doi.org/10.26434/chemrxiv.13584962.v1

Sustainable Electrochemical Decarboxylative Acetoxylation ofAminoacids in Batch and Continuous FlowManuel Köckinger, Paul Hanselmann, Dominique M. Roberge, Pierro Geotti-Bianchini, C. Oliver Kappe, DavidCantillo

Submitted date: 15/01/2021 • Posted date: 18/01/2021Licence: CC BY-NC-ND 4.0Citation information: Köckinger, Manuel; Hanselmann, Paul; Roberge, Dominique M.; Geotti-Bianchini, Pierro;Kappe, C. Oliver; Cantillo, David (2021): Sustainable Electrochemical Decarboxylative Acetoxylation ofAminoacids in Batch and Continuous Flow. ChemRxiv. Preprint.https://doi.org/10.26434/chemrxiv.13584962.v1

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredientsand synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation ofaliphatic carboxylic acids, which entails the generation of a new C(sp3)-O bond. This reaction has beentraditionally carried out using excess amounts of harmful lead(IV) acetate. A sustainable alternative tostoichiometric oxidants is the Hofer-Moest reaction, which relies in the 2-electron anodic oxidation of thecarboxylic acid. However, examples showing electrochemical acetoxylation of amino acids are scarce. Hereinwe present a general and scalable procedure for the anodic decarboxylative acetoxylation of amino acids inbatch and continuous flow mode. The procedure has been applied to the derivatization of several natural andsynthetic amino acids, including key intermediates for the synthesis of active pharmaceutical ingredients.Good to excellent yields were obtained in all cases. Transfer of the process from batch to a continuous flowcell signficantly increased reaction throughput and space-time yield, with excellent product yields obtainedeven in a single-pass. The sustainability of the electrochemical protocol has been examined by evaluating itsgreen metrics. Comparison with the conventional method demonstrates that an electrochemical approach hasa significant positive effect on the greenness of the process

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Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow

Manuel Köckinger,ab Paul Hanselmann,c Dominique M. Roberge,c Pierro Geotti-Bianchini,c C. Oliver Kappe*ab and David Cantillo*ab

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredients and

synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation of aliphatic carboxylic

acids, which entails the generation of a new C(sp3)-O bond. This reaction has been traditionally carried out using excess

amounts of harmful lead(IV) acetate. A sustainable alternative to stoichiometric oxidants is the Hofer-Moest reaction, which

relies in the 2-electron anodic oxidation of the carboxylic acid. However, examples showing electrochemical acetoxylation

of amino acids are scarce. Herein we present a general and scalable procedure for the anodic decarboxylative acetoxylation

of amino acids in batch and continuous flow mode. The procedure has been applied to the derivatization of several natural

and synthetic amino acids, including key intermediates for the synthesis of active pharmaceutical ingredients. Good to

excellent yields were obtained in all cases. Transfer of the process from batch to a continuous flow cell signficantly increased

reaction throughput and space-time yield, with excellent product yields obtained even in a single-pass. The sustainability of

the electrochemical protocol has been examined by evaluating its green metrics. Comparison with the conventional method

demonstrates that an electrochemical approach has a significant positive effect on the greenness of the process.

INTRODUCTION

Organic acetates are widespread among natural products,

where the acetoxy group typically plays a significant role in their

bioactivity.1 In fact, decoration of active molecules with acetoxy

moieties can improve their biological properties.1,2 Not

surprisingly, many synthetic and semi-synthetic acetoxy-

containing compounds are important active ingredients utilized

as pharmaceuticals,3 agrochemicals4 and other fine chemical

end products (Fig. 1). The presence of the acetoxy group in

pharmaceuticals often modulates their solubility and

pharmacokinetics, optimizing pharmacological and

physiochemical properties.5 Additionally, organic acetates can

also serve as intermediates for the synthesis of more complex

scaffolds, due to the ease with which the C(sp3)-OAc functional

group can be replaced by a range of nucleophiles in Lewis acid

catalyzed substitution reactions.6

Synthesis of acetates is very often carried out by acetylation

of alcohols using Ac2O or AcCl. When suitable hydroxyl groups

are not available, an alternative approach for the generation of

these valuable moieties is the decarboxylative acetoxylation of

aliphatic carboxylic acids. This strategy enables facile

generation of N,O-acetals from abundant amino acids, in

addition to other useful transformations. Several procedures

for the decarboxylative acetoxylation of carboxylic acids have

been developed during the past decades, typically relying on

the combination of acetate-containing oxidizing reagents and

metal catalysts (Fig. 2a).

Fig. 1 Examples of active ingredients featuring acetoxy groups

a. Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria. Email: oliver.kappe@uni-graz.at, david.cantillo@uni-graz.at.

b. Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.

c. Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland. Electronic Supporting Information (SI) available online

ARTICLE Journal Name

Fig. 2 (a) Synthesis of organic acetates by decarboxylative acetoxylation using conventional reagents and (b) general scheme of the electrochemical Hofer-Moest reaction.

The workhorse for decarboxylative functionalization of

organic compounds, including acetoxylation, have traditionally

been variations of the Kochi reaction, which involves the

utilization of excess amounts of Pb(OAc)4 as oxidant, and in

some cases Cu(II) catalysts.7 Despite the requirement of

stoichiometric amounts of toxic and cancerogenic Pb(IV)

reagents, the Kochi reaction has been employed both in

academia and industry for many years.8

More recently, some efforts have been devoted to replace

Pb(OAc)4 by less harmful reagent alternatives. In this context,

Xu and Tan have described a cobalt catalyzed version of the

Kochi reaction, in which PhI(OAc)2 is used as stoichiometric

oxidant.9 A photochemical method using excess amounts of

Cu(OAc)2 has been developed by Tunge and coworkers.10

Unfortunately these methods still require the utilization of

stoichiometric amounts of metals and oxidants, which results in

low atom economy and the generation of large amounts of

waste.

The Hofer-Moest reaction is a well-established

electrodecarboxylative functionalization of carboxylic acids (Fig.

2a).11 In this innately green procedure, 2-electron anodic

oxidation of an aliphatic carboxylic acid results in its

decarboxylation and the subsequent generation of a

carbocation. The carbocation can be trapped by a nucleophile,

usually an alcohol that is used as solvent, resulting in the

formation of ethers, or undergo rearrangements or

eliminations.12 This process is closely related to the venerable

Kolbe electrolysis,13 in which the oxidation stops at the radical

stage producing dimers.14 The Hofer-Moest reaction has re-

emerged in recent years, accompanying a general resurgence of

electrochemical methods for organic synthesis.15 In this

context, improved methodologies for the electrochemical

preparation of hindered alkyl ethers,16 amines,17 alkyl

fluorides18 and cubane functionalization19 via variations of the

Hofer-Moest reaction have been reported.20

Despite this progress, reports on electrochemical

decarboxylative acetoxylation have remained relatively rare,

possibly due to the lability of some of the electrolysis products.

Examples of decarboxylative acetoxylation of amino acids are

particularly scarce and limited to a small number of examples.21

Due to the importance of N,O-acetals and the generation of C-

O bonds in the synthesis of bioactive molecules,22 we

envisioned that the development of a general and scalable

electrochemical procedure for the decarboxylative

acetoxylation of amino acids would result in a sustainable

alternative to the currently employed stoichiometric reagents.

