An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow

Abstract

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet–Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into δ-lactones via telescoped reduction/cyclisation in continuous flow has also been explored.

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Introduction

The indoloquinolizidine skeleton is present in the structures of a variety of bioactive alkaloids, such as yohimibine, reserpine, corynantheidol and hirustine, among many others (Fig. 1).¹ Structurally diverse indoloquinolizidines like 1 thus represent an important synthetic goal in medicinal chemistry, but their systematic study and their use are hampered by the inherent complexity of the synthetic approaches leading to them.

Fig. 1 Naturally occurring alkaloids of the indoloquinolizidine type and the targets of this study (1).

A variety of strategies towards the preparation of these interesting compounds in enantiomerically pure form have been developed; they include multistep processes starting from materials available in the chiral pool,² organocatalytic strategies for the creation of the key stereocenters in these structures,³ and, most interestingly, cascade approaches for the fast assembly of the tetracyclic indoloquinolizidine system.⁴ Overall, the main limitations of the previous asymmetric Michael addition approaches are use of non-recyclable homogeneous catalyst and prolonged reaction times. In terms of previous approaches towards indoloquinolizidine, the reaction scalability and extended reaction times are notable drawbacks.

The execution of complex synthetic transformations in a way that aligns with the principles of green chemistry, and thus involves low environmental footprint, is not only highly desirable, but a must in view of the increasingly accelerated climate change. This endeavour, however, remains challenging owing to the still common step-by-step approach to the construction of molecular skeletons and the almost unavoidable use of harmful reagents and large volumes of solvents in the most reliable tools in the synthetic chemist handbook.⁵

With no doubt, the formulation of the principles of green chemistry has boosted the interest on continuous-flow chemistry and has contributed to the paradigm change from batch to flow in academic laboratories as well as in industrial chemical manufacturing, since work in continuous flow brings “intrinsic greenness” to overall processes.^6,7 The encouragement and recommendations from various regulatory agencies in favour of the implementation of continuous manufacturing at industrial level unlocks the preferential choice of this alternative over conventional batch reactions,⁸ and the reason for that can be found in the fact that flow processes, when implementable, offer clear advantages over batch processing from both the economic and the technical points of view. Thus, flow processes can be easily engineered to provide improved heat and mass transfer, by-product minimization, rapid reactions, scalability, superheating of solvents, real-time analysis, safety control, and the possibility of a 24/7 working regime.⁹

In a parallel manner, the requisite for enantiopure forms over racemates in approved drugs is also rising due to pharmaceutical regulations;¹⁰ therefore, the search for catalytic enantioselective transformations with large scale applicability is becoming more evident.¹¹

Amid the different possible approaches to simultaneously fulfil the requirements of sustainability and enantioselectivity, one of the most promising alternatives is the merging of asymmetric catalysis and flow processing, using polymer-supported (PS) organocatalysts in packed bed reactors (PBR). The advantages of this approach for the fast production of enantiomerically pure compounds in a simple and readily scalable manner have already been demonstrated.¹² The organocatalyst immobilisation strategy offers facile recovery and reuse after each reaction, cost minimisation and robustness which can be utilised to produce from milligrams to multigram scale of enantioenriched entities, while avoiding by design any metal contamination in the reaction products.

For the efficient synthesis of indoloquinolizidines (1) we considered translating from batch to flow one of the most efficient approaches developed to date; that is, combining the enantioselective Michael addition of a dialkyl malonate (2) onto a variety of substituted cinnamaldehydes (3), leading to the enantioenriched oxodiester (4) with a diastereoselective Pictet–Spengler/lactamization cascade with tryptamine derivatives (5).^4e (Scheme 1). As an additional bonus, we also planned to use 4 for the synthesis of enantio- and diastereomerically pure δ-lactones (6) using a telescoped continuous flow process.

Scheme 1 Retrosynthetic analysis for chiral lactones and indoloquinolizidines from enantiopure Michael adducts.

Jørgensen–Hayashi catalysts (7)¹³ are probably the most used organocatalysts for Michael-type additions.¹⁴ Very efficient immobilized versions of them (8) have been developed starting from readily available, enantiopure trans-4-hydroxyproline (Fig. 2).¹⁵ Some of these immobilized species have shown their suitability for use in continuous flow and, among them 8g, formally derived from cis-4-hydroxyproline,¹⁶ offers the important sustainability advantage of allowing work in continuous flow under solventless conditions. With the use of this catalyst, a variety of Michael-type adducts en route to enantiomerically pure important drugs (Paroxetine, Baclofen, Phenibut, Fluorophenibut, Rolipram) having been prepared.¹⁷

Fig. 2 Immobilized versions of the Jørgensen–Hayashi catalyst.

