A modular, low footprint and scalable flow platform for the expedient α-aminohydroxylation of enolizable ketones

Volume 23

Number 6

21 March 2021

Pages 2187-2542

Green

Chemistry

Cutting-edge research for a greener sustainable future

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ISSN 1463-9262

PAPER

Jean-Christophe M. Monbaliu et al.

A modular, low footprint and scalable ﬂow platform for the

expedient α-aminohydroxylation of enolizable ketones

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PAPER

A modular, low footprint and scalable ﬂow

platform for the expedient α-aminohydroxylation

of enolizable ketones†

Cite this: Green Chem., 2021, 23,

2336

Victor-Emmanuel H. Kassin, ^aRomain Morodo,^aThomas Toupy,^a

Isaline Jacquemin,^aKristof Van Hecke, ^bRaphaël Robiette ^cand

a

Jean-Christophe M. Monbaliu

*

The unique reactivity proﬁle of α-chloronitroso derivatives is expressed to its fullest potential through the

development of an integrated, modular and scalable continuous ﬂow process for the electrophilic

α-aminohydroxylation of various enolizable ketones. Flow conditions contribute to mitigating the high reactiv-

ity and toxicity of α-chloronitroso derivatives and provide an eﬃcient, versatile and safe protocol for the

α-aminohydroxylation of ketones with a minimal footprint. Fundamental aspects of the α-aminohydroxylation

process were computed by DFT and further supported the experimental observations, hence leading to the

unprecedented α-chloronitroso-based α-aminohydroxylation of primary, secondary and tertiary substrates.

Recycling of the carbon backbone of the α-chloronitroso derivatives provides a high atom economy for the

preparation of value-added molecules. This work showcases α-chloronitroso derivatives as economic and

eﬃcient vehicles for transferring electrophilic synthons of hydroxylamine toward nucleophilic enolates. A

representative range of precursors and analogs of pharmaceutical active ingredients, including WHO essentials

and drugs in shortage (such as epinephrine and ketamine), are prepared within minutes according to a fully

concatenated process. The process features sequential modules with distinct unit operations including chemi-

cal transformations and multiple in-line extractions. The process relies on an upstream chemical Generator

that manages the preparation of α-chloronitroso derivatives and that feeds downstream a series of

α-aminohydroxylation modules. The setup is amenable to the addition of libraries of compounds for feeding

upstream the process of discovery in medicinal chemistry and is transposable to pilot scale. Several layers of

in-line analytical procedures are featured to improve process control and safety.

Received 28th December 2020,

Accepted 1st February 2021

DOI: 10.1039/d0gc04395h

rsc.li/greenchem

Introduction

Nitrogen, which is the fourth element in abundance in bio-

genic material, is ubiquitous in biomolecules from peptides to

neurotransmitters. Nitrogen-containing organics are therefore

privileged scaﬀolds for active pharmaceutical ingredients

(APIs), among which β-amino alcohols and α-aminoketones

are abundantly represented (Fig. 1). The development of amin-

^aCenter for Integrated Technology and Organic Synthesis, MolSys Research Unit,

University of Liège, B-4000 Liège (Sart Tilman), Belgium.

Fig. 1 Representative examples of β-amino alcohol and α-aminoketone

APIs and biologically active compounds. Pseudoephedrine and ephedrine

are listed as WHO essential drugs,²⁰and are mainly used as sympathomi-

metic sinus decongestant and stimulant, respectively. Epinephrine, also

known as adrenalin, is a neurotransmitter and a WHO essential drug cur-

rently in shortage.^20–22Salbutamol is a β-amino alcohol active pharma-

ceutical listed as essential by WHO used mainly for the treatment of

E-mail: jc.monbaliu@uliege.be; http://www.citos.uliege.be

^bXStruct, Department of Chemistry, Ghent University, Krijgslaan 281-S3, B-9000

Ghent, Belgium

^cInstitute of Condensed Matter and Nanosciences, Université catholique de Louvain,

Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium

†Electronic supplementary information (ESI) available: Fluidic components,

experimental procedures, details of the fluidic setup and procedures (micro- and

mesoscale), oﬀ-line analysis with structural assignments (NMR and X-ray diﬀrac-

tion) and computations. CCDC 2046130–2046136. For ESI and crystallographic

data in CIF or other electronic format see DOI: 10.1039/d0gc04395h

asthma.²⁰Propranolol, another WHO essential β-amino alcohol, is

a

common β-blocker medication for treating cardiovascular conditions.²⁰

Ketamine and bupropion are two representative α-aminoketones prescribed

mainly for treating severe depression. Ketamine is listed as WHO essential.²⁰

2336 | Green Chem., 2021, 23, 2336–2351

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tially versatile intermediates for rapidly accessing various

β-amino alcohol and α-aminoketone scaﬀolds, which are com-

monly encountered in pharmaceuticals and other biologically

active molecules (Fig. 3a). In this context, Oppolzer’s seminal

work for electrophilic aminations of enolizable carbonyls with

α-chloronitroso compounds (Fig. 3b) is still a landmark.^57–62

Oppolzer’s amination was also amenable to stereoselective pro-

tocols, either using chiral auxiliaries on the substrate or chiral

nitroso compounds.

Fig. 2 Illustration and detailed mechanism for the electrophilic amin-

ation of enolizable ketone substrates (also known as the nitroso aldol

reaction) with α-chloronitroso derivatives 1a,b showing the formation of

an intermediate nitrone nit-2 and its subsequent solvolysis toward a free

α-aminohydroxylated ketone 3.

ation procedures starting from common, widely available sub-

strates therefore stimulates lots of research eﬀorts.^1–4Typical

amination procedures exploit the inherent nucleophilic nature

of nitrogen for its insertion on activated electrophilic

substrates.^5–11Alternative methods relying on the umpolung of

nitrogen, known as electrophilic aminations, are also abun-

dantly documented in the literature.^12–19

A variety of electrophilic amination reagents have been

reported, among which azodicarboxylates,^23–29diazoesters,³⁰

haloamines,^30–32hydroxylamines and derivatives,^30,32–35

oxaziridines,^11,36as well as nitroso derivatives are documen-

ted (Fig. 2). The latter class counts several subclasses that

share a common electrophilic NvO moiety that is modulated

through specific structural features. Nitroso derivatives are

versatile chemicals that have been used for formal amination

reactions starting from various substrates mainly through

hetero Diels–Alder,^37–44ene^40,45–48and O- or N-nitroso aldol

reactions.^48–51

Among nitroso derivatives, α-chloronitroso (also known as

1-chloro-1-nitroso or gem-chloronitroso) derivatives such as

1-chloro-1-nitrosocyclopentane 1a and 1-chloro-1-nitrosocyclo-

hexane 1b (Fig. 2) are underrepresented in the literature,

despite their inherent appealing reactivity profile. Alike other

nitroso derivatives, they can be involved in hetero Diels–

Alder^52–56and nitroso aldol reactions,^57–64yet unlike other

nitroso species, the carbon backbone is readily released

through solvolysis, hence avoiding tedious or wasteful de-

protection protocols to release the aminohydroxyl function

(Fig. 2). The mechanism, which is illustrated in Fig. 2 for a

Fig. 3 (a) α-Aminohydroxylated ketones obtained from the reaction of

enolizable ketones and α-chloronitroso 1a,b are versatile intermediates

for rapidly accessing various β-amino alcohol and α-aminoketone

nitroso-aldol reaction (i.e. the electrophilic amination of an scaﬀolds. (b) Oppolzer’s α-aminohydroxylation on chiral amides (N* =

(2R)- or (2S)-bornane-10,2-sultam) with 1b.^57–62(c) Large scale prepa-

ration of anti-inﬂammatory drug candidate BMS-561392 involving a key

electrophilic α-aminohydroxylation using 1a.⁶⁵(d) This work signiﬁcantly

extends the scope of the α-aminohydroxylation with α-chloronitroso

derivatives such as 1a to primary, secondary and tertiary enolizable sub-

enolizable substrate), involves the formation of an intermedi-

ate nitrone nit-2, which solvolyzes in lower alcohols or in

acidic water. The carbon backbone is released as a ketal (solvo-

lysis in lower alcohols) or as a ketone (acidic hydrolysis). The

α-aminohydroxylated ketones obtained accordingly are poten- strates under scalable ﬂow conditions.