For this purpose, the electrochemical reaction was thoroughly

optimized and then translated to a single pass continuous flow

process. Herein, we report our findings and demonstrate that

nearly quantitative yields of the target compounds can be

obtained in a single-pass through a flow cell. Furthermore, the

sustainability of the process is assessed by benchmarking its

green metrics with a standard decarboxylation procedure.

Results and Discussion

Batch Optimization of the Electrolysis Conditions

The investigation was initiated with a series of batch

experiments aimed to identify an optimal solvent system and

reaction temperature, as well as the most suitable electrode

materials. All batch optimization reactions were performed

under constant current in an undivided cell (IKA Electrasyn 5 mL

vial) using N-phthaloylglycine 1 as model substrate. The

reaction was initially carried out using acetic acid as solvent,

with graphite as the anode and stainless steel as the cathode.

Graphite is known to be a good anode material for non-Kolbe

electrolysis.23 Sodium acetate (NaOAc) was added as base. No

additional supporting electrolyte was added to the reaction

mixture. In the Hofer-Moest electrolysis, the base utilized (and

consequently the basic form of the substrate) is sufficient to

provide the necessary conductivity to the reaction solution.

Applying a constant current of 20 mA and 2 F/mol of charge 61%

conversion of the starting material and 95% selectivity toward

the target hemiaminal ester 2a was obtained (Table 1, entry 1).

Variable amounts of side product 3 were observed in some

cases. This compound is formed by cathodic reduction of the

carbonyl group and can be favored when proton reduction has

a high overpotential.24 Mixtures of AcOH with MeCN, which had

been shown as suitable solvents in previous studies,21a provided

significantly reduced selectivity (entries 2-4). In the presence of

MeCN, the carbocation was partially trapped by the nitrile,

resulting in the formation of the corresponding amide via an

electrochemical Ritter-type reaction.25 As expected, the

amount of the amide side-product increased with larger

proportions of MeCN as co-solvent, thus decreasing the

reaction selectivity (entry 2). Increase of the base concentration

had a negative effect in the reaction conversion (entries 5-7). As

mentioned above, in the Hofer-Moest reaction the base

typically deprotonates the carboxylic acid starting material. The

carboxylate is believed to form a layer at the anode surface.23

An excess of acetate would probably compete with the

carboxylate in approaching the anode, which explains the

reduced conversion with higher base concentrations. Notably,

slightly elevated temperatures provided higher current

efficiencies (entries 8 and 9). Further increase of the reaction

temperature (entry 10) resulted in a lower selectivity and at 65

°C (entry 11) a complex mixture of side products was formed.

Table 1 Optimization of reaction conditions for electrochemical decarboxylative

acetoxylation of N-phthaloylglycine 1 in batch mode.

Deviation from above Conversiona

[%]

Selectivitya

[%]

1 none 61 95

2 MeCN/AcOH 2/1 62 47

3 MeCN/AcOH 1/1 64 67

4 MeCN/AcOH 1/2 60 73

5 0.6 M NaOAc 28 95

6 0.8 M NaOAc 31 95

7 1.0 M NaOAcb 34 95

8 35°C 70 95

9 45°C 65 95

10 55°C 69 90

11 65°C 12 0

12 30 mA / 40 °C 61 95

13 0.1 M substrate 37 95

14 0.3 M substrate 48 95

15 glassy carbon anode 28 99

16 RVCc anode 48 60

17 graphite cathode 82 15

18d 40 °C; 8 F/mol >99 95

0.6 mmol scale. 1.5 cm2 electrode area. a measured by HPLC-UVVIS at 215 nm

bbase not fully dissolved. creticulated vitreous carbon. d 91% isolated yield.

Surprisingly, the substrate concentration had a significant

influence on the reaction efficiency, with 0.2 M being the

optimal value (entries 13 and 14). Next, other anode materials

were evaluated. Glassy carbon and reticulated vitreous carbon

provided lower conversion (entries 15 and 16), demonstrating

that graphite is a superior anode material for the reaction.

Utilization of graphite as cathode had a negative effect on

reaction selectivity (entry 17). In this case, reduction of the

carbonyl group of the phthaloyl protecting group was favored

over proton reduction and compound 3 was the major product

observed. Finally, using the optimal conditions (20 mA,

graphite/stainless steel, 0.2 M concentration and 40 °C) the

amount of charge was gradually increased. Full conversion of

the starting material and excellent selectivity were obtained

after 8 F/mol of charge had been applied (entry 18). The

excellent conversion and selectivity obtained enabled a simple

reaction workup, which consisted of evaporation of the solvent

and extraction using EtOAc/aqueous sodium citrate. Product 2a

could be isolated in 91% yield.

Decarboxylative Acetoxylation Scope

With the optimal conditions in hand, the scope and applicability

of the electrochemical procedure was evaluated. First, a series

of phthaloyl protected amino acids was converted to the

corresponding acetoxylated analogues (Fig. 3a). In addition to

the hemiaminal ester obtained from glycine (2a), other natural

hydrophobic side-chain-containing amino acids could be

derivatized using the electrochemical protocol. Thus, the

acetoxylation products from alanine (2b), valine (2c), leucine

(2d) and isoleucine (2e) were obtained in good to excellent

yields. Aryl-containing phenylalanine and C-phenylglycine could

also be selectively electrolyzed in good yields (2f and 2g).

Notably, an extractive workup was sufficient for isolation in

many cases, underlining the high selectivity of the process. It

should be pointed out that this electrolysis method is not

suitable for natural amino acids containing oxidatively labile

functional groups such as cysteine.

To further evaluate the functional group compatibility of the

anodic decarboxylative acetoxylation procedure, a series of

benzyl acetates was prepared from the corresponding aryl

acetic acids (Fig. 3b). Such an electrochemical approach and the

fact that the acetoxy group can be exchanged with relative ease

could lead to a convenient method for the preparation of

benzyl-functionalized compounds. Various 2-aryl propionic

acids were converted into the corresponding acetoxylated

derivatives in very good to excellent yields (4a-d). The method

was compatible with the presence of halogens in the aromatic

ring. Indeed, nearly quantitative yields were achieved with

fluorine (4b) and chlorine (4c) substituents. Diphenyl acetic acid

and phenyl cyclopentyl acetic acid also performed well (4e, 4f).

Notably, benzal diacetate (4g) could be prepared from O-acetyl

mandelic acid in excellent yield. All reactions were carried out

using the optimal reaction conditions without modification. The

current efficiency was higher for some derivatives and 3 F/mol

of charge was sufficient in some cases (see Fig. 3 footnote).

The electrochemical protocol for the decarboxylative

acetoxylation of amino acids was then applied to more complex

building blocks, enabling novel pathways for the synthesis of

some active ingredients (Fig. 3c). Intermediate 6, for example,

could be obtained in good yield from its carboxylic acid

precursor 5, which in turn can be prepared from glycine.

Compound 6 can be readily hydrolyzed via aqueous workup.