According to these precedents, we decided to explore the possibility of developing a continuous flow approach to indoloquinolizidines 1, where the key chiral center at C2 was created through a solvent-free organocatalytic Michael addition mediated by an immobilized Jørgensen–Hayashi catalyst (8), while the configuration at the C3 and C12b would result from the interplay of kinetic and thermodynamic factors in a subsequent domino Pictet–Splengler cyclization/lactamization sequence.

For our purposes, it was very important to identify immobilized catalysts of the 8-type able to provide high enantioselectivity in the Michael addition of malonates 2 to substituted cinnamaldehydes 3. After a preliminary screening, we concentrated our efforts on the catalyst 8f, which has been previously used with success in the Michael initiated cyclopropanation of enals with bromomalonates,^15h and 8k, which has been newly prepared for the purpose of this study.¹⁸

We first studied the addition of dimethyl malonate (2) to 4-fluorocinnamaldehyde (3a) in batch in the presence of these two polymer-supported organocatalysts (see Table S1 in the ESI for these optimization studies†). In this manner, we could establish that the hard Lewis acid Ca(OTf)₂ is required as an additive with 8k, while with 8f the reactions can be efficiently promoted with the simple addition of acetic acid. Enantioselectivities of 95–96% were achieved in these conditions. A library of oxodiesters 4′ was subsequently prepared in batch using catalyst 8k with moderate to good yield and excellent enantioselectivity (Scheme S2†). Once the suitability of 8k and 8f for the target additions were established in batch, the experimental conditions (reaction temperature, concentration, and flow rate) for the corresponding addition in flow were optimized (Table 1).

Table 1 Optimization for conjugate addition in flow ^a

No.	Cat.	Flow rate [μL min^−1]	Additive	Yield^b [%]	Solv.	t R [min]	ee^c [%]
a The reactions were performed in packed bed reactors containing 0.5 g (0.203 mmol) of 8k or 1.0 g (1.21 mmol) of 8f. b Isolated yield. c Determined by chiral HPLC using OJ-H column. d 0.05M DCM solution (2/3a molar ratio was 2 : 1). e 0.05M DCM solution (2/3a molar ratio was 15 : 1). f 0.2M DCM solution (ratio of 2 & 3 was 15 : 1). g 0.2M DCM solution (ratio of 2 & 3 was 15 : 1). In the case of neat reactions the (2/3a molar ratio was 2 : 1). In all experiments 1 equiv. of Ca(OTf)2, or 0.6 equiv. of AcOH were used. [CV = check valve, BPR = back pressure regulator].
1^d	8k	100 or 50	AcOH	Trace	DCM	—	—
2^d	8k	20	Ca(OTf)2	35	DCM	330	−91
3^e	8k	20	Ca(OTf)2	<5	DCM	—	—
4	8k	20	AcOH	15	Neat	125	−96
5^f	8k	20	Ca(OTf)2	<5	Neat	125	—
6^g	8f	100	AcOH	60	DCM	63	96
7	8f	100	AcOH	32	Neat	25	98
8	8f	50	AcOH	68	Neat	50	98
9	8f	20	AcOH	73	Neat	125	98

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Only traces of product were observed when the reaction was carried out in flow in the presence of catalyst 8k with acetic acid as an additive at 60 °C and flow rates of 50 or 100 μL min⁻¹ (entry 1). Even after a substantial decrease in flow rate under solventless conditions (entry 4), conversion remained low. On the other hand, although 8k worked well with Ca(OTf)₂ as an additive in batch, poor solubility of Ca(OTf)₂ in DCM had a negative impact on the use of this additive in continuous flow. Moreover, since Ca(OTf)₂ is soluble in dimethyl malonate, poor yields are recorded in the presence of this additive even at long residence times, probably due to leaching (entries 2 and 3). Again, working under solventless conditions did not improve the situation (entry 5).

Gratifyingly, the use of catalyst 8f with a large excess of dimethyl malonate at a flow rate of 100 μL min⁻¹ provided 4a in 60% isolated yield and 96% ee (entry 6). Importantly, the reaction mediated by 8f in the presence of AcOH tolerated well the use of solventless conditions, with 4a being obtained with improved enantioselectivity (98% ee) in 32% yield (entry 7). Further decreases in flow rate (entries 8 and 9) showed 50 μL min⁻¹ to be the optimal value, leading to 4a in 68% yield and 98% ee, with a reasonable 50 min residence time (entry 8).

