Csp³-Csp² Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth Reagents with Aryl, Heteroaryl, and Vinyl Halides and Triflates

Abstract

The palladium-catalyzed cross-coupling reaction of trialkylbismuth reagents with aryl and heteroaryl halides and triflates is reported. Moderate to good yields were obtained for the transfer of primary alkyl groups. The reaction tolerates numerous functional groups on the electrophilic and nucleophilic partners. The crosscoupling of a-bromostyrene with tris(1,3-dioxan-2-ylethyl)bismuth is also reported.The introduction of alkyl groups onto aryl and heteroaryl scaffolds is highly valuable in medicinal chemistry since it facilitates the search for new interactions between a bioactive compound and its receptor and the exploration of new binding pockets. 2 The transfer of alkyl groups via cross-coupling reactions between alkyl-metal species and aryl or heteroaryl halides and pseudo halides has emerged as a powerful approach for the preparation of such compounds. 3 However, the coupling of alkyl groups possessing hydrogen atoms in the b-position represents a significant challenge due to a slower reductive elimination 4 and the propensity of such groups to undergo b-hydride elimination. 5 To overcome these issues, novel ligands, catalysts, and additives have been developed for the coupling of alkylboron, 6 alkylzinc, 7 and alkylmagnesium 8 species. These advances have also found applications in the transfer of alkyl chains using organoaluminum, organogallium, and organoindium reagents. 9 Nevertheless, some of these methods suffer from poor functional-group tolerance or require excess organometallic species, strictly anhydrous conditions, or complex catalytic systems. Consequently, the development of simple and general procedures for the coupling of sp 3 groups is still highly desirable.Organobismuth reagents have found applications in C-C, C-O, and C-N bond-forming reactions, in part due to their unique reactivity, the low toxicity, and low costs associated with bismuth salts. 10 While the cross-coupling of triarylbismuth reagents is well documented, 11 to our knowledge, the coupling of trialkylbismuth species is unprecedented. 12 As part of our research program dedicated to studying the reactivity of organobismuth reagents, 13 we were interested in developing conditions for the transfer of alkyl groups onto highly functionalized scaffolds through cross-coupling reactions involving trialkylbismuthanes. In order to have high synthetic value, we aimed for a method that used commercially available ligands and catalysts, demonstrated excellent functional-group tolerance, and did not require isolation of the trialkylbismuth reagent.We recently reported the synthesis of tricyclopropylbismuth and its use in palladium-catalyzed cross-coupling reactions with aryl and heteroaryl halides and triflates. 14 As an extension to this methodology, the coupling of triethylbismuth with ethyl 4-bromobenzoate was shown to provide the cross-coupling product in good yield, demonstrating that the protocol is applicable to the transfer of primary sp 3 groups that are susceptible to b-hydride elimination. Encouraged by this result, we initiated...

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

“…Due to the borderline behavior of bismuth as a metal and a ligand, organobismuth species have been used as reagents and catalysts in a wide range of reactions. We reported a portfolio of methods for the construction of C–C [26–29], C–N [30] and C–O bonds [31–33] using triaryl- and trialkylbismuthines [34]. We also disclosed for the first time in 2007 the synthesis of tricyclopropylbismuth ( 24 ) and its use in N-cyclopropylation [35], palladium-catalyzed cross coupling [36] and carbonylative cross-coupling reactions [37].…”

Palladium‐Catalyzed Cross‐Coupling Reaction of Functionalized Aryl‐ and Hetero­arylbismuthanes with 2‐Halo(or 2‐Triflyl)­azines and ‐diazines

“…with chlorodiazine 4. Using conditions that we previously reported for the coupling of [21] and other trialkylbismuthanes, [24] we obtained 65 % yield of desired product 6 ( Table 1, Entry 1).…”

“…We demonstrated previously that 2-chloropyridines are very competent electrophiles in cross-coupling reactions with trialkylbismuth reagents. [24] We wanted to extend the scope of the reaction to include bromo and triflyl derivatives. Our results show that 2-bromopyridines are generally more reactive than the 2-chloro analogues (e.g., 9b vs. 9a, 9e vs. 9f), which is consistent with a palladium-mediated pathway that involves oxidative addition in the C-X bond.…”

“…Recently, we disclosed the first palladium-mediated cross-coupling reaction of tri-alkylbismuth reagents with a variety of scaffolds possessing reactive functional groups, including one example involving a 2-chloropyridine. [24] We report herein our study on the cross-coupling reaction of 2-halo(or 2-triflyl)pyridines, -pyrazines, -pyrimidines, and -pyridazines with functionalized aryl-and heteroarylbismuthanes.…”

Organobismuth Reagents: Synthesis, Properties and Applications in Organic Synthesis

“…In 2010, we prepared a set of R 3 Bi, where R is a primary alkyl group, by the addition of the corresponding Grignard reagents over bismuth chloride and we used them in situ in palladium-catalyzed crosscoupling reactions. 37 Other methods to prepare homoleptic trivalent alkylbismuth reagents include the addition of trialkylaluminum reagents, 38 lithium tetraethylaluminate, 39 organocadmium 40 and organosodium 41 reagents over inorganic bismuth salts (Step 3).…”