Recent Advances in Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts

Developments that result in high-yielding, low-cost, safe, scalable, and less-wasteful processes are the most important goals in synthetic organic chemistry. Continuous-flow reactions have garnered much attention due to many advantages over conventional batch reactions that include precise control of short reaction times and temperatures, low risk in handling dangerous compounds, and ease in scaling up synthesis. Combinations of continuous-flow reactions with homogeneous, metal-free catalysts further enhances advantages that include low-cost and ready availability, low toxicity, higher stability in air and water, and increased synthetic efficiency due to the avoidance of the time-consuming removal of toxic metal traces. This review summarizes recently reported continuous-flow reactions using metal-free homogeneous catalysts and classifies them either as acidic catalysts, basic catalysts, or miscellaneous catalysts. In addition, we compare the results between continuous-flow conditions and conventional batch conditions to reveal the advantages of using flow reactions with metal-free homogeneous catalysts.


Introduction
Developments that will result in high-yielding, low-cost, safe, scalable, and less-wasteful processes are the most important goals in synthetic organic chemistry. Continuous-flow reactions have garnered much attention due to many advantages over conventional batch reactions [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. The advantages include (1) precise control of short reaction times, (2) precise control of reaction temperatures, (3) low risk in handling dangerous compounds, (4) ease in scaling up synthesis, (5) integration of in-line monitoring technology and optimization algorithms that enable the rapid and autonomous optimization of reaction conditions, and (6) integration of in-line purification technologies that enhance productivity and reduce footprint. Combinations of continuous-flow reactions with homogeneous catalysts further enhance their advantages such as a low catalyst loading and a short reaction time [16][17][18][19][20][21][22]. In particular, the use of metal-free catalysts has many benefits such as (1) low-cost and ready availability, (2) low toxicity, (3) higher stability in air and water, and (4) increased synthetic efficiency because there is no need for time-consuming removal of toxic metal traces [17,18]. Risi, Massi, and coauthors recently reviewed continuous-flow syntheses using organocatalysts [20]. Their review targeted both homogeneous and heterogeneous reactions and introduced representative examples of flow, metal-free, and homogeneous catalysis. In this review, we focused on continuous-flow reactions using metal-free homogeneous catalysts. Recent reports (2017-2020) are comprehensively summarized in the order of acidic catalysts, basic catalysts, and miscellaneous catalysts. In addition, we compared the results between continuous-flow conditions and conventional batch conditions to reveal the advantages of the flow reactions using metal-free homogeneous catalysts.

Tropylium-Catalyzed Acetalization Reactions
Nguyen and coworkers reported metal-free acetalization reactions using tropylium salts as an organic Lewis acid [23]. Aromatic tropylium salts are recognized as stable analogues of tritylium salts [24]. The authors were the first to use tropylium ions as organic Lewis catalysts. Under optimized batch conditions, aldehyde 1 (0.83 M, 1.0 equiv.) was reacted with trialkyl orthoformate 2 (2.0 equiv.) in the presence of tropylium tetrafluoroborate 4 (5 mol%) at 70 °C for 5 h. A variety of acetal derivatives 5 were obtained (23 examples, up to 99% yield). The developed reaction was applied to continuous-flow synthesis ( Figure 1). A syringe pump was used to inject a solution of 1 (0.08 M, 1.0 equiv.), either 2 (2.0 equiv.), or ethylene epoxide (3) (4 equiv., concentration was determined by 1 H NMR analysis), and 4 (1 mol%) in acetonitrile into the coils of a tubular reactor (temperature: 90 °C, residence time: 45 min) at a flow rate of 0.1 mL/min. The reactor was immersed in an oil bath, and connected to a back-pressure regulator (BPR, 100 psi). The developed flow protocol afforded desired acetals 5 or 6 ( Figure 1; 10 examples, up to 99%) in yields that were equal to, or higher than, those using batch conditions (Table 1). Gram scale synthesis of acetals 5a-5c was demonstrated. The amount of tropylium tetrafluoroborate catalyst was reduced from 5 to 1 mol% by employing flow conditions. The reaction time was shortened (45 min) by using heating conditions (90 °C). The use of the BPR allowed heating above the boiling point of acetonitrile. The flow reaction allowed the highly efficient multi-gram synthesis of a range of acyclic acetals including volatile or gaseous compounds such as acetaldehyde and ethylene epoxide. The authors cautioned that this reaction might be difficult to perform under batch conditions because of the use of gaseous reagents.  Guo, Li, and coworkers reported cis-4-aminobenzodihydropyran synthesis using a trityliumcatalyzed interrupted Povarov reaction [25]. The family of triarylmethylium cations are stabilized as a result of delocalization of the positive charge over the three aromatic rings [26,27]. These researchers proposed and validated a mechanism of the Lewis acid-catalyzed reaction on the basis of the experimental data and prior study [28,29]. Salicylaldimine 11 is activated by complexation with tritylium ions to form the intermediate 12, and it is attacked by the electron-rich alkene 9 ( Figure 2). Under optimized batch conditions, a mixture of substituted salicylaldimine 11 (0.4 M, 1.0 equiv.), triphenylmethylium (tritylium) tetrafluoroborate (10) (TrBF4, 1 mol%), and electron-rich alkene 9 (2.0 equiv.) in anhydrous THF was stirred at room temperature. The desired products 13 were obtained in good to excellent yields (13 examples, up to 92% and cis:trans = 95:5). The authors demonstrated a one-flow synthesis of benzodihydropyran 13a from salicylaldehyde 7a, aniline 8a, and 2,3dihydrofuran 9a ( Figure 2). Solutions of 7a (1.1 M, 1.0 equiv.) and 8a (1.0 equiv.) in THF were added to an arrowhead mixer. The combined mixture passed through a reaction tube at 60 °C for 2 min. The generated water was removed by passing the reaction mixture through an absorbent column. The resultant dehydrated solutions of imine 11a, 9a (1.0 equiv.), and 1 mol% of TrBF4 (10) in THF were injected into a T-shape mixer. The resultant mixture was passed through a second reaction tube at 25 °C for 1 min. The desired product 13a was obtained in an 88% yield (cis:trans = 90:10). On the other hand, a decreased yield and cis/trans selectivity of 13a (60%, cis:trans = 70:30) were observed under the batch conditions even in the presence of MS4A (five beads) ( Table 2). The authors speculated that the carbocations were either deactivated or decomposed by residual water generated during the imine formation step.

