Highly Modular Flow Cell for Electroorganic ... - ACS Publications

Subscriber access provided by Fudan University

Full Paper

Highly Modular Flow Cell for Electro-Organic Synthesis Christoph Gütz, Andreas Stenglein, and Siegfried R. R Waldvogel Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017 Downloaded from http://pubs.acs.org on April 26, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Highly Modular Flow Cell for Electro-Organic Synthesis Christoph Gütz, Andreas Stenglein, Siegfried R. Waldvogel* Johannes Gutenberg University Mainz, Institute for Organic Chemistry, Duesbergweg 10-14, 55128 Mainz, Germany

ACS Paragon Plus Environment

1

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 27

Table of Contents Graphic


2

Page 3 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ABSTRACT. A highly modular electrochemical flow cell and its application in electroorganic synthesis is reported. This innovative setup facilitates many aspects; an easy adjustment of electrode distance, quick exchange of electrode material, and the possibility to easily switch between a divided or undivided cell. However, the major benefit of the cell is the exact thermal positioning of the electrode material into a Teflon piece. Thereby, the application of expensive and non-machinable electrode materials like boron-doped diamond or glassy carbon can easily be realized in flow cells. By this geometry, the maximum surface of such valuable electrode materials is exploited. The cell size can compete with classical preparative approaches in terms of performance and productivity. Optimization of reaction parameters and an easy up-scaling to larger flow cells is possible. By using this cell, starting material can be saved in the development of the electroorganic transformations. To demonstrate the utility of this particular cell two transformations of important building blocks for the fine chemical and pharmaceutical industry were established including an efficient and simple work-up protocol.

KEYWORDS. Electroorganic synthesis - flow electrolysis - isoxazole - nitrile - oxidation reduction.

INTRODUCTION The development of novel, efficient and economically benign techniques for the synthesis of fine chemicals and pharmaceutically active agent represents one of the major tasks of a process chemist. Electroorganic synthesis is one of these reemerging technologies. The application of electricity as reagent exhibits several advantages. For example, no oxidant or reducing agent is required, thereby no reagent waste occurs and the atomic efficiency is considerably high.


3


Page 4 of 27

Moreover, electricity is quite inexpensive compared to reducing agents or oxidizers. An excellent carbon footprint can be achieved when electricity originates from renewable energy sources, resulting in a highly sustainable method.1-8 Many novel and powerful transformations were recently published, like dehalogenations,9-14 allylic oxidations,15,16 oxidative cross couplings,17-20 N,N- or N,C-couplings.21 One of the major disadvantages of many electrochemical methods, which are described in literature, are that potentiostatic methods are applied. Up-scaling of these methods is problematic in terms of the three electrode arrangement and additionally results in prolonged reaction times. Therefore, only galvanostatic methods are used on a technical scale.22 As an additional challenge, no standardized and commercially available equipment is on the market and every research group applies their own home-made setup. Recently, we presented an approach for the fast screening of electrolysis parameters on a small batch scale for the development of electrosynthetic transformations.23 Nevertheless, this is only the first step towards the development of novel state-of-the-art processes on a technical scale. Simple up-scaling in larger batch cells is possible, but limited to reactor vessels of a few liters. Larger systems face some major drawbacks: First, efficient mixing, which is significantly important for a heterogeneous transformation, can be challenging in larger vessels. Secondly, heat transfer is hampered, since most heat is generated at and in between the electrodes by the electric resistance where no efficient chilling is possible. Thirdly, the volume-to-surface ratio decreases in larger batches, which limits the contact between substrate and electrode. To tackle these issues, a transfer to a continuous flow setup is desirable and advantageous. First examples for electrosysnthesis in a flow setup are already known, and can be divided into two major categories: On the one hand, micro flow cells are applied with quite low electrode surfaces


4

Page 5 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


and productivity.24-39 On the other hand, long channel flow cells are published, which can convert the substrate in a multi-gram per hour rate.40-47 However, the scope of transformations is limited to such electrolyses that tolerate a wide range of current densities. In both cases only undivided systems were applied. Only one specialized system for the production of an important pharmaceutical intermediate was realized in a divided cell.48 However, it was demonstrated that the transfer is possible and exhibits the following advantages. First, a high surface-to-volume ratio within the cell. Secondly, an adjustable electrode distance to decrease the electric resistance and the amount of supporting electrolyte. Thirdly, instable products can directly be exploited by a single passage through the cell. Fourthly, a good temperature control. Fifthly, a continuous synthesis enabling an up-scaling by increasing the cell or simple numbering up. Thus, the combination of flow chemistry and electrosynthesis represents the best way for large scale electroorganic synthesis. So far, there is no commercially available system with a modular setup, in which different kinds of electrodes can be applied. Therefore, a highly modular electrochemical flow cell is presented, which is now commercially available (see Experimental Section).

