Next Article in Journal
Enzyme-Assisted Aqueous Extraction of Cobia Liver Oil and Protein Hydrolysates with Antioxidant Activity
Next Article in Special Issue
Optimization of a Catalytic Chemoenzymatic Tandem Reaction for the Synthesis of Natural Stilbenes in Continuous Flow
Previous Article in Journal
Promotional Effect of Manganese on Selective Catalytic Reduction of NO by CO in the Presence of Excess O2 over M@La–Fe/AC (M = Mn, Ce) Catalyst
Previous Article in Special Issue
Boosting the Performance of Nano-Ni Catalysts by Palladium Doping in Flow Hydrogenation of Sulcatone
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Catalysts
Volume 10
Issue 11
10.3390/catal10111321
catalysts-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

by
Naoto Sugisawa
1,2,
Hiroyuki Nakamura
1 and
Shinichiro Fuse
3,*
1
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan
2
School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
3
Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(11), 1321; https://doi.org/10.3390/catal10111321
Submission received: 23 October 2020 / Revised: 9 November 2020 / Accepted: 9 November 2020 / Published: 13 November 2020
(This article belongs to the Special Issue Continuous-Flow Catalysis)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. 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.

2. Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts

2.1. Acidic Catalysts

2.1.1. 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 1H 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.

2.1.2. Tritylium-Catalyzed Interrupted Povarov Reactions

Guo, Li, and coworkers reported cis-4-aminobenzodihydropyran synthesis using a tritylium-catalyzed 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 2,3-dihydrofuran 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.

2.1.3. 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).

2.1.4. 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.

2.1.5. 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.

2.1.6. 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.

2.2. Basic Catalysts

2.2.1. Organocatalytic α-Trifluoromethylthiolation of Silylenol Ethers

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]. Under optimized batch conditions, a mixture of silylenol ether 30 (0.1 M, 1.0 equiv.), tetrahydrothiophene (31) (THT, 10 mol%), and N-(trifluoromethylthio)saccharin (32) (1.0 equiv.) in acetonitrile was stirred at 80 °C for 5 h. The desired products 33 were obtained (4 examples, up to 75% conversion). The authors investigated continuous-flow conditions in order to improve the reaction efficiency (Figure 8). A mixture of silylenol ether 30 (0.2 M, 1.0 equiv.), THT (31) (10 mol%), and biphenyl as an internal standard (1.0 equiv.) in acetonitrile, along with a solution of N-(trifluoromethylthio)saccharin (32) (1.0 equiv.), were injected into a glass reactor (internal volume: 10 μL, temperature: 60 °C, residence time: 10 min, Labtrix® Start, Chemtrix). The desired products 33 were obtained (Table 5, Figure 8; four examples, up to 52% conversion). The productivity and space-time yields of 33a via continuous-flow conditions were 1.5 and 200 times higher, respectively, than using batch conditions.

2.2.2. Solvent-Free Organocatalytic Synthesis of Cyclic Carbonates

Monbaliu and coworkers reported the solvent- and metal-free organocatalyzed transesterification of dimethyl carbonate (DMC) with 1,2-diols under continuous-flow conditions [41]. DMC has attracted attention as a less-toxic carbonyl source [42,43,44]. However, there are only a limited number of reports on the carbonation of glycerol with DMC under continuous-flow conditions using homogeneous catalysts [45,46]. The authors screened reaction parameters including residence time, temperature, glycerol/DMC molar ratios, and the amounts of catalysts. The best catalyst was identified as 2-tert-butyl-1,1,3,3-tetramethylguanidine (36) (Barton’s base). Under optimized flow conditions, liquid 1,2-diols 34 (neat, 1.0 equiv.), DMC (35) (3.0 equiv.) and Barton’s base (36) (1–2 mol%) were introduced into a T-mixer (Figure 9). The mixture was reacted in a coil reactor under conditions A–C (conditions A: 135 °C, 2 min, 1 mol% catalyst, 7 bar; conditions B: 160 °C, 4 min, 2 mol% catalyst, 7 bar; conditions C: 180 °C, 8 min, 2 mol% catalyst, 11 bar.) as shown in Figure 9. The desired products 37 were obtained (Figure 9; nine examples, up to 96%). The developed approach was applied to a pilot-scale synthesis that afforded 68.3 mol of glycerol carbonate per day (8 kg per day).

2.2.3. 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.

2.2.4. 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.