Chlorination/Epoxidation of Biobased Glycerol
Monbaliu and coworkers reported the transformation of biobased glycerol into oxiranes (epichlorohydrin and glycidol) under continuous-flow conditions [30]. The developed approach allowed economically and environmentally favorable chlorination/epoxidation using organocatalysts and aqueous solutions of hydrochloric acid and sodium hydroxide. Carboxylic acids have been used as catalysts in the chlorination of glycerol [31]. Briggs and coworkers and Yin and coworkers separately revealed that the catalytic efficiency of carboxylic acids is influenced by their steric hindrance [32,33] rather than their pKa [33]. Less hindered carboxylic acids tended to exert higher catalytic activity. Monbaliu and coworkers screened a library of homogeneous carboxylic acid catalysts, and identified pimelic acid 15 as the best example. Solutions of glycerol (14) (neat, 1.0 equiv.) in water, aqueous hydrochloric acid (36 wt%, 6.0 equiv.), and 15 (10 mol%) were injected into a PEEK T-shape mixer ( Figure 3). The reaction proceeded in a PFA capillary coil at 140 °C for 20 min under 8 bar. The desired 1,3-dichloro-2-propanol (16) was obtained in a 44% yield ( Figure 3, >99% conversion, 81% cumulated yield). Araujo Filho and coworkers reported the kinetics of sodium hydroxide-mediated epoxidation of 1,3-dichloro-2-propanol (16) under continuous-flow conditions [34]. Monbaliu and coworkers found that the upstream chlorination step directly concatenates the subsequent epoxidation step ( Figure 4). The resultant mixture and an aqueous solution of sodium hydroxide (4 M, 1.5 equiv. with respect to HCl) were injected into a PEEK T-mixer and reacted in a PFA capillary coil at room temperature for 10 min under 5.2 bar. The resultant mixture along with methyl tert-butyl ether (MTBE, 320 μL min −1 ) was then added to a second PEEK T-mixer. The biphasic solution was separated into an organic phase and an aqueous phase using a Zaiput Flow Technologies liquid-liquid separator (SEP-10) equipped with a hydrophobic membrane (pore size: 0.5 μm). The desired epichlorohydrin (19) and glycidol (20) were obtained in 44% and 30% yields, respectively ( Figure 4, >99% conversion, 74% cumulated yield).