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There is only one example in the recent literature that col was first validated on a series of model primary and sec-

illustrates a large-scale batch application relying on com- ondary enolizable ketone derivatives, and then broadened to

pound 1a (Fig. 3c). Compound 1a was used to install a qua- other enolizable ketones, including tertiary substrates. The

ternary center on a key intermediate toward anti-inflamma- protocol is versatile and also features options for controlling

tory compound BMS-561392 (Fig. 3c).⁶⁵This protocol was the α-aminohydroxylation of unsymmetrical enolizable

developed at Bristol-Myers Squibb and required labor- and ketones under thermodynamic and kinetic conditions. Last,

energy-intensive conditions. Besides, the authors indicated but not least, this protocol also enables the unprecedented

that “data substantiated that the aminating agent 1-chloro-1- α-aminohydroxylation of primary enolizable ketones, which is

nitrosocyclopentane was not safe to use”⁶⁵on such a prepara- very challenging to achieve under conventional batch con-

tive scale. The unstable and explosive nature of 1a imposed ditions. A DFT study indicated that the α-aminohydroxylation

−78 °C for the eﬀective amination of a leucine-derived enoliz- step is diﬀusion-controlled and supported the experimental

able amide.⁶⁵

observations. Besides the wide functional diversity obtained

With increasingly restrictive legislations both at the R&D through this method, the by-product of the reaction, i.e. the

and commercial scales, the use of reactive and potentially carbon backbone of the α-chloronitroso derivative (i.e. cyclo-

hazardous chemicals has become limiting if not impossible pentanone for 1-chloro-1-nitrosocyclopentane 1a) is recycl-

with conventional batch reactors. The concept of chemical able and readily transformed with hydroxylamine hydro-

generators under continuous flow conditions has been exten- chloride into the corresponding oxime for feeding Generator

sively documented by Kappe,^66–72hence providing a robust II, hence showcasing α-chloronitroso derivatives as economic

answer for exploiting reactive intermediates yet benefiting and eﬃcient vehicles for transferring electrophilic synthons

from all the safety and process advantages of continuous flow of hydroxylamine toward nucleophilic enolates.

operation. A continuous flow chemical generator actually relies

on stable and widely available precursors and on the concate-

nation of upstream operations aiming at the preparation of

unstable, toxic or reactive chemicals, which are next immedi-

ately consumed within downstream operations (Fig. 3d). Such

Experimental section

General information

a scheme alleviates the safety concerns of handling and stock- Conversion and yield were determined by HPLC/DAD or by

1

piling reactive chemicals. Building upon our expertise in devel- high field H NMR spectroscopy. Structural identity was con-

oping continuous flow processes^73–77and the handling of firmed by ¹H and ¹³C NMR spectroscopy (400 MHz Bruker

nitroso species,^37,38,78,79a solution was sought for exploiting, Avance spectrometer) in CDCl₃, CD₃OD or D₂O and by X-ray

under safe conditions, the unique reactivity of α-chloronitroso diﬀraction on single crystals of compounds rac-3g·HCl, 3q,

derivatives at its fullest.

3r, 3t·HCl, 3u, 5, 6 and 7 (CCDC 2046130–2046136†).

We describe herein the development of a low footprint, Compounds 6 and 7 are described in the ESI only, see sec-

modular, safe and scalable continuous flow process for the tions 2.3, 2.5 and 2.6†. The chemical shifts are reported in

electrophilic α-aminohydroxylation of various enolizable ppm relative to TMS as an internal standard or to the solvent

ketones (Fig. 3d). Building upon the highly reactive nature of residual peak. Solvents (diethyl ether, absolute ethanol,

α-chloronitroso derivatives, this flow process revisits methanol, hexanes, petroleum ether (40–60) and ethyl

Oppolzer’s classical procedure for the α-aminohydroxylation acetate) were used as received, unless otherwise stated.

of enolizable ketones and is amenable to either R&D or pro- Tetrahydrofuran (THF) and methyl tert-butyl ether (MTBE)

duction scales. Flow conditions contribute to mitigate the were distilled over Na/benzophenone. Sodium hypochlorite

high reactivity and toxicity of α-chloronitroso derivatives. The pentahydrate, tert-butanol, glacial acetic acid, acetoxime,

flow process features two chemical generators connected in 2-butanone oxime, cyclopentanone oxime, cyclohexanone

series: (a) Generator I for the preparation of strong organic oxime, cycloheptanone oxime, (−)-menthone, (+)-camphor,

oxidizer tert-butyl hypochlorite (tBuOCl) from common and acetophenone, propiophenone, 4′-methylpropiophenone,

stable precursors; (b) and Generator II for the generation of 3′-chloro-propiophenone, 4′-chloro-propiophenone, 4′-fluoro-

α-chloronitroso derivatives from stable and widely available propiophenone, 4′-(trifluoromethyl)-propiophenone, 2′-(tri-

oximes and tBuOCl (from Generator I). Generator II then fluoromethyl)-propiophenone,

feeds series of fluidic modules for the phenone, 3′-nitropropiophenone, 4′-methoxy-propiophenone,

α-aminohydroxylation of enolates with α-chloronitroso deriva- valerophenone, octanophenone, 1-(2-thienyl)-1-propanone,

tives, producing a variety of racemic α-aminohydroxylated 1,3-diphenylpropan-1-one, 1-(benzo[d][1,3]-dioxol-5-yl)

3′-(trifluoromethyl)-propio-

a

ketone hydrochlorides in water. Each fluidic element also propan-1-one, isobutyrophenone, 1,2-diphenylethan-1-one,

includes additional operations such as extraction, quench, cyclobutyl phenyl ketone, cyclopentyl phenyl ketone, 2-chlor-

hydrolysis and in-line analysis, hence providing a complex, ophenyl cyclopentyl ketone, cyclohexyl phenyl ketone, 2-phe-

fully integrated process. Generators I and II alleviate the nylcyclohexanone, lithium bis(trimethylsilyl)amide (ca. 26%

storage and handling of two toxic and unstable chemicals, in THF), hydroxylamine hydrochloride, sodium acetate tri-

i.e. tBuOCl and α-chloronitroso derivatives, hence drastically hydrate, pyridine, zinc chloride (ca. 25% in THF), sodium

improving the safety features of the process. The flow proto- bicarbonate, potassium tert-butoxide, potassium hydroxide,

2338 | Green Chem., 2021, 23, 2336–2351

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sodium borohydride and zinc dust, calcium chloride, potassium (BPR-1000). Downstream membrane separation relied on a

iodide, sodium thiosulfate, potassium bichromate were membrane separator from Zaiput Flow Technologies (SEP-200,

obtained from commercial sources and used as received.

equipped with a 1 µm pore hydrophobic membrane). In-line

analysis was optionally performed with an IR spectrometer

(FlowIR™ from Mettler-Toledo equipped with a DTGS detector

Experimental setup

Microfluidic setups. Microfluidic reactors consisted of using HappGenzel apodization, a Silicon probe connected via

modular continuous flow assemblies constructed from PFA a FlowIR™ sensor and a high pressure heated 50 µL cell) or a

tubing (1.58 mm outer diameter, 750 µm internal diameter) benchtop NMR (43 MHz Spinsolve™ ¹H NMR spectrometer

equipped with PEEK/ETFE connectors and ferrules (IDEX/ from Magritek® equipped with a flow-through cell).

Upchurch Scientific). Feed and collection lines consisted of

Computational study

PFA or PEEK tubing (1.58 mm outer diameter, 750 μm internal

diameter) equipped with PEEK/ETFE connectors and ferrules Calculations were carried out using the Jaguar 8.5 program

(IDEX/Upchurch Scientific). Liquid feeds were handled with package.⁸⁰Geometry optimizations were performed at the

high force Chemyx Fusion 6000 syringe pumps equipped with B3LYP-D3/6-31+G* level of theory. Solvent eﬀects were mod-

SS syringes and DuPont Kalrez O-rings or with HPLC pumps elled by using the polarizable continuum-Poisson method as

(ThalesNano micro HPLC). The coil reactors were thermoregu- incorporated in Jaguar, using the parameters for MTBE, i.e., a

lated with a Heidolph MR Hei-Tec equipped with a Pt-1000 dielectric constant of 2.6, and a solvent probe radius of 2.42 Å.

temperature sensor. Downstream pressure was regulated with Full calculation of vibrational frequencies was performed at

back pressure regulators from Zaiput Flow Technologies the B3LYP-D3/6-31+G* level using ultrafine grids to character-

(BPR-10) or from IDEX/Upchurch Scientific. Liquid–liquid ize the stationary points (local minima no imaginary frequen-

extraction was carried out with a Zaiput Flow Technologies cies and transition states one imaginary frequency) and to

membrane separator (SEP-10, equipped with a 1 µm pore obtain Gibbs free energy correction. The calculated reaction

hydrophobic membrane).

profile was verified for each transition state by following the

Mesofluidic setup – lab scale. Lab scale mesofluidic experi- intrinsic reaction coordinate (IRC). In Jaguar, the translational

ments were carried out in a Corning® Advanced-Flow™ Low partition function is computed for ideal gas standard con-

Flow Reactor (0.5 mL internal volume glass fluidic modules). ditions, corresponding to a pressure of 1 atm at 298.15 K. For

Feed and collection lines consisted of PFA tubing (1/8″ o.d.) solution reactions, the standard condition is instead 1 mol

equipped with PFA or SS Swagelok connectors and ferrules. L⁻¹. Accordingly, the free energy value computed in Jaguar was

Liquid feeds were handled with FLOM or ThalesNano micro corrected by a concentration term, equal to RT ln(V_mol_gas_1

HPLC pumps. The reactor was maintained at reaction temp- atm/V_mol_1 M), i.e., 1.89 kcal mol⁻¹at 298.15 K. Electronic

erature with a LAUDA Integral XT 280 thermostat and a energies were computed at the B3LYP-D3/6-311+G** level

LAUDA Proline RP845. Downstream pressure was regulated whereas solvation energies were obtained at the B3LYP-D3/6-

with a back pressure regulator from Zaiput Flow Technologies 31+G*(MTBE). A systematic attempt to locate all possible local

(BPR-10 or BPR-1000). Downstream membrane separation minima (at the B3LYP-D3/6-31+G* level) was made, with the

relied on

a

membrane separator from Zaiput Flow data presented referring to the lowest energy form.

