Mechanism-guided development of Cu(I)- and Cu(II)-catalyzed C(sp2)—O cross-coupling reactions for the practical and concise syntheses of 1,2-di- and tri-substituted acyclic vinylic ethers from structurally complex vinylic synthons and aliphatic alcohols Restricted; Files Only
Pham, San (Spring 2026)
Abstract
Vinylic ethers are electron‑rich alkenes with broad utility in synthesis, chemical biology, and materials science, and they constitute the defining structural motif of plasmalogens, a biologically essential class of phospholipids. Despite their importance, general and stereoselective methods for constructing structurally complex acyclic vinylic ethers—particularly those derived from weakly nucleophilic aliphatic alcohols—remain limited. This challenge is especially acute for the synthesis of Z-vinylic ethers, where existing strategies often rely on multistep sequences, harsh reaction conditions, or highly specialized substrates. Furthermore, initial attempts to extend previously reported Cu(I)- and Cu(II)-catalyzed C—O cross‑coupling reactions to structurally complex vinylic synthons and weakly nucleophilic aliphatic alcohols consistently failed, emphasizing the need for “reinventing the wheel.”
This dissertation describes the mechanism‑guided development of complementary Cu(I)- and Cu(II)-catalyzed C(sp²)–O cross‑coupling reactions that enable concise, stereoselective access to di‑ and trisubstituted acyclic vinylic ethers from structurally complex vinylic synthons and aliphatic alcohols. By first identifying and understanding side‑product formation, and then using established mechanistic literature to guide rational reaction redesign, I systematically addressed the intrinsic mechanistic bottleneck associated with aliphatic alcohols, namely their weak Lewis basicity and low Brønsted acidity, which limits productive Cu–alkoxide formation and promotes unproductive side reactions.
In Chapter 2, a Cu(I)-catalyzed Ullmann-type C(sp²)–O cross-coupling reaction was reconstructed to achieve the first stereospecific synthesis of Z‑1,2-disubstituted and trisubstituted vinylic ethers from vinylic halides and aliphatic alcohols. Mechanistic analysis revealed a delicate balance between oxidative addition, alcohol coordination/deprotonation, and unreported competing base-promoted-elimination/enyne-formation pathways. Leveraging CuI precatalyst, CyDMEDA ligand, and the Cs₂CO₃/DME base/solvent system enables effective vinylic C—O cross-coupling pathway with aliphatic alcohols while simultaneously suppressing side reactions.
Chapters 3 focus on Cu(II)-catalyzed Chan–Evans–Lam–type vinylic C—O cross-coupling reactions using vinylic pinacol boronate esters. Introduction of N‑alkyl imidazole ligands enabled efficient Cu(OAc)₂ paddlewheel dissociation, while dialkyl peroxide oxidants, most notably dicumyl peroxide, dramatically enhanced catalytic turnover by generating highly reactive Cu(II)-alkoxide species. These peroxide-enabled conditions provide rapid, high-yielding access to E‑selective vinylic ethers from aliphatic alcohols and vinylic Bpin substrates. These mechanistic insights were translated toward the more challenging Z‑selective Cu(II)-catalyzed vinylic ether synthesis in chapter 4, revealing heightened steric sensitivity during alcohol ligand exchange. Additive-assisted alcohol activation and catalyst speciation control enabled progress toward mild, stereoselective routes compatible with polymerization-prone substrates such as glycidol. Collectively, this work demonstrates how control of copper speciation, ligand effects, and redox turnover can overcome the longstanding limitations in vinylic ether synthesis.
Table of Contents
Table of Contents
Chapter 1. Introduction to Cu-Catalyzed Vinylic C(sp2)—O Cross-Coupling Reactions 1
1.1. Why acyclic vinylic ethers matter 1
1.2. Limitations of previous syntheses of acyclic vinylic ether (prior to 2021) 3
1.2.1. Previous syntheses of highly substituted acyclic vinylic ethers and total syntheses of plasmalogen 3
1.2.2. Previously developed Cu-catalyzed vinylic C—O cross-coupling reactions with aliphatic alcohols and their limitations 6
1.3. Research aims and motivation 13
1.3.1. Aim 1: Reconstructing Cu-catalyzed C(sp2)—O cross-coupling reactions for structurally complex vinylic synthons and aliphatic alcohols 13
1.3.2. Aim 2: Developing a concise total synthesis of plasmalogen 15
1.3.3. Forewords 16
Chapter 2 . Development of (Z)-Stereospecific Cu(I)-Catalyzed Ullmann-Type C—O Cross-Coupling Reaction 18
2.1. Mechanistic hypotheses and relevant scientific premises 18
2.1.1. Relevant mechanistic insights 18
2.1.2. Mechanistic hypotheses for reaction optimization 24
2.2. Reaction optimization with (Z)-vinylic iodide 1a and aliphatic alcohol 2a 28
2.2.1. Initial reaction development 28