Results Our flow cell consists of two Teflon pieces with a size of 100 x 40 x 16 mm. On one side, there is a 60 x 20 x 3 mm open space for the electrode. At the center of the cavity and the backside of the Teflon piece the connection for the power supply can be positioned. A gasket around the electrical connector guarantees that the connector and the electrolyte do not come in contact. This precaution avoids potential corrosion issues. The electrode (size 60 x 20 x 3 mm) is positioned into the cavity, so that its surface is co-planar with the Teflon piece. This can easily be achieved by thermal positioning using the following protocol: Teflon is heated up to 200 °C whereby the


5


Page 6 of 27

material expands strongly. The cold electrode is inserted. Upon reaching ambient temperature, the Teflon contracts and seals the gap between electrode and Teflon. The soft and partially fluid behavior of this particular polymer are beneficial. This thermal insertion ensures a very tight fit. Removal of the electrode can likewise be performed upon thermal treatment. At both ends of the Teflon-encased electrode there are inlets/outlets for the electrolyte, which can be connected to the tubing. The electrolyte is distributed via dendritic feeder at the top providing a sufficient flow across the electrode surface.

Figure 1: a) Cross-section of the Teflon piece with connection for tubing, inlet, outlet and free space for electrode. b) Complete half-cell containing the Teflon piece, the electrode and a


6

Page 7 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


stainless steel plate. c) Half-cell with gasket/spacer on top. d) Exploded drawing of a complete divided cell. For the undivided mode, the Nafion membrane and one gasket/spacer is omitted. On top of the Teflon piece, a gasket with variable height can be installed so that the gap between the electrode and the counter electrode can be adjusted between 0.12 mm (Teflon based gaskets) and up to 2.0 mm (EPDM gaskets). By using two spacers and a Nafion® membrane, a divided mode for the electrolysis cell is possible. A little overlap of the gasket with the electrode at the longitudinal side can seal the corners of the electrode, if necessary. Additionally, by application of pressure later the co-planar arrangement of electrode and Teflon piece is secured. When the second Teflon piece with the counter electrode is installed at the top by eight screws and two stainless steel plates, both electrodes press each other in the Teflon piece via the gasket. By this design, the electrodes need no positioning by screws, which provides an advantage for brittle materials like boron-doped diamond, graphite or glassy carbon. This setup provides an easy to use way to adjust the electrode distance, switching between a divided or undivided cell as well as simple exchange of electrode material. We equipped the system with common electrode materials such as platinum, gold, copper, nickel, stainless steel, leaded bronze (CuSn7Pb15), lead, glassy carbon, boron-doped diamond, and graphite. For pumping the electrolyte through gap of the flow cell, a membrane or peristaltic pump can be applied. Common commercially available DC power supplies can be used (0-60 V, see Experimental Section). To demonstrate the applicability and the performance of this modular cell, two test reactions were investigated. For the application of an undivided flow cell, we decided to establish a protocol for a domino-oxidation-reduction reaction we recently developed in batch.49 In this transformation oxime 1 is first oxidized at a graphite anode to the corresponding nitrile-N-oxide 2 and then reduced directly at the cathode to the desired nitrile 3. This electrochemical sequence is an


7


Page 8 of 27

excellent example for the ability of electrosynthesis to avoid harsh reaction conditions and reagent waste since commonly P4O10, thionyl chloride, acetic anhydride and other corrosive reagents have to be applied for the same transformation in conventional synthesis.50 As starting material for the flow cell process, 2,6-dichlorobenzaldoxime 1 was chosen. This represents a quite challenging derivative since in batch over-reduction to the monochloro by-product is observed. Furthermore, the yield in batch is only 40%.49

Figure 2: Domino-oxidation-reduction sequence for the synthesis of nitriles from aldoximes. As initial parameters for our studies we employed the optimized conditions from the batch process.49 Acetonitrile und methyl-tri-propylammonium methylsulfate (MTPS) served as electrolyte. Lead was used as cathode and graphite as anode material. The gap between the electrodes was 1 mm. An applied electricity of 2.47 F and a current density of 10 mA/cm2 were selected. The conversion was monitored by gas chromatography. Table 1. Optimization of domino oxidation reduction sequence in flow gap cell.a Flow Current density [mL/h] [mA/cm2]

Spacer [mm]

Yieldb (%)

Entry

Electrolyte MTPS in CH3CN/H2O

1c

0.012 M in 1:0

15

10

1

3 (18%), 2 (8%), 1 (19%), by-productsf (15%)

2c

0.012 M in 1:0

7.5

5

1

3 (8%), 2 (29%), 1 (0%), byproductsf (40%)

3c

0.012 M in 4:1

15

10

1

3 (20%), 2 (31%), 1 (33%)


8

Page 9 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4c

0.012 M in 4:1

7.5

5

1

3 (25%), 2 (34%), 1 (29%)

5c

0.012 M in 4:1

15

10

0.12

3 (21%), 2 (0%), 1 (52%), by-productsf (6%)

6c

0.012 M in 4:1

7.5

5

0.12

3 (39%), 2 (0%), 1 (31%), by-productsf (8%)

7c

0.1 M in 4:1

15

10

0.12

3 (32%), 2 (0%), 1 (30%), by-productsf (6%)

8c

0.1 M in 4:1

7.5

5

0.12

3 (58%), 2 (0%), 1 (11%), by-productsf (17%)

9c,d

0.0 M in 4:1

7.5

5

0.12

3 (30%), 2 (0%), 1 (46%)

10e

0.0 M in 11:1

8.5

5

0.12

3 (80%), 2 (0%), 1 (7%)

a

Reaction conditions: 1.38 g (7.26 mmol) 2,6-dichlorobenzaldoxime in 60 mL electrolyte, cathode: lead, anode: isostat. graphite, electrode surface 12 cm2, room temperature. bDetermined by GC integrals. cApplied electricity 2.47 F. dElectrolyte temperature: room temperature or 50°C. e Applied electricity 2.18 F. fSum of mono- and twofold dehalogenated product.