Retro-Claisen-Type C-C Bond Cleavage of Diketones with Tropylium Catalyst
Nguyen, Koenigs, and coworkers reported a retro-Claisen-type reaction for the synthesis of ester derivatives from 1,3-dicarbonyl compounds using tropylium tetrafluoroborate as an organic Lewis acid [35]. Under optimized batch conditions, a mixture of 1,3-dicarbonyl compound 21 (neat, 1.0 equiv.) and nucleophile 22 (alcohol or amine, 2.0 equiv.) was reacted in the presence of tropylium tetrafluoroborate (4) (10 mol%) at 100 °C for 16 h. The use of trifluoroethanol (TFE) as a solvent (room temperature, 24 h) afforded comparable results. A variety of esters and amides 23 were obtained by the two developed protocols under batch conditions (20 examples, up to 99%). Under optimized flow conditions, solutions of 1,3-dicarobonyl compounds 21 (0.50 M, 1.0 equiv.) and tropylium tetrafluoroborate (4) (5 mol%), along with either alcohols or amine (1 M, 2.0 equiv.), in TFE were injected into a 10 mL tubular reactor and heated to 150 °C for 30 min ( Figure 5). The desired products 23 were obtained in high to excellent yields ( Figure 5; six examples, up to 93%). The developed flow protocol used a decreased amount of catalyst (Table 3), and enabled multi-gram scale synthesis.

Sustainable Continuous-Flow Synthesis of Allantoin
Allantoin is widely used in the cosmetic and pharmaceuticals industries. Monbaliu and Salvadeo optimized its synthetic protocol under continuous-flow conditions based on a rational Design of Experiments (DoE) approach [36]. Solutions of glyoxylic acid (24) (8.7 M, 2.5 equiv.) and urea 25 (3.2 M, 1.0 equiv.) in water were injected into a PEEK T-mixer and reacted in a PFA coil at 120 °C for 6 min under 6 bar. The complete conversion of urea 25 into the desired product 26 was accomplished ( Figure 6). Glyoxylic acid was used as both a reactant and a Brønsted acid catalyst.

Tropylium-Promoted Prenylation Reactions of Phenols in Flow
Nguyen and coworkers achieved a prenylation of phenols using tropylium tetrafluoroborate as an organocatalyst [37]. The developed continuous-flow approach enabled a metal-free, inexpensive, and multiple-gram scale synthesis of 2,2-dimethylchromans in a short reaction time. The proposed reaction mechanism included a hidden Brønsted acid catalytic pathway similar to that reported in a study by Hintermann and coworkers [38]. Under optimized batch conditions, 4-methoxyphenol (27a) (0.01 M, 1.0 equiv.), isoprene (28) (2.0 equiv.), and tropylium tetrafluoroborate (4) (10 mol%) were reacted in 1,2-dichloroethane (DCE) at 60 °C for 24 h. The desired product 29a was obtained in a 60% yield. Under optimized flow conditions, a solution of phenol 27 (0.02 M, 1.0 equiv.) and 4 (2 mol%) in dichloromethane, and a solution of isoprene (28) (0.04 M, 2.0 equiv.) were injected into a 10 mL tubular reactor (temperature: 100 °C, residence time: 2 min) in a Vaportec R-series system (Figure 7). The desired prenylation products 29 were obtained in good to excellent yields (Figure 7; five examples, up to 96%). The flow reaction allowed quick access to 2,2-dimethylchromans with a decreased amount of catalyst. The observed yield of 29a was higher compared with that of batch reactions (Table 4). In addition, the developed protocol enabled 20 mmol scale synthesis and afforded higher yields.  Benaglia, Rossi, and coworkers reported the organocatalytic α-trifluoromethylthiolation of silylenol ethers in the presence of a catalytic amount of Lewis base [39], on the basis of their previous study of an α-thiofunctionalization reaction [40].

Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts
Lindhardt and coworkers reported the organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman (MBH) alcohols under continuous-flow conditions [47]. Tributylamine (TBA) was identified as a superior organocatalyst. On the basis of optimized batch conditions, the authors developed a continuous-flow protocol (Figure 10). Solutions of Morita-Baylis-Hillman alcohol 38 (0.2 M, 1.0 equiv.) and TBA (39) (1.5 equiv.) in chloroform, and trichloroacetic anhydride (40) (1.2 equiv.) also in chloroform, were injected into a T-connector, and the mixture was passed through a small premixing tubular reactor (room temperature, 2 min). The resultant mixture was then passed through a second heated tubular reactor (70 °C, 20 min). The desired products 41 were obtained in higher yields for all investigated entries compared with those of batch conditions ( Figure 10; six examples, up to 86%). Scaled-up syntheses of 41e and 41f (more than 10 grams) were demonstrated. Optimized batch conditions required 20 h to complete the reaction, but higher temperatures were employed in the flow reaction, which shortened the reaction time to 20 min. The use of a 500 psi back-pressure regulator (BPR) avoided the vaporization of chloroform and carbon dioxide, which can lead to an undesired segmentation of the flow. TBA worked as a base in the initial trichloroacetylation step and an organocatalyst in the subsequent decarboxylation step. Trichloroacetic anhydride was selected as the acetylation agent because it generated soluble salts (tributylammonium trichloroacetate) with TBA. Figure 10. Telescoped decarboxylative trichloromethylation of MBH-alcohols under continuous-flow conditions.

