The direct access to alkenes from HF₂C- or Cl₃C-substituted arenes and an organo sodium reagent

Abstract

The investigation of an organo sodium reagent with starting materials, such as aryl–CH_3−n(Hal)_n led to an unprecedented alkene synthesis for n = 2 (Hal = F) and for n = 3 (Hal = Cl), while the trifluoromethyl group n = 3 (Hal = F) proved to be inert under the identical reaction conditions. The alkene synthesis could be realised for a range of substrates bearing other functional groups that exhibit low reactivities towards organo sodium reagents.

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Reagents with alkali metal carbon bonds, such as in alkyl lithium or alkyl sodium species, are among the most reactive nucleophiles utilised broadly in organic synthesis. Alkyl lithium reagents are in use in organic synthesis and methodology for decades whereas alkyl sodium reagents are far less explored and are far less involved in synthetic methodologies. This large discrepancy is largely based on the much lower stability and higher reactivity of alkyl sodium reagents compared to the corresponding alkyl lithium reagents. Significant improvements have been reported by Hevia, Asako, Takai and others for the stabilisation of various types of alkyl sodium reagents by nitrogen-containing ligands, such as TMEDA (N¹,N¹,N²,N²-tetramethylethane-1,2-diamine) and Me₅tren (N¹-(2-(dimethyl-lamino)ethyl)-N¹,N²,N²-trimethyl-ethane-1,2-diamine), for applications in batch synthesis (Scheme 1).^1,2

Scheme 1 Ketone synthesis from a Weinreb amides and a benzyl sodium reagent in a batch reaction.

As an example, the freshly prepared, ligand-stabilized benzyl sodium reagents can be reacted with Weinreb amides for the efficient synthesis of ketones in a batch-type transformation.

To circumvent the use of complex amines for the stabilisation of alkyl sodium reagents, the use of a flow reactor allows the generation of such highly reactive alkyl sodium reagents in situ. The Knochel group pioneered in this respect and in a number of outstanding reports this approach for the synthesis of alkyl sodium reagents and their transformations in organic synthesis were described.³ Therein, the use of a flow reactor, where the reactive species are formed over a defined period of time, which is controlled by the flow rate through a flow bed reactor, is of high importance (Scheme 2). These highly reactive sodium reagents, such as 2, are generated from a simple alkyl chloride precursor (e.g. 1), and then brought to reaction with electrophiles, such as epoxides or oxetanes,⁴ or the sodium reagents are reacted with (hetero)aryl bromides for Br–Na exchange reactions or for the direct deprotonation of arenes (= sodiation) to name a few possible follow-up transformations.⁵

Scheme 2 Generation of an organo sodium reagent in a flow reactor and follow-up transformations.

In this report, we describe the transformations of alkyl sodium reagent 2 which is generated in a flow bed reactor with starting materials bearing multiple benzylic halide bonds.⁶

The CF₃ group is inert towards many reagents, and no reaction was observed when the alkyl sodium reagent 2 was added to Ph–CF₃ (see Table 1, entry 1). Therefore, we investigated the transformation of 2 with Ph–CCl₃ in n-hexane at room temperature for 16 hours reaction time (Scheme 3) and the results of this investigation are described below.

Scheme 3 Reaction of PhCCl₃ with the organo sodium reagent 1 generated in a flow reactor.

Table 1 Optimisation of the alkene synthesis of the organo sodium reagent 2 with (trichloromethyl)benzene

Entry	Conditions^a	Yield^b
a Other reaction conditions: PhCCl3 (0.5 mmol), n-hexane (3 mL), N2 atm., rt, 16 h.b Determined by GC analysis of the crude mixture with mesitylene as internal standard added after the reaction.c TMEDA (1.1 eq.) were added.
1	Ph–CF3 as starting material^c	0%
2	−78 °C^c	7%
3	0 °C^c	12%
4	rt (= 20 °C)^c	11%
5	50 °C^c	11%
6	No TMEDA additive, rt	33%
7	2.0 eq. of 2	22%
8	3.0 eq. of 2	33%
9	3.5 eq. of 2	43%
10	6.0 eq. of 2	37%
11	THF as solvent	13%
12	With molecular sieves 4 Å	40%
13	With NaH (1.0 eq.) as base	36%
14	With 2,6-lutidine (1.0 eq.) as base	36%
15	With BF3·OEt2 (0.5 eq.)	43%
16	1,2-Dimethoxyethane as solvent	20%
17	1.0 mL min^−1 flow rate	40%
18	Less concentrated (10 mL) n-hexane	38%
19	Higher concentrated (1 mL) n-hexane	39%
20	Inversed addition of PhCCl3 at 20 °C	36%
21	2 cooled to 0 °C then addition of PhCCl3	44%
22	2 cooled to −78 °C then addition of PhCCl3	51%

