Thiophenes direct arylations

The direct arylation (Heck) of thiophene by means of aryl halides and substituted thiophenes has been extensively studied by Lemaire and co-workers <1997TL8867, 1998JOM(567)49,2002TL1829, 2004T3221>. EWGs facilitate the reaction. With a 3-substituted thiophene, the major product was the 2-aryl derivative with 2-substituted thiophenes, the only product was the 5-aryl derivative. Yields ranged from 40% to 95%. The reaction has been extended to the synthesis of 2-arylbenzo[3]thiophenes as well (Equations 22 to 25). The yield improved on replacing the quaternary ammonium bromide by dicyclohexyl-18-crown-6. 

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. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

Palladium-catalyzed arylations of simple electron-rich five-membered heteroarenes with one heteroatom, such as furans, thiophenes, and pyrroles, with aryl iodides, bromides, or chlorides are among the most frequently studied direct arylation reactions [31, 39, 85]. These reactions usually afforded five-membered heterocycles, which were arylated at the position adjacent to the heteroatom in moderate to good yields. These reactions were mainly accomplished with electrophilic catalysts and proceeded more efficiently using aryl bromides with electron-withdrawing groups. This is in agreement with an electrophilic SEAr-type mechanism relying on a palladium(0)/palladium(ll) manifold [86]. Selected results of catalytic direct arylations of simple electron-rich five-membered heteroarenes (124—126) with aryl iodides, bromides, or chlorides are summarized in Table 9.2. 

Table 9.2 Representative examples of palladium-catalyzed direct arylations of furan (124), thiophene (125) and pyrrole (126).

Table 9.3 Representative examples of catalytic direct arylations of substituted furans (124), thiophenes (125), and pyrroles (126). 

Scheme 9.41 Palladium-catalyzed direct arylations of 3,4-disubstituted thiophenes 142 and 145.

Direct arylations of benzo[fo]furans, benzo[b]thiophenes, and indoles displayed different regioselectivity patterns. The chemical behavior of benzo[b]furans and benzo[fo]thiophenes are rather similar to those of non-benzannelated furans and thiophenes, respectively (Table 9.4). 

Okamoto, K., Housekeeper, J.B., Michael, F.E., Luscombe, C.K., 2013a. Thiophene based hyperbranched polymers with tunable branching using direct arylation methods. Polym. Chem. 4,3499-3506. 

Cross-coupling reactions of thiophenes by C-H functionalization have been extensively reviewed in the year 2014 (14ASC17). One important feature is a discussion of recent progress made in direct arylation and heteroarylation reactions involving thiophenes and other five-membered heterocycles containing one heteroatom. 

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

Recently, chelation-assisted oxidative rhodiumdirect arylations of het-eroarenes with arylboronic acids were developed [17]. Thus, thiophene derivative 52 was regioselectively arylated at position C-3 with stoichiometric amounts of TEMPO as the terminal oxidant. This methodology proved broadly applicable, allowing the efficient direct arylation with both electron-rich and electron-deficient aryl boronic acids. Notably, more stericaUy hindered boronic acids led to comparably high yields of isolated products (Scheme 9.18). 

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]. 

A variety of 2- or 3-substituted thiophenes, as well as benzothiophenes, have been subjected to the catalytic direct arylation [3, 9, 10]. As expected, 2,2 -bithio-phene can be diarylated at the 5,5 -positions (Equation 10.47) [72], although the use of a bulky phosphine is of key importance for this reaction. 2,2 -Bithiophene protected by benzophenone at the 5-position reacts with aryl bromides, initially with liberation of the ketone (see Scheme 10.6, to give 5-aryl-2,2 -bithiophene, which is then arylated at the 5 -position (Equation 10.48) [72]. 5-Bromo-2,2 -bithio-phenes undergo oxidative homocoupling in the presence of a palladium complex and a silver salt (Equation 10.49) [73]. 

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. 

Scheme 19.1 C-C bond formation via (a) Stille, Suzuki, Negishi, etc. coupling reaction conditions (b) direct arylation shown with a substituted thiophene and a substituted bromobenzene.

The mechanism of direct arylation has been studied experimentally and computationally and possible pathways include electrophilic aromatic substitution, Heck-type coupling and concerted metalation-deprotonation (CMD). The reaction pathway is dependent on the substrate and the catalytic system employed,however, most electron-rich (hetero)arenes seem to follow a base-assisted CMD pathway. Two catalytic cycles for the coupling of bromo-benzene and thiophene are shown in Schemes 19.5 and 19.6. Scheme 19.5 depicts a carboxylate-mediated process where C-H activation occurs... 

Scheme 8 Direct arylation of benzo(b)thiophenes using Pd/C.

Fagnou and co-workers succeeded to combine Heck cyclization with direct arylation in 2009. This interesting domino palladium-catalyzed Heck-intermolecular direct arylation reaction gave new access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene could be employed as the direct arylation coupling partner as well and resulted in yields up to 99% (Scheme 2.35). As the authors demonstrated, in addition to... 

In an effort to move away from precious metal catalysts, various reports in recent years have focused on the use of first-row metal catalysts for direct arylations [57-60]. As a representative example of these new developments, we illustrate in Scheme 23.15 the chelate-assisted ortho-C-H arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)j in conjunction with bidentate pyridine ligands, Zn-aryl reagents as aryl transfer reagents and 1,2-dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An interesting feature of this reaction is the hydrolysis of the imine moiety after work-up. The reaction conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and thiophenes. 

Since a few years, ruthenium- and iridium-based polypyridyl complexes are privileged photocatalysts in visible light photocatalysis. However, organic dyes should constitute a valuable alternative not only due to their relatively lower cost and wider availability but also by giving access to new transformations. The direct arylation of heteroarenes (e.g., furan, thiophene, and pyrrole)... 

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

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

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