2.3. Miscellaneous Catalysts

2.3.1. 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 pilot-scale synthesis under continuous-flow conditions (76% yield, 13.6 kg per day).

2.3.2. 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 2-propanol 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).

2.3.3. Organocatalytic Michael Addition of β-Ketoester to Nitroalkene

Benaglia and coworkers reported an organocatalytic Michael addition under continuous-flow conditions [55]. A solution of nitroalkene 54 (1 M, 1 equiv.) in toluene and a solution of β-ketoester 55 and Takemoto’s catalyst 56 [56] in toluene was injected into a glass microreactor (internal volume: 15 μL, temperature: 80 °C, residence time: 15 min, Labtrix® Start, Chemtrix) using syringe pumps (total flow rate: 1 μL/min). The desired product 57 was obtained in a 45% isolated yield (Figure 14).

2.3.4. 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 s (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.

2.3.5. N-Methylated Peptide Synthesis via Acyl N-Methylimidazolium Cation Generation Accelerated by a Brønsted Acid

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 high-yielding 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.), N-methyl 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 s (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.

3. 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, metal-free 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.

Acknowledgments

S.F. thanks JST-Mirai Program Japan (Grant Number JPMJMI18G7) and JSPS KAKENHI (Grant Number 17H03053 and 20K21188) for financial support.

Conflicts of Interest

The authors have no conflict of interest.

