What is lithiation?
Lithiation is a process where an atom within a molecule, usually a proton or halogen, is replaced with lithium, generating an organolithium species. Within organic synthesis, the most commonly used organolithiums contain C–Li, N–Li and O–Li bonds. In these species, the electron cloud is highly polarised towards the non-lithium atom, so the non-lithium atom can be considered to have a negative charge. This means that these species can either act as a base, through removal of a proton, or as a nucleophile, through addition into an electrophilic centre such as a carbonyl.
It is important to note that organolithium species, especially those with high pKaH, can also undergo halogen–lithium exchange leading to generation of a new, more stable, organolithium species [1, 2], as well as transmetallation to prepare other organometallics, Scheme 1.
Scheme 1: General overview of lithiation reactions from a commercially available organolithium species.
The first experimentation with organolithiums required their generation through use of lithium metal and an alkyl halide, however these days, within a standard research laboratory, it is unusual to generate alkyllithiums using this method due to the risks involved. More commonly, commercially available organolithiums are used, with the exact species chosen depending upon the desired outcome. For example:
- Tert-butyllithium (t-BuLi) and sec-butyllithium (s-BuLi) can be used as strong bases but are often used for halogen-metal exchange reactions. At the time of writing, the use of tert-butyllithium in continuous flow chemistry has not been undertaken, likely due to the extreme pyrophoricity of this reagent.
- N-Butyllithium (n-BuLi), lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide (LiHMDS) are commonly used bases, deprotonating other species to generate nucleophilic intermediates. n-BuLi and LiHMDS are usually acquired from commercial sources, whereas LDA is often prepared fresh.
Key considerations
In all cases, the use of organolithium reagents requires specialised handling. All are water and oxygen sensitive, and many are corrosive, pyrophoric and flammable; t-BuLi particularly so. In addition, temperature control is crucial, as many organolithiums are only stable at low temperatures: higher temperatures can cause degradation or unwanted side-reactions.
Benefits of continuous flow for lithiation
While the use of organolithiums to effect a range of transformations is thoroughly established within batch chemistry by virtue of the many named reactions available, such as the Shapiro reaction, Wittig rearrangement and the Corey–Seebach reaction, successful transfer into flow could further expand the wide-utility of these useful reagents. Many of these transformations require additives, such as HMPA and TMEDA, which can be toxic and require removal upon reaction completion. The control over temperature and stoichiometry afforded by flow chemistry, as well as the possibility for in-line purification or scavenging, means that the flexibility to tune and optimise these reactions whilst also allowing for safe and scalable handling could open the potential reactivity of these versatile species within drug design and natural product synthesis.
As noted above, when using organolithium reagents temperature control is crucial. The high surface-to-volume ratio of microreactors means that heat dissipation, temperature control and energy transfer can all be controlled effectively [3], which is imperative on industrial scale where control of heat can be an onerous task and thermal run-away a real possibility. This is where flow chemistry comes into its own, and recent advances in the use of organometallic reagents in flow has allowed industrial-scale production of key building blocks and APIs [4].
For balance it should be noted that large-scale use of organolithiums can lead to precipitates, either during the reaction or upon work-up, which can lead to challenges if using a flow chemistry set-up. However, there are some strategies under development to alleviate this problem, such as filtering of feed stock solutions, accurate temperature control, and development of clean-in-place techniques [3, 5].
At the time of writing, the use of organolithiums using continuous flow processing is mostly restricted to deprotonation. The following section will highlight some examples.
n-Butyllithium (n-BuLi)
Yoshida and co-workers exploited flow chemistry to avoid issues faced with β-elimination when generating 2-halovinyllithiums in batch mode, which was likely due to the lengthy timescales between organolithium preparation and use [6]. Flow chemistry allowed immediate generation and use of these unstable intermediates, and it was confirmed that control of the residence time offered by flow chemistry was key: increased residence time resulted in undesired elimination. Interestingly, in this case the use of flow allowed access to two temperature regimes: the first step was achieved using n-BuLi at 0 °C and the second step, with s-BuLi, at –78 °C, with rapid switching between temperatures possible that simply could not be achieved during batch processing, Scheme 2.
Scheme 2: Preparation of substituted 1,2-dichloroethane derivates using precise residence-time control.
Lithium Diisopropylamide (LDA)
LDA is a strong amide base, known to be more basic than nucleophilic by virtue of the two iso-propyl groups flanking the central nitrogen atom. Although LDA can be purchased commercially, chemists often prepare it in situ immediately prior to use to ensure consistency between batches [3].
Divergent lithiation of 2,3-dihalopyridines in flow mode has been reported by Brégent et al., where the temperature at which deprotonation occurred impacted upon the final product, Scheme 3 [7]. Reaction outcome could be tuned to the halogen dance by using a residence time of less than 60 seconds at –20 °C to furnish material in yields of 42–95% on a multi-gram scale, whilst deprotolithiation could be carried out in the same system simply by reducing the reaction temperature and increasing residence times to more than 60 seconds, with products isolated in 78–97% yields.
Scheme 3: Lithiation of 2,3-dihalopyridines in flow enabled excellent temperature control, with product isolated dependent on the reaction temperature and residence time.
