2012 Theses Doctoral
I. Multicatalysis: Development of a BiOTf₃-catalyzed Nucleophilic Addition/Hydrofunctionalization Reaction in the Synthesis of Complex Heterocycles; . . .
One of the major drawbacks to traditional syntheses is the requirement for iterative synthesis, which is not only chemically inefficient and time-consuming, but environmentally unfriendly due to waste generated during purification procedures. A way to circumvent problems posed by iterative synthesis is through the development of multicatalytic protocols, in which multiple, distinct synthetic steps can be performed in one reaction pot.
Saturated 5-membered oxygen- and nitrogen-containing heterocycles are extremely common structural motifs in many biologically important molecules--a multicatalytic synthetic strategy for their syntheses would be of incredible use. To that end, a bismuth(III) triflate-catalyzed hydroalkoxylation procedure was developed for the synthesis of substituted tetrahydrofurans. This operationally simple method successfully generated complex tetrahyrofurans in moderate to good diastereoselectivity with good functional group tolerance. An analogous hydroamination of non-basic N-tosyl amines was also developed and featured similar levels of diastereoselectivity and functional group compatibility. The methodology was part of a multicatalytic strategy combining nucleophilic additions to aliphatic aldehydes and N-tosyl imines to quickly generate complex 5-membered heterocycles in moderate to good diastereoselectivity. The palladium-pivalate catalytic system has emerged as one of the most efficient and general catalysts for the C-H arylation of arenes and heteroarenes with haloarene donors. Despite the importance of this class of catalytic reactions, the mechanistic understanding is limited by the lack of direct experimental evidence, especially in the context of Lewis basic heteroarene substrates.
To address this problem, we chose the catalytic C-H arylation of 2-methylthiazole as a representative reaction for a detailed mechanistic study. Direct kinetic evidence was provided for the involvement of a palladium(II) pivalate species in the C-H arylation of heteroarenes by identifying the resting state of the catalyst - complex 2a [(Cy₃P)(2-methylthiazole)Pd(Ph)(OPiv)] - and examining its reactivity. The pivalate ligand, in comparison to acetate, does not yield faster rates of C-H activation, but instead stabilizes the resting state of the catalyst against decomposition to inactive palladium species. An experimentally supported rationale for the superiority of the palladium(II) pivalate system in C-H arylation reactions was provided. The choice of phosphine ligand is an incredibly important aspect of catalyst design in many metal-catalyzed transformations, including direct arylations and cross-couplings.
A relatively unexplored area of study was the effect of the phosphine ligand on the C-H metalation step of palladium-catalyzed direct arylation reactions. Through our studies and related studies in the literature, we can conclude that the phosphine ligand is generally deactivating toward deprotonative metalation (CMD/EMD) pathways, however the phosphine ligand is necessary in the C5 arylation of triazole and C2 arylation of thiazole, as well as substituted pyridines. In the case of azoles, arylation probably proceeds via a mechanism different to that of C5 arylations; the phosphine ligand stabilizes catalytic intermediates, affording efficient C2 arylation of azoles. In the case of pyridine, the major issue is that of catalyst decomposition; in approaching catalyst design, one must balance tuning of the reactivity of the palladium catalyst toward C-H metalation versus protecting the catalyst during prolonged reaction times and high reaction temperatures.
Two common ligands in palladium catalysis, Cy₃P and t-Bu₃P, were directly compared in terms of their interaction with basic substrates. While complexes ligated to a single Cy₃P ligand were able to accommodate basic heteroarenes in the palladium coordination sphere, complexes with the bulkier t-Bu₃P ligand behaved very differently, which could have important ramifications on future catalyst design. Heteroaromatic substrates have typically provided challenges for the development of direct arylation protocols. However, how the properties of the substrate affect the rate-limiting metalation step of palladium-catalyzed direct arylation reactions was mostly unknown.
Thus, we correlated the rates of C-H metalation of azoles and substituted pyridines with various intrinsic properties of heterocycles, such as aromaticity, and pKₐ. It was found that for the C5 arylation of azoles, a stronger correlation on the rate of metalation with pKa was observed. Degree of aromaticity appears to have little correlation with the rates of C-H metalation of azoles and pyridines.
- Tundel_columbia_0054D_10388.pdf application/pdf 17.5 MB Download File
More About This Work
- Academic Units
- Thesis Advisors
- Sames, Dalibor
- Ph.D., Columbia University
- Published Here
- October 10, 2012
Title continues: ". . . II. C-H Arylation of Heteroarenes: Mapping the Mechanism of Palladium-Carboxylate Catalyzed Direct Arylation Reactions."