Initially, the gas chromatogram indicates a significant amount of dehalogenated by-product (Tab. 1, Entry 1). A similar result was achieved with a lower current density and a corresponding reduced flow rate (Tab. 1, Entry 2). Further observed by-products are dimerized or dehalogenated nitrile-N-oxide and unidentified decomposition products of 3, 2, and 1. They might be formed during both, electrolysis or injection into GC. By addition of water (ratio CH3CN:H2O = 4:1) the dehalogenated by-product could be efficiently suppressed (Tab. 1, Entries 3+4). Nevertheless, only a small amount of product 3 was obtained in respect to the starting material 1 and nitrile-N-oxide 2. The large amount of intermediate 2 indicates that the reduction to the nitrile at the cathode or the diffusion from anode to cathode was not sufficient. Thus, we replaced the EPDM-based spacer with a thickness of 1 mm by a Teflon spacer providing a gap of 0.12 mm to analyze the issue of diffusion between the electrodes (Tab. 1, Entries 5+6). Indeed, no nitrile-N-oxide 2, but more product 3, was identified, especially for a current density of 5 mA/cm2. To identify whether the


9


Page 10 of 27

amount of supporting electrolyte has an influence on the outcome of the electrochemical conversion, an elevated concentration of supporting electrolyte was applied. This led to an almost complete conversion of starting material 1 to the desired product 3, but also promoted the dehalogenation as side reaction (Tab. 1, Entries 7+8). However, the use of no supporting electrolyte in a 4:1 mixture of acetonitrile/water was successful with a similar applied voltage of about 6 V. A mixture of starting material and product was obtained, but no dehalogenated byproduct was traced (Tab. 1, Entry 9). This finding demonstrates that the selectivity without supporting electrolyte is much better, but mass transfer from anodic to cathodic regimes seems to be inefficient. To increase mass transfer, the electrolyte mixture was pre-heated to 50 °C and then employed in the electrochemical conversion. However, no change in the product composition was observed, which underlines that the mass transfer is not problematic. A major drain of electricity at the electrodes is attributed to the electrolysis of water. Consequently, by lowering the amount of water within the electrolyte this pathway was efficiently suppressed. However, for sufficient conductivity and suppression of the dehalogenation pathway to by-products a minimal amount of water is required. Best results were found when a ratio of acetonitrile to water 11:1 was employed (Tab. 1, Entry 10). Actually, this was the key finding to ensure a complete conversion of starting material with an excellent selectivity. Even less applied electricity was necessary to achieve an excellent conversion, reducing the retention time of the substrate in the cell down to 60 seconds. To determine the yield of the process, 60 mL of electrolyte was applied and collected after passing the flow cell. By applying two separate cells and connect them in a serial fashion the electrode surface can be increased from 12 to 24 cm2 (setup see SI). This reduced the reaction time and demonstrates the facile scalability of this setup. Thereby, the flow rate was doubled to 17 mL/h


10

Page 11 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


and reaction time was reduced to 3.5 h for 60 mL of solution. The productivity increased from 110 mg/h (12 cm2 electrode surface) to 220 mg/h (24 cm2 electrode surface).

Figure 3: Concept of the work-up protocol. Due to the high selectivity of the transformation a facile work-up protocol of the slightly yellow solution could be applied (Figure 3). After electrolysis (Figure 4, in black), the solvent was removed at reduced pressure (50 °C, 100 mbar) to obtain the crude product. The solvent can be directly reused for subsequent electrolyses. Recrystallization of 3 from ethanol/water (2:1) at –30 °C gave the pure product in 63% yield (Figure 4, in green).


11


Page 12 of 27

Figure 4: Black: Gas chromatographic analysis of the electrolyte directly after passing the flow cell. Green: Gas chromatographic analysis after crystallization. Compared to the batch process, the yield could be significantly increased from 41% to 63%, respectively.49 Furthermore, the work-up protocol is simple and no column chromatography is required. With respect to sustainability issues, this process is exceptional since only electricity and recyclable solvents are used. No supporting electrolyte or other reagents are necessary.