The resulting alcohol is used for the preparation of the potent

insecticide tetramethrin.26 This preparative method involving

electrochemistry in an alternative approach to the Mannich

Fig. 3 Scope of the electrochemical decarboxylative acetoxylation of (a) aminoacids (b) benzylic positions and (c) active ingredient intermediates. Isolated yields on a 0.6 mmol scale are shown. a Reaction completed after 8 F/mol. b 5 F/mol. c 3 F/mol. d Obtained as mixture of diastereomers. e 0.1 M substrate concentration.

reaction typically employed.27 Acetoxylated hydantoin 8 was

also obtained in very good yield via anodic oxidation of acid 7.

Notably, this intermediate can be employed for the preparation

of fosphenythoin,28 a prodrug used to administer the

antiepileptic phenythoin. Decarboxylative acetoxylation of

amino acid 9 yielded 90% of 10. Compound 10 is a viable

intermediate for the synthesis of ABT-670, a dopamine

agonist.8b

Translation to a Continuous Flow Electrolysis Cell

Electrochemical reactions rely upon the use of continuous flow

electrolysis cells for the scale up to pilot and manufacturing

scales.29 This is due to the fact that scaling up electrochemical

reactions in batch is troublesome. In addition to the mass

transfer limitations of batch cells, increasing the size of the

vessels has a negative effect on the electrode area to reaction

volume ratio.30 Moreover, the cell resistance increments as the

electrode distance augments in larger electrochemical setups.

Flow electrolysis cells, in contrast, can be readily scaled. The

small interelectrode distance (< 1mm) characteristic of flow

electrolysis cells ensures high mass transfer efficiency and a

very low cell resistance.31 Additionally, the electrode area-to-

volume ratio is very high and can remain constant during scale

up by simply maintaining constant the interelectrode distance.

Translation of electroorganic reactions to flow cells,32 even

initially on a small scale, is therefore essential to ensure that the

process can ultimately be scaled up.

Electrochemical reactions in continuous flow cells are often

carried out by processing the reaction mixture via recirculation

of the electrolyte.29,30 Using this strategy, a high conversion of

the starting materials can be usually achieved. Gas evolution

(e.g. hydrogen formation at the cathode), a significant issue for

single-pass processing, is not too problematic, as it is

continuously released from the reaction solution reservoir.

Electrolyte recirculation is, however, not a truly continuous

process, but a semi-batch strategy, as a stream of product

solution is not continuously obtained from the setup.32

Realization of high yielding single-pass flow electrochemical

reactions is highly valuable, as the process can be readily

integrated with subsequent synthetic steps.

Prior to attempting the anodic decarboxylative

acetoxylation procedure in a continuous flow cell in a single-

pass fashion (vide infra), the electrolysis was first evaluated

using a recirculation approach (Fig. 4). This preliminary

evaluation provided valuable information on the electrodes

performance and, moreover, a useful procedure for the

processing of reaction solutions in a semi-batch approach. All

flow electrolysis experiments were carried out in a parallel plate

flow cell recently described.33 The cell featured an electrode

surface contact area of 6.4 cm2 and a channel volume of 190 μL

(0.3 mm interelectrode distance). As the cell end plates were

made of aluminum, it could be easily heated to 40 °C by simply

placing it on a hot plate. The temperature was monitored using

a thermocouple inserted between the end plates and one of the

electrodes.

Initial attempts were performed using a graphite anode and

a stainless steel (AISI 316L) cathode. Electrolysis of

methylhippuric acid 9 was utilized as model substrate (Fig. 4),

as this is a particularly interesting reaction that is currently

carried out using lead acetate as oxidant.8b A reaction mixture

of analogous composition as the batch procedure was prepared

on a 5 mmol scale. Recirculation of the reaction mixture was

conducted with a syringe pump at a flow rate of 2.5 mL/min.

Although good conversion of the substrate was achieved, a

small amount of graphite particles appeared in the reaction

mixture as a suspension during the electrolysis. This

phenomenon was ascribed to detachment of graphite particles

from the anode surface due to the large amounts of CO2 evolved

during the oxidation. As graphite is a porous material, the

reaction mixture can be partially absorbed into the electrode.

Fig. 4 Electrochemical decarboxylative acetoxylation of methylhippuric acid (9) in a flow cell with recirculation of the electrolyte solution. (+)IG: impervious graphite anode. (-)Fe: stainless steel cathode.

Generation of gas bubbles from within the electrode material

can provoke such detachment of particles. Moreover, the

graphite anode appeared to soak with the reaction mixture,

which might lead to poor residence time distributions and

diminished reaction yields. This effect, which can also occur in

batch, may be exacerbated by the small pressure drop existing

in the flow cell caused by the high flow rates.

To solve the issues observed using standard graphite as the

anode material, impervious graphite was evaluated instead.

Impervious graphite is a composite material made of ca. 80%

synthetic graphite and 20% phenolic resin. This material is liquid

and gas tight, which avoids the problems of potential leakage of

the electrolyte through the electrode. Impervious graphite is

commonly utilized in the assembly of fuel cells but it is not

typically used in electrolysis. Gratifyingly, with impervious

graphite as the anode full conversion of the starting material

and excellent selectivity was observed when a current of 80 mA

and a charge of 5 F/mol were applied. No particles of graphite

were detached from the anode in this case and, importantly,

inspection of the electrode revealed that no reaction solution

had penetrated the material. Simple workup of the reaction

mixture by extraction with EtOAc/sodium citrate yielded 1.02 g

(98%) of 10. Notably, this isolated yield is superior to that

obtained with the batch cell (91%).

Single Pass Continuous Flow Electrolysis

We next turned out attention into developing a single-pass

continuous flow procedure. Thus, instead of recirculating the

output of the reactor to a solution reservoir, it was collected in

a separate vessel (Fig. 5). Impervious graphite was also utilized

in this case, and the starting stock solution had the same

Fig. 5 Optimization of the electrolysis conditions for the single-pass flow decarboxylative acetoxylation of 9. (+)IG: impervious graphite anode. (-)Fe: stainless steel cathode. Data is collected in Table S1.

composition as in the recirculation experiments (0.2 M 9 in

AcOH with 0.4 M NaOAc). One of the advantages of single pass

continuous processing using narrow-gap flow cells is that their

low volume, and therefore the very low residence time typically

used, enables rapid screening of the reaction conditions (Fig. 5).

Thus, while the reaction solution was uninterruptedly passed

through the cell, the pump flow rate and the cell current were

scanned (currents are expressed in F/mol in relation to the flow

rate; all numerical data is collected in Table S1 in the Supporting

Information). After steady state conditions had been ensured

(ca. 3-4 reactor volumes) aliquots of the crude reaction mixture

collected from the reactor output were diluted with acetonitrile

and analyzed by HPLC. As expected, lower current densities, and

thus lower flow rates for a given amount of charge favored high

ARTICLE Journal Name

conversions. Notably, excellent selectivities (99%) were

observed in all cases. Quantitative conversion of methylhippuric

acid (9) to compound 10 was achieved with a charge of 5 F/mol

when 100 mA current and 62 μL/min were applied. The current

efficiency achieved was therefore the same as the one obtained

with the recirculation approach.