References

  1. Yoshida, J.-I. Flash Chemistry: Fast Organic Synthesis in Micro Systems; Wiley VCH: Weinheim, Germany, 2008. [Google Scholar]
  2. Yoshida, J.-I.; Nagaki, A.; Yamada, T. Flash chemistry: Fast chemical synthesis by using microreactors. Chem. A Eur. J. 2008, 14, 7450–7459. [Google Scholar] [CrossRef] [PubMed]
  3. Yoshida, J.-I. Flash chemistry: Flow microreactor synthesis based on high-resolution reaction time control. Chem. Rec. 2010, 10, 332–341. [Google Scholar] [CrossRef] [PubMed]
  4. Yoshida, J.-I.; Takahashi, Y.; Nagaki, A. Flash chemistry: Flow chemistry that cannot be done in batch. Chem. Commun. 2013, 49, 9896–9904. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Ley, S.V.; Fitzpatrick, D.E.; Ingham, R.; Myers, R.M. Organic synthesis: March of the machines. Angew. Chem. Int. Ed. 2015, 54, 3449–3464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Baumann, M.; Baxendale, I.R. The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry. Beilstein J. Org. Chem. 2015, 11, 1194–1219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Gutmann, B.; Cantillo, D.; Kappe, C.O. Continuous-flow technology—A tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 2015, 54, 6688–6728. [Google Scholar] [CrossRef]
  8. Fabry, D.C.; Sugiono, E.; Rueping, M. Online monitoring and analysis for autonomous continuous flow self-optimizing reactor systems. React. Chem. Eng. 2016, 1, 129–133. [Google Scholar] [CrossRef]
  9. Kobayashi, S. Flow “Fine” synthesis: High yielding and selective organic synthesis by flow methods. Chem. Asian J. 2016, 11, 425–436. [Google Scholar] [CrossRef]
  10. Rossetti, I.; Compagnoni, M. Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry. Chem. Eng. J. 2016, 296, 56–70. [Google Scholar] [CrossRef]
  11. Fanelli, F.; Parisi, G.; DeGennaro, L.; Luisi, R. Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis. Beilstein J. Org. Chem. 2017, 13, 520–542. [Google Scholar] [CrossRef] [Green Version]
  12. Shukla, C.A.; Kulkarni, A.A. Automating multistep flow synthesis: Approach and challenges in integrating chemistry, machines and logic. Beilstein J. Org. Chem. 2017, 13, 960–987. [Google Scholar] [CrossRef] [PubMed]
  13. Plutschack, M.B.; Pieber, B.; Gilmore, K.; Seeberger, P.H. The Hitchhiker’s guide to flow chemistry. Chem. Rev. 2017, 117, 11796–11893. [Google Scholar] [CrossRef] [PubMed]
  14. Britton, J.; Raston, C.L. Multi-step continuous-flow synthesis. Chem. Soc. Rev. 2017, 46, 1250–1271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Gérardy, R.; Emmanuel, N.; Toupy, T.; Kassin, V.-E.; Tshibalonza, N.N.; Schmitz, M.; Monbaliu, J.-C.M. Continuous flow organic chemistry: Successes and pitfalls at the interface with current societal challenges. Eur. J. Org. Chem. 2018, 2018, 2301–2351. [Google Scholar] [CrossRef]
  16. Zhao, D.; Ding, K. Recent advances in asymmetric catalysis in flow. ACS Catal. 2013, 3, 928–944. [Google Scholar] [CrossRef]
  17. Finelli, F.G.; Miranda, L.S.M.; De Souza, R.O.M.A. Expanding the toolbox of asymmetric organocatalysis by continuous-flow process. Chem. Commun. 2015, 51, 3708–3722. [Google Scholar] [CrossRef] [PubMed]
  18. Atodiresei, I.; Vila, C.; Rueping, M. Asymmetric organocatalysis in continuous flow: Opportunities for impacting industrial catalysis. ACS Catal. 2015, 5, 1972–1985. [Google Scholar] [CrossRef]
  19. Len, C.; Bruniaux, S.; Delbecq, F.; Parmar, V.S. Palladium-catalyzed suzuki–miyaura cross-coupling in continuous flow. Catalysts 2017, 7, 146. [Google Scholar] [CrossRef]
  20. De Risi, C.; Bortolini, O.; Brandolese, A.; Di Carmine, G.; Ragno, D.; Massi, A. Recent advances in continuous-flow organocatalysis for process intensification. React. Chem. Eng. 2020, 5, 1017–1052. [Google Scholar] [CrossRef]
  21. Yu, T.; Ding, Z.; Nie, W.; Jiao, J.; Zhang, H.; Zhang, Q.; Xue, C.; Duan, X.-H.; Yamada, Y.M.A.; Li, P. Recent advances in continuous-flow enantioselective catalysis. Chem. Eur. J. 2020, 26, 5729–5747. [Google Scholar] [CrossRef]
  22. Koóš, P.; Markovič, M.; Lopatka, P.; Gracza, T. Recent applications of continuous flow in homogeneous palladium catalysis. Synthesis 2020, 52. [Google Scholar] [CrossRef]