To test this flow cell for its applicability in a divided mode, we studied a second transformation. As starting material, we used the same oxime 1 as before. The divided cell setup including a separator will intercept the reduction of the nitrile-N-oxide 2 to the nitrile 3 at the cathode. Consequently, the nitrile-N-oxide 2 was accumulated in the anolyte. 2 is an excellent precursor for


12

Page 13 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1,3-dipolar cycloadditions.51-54 As reaction partner we chose methyl acetoacetate 4, since the corresponding product 5 serves as an important building block in pharmaceutical applications, e.g. for the synthesis of the penicillin derivative dicloxacillin 6 (Fig. 5) or novel FXR agonists.51,55,56

Figure 5: Electrochemical oxidation in a divided cell followed by a 1,3-dipolar cycloaddition and further formal transformation to dicloxacillin 6.57 Beside the implementation of an electrochemical process into the transformation, we tried to circumvent time-consuming purification steps upon generation of the nitrile-N-oxide 2. Since in the previous process, 2 was already observed as an intermediate, we decided to test first the conditions used in the previous synthesis, wherein 2 was already observed as an intermediate. Initially, it was important to elucidate if the cycloaddition can be performed in the established solvent mixture. Hence, we ran some test reactions with nitrile-N-oxide 2 as starting material in different electrolyte compositions (Table 2).

Table 2. Optimization of cycloaddition: variation of the electrolyte.a


13


Entry


Base

Yield 5b

1

0.1 M in 1:0

-

-

2

0.1 M in 1:0

NEt3

-

3

0.1 M in 4:1

-

-

4

0.1 M in 4:1

NEt3

100%

Page 14 of 27

a

Reaction conditions: 30 mg (0.16 mmol) 2, 28 mg (0.24 mmol) methyl acetoacetate (4), 5 mL solvent, 22 mg (30.5 µL, 0.22 mmol) NEt3, 134 mg (0.5 mmol) MTPS. Reaction time 1 h at 22 °C. b Determined by GC integrals.

The test reactions revealed that cycloaddition is possible and highly selective in a mixture of acetonitrile/water (4:1) and triethylamine (Table 2, Entry 4). Without water or triethylamine no conversion was observed (Table 2, Entry 1-3). Subsequently, we focused on the optimization of the electrochemical oxidation to the nitrile-Noxide 2. Since in a flow process the parameters current density, flow rate and applied electricity are not independent, it is more efficient to start the initial screening with batch-type cells. As catholyte the previous mixture for the transformation in the undivided cell was applied, the anolyte consisted of a mixture of acetonitrile, water and MTPS combined with 4 and triethylamine. As cathode stainless steel and graphite as anode were employed at a current density of 10 mA/cm2 and an applied electricity of 2.5 F. Formation of the desired nitrile-N-oxide 2 was observed in significant amounts, but no cyclization to isoxazole 5 occurred (Table 3, Entry 1). This result suggested that triethylamine or 4 are decomposed during electrolysis before reacting with 2. We then decided to separate both transformations and run the electrosynthesis without addition of triethylamine and 4 and add them directly after electrolysis (Table 3, Entry 2). A significant increase of isoxazole 5 was detected, demonstrating that addition, after electrolysis is preferable. Nevertheless, a large amount of starting material was still not consumed. A possible reason for this


14

Page 15 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


could be the fact that during electrolysis the formation of a thin film on the graphite anode was observed, which dissolved afterwards. This film formation or fouling can also be problematic for a later flow electrolysis and should definitely be avoided. A gas chromatographic analysis of this film revealed that pure 2 crystallized onto the electrode surface. It turned out, that water in the electrolyte decreased the solubility of 2. However, water is only required for the successful cyclization and not for the electrolysis in the anodic compartment. So, we excluded the water from the anolyte. In contrast, for the catholyte the water is important, so that hydrogen can be evolved at the cathode instead of decomposing the supporting electrolyte. By applying acetonitrile and MTPS as anolyte and addition of water, triethylamine and 4 upon electrolysis we achieved the desired isoxazole 5 in a high selectivity (Table 3, Entry 3). This demonstrated that water in the anolyte had a quite negative effect onto the conversion. Table 3. Optimization of electrolysis parameters in batch cell.1 Entry


Addition for Cyclization

Yieldd (%)

1a,e

0.063 M in 4:1

Prior electrolysis

5 (0%), 2 (52%), 1 (23%)

2b,e

0.063 M in 4:1

After electrolysis

5 (17%), 2 (0%), 1 (30%)

3c,e

0.063 M in 1:0

After electrolysis

5 (69%), 2 (0%), 1 (4%)

a

Additive solution added before electrolysis: 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol) NEt3.

b

Additive solution after electrolysis: 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol) NEt3.

c

Additive solution after electrolysis: 7 mL H2O, 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol) NEt3. d e

Determined by GC integrals.

Anolyte: 600 mg (3.16 mmol) 1, 35 mL solvent, 600 mg (2.23 mmol) MTPS. Catholyte: 28 mL

CH3CN, 7 mL H2O, 600 mg (2.23 mmol) MTPS.