Technologies (SEP-10, equipped with a 1 µm pore hydro-

phobic membrane). In-line analysis was performed on an in-

Typical runs

line IR (FlowIR™ from Mettler-Toledo equipped with a DTGS CAUTION: Reactor setups involving tBuOCl, 1-chloro-1-nitroso-

detector using HappGenzel apodization, a Silicon probe con- cyclopentane (1a) and 1-chloro-1-nitrosocyclohexane (1b) were

nected via a FlowIR™ sensor and a high pressure heated covered in thin foil to prevent light exposure. tBuOCl, 1a and

1

10 µL cell) or a benchtop NMR (43 MHz Spinsolve™ H NMR 1b are reactive and unstable species with a pungent smell that

spectrometer from Magritek® equipped with a flow-through decompose under heat or UV irradiation. They must be

cell).

handled with great care under a fume hood in the absence of

Mesofluidic setup – pilot scale. Mesofluidic experiments direct light.^81,82If necessary, storage over CaCl₂at −8 °C in a

were carried out in a Corning® Advanced-Flow™ G1 Reactor brown glass bottle is recommended. Careful neutralization of

(8 mL internal volume glass fluidic modules for the prepa- tBuOCl over thioanisole⁸³and of 1a,b over triphenyl-

ration of tBuOCl and 1a,b) or in a Corning® Advanced-Flow™ phosphine⁸⁴is strongly advised before disposal.

G1 SiC Reactor (8 mL internal volume silicon carbide fluidic

Concatenated continuous flow preparation of 1-chloro-1-

modules for the preparation of rac-3b and rac-3k). Feed and nitrosocyclopentane 1a (lab scale). The feed solution of

collection lines consisted of PFA tubing (1/8″ or 1/4″ o.d.) sodium hypochlorite (1.5 M in water) and an aqueous solution

equipped with PFA or SS Swagelok connectors and ferrules. of acetic acid and tert-butanol (1 M, 1 : 1) were both injected at

Liquid feeds were handled with Corning® dosing lines (FUJI 0.1 mL min⁻¹and reacted in a PFA capillary coil for 5 min at

Technologies™ and HNP Mikrosysteme pumps). The reactor 25 °C. MTBE was injected downstream (0.2 mL min⁻¹) and

was maintained at reaction temperature with a LAUDA Integral tBuOCl was extracted through a short column loaded with

XT 280 thermostat. Downstream pressure was regulated with a glass beads (ϕ = 0.1 mm). After liquid–liquid separation

back pressure regulator from Zaiput Flow Technologies through a hydrophobic membrane separator, the organic

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permeate was mixed with a solution of cyclopentanone oxime 1 : 1 MTBE/MeOH mixture were added dropwise at room temp-

4a (1 M in MTBE, 0.2 mL min⁻¹) through a PEEK T-mixer and erature. The mixture was left under intense stirring for 1 h to

reacted in a PFA capillary coil (2 mL internal volume, 5 min complete neutralization (the neutralization rate was measured

residence time) at 25 °C. The reactor eﬄuent was passed through HPLC/DAD by monitoring the formation of triphenyl-

through an in-line IR spectrometer for reaction monitoring phosphine oxide, see ESI, section 2.2.15†). Upon neutraliz-

and then quenched with a stream of aqueous sodium carbon- ation, the characteristic blue color of 1a slowly faded away.

ate (10 wt%, 0.2 mL min⁻¹) under 5 bar of counterpressure.

Concatenated continuous flow α-aminohydroxylation of pro-

Downstream liquid–liquid separation through a hydrophobic piophenone 2b. A feed solution of sodium hypochlorite

membrane separator yielded 1-chloro-1-nitrosocyclopentane (1.5 M) and an aqueous mixture of acetic acid and tert-butanol

(1a) in MTBE (0.5 M). The aqueous retentate was redirected to (1 M, 1 : 1) were both injected at 0.1 mL min⁻¹though a PEEK

a waste container.

T-mixer and reacted in a PFA capillary coil for 5 min at 25 °C.

Concatenated continuous flow preparation of 1-chloro-1- MTBE was injected downstream the reactor (0.2 mL min⁻¹) to

nitrosocyclopentane 1a (mesofluidic scale). An aqueous solu- extract tBuOCl through a short column loaded with glass

tion containing tert-butanol (1 M) and acetic acid (1 M) was beads (ϕ = 0.1 mm). The biphasic mixture was next processed

reacted with another aqueous solution of sodium hypochlorite through a membrane separator. The aqueous retentate was

(2.25 M) in a Corning® Advanced-Flow™ Low Flow Reactor redirected to a waste tank. The organic permeate (tBuOCl, 1 M

(4 fluidic modules connected in series, 2.0 mL total internal in MTBE) was redirected toward a PEEK T-mixer where it was

volume, operated at 25 °C). MTBE was subsequently injected mixed with a stream of cyclopentanone oxime (4a, 1 M in

into the system and two additional fluidic modules were used MTBE, 0.2 mL min⁻¹). The resulting mixture was reacted in a

for the extraction (1 mL total internal volume, operated at PFA capillary coil (2 mL internal volume, 5 min residence

25 °C). The resulting biphasic stream was processed through a time) at 25 °C. The reactor eﬄuent was connected to an in-line

hydrophobic membrane separator. The organic permeate IR spectrometer for reaction monitoring and then quenched

(tBuOCl, 1 M in MTBE) was next mixed with a solution con- with a stream of aqueous sodium carbonate (10 wt%, 0.2 mL

taining cyclopentanone oxime (4a, 1 M in MTBE) and reacted min⁻¹). Downstream liquid–liquid separation through a hydro-

into a second reactor consisting of 3 fluidic modules con- phobic membrane separator yielded 1-chloro-1-nitrosocyclo-

nected in series (1.5 mL total internal volume, operated at pentane (1a) in MTBE (0.5 M). The organic permeate was

10 °C). The eﬄuent was next passed through an in-line IR passed through a short column loaded with molecular sieve

spectrometer for real-time monitoring under 5 bar of counter- (MS

3 Å) prior to further downstream processing. The

pressure. All pumps were set to 2 mL min⁻¹, aﬀording an esti- upstream enolization reaction involved two pumps used to

mated residence time of 30 s for the preparation of tBuOCl deliver a solution of propiophenone (2b, 0.5 M in dry THF)

and of 22.5 s for the preparation of 1a.

and LiHMDS (0.5 M in dry THF). Both pumps were set to

Concatenated continuous flow preparation of 1-chloro-1- 0.4 mL min⁻¹and the resulting mixture was reacted in a PFA

nitrosocyclopentane 1a (pilot⁸¹scale). An aqueous solution capillary coil (0.8 mL internal volume, 1 min residence time)

containing tert-butanol (1 M) and acetic acid (1 M) was mixed at 0 °C. The reactor eﬄuent from the enolization step was

with an aqueous solution of sodium hypochlorite (2.25 M) in a mixed with the stream of 1a through a PEEK T-mixer and

Corning® Advanced-Flow™ G1 Reactor (2 fluidic modules con- reacted in a PFA capillary coil (1.2 mL internal volume, 1 min

nected in series, 16 mL total internal volume, operated at residence time) at 0 °C. The reactor eﬄuent was next mixed

25 °C). MTBE was subsequently injected into the system and through a PEEK T-mixer with an aqueous solution of HCl

the extraction was carried out in an additional fluidic module (6 M) injected with a pump set at 0.4 mL min⁻¹. The mixture

(8 mL internal volume, operated at 25 °C). The resulting bipha- was reacted in a PFA capillary coil (1.6 mL internal volume,

sic stream was processed into a membrane separator. The 1 min residence time) at 60 °C. The entire setup was operated

organic permeate (tBuOCl, 1 M in MTBE) was next mixed with under 5 bar of counterpressure. A final liquid–liquid mem-

a solution containing cyclopentanone oxime (4a, 1 M in brane separator was inserted downstream and the aqueous

MTBE) and reacted in an additional fluidic module (8 mL retentate was collected at steady state, diluted with MeOH, and

internal volume, operated at 10 °C). The eﬄuent was next analyzed by HPLC/DAD (97% conv., 90% yield).

passed through an in-line IR spectrometer for real-time moni-

General

continuous

flow

protocol

for

the

toring under 5 bar of counterpressure. The reactor eﬄuent was α-aminohydroxylation of enolizable ketones 2a-u. The pumps

neutralized in a collection tank containing a solution of tri- used to deliver ketones 2a-u (0.5 M in dry THF) and LiHMDS

phenylphosphine (1 M in a 1 : 1 MTBE/MeOH mixture). All (0.5 M in dry THF) were both set to 0.1 mL min⁻¹. Both

pumps were set to 15 mL min⁻¹, aﬀording an estimated resi- streams were mixed through a PEEK T-mixer. The mixture was

dence time of 36 s for the preparation of tBuOCl and of 18 s reacted in a PFA capillary coil (0.2 mL internal volume, esti-

for the preparation of 1a.

