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Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

Fulton, Tyler J. and Townsend, Katherine M. and Krout, Michael R. (2019) Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides. Journal of Visualized Experiments (147). Art. No. e59775. ISSN 1940-087X. https://resolver.caltech.edu/CaltechAUTHORS:20190617-125540871

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Abstract

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls represents an important method to generate C–C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild “one-pot” preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.3791/59775DOIArticle
ORCID:
AuthorORCID
Fulton, Tyler J.0000-0002-9343-2456
Krout, Michael R.0000-0002-0539-6986
Additional Information:© 2019 Journal of Visualized Experiments. PUBLISHED: 5/26/2019. The authors thank the American Chemical Society (ACS) Petroleum Research Fund Undergraduate New Investigator Program (Award No. 58488-UNI1), the ACS and Pfizer (SURF support to T.J.F.), Bucknell University (research fellowships to T.J.F.), and the Department of Chemistry (research fellowship to K.M.T.) for generous support of this work. Dr. Peter M. Findeis and Brian Breczinski are acknowledged for experimental and instrumentation assistance.
Funders:
Funding AgencyGrant Number
American Chemical Society Petroleum Research Fund58488-UNI1
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
Bucknell UniversityUNSPECIFIED
Issue or Number:147
Record Number:CaltechAUTHORS:20190617-125540871
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190617-125540871
Official Citation:Fulton, T. J., Townsend, K. M., Krout, M. R. Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides. J. Vis. Exp. (147), e59775, doi:10.3791/59775 (2019).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96472
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Jun 2019 20:16
Last Modified:03 Oct 2019 21:22

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