Benzothiophene electron-rich

Benzothiophene, like thiophene, is a n-electron rich heterocycle. Unlike thiophene, electrophilic attack occurs selectively at the P-position (or 3-position) [10a, Ila] however, substitution at the a-center (2-position) can also be achieved [11b]. The order of positional reactivity, based on nitration, is 3 > 2 > 6 > 5 > 4 > 7 [1 la, 12a]. Also, halogenation under acidic conditions affords the 3-halobenzothiophene [11c, 13a]. In terms of metalation chemistiy, deprotonation occurs preferentially at the 2-position (a) [lid, 13b] metal-halogen exchange is also favored at the a-center over the P-center [12b]. 

However, a truly general method for electron-rich heterocycle arylation was not reported until 2007 [38], Electron-rich, bulky butyl-di-l-adamantylphosphine or /er/-buty I dicyclohexyl phosphine in combination with Pd(OAc)2 afforded the best results, and the former was chosen because of cost considerations. Interestingly, electron-rich AMieterocyclic carbene ligands that facilitate oxidative addition of aryl chlorides to low-valent transition metals are inefficient in heterocycle arylation. A number of structurally diverse electron-rich heterocycles are reactive (Scheme 3). Thiophene, benzothiophene, 1,2- and 1,3-oxazole derivatives, benzofuran, thiazoles, benzothiazole, 1-alkylimidazoles, 1-alky 1-1,2,4-triazoles, and caffeine can be arylated. Electron-rich, electron-poor, and heteroaryl chlorides can be used. 

Furan and thiophene rings are electron-rich, five-membered aromatic systems. The donation of a pair of electrons by the heteroatom into the 7t-system is essential to the aromaticity of these compounds. Due to the highly electronegative oxygen heteroatom, the aromaticity of hiran is comparable to pyrrole. The aromaticity of benzofuran is comparable to indole for similar reasons. On the other hand, the aromaticity of thiophene resembles benzene due to the decreased electronegativity of the sulfur heteroatom. For similar reasons, the aromaticity of benzothiophene is comparable to naphthalene. ... 

The electron-rich thiophene and benzothiophenes are widely used as isosteres of their phenyl cousins in medicinal chemistry. These ring systems can be found in many pharmaceuticals with varied therapeutic applications such as the inhibition of platelet aggregation, treatment of asthma, chronic obstructive pulmonary disorder (COPD), bipolar disorder, psychosis, and prevention of osteoporosis, among many others. ... 

Furans, thiophenes, and pyrroles are arylated at the electron-rich C-2 positions. Further arylation occurs at C-5. Similarly, arylations at C-2 positions of benzofu-rans, benzothiophenes, and indoles take place preferentially. 

Silver(I) carbonate is responsible for generating an aryl silver species, which can subsequently undergo transmetalation with Pd. To prevent protodecarboxylation and decarboxylative homocoupling, tricyclohexylphosphine was required to accelerate transmetalation and reductive elimination. Electron-rich, electron-deficient, and heterocyclic benzoic acids were compatible coupling partners and a wide range of functional groups were tolerated for both thiophene and carboxylic acid moieties. Additional heterocycles such as benzothiophenes and 2-methylfuran could also be arylated. 

In parallel with Itami s report, the Jin group of Tohoku University published a mechanistically similar approach to dibenzopentalenes [50]. In their work, o-alkynylhaloarenes are coupled with diarylacetylenes by the C-H activation melange of Pd(OAc)2/DBU/CsOPiv (Scheme 2.17). The substrate scope showed the reaction to be general in contrast to the Itami report electron-poor (14o, 14q) and electron-rich (14n, 14p) functional groups were tolerated on either substrate and gave the dibenzopentalenes in excellent yields (70-89%). Heteroaryl-alkynyl chlorides were also viable substrates, as thiophene, benzothiophene, and pyridine... 

The Pd-catalyzed intramolecular oxidative C-H/C-H coupling of diaryl sulfides to form DBTs was developed by Zhou and coworkers (Scheme 4.5) [9]. This approach afforded various DBTs in moderate to good yields with tolerance of a broad range of substrates. Remarkably, the benzo[l,2-fi 4, 5-fi ]bis[fi]benzothiophene was successfully synthesized by this protocol, which could be used as an organic semiconductor for field-effect transistors. Furthermore, they found that diaryl sulfides bearing electron-rich substituents... 

The difficult translation of SOMO activation to cyclic ketones was achieved with the help of catalyst 6, which was developed earUer for Diels-Alder reactions of cyclic ketones via iminium activation. The difficulty Hes in the fact that aldehydes and ketones exhibit largely different steric and electronic properties with respect to catalyst interactions [16]. Competitive catalyst degradation under the oxidative conditions (i.e., oxidation of the methyl group attached to furan) was circumvented by transforming the methyl into a trifluoromethyl group, or by direct replacement of the furyl ring with less electron-rich heteroaryl systems such as benzofuran (8) or benzothiophene (9), which are less sensitive to oxidation (Scheme 39.5). 

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