Neutralization of

mated 1 min residence time) at 0 °C. The reactor eﬄuent was

1a. next mixed through a PEEK T-mixer with 1-chloro-1-nitroso-

1-chloro-1-nitrosocyclopentane

CAUTION: the neutralization of 1a is exothermic. To 5 mL of a cyclopentane (1a, 0.5 M in MTBE, 0.11 mL min⁻¹) and redir-

stirred solution of 1a (1 M, 5 mmol, 1 equiv.), 20 mL of a solu- ected toward a PFA capillary coil (0.31 mL internal volume,

tion of triphenylphosphine (0.25 M, 5 mmol, 1 equiv.) in a 1 min residence time) operated at 0 °C. The reactor eﬄuent

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was next mixed through a PEEK T-mixer with an aqueous solu- propiophenone 2b and 1-(3-chlorophenyl)propan-1-one 2k

tion of HCl (6 M) injected with a pump set to 0.3 mL min⁻¹

(0.5 M in dry THF) and 1a (0.5 M in MTBE) were both set to

.

The mixture was reacted in PFA capillary coil (0.61 mL internal 30 mL min⁻¹and injected in a Corning® Advanced-Flow™ G1

volume, 1 min residence time) at 60 °C. The entire setup was SiC Reactor (6 fluidic modules connected in series, 48 mL

operated under 5 bar of counterpressure. A final liquid–liquid internal volume, 48 s residence time at 0 °C). The reactor

membrane separator was inserted downstream and the eﬄuent was directly collected in aqueous HCl (1 M) under vig-

aqueous retentate was collected at steady state, diluted with orous stirring to hydrolyze the intermediate nitrone (nit-

MeOH, and analyzed by HPLC/DAD. Conversion and isolated 2b,2k). Conversion and isolated yield: starting from propiophe-

yield: starting from acetophenone 2a (3a, 70% conv., 62% none 2b (3b, 98% conv., 82% isolated yield) or 1-(3-chlorophe-

yield), propiophenone 2b (3b, 97% conv., 90% yield), 1-(p- nyl)propan-1-one 2k (3k, 88% conv., 73% isolated yield).

tolyl)propan-1-one 2c (3c, 96% conv. 88% yield), 1-(4-methoxy-

Semi batch preparation of norephedrine. The aqueous

phenyl)propan-1-one 2d (3d, 97% conv., 78% yield), 1-(benzo reactor eﬄuent from the previous pilot scale experiment with

[d][1,3]dioxol-5-yl)propan-1-one 2e (3e, 80% conv., 74% yield), 2b was poured in a separatory funnel in the presence of

1-(4-chlorophenyl)propan-1-one 2f (3f, 97% conv., 95% yield), 250 mL of HCl (1 M) and extracted with Et₂O (3 × 250 mL). The

1-(4-(trifluoromethyl)phenyl)propan-1-one 2g (3g, 79% conv., aqueous layer was concentrated under vacuum and the crude

73% yield), 1-(4-fluorophenyl)propan-1-one 2h (3h, 91% conv., residue was dissolved in 700 mL of MeOH. Subsequently,

86% yield), 1-(3-(trifluoromethyl)phenyl)propan-1-one 2i (3i, 40.7 g (1.1 mol, 2.2 equiv.) of NaBH₄were added portion wise

75% conv., 64% yield), 1-(3-nitrophenyl)propan-1-one 2j (3j, over 60 min and the mixture was stirred for 2 h at 0 °C. Then,

75% conv., 65% yield), 1-(3-chlorophenyl)propan-1-one 2k (3k, 3 M HCl (400 mL) were added to adjust the pH to 1. The

88% conv., 80% yield), 1-(2-(trifluoromethyl)phenyl)propan-1- solvent (MeOH) was then removed under reduced pressure

one 2l (3l, 77% conv., 49% yield), 1-(thiophen-2-yl)propan-1- and 700 mL of a 2 : 1 HCl/AcOH mixture were added to the

one 2m (3m, 93% conv., 60% yield), 1-phenylpentan-1-one 2n resulting solution. Afterwards, 162.5 g (2.5 mol, 5 equiv.) of

(3n, 83% conv., 79% yield), 1-phenyloctan-1-one 2o (3o, 76% zinc dust were added at 0 °C and the resulting suspension was

conv., 72% yield), 1,3-diphenylpropan-1-one 2p (3p, 89% vigorously stirred for 3 days at room temperature. The resulting

conv., 74% yield), 2-methyl-1-phenylpropan-1-one 2q (3q, 85% solid residue was removed by filtration and the pH of the fil-

conv., 82% yield), cyclobutyl(phenyl)methanone 2r (3r, 87% trate was adjusted to 14 using a 50 wt% sodium hydroxide

conv., 84% yield), cyclohexyl(phenyl)methanone 2s (3s, 78% aqueous solution. Brine (250 mL) was added and the crude

conv., 75% yield), cyclopentyl(phenyl)methanone 2t (3t, 82% reaction mixture was extracted with Et₂O (5 × 500 mL) to give a

conv., 72% yield), (2-chlorophenyl)(cyclopentyl)methanone 2u colorless ethereal solution. The ethereal solution was dried

(3u, 98% conv., 80% yield).

over MgSO₄, filtered and concentrated under reduced pressure

Continuous flow protocol for the α-aminohydroxylation of to give crude norephedrine as a white solid. The solid was

ketone 2v under thermodynamic or kinetic conditions. The then recrystallized in Et₂O/hexane (1 : 2) to give 43 g (59%

pumps used to deliver 2-phenylcyclohexan-1-one (2v, 0.5 M in overall isolated yield) of pure norephedrine.

dry THF) and either LiHMDS (0.5 M in dry THF, kinetic con-

ditions) or potassium tert-butoxide (0.5 M in dry THF, thermo-

dynamic conditions) were both set to 0.1 mL min⁻¹. Both

streams were mixed through a PEEK T-mixer and the resulting

Results and discussion

Continuous flow preparation of α-chloronitroso species

mixture was reacted in a PFA capillary coil (0.2 mL internal

volume, 1 min residence time) at either 0 °C (kinetic con- α-Chloronitroso species are typically prepared from a variety of

ditions) or 25 °C (thermodynamic conditions). The reactor substrates,^85–89although the corresponding oximes are typi-

eﬄuent was next mixed through a PEEK T-mixer with 1-chloro- cally privileged substrates. The most represented protocols use

1-nitrosocyclopentane (1a, 0.5 M in MTBE, 0.11 mL min⁻¹). chlorine-based oxidizers. Procedures based on chlorine gas

The resulting mixture was reacted in a PFA capillary coil were amongst the earliest reported.^{65,84,90–96}Given the hazards

(0.31 mL internal volume, 1 min residence time) at 0 °C. The related with the handling of Cl₂gas on a preparative scale, a

reactor eﬄuent was next mixed through a PEEK T-mixer with procedure relying on its in situ generation from aqueous H₂O₂/

an aqueous solution of HCl (6 M) injected with a pump set at HCl was reported by Terent’ev for the preparation of various

0.3 mL min⁻¹. The mixture was reacted in a PFA capillary coil α-chloronitroso compounds.⁹⁷Alternative methods based on

(0.61 mL internal volume, 1 min residence time) at 60 °C. The N-chloroderivatives such as N-tert-butyl-chlorocyanamide,⁹⁸

entire setup was operated under 5 bar of counterpressure. A N,N′-dichloro bis(2,4,6-trichlorophenyl)urea,⁹⁹1-chloro-1H-

final liquid–liquid membrane separator was inserted down- benzo[d][1,2,3]triazole,⁷⁹or N-chlorosuccinimide,⁸²provided a

stream and the aqueous retentate was collected at steady state, low atom economy¹⁰⁰and

a high environmental factor

diluted with MeOH, and analyzed by HPLC/DAD (kinetic con- (E-factor).¹⁰¹Hypochlorites have attracted attention for con-

ditions: 3v-1, 77% conv., 66% isolated yield; thermodynamic verting oximes into α-chloronitroso compounds since the early

conditions: 3v-2, 81% conv., 71% isolated yield).