With these optimized conditions we explored the substrate scope in the solvent free conjugate addition reaction (Scheme 2). A continuous flow assembly was set up by placing 1 g of catalyst 8f (f = 1.21) in an Omnifit© column (10 mm bore size and 70 mm maximum adjustable height) with outer jacket having oil circulation for heating (60 °C), with the reactants being flowed by a Vapourtec SF-10 pump (Fig. S3, ESI†). The height of the catalyst bed was ca. 3.2 cm after swelling with dimethyl malonate. This simple device could be used for the gram-scale preparation of a family of enantiopure oxodiesters 4 in a sequential manner. For instance, compound 4b was prepared from a homogeneous mixture of dimethyl malonate 2 (2 equiv., 98.48 mmol), trans-cinnamaldehyde 3b (1 equiv., 49.24 mmol), and acetic acid (0.6 equiv., 25.97 mmol) circulated at a flow rate of 50 μL min⁻¹ at 60 °C for 4.5 h. A back pressure regulator (BPR) loaded at 75 psi was used to prevent the formation of bubbles inside the catalyst gel. To our delight, 19.94 mmol of dimethyl (R)-2-(3-oxo-1-phenylpropyl)malonate 4b with 97% ee were obtained in the experiment, corresponding to a TOF of 3.66 mmol_4b h⁻¹ mmol_8f⁻¹. Before performing the next preparative experiment, the packed bed of catalyst 8f was simply washed with acetic acid (200 μL min⁻¹ for 30 min) and ethyl acetate (200 μL min⁻¹ for 30 min). In this manner, we explored the scope of the asymmetric Michael reaction with up to seven β-(hetero)aryl substituted α,β-unsaturated aldehydes.

Scheme 2 Scope of enantioselective conjugate addition under solvent free conditions in continuous flow, flow rate = 50 μL min⁻¹. ^aee was determined after cyclization with tryptamine (5), for entry 4f flow rate was 100 μL min⁻¹. TOF in mmol₄ mmol_8f⁻¹ h⁻¹.

The reaction worked well with 4-methoxycinnamaldehyde (3c), bearing an electron-donating substituent on the aryl group, to afford 11.47 mmol of dimethyl (R)-2-(1-(4-methoxyphenyl)-3-oxopropyl)malonate (4c) with 96% ee in 4 hours. Substrates bearing weak electron withdrawing groups such 4-fluorocinnamaldehyde (3a); 4-chlorocinnamaldehyde (3d) and 4-bromocinnamaldehyde (3e) also afforded product 4a (18.39 mmol, 3.38 mmol h⁻¹), 4d (8.10 mmol, 2.68 mmol h⁻¹) and 4e (4.74 mmol, 1.12 mmol h⁻¹) with excellent enantioselectivity of 98, 97 and 97% respectively. Noteworthy, compounds 4a and 4b are key intermediate for the synthesis of antidepressant drugs (−)-Paroxetine and (−)-Femoxetine, while 4d is a precursor of the peptidomimetic inhibitor Roche-1.¹⁹ In the case of compound 4e, a larger excess (6 equiv.) of dimethyl malonate was used to ensure the solubility of the starting aldehyde. Likewise, due to poor solubility of 4-nitrocinnamaldehyde (3f), 10.4 equiv. of dimethyl malonate was used to obtain 1.65 mmol of compound 4f in 3.18 hours at a 100 μL min⁻¹ flow rate. Additionally, the reaction of (E)-3-(furan-2-yl)acrylaldehyde (3g) with dimethyl malonate afforded 6.02 mmol (1.58 mmol h⁻¹) of oxodiester 4g with 92% ee. It is remarkable that the reaction exhibits an important dependence on the nature of the dialkyl malonate partner. Thus, when the use of diethyl malonate was tested in front of trans-cinnamaldehyde, poor reaction performance was observed. Catalyst 8k was also tested in the reaction, for the formation of ent-4b′. Much lower conversion was observed, and flow rate was accordingly reduced to 20 μL min⁻¹. In this manner, 1.00 g of ent-4b′ with 92% ee could be obtained in 4.5 h operation.