  23. Lyons, D.J.M.; Crocker, R.D.; Enders, D.; Nguyen, T.V. Tropylium salts as efficient organic Lewis acid catalysts for acetalization and transacetalization reactions in batch and flow. Green Chem. 2017, 19, 3993–3996. [Google Scholar] [CrossRef]
  24. Lyons, D.J.M.; Crocker, R.D.; Blümel, M.; Nguyen, T.V. Promotion of organic reactions by non-benzenoid carbocyclic aromatic ions. Angew. Chem. Int. Ed. 2017, 56, 1466–1484. [Google Scholar] [CrossRef] [PubMed]
  25. Liu, J.; Xu, J.; Li, Z.; Huang, Y.; Wang, H.; Gao, Y.; Guo, T.-F.; Ouyang, P.; Guo, K. Carbocation organocatalysis in interrupted povarov reactions to cis-fused pyrano-and furanobenzodihydropyrans. Eur. J. Org. Chem. 2017, 2017, 3996–4003. [Google Scholar] [CrossRef]
  26. Horn, M.; Mayr, H. A comprehensive view on stabilities and reactivities of triarylmethyl cations (tritylium ions). J. Phys. Org. Chem. 2012, 25, 979–988. [Google Scholar] [CrossRef]
  27. Naidu, V.R.; Ni, S.; Franzen, J. The carbocation: A forgotten lewis acid catalyst. ChemCatChem 2015, 7, 1896–1905. [Google Scholar] [CrossRef]
  28. Maji, B.; Mayr, H. Nucleophilic reactivities of schiff bases. Z. Nat. B 2013, 68, 693–699. [Google Scholar] [CrossRef]
  29. Follet, E.; Mayer, P.; Berionni, G. Structures, lewis acidities, electrophilicities, and protecting group abilities of phenyl-fluorenylium and tritylium ions. Chem. Eur. J. 2016, 23, 623–630. [Google Scholar] [CrossRef]
  30. Morodo, R.; Gérardy, R.; Petit, G.; Monbaliu, J.-C.M. Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof. Green Chem. 2019, 21, 4422–4433. [Google Scholar] [CrossRef]
  31. Santacesaria, E.; Vitiello, R.; Tesser, R.; Russo, V.; Turco, R.; Di Serio, M. Chemical and technical aspects of the synthesis of chlorohydrins from glycerol. Ind. Eng. Chem. Res. 2013, 53, 8939–8962. [Google Scholar] [CrossRef] [Green Version]
  32. Bell, B.M.; Briggs, J.R.; Campbell, R.M.; Chambers, S.M.; Gaarenstroom, P.D.; Hippler, J.G.; Hook, B.D.; Kearns, K.; Kenney, J.M.; Kruper, W.J.; et al. Glycerin as a renewable feedstock for epichlorohydrin production. The GTE process. CLEAN Soil Air Water 2008, 36, 657–661. [Google Scholar] [CrossRef]
  33. Hou, X.; Fu, Y.; Zhu, X.; Yin, H.; Wang, A. Chlorination of glycerol with HCl to 1,3-dichloro-2-propanol catalyzed by aliphatic carboxylic acids. Asia Pac. J. Chem. Eng. 2015, 10, 626–632. [Google Scholar] [CrossRef]
  34. Filho, C.A.D.A.; Heredia, S.; Eränen, K.; Salmi, T. Advanced millireactor technology for the kinetic investigation of very rapid reactions: Dehydrochlorination of 1,3-dichloro-2-propanol to epichlorohydrin. Chem. Eng. Sci. 2016, 149, 35–41. [Google Scholar] [CrossRef]
  35. Hussein, M.A.; Huynh, V.T.; Hommelsheim, R.; Koenigs, R.M.; Nguyen, T.V. An efficient method for retro-Claisen-type C–C bond cleavage of diketones with tropylium catalyst. Chem. Commun. 2018, 54, 12970–12973. [Google Scholar] [CrossRef]
  36. Salvadeo, E.; Monbaliu, J.-C.M. Development of a sustainable continuous flow approach toward allantoin. J. Flow Chem. 2020, 10, 251–257. [Google Scholar] [CrossRef]
  37. Omoregbee, K.; Luc, K.N.H.; Dinh, A.H.; Nguyen, T.V. Tropylium-promoted prenylation reactions of phenols in continuous flow. J. Flow Chem. 2020, 10, 161–166. [Google Scholar] [CrossRef]
  38. Dang, T.T.; Boeck, F.; Hintermann, L. Hidden brønsted acid catalysis: Pathways of accidental or deliberate generation of triflic acid from metal triflates. J. Org. Chem. 2011, 76, 9353–9361. [Google Scholar] [CrossRef]
  39. Abubakar, S.S.; Benaglia, M.; Rossi, S.; Annunziata, R. Organocatalytic α-trifluoromethylthiolation of silylenol ethers: Batch vs. continuous flow reactions. Catal. Today 2018, 308, 94–101. [Google Scholar] [CrossRef]
  40. Denmark, S.E.; Rossi, S.; Webster, M.P.; Wang, H. Catalytic, enantioselective sulfenylation of ketone-derived enoxysilanes. J. Am. Chem. Soc. 2014, 136, 13016–13028. [Google Scholar] [CrossRef] [Green Version]
  41. Wang, Z.; Gérardy, R.; Gauron, G.; Damblon, C.; Monbaliu, J.-C.M. Solvent-free organocatalytic preparation of cyclic organic carbonates under scalable continuous flow conditions. React. Chem. Eng. 2019, 4, 17–26. [Google Scholar] [CrossRef]