15


Page 16 of 27

With these optimized parameters in hand, we started to transfer the process to the flow electroysis cell. As spacer between the electrodes and the Nafion® 324 separator we used a 1 mm EPDM foil for each half-cell. To evaluate the efficiency of the flow electrolysis we first focussed on the formation of the nitrile-N-oxide 2 without later cyclization. Table 4. Optimization of flow parameters for electrolysis.a Entry

Electrolyte MTPS in CH3CN

Flow [mL/h ]

Current density Applied Spacer [mA/cm2] electricity [F] [mm]

1

0.1 M

18.5

10

2

1

2 (26%), 1 (26%)

2

0.1 M

9.5

10

3.9

1

2 (34%), 1 (14%)

3

0.1 M

14.5

8

2

1

2 (29%), 1 (27%)

4

0.1 M

9.5

5

2

1

2 (40%), 1 (23%)

5

0.1 M

7.5

5

2.48

1

2 (47%), 1 (16%)

6

0.012 M

8.5

5

2.18

1

2 (62%), 1 (12%)

7

0.012 M

8.5

5

2.18

0.12

2 (27%), 1 (48%)

8

0.012 M

8.5

5

2.18

0.25

2 (10%), 1 (44%)

Yieldb (%)

a

Reaction conditions: anolyte: 1.38 g (7.26 mmol) 1, 60 mL acetonitrile, supporting electrolyte MTPS. Catholyte: 55 mL CH3CN, 5 mL H2O, supporting electrolyte MTPS. Anode: graphite, cathode: stainless steel. Electrode surface: 12 cm2. bDetermined by GC integrals. Initially, electrolyte composition was kept constant with a high concentration of supporting electrolyte. In addition, we analyzed the influence of different flow rates, current densitiy and applied electricity. It turned out that the best results were achieved at a current density of 5 mA/cm2, a flow rate of 7.5 mL/h and 2.48 F (Table 4, Entry 5). Comparable results were obtained at higher flow rates and less applied electricity (Table 4, Entry 4). Higher current densities and higher flow rates, however, led to a diminished production of nitrile-N-oxide 2 (Table 4, Entries 1-3). A decrease in the amount of supporting electrolyte to a concentration of 0.012

M

of MTPS

gave the best result for the transformation (Table 4, Entry 6). Only when no supporting electrolyte


16

Page 17 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


was applied the cell voltage increased and the conversion decreased over a period of time, which is due to a nitrile-N-oxide film formation on the graphite electrode. This effect is hampered by the addition of supporting electrolyte. It is remarkable that a narrower gap between the electrode and the Nafion® membrane of 0.25 or 0.12 mm decreases the efficiency of the process (Table 4, Entries 7 and 8). A reason could be the hydrogen evolution at the stainless steel cathode, which leads to fast generation of bubbles and conductivity problems, especially at higher current density. Another reason for the lower rate of conversion could be the decrease of the retention time from 8.5 min to 2.1 (0.25 mm gap) or 1.0 min (0.12 mm). For the determination of yield for the best electrolysis conditions (Table 4, Entry 6) we collected 60 mL of the electrolyte solution after passing the flow cell and added the corresponding amount of triethylamine, water and 4 and stirred the solution for 1.5 h at 22 °C. Again, it is also possible to combine two separate flow cells in a serial manner to increase the electrode surface from 12 cm2 to 24 cm2 (see setup in the SI). Thereby, the flow rate can be doubled, reaction time reduced to half and the productivity increased from 176 mg/h to 353 mg/h. In the end, online mixing of trapping mixture after electrolysis is viable by extra pumping (for triethylamine and water, and for 4, respectively, due to stability issues of 4 in basic media. Schematic setup see SI). As described above, cyclization occurred very fast and efficiently resulting in a full conversion of the nitrile-N-oxide 2 to 5. For work-up, we removed the solvent at reduced pressure. Fractioning of layers was achieved by addition of ethyl acetate (Figure 6). To remove possible polymeric byproducts we filtered through a pad of silica gel (eluent ethyl acetate: cyclohexane, 1:1) and removed the solvents (100 mbar, 50 °C) and volatile by-products at reduced pressure (75-80 °C, 1 * 10-3 mbar). The residue was distilled (100 °C, 1 * 10-3 mbar) or crystallized from n-heptane to obtain the highly pure product (99% GC) as colorless solid in a yield of 60% (Figure 7). The same


17


Page 18 of 27

yield was obtained in a batch cell, which indicates that the transfer of the process into a flow cell can be realized without loss of yield. Additionally, in comparison to the conventional synthesis of this building block, the yield could be slightly increased from 53 to 60%.55

Figure 6: Strategy for work-up when trapping 2 as isoxazole 5.

In addition to the increase of yield, the avoidance of reagent waste and work-up between the generation of nitrile-N-oxide 2 and cyclization to isoxazole 5 saves time and makes this electrochemical transformation much more sustainable and economic.


18

Page 19 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 7: Gas chromatographic analysis: Black: after passing the flow cell and prior trapping. Green: 1.5 h after addition of 4, H2O and NEt3. Red: After distillation at 100°C, 1*10-3 mbar or crystallization from n-heptane.