In the previous example, the LDA was freshly prepared, but in batch mode. The opportunity to prepare LDA in flow, therefore, removes the requirement for a batch process entirely. Wirth and co-workers reported the use of a flow system for both preparation of LDA in situ and the safe use of ethyl diazoacetate to access tertiary diazoalcohols, Scheme 4 [8]. As well as a useful example of in-line LDA preparation, the use of flow chemistry circumvented safety issues in relation to using large quantities of the potentially explosive material ethyl diazoacetate, issues surrounding the instability of the intermediate ethyl lithiodiazoacetate at temperatures over –50 °C, and the unreliable nature of the batch reaction in terms of yield.
Scheme 4: Preparation of LDA in situ, then use to deprotonate ethyl diazoacetate to access tertiary diazoalcohols.
Lithium bis(trimethylsilyl)amide (LiHMDS)
The final base that will be showcased in this overview is lithium bis(trimethylsilyl)amide (LiHMDS). LiHMDS is an even-bulkier base than LDA and has a slightly lower pKaH, therefore is viewed as less aggressive than LDA.
Ley and co-workers used LiHMDS for synthesis of a family of casein kinase I inhibitors using a continuous flow system due to difficulties when using organolithiums in batch, including rapid decomposition of the intermediate and difficulties controlling the exotherm, Scheme 5 [9]. A mixture of picoline and ethyl 4-fluorobenzoate was combined with a solution of LiHMDS, pre-cooled to 0 °C, and the mixture maintained at 0 °C. At the time, a dual pump system was required to ensure consistent supply of LiHMDS, without degradation, over a long period, although innovations in the field mean this is no longer necessary. This solution was then warmed to room temperature, resulting in a 2-hour residence time overall. The reaction between the picoline and electrophile occurred in the second stage of the flow reactor. The final product was isolated in 94% yield and excellent purity through precipitation of the exiting stream into hexane.
Scheme 5: Use of LiHMDS to access precursors that could be further elaborated into casein kinase I inhibitors.
Other lithium bases
Other lithium bases have been reported for use in flow, including phenyl lithium and hexyl lithium, although their use is not as prevalent as those outlined above [3]. In addition, as the field expands, the opportunity to utilise enantioselective deprotonation techniques for even more efficient synthesis becomes more likely.
References
[1] Über die Austauschbarkeit von aromatisch gebundenem Wasserstoff gegen Lithium mittels Phenyl-lithiums (G. Wittig, U. Pockels and H. Dröge, Chem. Ber., 1938, 71, 9, 1903 – 1912) https://doi.org/10.1002/cber.19380710922
[2] (Z)-2-Ethoxyvinyllithium: A Remarkably Stable and Synthetically Useful 1,2-Counterpolarized Species (K. S. Y. Lau, M. Schlosser, J. Org. Chem., 1978, 43, 8, 1595 – 1598) https://doi.org/10.1021/jo00402a028
[3] Organolithium Bases in Flow Chemistry: A Review (M. Power, E. Alcock and G. P. McGlacken, Org. Proc. Res. Dev., 2020, 24, 1814 – 1838) https://dx.doi.org/10.1021/acs.oprd.0c00090
[4] Flow chemistry as green technology for the genesis and use of organometallic reagents in the synthesis of key building blocks and APIs – An update (P. Natho and R. Luisi, Tetrahedron Green Chem., 2023, 2, 100015) https://doi.org/10.1016/j.tgchem.2023.100015
[5] Efficient Cleaning Method for Flow Reactors in Flow Lithiation Reactions Under Water-free Conditions (K. Machida, H. Kawachi, R. Iwasaki, T. Sakaguchi, A. Murakami and A. Nishiyama, Org. Proc. Res. Dev., 2024, 28, 1668 – 1674) https://pubs.acs.org/doi/10.1021/acs.oprd.3c00321
[6] Lithiation of 1,2-Dichloroethene in Flow Microreactors: Versatile Synthesis of Alkenes and Alkynes by Precise Residence-Time Control (A. Nagaki, C. Matsuo, S. Kim, K. Saito, A. Miyazaki and J. Yoshida, Angew. Chem. Int. Ed., 2012, 51, 3245 – 3248) http://dx.doi.org/10.1002/anie.201108932
[7] Continuous-Flow Divergent Lithiation of 2,3-Dihalopyridines: Deprotolithiation versus Halogen Dance (T. Brégent, M. V. Ivanova, T. Poisson, P. Jubault and J. Legros, Chem. Eur. J., 2022, 28, e202202286) https://doi.org/10.1002/chem.202202286
[8] Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow (S. T. R. Müller, T. Hokamp, S. Ehrmann, P. Hellier and T. Wirth, Chem. Eur. J., 2016, 22, 11940 – 11942) https://dx.doi.org/10.1002/chem.201602133
[9] The application of flow microreactors to the preparation of a family of casein kinase I inhibitors (F. Venturoni, N, Nikbin, S. V. Ley and I. R. Baxendale, Org. Biomol. Chem., 2010, 8, 1798 – 1806) https://doi.org/10.1039/b925327k
