Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran

Burrows, James; Kamo, Shogo; Koide, Kazunori

doi:10.1126/science.abk3099

Cited by 78 publications

(86 citation statements)

References 78 publications

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“…In fact, lithium's low reduction potential allows for it to be easily ionized in the presence of strongly Lewis basic ligands such as ammonia or alkylamines. 24,25 During this type of dissolution process the s electron from Li-metal is ionized into solution which leads to the characteristic blue hue of a solvated electron under relatively dilute conditions and a fiery bronze color at high concentrations (Figure 1D). Understanding the fundamental nature of the alkali metal electrides has been an ongoing topic of research for over a century.…”

Section: Formation Of Lithiummentioning

confidence: 99%

Preparation of Highly Reactive Lithium Metal Dendrites for the Synthesis of Organolithium Reagents

Crockett

Aguirre

Jimenez

et al. 2022

Preprint

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A long-standing problem in the area of organolithium chemistry has been the need for a highly reactive Li–metal source that mimics Li–powders but has the advantage of being freshly prepared from inexpensive and readily available Li–sources. Here we report a simple and convenient activation method using liquid ammonia that furnishes a new Li–metal source in the form of crystalline Li–dendrites. The Li–dendrites were shown to have ca 100 times greater surface area than conventional Li–sources created by prototypical mechanical activation methods. Concomitant with the surface area increase, the Li–dendrites are 19 times more reactive than Li–powders which are currently the industry standard for the preparation of organolithium compounds. These features were leveraged for the reproducible synthesis of organolithium reagents over a range of common laboratory scales.

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Section: Formation Of Lithiummentioning

confidence: 99%

Preparation of Highly Reactive Lithium Metal Dendrites for the Synthesis of Organolithium Reagents

Crockett

Aguirre

Jimenez

et al. 2022

Preprint

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“… 14 The harsh and challenging conditions of this methodology mean that it is not favored in industrial settings as it presents several safety challenges with copious amounts of ammonia required upon scale-up. 15 , 16 While there have been several efforts to produce an ammonia-free Birch reduction, the methodologies have only been demonstrated on small scales 17 − 19 and in some cases, they led to over-reduction of the Birch-type products. 20 − 22 A recent report by Koide and co-workers demonstrated that a Birch reduction could be achieved by replacing ammonia with ethylenediamine in THF and lithium metal as the reducing agent.…”

Section: Introductionmentioning

confidence: 99%

High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor

Lee

Love

Mansouri

et al. 2022

Org. Process Res. Dev.

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We report the development of a single-pass electrochemical Birch reduction carried out in a small footprint electrochemical Taylor vortex reactor with projected productivities of >80 g day –1 (based on 32.2 mmol h –1 ), using a modified version of our previously reported reactor [ Org. Process Res. Dev. 2021 , 25 , 7, 1619–1627], consisting of a static outer electrode and a rapidly rotating cylindrical inner electrode. In this study, we used an aluminum tube as the sacrificial outer electrode and stainless steel as the rotating inner electrode. We have established the viability of using a sacrificial aluminum anode for the electrochemical reduction of naphthalene, and by varying the current, we can switch between high selectivity (>90%) for either the single ring reduction or double ring reduction with >80 g day –1 projected productivity for either product. The concentration of LiBr in solution changes the fluid dynamics of the reaction mixture investigated by computational fluid dynamics, and this affects equilibration time, monitored using Fourier transform infrared spectroscopy. We show that the concentrations of electrolyte (LiBr) and proton source (dimethylurea) can be reduced while maintaining high reaction efficiency. We also report the reduction of 1-aminonaphthalene, which has been used as a precursor to the API Ropinirole. We find that our methodology produces the corresponding dihydronaphthalene with excellent selectivity and 88% isolated yield in an uninterrupted run of >8 h with a projected productivity of >100 g day –1 .

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“…We have been interested in the development of alkali-metal-promoted reductive transformations of unsaturated compounds [20][21][22][23][24] by using reduction-resistant electrophiles as key reagents. [25][26][27] In one hand, this class of electrophiles such as trialkoxyboranes are resistant to single electron reduction so that they can coexist in the same pot where the reduction of unsaturated substrates takes place.…”

Section: Introductionmentioning

confidence: 99%

Reductive anti-dimagnesiation and dialumination of alkynes: Synthesis and reactions of trans-1,2-dimetalloalkenes

Takahashi

Kurogi

Yorimitsu

2022

Preprint

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Given the great significance of polar reactive organometallic species in synthesis for more than one century, generation and use of stereodefined 1,2-dimetallated alkenes should be fascinating yet has been very challenging. Here we report reductive anti-1,2-dimetalation of alkynes to easily and stereoselectively generate trans-1,2-dimagnesio- and 1,2-dialuminoalkenes that are difficult to prepare, reasonably stable, and thus useful for organic synthesis. The key for the success is the use of sodium dispersion as a powerful reducing agent and organomagnesium and organoaluminum halides as reduction-resistant electrophiles counterintuitively. Highly nucleophilic 1,2-dimagnesioalkenes serve as dual Grignard reagents and react with various electrophiles to afford anti-difunctionalized alkenes. Interestingly, 1,2-dialuminoalkenes react with paraformaldehyde with dearomatization of the aryl moieties to form the corresponding dearomatized 1,4-diols, the overall reaction being regarded as alkynyl-directed dearomatization of arenes. Our anti-1,2-dimetalation including structural and computational investigation provides a new powerful tool and unique insight in the development of organometallic chemistry and organic synthesis.

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Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran

Cited by 78 publications

References 78 publications

Preparation of Highly Reactive Lithium Metal Dendrites for the Synthesis of Organolithium Reagents

Preparation of Highly Reactive Lithium Metal Dendrites for the Synthesis of Organolithium Reagents

High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor

Reductive anti-dimagnesiation and dialumination of alkynes: Synthesis and reactions of trans-1,2-dimetalloalkenes

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