At this point, it is interesting to realize the operational advantages associated to the use of the immobilized catalyst 8f for the preparation of 4 in continuous flow: besides the suppression of solvent use (excess of dimethyl malonate can be easily removed by evaporative distillation), reuse of the PBR containing the catalyst only requires intermediate washing, and scale-up to the decimol scale can be simply achieved by reasonable extension of the operation time. For instance, the preparation of 100 mmol of enantiopure 4a would require some 22 h operation under the standard operation conditions.

Next, the study of the continuous-flow synthesis of indoloquinolizidines 1 from enantiopure oxodiesters 4 was undertaken. The desired Pictet–Spengler cyclization with subsequent lactamization process was first studied by reacting dimethyl (R)-2-(1-(4-fluorophenyl)-3-oxopropyl)malonate (4a) and tryptamine (5) in presence of trifluoroacetic acid (TFA), as summarized in Table 2. The continuous flow set-up consisted of two syringe or peristaltic pumps to deliver the reagents, T-mixer, check valve to prevent back flow, coil reactor with acid resistant PTFE tube (5 mL volume), a heating source from Vapourtec R-series and a BPR loaded at 40 psi (Fig. S4†). A solution of 4a and 5 in dichloromethane (DCM) was flown by one of the pumps, and a solution of TFA in DCM was flown by the other pump. At the outset, equimolar solutions of 4c + 5 and TFA in DCM were circulated at 50 μL min⁻¹ each at 20 °C, which resulted in no lactamization (Table 2, entry 1). By increasing the temperature to 55 °C, compound 1a was formed in 35% yield with 92% ee (entry 2). We attributed this rather low yield to the incomplete cyclization of the unstable, epimerizable intermediates Int. a and Int. b, since we observed that these intermediates slowly undergo non-diastereoseletive lactamization in CDCl₃ or CD₂Cl₂ in NMR tubes on standing. Due to the unstable nature of these intermediates, we are not able to isolate them. We hypothesized that higher temperature and the presence of additional acid promoter would accelerate the reaction and, to our delight (entry 5), when 2.5 equiv. of TFA were used at 55 °C and flow rate was reduced to 50 μL min⁻¹ for each reactant, the cascade process took place to completion, affording 1c in 76% isolated yield with 93% ee with residence time of 50 min (entry 5).

Table 2 Optimization for diastereoselective synthesis of indoloquinolizidines in flow^a

Entry	TFA equiv.	Flow rate [μL min^−1]	Temp.	Yield^b	t R	ee^c
a Compound 4a with 96% ee (0.1 mmol, 1 equiv., 10 mM solution in 10 mL solvent) + 1.5 equiv. of 5, trifluoroacetic acid (2.5 equiv., 25 mM solution in 10 mL DCM). b Isolated yields. c Determined by chiral HPLC using AD-H column. d Performed with 23 mM concentration of 4a. >20/1 dr was observed. Flow rate = 50 μL min^−1 for each syringe.
1	1	50	20	—	50	—
2	1	100	55	35	25	92
3	2	100	55	40	25	91
4	2	50	55	56	50	93
5	2.5	50	55	76	50	93
6^d	2.5	50	55	49	50	92
7	10	100	80	Traces	25	—
8	2.5	50	55	40	50	90
9	2.5	50	55	—	50	—
10	2.5	50	55	Traces	50	—
11	2.5	50	55	—	50	—

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When the concentration of the solution of 4a and 5 in DCM was increased to 23 mM with the purpose of increasing productivity, the yield of 1a dropped significantly (entry 6). In the same manner, the use of a ten-fold excess of TFA had a deleterious effect (entry 7). Likewise, a drastic decrease in yield was observed when THF was used as a solvent (entry 8). Other solvents like ethanol, DMF, DMSO were ineffective (entries 9–11).

The optimized conditions of entry 5 were next applied for the synthesis of a family of indoloquinolizidines (ent-1′) in continuous-flow (Scheme 3). In all cases moderate to very good yield and excellent diastereselectivity were observed, with preservation of the enantiopurity of the oxodiester precursors. The samples of the starting oxodiesters used in this study had been prepared in batch by using catalyst 8k, and thus belonged to the S-enantiomeric series (see ESI, Scheme S2†). It is to be mentioned that the same catalyst sample 8k was used throughout the synthesis campaign of library of 4′ series, the re-conditioning between successive preparations simply involving washings with ethyl acetate and DCM and drying at 40 °C.

Scheme 3 Scope of diastereoselective Picetet–Splengler-lactamisation domino reaction in continuous flow. Reactor volume 5 mL, flow rate = 50 μL min⁻¹ for each, residence time (t_R) = 50 min. >20/1 dr.

