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Nature Communications volume 15, Article number: 4873 (2024 ) Cite this article 2-(2-Chloroacetamido)-5-Nitro-2'-Chlorobenzophenone
![Convergent approach for direct cross-coupling enabled by flash irreversible generation of cationic and anionic species | Nature Communications](http://cdn.globalso.com/jingyepharma/Moxonidine1.png)
In biosynthesis multiple kinds of reactive intermediates are generated, transported, and reacted across different parts of organisms, enabling highly sophisticated synthetic reactions. Herein we report a convergent synthetic approach, which utilizes dual intermediates of cationic and carbanionic species in a single step, hinted at by the ideal reaction conditions. By reactions of unsaturated precursors, such as enamines, with a superacid in a flow microreactor, cationic species, such as iminium ions, are generated rapidly and irreversibly, and before decomposition, they are transported to react with rapidly and independently generated carbanions, enabling direct C-C bond formation. Taking advantage of the reactivity of these double reactive intermediates, the reaction take place within a few seconds, enabling synthetic reactions which are not applicable in conventional reactions.
Proteins are organic molecules with unique functions. In organisms, proteins such as enzymes are intertwined to perform organic reactions and synthesize biogenic molecules, which are essential for maintaining life1. Such biosynthesis, which takes full advantage of organic molecules, is one of the ideal goals in organic chemistry. During biosynthesis, multiple kinds of “reactive intermediates” are generated, transported, and reacted across different parts of living organisms2. The mobility of these intermediates enables high selectivity, even though the reactions occur at rates close to diffusion-limited reactions. In such reactions, the selectivity depends on the rate of transport of the reactants instead of their reaction kinetics. Thus, biological reactions are often considered to occur under ideal reaction conditions, and it is expected that excellent reaction selectivity using active intermediates can be achieved by approaching such conditions in organic synthetic reactions3.
We studied the organic synthesis mediated by highly reactive intermediates. In particular, we utilized flow microreactors to develop methods for the fast generation and reactions of short-lived anionic species, which ordinal batch reactors cannot handle4. In these methods, unstable anionic species, particularly carbanions, are rapidly and irreversibly generated and immediately react with electrophiles. This leads to the complete conversion of starting materials into highly reactive intermediates, which enable subsequent fast reactions. “Flash” chemistry5, which utilizes the anionic reactive intermediates in rapid reactions, has enabled various chemical transformations that traditional methods cannot achieve.
Cations, which are unstable species as well as anions, are also important reactive intermediates, with organic cations being the most significant for organic synthesis6. Among a wide range of conventional methods to generate organic cations, such as acid-promoted methods7, diazotization8, and chemical oxidation9, those involving Lewis acids are the most frequently utilized. Since this method reversibly generates cations, the concentration of the cations is low, making the reaction slow. To overcome this drawback, organic electrosynthesis10,11,12, which generates relatively stable organic cations irreversibly, has been developed. Owing to their high reactivity, electrochemically generated cations can react rapidly with nucleophiles. However, in most electrochemical reactions, anodic oxidation requires several hours to generate cationic species13, resulting in a slower reaction. We envisaged that if highly unstable and reactive cationic species were generated rapidly, this would lead to a new synthetic approach, where multiple reactive intermediates are utilized in different locations, mimicking an idealized reaction system, such as biosynthesis.
This article reports a proof-of-concept study that uses flowmicro methods to demonstrate cationic species’ irreversible and rapid generation, followed by their reactions with rapidly generated carbanions and a direct cross-coupling reaction to generate carbon-carbon bonds within seconds. These achievements showcase a simultaneous use of multiple highly-reactive intermediates, which transform the “flash chemistry” into “flash synthesis,” leading to a new synthetic chemistry (Fig. 1).
A schematic for convergent approach for direct cross-coupling. In the left reactor, short-lived cations are generated, and in the right reactor, short-lived anions are generated. Those cationic and anionic species proceed to flash reactions before they decompose.
