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Title:The development of palladium-catalyzed cross-coupling reactions of allylic silanolate salts with aromatic bromides
Author(s):Werner, Nathan S.
Director of Research:Denmark, Scott E.
Doctoral Committee Chair(s):Denmark, Scott E.
Doctoral Committee Member(s):Moore, Jeffrey S.; Burke, Martin D.; Girolami, Gregory S.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):palladium-catalyzed
cross-coupling
catalysis
silanol
silanolate
aromatic bromide
allyl arene
allylic
site-selective
asymmetric
enantioselective
stereospecific
diastereoselective
syn SE'
stereochemical course
Abstract:The palladium-catalyzed cross-coupling of allylic silanolate salts with a wide variety of aromatic bromides was developed. The coupling of sodium allyldimethylsilanolate and 2-butenyldimethylsilanolate required extensive optimization to deliver the expected products in high yields. The reaction of the allyldimethylsilanolate takes place at 85 °C under “ligand-less’ conditions in 1,2-dimethoxyethane with allylpalladium chloride dimer (2.5 mol %) to afford 73–95% yields of the allylation products. Both electron-rich and sterically hindered bromides reacted smoothly, whereas electron-poor bromides cross-coupled in poor yield because of a secondary isomerization to the 1-propeneyl isomer (or concommitant polymerization). A modified protocol that employs an electron-rich phosphine ligand (SPhos), a lower reaction temperature (40 °C), and a less polar solvent (toluene) delivers the expected products from electron-poor bromides without isomerization. The 2-butenyldimethylsilanolate (E/Z, 80:20) required additional optimization to maximize the formation of the branched (gamma-coupled) product and resulted in the development of two distinct protocols for gamma-selective coupling. The first protocol took advantage of a remarkable influence of added alkenes (dibenzylideneacetone and norbornadiene) and led to good selectivities for a large number of electron-rich and electron-poor bromides in 40–83% yields. However, bromides containing coordinating groups (particularly in the 2-position) gave lower, and in one case even reversed, site-selectivity. Electron-rich aromatic bromides reacted sluggishly under this protocol and led to lower product yields. The second protocol employed a sterically bulky phosphonium tetrafluoroborate salt (t-BuCy2PH+BF4−) and resulted in 73–94% yields and excellent site-selectivity (gamma/alpha, 25:1–>99:1) in the coupling of electron-rich, electron-poor, sterically hindered, and heteroaromatic bromides. The use of a configurationally homogeneous (Z)-silanolate and nontransferable diethyl groups were critical to achieving excellent results. A unified mechanistic picture involving initial gamma-transmetalation followed by direct reductive elimination or sigma–pi isomerization can rationalize all of the observed trends. The stereochemical course of palladium-catalyzed cross-coupling reactions of an enantioenriched, alpha-substituted, allylic silanolate salt with aromatic bromides was determined. The allylic silanolate salt was prepared in high geometrical (Z/E, 94:6) and high enantiomeric (94:6 er) purity by a copper-catalyzed SN2’ reaction of a resolved carbamate. Eight different aromatic bromides underwent cross-coupling with excellent constitutional site-selectivity and excellent stereospecificity. Stereochemical correlation established that the transmetalation event proceeds through a syn SE’ mechanism with is interpreted in terms of an intramolecular delivery of the arylpalladium electrophile through a key intermediate that contains a discrete Si–O–Pd linkage. The catalytic, asymmetric palladium-catalyzed cross-coupling of sodium 2-butenylsilanolate with aromatic bromides was investigated. A wide range of chiral ligands including olefin, bidentate phosphine, monodentate phosphine, and cyclic and acyclic stereogenic at phosphorus ligands were evaluated. Commonly used chiral, bidentate phosphine ligands provided ineffective palladium-catalysts for the coupling of 2-butenyldimethylsilanolate with aromatic bromides. A catalyst derived from the monodentate phosphine ligand neomenthyldiphenylphosphine (20 mol %) and Pd(dba)2 (5 mol %) provided moderate enantioselectivity (75:25 er) and modest site-selectivity (5.7:1 gamma/alpha) in the coupling. Increased site-selectivity (up to >99:1) was obtained from reactions employing bulky di or trialkylphosphine ligands.
Issue Date:2011-08-26
URI:http://hdl.handle.net/2142/26271
Rights Information:Copyright 2011 Nathan S. Werner
Date Available in IDEALS:2013-08-27
Date Deposited:2011-08


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