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After aqueous work-up we identified the alkene 4a (E : Z = >95 : <5) as product formed in the transformation (11%, Table 1, entry 4) alongside a large amount of the Wurtz-type coupling product 5 as well as the starting material 1 (detected by GC-MS analysis) and some side-products formed in minor amounts. This unusual transformation of a benzylic CCl₃ group towards an alkene caused us to optimise this reaction with the alkyl sodium reagent 2 to minimize the amount of the Wurtz-type side-product 5 and to increase the yield of the desired alkene 4a. The results of this investigation are summarized in Table 1.

As can be seen from Table 1, the modification of the reaction temperature had rather limited influence on the performance of the formation of 4a (entries 2–5) so that the following optimisation efforts were performed at room temperature. When the amount of the alkyl sodium reagent 2 was increased up to 3.5 equivalents with respect to the Ph–CCl₃ starting material, a steady increase in the yield of 4a (detected by GC analysis) was observed. However, a further increase of the amount of 2 to 6.0 eq. resulted in no further increase in the yield of 4a. Accordingly, the optimization was continued with 3.5 eq. of 2 at room temperature. The change of the solvent towards THF (entry 11), the addition molecular sieves or bases (entries 12–14), nor the addition of a Lewis acid (entry 15) were ground-breaking to increase the yield of 4a. Also 1,2-dimethoxyethane as solvent did not influence the yield of 4a significantly (entry 16). The reduction of the flow rate (entry 17) as well as the modification of the concentration of the PhCCl₃ in n-hexane (entries 18/19) had also little effect on the yield of 4a and we finalized our attempt to optimize the yield of 4a by inverse addition at different temperatures (entries 20–22), but to no avail. Unfortunately, we could not identify reaction conditions where the alkene 4a was formed in good to very good yields and the Wurtz byproduct 5 could be suppressed.

From a mechanistic point of view, the reaction of 2 with Ph–CCl₃ could proceeds via a Cl–Na exchange reaction to afford a carbenoid-type intermediate [A = Ph–CCl₂Na] and regenerate the alkyl chloride starting material 1 (Scheme 4). These two compounds could then undergo a nucleophilic substitution to generate the carbon–carbon single bond in B. Upon the addition of another equivalent of 2, another Cl–Na exchange seems to occur to generate a second carbenoide-type intermediate C. The formation of the final alkene 4a could then proceed via an α-elimination of NaCl affording the carbene D and a 1,2-H-shift leading to the formation of the alkene 4a.

Scheme 4 Proposed reaction mechanism for the formation of 4a from 2 and (trichloromethyl)benzene.

Alternatively, an intermolecular reaction of two carbenoide-type intermediates (2 × C) can be envisaged, to realize the 1,2-hydrogen transfer. These assumptions have to be taken into account based on experiments with a deuterium-marked alkyl chloride 1-D₂ as well as the quenching of the reaction with D₂O are considered (see below).

(Difluoromethyl)benzene, unlike (fluoromethyl)benzene, is relatively affordable and was chosen as starting material for the transformation with the alkyl sodium reagent 2 (Scheme 5). The result of the first test reaction with (difluoromethyl)benzene was surprising, in that respect that again the alkene 4a was formed as main product; albeit in higher yields (>50%) compared to the transformations with (trichloromethyl)benzene.⁷

Scheme 5 Application of (difluoromethyl)benzene with the organo sodium reagent 2 generated in a flow reactor.

We then performed an optimisation with respect to the equivalents of 2 needed and the reaction temperature to obtain 4a in good yields. The results of these experiments are summarised in Table 2.

Table 2 Optimisation of the alkene synthesis of the organo sodium reagent 2 with (difluoromethyl)benzene

Entry	Conditions^a	Yield^b
a Other reaction conditions: PhCHF2 (0.5 mmol), n-hexane (3 mL), N2 atm., rt, 16 h.b Determined by GC analysis of the crude mixture with mesitylene as internal standard, added after the reaction.
1	2.5 eq. of 2	53%
2	4.0 eq. of 2	73%
3	4.5 eq. of 2	74%
4	5.0 eq. of 2	80%
5	0·°C	74%
6	−78 °C	75%
7	0 °C, 1 h	74%

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The results illustrate that also for this transformation towards 4a the amount of 2 is decisive. The highest yield of 4a (80%) was isolated when 5.0 equivalents of 2 were applied while the temperature of the addition had only a minimal effect on the yield of 4a. Accordingly, we assumed that the other parameters investigated in Table 1 for the transformation of (trichloromethyl)benzene with 2 would behave similarly and decided not to run those experiments again. Although we identified 5.0 eq. of 2 to give the highest yield, we decided to reduce the amount of 2 to 3.5 eq. and perform the reactions of 2 with some other functionalised arenes bearing the CHF₂ group. The selection for the CHF₂-functionalised arenes were made with respect to the hitherto known reactivity of 2 towards functional groups and naturally, functional groups, such as carbonyl groups and other carbonyl derivatives in a broad sense were not considered at this point. The results of the transformations of 2 with those selected CHF₂-functionalised arenes are summarized in Scheme 6.

