Palladium-Catalyzed C-C Bond and C-S Bond Forming Reactions of Sulfoxides

Transition metal catalyzed C-C bond and C-S bond forming reactions offer a new opportunity to construct sulfur-containing compounds. However, preparation of sulfoxides through this pathway remains sporadic, probably due to the very weakly acidic -protons or instability of sulfenate anion, a key nucleophile to produce sulfoxides. To this end, this dissertation investigated the novel approaches to prepare sulfoxides via palladium catalyzed -arylation of methyl sulfoxides and S-arylation of sulfenate anions. In chapter 1, the palladium catalyzed alpha arylation of unactivated sulfoxides is introduced. The weakly acidic alpha protons of sulfoxides are reversibly deprotonated by LiOtBu, and an indole-based phosphine ligated palladium complex facilitates the arylation reactions. A variety of (hetero)aryl methyl sulfoxides were successfully cross coupled with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including DMSO) proved to be suitable under the optimized conditions. Moreover, aryl chlorides were employed as electrophiles in our protocol by using Buchwald-type precatalyst. This method was utilized to synthesize bioactive benzyl sulfoxide intermediates In chapter 2, we presented a novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides. Optimization of the reaction conditions was led by High-Throughput Experimentation (HTE) techniques. A single Pd(dba)2/NiXantPhos based catalyst successfully promotes a triple relay process involving sulfoxide -arylation, C-S bond-cleavage, and C-S bond-formation. Byproduct benzophenone is formed by an additional palladium-catalyzed process. It is noteworthy that palladium catalyzed benzylative substitution to cleavage C-S bond of sulfoxides is unprecedented. A wide range of (hetero)aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85-99%). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides and DMSO could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst. In chapter 3, we investigated diaryl sulfoxides generation from aryl benzyl sulfoxides and aryl chlorides via three sequential catalytic cycles all promoted by a NiXantPhos-based palladium catalyst. The key step is S-arylation of a sulfenate anion. An air- and moisture-stable palladacyclic precursor derived from NiXantPhos efficiently facilitated the transformation. Various functional groups, especially those with acidic protons, were tolerated. This method can also be extended to methyl and dibenzyl sulfoxides substrate

Palladium-Catalyzed Direct α‑Arylation of Methyl Sulfones with Aryl Bromides

A direct and efficient approach for palladium-catalyzed arylation of aryl and alkyl methyl sulfones with aryl bromides has been developed. The catalytic system affords arylated sulfones in good to excellent yields (73–90%)

Palladium-Catalyzed Direct Intermolecular α‑Arylation of Amides with Aryl Chlorides

An efficient catalytic system for the direct intermolecular α-arylation of acetamide derivatives with aryl chlorides is presented. Chemoselectivities up to 10:1 in the mono- and diarylation of acetamides were achieved by careful selection of bases, solvents, and stoichiometry. Bis-arylated amides were prepared in up to 95% yield

Palladium-Catalyzed α‑Arylation of Benzylic Phosphine Oxides

A novel approach to prepare diarylmethyl phosphine oxides from benzyl phosphine oxides via deprotonative cross-coupling processes (DCCP) is reported. The optimization of the reaction was guided by High-Throughput Experimentation (HTE) techniques. The Pd­(OAc)₂/Xantphos-based catalyst enabled the reaction between benzyl diphenyl or dicyclohexyl phosphine oxide derivatives and aryl bromides in good to excellent yields (51–91%)

RNA polymerase II trapped on a molecular treadmill: Structural basis of persistent transcriptional arrest by a minor groove DNA binder.

Elongating RNA polymerase II (Pol II) can be paused or arrested by a variety of obstacles. These obstacles include DNA lesions, DNA-binding proteins, and small molecules. Hairpin pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA in a sequence-specific manner and induce strong transcriptional arrest. Remarkably, this Py-Im-induced Pol II transcriptional arrest is persistent and cannot be rescued by transcription factor TFIIS. In contrast, TFIIS can effectively rescue the transcriptional arrest induced by a nucleosome barrier. The structural basis of Py-Im-induced transcriptional arrest and why TFIIS cannot rescue this arrest remain elusive. Here we determined the X-ray crystal structures of four distinct Pol II elongation complexes (Pol II ECs) in complex with hairpin Py-Im polyamides as well as of the hairpin Py-Im polyamides-dsDNA complex. We observed that the Py-Im oligomer directly interacts with RNA Pol II residues, introduces compression of the downstream DNA duplex, prevents Pol II forward translocation, and induces Pol II backtracking. These results, together with biochemical studies, provide structural insight into the molecular mechanism by which Py-Im blocks transcription. Our structural study reveals why TFIIS fails to promote Pol II bypass of Py-Im-induced transcriptional arrest

Palladium-Catalyzed Arylation of Aryl Sulfenate Anions with Aryl Bromides under Mild Conditions: Synthesis of Diaryl Sulfoxides

A palladium-catalyzed arylation of aryl sulfenate anions generated from aryl 2-(trimethylsilyl)­ethyl sulfoxides and CsF has been developed. This protocol is effective for the synthesis of diaryl sulfoxides and heteroaryl aryl sulfoxides under mild conditions employing aryl bromides. Various functional groups, including those with acidic protons, are well tolerated

Transition-metal-free formal cross-coupling of aryl methyl sulfoxides and alcohols via nucleophilic activation of C-S bond

Cross-coupling processes without the use of transition metals are challenging to achieve. Here, the authors show a transition-metal-free cross-coupling utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers and propose a nucleophilic addition mechanism based on experiments and theory

Palladium-Catalyzed Direct C-H Arylation of 3-(Methylsulfinyl)thiophenes

A palladium-catalyzed direct arylation of (3-thiophene)S(O)Me derivatives has been developed. This protocol is effective for the selective synthesis of 2-arylated and 2,5-diarylated sulfinylthiophene derivatives with as low as 0.5 mol % catalyst loading. Various functional groups are well tolerated. A method to install two different aryl groups on 3-(methylsulfinyl)thiophenes is also introduced.Fil: Jiang, Hui. University of Pennsylvania; Estados Unidos. Southern University Of Science And Technology; ChinaFil: Bellomo Peraza, Ana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pennsylvania; Estados UnidosFil: Zhang, Mengnan. University of Pennsylvania; Estados UnidosFil: Carroll, Patrick J.. University of Pennsylvania; Estados UnidosFil: Manor, Brian C.. University of Pennsylvania; Estados UnidosFil: Jia, Tiezheng. Southern University Of Science And Technology; ChinaFil: Walsh, Patrick J.. University of Pennsylvania; Estados Unido

Palladium-Catalyzed Arylation of Alkyl Sulfenate Anions

A unique palladium-catalyzed arylation of alkyl sulfenate anions is introduced that affords aryl alkyl sulfoxides in high yields. Due to the base sensitivity of the starting sulfoxides, sulfenate anion intermediates, and alkyl aryl sulfoxide products, the use of a mild method to generate alkyl sulfenate anions was crucial to the success of this process. Thus, a fluoride triggered elimination strategy was employed with alkyl 2-(trimethylsilyl)­ethyl sulfoxides to liberate the requisite alkyl sulfenate anion intermediates. In the presence of palladium catalysts with bulky monodentate phosphines (SPhos and Cy-CarPhos) and aryl bromides or chlorides, alkyl sulfenate anions were readily arylated. Moreover, the thermal fragmentation and the base promoted elimination of alkyl sulfoxides was overridden. The alkyl sulfenate anion arylation exhibited excellent chemoselectivity in the presence of functional groups, such as anilines and phenols, which are also known to undergo palladium catalyzed arylation reactions