The single pass flow electrochemical reaction showed a very

high stability. The reaction could be conducted uninterruptedly

for 12 h with constant outcome. The high selectivity of the

reaction again allowed extraction as workup, without the need

for chromatographic purification. A yield of 94% (8.4 mmol,

1.74 g) was isolated for the long run experiment. Importantly,

the reaction throughput could be increased by more than 5-fold

with respect to batch. The space-time-yield for the single pass

electrochemical reaction was approximately 100 times higher

than in the small scale batch experiments.

Gas Evolution: Mass Balance and Selectivity Implications

Large amounts of gas evolution were observed during the

anodic decarboxylative acetoxylations described above, both in

batch and flow mode. Gas evolution occurs on the cathode (H2

gas from the reduction of protons) as well as on the anode

(CO2). Gas forming electrochemical reactions are often

problematic when tackling single-pass electrolysis experiments.

In this case, abnormally high amounts of gases were usually

observed. This is due to the fact that the reaction solvent

(AcOH) can also be electrolyzed, causing the formation of

additional amounts of gas (H2 + CO2 + ethane). We hypothesized

that, at a late stage of the reaction, when the concentration of

the starting material is low, the anodic oxidation of AcOH could

in fact become favored. To study this effect, we evaluated the

mass balance of reaction mixtures to which increasing amounts

Fig. 6 Conversion rates of substrate and AcOH in a 3 mL electrolysis cell at a constant

current of 20 mA/cm2.

of charge had been applied. For this purpose, amino acid 1 was

used as model substrate. Combining the mass loss data due to

gas evolution with the reaction conversion, we could establish

the proportion of substrate (1) and AcOH that had been

oxidized in each step (Fig. 6). Notably, even when 2 F/mol of

charge were applied, a large amount of AcOH appeared to be

electrolyzed. As expected, as more charge was applied and the

concentration of 1 decreased, the amount of solvent

electrolyzed increased accordingly. Ultimately, full conversion

of 1, which required 8 F/mol in batch, led to the formation of

ca. 137 mL of gas in total.

It should be mentioned that the fact that the solvent can be

readily oxidized under analogous conditions as the substrate,

ensured that overoxidation reactions (i.e., degradation of the

product) did not occur. This phenomenon explains that

excellent selectivities were achieved for most reactions.

Process Green Metrics and Sustainability Qualitative Indicators

Electrochemical methods are considered as “inherently

green”.34 Yet, the substitution of chemical oxidants or

reductants by electricity does not guarantee that the resulting

process is sustainable.35 For this reason, we decided to assess

the sustainability of our electrochemical method for the

synthesis of the model compound 10 in terms in green metrics

as well as qualitative indicators. They were also compared with

those for the literature conventional methodology using

Pb(OAc)4 and a copper catalyst.8b,36

Green metrics recommended in the CHEM21 toolkit37 were

utilized (Table 2). The formulas and values for the calculation

are reported in Tables S2 and S3. Notably, the electrochemical

method provided nearly quantitative yield (98%; electrolyte

recirculation mode) while the conventional procedure only

yielded 74% of 10. The atom economy of the two processes

probably caused the most striking difference between the green

metrics (75% and 25% for the electrochemical and conventional

procedures, respectively). Unfortunately, no substrate

concentration or amounts of solvents were reported in the

Pb(OAc)4 procedure.8b Thus, a partial process-mass intensity

(PMI) considering only the reactants was compared. Similar to

the atom economy, the electrochemical method was clearly

superior. The PMI for the electrochemical reaction, including

solvent, is 24.38 The electrochemical process also outperformed

the Pb(OAc)4 procedure in terms of reaction mass efficiency

(RME).

Table 2 Green metrics for the electrochemical decarboxylative acetoxylation of

methylhippuric acid (9) and comparison with the conventional Pb(OAc)4 process

Recirculation Pb(OAc)4

Yield 98 74

Atom Economy 75 25

PMI (without solvent) 1.8 4.6

PMI 24 -

Reaction mass efficiency 57 22

EcoScale 91 61

The EcoScale is a semi-quantitative analysis that takes into

account ecological and economical parameters.39 The

maximum score is 100, and several reaction parameters (yield,

use of harmful or expensive chemicals, etc.) “penalize” and

subtract points from the total score. The electrochemical

process scored an excellent 91 in the EcoScale. The

conventional method utilizing stoichiometric reagents scored

61 (Table 2).

One of the most compelling advantages of the

electrochemical method is its cost efficiency, especially if the

fact that the electrodes can be reutilized for very long periods is

taken into account (the impervious graphite electrode was used

for many weeks without apparent degradation or fouling). The

cost of the electrical power required for the electrochemical

reaction, ca. 3 kWh per kilogram of product, is practically

insignificant compared to the cost of Pb(OAc)4. Preparation of 1

kg of material requires 3.2 kg of Pb(OAc)4. The cost difference

difference can be as high as 3 orders of magnitude. Comparison

of the costs of all reagents/catalysts involved in the

electrochemical and conventional processes, NaOAc +

electricity vs Pb(OAc)4 + Cu(OAc)2, revealed that the cost of the

reagents for the lead-based reaction is ca. 50 times higher than

for the electrochemical procedure.40 This estimation does not

consider the cost associated with the management of Pb-

contaminated waste.

A comparison of qualitative indicators between the two

methods is collected in Table 3. The assessment of qualitative

sustainability is shown by colored flags (green, amber, red),

where a green flag stands for “preferred”, amber for “is

acceptable-some issues” and a red flag is “undesirable”. The use

of electricity instead of stoichiometric reagents can be assigned

with a green flag. The electrochemical reaction operates within

the recommended energy efficient temperature window (0-

70 °C, green flag), whereas the Pb(OAc)4 reaction uses refluxing

toluene (111 °C, amber flag) therefore being less energy

efficient. Moreover, the fact that the solvent is heated to reflux

Table 3 Qualitative sustainability indicators for the electrochemical decarboxylative

acetoxylation of methylhippuric acid (9) and the conventional Pb(OAc)4 process.

Electrochemical Pb(OAc)4

Type of reaction Electricity Stochiometric Reagent

Reactor type Flow Batch

T [°C] 40 111

Reflux No yes

Workup Extraction Chromatography

Solvent AcOH Toluene

Health Concerns No H-360Df

Environmental

implications

No H-410

grants an additional red flag to the conventional process

according to the CHEM21 toolkit.37 Other parameters,

particularly those regarding environmental and health concern,

not surprisingly clearly favor the use of electrochemistry instead

of excess amounts of toxic and environmentally unfriendly

Pb(OAc)4 and Cu(OAc)2 (Table 3). Importantly, the use of

Pb(OAc)4 results in the formation of large amounts of Pb-

containing waste, while in the electrochemical protocol only H2

and CO2 are released as byproducts. H2 can be easily reutilized

for, for example, hydrogenations of other scaffold in separate

processes,41 or for the generation of energy as a fuel.42

Conclusion

We have developed a general, sustainable and scalable

electrochemical procedure for the decarboxylative

acetoxylation of amino acids and other aliphatic carboxylic

acids. Using inexpensive electrode materials, simple electrolysis

of the starting material in AcOH containing NaOAc as base have

provided very good to excellent yield of the target acetoxylated

compounds. The electrochemical procedure has been

translated to a continuous flow electrochemical cell. Excellent

conversion and selectivity has been achieved both in a single-

pass processing and with recirculation of the electrolyte.