1960s,¹⁰²and either inorganic¹⁰³or organic^38,102hypochlorites

Pilot scale α-aminohydroxylation of enolizable ketones 2b can be utilized. Among organic hypochlorites, tBuOCl (Fig. 4)

and 2k. The pumps used to deliver the enolates derived from emerged as a convenient and readily available reagent. The

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extraction with an organic solvent. Chlorinated solvents such

as dichloromethane and chloroform gave high extraction

eﬃciency and facilitated the in-line NMR monitoring of the

reaction, yet their environmental impact led us to consider

MTBE as a greener alternative. Compared to other ethereal sol-

vents, MTBE is considered as a safer option since it does not

form potentially explosive peroxides and does not react with

tBuOCl.^65,104A column packed with glass beads (φ = 0.1 mm)

was inserted before the membrane separator to enhance the

extraction eﬃciency, giving tBuOCl in 98% yield (ESI, Fig. S1

and Table S3†). The aqueous eﬄuent from the membrane

separator was collected in a waste. The ability to produce

tBuOCl in a first generator and to directly use it downstream

for reaction with oximes enhances process safety, since it

avoids its isolation and storage. Adjustment of the flow of

MTBE enabled the preparation of a 1 M solution. During the

preliminary development stages of the flow process toward

tBuOCl, oﬀ-line redox titration was carried out to determine

its concentration after extraction (ESI, section 2.2.2†). After

optimization, oﬀ-line titration was conveniently replaced with

Fig. 4 (a) The method of Mintz and Walling⁸¹for the preparation of

tBuOCl in batch. (b) Simpliﬁed microﬂuidic ﬂowchart (Generator I) for

the preparation of tert-butyl hypochlorite (tBuOCl) showcasing the

extraction module. The column packed with glass beads upstream the

membrane separator is omitted for clarity (ESI for details, section 1.5.1†).

An in-line, low ﬁeld NMR can be inserted downstream to monitor the

conversion of tBuOH into tBuOCl (see ESI section 2.2.3†).

1

in-line low field H NMR monitoring (ESI, section 2.2.3†). The

first procedures were reported using trichlorofluoromethane organic eﬄuent can be collected over CaCl₂and stored at low

as solvent, a banned chemical responsible for the ozone layer temperatures, preferably in a brown glass bottle. Samples

depletion.³⁸

could be maintained accordingly for several months, yet a

A typical procedure for the preparation of tBuOCl follows direct concatenation to downstream operations is highly desir-

an adaptation of the method of Mintz and Walling⁸¹and con- able for mitigating chemical hazards.

sists of reacting sodium hypochlorite with tert-butanol in the

Since the cyclopentyl and cyclohexyl nitroso derivatives 1a,b

presence of acetic acid at 0 °C in the dark (Fig. 4a). are the most described α-chloronitroso reagents for electrophi-

Commercial bleach can advantageously replace aqueous solu- lic amination reactions in the literature,^57–62,65they were

tions of reagent grade sodium hypochlorite. The formation of selected as model compounds for the optimization of

tBuOCl is almost instantaneous, and it separates from the Generator II (Fig. 5b). The corresponding cyclopentanone and

aqueous reaction mixture. The absence of precipitates makes cyclohexanone oximes 4a,b, respectively, are readily available

the transposition under continuous flow conditions straight-

forward, yet it was never reported.

tBuOCl is an extremely potent electrophilic chlorinating

agent that oﬀers one of the most convenient and atom-econ-

omic procedures for accessing α-chloronitroso species from

oximes. Unlike chlorine, its handling is facilitated by its liquid

nature, although its toxicity, photo- and thermal instability

raise significant safety concerns even for lab scale operation.

Handling of tert-butyl hypochlorite as a secondary oxidizer

thus justifies a flow protocol to maintain discrete amounts at

any time upon operation. The formation of tBuOCl is con-

veniently achieved from widely accessible commercial com-

pounds, including aqueous NaOCl, AcOH and tBuOH. Under

continuous flow, the formation of tBuOCl is completed (>99%

conversion) within 5 min of residence time with an optimal

NaOCl/tBuOH/AcOH ratio of 1.5 : 1 : 1 (Fig. 4b).

Generator I was constructed from PFA coils and HPLC-type

connectors. In a typical procedure, a feed solution of NaOCl in

Fig. 5 (a) Use of tBuOCl for the conversion of oximes 4a,b into the

water (1.5 M) and a feed solution of tBuOH (1 M) and AcOH corresponding α-chloronitroso species 1a,b. The advancement of the

(1 M) in water were injected at 0.1 mL min⁻¹through a static

T-mixer and reacted for 5 min at 25 °C in a PFA coil; a stream

reaction can be qualitatively monitored with the appearance of the

typical blue color of nitroso derivatives 1a,b. Typical reaction conditions

imply the slow addition of tBuOCl at room temperature over 30 min. (b)

Simpliﬁed microﬂuidic ﬂowchart for Generator II for the production of

of MTBE was injected downstream to extract tBuOCl. Although

tBuOCl is poorly soluble in aqueous medium, its recovery

model α-chloronitroso species 1a,b showcasing the in-line IR and the

through membrane separation was drastically enhanced upon extraction module.

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and can be ordered on the multikilogram scale (Fig. 5a). The each) embedded with a heat exchanger and connected in

next step thus consisted in the downstream use of tBuOCl for series to mimic the microfluidic configuration of Generators

the conversion of oximes 4a,b into 1a,b (Fig. 5b).

I–II (Fig. 4b and 5b). Upon minimal readjustment of the

One of the main challenges for optimizing the second gen- process conditions (ESI, section 2.2.13†), the process was then

erator relied on the appropriate selection of an oﬀ- or in-line transposed to pilot scale with a modular Corning® Advanced-

analytic protocol to monitor reaction optimization. The Flow™ G1 reactor (Fig. 6).

unstable nature of α-chloronitroso species precluded direct iso-

The transposition of Generator I to the pilot scale involved

lation and characterization via typical oﬀ-line analytic pro- 2 G1 fluidic modules (FMs) connected in series (8 mL internal

cedures such as NMR, GC and HPLC. We opted for non- volume each) and operated at 25 °C for the reaction of an

destructive in-line IR spectroscopy (ESI, section 2.2.18†), pro- aqueous solution containing tert-butanol (1 M) and acetic acid

viding a very convenient protocol to optimize reaction para- (1 M) with aqueous sodium hypochlorite (2.25 M) within 36 s

meters by monitoring the relative variations of the specific of residence time. The eﬄuent from Generator I was mixed

vibration bands of the starting oxime (˜υ_OH= 3550–3600 cm⁻¹

˜υ_CN= 1665–1720 cm⁻¹) and of the corresponding nitroso formed in an additional FM (8 mL internal volume) operated

derivatives (˜υ_NO= 1539–1621 cm⁻¹).

at 25 °C. The resulting biphasic stream was next processed

,

with a stream of MTBE and the extraction of tBuOCl was per-

The organic eﬄuent coming from the upstream Generator through a pilot scale membrane separator (Zaiput Flow

I, consisting of a 1 M solution of tBuOCl in MTBE, was then Technologies liquid–liquid separator SEP-200) equipped with a

redirected to the upstream section of the Generator II (Fig. 5b), PTFE hydrophobic membrane (1 μm pore size). Qualitative

1

where it was mixed with a solution of oxime 4a (1 M in MTBE, monitoring was carried out through in-line low field H NMR

0.1 mL min⁻¹) and reacted at 10 °C for 5 min in a PFA coil. (ESI, section 2.2.3†). The MTBE permeate (tBuOCl, 1 M) was

The reactor eﬄuent was continuously extracted with an next redirected to Generator II, where it quantitatively reacted

aqueous 10 wt% Na₂CO₃solution and separated through with oximes 4a,b into another FM (8 mL internal volume)

hydrophobic membrane technology. The final extraction was operated at 10 °C with a residence time of 18 s (Fig. 6).

paramount to remove traces of acetic acid, tBuOH and other

The outlet of Generator II was connected through a

by-products that would otherwise interfere with downstream sampling loop to an in-line IR spectrometer for real-time

operations. The aqueous stream was redirected to a waste and monitoring. The reactor eﬄuent was collected in a tank con-

the organic permeate was collected. Residual water in the taining a solution of triphenylphosphine (1 M) for chemical

organic stream (1a in MTBE) was determined by Karl-Fisher destruction.^84,105,106Once the generation of nitroso was vali-

titration (ESI, section 2.2.19†). The titration results empha- dated on the pilot scale, the α-aminohydroxylation step was

sized that the membrane performed very well, with a residual considered.

water content of 19 ppm in the organic MTBE permeate;

further drying with MS 3 Å decreased the moisture content to

3

ppm. Downstream telescoping with the actual

α-aminohydroxylation would therefore require the addition of

a drying column filled with MS 3 Å on the permeate prior to

injection over enolates (see section “α-Aminohydroxylation on

model ketones 2a,b” below).