2.2.2. Comprehensive reaction optimization 36
2.3. Substrate scope study 42
2.3.1. (Z)-1,2-disubstituted vinylic ether synthesis from vinylic iodides + aliphatic alcohols 42
2.3.2. Trisubstituted vinylic ether synthesis 44
2.3.3. Notable cases of incompatible substrate scope 45
2.4. Mechanistic discussion 46
2.5. Conclusion and future works 48
2.6. Forewords for chapters 3 + 4: Translating lessons from Chapter 2 into the development of Cu(II)-Catalyzed Methods 49
Chapter 3 . Development of (E)-Selective Cu(II)-Catalyzed Chan-Evans-Lam-(CEL)-Type C—O Cross-Coupling Reaction 50
3.1. Mechanistic hypotheses 50
3.1.1. Canonical Cu(II)-catalyzed C—O cross-coupling reaction mechanism proposed by Stahl and coworkers for aryl ether synthesis 50
3.1.2. Mechanistically informed hypotheses and optimization strategies 52
3.1.3. Integrated working expectation 58
3.2. Initial reaction optimization with (E)-vinylic boron and aliphatic alcohol 59
3.2.1. Discovery of Cu(OAc)2 / NPI / DTBP – mediated C—O cross-coupling reaction conditions 59
3.2.3. Other mechanistically informative experiments 69
3.2.4. Summary and preliminary substrate scopes of initial reaction optimization 74
3.3. Breakthrough with dicumyl peroxide (DCP) oxidant and complete substrate scope study 78
3.3.1. Mechanistic hypotheses and literature precedents for dialkyl peroxide screening 78
3.3.2. Comprehensive reaction optimization 80
3.3.3. Substrate scope with DCP oxidant 81
3.4. Mechanistic investigation and revised mechanism for our Cu(II)-catalyzed vinylic C—O cross-coupling reaction 84
3.4.1. Reaction progress monitoring – Comparison between DTBP and DCP conditions 84
3.4.2. Reaction kinetics are dependent on Cu, vinylic Bpin, and oxidant loadings 87
3.4.3. Vinylic Bpin undergoes faster transmetalation than aryl Bpin 89
3.4.4. Preliminary high‑resolution mass spectrometry (HRMS) analysis of Cu(OAc)2 / NPI / DTBP / CH2Cl2 reaction conditions 89
3.4.5. Revised mechanism for Cu(OAc)2 / NPI / DCP – catalyzed vinylic C—O cross-coupling reaction with aliphatic alcohols 92
3.5. Conclusion 94
Chapter 4 . Current Development of Cu(II)-Catalyzed CEL-type Z-Vinylic Ether Synthesis – Progress Towards Plasmalogen Synthesis 96
4.1. Mechanistic framework for (Z)-selective Cu(II)-catalyzed CEL-type C—O cross-coupling reaction – Lessons learned from Chapters 2 + 3 96
4.1.1. Initial attempts to apply Cu(OAc)2 / NPI / DTBP or DCP conditions to (Z)-vinylic C—O cross-coupling reaction 96
4.1.2. Mechanistic model and optimization strategies 98
4.2. Current progress towards Cu(II)-catalyzed (Z)-vinylic C—O cross-coupling reaction with aliphatic alcohols 101
4.2.1. Initial reaction optimization of Cu(II)-catalyzed (Z)-vinylic C—O cross-coupling reaction 101
4.2.2. Improvement of alcohol deprotonation as the primary optimization strategy 106
4.2.3. Mechanistic significance of the DTBMP additive on the operative alcohol ligand exchange with (Z)-vinylic—(NPI)2Cu(III)—(Ocumyl)2 complex 110
4.3. Preliminary Cu(II)-catalyzed (Z)-selective vinylic C—O cross-coupling reaction with polymerization-prone glycidol 2z 111
4.3.1. Brief background and my initial unsuccessful attempt to apply my Cu(I)-catalyzed reaction for glycidol 2z 111
4.3.2. Z-selective Cu(II)-catalyzed vinylic C—O cross-coupling reaction provides the first promising gateway to a one-step synthesis of the elusive (Z)-glycidyl vinylic ether product 112
4.4. Conclusion and future works 114
4.4.1. Regarding Z-selective Cu(II)-catalyzed C—O cross-coupling reaction with (Z)-vinylic Bpin and aliphatic alcohol 114
4.4.2. Regarding progress towards concise plasmalogen synthesis 115
Supporting Information (adapted from Org. Let. 2023 and 2025) 116
S1. General considerations 116
S1.1. General experimental and analytical considerations: 116
S1.2. Personal notes on the storage of some key/sensitive catalysts and reagents: 118
S1.3. Aliphatic alcohols and vinylic synthons in published / successful vinylic ether synthesis 119
S2. Experimental section for chapter 2 (adapted from Org. Lett. 2023) 121
S2.1. Experimental procedures for Cu(I)-catalyzed C—O cross-coupling reaction 121
S2.2. Substrate scopes 128
S2.3. Synthesis of starting vinylic synthons 151
S2.4. Control experiments 159
S2.5. Other unreported substrate pairs 162
S3. Experimental section for chapter 3 and chapter 4 (adapted from Org. Lett. 2025) 163
S3.1. Experimental procedures for Cu(II)-catalyzed C—O cross-coupling reactions 163
S3.2. Substrate scopes 175
S3.3. Additional optimization studies 197
S3.4. Mechanistic experiments 203
S3.5. Syntheses of other vinylic borons (adapted directly from ref. 43) 217
S3.6. Incompatible substrates 220
S3.7. Experimental protocol for current (Z)-vinylic ether study 221
References 231
NMR spectra of new compounds 240
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