Implementation of impervious graphite as the anode material

has enabled stable flow processes and avoided losses of product

due to soaking of the electrode with the reaction solution.

Under flow conditions, in a flow cell of only 190 μL volume, the

reaction throughput has been multiplied more than 5-fold with

respect to batch, and the space-time yield increased by two

orders of magnitude. Analysis of the green metrics of the

electrochemical procedure and its comparison with a

conventional method confirmed the remarkable sustainability

of this robust protocol.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

The CCFLOW project (Austrian Research Promotion Agency FFG

No. 862766) is funded through the Austrian COMET Program by

the Austrian Federal Ministry of Transport, Innovation and

Technology (BMVIT), the Austrian Federal Ministry of Digital

and Economic Affairs (BMDW), and the State of Styria (Styrian

Funding Agency SFG).

References

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40 Costs analysis based on TCI prices as of Dec-1 2020 for sodium acetate (21€/300 g), lead tetraacetate (420€/500g) and copper acetate monohydrate (35€/500g). The cost of 3 kWh of electrical power is below 1€. Electrochemical method: 58 € reagents per kg of product. Pb(OAc)4 method: 2696 € reagents per kg of product.

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download fileview on ChemRxivMS_E-Decarboxylative Acetoxylation.pdf (736.19 KiB)

S1

Supporting Information

Sustainable Electrochemical Decarboxylative Acetoxylation of

Aminoacids in Batch and Continuous Flow

Manuel Köckinger,ab Paul Hanselmann,c Dominique M. Roberge,c Pierro Geotti-

Bianchini,c C. Oliver Kappe*ab and David Cantillo*ab

a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria.

Email: oliver.kappe@uni-graz.at, david.cantillo@uni-graz.at.

b Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical

Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.

c Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland.

S2

Contents

1. Materials and Methods ....................................................................................................................... 3

2. General Procedure A for the Preparation of acetates 2a-g, 3a-g and 5-7 ........................................... 4

2.1. (1,3-Dioxoisoindolin-2-yl)methyl acetate (2a) ............................................................................ 4

2.2. rac-1-(1,3-Dioxoisoindolin-2-yl)ethyl acetate (2b) .................................................................... 4

2.3. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl acetate (2c) .................................................. 4

2.4. rac-1-(1,3-Dioxoisoindolin-2-yl)-3-methylbutyl acetate (2d) .................................................... 5

2.5. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-methylbutyl acetate (2e) ..................................................... 5

2.6. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-phenylethyl acetate (2f) ...................................................... 5

2.7. rac-(1,3-Dioxoisoindolin-2-yl)(phenyl)methyl acetate (2g) ....................................................... 6

2.8. rac-1-Phenylethyl acetate (3a) .................................................................................................... 6

2.9. rac-1-(4-Fluorophenyl)ethyl acetate (3b) .................................................................................... 6

2.10. rac-1-(4-Chlorophenyl)ethyl acetate (3c) ................................................................................ 6

2.11. rac-1-(p-Tolyl)ethyl acetate (3d) ............................................................................................. 7

2.12. Benzhydryl acetate (3e) ........................................................................................................... 7

2.13. rac-Cyclopentyl(phenyl)methyl acetate (3f) ........................................................................... 7

2.14. Phenylmethylene diacetate (3g) ............................................................................................... 7

2.15. (1,3-Dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)methyl acetate (5) ................................. 8

2.16. (2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)methyl acetate (6) ................................................ 8

2.17. (3-methylbenzamido)methyl acetate (7) .................................................................................. 8

3. Description of the Flow Electrolysis Cell and Flow Setup................................................................. 9

a Determined by HPLC peak integration area (215 nm) .......................................................................... 10

4. Flow Electrolysis .............................................................................................................................. 11

4.1. Recirculation ............................................................................................................................. 11

4.2. Single Pass Electrolysis ............................................................................................................. 11

5. Green Metrics ................................................................................................................................... 12

5.1. Amounts and quantities used for Green Metrics Calculations .................................................. 12

6. References ......................................................................................................................................... 13

7. NMR spectra ..................................................................................................................................... 14

S3

1. Materials and Methods

All solvents and chemicals were obtained from standard commercial vendors (Sigma-Aldrich/Merck, VWR, TCI and

Fluorochem) and were used without any further purification, unless otherwise noted. 1H NMR spectra were recorded

on a Bruker 300 MHz instrument. 13C NMR spectra were recorded on the same instrument at 75 MHz. 19F NMR

spectra were recorded at 282 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal

standard. The letters s, d, dd, t, q, and m are used to indicate singlet, doublet, doublet of doublets, triplet, quadruplet,

and multiplet. Analytical HPLC analysis was carried out on Shimadzu instrument using a C18 reversed-phase (RP)

analytical column (150 mm × 4.6 mm, particle size 5 μm) at 37 °C using mobile phases A (H2O/MeCN (90:10 v/v)

+ 0.1% TFA) and B (MeCN + 0.1% TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: start at

3 % solvent B, increase to 5 % solvent B until 3 min, increase to 30 % solvent B until 7 min and finally increase to

100 % solvent B until 10 min. Melting points were obtained on a Stuart melting point apparatus in open capillary

tubes. Column chromatography was carried out using a Biotage Isolera automated flash chromatography system.

Phthalimide protected amino acids were prepared according to literature starting from commercially available amino

acids.S1,S2 3-Carboxymethyl-5,5-diphenyl hydantoin was prepared according to literature.S3 Graphite and impervious

graphite electrodes were washed with MeOH, acetone and DCM under sonication and polished with h. After drying

the electrodes were polished with a whetstone (3000 grit) prior the electrochemical experiments.

S4

2. General Procedure A for the Preparation of acetates 2a-g, 3a-g and 5-7

A 5 mL IKA Electrosyn vial equipped with a stirrer bar was charged with 3 mL of a solution of 100 mg NaOAc and

substrate (0.6 mmol if not stated differently) in dry AcOH. After assembly of the electrochemical cell, equipped with

a standard IKA graphite anode and an IKA stainless steel cathode, the solution was electrolyzed under a constant

current of 20 mA. After a current of 3.5 – 10 F had been passed (vide infra) the reaction mixture was collected from

the vial. The electrodes were washed with warm EtOAc to retrieve any product absorbed in the anode. The solutions

were combined and concentrated under reduced pressure. The crude product was dissolved in 20 mL EtOAc and

washed with a 20% aqueous solution of sodium citrate (2 × 20 mL). The organic phase was dried over Na2SO4 and

concentrated under reduced pressure.