The conversion toward compound 1a was quantitative, and

the process was extended for the production of 1b and per-

formed likewise. The organic eﬄuent can be collected over

CaCl₂and stored at −8 °C, preferably in a brown glass bottle.

Samples could be maintained accordingly up to 2 weeks, yet a

direct concatenation to downstream operations is highly desir-

able. In view of the preparation of rac-α-aminohydroxylated

ketones, the development of a reliable Generator II of nitroso

1a,b was considered as suﬃcient milestone, although

Generator II was also amenable for the preparation of a small

library of other α-chloronitroso derivatives (see ESI section

2.2.17† for details) upon minor temperature adjustments.

Fig. 6 Close-up of the pilot scale Generator II relying on an 8 mL

internal volume Corning® Advanced-Flow™ G1 reactor ﬂuidic module

with integrated HEART™-shape static mixers (courtesy of Corning®).

The total residence time is 18 s, yet the characteristic blue color accom-

panying the formation of α-chloronitroso 1a,b appears nearly instan-

taneously after the injection of tBuOCl and oximes 4a,b. FM1: ﬂuidic

module; H1,2: in/outlets for thermoﬂuid; I1: inlet for tBuOCl (1 M MTBE,

feeding from backside); I2: inlet for oximes 4a,b (1 M MTBE, feeding

Assessment of scalability for Generators I–II

With the optimization of Generators I–II on the microfluidic

scale, we next envisioned its progressive scalability from lab to

pilot scales. The first step of the transposition relied on a

modular Corning® Advanced-Flow™ Low Flow reactor. The

mesofluidic setup consisted of glass fluidic modules (0.5 mL from backside); O1: outlet for α-chloronitroso 1a,b in MTBE.

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α-Aminohydroxylation on model ketones 2a,b

total reaction time). LC monitoring however indicated that the

reaction with cyclopentyl α-chloronitroso 1a was faster and

more selective than with 1b. This observation was further con-

firmed under microfluidic conditions (ESI, section 2.2.16†),

hence further trials were only conducted with 1a.

The ability to produce a reliable and steady stream of 1a,b

opens up new possibilities for downstream electrophilic amin-

ation setup. We shifted gears for revisiting Oppolzer’s^57–62

electrophilic amination under continuous flow conditions.

Two simple enolizable ketones were selected as model sub-

strates: acetophenone 2a and propiophenone 2b. While the

electrophilic amination with ketone 2a was never reported in

the literature, 2b served as a privileged target in Oppolzer’s

work, since it is a fast track entry toward (pseudo)ephedrine

and related APIs. 2b would hence set boundaries and would

help us to calibrate our protocol.

The typical procedure in Oppolzer’s original papers relied

on the formation of a sodium enolate at low temperature, fol-

lowed by the electrophilic amination with 2b in the presence

of a Lewis acid, such as ZnCl₂or Zn(OTf)₂. A direct transposi-

tion under microfluidic conditions systematically led to clog-

ging. However, computations on model compounds indicated

that the reaction in the presence and in the absence of ZnCl₂

provides similar reaction profiles, hence indicating that Zn²⁺

catalysis is in fact not mandatory for this reaction (ESI, sec-

tions 2.2.7 and 4.1†). Accordingly, going back to batch prelimi-

nary optimizations (Fig. 7), lithium bis(trimethylsilyl)-amide

(LiHMDS) was identified as the best performing base for the

rapid and complete enolization of 2b in the presence of

nitroso compounds 1a,b (ESI, section 2.2.14†) and in the

absence of any Lewis acid at −78 °C in THF/MTBE (30 min

Complete conversion to nitrone nit-2b was reached after

90 min in batch. Nitrone nit-2b was next hydrolyzed with

aqueous HCl (1 M) for 12 h at room temperature, leading to

the desired α-aminohydroxylated ketone rac-3b (in 90% iso-

lated yield; Fig. 7a). From this preliminary optimization, it

came out that the slow addition of 1a at low temperature was

critical to avoid vigorous exothermic decomposition. With this

in hand, the α-aminohydroxylation was attempted on aceto-

phenone 2a. The conversion was complete, yet the product

obtained was not the expected α-aminohydroxylated ketone 3a,

but amidoxime 5 (Fig. 7a), the structure of which was con-

firmed by X-ray diﬀraction.¹⁰⁷We reasoned that the formation

of 5 would occur from two consecutive α-aminohydroxylations

on 2a. Further optimizations did not yield the desired

α-aminohydroxylated ketone compound (3a).

In order to identify the main parameters governing the reac-

tivity and the selectivity of the α-aminohydroxylation, compu-

tations (see ESI, section 4.2†) were undertaken starting from

the lithium enolates en-2a and en-2b (Fig. 7b). Experimentally,

a second amination is only observed in the case of 2a, leading

after hydrolysis to amidoxime 5. Our calculations predicted

that for both en-2a and en-2b, the electrophilic amination with

1a proceeds with no enthalpy barrier, meaning that it is extre-

mely fast and diﬀusion-controlled. The main hypothesis was

that the second electrophilic amination proceeds through

deprotonation of nit-2a,b by enolate en-2a,b to form en-nit-2a

and en-nit-2b, respectively. The latter would then add onto

another equivalent of 1a to yield bisnitrone adducts (bis-nit-2a

and bis-nit-2b) upon the elimination of chloride. These latter

would next undergo acidic hydrolysis to yield the corres-

ponding amidoximes, yet experimentally this only happens for

2a. Our computational study revealed that the acid–base equili-

brium toward en-nit-2a and en-nit-2b involves a low free

energy barrier (ΔG^‡= 3.7 and 9.4 kcal mol⁻¹for nit-2a and nit-

2b, respectively) and is highly displaced toward the formation

of en-nit-2a and en-nit-2b (ΔG = −22.8 and −19.7 kcal mol⁻¹

for en-nit-2a and en-nit-2b, respectively). Subsequent addition

onto cyclopentyl α-chloronitroso 1a occurs with a free energy

barrier of 11.4 and 19.5 kcal mol⁻¹for en-nit-2a and en-nit-2b,

respectively. These results indicate that the selectivity for the

first amination vs. the second amination must be determined

by the competition between the addition onto 1a and the

deprotonation of nit-2a and nit-2b, respectively. In both

cases, for en-2a,b, the addition onto 1a (first amination) is

diﬀusion-controlled (vide supra). Concerning the deprotona-

Fig. 7 (a) Electrophilic amination of acetophenone 2a and propiophe- tion, for nit-2a, it involves a free energy barrier of 3.7 kcal

mol⁻¹, meaning that the rate of this step (k ∼ 6.10⁹M⁻¹s⁻¹) is

none 2b with cyclopentyl α-chloronitroso 1a under optimized con-

ditions. (b) Computations at the B3LYP-D3/6-311+G**(MTBE)//

B3LYP-D3/6-31+G*(MTBE) level of theory for the electrophilic amination

of the enolates of acetophenone (en-2a) and of propiophenone (en-2b),

respectively. Free energy barriers are indicated in orange (kcal mol⁻¹).

Cp = cyclopentyl. See ESI (section 4.2†) for details.

also at, or very close to, the diﬀusion limit. In the case of nit-

2a, the free energy barrier is higher (9.4 kcal mol⁻¹),

predicting a rate significantly lower than the diﬀusion limit

(k ∼ 2.10⁵M⁻¹s⁻¹).

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From our computational study, it became clear that in the

case of ketone 2a, the second amination is competitive, hence

leading to the bis-amination product 5 in the presence of a

local excess of enolate en-2a. Any inhomogeneity in the reac-

tion mixture (typically related to ineﬃcient mixing in batch)

leads to poor control of the local stoichiometry, hence trigger-

ing side reactions. It is now well accepted that reactions sensi-

tive to local stoichiometry can be advantageously developed

under continuous flow conditions, often with a significant

reduction in side reactions.^74,108

With this mechanistic understanding, we envisioned the

transposition of the electrophilic amination of model ketones

2a,b under microfluidic conditions. Three steps had to be

implemented according to a concatenated microfluidic setup

relying on three modules (Fig. 8a). The first module was dedi-

cated to the enolization of ketones 2a,b with LiHMDS. The

improved heat exchange eﬃciency under continuous flow con-

ditions is typically exploited to perform highly exothermic reac-

tions at higher temperatures than batch would normally

allow.^108,109Upon optimization, the enolization of ketone 2a in

module I required 1 min of residence at 0 °C with 1.1 equiv. of

LiHMDS in THF (0.5 M), rather than typically −78 °C in batch.

The eﬄuent of module I was then directly mixed with a stream

of 1a (0.5 M in MTBE), in provenance from Generator II that

was operated continuously to feed the electrophilic amination.

