Silicon-Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles

A wide array of cross-coupling methods for the formation of C–C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C–heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C–Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr_2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., −20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C–X bond cleavage

Enantioselective Synthesis of α-Aminosilanes by Copper-Catalyzed Hydroamination of Vinylsilanes

The synthesis of α-aminosilanes by a highly enantio- and regioselective copper-catalyzed hydroamination of vinylsilanes is reported. The system employs Cu-DTBM-SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O-benzoylhydroxylamines as the electrophilic nitrogen source. This hydroamination reaction is compatible with differentially substituted vinylsilanes, thus providing access to amino acid mimics and other valuable chiral organosilicon compounds.National Institutes of Health (U.S.) (Award GM58160

Methods in organosilane assembly

Dialkylsilanediols are a novel class of non-hydrolyzable analogues of the tetrahedral intermediate of amide hydrolysis, shown to be good inhibitors of HIV-1 protease, angiotensin converting enzyme (ACE), and thermolysin. An impediment to utilization of these silanediol structures, however, has been the methods for their assembly. This research describes the reductive lithiation of hydridosilanes and alkoxysilanes, and the use of the resulting silyl anions to develop efficient methods to synthesize silanediol precursors. In the first part of research, lithiation of hydridosilanes was studied. As part of this study, a simple 1H NMR method was developed for monitoring and analyzing the progress of lithiation. In addition, this method was converted to a titration for silyllithium reagents using BHT as an internal standard. Silanediols 107 and 177 are analogues of a potent chymase inhibitor, NK-3201 (82). In the second part, diphenylsilanes 108 and 170, precursors to silanediols 107 and 177, were synthesized using addition of silyllithium to sulfinimine 113 as a key step. In the third part, lithiation of alkoxysilanes was studied. (Si,O)-Dianions, generated from lithiation of silane alcohol 175 or 2,2-diphenyl-1-oxa-2-silacyclopentane (225), were reacted with a wide variety of electrophiles to give potentially useful silicon-containing building blocks. Addition of the (Si,O)-dianion 284 to sulfinimines gave silanediol inhibitor precursors with full control of stereochemistry. In the last part, a new method featuring 1,1-diphenyl-2-azaallyllithium chemistry were utilized to synthesize a series of protected α-amino silanes 323, 329 - 331.Chemistr

Methodological advancements in microfluidic and carbonylation PET radiochemistry

Along with the progress of PET as a powerful imaging tool in medicine, there has been increasing demand for new labeling methods. The main aim of this PhD dissertation was to develop novel labeling methodologies using the positron emitter carbon-11. Advancements within the field of palladium-mediated carbonylation reaction are discussed in the first part of the thesis. Paper I describes the development of a Pd-ligand complex where [11C]carbon monoxide (11CO) is efficiently trapped and incorporated as a part of the CO- insertion procedure. The consequent carbonylation reaction proceeds smoothly in good and reproducible yields using aryl halides or triflates as substrates. As a proof of concept, the utility of the protocol was applied to the synthesis of a candidate radioligand for the histamine type-3 receptor. The same protocol was further improved using microwave heating in paper II. An improved yield was observed in the 11C-aminocarbonylation of electron deficient aryl halides and even allowing for the use of an aryl chloride as substrate. Moreover, high yields for hydroxy- and alkoxycarbonylation were obtained when efficient microwave-energy absorbent nucleophiles, such as water and alcohol, were utilized as co-solvents. In paper III, an efficient and convenient carbonylative approach for the direct synthesis of 11C-labeled aryl methyl ketones from aryl halides is presented, employing [11C]methyl iodide (11CH3I) as the radioactive precursor under Co2(CO)8-mediated conditions. A total of ten model (hetero)aryl methyl ketones were obtained in a 22-63% decay-corrected radiochemical yield, based on radioactivity in the solution at the end of synthesis. The increasing demand of rapid labeling procedures has stimulated the development of emerging technologies such as microfluidics for more flexible and efficient radioligand supply. To this end, in the second part of the thesis, microfluidic-assisted radiochemistry was evaluated for the labeling with fluorine-18 and carbon-11. Firstly, in paper IV, a commercially available microfluidic (MF) platform was evaluated using the two-step preparation of 18F-fluorobenzyl amines via a reductive amination reaction. The microfluidic apparatus allowed for rapid parameter optimization and was also applied preparatively to produce adequate radioactivities for PET applications. Finally, in paper V, a novel gas-liquid segmented microfluidic platform was developed. The large gas-to-liquid interfacial area generated by the segmented approach facilitated the 11CO insertion even while less reactive Pd-ligand species were applied. The Pd- mediated 11C-carbonylation reaction proceeded smoothly on this platform and good to excellent radiochemical yields were observed. Twelve compounds were successfully radiolabeled in a RCY range of 41-99%, including the well establiched D2 receptor radioligands [11C]raclopride and [11C]FLB 457

