Semester
Fall
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
Eberly College of Arts and Sciences
Department
Chemistry
Committee Chair
Brian V. Popp
Committee Member
Gregory B. Dudley
Committee Member
Brian S. Dolinar
Committee Member
Hacer Karatas Bristow
Committee Member
Jianli (John) Hu
Abstract
Benzene rings are some of the most prevalent motifs found in small molecule drugs with only a few dominant substitution patterns, 1-, 1,2-, 1,4-, and 1,2,4-. Nucleophilic aromatic substitution and electrophilic aromatic substitution are traditional methods for the synthesis of substituted benzenes and are robust and commonly used by chemical manufacturers, which explains in part the observed distribution of substitution patterns. Current methods to access substituted benzenes comprise of transition-metal-catalyzed C-H activation, transition-metal-catalyzed cross-coupling, and aryne chemistry. In general, the present methods require directing/leaving groups in specific positions to proceed, which inherently puts a limitation on substrate scope. Transition-metal-catalyzed [2+2+2] alkyne cyclotrimerization is a versatile, general, and economic method for the synthesis of substituted benzenes in a single step, however, regioselectivity and diversity of substituents remain an issue. Alkyne surrogates have unique electronic and steric properties that offer opportunities in addressing these issues. Vinyl sulfone, a recognized alkyne surrogate, was explored in intermolecular [2+2+2] cyclotrimerization with alkynes for the synthesis of multi-substituted benzenes.
Phenyl vinyl sulfone (PVS) was used as an intermolecular coupling partner with terminal aromatic alkynes in a three-component coupling (3CC) under nickel-catalysis for the synthesis of substituted benzenes. It was shown that exclusive regioselectivity for the meta-terphenyl product could be accessed in a single step in moderate to good yields. Investigation of the mechanism revealed that the regioselectivity was controlled through an oxidatively cyclized nickelacyclopentene intermediate between the PVS and alkyne. It was found that PVS not only participated in the 3CC, but also acted as a sulfinic acid scavenger producing 1,2- bis(phenylsulfonyl)ethane as a byproduct.
After development of a new Xantphos-nickel ligand-catalyst system the 3CC was expanded to include internal alkynes, namely phenylpropynes and alkyl-phenyl-propiolates. After optimization of the reaction conditions, it was found that benzonitrile as an additive aided in product formation, with no observed participation of the nitrile moiety. The underrepresented 1,2,3,4-substituted benzene products were synthesized in moderate to good yields as a mixture of synthetically useful polymer precursors, diphenyl-substituted phthalates, isophthalates, and terephthalates, with selectivity towards the isophthalate isomer. Unfortunately, unprotected alcohols, tertiary amines and amides were not tolerated.
The newly developed nickel pre-catalyst also showed that trans-substituted vinyl sulfones could be tolerated in the 3CC with both terminal and internal alkynes, leading to tri- and penta-substituted benzenes. New opportunities in transition-metal-catalyzed benzannulation chemistry have been unlocked through 3CC involving PVS, which led to the synthesis of underrepresented substitution patterns such as 1,3-, 1,2,3,4-, and 1,2,3,4,5- in a single step with moderate to good yields.
Recommended Citation
Long, Stephen M., "Nickel-Catalyzed Regioselective Three-Component Coupling of Phenyl Vinyl Sulfones with Alkynes" (2024). Graduate Theses, Dissertations, and Problem Reports. 12664.
https://researchrepository.wvu.edu/etd/12664
