Exploration of dinuclear Pd(I) catalysis & synthetic developments with $(Me_{4}N)SCF_{3}$ as a bench stable and versatile reagent to access high value compounds

Scattolin, Thomas; Schoenebeck, Franziska (Thesis advisor); Enders, Dieter (Thesis advisor)

Aachen (2018, 2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2018


Transition metal catalyzed processes became ubiquitous during the last century allowing the access to molecules that could not be envisioned before. In particular, highlighted in this thesis are the processes involving palladium. While most new methodologies, involving sensitive Pd(0) species, are well documented and understood, they come with sustainability challenges. More recently palladium in its odd oxidation state (I) has been proved competent in successful cross-coupling reactions promoted by dimeric Pd(I) complexes containing a well-characterized Pd-Pd bond. Despite the little information available on the exact mechanism of action of these Pd(I) species, our group has shown interesting features of the dimeric [PdI(µ-Br)(PtBu3)]2 and [PdI(µ-I)(PtBu3)]2. For example, the [PdI(µ-I)(PtBu3)]2 dimer has been shown to be completely air and moisture stable and, unlike the sensitive Pd(0) based catalysts, can be kept under normal laboratory atmosphere for months without decay. First, this thesis will showcase our investigations on organometallic processes and more particularly on the mechanism of activation of the PdI(µ-Br)(PtBu3)]2 and [PdI(µ-I)(PtBu3)]2 dimers, as well as their reactivity in presence of various nucleophiles. Our study showed that depending on the nucleophile employed and their relative strength we could tune the reactivity of those Pd(I) species. Relying on the robustness, air and moisture stability of the [PdI(µ-I)(PtBu3)]2 dimer, we developed an efficient and high yielding Kumada-Corriu cross-coupling protocol employing aryl bromides and iodides with aryl Grignard reagents. The reaction proceeds within very short reaction times under air atmosphere without the need for careful reaction control measures. The coupling protocol was extended to the chemoselective alkylation of aryl bromides and iodides using Grignard (Kumada-Corriu cross-coupling) or zinc reagents (Negishi cross-coupling) in presence of other potential reactive sites such as chlorides or trifluoromethanesulfonates. Building on the experience of our group in Pd(I) catalyzed trifluoromethylthiolation and trifluoromethylselenolation, we also developed a more general protocol to couple alkyl and aryl thiolates chemoselectively with aryl bromides and iodides. A wide range of highly functionalized thioethers were isolated in excellent yields. We showed that the Pd(I) dimer species generated during the reaction could easily be recovered by column chromatography under normal conditions and were shown to be as efficient in promoting the formation of thioethers over five consecutive rounds of recycling. Our proposed mechanism based on the direct reactivity of Pd(I) has been carefully confirmed by means of DFT calculations indicating a strong driving force while giving information concerning the most reactive Pd(I) species, the [Pd2I(µ-I)(µ-SR)(PtBu3)2] containing two different bridging units. In a following subchapter, aryl and alkyl selenolates were shown to be suitable nucleophiles in the functionalization of aryl iodides and bromides using the same protocol, while we demonstrated an interesting cross-chalcogenation of selenoethers to generate thioethers using a key ability of our Pd(I) dimeric systems to exchange their bridging units. The second chapter of this thesis is centered on the understanding and investigation of the new reactivity of the tetramethylammonium trifluoromethanethiolate (Me4N)SCF3 discovered during the course of my PhD studies. We showed that in presence of various protonated nucleophiles, the trifluoromethanethiolate anion can be used to generate thiocarbonyl fluoride, a gaseous species mostly unexplored to date due to difficulties to access it. We explored the mechanism of activation of the (Me4N)SCF3 reagent and the various reactivities accessible with it.We developed a broadly applicable approach to access widely functionalized isothiocyanates from primary amines. The method was only accompanied with the formation of salts byproducts which could easily be removed by filtration on a short pad of celite as the sole purification technique required in the isolation of the desired isothiocyanates in high yields. Isothiocyanates of pharmaceutical targets as well as unsymmetrical cyclic thioureas were obtained in excellent isolated yields. In a next subchapter we explored the reactivity of secondary amines with the (Me4N)SCF3 reagent and demonstrated the highly efficient synthesis of thiocarbamoyl fluorides, an underexplored class of compounds. Thiocarbamoyl fluorides were then employed in a one-pot protocol to access highly functionalized trifluoromethylated amines. The unique reactivity behavior of the (Me4N)SCF3 reagent coupled with the fact that only inorganic salts are formed as byproducts of the transformation allowed us to access variously substituted trifluoromethylated amines after filtration on a short pad of celite as the sole purification technique required. Nitrogen containing pharmaceutically relevant targets were trifluoromethylated in excellent isolated yields as demonstrated by the synthesis of the N-CF3 analogue of sildenafil (Viagra®).With those first sets of results on the reactivity behavior of the (Me4N)SCF3 reagent in hands and using state-of-the-art Born-Oppenheimer molecular dynamics coupled with in-depth ReactIR monitoring of the formation of isothiocyanates substrates, we could unravel the mechanism of activation of the SCF3 anion and demonstrate the key role of the tetramethylammonium cation. We showed that the electrophilic S=CF2 was liberated in minute quantities in a chain propagation manner and that no build up in concentration in this species was observed explaining the high selectivity of our developed methodologies. The last subchapter of this thesis details the last use of the (Me4N)SCF3 reagent for the efficient synthesis of acyl fluorides from carboxylic acids. A selection of aliphatic and aromatic acyl fluorides were isolated after rapid reaction periods. Acyl fluoride analogues of carboxylic acids containing pharmaceutical targets were easily accessed in excellent yields. We could also demonstrate and confirm further the wide applicability of acyl fluorides to the formation of challenging amide bonds as exemplified by the synthesis of the adamantyl amide of biotin (vitamin B7). Finally, relying on the mildness of our approach we could fully characterize three N-protected amino acid fluorides, which were formed in excellent isolated yields without racemization.