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Abstract The Birch reduction of biaryls generally converts one of the two arenes into a cyclohexa-1,4-diene. Biaryls are more reactive than monocyclic arenes under the Birch conditions. Unlike the reduction of monocyclic arenes, biaryl reduction proceeds through two consecutive electron transfer steps before the protonation of the dianion intermediate. The biaryl reductions and subsequent alkylations in one pot rapidly increase the molecular complexity and thus have been used in the synthesis of natural products and drug-like molecules. 1 Introduction 2 The Physical Organic Chemistry of the Birch Reduction of Biaryls 3 Biaryls as the Mediators of Electron Transfer 4 Methods for the Dissolving-Metal Reduction of Biaryls 5 Intercepting the Biaryl Reduction Intermediates with Electrophiles 6 Synthetic Applications of the Dissolving-Metal-Mediated Reductions of Biaryls 7 Outlook
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Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran
The Birch reduction dearomatizes arenes into 1,4-cyclohexadienes. Despite substantial efforts devoted to avoiding ammonia and cryogenic conditions, the traditional, cumbersome, and dangerous procedure remains the standard. The Benkeser reduction with lithium in ethylenediamine converts arenes to a mixture of cyclohexenes and cyclohexanes; this is operationally easier than the Birch reduction but does not afford 1,4-cyclohexadienes. Here, we report a Birch reduction promoted by lithium and ethylenediamine (or analogs) in tetrahydrofuran at ambient temperature. Our method is easy to set up, inexpensive, scalable, rapid, accessible to any chemical laboratory, and capable of reducing both electron-rich and electron-deficient substrates. Our protocol is also compatible with organocuprate chemistry for further functionalization.
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- Award ID(s):
- 1955758
- PAR ID:
- 10329223
- Date Published:
- Journal Name:
- Science
- Volume:
- 374
- Issue:
- 6568
- ISSN:
- 0036-8075
- Page Range / eLocation ID:
- 741 to 746
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1126/science.abk3099