Screening of the electrophilic amination conditions on

model ketones 2a,b emphasized that the electrophilic amin-

ation reaction could advantageously be performed at a much

higher temperature in flow (0 °C) than in batch (typically

−78 °C), while avoiding decomposition and reaching almost

quantitative conversion within 1 min of residence time

(Fig. 8b). Higher temperatures than 0 °C for shortening the

residence time even further are not advised in flow since two

runs at room temperature led to the explosive decomposition

of the reaction mixture.

Fig. 8 (a) Fully concatenated setup showing Modules I (enolization), II

(electrophilic amination, connected upstream to Generator II) and III

(hydrolysis) for the electrophilic amination of enolizable ketones 2a,b

with α-chloronitroso 1a. The organic permeate was further processed to

recover cyclopentanone, which could be converted back to cyclopenta-

none oxime 4a with 83% yield and could be used to feed Generator II.

(b) Screening of the reaction conditions for the electrophilic amination

of model substrate 2b with nitroso 1a under continuous ﬂow conditions.

The number in the isovalue plot indicates the HPLC conversion of 2b. At

room temperature, exothermic decomposition of nitroso 1a occurred

leading to either clogging or rupture of module II.

The final hydrolysis of nitrone nit-2a,b was performed in

module III. The eﬄuent from module II was immediately

mixed with aqueous HCl (6 M) at 0.3 mL min⁻¹and reacted in

a PFA coil. Increasing the temperature from room temperature

to 60 °C in module III led to a significant reduction in reaction

time, conversions up to 97% being attained within 1 min. The

conversion of ketones 2a,b was of 70 and 96%, respectively,

with a quantitative selectivity within 3 min of total residence

time toward the desired α-aminohydroxylated ketones 3a,b (as

their hydrochlorides), with no traces of the bisamination

product 5. The fast mixing and fine control on the local stoi- carefully engineered in order to avoid the contamination of

chiometry, as well as the eﬀective concatenation helped sup- active pharmaceutical ingredient intermediates with poten-

pressing the occurrence of an amidoxime by-product 5. tially toxic nitroso compounds.

Besides, the electrophilic amination on primary enolizable

ketones was never reported with nitroso derivatives.

The insertion of a hydrophobic membrane separator, com-

bined with an upstream hydrolysis with hydrochloric acid, pro-

A final in-line membrane separation step was integrated to vided a simple yet elegant and robust solution to segregate the

module III to eﬀect continuous separation between the nitroso-containing

organic permeate from the

aqueous stream containing essentially pure 3a,b as their α-aminohydroxylated ketone hydrochlorides in water. The

hydrochlorides and the organic eﬄuent containing traces of organic permeate was treated with PPh₃(1 M in THF) to neutral-

unreacted nitroso 1a and any other organic by-products (ESI, ize any leftover of 1a. The aqueous eﬄuent was collected, and

section 2.2.20†). The design of the downstream extraction was processed to recover 3a,b as free bases (ESI, section 2.2.7†). The

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aspects of recovering and reusing the nitroso carbon backbone

from the organic permeate were also considered. The permeate

was further processed to recover cyclopentanone, that could be

converted back to cyclopentanone oxime 4a with 83% isolated

yield (ESI, section 2.2.9†). The recovery of the carbon backbone

of nitroso 1a significantly reduces the overall footprint of the

process, since the cyclopentyl backbone is only borrowed as a

vehicle for transferring a hydroxylamine electrophilic synthon

to the enolizable ketone substrate (Fig. 8a).

Scope of the α-aminohydroxylation with nitroso 1a

With a fully functional continuous flow system including a

chemical generator for nitroso species 1a and a modular setup

for the electrophilic amination of model enolizable ketones,

we aimed at pushing further the horizon of the microfluidic

setup. An ideal scenario would be to keep the same setup

while only changing the feed solution of enolizable ketone

substrates and assess its potential for the edition of discrete

libraries of α-aminohydroxylated ketones. Following this idea,

the setup was left unchanged and the reactor was fed with

various enolizable ketones (Fig. 9 and 10), preferably bearing

an aromatic ring to facilitate oﬀ-line LC monitoring.

We began exploring the scope of this protocol with deriva-

tives of propiophenone 2b-l, from which several biologically

active molecules can be accessed through this procedure,

including norephedrine (from 3b), cathinone (from 3b),

mephedrone (from 3c) and bupropion (from 3k).

Feed solutions of ketones 2b-l were prepared in dry THF

(0.5 M) and successively subjected to electrophilic amination

with nitroso 1a, giving the corresponding hydrochlorides of

α-aminohydroxylated ketones rac-3b-l. Neutralization, followed

by extraction in MTBE and evaporation gave rac-3b-l free bases

in 49–95% isolated yield (for some examples, the hydro-

chloride was isolated and analyzed, see ESI, sections 2.3, 2.5

and 2.6†). Analytical samples were obtained through either

recrystallization or after column chromatography on silica gel.

The lowest conversion and isolated yield concerned rac-3l that

features an ortho-CF₃group, which might sterically hamper

the reaction. For all other propiophenone-related substrates,

EWG-substituted derivatives came with a slightly lower conver-

sion, which most likely relates to a lower nucleophilicity of the

corresponding enolates. The diﬀerence with EDG-substituted

propiophenone derivatives is, however, diﬃcult to exploit

according to a Hammett relationship.

The conditions are also amenable to heteroaromatic ketone

2m (93% conv.) and sterically more demanding 2n (83% conv.)

and 2o (76% conv.). Besides secondary ketones (2b-p), the elec-

trophilic amination under flow conditions was also success-

fully applied to a variety of tertiary enolizable ketones, hence

providing quaternary α-aminohydroxylated ketones 3q-u in

good to high isolated yields (72–84%). Unexpected oxidation

products were obtained for two additional substrates (diethyl

malonate and 2-phenylacetophenone) that are only described

in the ESI (sections 2.3, 2.5 and 2.6†).

Fig. 9 Scope of the electrophilic amination on primary, secondary and

tertiary ketones. Conversion and isolated yield (in parentheses) are indi-

cated. All compounds were obtained according to the setup described

in Fig. 8a. See also Fig. 10.

Our interest toward ketamine and analogs⁷⁵prompted us to

consider (rac)-2-phenylcyclohexanone (2v) as a substrate. In

2346 | Green Chem., 2021, 23, 2336–2351

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was simplified to spare resources, and we focused the eﬀorts on

the most critical steps (module 2). The hydrolysis of the nitrone

was carried out in a collection tank. Two pharmaceutically rele-

vant intermediates were selected as demonstrators, namely,

2-(hydroxyamino)-1-phenylpropan-1-one (rac-3b) and 1-(3-chloro-

phenyl)-2-(hydroxyamino)propan-1-one (rac-3k), which are

advanced intermediates for the preparation of norephedrine and

bupropion, respectively.

The process was then transposed to pilot scale with a

Corning® Advanced-Flow™ G1 SiC Reactor (ESI sections 1.5.8

and 2.2.21†). Silicon carbide was selected here rather than

glass to avoid any corrosion issue with LiHMDS. The setup for

the pilot scale α-aminohydroxylation involved several G1 SiC

FMs connected in series (about 48 mL total internal volume)

and operated at 0 °C. To simplify the setup, preformed solu-

tions of the enolates (0.5 M) derived from 2b (en-2b) or 2k (en-

2k) were prepared by mixing LiHMDS with the enolizable sub-

strate and maintaining the feed solutions at 0 °C. The reactor

eﬄuent from pilot scale Generator II was dried with MS 3 Å

and was reacted with enolates en-2b,k. With a total flow rate of

60 mL min⁻¹, a shorter residence time than for the microflui-

dic scale was obtained (48 s). The reactor eﬄuent was collected

directly in aqueous HCl (1 M) to perform the hydrolysis of the

intermediate nitrones nit-2b,k toward the corresponding

α-aminohydroxylated ketones rac-3b and rac-3k in the collec-

tion flask. Samples were collected at steady state and hydro-

lyzed prior to LC analysis. Daily productivities of 3.49 kg (98%

conv., 82% isolated yield) and of 3.19 kg (88% conv., 73% iso-

lated yield) were achieved for rac-3b and rac-3k, respectively.

Both compounds were further reduced in batch for the prepa-

ration of norephedrine and analogs.

Fig. 10 (a) Adaptation of the microﬂuidic setup to 2-phenylcyclohexa-

none (2v) for the electrophilic amination under kinetic or thermo-

dynamic conditions. (b) Details of the area of interest for the ¹³C APT

spectra of the kinetic and thermodynamic α-aminohydroxylated ketones

3v-1,2 compared to the starting ketone 2v.

contrast to the other substrates of the study, 2v bears two

potentially enolizable positions, hence providing either a

direct precursor of norketamine and ketamine (3v-2) or an

analog (3v-1, Fig. 10). The selectivity between the two enoliz-

able sites is a classical control of kinetic vs. thermodynamic

conditions for the generation of the corresponding enolates

kin-en-2v and therm-en-2v. Module I of the microfluidic plat-

form described in Fig. 8a was adapted accordingly (Fig. 10):

the formation of kin-en-2v was obtained as previously, within

1 min of residence time at 0 °C with LiHMDS (0.5 M in THF),

while the formation of therm-en-2v was performed at room

temperature, within 1 min of residence time with tBuOK

(0.5 M in THF). The rest of the setup was left unchanged.