Since it is well established that the cascade Pictet–Spengler plus lactamization sequence performed in batch requires working at low concentration for success,²⁰ this being confirmed by our own observations when the process is performed in continuous flow (Table 2, entry 6), any desired increase in production should be tackled from the perspective of an increased throughput, using either a sequential or a parallel numbering up strategy. With this purpose, we combined three coiled reactors (5 + 5 + 10 mL volume) to give a total reactor volume of 20 mL, and the flow rates of the 10 mM solutions of 4 + 5 and 25 mM TFA in DCM were increased to 200 μL min⁻¹ each, which corresponds to a theoretical fourfold increase in production, keeping a constant residence time of 50 min (Scheme 4; see ESI, Fig. S5† for the actual reactor image). Enantiopure compounds prepared using catalyst 8f (Scheme 2) were used to perform the large-scale synthesis of indoloquinolizidines (Scheme 4).

Scheme 4 Scope of the diastereoselective Pictet–Splengler-lactamisation domino reaction in continuous flow. Reactions carried out on 1 mmol scale. Reactor volume = 20 mL, flow rate = 200 μL min⁻¹ each, residence time (t_R) = 50 min, ^at_R = 100 min (65% yield), t_R = 50 min (48%). >20/1 dr.

In the initial experiment, a 10 mM solution of dimethyl (R)-2-(3-oxo-1-phenylpropyl)malonate 4b in 100 mL DCM and a 25 mM TFA solution in DCM (100 mL) were flown at a flow rate of 200 μL min⁻¹ each at 55 °C to afford 1b in 48% yield. However, lowering the flow rate of each of the solutions to 100 μL min⁻¹ resulted in a remarkable increase in yield of 1b to 65%, with 97% enantioselectivity. Likewise, the oxodiester 4c, bearing an electron donating methoxy group in the para position, also worked well to afford compound 1c in 55% yield with 96% ee (dr = 90 : 10). Subsequently, the reaction of 4a, 4d and 4e were also performed in flow to efficiently produce the tetracyclic products 1a, 1d and 1e in good yield and excellent enantioselectivity (Scheme 4). Compound 4f bearing a para nitro group also worked to provide 1f in 73% yield with 91% ee. Finally, the reaction of dimethyl (R)-2-(1-(furan-2-yl)-3-oxopropyl)malonate (4g) also worked well to afford 1g in 53% yield and 92% ee.

As an additional bonus of these studies, we decided to explore the conversion of oxodiesters 4 into enantiopure, trans-3,4-disubstituted δ-lactones 6. Chiral lactones are an important class of compounds which shows interesting biological properties.²¹ In particular, batch synthesis of δ-lactones involves the chemoselective reduction of oxodiesters using NaBH₃CN at 0 °C, followed by basic workup and silica-gel mediated cyclisation.¹⁹ To avoid the additional work-up step, possibility of exotherms, and prolonged reaction time we have established a continuous flow protocol for the chemoselective reduction of oxodiester 4a at room temperature, and we have telescoped this step with a cyclisation induced by the acidic resin Amberlyst-15. In this manner, the whole reduction-cyclisation sequence can be performed in continuous flow, in a very short time and without isolating the intermediate alcohol (Scheme 5). To perform the telescoped process, a 5 mL coiled reactor was combined with an Omnifit© PBR (6.6 mm bore size × 70 mm height) filled with 1.5 g of Amberlyst-15 (see ESI, Fig. S6†). Then, a 35 mM solution of compound 4a (0.35 mmol + 0.42 mL acetic acid in THF) and 53 mM solution of NaBH₃CN in THF were circulated at 200 μL min⁻¹ through the coiled reactor at 25 °C and the Amberlyst-15 packed bed reactor (Temp = 50 °C) to afford lactone 6 in 53% isolated yield and 95.5% ee, with >20/1 dr in only 20 min of residence time. Although this is beyond the goals of the present study, the extension of this methodology to the preparation of diversely substituted enantiopure lactones 6 looks straightforward.

Scheme 5 Continuous flow distereoselective reductive cyclisation.