  42. Fiorani, G.; Perosa, A.; Selva, M. Dimethyl carbonate: A versatile reagent for a sustainable valorization of renewables. Green Chem. 2018, 20, 288–322. [Google Scholar] [CrossRef]
  43. Tundo, P.; Musolino, M.; Aricò, F. The reactions of dimethyl carbonate and its derivatives. Green Chem. 2018, 20, 28–85. [Google Scholar] [CrossRef]
  44. Selva, M.; Perosa, A.; Rodríguez-Padrón, D.; Luque, R. Applications of dimethyl carbonate for the chemical upgrading of biosourced platform chemicals. ACS Sustain. Chem. Eng. 2019, 7, 6471–6479. [Google Scholar] [CrossRef]
  45. Nogueira, D.O.; De Souza, S.P.; Leão, R.A.C.; Miranda, L.S.M.; De Souza, R.O.M.A. Process intensification for tertiary amine catalyzed glycerol carbonate production: Translating microwave irradiation to a continuous-flow process. RSC Adv. 2015, 5, 20945–20950. [Google Scholar] [CrossRef]
  46. Van Mileghem, S.; De Borggraeve, W.M.; Baxendale, I.R. A robust and scalable continuous flow process for glycerol carbonate. Chem. Eng. Technol. 2018, 41, 2014–2023. [Google Scholar] [CrossRef]
  47. Enevoldsen, M.V.; Overgaard, J.; Pedersen, M.S.; Lindhardt, A.T. Organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman adducts in batch and continuous flow. Chem. Eur. J. 2018, 24, 1204–1208. [Google Scholar] [CrossRef] [PubMed]
  48. Sugisawa, N.; Nakamura, H.; Fuse, S. Micro-flow synthesis of β-amino acid derivatives via a rapid dual activation approach. Chem. Commun. 2020, 56, 4527–4530. [Google Scholar] [CrossRef]
  49. Otake, Y.; Nakamura, H.; Fuse, S. Rapid and mild synthesis of amino acid N-carboxy anhydrides: Basic-to-acidic flash switching in a microflow reactor. Angew. Chem. Int. Ed. 2018, 57, 11389–11393. [Google Scholar] [CrossRef] [PubMed]
  50. Sugisawa, N.; Otake, Y.; Nakamura, H.; Fuse, S. Single-step, rapid, and mild synthesis of β-amino acid N-carboxy anhydrides using micro-flow technology. Chem. Asian J. 2019, 15, 79–84. [Google Scholar] [CrossRef] [Green Version]
  51. Gérardy, R.; Estager, J.; Luis, P.; Debecker, D.P.; Monbaliu, J.-C.M. Versatile and scalable synthesis of cyclic organic carbonates under organocatalytic continuous flow conditions. Catal. Sci. Technol. 2019, 9, 6841–6851. [Google Scholar] [CrossRef]
  52. Schober, L.; Ratnam, S.; Yamashita, Y.; Adebar, N.; Pieper, M.; Berkessel, A.; Hessel, V.; Gröger, H. An asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in aqueous medium running in flow mode. Synthesis 2019, 51, 1178–1184. [Google Scholar] [CrossRef] [Green Version]
  53. Rulli, G.; Duangdee, N.; Hummel, W.; Berkessel, A.; Gröger, H. First tandem-type one-pot process combining asymmetric organo- and biocatalytic reactions in aqueous media exemplified for the enantioselective and diastereoselective synthesis of 1,3-diols. Eur. J. Org. Chem. 2017, 2017, 812–817. [Google Scholar] [CrossRef]
  54. Raj, M.; Vishnumaya, V.; Ginotra, A.S.K.; Singh, V.K. Highly enantioselective direct aldol reaction catalyzed by organic molecules. Org. Lett. 2006, 8, 4097–4099. [Google Scholar] [CrossRef] [PubMed]
  55. Caruso, L.; Puglisi, A.; Gillon, E.; Benaglia, M. Organocatalytic michael addition to (D)-mannitol-derived enantiopure nitroalkenes: A valuable strategy for the synthesis of densely functionalized chiral molecules. Molecules 2019, 24, 4588. [Google Scholar] [CrossRef] [Green Version]
  56. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, A.X.; Takemoto, Y. Enantio- and diastereoselective michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 2005, 127, 119–125. [Google Scholar] [CrossRef]
  57. Jin, H.; Zhang, Q.; Li, E.; Jia, P.; Li, N.; Huang, Y. Phosphine-catalyzed intramolecular Rauhut–Currier reaction: Enantioselective synthesis of hydro-2H-indole derivatives. Org. Biomol. Chem. 2017, 15, 7097–7101. [Google Scholar] [CrossRef]
  58. Li, K.; Gonçalves, T.P.; Huang, K.; Lu, Y. Dearomatization of 3-nitroindoles by a phosphine-catalyzed enantioselective [3 + 2] annulation reaction. Angew. Chem. Int. Ed. 2019, 58, 5427–5431. [Google Scholar] [CrossRef]
