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Selective Terminal Heck Arylation of Vinyl Ethers with Aryl Chlorides: A Combined Experimental-Computational Approach Including Synthesis of Betaxolol
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 71, no 10, 3896-3903 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 71, no 10, 3896-3903 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97433OAI: oai:DiVA.org:uu-97433DiVA: diva2:172383
Available from: 2008-08-27 Created: 2008-08-27 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity
Open this publication in new window or tab >>Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.

For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.

Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.

Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).

Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 76
Heck reaction, aryl chloride, vinyl ether, regioselective, stereoselective, palladium, chelation control, microwave
National Category
Medicinal Chemistry
urn:nbn:se:uu:diva-9202 (URN)978-91-554-7256-6 (ISBN)
Public defence
2008-09-24, B42, BMC, Husarg. 3, Uppsala, 13:15
Available from: 2008-08-27 Created: 2008-08-27Bibliographically approved

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