Conclusions

In summary, we have developed a rapid and solvent-free, continuous flow protocol for the preparation of enantiopure oxodiesters 4 using polymer-supported Jørgensen–Hayashi catalysts to perform enantioselective Michael additions at the multi-gram scale through safe and operationally simple procedures. We have also demonstrated the successful use of these enantiopure Michael adducts in the expedient diastereoselective synthesis of complex indoloquinolizidines 1 through a domino Pictet–Spengler plus lactamization sequence performed in continuous flow. Moreover, we have also shown the possibility of using enantiopure Michael adducts 4 as starting materials for a telescoped, diastereoselective synthesis of trans-3,4-disubstituted δ-lactones in continuous flow through a safe process taking place at near ambient temperature with short residence time. In comparison with previous reports, we are able to achieve a rapid, solvent-free, scalable synthesis of Michael adducts and also an expedient and scalable continuous flow synthesis of diverse indoloquinolizidines. We believe that the use of highly recyclable, robust and enantioselective organocatalysts working in solventless conditions will pave the way for the development of further applications of enantiopure indoloquinolizidine alkaloid derivatives.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was funded by MINECO/FEDER (grant PID2019-109236RB-I00), MICINN through Severo Ochoa Excellence Accreditation 2020-2023 (CEX2019-000925-S, MIC/AEI), and the CERCA Program/Generalitat de Catalunya. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 890452.