Under kinetic conditions for the formation of the enolate,

the electrophilic amination occurred selectively at the least

substituted position, thus leading to the formation of the

corresponding secondary α-aminohydroxylated ketone 3v-1 in

66% isolated yield (77% conv.). With module I operated at

room temperature for the enolization of 2v with tBuOK, the

electrophilic amination occurred selectively at the thermo-

dynamic position, yielding α-aminohydroxylated ketone 3v-2 in

71% isolated yield (81% conv.).

Discussion on the overall footprint of the electrophilic amination

Besides the unquestionable safety assets of such an integrated

platform that concatenates two upstream continuous flow gen-

erators of highly reactive species (tBuOCl and nitroso 1a), its

versatility was also demonstrated through the generation of

libraries of structurally diverse α-aminohydroxylated ketones.

On the microfluidic scale, the electrophilic amination platform

could be deployed for feeding upstream the process of discovery

of new hits/leads in medicinal chemistry, or at least accelerating

the preparation of α-aminoketone and β-amino alcohol

scaﬀolds. Besides operation at the lab scale, we have also

demonstrated the scalability of each step, opening up perspec-

tives on the production scale with low footprint reactors. The

fully concatenated system, including Generators I–II and the

3 modules for the electrophilic amination step was successfully

transposed to pilot scale in a commercial mesofluidic reactor

with a minimal footprint (L × W × H 94 × 42 × 40 cm), excluding

the auxiliaries, i.e. pumps, thermostats and in/oﬀ-line analytical

devices. The assets of flow chemistry were clearly demonstrated

Assessment of scalability for the electrophilic amination

With a wide chemical compatibility and the potential for rapidly in terms of high heat exchange eﬃciency (with reactions per-

accessing libraries of structurally diverse α-aminohydroxylated formed at much higher temperatures than conventional batch

ketones, this method has proven its added-value for R&D appli- processes) and in terms of mixing eﬃciency and control over

cations. In the next stage of the project, we wanted to assess the the local stoichiometry (with the suppression of a bisamination

scalability of the critical electrophilic amination step. The setup by-product for a model primary ketone).

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Besides process performance, the chemistry developed is (<0.1 for oil refining; <1–5 for bulk chemicals; 5–50 for fine

also advantageous according to its calculated environmental chemicals and 25–100 for pharmaceuticals). Since the context

factor (E-factor) (ESI, section 3.1†). The E-factor was calculated of this research is at the interface between fine chemicals and

according to the equation [E-Factor = (mass of total inputs) − pharmaceuticals, an E-factor comprised between 5–100 would

(mass of valuable products)/mass of valuable products] and be acceptable.

following the recommendations of Andraos.¹¹⁰The two main

From the analysis of the E-factors presented in Table 1, it

elements of the process, namely the preparation of nitroso 1a can be seen that our electrophilic amination procedure is very

and the electrophilic amination on acetophenone 2b as a favorable (entry 1). It outclasses previous protocols for the

model substrate, were compared with similar strategies preparation of nitroso 1a with an E-factor = 6. It is also worth

reported in the literature, and their respective E-factors were mentioning that the carbon backbone of 1a is recyclable (see

calculated and compared (see Table 1). As a brief reminder, above). For the electrophilic amination, one can see from

E-factor values inherently relate to the nature of the process Table 1 that a calculated E-factor of 11 was obtained for this

protocol (entry 5), which is very competitive given the complex-

ity of the sequence, despite the fact that the protocol produces

racemic α-aminohydroxylated ketones (enantioselective

Table 1 Calculated environmental factors (E-factors) for the prepa-

version: see entry 8, E-factor = 26).

ration of 1a and the subsequent electrophilic amination step

A more refined analysis was next performed using the semi-

quantitative EcoScale from EcoSynth.^114,115The EcoScale con-

siders various parameters with a direct impact on the output

of a reaction (i.e. yield, costs of chemicals, safety, technical

setup, energy requirements, as well as work up & purification).

Generator I is associated with an honourable score of 81% on

the EcoScale, while Generator II is associated with a score of

76% (ESI, section 3.2†). The electrophilic amination on 2b as

described in this manuscript came with a score of 60% (the

calculation does not consider the recycling of the carbon back-

bone of nitroso 1a that ultimately makes the process even

more appealing), which constitutes a significant improvement

compared to the score of 43% obtained for the adaptation of

Oppolzer’s original amination in batch.

Starting

Entry material

Reagents and

solvents

Product

E-factor

Preparation of α-chloronitroso 1a

1

tBuOCl MTBE

6^a

2

34% aq. HCl

37% aq. H₂O₂

CH₂Cl₂

32 (ref. 97)

3

4

11 (ref. 79)

12 (ref. 99)

Electrophilic amination on propiophenone 2b and derivatives

11^a

Conclusion

5

This work discloses a unique, scalable and eﬃcient continu-

ous flow strategy for the preparation of libraries of

α-aminohydroxylated ketones in good to high isolated yields

from the corresponding enolizable ketones and reactive

α-chloronitroso 1a. A library of 22 α-aminohydroxylated

ketones was prepared starting from primary, secondary and

tertiary ketones, hence opening the way to several intermedi-

ates for pharmaceutical production (including WHO essen-

tials and drugs on shortage). The development of a fully con-

catenated setup, featuring two upstream generators, enables

to exploit the unique reactivity profile of α-chloronitroso

derivatives to its fullest potential while mitigating chemical

risk. The main assets of continuous flow processing, includ-

ing high heat exchange and mixing eﬃciencies, the pro-

duction of discrete amounts of toxic and potentially explosive

compounds as well as the integration of in-line analytics were

very supportive for the design of a modular, safe and eﬃcient

integrated flow protocol. The careful selection of reaction

conditions and chemicals, as well as the design of simple yet

robust downstream purification and recycling protocols con-

tributed to a significant reduction in overall footprint.

Beyond the development of robust conditions in conjunction

6

7

8

18 (ref. 111)

10 (ref. 112)

26 (ref. 59)

9

34 (ref. 113)

^aThis work.

2348 | Green Chem., 2021, 23, 2336–2351

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with favorable metrics, this work also discloses a versatile

platform amenable to either discovery on lab scale or to pro-

duction at commercial scale. While maintaining a compact

and highly integrated reactor setup design (<2 m²including

the auxiliaries) for the final demonstrator, a productivity

of up to 3.49 kg per day of high value-added

α-aminohydroxylated ketone intermediates was achieved.

Work is now undergoing for the development of recyclable

chiral α-chloronitroso derivatives, which would not only serve

as vehicles for NH₂OH, but also for transferring stereochemi-

cal information to the ketone substrates.

10 R. Dorel, C. P. Grugel and A. M. Haydl, Angew. Chem., Int.

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Conﬂicts of interest

There are no conflicts to declare.

19 Z. Zhou and L. Kürti, Synlett, 2019, 30, 1525–1535.

20 WHO Model Lists of Essential Medicines, https://www.

who.int/medicines/publications/essentialmedicines/en/,

(Accessed on December 28, 2020).

21 Drug shortages, https://www.fda.gov/drugs/drug-safety-

and-availability/drug-shortages, (Accessed on December

28, 2020).

Acknowledgements

This work was supported by the University of Liège (Welcome

Grant WG-13/03, JCMM) and by the F.R.S.-FNRS (Incentive

grant for scientific research MIS F453020F, JCMM).

Computational resources were provided by the “Consortium

des Équipements de Calcul Intensif” (CÉCI), funded by the

“Fonds de la Recherche Scientifique de Belgique” (F.R.S.-FNRS)

under Grant No. 2.5020.11 and by the Walloon Region. VEK

and TT are FRIA PhD fellows. KVH thanks the Research

Foundation – Flanders (FWO) (projects AUGE/11/029 and

G099319N) for funding. RR is a Maître de recherche of the F.R.

S.-FNRS. The authors thank Florence Houdouin and Geofrey

Vandendeyck for their experimental support. Dr Guillaume

Gauron and Alessandra Vizza (Corning SAS) are acknowledged

for the loan of the AFR reactors and the logistic, technical and

scientific support for the scalability trials.

22 Shortages

catalogue,

https://www.ema.europa.eu/en/

human-regulatory/post-authorisation/availability-medicines/

shortages-catalogue, (Accessed on December 21, 2020).

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Article Doi

A modular, low footprint and scalable flow platform for the expedient α-aminohydroxylation of enolizable ketones

DOI: 10.1039/d0gc04395h

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Full text of DOI:10.1039/d0gc04395h

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