Scheme 6 Scope and limitation of the alkene synthesis of the organo sodium reagent 2 with (difluoromethyl)benzene derivatives.

With 3.5 eq. of the organo sodium reagent 2 applied, the product 4a could be isolated in 70% yield. Electron donation groups, such the methyl substituent in 4b or the methoxy substituent in 4c reduced the yield only slightly.

The difluoromethyl-substituted biphenyl derivative 4d as well as the product 4e bearing a naphthyl moiety could be isolated in reasonable 78% and 77% yield, respectively. When we applied (difluoromethyl)-4-fluorobenzene as starting material, we experienced an unusual result. The 4-fluoro substituent seems to have reacted with the organo sodium reagent 2, resulting in the introduction of an additional alkyl substituent in 6. The product 6 was isolated in 59% total yield as a mixture consisting of various stereoisomers.⁸

From a mechanistic point of view, it seems reasonable that the C–H acidity of the aryl–CHF₂ proton is enhanced and that a deprotonation with 2, reacting as a strong base, is possible. Thereby a similar species to the Ph–CCl₂Na species A is formed alongside the corresponding alkane, which was detected by GCMS analysis. A carbon–carbon bond formation with the intermediate Ph–CF₂Na and 2 must therefore proceed via a carbene-type intermediate to form the intermediate C′ (see Scheme 7).⁹ Only if we assume that similar intermediates of type C/C′ are formed the results of the deuterium-labelling experiments can be explained. Therefore, we prefer a concerted intermolecular reaction from C and C′ realizing the hydrogen transfer/β-elimination process to afford the observed product 4a in one step.

Scheme 7 Control experiments of (trichloromethyl)benzene and (difluoro-methyl)benzene with the deuterated version of the organo sodium reagent 2-D₂ for the synthesis of 4a-D₂.

When the chlorinated starting material 1 for the synthesis of 2 was substituted with the dideuterated derivative (for the synthesis of the organo sodium reagent 2-D₂), the corresponding dideuterated alkene 4a-D₂ was isolated in 45% yield from PhCCl₃ and in 65% yield from PhCHF₂, respectively (Scheme 7). By ¹H and ²H NMR analysis the deuterium incorporation of >95% for the 1-position and >95% for the 2-position was observed when (difluoromethyl)-benzene was applied as starting material. The result that led to the mechanistic proposal is that the same reaction utilizing (trichloromethyl)benzene as starting material led to an almost identical ¹H and ²H NMR with >95% deuterium incorporation for the 1-position and >95% for the 2-position.

On the other hand, when the non-deuterated organo sodium reagent 2 was reacted with (trichloromethyl)benzene and the mixture was quenched with D₂O, no deuterium incorporation in the resulting alkene 4a was obtained.

This means that one deuterium atom in both cases migrates from the 2-position into the benzylic carbon at C1 and that no anionic intermediates are present when the reactions are quenched with H₂O or D₂O.

In comparison to the transformations with the organo sodium reagent 2, the reactions with n-BuLi gave deviating results (Scheme 8). First, the transformation of PhCCl₃ with n-BuLi led to the alkane 7 instead of the alkene 4a when reacted with 2. Second, the application of (trifluoromethyl)benzene which was inert when reacting with 2 reacted with n-BuLi to a number of unidentified products (GCMS analysis). Third, also the transformation of (difluoromethyl)benzene with n-BuLi led to a number of products (GCMS analysis) did not lead to the alkene 4a as was observed when the organo sodium reagent 2 was used. The steric hindrance of 2 is higher as in n-BuLi but it seems somewhat unlikely that this difference is crucial for the different reaction pathways of 2 and n-BuLi observed in this short study.

Scheme 8 Comparison of the reported transformations utilising n-BuLi instead of 2.

