Palladium‐Catalyzed Desulfitative CC Cross‐Coupling Reaction of (Hetero)Aryl Thioesters and Thioethers with Arylsiloxanes

Abstract

Abstract:The first desulfitative Hiyama-type crosscoupling protocol is reported and exemplified by the synthesis of substituted 5-chloro-3-arylpyrazinones. The method has also been successfully applied for the arylation of other (hetero)aryl thioethers and thioesters.Keywords: copper(I); cross-coupling; desulfitative procedure; Hiyama reaction; homogeneous catalysis; pyrazinones Palladium-catalyzed C À C and C À heteroatom bondforming cross-coupling reactions are among the most powerful methods in organic synthesis.[1] Such procedures involve the coupling of an activated electrophilic partner with a nucleophilic organometallic donor through a palladium-assisted cross-coupling cascade. For this purpose a number of organometallic donors have been explored, mainly organoborons, [2] organostannanes, [3] and organozinc reagents. [4] Seminal work by Liebeskind and co-workers describes the coupling of aryl or heteroaryl thioethers with organoboron, organotin or organoindium compounds.[5] However instability, difficulty in preparation and, most importantly, toxicity of most organometallic reagents keep chemists searching for alternatives. Hiyama demonstrated the potential of the use of organosilicon reagents as nucleophilic coupling partners having the advantage of being environmentally safe and posing no toxicity hazards.[6] Since then, an increasing number of publications has appeared dealing with the coupling of activated (hetero)aromatic systems with organosilicon reagents, applying this Hiyama protocol. [7] Denmark et al. have successfully applied a variety of silanols as active transmetallating species. [8] However, nearly all Hiyama protocols have focused on the coupling of C À X electrophiles, X being halide or triflate. Until now, we are unaware of any example of Hiyama coupling with activated C sp 2 À S electrophiles. Pursuant to our long-standing interest in the synthesis and decoration of the pyrazin-2(1H)-one scaffold [9] and to our recently described protocol for the transition metal-catalyzed orthogonal decoration of the 2(1H)-pyrazinone scaffold using a sulfur linker, [10] we were keen to investigate whether a desulfitative Hiyama-type reaction at the C-3 position of 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones would be possible. Tests were performed with 5-chloro-1-(4-methoxybenzyl)-3-(phenylsulfanyl)pyrazin-2(1H)-one (1a) and trimethoxyphenylsilane as a model system. Applying the standard conditions for the Hiyama process [5 mol% Pd(II), 10 mol% ligand, 2 equiv. TBAF, THF], 75% conversion of the starting material was observed (Table 1, entry 1). However, surprisingly, the major product turned out to be the C-3 methoxylated pyrazinone and only 35% of the expected C-3 arylated compound was observed.[11] To our satisfaction we found that addition of CuI [12] effectively suppressed the formation of 4a, hence acting as a reaction switch between methoxylated and arylated products. After extensive investigation of the reaction parameters, we found that 1.5 equiv. of phenyltrimethoxysilane 2a, 5 mol% of PdA C...

The Liebeskind–Srogl Cross‐Coupling Reaction and its Synthetic Applications

“…The same group also reported the first desulfitative C−C cross‐coupling reaction between thioethers and various arylsiloxanes, which afforded the corresponding arylated compounds in excellent yields (Scheme ) . However, when alkyl‐ or vinylsiloxanes were employed under the optimized conditions, only methoxylated products were obtained in very high yields, with no trace of the alkylated products.…”

“…In 2008, the Van der Eycken group reported a Liebeskind–Hiyama‐type cross‐coupling reaction of thiol esters 1 with various arylsiloxanes ( 15 ) for the first time (also called a desulfitative Hiyama‐type cross‐coupling reaction; Scheme ) . The major side reaction in this process was the competing transmetalation of the alkoxy group in compounds 15 .…”

Metal‐Catalyzed Synthesis and Use of Thioesters: Recent Developments

“…Similarly non‐polarized stoichiometric coupling partners are organosilanes, which were used (1.1 to 1.2 equivalents) by Van der Eyckens and co‐workers in a thioester‐Hiyama coupling . This method requires stoichiometric activation by fluoride (2.0 equiv) as well as copper iodide (1.0 equiv) in THF at 60 °C combined with Pd(PPh 3 ) 4 (5 mol %) to give products ranging from 79 to 98 % isolated yields in 0.5–3.5 h. The other end of the polarity scale concerning the organometallic partner was covered by the same group by developing a thioester‐Kumada coupling, where slow addition of the Grignard solution (1.2 equivalents) by a syringe pump at room temperature was key to success combined with a catalytic system consisting of Pd(dba) 2 (5 mol %) and tris(2‐furyl)phosphine (TFP) (10 mol %) in a THF/ N ‐methylpyrrolidone (NMP) solvent mixture with isolated yields ranging from 23–96 %.…”

A Domino Desulfitative Coupling/Acylation/Hydration Process Cocatalyzed by Copper(I) and Palladium(II): Synthesis of Highly Substituted and Functionalized Pyrimidines

“…Among these methodologies, Cu(I) carboxylate‐mediated, Pd‐catalyzed cross‐coupling reactions of boronic acids with different sulfur compounds including thioesters, alkynyl thioethers, and thioamides, have attracted extensive interest in the organic synthetic community 3. Different nucleophilic partners such as organozinc reagents,4 organostannanes,5 organoindium,6 and arylsiloxanes7 have also been used in the CS cleavage reaction followed by the CC bond formation. More recently, this Pd‐catalyzed reaction has been modified to allow the coupling of cyclic thionocarbamates with alkynes 8.…”