Thiolates cross-coupling

During the cross-couplings to form C—N, C—O, C—S, and C—P bonds, the arylpalladium halide complexes are converted to arylpalladium amide, alkoxide, thiolate, and phosphide complexes. Examples of each type of complex have now been isolated, and the reductive elimination of the organic products has been studied. Although the reductive elimination to form carbon-hydrogen and carbon-carbon bonds is common, reductive elimination to form carbon-heteroatom bonds has been studied only recently. This reductive elimination chemistry has been reviewed.23... 

Savarin, C. Srogl, J. Liebeskind, L. S. Thiol ester-boronic acid cross-coupling. Catalysis using alkylative activation of the Pd thiolate intermediate. Org. Lett. 2000, 2, 3229-3231. 

Thieno[3,4-Z ]thiophene (25) has been obtained (>50% yield) from 3,4-dibromothiophene (332) by a sequence involving Pd(II)-Cu(l) catalysed cross-coupling with trimethylsilylethyne giving (333), bromine-lithium exchange, thiolation with elemental sulfur (334) and ring-closure in aqueous medium (Scheme 27) (90SC2275). 

The general reaction mechanism has been shown to involve typical steps for cross-coupling [98, 113]. Oxidative addition of an aryl halide generates a Pd(II) species that undergoes transmetalation to form a Pd(II)-thiolate. C-S reductive elimination provides the aryl sulfide and regenerates the Pd(0) catalyst. More recently, Hartwig reported a detailed mechanistic analysis of the Pd/Josiphos system derived from different Pd precursors. The dominant Pd species were found to be off the catalytic cycle, which accounted for differences in rates between stoichiometric and catalytic reactions [114]. Thioketones are also effective thiolate nucleophiles for C-S bond formation. The reaction involves tandem Pd-catalyzed thioenolate alkylation, followed by 5-arylation (8) [102]. Presumably, the arylation process proceeds by a similar mechanism to related Pd-catalyzed transformations. 

C.i. Palladium-Catalyzed Cross-Coupling of Thiolates with Aryl and Vinyl Halides... 

Reductive elimination is the product-forming step in some of the most important catalytic cycles, including hydrogenation, the Monsanto acetic acid process, and various types of cross-couplings. For this reason, detailed studies of this process have been conducted. Hrese studies have revealed examples of reductive eliminations to form H-H and C-H bonds, as well as reductive eliminations to form C-G and C-X bonds (in which X = halide, amide, alkoxide, thiolate, and phosphide). The mechanisms of these processes include the same pathways as have been deduced for oxidative addition (i.e., concerted, ionic, and radical), because reductive elimination is the same as oxidative addition, but in the reverse direction. 

Recent renaissance in Ulmann chemistry has opened new opportunities for successful implementation of novel cross-coupling approaches, especially useful for carbon-heteroatom bond formation under mild conditions with copper compounds. Numerous publications have appeared dealing with thiolation and selenation of aryl-and alkenyl halides using various Cu complexes as catalysts. A high reaction temperature of 200-300 °C [55] was significantly reduced, to 100 °C and less. Therefore, a simplified reaction technique and cheaper solvents may be utilized in synthetic procedures. Lower temperature was also of much importance to avoid side reactions. 

The thiolate residue must be fully scavenged by an equivalent of the Cu(I) and, as dictated by a balanced reaction, the presence of a full equivalent of a strongly bonding third valence for the -B(OH)2 fragment is required, in this case, the carboxylate. The mechanistic requirement of a stoichiometric quantity of a Cu(I) carboxylate for pH-neutral desulfltative cross-coupling will be incompatible with any desulfltative bioconjugative transformations of biomolecules, such as proteins, that must be carried out in water. 

Dibromothiophene (14) can be converted into 2 in two steps in an overall yield of 39% (Scheme 32). Sonogashira cross-coupling with trimethylsilylacetylene provided 146. Transmetallation then addition of elemental sulfur gave the corresponding thiolate, thermal cyclization of which afforded thieno[3,4-b]thio-phene (2) as a colorless oil [55]. Using phenylacetylene instead of trimethylsilylacetylene led to 2-phenylthieno[3,4-h]thiophene in 19% yield from the dihalide [54]. 

This disulfide offers a straightforward entry to Z-l,2-bis-alkyl-sulfanyl-alkenes, which are not available in satisfying yields from aliphatic disulfides. As shown in eq 12, the protected disulfide first adds to the triple bond via a cross-coupling reaction catalyzed by Pd°. The adduct is converted through deprotection with TBAF to the bis-vinyl thiolate, which reacts with methyl iodide to give the corresponding bis-alkylsulfide (eq 12). ... 

Guillon J, Forfar I, Desplat V, Fabre SB, Thiolat D, Massip S, Carrie H, Mossalayi D, Jarry C (2007a) Synthesis of new 4-( )-aIkenylpyrrolo[l,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions. J Enzyme Inhib Med Chem 22(5) 541-549. doi 10. 1080/14756360701425089... 

Guy has explored copper-mediated S-arylation of thiols and aryl boronic acids [67]. Earlier studies revealed that the reactions were slow for S-arylation under the conditions developed previously for N- and O-arylation reactions because of a significant disulfide formation. However, it was shown later that the reaction of a wide range of electronically diverse aryl boronic acids with a range of thiolate substrates proceeded well when heated at 155 °C in DME affording cross-coupled products in good yields. Similarly cysteine phenyl sulfide 103 and an arylthio glycoside 104 were also prepared in 50-80% yields (Scheme 3.46). 

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