  59. Kondo, M.; Wathsala, H.D.P.; Sako, M.; Hanatani, Y.; Ishikawa, K.; Hara, S.; Takaai, T.; Washio, T.; Takizawa, S.; Sasai, H. Exploration of flow reaction conditions using machine-learning for enantioselective organocatalyzed Rauhut–Currier and [3 + 2] annulation sequence. Chem. Commun. 2020, 56, 1259–1262. [Google Scholar] [CrossRef]
  60. Fuse, S.; Mifune, Y.; Takahashi, T. Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor. Angew. Chem. Int. Ed. 2013, 53, 851–855. [Google Scholar] [CrossRef] [Green Version]
  61. Fuse, S.; Mifune, Y.; Nakamura, H.; Tanaka, H. Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation. Nat. Commun. 2016, 7, 13491. [Google Scholar] [CrossRef]
  62. Mifune, Y.; Nakamura, H.; Fuse, S. A rapid and clean synthetic approach to cyclic peptides via micro-flow peptide chain elongation and photochemical cyclization: Synthesis of a cyclic RGD peptide. Org. Biomol. Chem. 2016, 14, 11244–11249. [Google Scholar] [CrossRef] [PubMed]
  63. Fuse, S.; Masuda, K.; Otake, Y.; Nakamura, H. Peptide-chain elongation using unprotected amino acids in a micro-flow reactor. Chem. Eur. J. 2019, 25, 15091–15097. [Google Scholar] [CrossRef] [PubMed]
  64. Fuse, S.; Otake, Y.; Nakamura, H. Peptide synthesis utilizing micro-flow technology. Chem. Asian J. 2018, 13, 3818–3832. [Google Scholar] [CrossRef] [PubMed]
  65. Otake, Y.; Shibata, Y.; Hayashi, Y.; Kawauchi, S.; Nakamura, H.; Fuse, S. N-Methylated peptide synthesis via generation of an acyl N-methylimidazolium cation accelerated by a brønsted acid. Angew. Chem. Int. Ed. 2020, 59, 12925–12930. [Google Scholar] [CrossRef] [PubMed]
  66. Ueki, H.; Ellis, T.K.; Martin, C.H.; Boettiger, T.U.; Bolene, S.B.; Soloshonok, V.A. Improved synthesis of proline-derived Ni(II) complexes of glycine: Versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of α-amino acids. J. Org. Chem. 2003, 68, 7104–7107. [Google Scholar] [CrossRef]
  67. Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. Simple, mild, and practical esterification, thioesterification, and amide formation utilizingp-toluenesulfonyl chloride and N-methylimidazole. Adv. Synth. Catal. 2003, 345, 1209–1214. [Google Scholar] [CrossRef]
Catalysts 10 01321 g001 550
Figure 1. Tropylium-catalyzed acetalization reactions under continuous-flow conditions.
Figure 1. Tropylium-catalyzed acetalization reactions under continuous-flow conditions.
Catalysts 10 01321 g001
Catalysts 10 01321 g002 550
Figure 2. TrBF4-catalyzed interrupted Povarov reaction under flow conditions.
Figure 2. TrBF4-catalyzed interrupted Povarov reaction under flow conditions.
Catalysts 10 01321 g002
Catalysts 10 01321 g003 550
Figure 3. Chlorination of glycerol catalyzed in a flow of pimelic acid. Conversion and yield were determined by GC/FID (Gas Chromatography/Flame Ionization Detection) analysis.
Figure 3. Chlorination of glycerol catalyzed in a flow of pimelic acid. Conversion and yield were determined by GC/FID (Gas Chromatography/Flame Ionization Detection) analysis.
Catalysts 10 01321 g003
Catalysts 10 01321 g004 550
Figure 4. Transformation of glycerol into oxiranes by chlorination/epoxidation sequence under continuous-flow conditions. Conversion and yield were determined by GC/FID analysis.
Figure 4. Transformation of glycerol into oxiranes by chlorination/epoxidation sequence under continuous-flow conditions. Conversion and yield were determined by GC/FID analysis.
Catalysts 10 01321 g004
Catalysts 10 01321 g005 550
Figure 5. Retro-Claisen alcoholysis and aminolysis in flow.
Figure 5. Retro-Claisen alcoholysis and aminolysis in flow.
Catalysts 10 01321 g005
Catalysts 10 01321 g006 550
Figure 6. Continuous-flow synthesis of allantoin. Conversion was calculated via HPLC analysis.
Figure 6. Continuous-flow synthesis of allantoin. Conversion was calculated via HPLC analysis.
Catalysts 10 01321 g006
Catalysts 10 01321 g007 550
Figure 7. Tropylium-catalyzed prenylation reactions of phenols under continuous-flow conditions.
Figure 7. Tropylium-catalyzed prenylation reactions of phenols under continuous-flow conditions.
Catalysts 10 01321 g007
Catalysts 10 01321 g008 550
