3,4,5-trimethoxybenzoyl)-5-aryl-thiophenes. " The a-mercapto-ketone anion was generated in situ by treating 0-ethyI-5-[2-oxo-2-(3,4,5-trimethoxyphenyl)-ethyl]dithiocarbonate with piperidine. Reaction of the a-mercapto anion with P-chloro-arylcinnamonitriles under thermal conditions afforded the desired thiophene. Much like the 2-amino derivatives, these 3-amino-2-(3,4,5-trimethoxy-benzoyl)-5-aryl-thiophenes were shown to be potent anti-proliferation and anti-tubulin agents as well. 

The palladium-catalysed arylation of arenes with aryl halides and triflates is of a great importance in the synthesis of a wide variety of tri- and polycyclic aromatic systems, and is one of the simplest ways to arylated thiophenes, fiirans and certain other heterocycles [55-63]. 

Since 2007, the development of C-H arylation methods to synthesize arylated thiophenes and furans has accelerated representative reaction conditions are summarized in Scheme 17.17 and described in the following. 

A similar tanporary ester C2-blocking group strategy was later used by Doucet and co-workers to selectively obtain C5-arylated thiophenes. " The authors... 

The removal of AAT sulfur compounds from the diesel fuel feedstock by extractive desulfurization (EDS), either adsorption or solvent extraction, is a viable alternative to HDS." This approach is based on the polarity difference between the AAT family of compounds and the hydrocarbons found in the diesel fraction. Because AATs comprise several dozen different compounds, they represent a range of solvent polarities, in some cases quite similar to the aromatic compounds found in diesel fuel. The critical polarity difference between individual hydrocarbon and thiophenic compounds is therefore variable, and in some cases may be insufficient to allow a functional separation by extraction. Polarity difference can, however, be increased by oxidizing the thiophenic sulfur to the corresponding more polar mono- and dioxides, the alkylated-aryl-thiophene-sulfoxide or sulfone (AATS). This in turn facilitates the separation, and several EDS processes therefore are designed to oxidize the AAT before extraction of the sulfur." ... 

There are valid chemical reasons for the S5mergism between HDS and EDS. These surround the difficulties of treating alkyl-aryl-thiophene sulfur containing compounds in naphtha and gas-oil by high-severity hydrogenation, while the same compounds are readily oxidized under mild process conditions. It therefore makes sense to remove some of the sulfur via the conventional HDS processing, perhaps to reach 350—750 wppm S, and then to remove the rest via EDS. 

The most convenient method for the preparation of arylated thiophenes is palladium-catalyzed direct arylation [34—36]. This methodology is an atom-economical... 

The environmentally benign synthesis of arylated thiophenes 147 in pure water is possible via desulfinylative cross-coupling between nucleophilic 2-thienylsulfinates 146 and differently substituted bromoarenes (Scheme 58, Table 36) [356]. The reaction proceeds efficiently within short reaction times in the presence of tetrakis (triphenylphosphine)palladium(O) (Pd(PPh3)4) without the need for additives, base, cocatalysts, or water-soluble ligands. Additionally, the apphcation of a highly aqueous solvent mixture consisting of water and iV,A -dimethylformamide at a ratio of 3 1... 

A new promising method for the synthesis of mixed biaryls consists in the reaction of the ethanolamine esters of diarylboronic acids with NBS in dichloro-methane/aqueous buffer at pH 9. In this way, 2- and 3-phenylthiophen, 2,2 -bi-thienyl, and 2-(2-thienyl)furan were obtained. The nitration of 2,3 -bithienyl has been studied. 2-Nitro-2 -amino-3,3 -bithienyl and 3-nitro-3 -amino-2,2 -bithienyl have been found to be stable. Carbonyl derivatives of 2-aryl-thiophens have been prepared, and reactivity constants for 2-aryl-thiophens determined. Some 2,5-bis(4 -n-alkyldiphenyl-4"-yl)thiophens, which are liquid crystals, have been prepared from the corresponding 1,4-diketones and P4S10. Various naphthyl-thiophens have been synthesized in order to study their anti-inflammatory and antibacterial properties. ... 

The cross-coupling between an aromatic halide and 3-bromothiophene is also investigated leading to 3-aryl-thiophenes (Scheme 15.12). The latter are of great interest in the synthesis of poly(3-substituted) thiophenes. 

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