Arylation of thiophenes

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

Of preparative interest is the improvement effected in the Gomberg-Bachmann-Hey arylation of thiophene by conducting the reaction in a non-aqueous solvent with 18-crown-6 as catalyst (80T3327). 

By synthesizing bromoalkyl-sulfur and -oxygen based heterocycles, Lautens was able to extend the strategy to include the synthesis of polycyclic thiophenes and furans [83, 84], Under similar reaction conditions to those used for nitrogen-based heterocycles, polycyclic products were obtained in good to excellent yields (Scheme 35). The electronic nature of the aryl iodide had a large impact on the observed yields, as electron-deficient aryl iodides worked well, while little to no product was obtained with electron-rich ones. Based upon these results, Lautens proposed that the mechanism of direct arylation of thiophenes occurs through an electrophilic metalation mechanism. 

Another unexpected hydrogenolysis reaction was discovered by Lautens while attempting to expand the scope of the cvf/to-alkylation/dircct arylation of thiophenes. When benzyl chlorides were used as alkylating agents, significant amounts of the orffto-benzylation/hydrogenolysis product were obtained. An optimization of the reaction conditions led to an efficient synthesis of diarylmethanes (Scheme 41) [92], This reaction is unique compared to the aforementioned... 

Palladium-mediated oxidative arylation of thiophene has also been reported <8SJ0CS272>. Thus, treatment of 2-formylthiophene with palladium acetate in a mixture of acetic add and benzene gave 2-formyl-4-phenylthiophene (30%), 2-formyl-5-phenylthiophene (5%) and 5,5 -diformyl-2,2 -bithienyl (16%). It has been suggested that preliminary palladation of benzene would lead to 4-phenylation of the thiophene, while palladation of the thiophene would produce the 5-phenylated product. 

Among intermolecular reactions, an interesting example is arylation of thiophene with diiodopyrrole 519 where the respective bithiophene 520 was obtained in 78% yield [93], respectively. Scheme 49. 

Scheme 9.16 Rhodium-catalyzed direct arylation of thiophene 46. ...

Scheme 9.18 Chelation-assisted oxidative rhodium-catalyzed direct arylation of thiophene 52.

Finally, a direct arylation of thiophene (106) was accomplished with sulfonyl chloride 107 at a relatively high reaction temperature, which most likely proceeded via a radical-based mechanism (Scheme 9.38) [51]. 

In 2002, Miura [71a] reported palladiumotalyzed multiple C-H arylations of thiophenes. For example, under optimized catalytic conditions [Pd(OAc)2/P(t-Bu)2(o-biphenyl)/Cs2C03 in refluxing o-xylene], thiophene-2Substituted thiophenes, even with electron-withdrawing groups, were also triarylated. This process involves palladium-catalyzed and base-promoted hydrolytic C-N fission, followed by decarboxylative C-C cleavage. Thereafter, Miura also reported this type of reaction [71b] and expanded it to synthesize tetraarylthiophenes [71cj. 

Scheme 17.16 C-H arylation of thiophenes and furans with aryl halides (2001-2006).

C-H arylation of thiophenes. In the presence of a palladium catalyst, AgNOj, and KF, bromothiophene was chemoselectively with aryl iodides to afford the corresponding coupling products without loss of bromide. In 2006, Itami [32] accomphshed the first rhodium-catalyzed C-H arylation of thiophenes with aryl iodides (Scheme 17.16). 

Scheme 17.18 P-Selective C-H arylation of thiophenes with aryl iodides.

In 2011, Schipper [94] reported the synthesis of potent organic electronics material through a palladium-catalyzed C-H arylation of thiophenes. For example, compound 76, a donor material in heterojunction solar cells [96], and compound 77, a fluorescent marker for in vivo optical imaging [97], can be rapidly synthesized by C-H/C-X coupling of the corresponding thiophenes and aryl halides without any prefunctionalization of the thiophene moieties. Shinokubo and Itami [95] demonstrated the synthesis of photochromic diarylethenes 78 through two palladium-catalyzed C-H arylations of thiophenes. 

In 2011, Itami and Studer [183] developed a palladium-catalyzed C4-selective arylation of thiophenes and thiazoles with arylboronic acids. Although they had already reported the C4(/J)-selective arylation of thiophenes with aryl iodides [88] (Scheme 17.18), this C-H/C-B coupling method [using a Pd"/hipy or phen/TEMPO ((2,2,6,6-tetramethylpiperidin-l-yl)oxyl) catalyst system] enabled the use of thiazoles as aryl nucleophiles. They also applied this coupling reaction to the synthesis of the core structure of SCH-785532, which is known as a BACE inhibitor. In the same year, Itami [184] reported a direct arylation of a PAH with arylboronic acids to generate a 7t-expanded PAH. Treatment of pyrene 142 with arylboroxine 143 in the presence of Pd(OAc)2 and o-chloranil as an oxidant, followed by cydiza-tion under stoichiometric FeClj, produced PAH 144. Key to the unprecedented C-H arylation was a notable combination of Pd" and o-chloranil. 

Other examples of applications to C-H arylation of thiophenes with aryl halides (a) Liu, C.-Y., Zhao,... 

This method is based on the direct C-H arylation of thiophenes catalyzed by palladium. Unlike GRIM polymerization, this method does not require organometallic intermediates and hence it is compatible with various pendant... 

Scheme 3.13 Palladium-catalyzed decarboxylative C-H bond arylation of thiophenes, as described by Su and coworkers [26].

Yanagisawa, S. Itami, K. Tetrahedron. 2011, 67, 4425 4430. Fagnou has demonstrated a-selective arylation of thiophenes with alternative electron-deficient phosphines. Rene, O. Fagnou, K.Adv. Synth. Catal. 2010,352, 2116-2120. 

Though radical arylations of thiophene have been largely replaced in recent years by transition metal-catalysed arylation processes, modem demands for... 

Halothiophenes are usually substrates for reactions initiated by electron transfer. As an example, arylation of thiophene with xmsubstituted benzene by an SrmI mechanism was demonstrated [198]. The reaction was initiated by electron transfer from a complex of t-BuONa with 4,7-diphenyl-l,10-phenanthroline to 3-iodothiophene (Scheme 133). The radical anion 90 formed disproportionates to give radical 91 and 1. Addition of radical 91 to benzene gives rise to a new radical 92 which after deprotonation proceeds to anion radical 93. This, in turn, transfers the electron to the next molecule of substrate, giving the final product and thus propagating the chain reaction (Scheme 133) [198]. 

Transition Metal-Catalyzed Direct Arylation of Thiophenes with Aryl Halides... 

Direct Arylation of Thiophenes Without a Palladium Catalyst... 

An alternative method for the direct arylation of thiophenes via C-H bond functionalization is a one-pot C-H borylation/Suzuki-Miyaura reaction sequence (Scheme 16) [66]. The first step is the generation of the organoboron intermediates 33 and 36 from the thiophenes 32 and 35 by means of an iridium catalyst. The second step, the Suzuki-Miyaura cross-coupling, can be accomplished subsequently by adding an aryl bromide to the solution of crude boronate esters without the necessity to remove the spent iridium catalyst beforehand. 

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