Figure 8. α-Trifluoromethylthiolation of silylenol ethers. The yield of 33a was determined via 1H NMR analysis or GC analysis, while the yields of 33b–d were determined via 19F NMR analysis.
Figure 8. α-Trifluoromethylthiolation of silylenol ethers. The yield of 33a was determined via 1H NMR analysis or GC analysis, while the yields of 33b–d were determined via 19F NMR analysis.
Catalysts 10 01321 g008
Catalysts 10 01321 g009 550
Figure 9. Chemical structures of synthesized cyclic carbonates. Conversions and yields were determined via GC/FID analysis and 1H NMR analysis in CDCl3 with mesitylene as an internal standard. a NMR yield.
Figure 9. Chemical structures of synthesized cyclic carbonates. Conversions and yields were determined via GC/FID analysis and 1H NMR analysis in CDCl3 with mesitylene as an internal standard. a NMR yield.
Catalysts 10 01321 g009
Catalysts 10 01321 g010 550
Figure 10. Telescoped decarboxylative trichloromethylation of MBH-alcohols under continuous-flow conditions.
Figure 10. Telescoped decarboxylative trichloromethylation of MBH-alcohols under continuous-flow conditions.
Catalysts 10 01321 g010
Catalysts 10 01321 g011 550
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.
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.
Catalysts 10 01321 g011
Catalysts 10 01321 g012 550
Figure 12. Carbonation of 1,2-diols under flow conditions. Yields were determined either via GC/FID analysis or 1H NMR analysis with mesitylene as an internal standard (isolated yields are indicated in parentheses). a 2.25 equiv. of DMC. b Diol 34 was pumped as a solution in DMSO. c Residence time = 9 min.
Figure 12. Carbonation of 1,2-diols under flow conditions. Yields were determined either via GC/FID analysis or 1H NMR analysis with mesitylene as an internal standard (isolated yields are indicated in parentheses). a 2.25 equiv. of DMC. b Diol 34 was pumped as a solution in DMSO. c Residence time = 9 min.
Catalysts 10 01321 g012
Catalysts 10 01321 g013 550
Figure 13. The asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in an aqueous medium under flow conditions. The conversions were determined via 1H NMR analysis of the crude reaction mixtures. The ee was determined via HPLC analysis after preparative TLC (Thin-Layer Chromatography).
Figure 13. The asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in an aqueous medium under flow conditions. The conversions were determined via 1H NMR analysis of the crude reaction mixtures. The ee was determined via HPLC analysis after preparative TLC (Thin-Layer Chromatography).
Catalysts 10 01321 g013
Catalysts 10 01321 g014 550
Figure 14. Organocatalyzed Michael addition to D-mannitol-derived enantiopure nitroalkene under flow conditions.
Figure 14. Organocatalyzed Michael addition to D-mannitol-derived enantiopure nitroalkene under flow conditions.
Catalysts 10 01321 g014
Catalysts 10 01321 g015 550
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 s (flow rate = 2.1 mL min−1). c Yields were determined via 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
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 s (flow rate = 2.1 mL min−1). c Yields were determined via 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
Catalysts 10 01321 g015
Catalysts 10 01321 g016 550
Figure 16. Amidation via acyl N-methylimidazolium cation generation under flow conditions. The yield of the epimer was determined via HPLC-UV analysis. a 1.3 equiv. of DIEA, 1.4 equiv. of 2,4-dimetyl-3-pentylchloroformate, 10 mol% of HCl was used.
Figure 16. Amidation via acyl N-methylimidazolium cation generation under flow conditions. The yield of the epimer was determined via HPLC-UV analysis. a 1.3 equiv. of DIEA, 1.4 equiv. of 2,4-dimetyl-3-pentylchloroformate, 10 mol% of HCl was used.
Catalysts 10 01321 g016
Table
Table 1. Comparison between the continuous-flow conditions and conventional batch conditions of tropylium-catalyzed acetalization reactions.
Table 1. Comparison between the continuous-flow conditions and conventional batch conditions of tropylium-catalyzed acetalization reactions.
EntryReactorConcentration/MCatalyst Loading/
mol%		Reaction TimeTemperature/°CProductYield/%
1batch0.8355 h705a92