Silenes as novel synthetic reagents

Several syntheses of aryltris(trimethylsilyl)silanes were investigated and finally a novel route was developed starting from tetrakis(trimethylsilyl)silane, the mechanism for which was investigated. This new robust and reproducible synthesis involved a halogen-metal exchange and exploited a Schlenk equilibrium and was used to produce phenyltris(trimethylsilyl)silane in high yield (-70 %) on scales of up to 20 g. Phenyltris(trimethylsilyl)silane was used as the starting material for the synthesis of silene precursors; 1-hydroxyalkylphenyltrisilanes (silyl alcohols), involving KO'Bu-mediated formation of phenyltris(trimethylsilyl)silylpotassium, transmetallation to the silylmagnesium bromide and addition of an aldehyde. Following optimisation and mechanistic studies on this reaction, it could be employed in the synthesis of several alkyl-analogues. Silenes were generated from the silyl alcohols by the modified Peterson olefination. Extensive optimisation and mechanistic studies led to a procedure that involved the use of "BuLi as a base to cause a 1,3-Si, O TMS migration which was followed by the addition of catalytic amounts of lithium bromide to induce elimination of MegSiOLi to give the silene. Silene generation in the presence of a diene afforded [4+2] silacycloadducts containing an alkene in the β-position to silicon, along with small amounts of ene products and silene dimers. The silacycles were formed with satisfactory diastereoselectivity with the major isomer constituting 70-80 % of the mixture. A range of dienes were screened for reaction with various silenes. The resulting silacycles were shown to be useful synthetic intermediates by their conversion into lactones. This involved hydrogenation of the carbon-carbon double bond followed by a Fleming-Tamao oxidation to afford diols, initiated by protodesilylation of the Si-phenyl group. Subsequent TPAP, NMO oxidation of the diols produced the desired lactones from which NOESY and other NMR experiments were used to deduce the stereochemistry. In addition, silacycles without substitution on the carbon-carbon double bond could be converted into bishomoallyhc alcohols by omission of the hydrogenation and direct Fleming-Tamao oxidation, thus exploiting the latent reactivity of the allylic silane

Regioselective Anti-Silyllithiation of Propargylic Alcohols

Among the known hydrosilylation or carbosilylation conditions of alkynes, anti-addition of the two units across the triple bond is considered rare compared to the syn counterpart. For anti-silylative vicinal difunctionalizations, transition-metal catalysts, such as ruthenium or palladium complexes, are generally required. Accordingly, silyl alkali metals have not been employed for those anti-addition transformations. Here we demonstrate that silyllithiums can add across the triple bond of a series of propargylic alkoxides regioselectively in an anti-fashion. Upon treatment with a variety of electrophiles, the trisubstituted alkenyl lithium intermediates were transformed into highly functionalized β-silyl allylic alcohols with high regiocontrol, eventually providing tri- or tetrasubstituted alkenylsilanes stereoselectively. A classic trick for anti-addition with propargylic alkoxides has transformed anti-silylative functionalizations into a robust and reliable strategy