In summary, we were able to establish a novel highly modular flow cell for the transfer of electroorganic conversions from batch cells to flow system. The setup allows easy adjustment of electrode materials, electrode gap and flow. By thermal positioning of the electrode into the Teflon frame even non-machinable electrode materials like boron-doped diamond or glassy carbon can be applied. Additionally, the cell can operate in an undivided or a divided mode, which increases


19


Page 20 of 27

the utility of electrosynthesis in flow enormously. Fast determination of the process parameters in a small, economic scale can be realized. Thereby, the setup represents the first step towards process development of electroorganic transformations. This was demonstrated by the development of two electrochemical conversions in flow. For both an increased yield was obtained, which exhibit the potential of electrochemistry in organic synthesis.

Experimental Section

General Information. 2,6-Dichlorobenzaldoxime (97% purity, Abcr) and acetonitrile (HPLCgrade, Fluka) are commercially available and were used without further purification. Methyl-tripropylammonium methyl sulfate (MTPS) was synthesized accordingly to methyl-triethylammonium methylsulfate (MTES) in 90% yield.17 1H NMR and

13

C NMR spectra were

recorded at 25 °C by using a Bruker AV II 400 (Bruker, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces of CHCl3 in the corresponding deuterated solvent. Gas chromatography was performed on a Shimadzu GC-2025 (Shimadzu, Japan) using a ZB-5 column (Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 mm, carrier gas: hydrogen). As power source a Z60-3.5 (TDK Lambda, Achern, Germany; dc output 0-60 V (±0.01V and 03.5 A (±1 mA) was applied. The electric current was adjusted for the given current density, whereas the voltage was set freely. For pumping the electrolytes membrane pumps “Dosierpumpe Ritmo R 033/7-16” (Fink Chem + Tec GmbH & Co.KG, Leinfelden-Echterdingen, Germany) were used. Recently, the electrochemical flow cell is commercially available as ElectraSyn flow from IKA

Werke

GmbH

&

Co.

KG,

Staufen,

Germany


20

Page 21 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(http://www.ikaprocess.de/Produkte/Kontinuierliche-Elektrosynthese-cph-45/). Filtration column chromatography was performed on silica gel 60 M (0.060-0.200 mm, Macherey-Nagel GmbH & Co, Düren, Germany). As eluent a mixture of ethyl acetate and cyclohexane was used. Synthesis of 2,6-dichlorobenzonitrile 3. 1.38 g (7.26 mmol) 2,6-dichlorobenzaldoxime 1 were dissolved in 55 mL acetonitrile and 5 mL deionized water and pumped via a membrane pump through the electrochemical flow gap cell equipped with a lead cathode, an isostatic graphite anode (electrode surface 12 cm2) and a 0.12 mm Teflon spacer without any separator membrane. A current density of 5 mA/cm2 (I = 60 mA) and a flow rate of 8.5 mL/h were applied which corresponds to an applied electricity of 2.18 F. Alternatively, two electrochemical flow cells were connected in series, which lead to a flow rate of 17 mL/h and a current I = 2 x 60 mA = 120 mA). After passing the flow cell, the solvent was removed under reduced pressure and the residue (1.172 g) was recrystallized from ethanol / water (2:1, 17 mL) at -30 °C and washed with further 30 mL of the mixture. Drying under reduced pressure gave the desired product 3 as colorless needles in 62% yield (774 mg, 4.5 mmol). Analytical data are in accordance with the literature.49 Synthesis of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate 5 via batch electrolysis. The electrolysis was performed in a divided glass cell with a Nafion® 324 separator (see SI) and an isostatic graphite anode and a lead cathode (total size 20 x 70 x 3 mm, immersion depth 20 x 40 x 3 mm). The current density j was 10 mA/cm2, which corresponds to a current I of 80 mA, and the applied electricity was 2.18 F (664 C). As catholyte, a solution of 28 mL acetonitrile, 7 mL deionized water and 600 mg (2.23 mmol) MTPS was applied. As anolyte a solution of 600 mg (3.16 mmol) 2,6-dichlorobenzaldoxime 1, 35 mL acetonitrile and 600 mg (2.23 mmol) MTPS was used. After electrolysis the solution was transferred to a round bottom flask and a freshly prepared solution of 560 mg (4.82 mmol) methyl acetylacetonate 4, 7 mL water and 560


21


Page 22 of 27

µl (4.02 mmol) triethylamine was added and stirred for 1.5 h at 22°C. The work-up protocol was similar to that of the flow protocol. Synthesis of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate 5 via flow electrolysis. For the catholyte, 0.2 g (0.74 mmol) methyl-tri-ethylammonium methylsulfate (MTPS) were dissolved in 55 mL acetonitrile and 5 mL deionized water. For the anolyte, 1.38 g (7.26 mmol) 2,6-dichlorobenzaldoxime 1 and 0.2 g (0.74 mmol) methyl-tri-ethylammonium methylsulfate (MTPS) were dissolved in 60 mL acetonitrile. Each solution was pumped via membrane pump through the electrochemical flow gap cell equipped with a stainless steel cathode, an isostatic graphite anode (electrode surface 12 cm2) and two 1 mm EPDM spacer (each between the half-cell Teflon piece and the membrane) with a Nafion® 324 separator membrane. A current density of 5 mA/cm2 (I = 60 mA) and a flow rate of 8.5 mL/h were applied which corresponds to an applied electricity of 2.18 F. Alternatively, two electrochemical flow cells were stacked which lead to a flow rate of 17 mL/h and a current I = 2 x 60 mA = 120 mA). After passing the flow cell 1.026 g (8.8 mmol, 1.2 equiv.) acetoacetate methyl ester, 2.1 mL (1.53 g, 15.15 mmol, 2.1 equiv.) triethylamine and 12 ml deionized water were added and the solution was stirred for 1.5 h at room temperature (22 °C). The solvent was removed under reduced pressure and the residue was dissolved in 50 mL ethyl acetate and 50 mL water. The organic phase was separated and the aqueous phase extracted two time with 50 mL ethyl acetate. The combined organic phases were washed with 50 mL brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was filtered through a pad of silica (3.5 cm Ø, 3 cm2 height), eluent 70 mL ethylacetate / cyclohexane 1:1. Solvent was removed under reduce pressure and volatile impurities were distilled at 75-80°C and 1 * 10-3 mbar. Distillation at 100 °C and 1 * 10-3


22

Page 23 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mbar or crystallized from n-heptane (15 mL) provides the desired product 5 as white crystals in 60% yield (1.247 g, 4.36 mmol). Analytical data match to the literature.51


23


Page 24 of 27

ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Technical and explosion drawings and pictures of modular flow gap cell (PDF)

AUTHOR INFORMATION Corresponding Author * E-Mail: [email protected]. Phone: +49 6131 39 26069. ORCID: 0000-0002-79499638

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources Federal Ministry of Education and Research project MANGAN (FKZ 03S0506). Federal Ministry of Education and Research project EPSYLON (FKZ 13XP5016D). Carl-Zeiss-Stiftung project ELYSION. ABBREVIATIONS MTPS = tripropylmethylammonium methyl sulfate [Pr3MeN]OSO3Me. REFERENCES


24

Page 25 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(1) Steckhan, E.; Arns, T.; Heineman, W. R.; Hilt, G.; Hoormann, D.; Jörissen, J.; Kröner, L.; Lewall, B.; Pütter, H. Chemosphere 2001, 43, 63. (2) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301. (3) Sheldon, R. A. Green Chem. 2007, 9, 1273. (4) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Green Chem. 2010, 12, 2099. (5) Schäfer, H. J.; Harenbrock, M.; Klocke, E.; Plate, M.; Weiper-Idelmann, A. Pure Appl. Chem. 2007, 79, 2047. (6) Schäfer, H. J. C. R. Chim. 2011, 14, 745. (7) Yoshida, J.-i.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265. (8) Waldvogel, S. R.; Janza, B. Angew. Chem. Int. Ed. 2014, 53, 7122. (9) Raess, P. W.; Mubarak, M. S.; Ischay, M. A.; Foley, M. P.; Jennermann, T. B.; Raghavachari, K.; Peters, D. G. J. Electroanal. Chem. 2007, 603, 124. (10) Wolf, N. L.; Peters, D. G.; Mubarak, M. S. J. Electrochem. Soc. 2006, 153, E1. (11) Peters, D. G. In Organic Electrochemistry; 4th ed.; Lund, H., Hammerich, O., Eds.; Marcel Dekker: New York, 2001, p 341. (12) Beck, F. In Elektroorganische Chemie; Beck, F., Ed.; Akademie-Verlag: Berlin, 1974, p 183. (13) Torii, S. In Electroorganic Reduction Synthesis; Torii, S., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2006, p 331. (14) Gütz, C.; Selt, M.; Bänziger, M.; Bucher, C.; Römelt, C.; Hecken, N.; Gallou, F.; Galvão, T. R.; Waldvogel, S. R. Chem. Eur. J. 2015, 21, 13878. (15) Waldvogel, S. R.; Selt, M. Angew. Chem. Int. Ed. 2016, 55, 12578. (16) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77. (17) Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2014, 53, 5210. (18) Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2010, 49, 971. (19) Wiebe, A.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2016, 55, 11801. (20) Lips, S.; Wiebe, A.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2016, 55, 10872. (21) Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2016, 55, 9437. (22) Pütter, H. In Organic Electrochemistry; 4th ed.; Lund, H., Hammerich, O., Eds.; Marcel Dekker: New York, 2001, p 1259. (23) Gütz, C.; Klöckner, B.; Waldvogel, S. R. Org. Process Res. Dev. 2016, 20, 26. (24) Bouzek, K.; Jiřičný, V.; Kodým, R.; Křišťál, J.; Bystroň, T. Electrochim. Acta 2010, 55, 8172. (25) Ziogas, A.; Kolb, G.; O’Connell, M.; Attour, A.; Lapicque, F.; Matlosz, M.; Rode, S. J. Appl. Electrochem. 2009, 39, 2297. (26) Attour, A.; Dirrenberger, P.; Rode, S.; Ziogas, A.; Matlosz, M.; Lapicque, F. Chem. Eng. Sci. 2011, 66, 480. (27) Watts, K.; Baker, A.; Wirth, T. J. Flow. Chem. 2014, 4, 2. (28) Suga, S.; Okajima, M.; Fujiwara, K.; Yoshida, J.-i. J. Am. Chem. Soc. 2001, 123, 7941.