2flow0.08145 min905a99
3batch0.8355 h705b91
4flow0.08145 min905b96
5batch0.8355 h705c99
6flow0.08145 min905c98
7batch0.8355 h705d90
8flow0.08145 min905d94
9batch0.8355 h705e95
10flow0.08145 min905e95
11batch0.8355 h705f75
12flow0.08145 min905f86
13batch0.8355 h705g36
14flow0.08145 min905g80
Table
Table 2. Comparison between the continuous-flow conditions and conventional batch conditions of TrBF4-catalyzed interrupted Povarov reaction.
Table 2. Comparison between the continuous-flow conditions and conventional batch conditions of TrBF4-catalyzed interrupted Povarov reaction.
EntryReactorCatalyst Loading/mol%Reaction Time/minTemperature/°CYield/%cis:trans
1batch110 ar.t.d6070:30
2flow12 b, 1 c60, 258890:10
a Total time for imine formation and interrupted Pavarov reaction. b Time for imine formation. c Time for interrupted Pavarov reaction. d Room temperature.
Table
Table 3. Comparison between the continuous-flow conditions and conventional batch conditions of retro-Claisen alcoholysis and aminolysis.
Table 3. Comparison between the continuous-flow conditions and conventional batch conditions of retro-Claisen alcoholysis and aminolysis.
EntryReactorConcentration/MCatalyst Loading/mol%Reaction TimeTemperature/°CProductYield/%
1batchneat1016 h10023a94
2batch1.671024 hr.t. a23a89
3flow0.25530 min15023a93
4batchneat1016 h10023b97
5batch1.671024 hr.t. a23b85
6flow0.25530 min15023b91
7batchneat1016 h10023c82
8flow0.25530 min15023c84
9batchneat1016 h10023d85
10flow0.25530 min15023d84
11batchneat1016 h10023e76
12batch1.671024 hr.t. a23e80
13flow0.25530 min15023e81
14batchneat1016 h10023f70
15flow0.25530 min15023f78
a Room temperature.
Table
Table 4. Comparison between the continuous-flow conditions and conventional batch conditions of tropylium-catalyzed prenylation reactions.
Table 4. Comparison between the continuous-flow conditions and conventional batch conditions of tropylium-catalyzed prenylation reactions.
EntryReactorCatalyst Loading/mol%Reaction TimeTemperature/°CProductYield/%
1batch1024 h6029a60
2flow22 min10029a88
Table
Table 5. Comparison between the continuous-flow conditions and conventional batch conditions of α-trifluoromethylthiolation of silylenol ethers.
Table 5. Comparison between the continuous-flow conditions and conventional batch conditions of α-trifluoromethylthiolation of silylenol ethers.
EntryReactorCatalyst Loading/mol%Reaction TimeTemperature/°CProductConversion/%
1batch105 h8033a74
2flow1010 min6033a52
Table
Table 6. Comparison between the continuous-flow conditions and conventional batch conditions of the asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in an aqueous medium.
Table 6. Comparison between the continuous-flow conditions and conventional batch conditions of the asymmetric organocatalytic aldol reaction of a hydrophobic aldehyde in an aqueous medium.
EntryReactorCatalyst Loading/mol%Reaction Time/minTemperatureYield/%ee/%
1batch3.660r.t. a6791
2flow3.660r.t. a7489
a Room temperature.
Table
Table 7. Comparison between the continuous-flow conditions and conventional batch conditions of Rauhut-Currier reaction and [3 + 2] annulation sequence.
Table 7. Comparison between the continuous-flow conditions and conventional batch conditions of Rauhut-Currier reaction and [3 + 2] annulation sequence.
EntryReactorCatalyst Loading/mol%Reaction TimeTemperature/°CProductYield/% aee/%
1batch20<0.5 h8061a6592
2flow20<26 s8061a7894
a Yields were determined via 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sugisawa, N.; Nakamura, H.; Fuse, S. Recent Advances in Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts. Catalysts 2020, 10, 1321. https://doi.org/10.3390/catal10111321

AMA Style

Sugisawa N, Nakamura H, Fuse S. Recent Advances in Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts. Catalysts. 2020; 10(11):1321. https://doi.org/10.3390/catal10111321

Chicago/Turabian Style

Sugisawa, Naoto, Hiroyuki Nakamura, and Shinichiro Fuse. 2020. "Recent Advances in Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts" Catalysts 10, no. 11: 1321. https://doi.org/10.3390/catal10111321

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop