Thiophenes biaryl coupling

One of the most recent developments in the area of biaryl coupling is the use of higher order mixed diarylcyanocuprates these kinetically prepared higher-order cuprates function well at very low temperatures to yield unsymmetrical coupling products (Scheme 135) <94TL815>. Two dissimilarly substituted thiophenes have also been coupled by this procedure. 

This biaryl coupling reaction can be viewed to proceed via oxidative addition of the iodoarene followed by electrophilic C—H activation of the thiophene 43 by the cationic arylrhodium(lll) intermediate this pathway was found to be facilitated by... 

Thienylboronic acids are useful building blocks for preparing biaryls and heterobiaryls employing the Suzuki reaction. In one case, a Suzuki coupling between thiophene-3-boronic... 

The two coupling reactions appear to have a common free-radical intermediate. Functional groups already in the aromatic compound, Axil, orient ortbo-para regardless of their nature. The reactions are most valuable for the preparation of biaryls of unequivocal structure when the hydrocarbon, Ar H, is unsubstituted. Good directions are given for the synthesis of p-bromobiphenyl (35%), and the literature of the reaction has been reviewed. Among the hydrocarbons prepared in this way are a- and yS-phenylnaphthalenes, o-, m-, and p-methylbiphenyls and m- and p-terphenyls. Thiophene and pyridine nuclei also have been aryl-ated. ... 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Liebeskind reported a new method for cross-coupling heteroaromatic thioethers with boronic acids [56]. This required the use of copper(I) thiophene-2-carboxyhc acid (CuTC) but allowed the reaction to be conducted under mild and neutral reaction conditions from readily available starting material. As an example, thiomethylpyridine 161 was cross-coupled to boronic acid 162 to afford the biaryl 163. 

Thienylboronic acids are useful building blocks for preparing biaryls and heterobiaryls employing the Suzuki reaction. In one case, a Suzuki coupling between thiophene-3-boronic acid and iodocyclopropane 99 was promoted by cesium fluoride to furnish the adduct 100 with retention of configuration [74]. In another example, the union between thiophene-3-boronic acid and 5-bromo-2,2-dimethoxy-l,3-mdandione (101) provided ninhydrin derivative 102 [75]. 

The Suzuki reaction of j9-chlorobenzoyl chloride and thiophene-2-boronic acid was carried out under anhydrous conditions to furnish ketone 118 [81], providing an alternative synthesis of ketones. Behaving like simple aryl halides, iodothiophenes served as coupling partners with phenylboronic acid [82] and thienylboronic acid [83] to deliver biaryls 119 and 120, respectively. 

The Ullmann reaction was used in the coupling of a wide variety of aryl halides, Ar-X, where the Ar includes mono-, di-, poly-substituted phenyl [4,5,14], naphthalene [4,5,15,16], azulene [17], pyridine [18], pyrimidine [19], thiophene [4,5,20], carbazole [21], and even ferrocene [22], while X = I, Br, Cl. The reaction was successfully used in the intramolecular cyclization reactions affording four- [23], five- [24], six-membered [25], and some other larger rings [6]. Selected examples where halides 10-13 were converted to biaryls 14-17 are given in the Scheme 2 [14,16,17,19]. 

The homo-coupling Ullmann reaction can be performed at room temperature or bellow by metallation of suitable substrates such as relatively acidic arenes or aryl hahdes with the -BuLi (or other strong bases) followed by addition of Cu(II) salts [28], Aryllithium reagent undergoes transmetallation with the Cu(II) salts to form diarylcopper(II) which is prone to rapid reductive elimination of the biaryl with extrusion of a copper nrirror. Benincori and coworkers [28] described an efficient procedure for the homo-coupling reaction of bromide 21 via diarylcopperfll) 22 under very mild reaction conditions, where the 3,3 -bibenzo[b]thiophene (23) was obtained in 56% yield. Scheme 4. 

In 2012, Itami and Yamaguchi discovered the bisoxazoHne-Pd catalysts such as 173 and 174 that enable the synthesis of hindered heterobiaryls by direct C-H coupling. Moreover, they demonstrated the first enantioselective C-H biaryl cross-coupling (Scheme 17.49) [227]. For example, when an n-PrOH solution of thiophene 175 and arylboronic acid 176 was treated with a Pd(OAc)2/biox 174 catalyst and TEMPO at 70 °C under air, (S)-177 was obtained in 41% ee (63% yield). When a more hindered arylboronic add 178 was used, the enantiometric excess of product (S)-179 was increased to 72% at the expense of lower yield. 

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