2.1. (1,3-Dioxoisoindolin-2-yl)methyl acetate (2a)

Product 2a was obtained as a white solid (176 mg, 91% yield). Mp. 109-110 °C (lit.4 109-109 °C). 1H NMR (300

MHz, Chloroform-d) δ = 7.85 (ddd, J = 42.9, 5.5, 3.1 Hz, 4H), 5.71 (s, 2H), 2.07 (s, 3H). 13C NMR (75 MHz,

Chloroform-d) δ = 169.9, 166.9, 134.8, 131.9, 124.1, 60.9, 20.8. MS ESI (m/z): [M+H]+ calcd. for C11H9NO4,

220.060434; found, 220.060184. These data are in agreement with those reported previously in the literature.S4

2.2. rac-1-(1,3-Dioxoisoindolin-2-yl)ethyl acetate (2b)

Product 2b was obtained as a white solid (139 mg, 99% yield). Mp. 102-103 °C (lit.S4 101-102 °C). 1H NMR (300

MHz, Chloroform-d) δ 7.79 (ddd, J = 37.2, 5.5, 3.1 Hz, 4H), 6.72 (q, J = 6.5 Hz, 1H), 2.04 (s, 3H), 1.83 (d, J = 6.5

Hz, 3H). 13C NMR (75 MHz, Chloroform-d) δ 169.6, 166.9, 134.5, 131.7, 123.8, 71.8, 20.9, 18.2. MS ESI (m/z):

[M+H]+ calcd. for C12H11NO4, 234.076084; found, 234.076425. These data are in agreement with those reported

previously in the literature.S4

2.3. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-methylpropyl acetate (2c)

Product 2c was obtained as a colorless solid (133 mg, 85% yield). Mp. 90-91 °C (lit.S4 89-90 °C). 1H NMR (300

MHz, Chloroform-d) δ 7.80 (ddd, J = 37.8, 5.4, 3.0 Hz, 5H), 6.21 (d, J = 10.4 Hz, 1H), 2.88 (dp, J = 10.6, 6.7 Hz,

1H), 2.07 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, Chloroform-d) δ = 169.9,

S5

167.0, 134.5, 131.6, 123.8, 79.4, 29.6, 20.8, 19.0, 17.9. MS APPI (m/z): [M]- calcd. for C14H15NO4, 261.1002; found,

261.1009. These data are in agreement with those reported previously in the literature.S4

2.4. rac-1-(1,3-Dioxoisoindolin-2-yl)-3-methylbutyl acetate (2d)

Product 2d was obtained after flash column chromatography (EtOAc/petroleum ether) as a colorless solid (120 mg,

75% yield). Mp. 66-67 °C (lit.S4 64-65 °C). 1H NMR (300 MHz, Chloroform-d) δ 7.82 (ddd, J = 38.0, 5.5, 3.1 Hz,

4H), 6.71 (dd, J = 8.2, 6.7 Hz, 1H), 2.34 – 1.97 (m, 5H), 1.61 (dq, J = 7.9, 6.3 Hz, 1H), 0.97 (dd, J = 8.8, 6.6 Hz,

6H).13C NMR (75 MHz, Chloroform-d) δ = 169.6, 166.9, 134.4, 131.6, 123.7, 73.7, 39.7, 24.7, 22.6, 22.1, 20.9. MS

ESI (m/z): [M+H]+ calcd. for C15H17NO4, 276.123034; found, 276.123517. These data are in agreement with those

reported previously in the literature.S4

2.5. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-methylbutyl acetate (2e)

Product 2e was isolated as a mixture of E/Z isomers as white solid (148 mg, 90% yield). Mp. 68-69 °C (lit.S4 70-71).

1H NMR (300 MHz, Chloroform-d) δ 7.78 (ddd, J = 36.2, 5.5, 3.1 Hz, 5H), 6.27 (dd, J = 10.5, 4.7 Hz, 1H), 2.88 –

2.51 (m, 1H), 2.06 (s, 3H), 1.49 (dddd, J = 100.9, 13.8, 7.6, 3.7 Hz, 1H), 1.05 – 0.78 (m, 7H).13C NMR (75 MHz,

Chloroform-d) δ = 169.9, 169.9, 167.0, 134.5, 131.5, 131.5, 123.8, 78.3, 78.1, 35.4, 35.3, 25.2, 24.4, 20.8, 20.8, 15.1,

14.1, 10.7, 10.5. MS APPI (m/z): [M]- calcd. for C15H17NO4, 275.1158; found, 275.1166. These data are in agreement

with those reported previously in the literature.S4

2.6. rac-1-(1,3-Dioxoisoindolin-2-yl)-2-phenylethyl acetate (2f)

Product 2f was obtained after flash column chromatography (EtOAc/petroleum ether) as a white solid (139 mg, 75%

yield). Mp. 137-138 °C (lit.S4 137-138). 1H NMR (300 MHz, Chloroform-d) δ 7.76 (ddd, J = 33.9, 5.5, 3.1 Hz, 4H),

7.29 – 7.08 (m, 5H), 6.85 (dd, J = 8.7, 6.6 Hz, 1H), 3.74 – 3.47 (m, 2H), 2.07 (s, 3H). 13C NMR (75 MHz, Chloroform-

d) δ 169.6, 166.9, 135.1, 134.5, 131.5, 129.4, 128.8, 127.3, 123.8, 75.2, 37.4, 20.9. MS ESI (m/z): [M+H]+ calcd. for

C18H15NO4, 310.107384; found, 310.107374. These data are in agreement with those reported previously in the

literature.S4

S6

2.7. rac-(1,3-Dioxoisoindolin-2-yl)(phenyl)methyl acetate (2g)

Product 2g was obtained as a colorless solid (120 mg, 68% yield). Mp. 107-108 °C (lit.S4 106-107 °C). 1H NMR (300

MHz, Chloroform-d) δ 7.80 (ddd, J = 37.5, 5.5, 3.0 Hz, 4H), 7.68 (s, 1H), 7.61 – 7.51 (m, 2H), 7.43 – 7.31 (m, 3H),

2.21 (s, 3H). 13C NMR (75 MHz, Chloroform-d) δ 169.4, 166.4, 135.1, 134.6, 131.7, 129.1, 128.6, 126.5, 123.9, 74.3,

20.9. MS ESI (m/z): [M+H]+ calcd. for C17H13NO4, 296.091734; found, 296.092274. These data are in agreement

with those reported previously in the literature.S4

2.8. rac-1-Phenylethyl acetate (4a)

Product 4a was obtained after flash column chromatography (EtOAc/petroleum ether) as a colorless oil (77 mg, 78%

yield). 1H NMR (300 MHz, Chloroform-d) δ 7.39 – 7.22 (m, 5H), 5.86 (q, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.52 (d, J =

6.6 Hz, 3H). 13C NMR (75 MHz, Chloroform-d) δ 170.5, 141.8, 128.6, 128.0, 126.2, 72.5, 22.4, 21.5. MS ESI (m/z):

[M-H]- calcd. for C10H12O2, 163.076453; found, 163.07617. These data are in agreement with those reported

previously in the literature.S5

2.9. rac-1-(4-Fluorophenyl)ethyl acetate (4b)

Product 3b was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (106 mg, 97% yield). 1H

NMR (300 MHz, Chloroform-d) δ 7.36 – 7.29 (m, 2H), 7.07 – 6.99 (m, 2H), 5.85 (q, J = 6.6 Hz, 1H), 2.06 (s, 3H),

1.52 (d, J = 6.6 Hz, 3H).19F NMR (282 MHz, Chloroform-d) δ -114.42 (tt, J = 8.5, 5.4 Hz).13C NMR (75 MHz,

Chloroform-d) δ 170.4, 162.4 (d, J = 246.0 Hz), 137.6 (d, J = 3.2 Hz), 128.0 (d, J = 8.2 Hz), 115.5 (d, J = 21.5 Hz),

71.8, 22.3, 21.5. MS ESI (m/z): [M-H]- calcd. for C10H11FO2, 181.067031; found, 181.066767. These data are in

agreement with those reported previously in the literature.S6

2.10. rac-1-(4-Chlorophenyl)ethyl acetate (4c)

Product 4c was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (119 mg, 99% yield). 1H NMR

(300 MHz, Chloroform-d) δ 7.34 – 7.28 (m, 4H), 5.83 (q, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H). 13C

NMR (75 MHz, Chloroform-d) δ 170.4, 140.3, 133.7, 128.8, 127.7, 71.7, 22.3, 21.4. MS APCI (m/z): [M-H]- calcd.

S7

for C10H10ClO2, 197.0369; found, 197.0377. These data are in agreement with those reported previously in the

literature.S6

2.11. rac-1-(p-Tolyl)ethyl acetate (4d)

Product 4d was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (105 mg, 98% yield). 1H

NMR (300 MHz, Chloroform-d) δ 7.22 – 7.04 (m, 4H), 5.78 (q, J = 6.6 Hz, 1H), 2.27 (s, 3H), 1.99 (s, 3H), 1.45 (d,

J = 6.6 Hz, 3H).13C NMR (75 MHz, Chloroform-d) δ 170.6, 138.8, 137.8, 129.3, 126.3, 72.4, 22.2, 21.5, 21.3. MS

APCI (m/z): [M-H]- calcd. for C11H13O2, 177.0915; found, 177.0922. These data are in agreement with those reported

previously in the literature.S6

2.12. Benzhydryl acetate (4e)

Product 4e was obtained after flash column chromatography (EtOAc/petroleum ether) as a colorless oil (80 mg, 59%

yield). 1H NMR (300 MHz, Chloroform-d) δ 7.41 – 7.23 (m, 10H), 6.91 (s, 1H), 2.18 (s, 3H).13C NMR (75 MHz,

Chloroform-d) δ 170.2, 140.3, 128.6, 128.0, 127.2, 21.4. MS APCI (m/z): [M+H]+ calcd. for C15H15O2, 227.1072;

found, 227.1065. These data are in agreement with those reported previously in the literatureS7

2.13. rac-Cyclopentyl(phenyl)methyl acetate (4f)

Product 4f was obtained as a colorless oil (120 mg, 92% yield). 1H NMR (300 MHz, Chloroform-d) δ 7.36 – 7.24

(m, 5H), 5.54 (d, J = 9.1 Hz, 1H), 2.45 – 2.29 (m, 1H), 2.05 (s, 3H), 1.82 (m, 1H), 1.67 – 1.36 (m, 6H), 1.16 (m,

1H).13C NMR (75 MHz, Chloroform-d) 13C NMR (75 MHz, Chloroform-d) δ 170.1, 169.5, 142.8, 60.6, 21.3, 20.9,

20.2.MS APCI (m/z): [M-H]- calcd. for C14H18O2, 217.1228; found, 217.1222. These data are in agreement with those

reported previously in the literature.S5

2.14. Phenylmethylene diacetate (4g)

Product 4g was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (109 mg, 87% yield). 1H NMR

(300 MHz, Chloroform-d) δ 7.68 (s, 1H), 7.56 – 7.48 (m, 2H), 7.45 – 7.39 (m, 3H), 2.13 (s, 6H).13C NMR (75 MHz,

S8

Chloroform-d) δ 168.9, 135.6, 129.9, 128.7, 126.8, 89.8, 21.0. MS APCI (m/z): [M-H]- calcd. for C11H11O4, 207.0657;

found, 207.0664. These data are in agreement with those reported previously in the literature.S8

2.15. (1,3-Dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)methyl acetate (6)

Product 6 was obtained after flash column chromatography (EtOAc/petroleum ether) as a white solid (98 mg, 73%

yield). Mp. 64-67 °C. 1H NMR (300 MHz, Chloroform-d) δ 5.50 (s, 2H), 2.37 (m, 4H), 2.04 (s, 3H), 1.86 – 1.71 (m,

4H). 13C NMR (75 MHz, Chloroform-d) δ 170.1, 169.5, 142.8, 60.6, 21.3, 20.9, 20.2. MS ESI (m/z): [M+H]+ calcd.

for C11H13NO4, 224.091734; found, 224.091873.

2.16. (2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)methyl acetate (8)

Product 8 was obtained after flash column chromatography (EtOAc/petroleum ether) as a white solid (79 mg, 81%

yield). Mp. 158-165 °C (decomp.) (lit.S9 162-163 °C). 1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.46 – 7.33

(m, 10H), 5.47 (s, 2H), 2.00 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ = 172.5, 169.4, 153.6, 139.2, 128.7, 128.4,

126.7, 69.3, 61.7, 20.5.MS ESI (m/z): [M+H]+ calcd. for C18H16N2O4, 325.118283; found, 325.118429. These data

are in agreement with those reported previously in the literature.S9

2.17. (3-methylbenzamido)methyl acetate (10)

Product 10 was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (112 mg, 90% yield). 1H NMR

(300 MHz, Chloroform-d) δ 7.63 – 7.37 (m, 3H), 7.29 – 7.27 (m, 1H), 5.39 (d, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.02 (s,

3H). 13C NMR (75 MHz, Chloroform-d) δ 172.2, 167.9, 138.6, 133.2, 133.1, 128.6, 128.1, 124.4, 64.8, 21.4, 21.0.

MS ESI (m/z): [M+H]+ calcd. for C11H13NO3, 208.09682; found, 208.097444. These data are in agreement with those

reported previously in the literature.S10

S9

3. Description of the Flow Electrolysis Cell and Flow Setup

The flow electrolysis cell used in this work followed a typical parallel plates arrangement and has been described in

detail in a previous publication (Figure S1).S11 The two electrode plates were placed in parallel and separated by a

Mylar film incorporating a reaction channel (6.4 cm2 contact area, 190 µL). Graphite (IG-15, GTD Graphit

Technologie GmbH, 50 × 50 × 3 mm) or impervious graphite (FC-GR347B, Graphtek LLC, 50 × 50 × 5 mm) were

used as anode. AISI 316L stainless steel plate (GoodFellow, 50 × 50 × 0.2 mm) was used as cathode. A thermocouple

was installed between one of the aluminum end pates and electrode for temperature monitoring.

6.4 cm2 190 µL

0.3 mm thickness

Fig. S1. Exploded view of the flow electrolysis cell and details on the interelectrode separator. Images reproduced from

reference S11.

The setup for the flow electrolysis (Figure S2) utilized a syringe pump [B] to pass the reaction mixture [A] through

the flow cell [C], either in a single-pass or with recirculation of the electrolyte. The flow cell was power using a DC

power supply [D] (PeakTech 6225A). The flow cell was heated by simply placing it on a heating plate (E) and the

temperature was monitored by a thermocouple (F). Further experimental details are provided in Section 4 (Page S11).

Fig. S2 Photograph of the continuous flow setup utilized for the electrolysis experiments

S10

Table S1. Detailed optimization data for the single-pass continuous flow electrolysis of 9 (Fig. 5 in the

manuscript). The setup described on Fig. S1 and S2 was used.

F/mol μL/min Current (mA) Yield (%) F/mol μL/min Current (mA) Yield (%)

2 62 40 82 2.5 248 199 71

2.5 62 50 89 3 248 239 73

3 62 60 95 3.5 248 279 76

3.5 62 70 96 4 248 319 78

4 62 80 95 4.5 248 359 78

4.5 62 90 96 5 248 399 80

5 62 100 99 2 372 239 60

2 124 80 75 2.5 372 299 67

2.5 124 100 81 3 372 359 71

3 124 120 84 3.5 372 419 74

3.5 124 140 89 4 372 479 78

4 124 160 87 4.5 372 538 78

4.5 124 179 88 5 372 598 81

5 124 199 88 2 496 319 60

5.5 124 219 88 2.5 496 399 62

6 124 239 89 3 496 479 64

2 248 160 70 3.5 496 558 66

a Determined by HPLC peak integration area (215 nm)

S11

4. Flow Electrolysis

4.1. Recirculation

A dry 25 mL volumetric flask was charged with 966 mg (5 mmol) of methyl hippuric acid 9 and 820 mg (10 mmol)

NaOAc and filled up to volume with dry AcOH. The solution was pumped through the flow cell with a flow rate of

2.5 mL/min, and outlet of the reactor was connected back to the solution reservoir. Once the flow of liquid had been

stabilized (no air present in the flow cell) and the cell temperature reached 40 °C a current of 80 mA was applied.

The power supply was turned off after 5 F/mol of charge had been applied (10 h). Then, the pump inlet was removed

from the solution reservoir to let air pass through the reactor and push the remaining reaction mixture to the collection

vessel. Product 10 was obtained after extraction with CH2Cl2/20% aq. citrate as a colorless oil (1.012 g, 98% yield). 1H NMR (300 MHz, Chloroform-d) δ 7.63 – 7.37 (m, 3H), 7.29 – 7.27 (m, 1H), 5.39 (d, J = 7.3 Hz, 2H), 2.33 (s,

3H), 2.02 (s, 3H). 13C NMR (75 MHz, Chloroform-d) δ 172.2, 167.9, 138.6, 133.2, 133.1, 128.6, 128.1, 124.4, 64.8,

21.4, 21.0. MS ESI (m/z): [M+H]+ calcd. for C11H13NO3, 208.09682; found, 208.097444. These data are in agreement

with those reported previously in the literature.S10

4.2. Single Pass Electrolysis

A stock solution containing methyl hippuric acid 9 (0.2 M) and NaOAc (0.4 M) in dry AcOH was pumped with a

flow rate of 62 µL/min through the flow cell, which had been heated to 40 °C. Once the cell has been filled with

reaction mixture, a current of 100 mA was applied. Under steady state conditions, the reaction mixture was collected

from the reactor output for 12 h (20 mmol). Product 7 was obtained after extraction with CH2Cl2/20% aq. citrate as

a colorless oil (1.74 g, 94% yield). 1H NMR (300 MHz, Chloroform-d) δ 7.63 – 7.37 (m, 3H), 7.29 – 7.27 (m, 1H),

5.39 (d, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.02 (s, 3H). 13C NMR (75 MHz, Chloroform-d) δ 172.2, 167.9, 138.6, 133.2,

133.1, 128.6, 128.1, 124.4, 64.8, 21.4, 21.0. MS ESI (m/z): [M+H]+ calcd. for C11H13NO3, 208.09682; found,

208.097444. These data are in agreement with those reported previously in the literature.S10

S12

5. Green Metrics

% 𝑌𝑖𝑒𝑙𝑑 =moles of product

moles of limiting reactant× 100

% 𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 = 100 −final moles of limiting reactant

initial moles of limiting reactant× 100

% 𝑆𝑒𝑙𝑒𝑐𝑡𝑖𝑣𝑖𝑡𝑦 =% Yield

% Selectivity× 100

𝐴𝐸 =molecular weight of product

total molecular weight of reactants× 100

𝑅𝑀𝐸 =mass of isolated product

total mass of reactants× 100

𝑃𝑟𝑜𝑐𝑒𝑠𝑠 𝑀𝑎𝑠𝑠 𝐼𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 (𝑃𝑀𝐼) =total mass in a process or process step

mass of product

5.1. Amounts and quantities used for Green Metrics Calculations

Table S2. Values used for the assessment of the green metrics for the electrochemical recirculation flow protocol

Role Chemical Mass [g] Volume

[mL] MW

Density

[g/mL] Mol

Reactant Methylhippuric acid 0.966 193.20 0.005

Reactant NaOAc 0.820 82.03 0.010

Solvent AcOH 24.37 23.21 1.05

Reaction total 25.16

Product (3-methylbenzamido)methyl

acetate 1.01 207.23 0.00488

Table S3. Values used for the assessment of the green metrics for the Pb(OAc)4 batch protocol

Role Chemical Mass

[g]

Volume

[mL] MW

Density

[g/mL] Mol

Reactant Methylhippuric acid 10 193.20 0.051760

Reactant Pb(OAc)4 25.25 443.38 0.05695

Catalyst Cu(OAc)2 0.94 199.65 0.00471

Solvent toluene

Reaction total

Product (3-methylbenzamido)methyl

acetate 7.95 207.23 0.0384

S13

6. References

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S2 I. Le Roy, D. Mouysset, S. Mignani, M. Vuilhorgne and L. Stella, Tetrahedron, 2003, 59, 3719–3727.

S3 Chin. Pat., CN101863833B, 2010.

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S5 S. Y. Lee, J. M. Murphy, A. Ukai and G. C. Fu, J. Am. Chem. Soc., 2012, 134, 15149–15153.

S6 I. Yun, J. Y. Park, J. Park and M. J. Kim, J. Org. Chem., 2019, 84, 16293–16298.

S7 S. Senaweera, K. C. Cartwright and J. A. Tunge, J. Org. Chem., 2019, 84, 12553–12561.

S8 H. Senboku, K. Sakai, A. Fukui, Y. Sato and Y. Yamauchi, ChemElectroChem, 2019, 6, 4158–4164.

S9 N. Banjac, G. Ušćumlić, N. Valentić and D. Mijin, J. Solution Chem., 2007, 36, 869–878.

S10 M. V. Patel, T. Kolasa, K. Mortell, M. A. Matulenko, A. A. Hakeem, J. J. Rohde, S. L. Nelson, M. D.

Cowart, M. Nakane, L. N. Miller, M. E. Uchic, M. A. Terranova, O. F. El-Kouhen, D. L. Donnelly-Roberts,

M. T. Namovic, P. R. Hollingsworth, R. Chang, B. R. Martino, J. M. Wetter, K. C. Marsh, R. Martin, J. F.

Darbyshire, G. Gintant, G. C. Hsieh, R. B. Moreland, J. P. Sullivan, J. D. Brioni and A. O. Stewart, J. Med.

Chem., 2006, 49, 7450–7465.

S11 W. Jud, C. O. Kappe and D. Cantillo, Chemistry–Methods, 2020, cmtd.202000042.

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7. NMR spectra

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