References

1. (a) The Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Academic Press, New York, 1998, vol. 50; (b) C. Szántay and K. Honty, in The Chemistry of Heterocyclic Compounds, ed. J. E. Saxton, Wiley, New York, 1994, vol. 25, pp. 161–216.
2. For some examples, see: (a) M. Amat, M. Pérez, A. T. Managlia, N. Casamitjana and J. Bosch, Org. Lett., 2005, 7, 3653–3656; (b) G. Stork, P. C. Tang, M. Casey, B. Goodman and M. Toyota, J. Am. Chem. Soc., 2005, 127, 16255–16262; (c) M. Amat, M. M. M. Santos, O. Bassas, N. Llor, C. Escolano, A. Gómez-Esqué, E. Molins, S. M. Allin, V. McKee and J. Bosch, J. Org. Chem., 2007, 72, 5193–5201; (d) M. Amat, A. Gómez-Esqué, C. Escolano, M. M. M. Santos, E. Molin and J. Bosch, J. Org. Chem., 2009, 74, 1205–1211.
3. For some recent approaches to the indoloquinolizidine skeleton involving either metal-catalyzed or organocatalytic processes, see: (a) A. Olmos, B. Louis and P. Pale, Chem. – Eur. J., 2012, 18, 4894–4901; (b) M. P. Lalonde, M. A. McGowan, N. S. Rajapaksa and E. N. Jacobsen, J. Am. Chem. Soc., 2013, 135, 1891–1894; (c) M. Amat, F. Arioli, M. Pérez, E. Molins and J. Bosch, Org. Lett., 2013, 15, 2470–2473; (d) Y. Liu, Q. Wang, Y. Zhang, J. Huang, L. Nie, J. Chen, W. Cao and X. Wu, J. Org. Chem., 2013, 78, 12009–12017; (e) V. Gobe and X. Guinchard, Org. Lett., 2014, 16, 1924–1927; (f) A. Younai, B.-S. Zeng, H. Y. Meltzer and K. A. Scheidt, Angew. Chem., Int. Ed., 2015, 54, 6900–6904; (g) X. chen, L. Yu, H. Wang, W. Zhang, P. Tang and F. Chen, Chem. Commun., 2021, 57, 11669–11672.
4. (a) J. Franzén and A. Fisher, Angew. Chem., Int. Ed., 2009, 48, 787; (b) W. Zhang and J. Franzén, Adv. Synth. Catal., 2010, 352, 499; (c) X. Y. Wu, X. Y. Dai, L. L. Nie, H. H. Fang, J. Chen, Z. J. Ren, W. G. Cao and G. Zhao, Chem. Commun., 2010, 46, 2733–2735; (d) H. Fang, X. Wu, L. Nie, X. Dai, J. Chen, W. Cao and G. Zhao, Org. Lett., 2010, 12, 5366–5369; (e) M. Rueping, C. M. R. Volla, M. Bolte and G. Raabe, Adv. Synth. Catal., 2011, 353, 2853–2859; (f) X.-Y. Wu, X.-Y. Dai, H.-H. Fang, L.-L. Nie, J. Chen, W. G. Cao and G. Zhao, Chem. – Eur. J., 2011, 17, 10510–10514; (g) H.-L. Zhu, J.-B. Ling and P.-F. Xu, J. Org. Chem., 2012, 77, 7737–7743; (h) G. He, B. List and M. Christmann, Angew. Chem., Int. Ed., 2021, 60, 13591–13596.
5. (a) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, 2000; (b) P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301–312; (c) R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437–1451; (d) H. C. Erythropel, J. B. Zimmerman, T. M. de Winter, L. Petitjean, F. Melnikov, C. H. Lam, A. W. Lounsbury, K. E. Mellor, N. Z. Janković, Q. Tu, L. N. Pincus, M. M. Falinski, W. Shi, P. Coish, D. L. Plata and P. T. Anastas, Green Chem., 2018, 20, 1929–1961; (e) For a recent essay on sustainable chemistry, see: K. Kümmerer, Angew. Chem., Int. Ed., 2017, 56, 16420–16421.
6. (a) S. G. Newman and K. F. Jensen, Green Chem., 2013, 15, 1456–1472; (b) L. Rogers and K. F. Jensen, Green Chem., 2019, 21, 3481–3498; (c) D. Dallinger and C. O. Kappe, Curr. Opin. Green Sustainable Chem., 2017, 7, 6–12.
7. (a) R. Ciriminna and M. Pagliaro, Org. Process Res. Dev., 2013, 17, 1479–1484; (b) S. Falß, N. Kloye, M. L. Holtkamp, A. Prokofyeva, T. Bieringer and N. Kockmann, in Handbook of Green Chemistry, Green Chemical Engineering, Wiley Online Library, 2019, vol. 12; (c) Flow Chemistry in Drug Discovery, ed. J. Alcazar, A. de la Hoz and A. Diaz-Ortiz, Topics in Medicinal Chemistry, Springer, vol. 38, 2022.
8. https://www.regulations.gov/document/FDA-2019-D-0298-0002 .
9. For some recent reviews on flow chemistry, see: (a) M. B. Plutschack, B. Pieber, K. Gilmore and P. H. Seeberger, Chem. Rev., 2017, 117, 11796; (b) J. Wegner, S. Ceylan and A. Kirschning, Adv. Synth. Catal., 2012, 354, 17–57; (c) J. C. Pastre, D. L. Browne and S. V. Ley, Chem. Soc. Rev., 2013, 42, 8849–8869; (d) R. Gérardy, N. Emmanuel, T. Toupy, V.-E. Kassin, N. N. Tshibalonza, M. Schmitz and J.-C. M. Monbaliu, Eur. J. Org. Chem., 2018, 2301–2351; (e) R. L. Hartman, Curr. Opin. Chem. Eng., 2020, 29, 42–50; (f) S. B. Ötvös and O. Kappe, Green Chem., 2021, 23, 6117–6138; (g) A. S. Burange, S. M. Osman and R. Luque, iScience, 2022, 25, 103892; (h) A. Bonner, A. Loftus, A. C. Padgham and M. Baumann, Org. Biomol. Chem., 2021, 19, 7737–7753; (i) T. Yu, Z. Ding, W. Nie, J. Jiao, H. Zhang, Q. Zhang, C. Xue, X. Duan, Y. M. A. Yamada and P. Li, Chem. – Eur. J., 2020, 26, 5729–5747; (j) W.-J. Yoo, H. Ishitani, B. Laroche and S. Kobayashi, J. Org. Chem., 2020, 85, 5132–5145.