Micro-Flow Synthesis of β-Amino Acid Derivatives via a Rapid Dual Activation Approach
The syntheses of β-amino acid derivatives have been demonstrated using rapid dual activation (<3.3 s) of both β-amino acid N-carboxy anhydride and alkyl chloroformate under micro-flow conditions [48]. A single-step micro-flow synthesis of amino acid N-carboxy anhydride was previously reported [49,50]. Solutions of β-phenylalanine-NCA (42) (0.30 M, 1.0 equiv.), isobutyl chloroformate (43) (1.0 equiv.), and N-methylmorpholine (2.0 equiv.) in CH2Cl2 were injected into a T-shape mixer at 20 °C ( Figure 11). The resultant mixture was passed through a Teflon tube for 3.3 s. The reaction mixture and a solution of amine 44 (1.0 equiv.) and 4-dimethylaminopyridine (45) (DMAP, 10 mol%) in CH2Cl2 were injected into the second T-shape mixer at 20 °C and reacted in the Teflon tube for 7.0 s. A catalytic amount of DMAP activated the mixed carbonic anhydride moiety to generate a highly active acyl pyridinium cation 46. The mixture was poured into a solution of amine (1.0-2.0 equiv.) or thiol (1.0 equiv.) and diisopropylethylamine (1.0 equiv.). The desired products 47 were obtained in good yields ( Figure 11; nine examples, up to 90%). In addition, dihydrouracil synthesis was performed. The desired products 48a and 48b were obtained in good yields without a second nucleophile. The yield of the reaction was not reproducible under batch conditions due to batch-to-batch differences in the mixing efficiency. Figure 11. The synthesis of β-amino acid derivatives from β-NCA under micro-flow conditions. a 2.0 equiv. of diisopropylamine was used. b Cyclization was carried out at 100 °C for 2 h in toluene.

Organocatalytic Synthesis of Cyclic Carbonates under Continuous-Flow Conditions
Monbaliu and coworkers reported an efficient organocatalytic process for the synthesis of cyclic organic carbonates from the corresponding 1,2-diols under continuous-flow conditions [51]. The authors used tetrabutylammonium bromide (49) as an inexpensive, air-stable, and less toxic organic catalyst (Figure 12). To a PEEK T mixer were injected 1,2-diols 34 (neat, 1.0 equiv.), 49 (3.5 mol%), and DMC (35) (2.25 or 3.0 equiv.). The mixture was then heated in a stainless-steel capillary coil at 180 °C for 3 min. The desired products 37 were obtained from a wide range of functionalized diols in good to excellent yields ( Figure 12; 20 examples, up to 95%). The developed process allowed pilotscale synthesis under continuous-flow conditions (76% yield, 13.6 kg per day).

Asymmetric Organocatalytic Aldol Reaction of a Hydrophobic Aldehyde
Gröger and coworkers reported the one-flow asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in an aqueous medium [52]. The authors previously developed a one-pot process under batch conditions [53], and the developed process was extended to continuous-flow synthesis. Under flow conditions, a solution of 3-chlorobenzaldehyde (50) (0.50 M, 1.0 equiv.) in 2propanol and phosphate buffer with a solution of Singh's catalyst (51) (3.6 mol%) [54], acetone (52) (9.0 equiv.), 2-propanol, and phosphate buffer were injected into a T shape mixer and reacted in a Teflon tube at room temperature for 60 min (Figure 13). The desired product 53 was obtained in a 74% conversion and with an 89% ee. The flow process afforded almost equal or slightly better results than the batch process (Table 6; 67% conversion, 91% ee).

Exploration of an Enantioselective Organocatalyzed Rauhut-Currier Reaction and [3 + 2] Annulation under Flow Conditions Using Machine-Learning
Sasai, Takizawa, Washio, and coworkers developed a highly atom-economical enantioselective organocatalyzed Rauhut-Currier reaction [57] and [3 + 2] annulation [58] sequence of dienone with allenoate under micro-flow conditions using machine learning [59]. Optimization of the reaction conditions was supported by Gaussian process regression (GPR). Solutions of dienone 58 (0.02 M, 1.0 equiv.), allenoate 59 (2.0 equiv.), and a chiral phosphine catalyst 60 (20 mol%) in toluene were injected into a micro-mixer (Comet X-01) and reacted in a stainless-steel tube at 80 °C. The desired highly functionalized chiral spirooxindole analogues 61 were obtained within 26 sec (Figure 15; 19 examples, up to 92%). On the other hand, a decreased yield and ee of 61a (65%, 92% ee) were observed under the batch conditions ( Table 7). The authors described that the rapid mixing under micro-flow conditions suppressed the undesired side reactions. Figure 15. Rauhut-Currier reaction and [3 + 2] annulation sequence under flow conditions. Enantiomeric excess was determined via HPLC analysis. a 1.5 equiv. of allenoate 59. b Residence time = 21 sec (flow rate = 2.1 mL min −1 ). c Yields were determined via 1 H NMR analysis using 1,3,5trimethoxybenzene as an internal standard. Our group has developed efficient processes for the synthesis of peptides [60][61][62][63][64] using a rapid mixing technology of the micro-flow synthesis [1][2][3][4]. We recently developed the synthesis of highyielding N-methylated peptides without severe racemization via N-methyl imidazolium cation formation in the presence of HCl [65]. The key to success was the addition of a catalytic amount of HCl. We speculated that a mixed carbonic anhydride coordinated with the proton would enhance the electrophilicity. Under optimized flow conditions, a solution of N-protected amino acid 62 (0.33 M, 1.0 equiv.), diisopropylethylamine (1.0 equiv.), dimethylbenzylamine 63 (5 mol%) in 1,4-dioxane, and isopropyl chloroformate 64 (1.0 equiv.) in 1,4-dioxane was injected into a T shape mixer ( Figure  16). The mixed carbonic anhydride formation was completed at 60 °C in 5.0 s. The resultant mixture containing mixed carbonic anhydride and a solution of N-methylated amino acid 65 (1.0 equiv.), Nmethyl imidazole (66) (NMI, 10 mol%), and HCl (67) (15 mol%) in 1,4-dioxane was injected into a T shape mixer and reacted in a Teflon tube at 60 °C for 2 min. The desired N-methylated peptides 70 were obtained in high yields ( Figure 16; 16 examples, up to >99%). Our experimental results showed that the use of a catalytic amount of 63 containing two methyl groups was the most suitable for the formation of the mixed carbonic anhydride 68. The use of highly electrophilic N-methylimidazolium cation 69 [66] enabled the amidation of sterically hindered N-methyl amino acids. We used NMI due its comparable reactivity, lower toxicity, and cost compared with that of DMAP [67]. A reduced (ca. 15%) yield was observed when the developed reaction was carried out under batch conditions. Surprisingly, the dimethylbenzyl amine-catalyzed mixed carbonic anhydride formation was extremely rapid, and was completed in 0.5 sec (20 °C) using 10 mol% of the catalyst for a turnover frequency (TOF) of 14,400 h −1 [65]. We speculated that the micro-flow conditions successfully avoided an undesired decomposition of the unstable acyl ammonium cation, such as in decarboxylation, and, thus, flow conditions afforded higher yields compared with batch conditions.

Conclusions
This review summarized continuous-flow reactions that use metal-free homogeneous catalysts. The TOF of metal-free catalysts was usually lower than that of metal catalysts. Therefore, homogeneous reaction systems were usually preferable in order to avoid an undesired decrease in the turnover of metal-free catalysts. In addition, catalyst activity can be easily enhanced by heating above the boiling points of solvents in a continuous-flow reactor using BPR. In particular cases, metalfree catalysts exerted a high TOF (see Section 2.3.5). The use of continuous-flow conditions is valuable to avoid undesired reactions whereby generated reaction intermediates are unstable. The future combination of continuous-flow reactions that use metal-free homogeneous catalysts and in-line monitoring technology is highly desirable in order to more rapidly acquire reaction data. The obtained data is valuable for determining kinetic parameters that might afford insights into reaction mechanisms. In addition, the integration of optimization algorithms enables a rapid and autonomous optimization of reaction conditions. Reports of continuous-flow reactions using metal-free homogeneous catalysts remain very limited. Hopefully, more and more reactions will be reported and many high-yielding, low-cost, safe, scalable, and less wasteful continuous-flow processes using metal-free homogeneous catalysts will be developed in the near future.
Author Contributions: N.S. and S.F. decided the subject of this review. N.S. selected the case studies and wrote the first draft of the review. S.F. and H.N. helped to improve the content. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.