25


Page 26 of 27

(29) Yoshida, J.-i. Chem. Commun. 2005, 4509. (30) Horii, D.; Atobe, M.; Fuchigami, T.; Marken, F. J. Electrochem. Soc. 2006, 153, D143. (31) Horcajada, R.; Okajima, M.; Suga, S.; Yoshida, J.-i. Chem. Commun. 2005, 1303. (32) Horii, D.; Amemiya, F.; Fuchigami, T.; Atobe, M. Chem. Eur. J. 2008, 14, 10382. (33) Suga, S.; Okajima, M.; Fujiwara, K.; Yoshida, J.-i. QSAR & Combinatorial Science 2005, 24, 728. (34) Kashiwagi, T.; Amemiya, F.; Fuchigami, T.; Atobe, M. Chem. Commun. 2012, 48, 2806. (35) Watts, K.; Gattrell, W.; Wirth, T. Beilstein J. Org. Chem. 2011, 7, 1108. (36) Arai, K.; Watts, K.; Wirth, T. ChemistryOpen 2014, 3, 23. (37) Kashiwagi, T.; Elsler, B.; Waldvogel, S. R.; Fuchigami, T.; Atobe, M. J. Electrochem. Soc. 2013, 160, G3058. (38) Atobe, M. Current Opinion in Electrochemistry 2017, 2, 1. (39) Arai, T.; Tateno, H.; Nakabayashi, K.; Kashiwagi, T.; Atobe, M. Chem. Commun. 2015, 51, 4891. (40) Green, R.; Brown, R.; Pletcher, D. J. Flow. Chem. 2015, 5, 31. (41) Hill-Cousins, J. T.; Kuleshova, J.; Green, R. A.; Birkin, P. R.; Pletcher, D.; Underwood, T. J.; Leach, S. G.; Brown, R. C. D. ChemSusChem 2012, 5, 326. (42) Green, R. A.; Brown, R. C. D.; Pletcher, D. J. Flow. Chem. 2016, 6, 191. (43) Chapman, M. R.; Shafi, Y. M.; Kapur, N.; Nguyen, B. N.; Willans, C. E. Chem. Commun. 2015, 51, 1282. (44) Kuleshova, J.; Hill-Cousins, J. T.; Birkin, P. R.; Brown, R. C. D.; Pletcher, D.; Underwood, T. J. Electrochim. Acta 2012, 69, 197. (45) Kuleshova, J.; Hill-Cousins, J. T.; Birkin, P. R.; Brown, R. C. D.; Pletcher, D.; Underwood, T. J. Electrochim. Acta 2011, 56, 4322. (46) Stalder, R.; Roth, G. P. ACS Medicinal Chemistry Letters 2013, 4, 1119. (47) Roth, G. P.; Stalder, R.; Long, T. R.; Sauer, D. R.; Djuric, S. W. J. Flow. Chem. 2013, 3, 34. (48) Gütz, C.; Bänziger, M.; Bucher, C.; Galvão, T. R.; Waldvogel, S. R. Org. Process Res. Dev. 2015, 19, 1428. (49) Hartmer, M. F.; Waldvogel, S. R. Chem. Commun. 2015, 51, 16346. (50) Mowry, D. T. Chem. Rev. 1948, 42, 189. (51) Huang, H.; Si, P.; Wang, L.; Xu, Y.; Xu, X.; Zhu, J.; Jiang, H.; Li, W.; Chen, L.; Li, J. ChemMedChem 2015, 10, 1184. (52) Dadiboyena, S.; Xu, J.; Hamme Ii, A. T. Tetrahedron Lett. 2007, 48, 1295. (53) Sheng, S.-R.; Liu, X.-L.; Xu, Q.; Song, C.-S. Synthesis 2003, 2003, 2763. (54) Epple, R.; Russo, R.; Azimioara, M.; Cow, C.; Xie, Y.; Wang, X.; Wityak, J.; Karanewsky, D.; Gerken, A.; Iskandar, M.; Saez, E.; Martin Seidel, H.; Tian, S.-S. Bioorganic & Medicinal Chemistry Letters 2006, 16, 4376. (55) Genin, M. J.; Bueno, A. B.; Agejas Francisco, J.; Manninen, P. R.; Bocchinfuso, W. P.; Montrose-Rafizadeh, C.; Cannady, E. A.; Jones, T. M.; Stille, J. R.; Raddad, E.; Reidy, C.; Cox, A.; Michael, M. D.; Michael, L. F. J. Med. Chem. 2015, 58, 9768. (56) Chen, W.; Huang, Y.-j.; Gundala, S. R.; Yang, H.; Li, M.; Tai, P. C.; Wang, B. Biorg. Med. Chem. 2010, 18, 1617. (57) Singh, G. R.; Suyog, J.; Vardhman Chemtech Ltd., WO2012164355 (A1).


26

Page 27 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



27

Highly Modular Flow Cell for Electroorganic ... - ACS Publications

Recommend Documents