10. L. A. Nguyen, H. He and C. Pham-Huy, Int. J. Biomed. Sci., 2006, 2, 85–100.
11. For a pioneering review, see: H.-U. Blaser, B. Pugin and F. Spindler, J. Mol. Catal. A: Chem., 2005, 231, 1–20.
12. (a) C. Rodríguez-Escrich and M. A. Pericàs, Chem. Rec., 2019, 19, 1872–1890; (b) I. Atodiresei, C. Vila and M. Rueping, ACS Catal., 2015, 5, 1972–1985; (c) T. Tsubogo, T. Ishiwata and S. Kobayashi, Angew. Chem., Int. Ed., 2013, 52, 6590–6604; (d) K. Masuda, T. Ichitsuka, N. Koumura, K. Sato and S. Kobayashi, Tetrahedron, 2018, 74, 1705–1730; (e) F. Herbrik, M. Sanz, A. Puglisi, S. Rossi and M. Benaglia, Chem. – Eur. J., 2022, 28 DOI:10.1002/chem.202200164; (f) H. Ishitani, Y. Furiya and S. Kobayashi, Chem. – Asian J., 2020, 15, 1688; (g) S. Rossi, R. Porta, D. Brenna, A. Puglisi and M. Benaglia, Angew. Chem., Int. Ed., 2017, 56, 4290–4293; (h) S. Ogasawara and Y. Hayashi, Synthesis, 2017, 424; (i) T. Tsubogo, H. Oyamada and S. Kobayashi, Nature, 2015, 520, 329; (j) C. De Risi, O. Bortolini, A. Brandolese, G. Di Carmine, D. Ragno and A. Massi, React. Chem. Eng., 2020, 5, 1017–1052; (k) Catalyst Immobilization: Methods and Applications, ed. M. Benaglia and A. Puglisi, Wiley, 2020.
13. (a) J. Franzén, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 18296–18304; (b) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794–797; (c) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212–4215.
14. For some reviews on the applications of Jørgensen–Hayashi catalysts, see: (a) A. Mielgo and C. Palomo, Chem. – Asian J., 2008, 3, 922–948; (b) K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht and K. A. Jørgensen, Acc. Chem. Res., 2011, 45, 248–264; (c) B. S. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov and K. A. Jørgensen, Angew. Chem., Int. Ed., 2015, 54, 13860–13874.
15. (a) E. Alza and M. A. Pericàs, Adv. Synth. Catal., 2009, 351, 3051–3056; (b) E. Alza, S. Sayalero, X. C. Cambeiro, R. Martín-Rapún, P. O. Miranda and M. A. Pericàs, Synlett, 2011, 464–468; (c) E. Alza, S. Sayalero, P. Kasaplar, D. Almasşi and M. A. Pericàs, Chem. – Eur. J., 2011, 17, 11585–11595; (d) P. Riente, C. Mendoza and M. A. Pericàs, J. Mater. Chem., 2011, 21, 7350–7355; (e) X. Fan, C. Rodríguez-Escrich, S. Sayalero and M. A. Pericàs, Chem. – Eur. J., 2013, 19, 10814–10817; (f) X. Fan, C. Rodríguez-Escrich, S. Wang, S. Sayalero and M. A. Pericàs, Chem. – Eur. J., 2014, 20, 13089–13093; (g) C. A. Mak, S. Ranjbar, P. Riente, C. Rodríguez-Escrich and M. A. Pericàs, Tetrahedron, 2014, 70, 6169–6173; (h) P. Llanes, C. Rodríguez-Escrich, S. Sayalero and M. A. Pericàs, Org. Lett., 2016, 18, 6292–6295; (i) J. Lai, S. Sayalero, A. Ferrali, L. Osorio-Planes, F. Bravo, C. Rodríguez-Escrich and M. A. Pericàs, Adv. Synth. Catal., 2018, 360, 2914–2924; (j) C. Lizandara-Pueyo, X. M. Fan, C. Ayats and M. A. Pericàs, J. Catal., 2021, 393, 107–115; (k) Y. Hayashi, S. Hattori and S. Koshino, Chem. – Asian J., 2022, 17, e202200314.
16. I. Arenas, A. Ferrali, C. Rodríguez-escrich, F. Bravo and M. A. Pericàs, Adv. Synth. Catal., 2017, 359, 2414–2424.
17. (a) S. B. Ötvös, M. A. Pericàs and C. O. Kappe, Chem. Sci., 2019, 10, 11141–11146; (b) S. B. Ötvös, P. Llanes, M. A. Pericàs and C. O. Kappe, Org. Lett., 2020, 22, 8122–8126; (c) B. S. Nagy, P. Llanes, M. A. Pericàs, C. O. Kappe and S. B. Ötvös, Org. Lett., 2022, 24, 1066–1071.
18. Details for the preparation of 8f and 8k can be found in the ESI.†.
19. S. Brandau, A. Landa, J. Franzén, M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006, 45, 4305–4309.
20. (a) I. T. Raheem, P. S. Thiara, E. A. Peterson and E. N. Jacobsen, J. Am. Chem. Soc., 2007, 129, 13404–13405; (b) M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 10796–10797; (c) M. L. Van Linn and J. M. Cook, J. Org. Chem., 2010, 75, 3587–3599.
21. P. Kowalczyk, B. Gawdzik, D. Trzepizur, M. Szymczak, G. Skiba, S. Raj, K. Kramkowski, R. Lizut and R. Ostaszewski, Materials, 2021, 14, 2956.

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Footnote

† Electronic supplementary information (ESI) available: Synthetic procedure, characterisation data, copies of NMR spectra. CCDC 2159378. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ob01462a

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