To achieve the rapid and irreversible generation of cationic species, we focused on the reactions of vinyl compounds with a strong Brønsted acid as a strong proton donor (Fig. 2)14. Among a variety of methods for generating cationic species, the use of strong acid may provide a rapid generation of those unstable species without the specific equipment such as flow electrolysis devices. We selected enamines as precursors for iminium ions, and trifluoromethanesulfonic acid (TfOH, pKa 2.6 in acetonitrile15 as the proton source because of its high acidity and ease of handling16. The reaction of enamines with strong acids generates iminium ions; however, since the enamines may work as nucleophiles, the generated cations easily react with the enamines, resulting in dimerization. Actually, the reaction of enamine 1a with TfOH in a batch reactor followed by the addition of allyltrimethylsilane afforded a small amount of the desired product 3, and dimer 4 was obtained as the major product at each reaction temperature (Fig. 2, Method A and B, for yields of dimer 4 see Supplementary Table 2 for detail). The reactions of 1a with TfOH in the presence of allyltrimethylsilane showed similar results (Fig. 2 and Method C and D). However, altering the sequence of reagent addition affected the result: methods A and C, where the solution of 1a was added to the solution of TfOH, resulting in a higher yield of 3 than the reverse-drop method (Method B and D) respectively. This tendency suggests the mixing efficiency affects the reaction efficiency. The batch reactions with 1.0 equivalent of TfOH also resulted in low yields (see Supplementary Information). The above investigations, where dimer 4 was obtained more abundantly than the desired product 3, indicate that the generated iminium ion 2a rapidly reacted with the surrounding enamine 1a. Thus, to achieve the selective generation of 2a for its reactions with nucleophiles, 1a must be converted to 2a before the dimerization.
aMethods (A–D) were done in a batch system, and Method E was done in a flow system composed of two micromixers. Yields were determined by GC. a Schematic for a flow reactor. M2 is T-shaped mixer with 250 µm inner diameter. b Dependency of yields of 3 and mixing time on flow rates and mixer M1. The reaction time between 1a with TfOH is 0.041 s. For mixers, the alphabet (V and T) denotes the shape of the mixer, whereas the number denotes its inner diameter (µm). bars: yield (%), dots: mixing time (millisecond) determined by Villermaux–Dushman method. c Yields of 3 and 4 (dimer) determined by GC. Batch: method C at − 40 °C, flow: V250, 20 mL/min. d Contour maps of yields of 3 (left) and 5 (right) using a V-250 mixer. Horizontal axis: residence time (s), vertical axis: temperature (°C), the designated number on the circle dot: yield of 3 and 5 (%). e, f Low-temperature NMR analyses of 2a (e) and 2c (f). The cationic species were generated in a flow microreactor using CD2Cl2 as a solvent and were flowed into an NMR sample tube cooled at − 78 °C. 1H NMR analyses were done at − 78 °C.
To improve reaction selectivity, flow microreactors have attracted considerable attention for decades17,18. In particular, their fast mixing characteristics remarkably affect fast reactions19,20. We have demonstrated that the fast mixing of flow micromixers enabled selective reactions of a sulfur cation with styrenes before their cationic polymerization21. Based on this idea, we envisaged that flow microreactor would achieve the selective generation of iminium ion 2a before their reaction with 1a, and thus, investigated the reactions of enamines, TfOH, and allylsilanes in a flow microreactor (Fig. 2a). Surprisingly, the desired product was obtained in high yield, especially at a higher flow rate (Fig. 2b, bars) This indicates that the condition improving the mixing efficiency is beneficial for this transformation22, which was supported by the reactions using other micromixers. The reactions with a thinner and sharper-angled micromixer, which has a better-mixing efficiency23, showed higher yield.
For a deeper understanding of the mixing efficiency, we explored the Villermaux–Dushman method, which assesses the mixing efficiency of micromixers and estimates the mixing time of aqueous medium24. Based on Yin’s condition25, we estimated the mixing time of the solutions introduced into the V-shaped 250 µm micromixer (Fig. 2b, dots). The results clearly showed the difference; the condition with the smallest flow rate (2.5 mL/min) had a longer mixing time (more than 1 millisecond), whereas that of other conditions was less than 0.1 millisecond. Although these values are those of aqueous medium, the tendency and scale of the mixing time must be the same. The T-shaped mixers also showed longer mixing times than those of the V-shaped mixer. Although an advanced analysis such as CFD simulation must be necessary to gain an accurate one, we calculated the Damköhler number of these conditions to be below 0.1 (see Supplementary Information). This indicates that the mass transport is enough faster than the reaction, which is supported by the fact that a higher flow rate than 10 mL/min did not change the product yields26. The generation of dimer 4 supports this idea. The best results under the batch condition (Method C, −40 °C) showed non-negligible amount of 427, which is derived from the reaction of 1a with 2a, whereas the flow condition (V250, 20 mL/min) showed less amount of 4 (Fig. 2c). Thus, these investigations proved that the reactions with short mixing time can trigger the desired reaction between TfOH and enamine 1a before it reacts with 2a. These results indicate that the flow microreactor plays a crucial role in the rapid generation of the iminium ion by adding superacids.
Accurate controllability of the reaction time28,29 and temperature is also a significant characteristic of flow microreactors30,31 We have previously reported that the controllability of flow microreactors can control various unstable and reactive species32. Inspired by this previous success, we screened the reaction time in the range of decamilliseconds to seconds and the reaction temperature. The results are summarized as the contour map in the left part of Fig. 2d, revealing that the reaction condition with 21 milliseconds of the reaction time and 15 °C of the reaction temperature affords the highest yield of this transformation. This map also indicates that conditions with a lower temperature and shorter reaction time gave a lower product yield, suggesting that these conditions are insufficient for the generation of the iminium ion. In addition, the lower yield at higher temperatures and longer reaction times could be derived from the decomposition of the iminium ion, such as the β-elimination of the generated iminium to afford the starting enamine. Although 1a was not detected after the reactions, the amount of dimer 4, which is generated from 1a with iminium ion 2a was increased when the reaction time and temperature increased. This indicates that at such conditions, 2a was decomposed to 1a (Supplementary Table 6 for details). Thus, this contour map can be regarded as a visualization of the stability and reactivity of the generated cation (2a). We then investigated the reaction mediated by a 6-membered ring iminium ion (2b) and determined the yield of the corresponding product 5 (Fig. 2d, right). Comparing these two contour maps shows that the pyrrolidine-type product 3 can be obtained in higher yields at higher temperatures and longer reaction times.
The irreversible generation of the cationic species was confirmed using a low-temperature NMR study. The reacting solution emitted from the flow reactor was captured in an NMR test tube cooled at −78 °C, and immediately its 1H NMR was measured at the same temperature. The NMR chart shows a highly deshielded proton Ha (9.49 ppm, shown in Fig. 2e), indicating the generation of iminium ion 2a as well as oxocarbenium ion 2c (Fig. 2f, Hb was appeared at 10.07 ppm). Notably, these NMR charts did not show the precursors (enamine 1a for 2a and acetal 1c for 2c), significantly supporting the irreversible generation of the iminium and oxonium cations. It is noteworthy that the irreversible generation of the iminium ion is crucial for its reaction. When using weaker acids such as benzoic acid (pKa 22), acetic acid (pKa 24), and trifluoroacetic acid (pKa 12 in acetonitrile)33, their reactions with 1a and allyltrimethylsilane in the flow microreactor did not afford 3.
After establishing the flash generation of the cationic species, we investigated their reactions with various carbon nucleophiles (Table 1). C-C bond formed with neutral nucleophiles resulted in good to high yields of the corresponding products (entries 1–9). These nucleophiles are incompatible with conventional methods for reversible cation generation. In addition, the cations were generated within 82 ms, much faster than conventional electrochemical methods34, resulting in a reaction time of only 20 s.
We attempted to develop reactions between multiple reactive species using the flash generation of cationic species and their reactions with neutral nucleophiles. Our flow strategy aimed to enable a reaction between the cationic species and carbanions, providing a direct cross-coupling involving C-C bond formation. As a feasibility study, we investigated the reactions of the iminium cation with alkyl metal species as carbanions (nBu−) and different counter ions (Li+, MgCl+, and ZnCl+; Table 1, entries 10–12). Direct cation-anion coupling afforded the desired product 13, where a sp3-sp3 C-C bond was formed in high yield by virtue of the fast mixing and precise time control together with the precise temperature control of the flow systems. Surprisingly, these cross-coupling reactions were completed within 0.069 s owing to the high reactivities of both the cationic species and carbanions. The flow microreactors enabled the direct cross-coupling of the reactive species that selectively proceeded without a side reaction, such as the β-elimination of the cation and protonation of the anions by the solvent (dichloromethane). On the other hand, we tested the reaction of anodically generated 1a with n-butyllithium in a batch reactor, and found no desired product 13, presumably because that the abundance of the supporting electrolyte in the surroundings led to the side reaction with nBuLi. As the electronegativity of the counter ion increased (Li:0.98, Mg:1.31, and Zn:1.65), the flow reaction yield decreased, suggesting that reactive anions are suitable for direct reactions with the cationic species. Moreover, the reaction of the lithium species required the shortest time to complete (0.36 s). This suggests that because of its high reactivity, n-BuLi could react with the onium cation before decomposition. Additionally, the most effective way to achieve rapid reactions is through the direct reaction of cationic species with carbanions bearing a lithium counter ion.
Finally, we attempted to establish a biosynthesis-inspired reaction system in which multiple reactive intermediates were generated and reacted in flow condition. We have reported a linear reaction integration in which several intermediates are generated and reacted individually35. Based on the concept of reaction integration36, we designed a convergent-type integration that generated cationic species irreversibly at one location and carbanions at another location (Table 2), enabling the simultaneous utilization of multiple reactive intermediates. As carbanions, aryl lithiums, which were generated from the corresponding aryl bromides with nBuLi in the flow microreactor29, were utilized for this transformation. The coupling of the iminium and oxonium cations with the aryl anions in a flow microreactor resulted in the formation of sp3-sp2 carbon-carbon bonds and the synthesis of the coupling products in good to high yields (entries 1–12). Various aryl anions, including ones cannot be utilized in batch reactors due to their short lifetime (entry 3 and 10)37, were used in the reaction with pyrrolidine-type iminium cations 2a, 2d, and 2e (entries 1–10). Moreover, this convergent reaction demonstrated some examples that were not achieved by conventional methods: the mono-selective coupling of dibromoarenes (entry 4)38, in which transition-metal-catalyzed cross-coupling is seldom achieved, and the reaction at the meta-position of an electron-donating group (entry 6), whose selectivity is prohibited in Friedel-Crafts-type reactions39. Iminium cations bearing other protecting groups, tert-butoxycarbonyl (Boc) and allyloxycarbonyl (Alloc), which can be easily deprotected under acidic conditions, were used in this reaction system (entries 8–10). Especially, by virtue of the high reactivity, the coupling reaction within one second was demonstrated (entry 10). The reactions of more unstable cations also afforded the products good to high yields (entries 11 and 12). These results demonstrate the effectiveness of this rapid generation and reaction concept, resulting in direct cross-coupling of various substrates.
In addition to the flash formation of sp3-sp3 and sp3-sp2 C-C bonds, we investigated the cross-coupling involving sp3-sp C-C bond formation40. The sp anions were generated from the terminal alkynes and n-butyllithium in the flow reactor, which subsequently reacted with the iminium cations to afford the coupling products in good to high yields (Table 2, entries 13–21). Iminium cations with increased instability (entries 20 and 21) and sp anions bearing electrophilic functionalities (entries 14–16)41 were also applicable in this convergently integrated reaction. Because traditional reactions are inefficient for such transformations, introducing alkynyl groups to the α-position of pyrrolidines bearing electron-withdrawing groups in this rapid convergent reaction demonstrated great synthetic utility. As well as the iminium ions, this integrated flow system allowed the generation of thionium ion 2 f, which reacted with sp anion to afford the coupling product in a good yield (entry 22).
Further investigation of sp3-sp coupling showed that repeated lithiation of the alkyne and sp3-sp coupling yielded unsymmetrical alkynes (Fig. 3). The first alkynylation reaction proceeded rapidly, and after deprotection and isolation, the next alkynylation completed within 2.8 s after the activation of the precursor. This series of reactions enabled the rapid synthesis of unsymmetrical alkynes bearing N-containing cyclic motifs. Four types of reactive intermediates were separately generated in different flow paths, and once mixed, their coupling reaction proceeded instantly. This system controls the flow reaction space, regulating the generation time and reactions of the reactive intermediates. Therefore, convergently integrated rapid reactions demonstrated a swift construction of molecular complexity, including alkynes bearing different pyrrolidines at both carbons.
a Flow microreactor system composed of two V-shaped micromixers (inner diameter: 250 μm) and four T-shaped ones (inner diameter: 250 μm) was used. Typical reaction condition for the first reaction: cation precursor (0.05 M), TfOH (0.05 M, 2.0 eq), trimethylsilyl acetylene (0.18 M, 4.3 eq), and nBuLi (0.60 M, 3.6 eq) at − 10 °C. Typical reaction condition for the second reaction: cation precursor (0.05 M), TfOH (0.05 M, 2.0 eq), terminal alkyne (0.18 M, 8.6 eq), and nBuLi (0.60 M, 7.2 eq) at − 10 °C.
In summary, the bio-inspired convergent approach of double intermediates was demonstrated by virtue of flow microreactors. Flow microreactor’s capability of rapid and highly selective reactions enabled the synthetic method, in which acidic activation of unsaturated precursors irreversibly generates cationic species, preventing undesired dimerization reactions. Cationic species and carbanions were respectively generated in different parts of the flow system, and met together before they decompose, enjoying their high reactivities. It is anticipated that this series of “flash” reactions could achieve complicated syntheses by taking advantage of multiple reactive intermediates, and further investigation is currently underway.
Flow microreactors are composed of stainless steel T- and V-shaped micromixers with inner diameter of 250 μm, stainless steel microtube reactors with 1000, 500, and 250 μm inner diameter, and PTFE tube with inner diameter of 1000 μm.
A flow microreactor system consisting of a V-shaped micromixer (M1) and a T-shaped micromixer (M2), two microtube reactors (R1 and R2), and three pre-cooling units (P1–P3) was used. The flow microreactor system was dipped in a cooling bath. A solution of cation precursor (0.0500 M in CH2Cl2) and a solution of TfOH (0.050 M in CH2Cl2) was introduced into M1 using syringe pumps. The mixed solution was passed through R1 and was mixed with a solution of the nucleophile (0.20 M in CH2Cl2) in M2. The resulting solution was passed through R2. After a steady state was reached, an aliquot of the product solution was collected and treated with TBAF, Et3N, and brine.
A flow microreactor system consisting of a V-shaped micromixer (M1), two T-shaped micromixers (M2 and M3), three microtube reactors (R1 and R2), and four pre-cooling units (P1–P4) was used. The flow microreactor system was dipped in a cooling bath. A solution of the cation precursor (0.0500 M in CH2Cl2) and a solution of TfOH (0.050 M in CH2Cl2) was introduced into M1 using syringe pumps. The mixed solution was passed through R1 to M3. Whereas, a solution of the anion precursor (0.18 M in THF) and a solution of n-BuLi (0.60 M in n-hexane) were introduced into M2 using syringe pumps, and the mixed solution was passed through R2 to M3. Those solutions are mixed in M3, and the resulting solution is passed through R3. After a steady state was reached, an aliquot of the product solution was collected and treated with brine.
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Experimental procedures, characterization of new compounds, and all other data supporting the findings are available in the Supplementary Information. All data were available from the corresponding author upon request.
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This work was supported by JSPS KAKENHI Grant Numbers, JP20KK0121 (Y.A. and A.N., Fostering Joint International Research (B)), JP21H01936 (A.N., Grant-in-Aid for Scientific Research (B)), JP21H01706 (A.N., Grant-in-Aid for Scientific Research (B)), JP19K22186 (A.N., Grant-in-Aid for Challenging Exploratory Research), JP20K15276 (Y.A., Grant-in-Aid for Early-Career Scientists), and JP21H05080 (A.N., Grant-in-Aid for Transformative Research Areas (B)). This work was also partially supported by AMED (A.N., JP21ak0101156), the Core Research for Evolutional Science and Technology (CREST, A.N., JPMJCR18R1), New Energy and Industrial Technology Development Organization (NEDO, A.N., JPNP14004 and JNPN19004), the Japan Keirin Autorace Foundation (Y.A. and A.N.), and the Ogasawara Foundation for the Promotion of Science & Engineering (A.N.). The authors are grateful to Ms. Eriko Kusaka (Kyoto University) for her kind assistance of NMR analyses. The authors are indebted to Prof. Atsushi Minami (Tokyo Institute of Technology) for many discussions concerning biosynthesis. The authors express their sincere thanks to Dr. Shusaku Asano (Kyushu University) for helpful discussions and comments about the quantification of the performance of flow microreactors.
Department of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Hokkaido, Japan
Hiroki Soutome, Hiroki Yamashita, Yutaka Shimizu, Masahiro Takumi, Yosuke Ashikari & Aiichiro Nagaki
Yokohama Technical Center, AGC Inc, Yokohama, Kanagawa, Japan
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H.S. and A.N. conceived and designed the experiments. H.S., H.Y., Y.S., and M.T. conducted experiments. Y.A. and A.N. supervised the experiments. H.S., Y.A., and A.N. wrote the manuscript.
The authors declare no competing interests.
Nature Communications thanks Milad Abolhasani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Soutome, H., Yamashita, H., Shimizu, Y. et al. Convergent approach for direct cross-coupling enabled by flash irreversible generation of cationic and anionic species. Nat Commun 15, 4873 (2024). https://doi.org/10.1038/s41467-024-48723-1
DOI: https://doi.org/10.1038/s41467-024-48723-1
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