In summary, we have identified a reaction pathway from (trichloromethyl)benzene and more efficiently from (difluoro-methyl)benzene and derivatives towards identical alkenes. The experiments with deuterium-labelled starting material 2 resulted in almost identical ¹H and ²H NMR spectra which led us to the conclusion that similar reaction pathways are at work. The reactivity of the organo sodium reagent 2 towards many functional groups is known but the combination of the herein presented reactivity and the known transformation with additional functional groups could open up new pathways to access complex structures in such reaction utilizing organo sodium reagents.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d6ob00838k.

References

1. (a) J. M. Tarascon, Nat. Chem., 2010, 2, 510; (b) E. Nakamura and K. Sato, Nat. Mater., 2011, 10, 158; (c) P. B. De, S. Asako and L. Ilies, Synthesis, 2021, 3180; (d) N. Davison, C. L. McMullin, L. Zhang, S. X. Hu, P. G. Waddell, C. Wills, C. Dixon and E. Lu, J. Am. Chem. Soc., 2023, 145, 6562; (e) D. R. Armstrong, M. G. Davidson, D. Garcia-Vivo, A. R. Kennedy, R. E. Mulvey and S. D. Robertson, Inorg. Chem., 2013, 52, 12023.
2. (a) A. Tortajada, D. E. Anderson and E. Hevia, Helv. Chim. Acta, 2022, 105, e202200060; (b) L. J. Bole, A. Tortajada and E. Hevia, Angew. Chem., Int. Ed., 2022, 61, e202204262; (c) D. E. Anderson, A. Tortajada and E. Hevia, Angew. Chem., Int. Ed., 2024, 63, e202313556; (d) D. E. Anderson, L. A. Malaspina, S. Grabowsky and E. Hevia, Angew. Chem., Int. Ed., 2025, 64, e202511492; (e) I. Takahashi, A. Tortajada, D. E. Anderson, L. Ilies, E. Hevia and S. Asako, Nat. Synth., 2025, 4, 816; (f) S. Asako, I. Takahashi, H. Nakajima, L. Ilies and K. Takai, Commun. Chem., 2021, 4, 76; (g) S. Asako, H. Nakajima and K. Takai, Nat. Catal., 2019, 2, 297; (h) U. Ogi, S. Ikeda, K. Okano, M. Horie and A. Mori, Chem. – Eur. J., 2025, 31, e202500355.
3. (a) J. H. Harenberg, R. R. Annapureddy, K. Karaghiosoff and P. Knochel, Angew. Chem., Int. Ed., 2022, 61, e202203807; (b) J. H. Harenberg, N. Weidmann, K. Karaghiosoff and P. Knochel, Angew. Chem., Int. Ed., 2021, 60, 731.
4. (a) D. Arnodo, S. Ghinato, S. Nejrotti, M. Blangetti and C. Prandi, Chem. Commun., 2020, 56, 2391; (b) E. Vrancken, A. Alexakis and P. Mangeney, Eur. J. Org. Chem., 2005, 1354; (c) T. Imai, S. Nishida and T. Tsuji, J. Chem. Soc., Chem. Commun., 1994, 2353; (d) S. Wang, A. Kaga and H. Yorimitsu, Synlett, 2021, 219; (e) A. Maercker and M. Passlack, Chem. Ber., 1983, 116, 710.
5. J. H. Harenberg, N. Weidmann, A. J. Wiegand, C. A. Hoefer, R. R. Annapureddy and P. Knochel, Angew. Chem., Int. Ed., 2021, 60, 14296.
6. For a previous reports concerning the application of organo sodium reagent 2 with (Weinreb) amides, see: (a) P. Knupe-Wolfgang, B. Mahn and G. Hilt, Org. Lett., 2024, 26, 6972; (b) P. Knupe-Wolfgang and G. Hilt, Synthesis, 2025, 3263.
7. The higher homologues (tribromomethyl)benzene and (triiodomethyl)benzene were not investigated based on the high price for the bromo-derivative while the triiodomethyl-derivative seems not to be commercially available. Also, these compounds are rarely used as starting materials in organic synthesis. Therefore, we pointed our attention towards fluorinated toluene derivatives. For a reference concerning exchange reactions of PhCCI₃, see: K. K. K. Goh, A. Sinha, C. Fraser and R. D. Young, RSC Adv., 2016, 6, 42708.
8. The mixture consists of E/Z isomers as well as diastereomers based on the two stereogenic centers so that up to eight isomers are possible (see SI).
9. (a) J. Villieras and M. Rambaud, Synthesis, 1980, 644; (b) J. Villieras, P. Perriot and J. F. Normant, Synthesis, 1979, 968; (c) J. Villieras, P. Perriot and J. F. Normant, Bull. Soc. Chim. Fr., 1977, 765; (d) J. Villieras, C. Bacquet and J. F. Normant, Bull. Soc. Chim. Fr., 1975, 1797.

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