Electrochemical: N -demethylation of tropane alkaloids

Article abstract of DOI:10.1039/d0gc00851f

A practical, efficient, and selective electrochemical N-demethylation method of tropane alkaloids to their nortropane derivatives is described. Nortropanes, such as noratropine and norscopolamine, are important intermediates for the semi-synthesis of the medicines ipratropium or oxitropium bromide, respectively. Synthesis was performed in a simple home-made electrochemical batch cell using a porous glassy carbon electrode. The reaction proceeds at room temperature in one step in a mixture of ethanol or methanol and water. The method avoids hazardous oxidizing agents such as H2O2 or m-chloroperbenzoic acid (m-CPBA), toxic solvents such as chloroform, as well as metal-based catalysts. Various key parameters were investigated in electrochemical batch or flow cells, and the optimized conditions were used in batch and flow-cells at gram scale to synthesize noratropine in high yield and purity using a convenient liquid-liquid extraction method without any need for chromatographic purification. Mechanistic studies showed that the electrochemical N-demethylation proceeds by the formation of an iminium intermediate which is converted by water as the nucleophile. The optimized method was further applied to scopolamine, cocaine, benzatropine, homatropine and tropacocaine, showing that this is a generic way of N-demethylating tropane alkaloids to synthesize valuable precursors for pharmaceutical products.

Full text of DOI:10.1039/d0gc00851f

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Electrochemical N-demethylation of tropane
alkaloids†
Cite this: DOI: 10.1039/d0gc00851f
Ali Alipour Najmi,a Zhangping Xiao,b Rainer Bischoff, a Frank J. Dekkerb and
a
Hjalmar P. Permentier
*
A practical, efficient, and selective electrochemical N-demethylation method of tropane alkaloids to their
nortropane derivatives is described. Nortropanes, such as noratropine and norscopolamine, are important
intermediates for the semi-synthesis of the medicines ipratropium or oxitropium bromide, respectively.
Synthesis was performed in a simple home-made electrochemical batch cell using a porous glassy
carbon electrode. The reaction proceeds at room temperature in one step in a mixture of ethanol or
methanol and water. The method avoids hazardous oxidizing agents such as H2O2 or m-chloroperben-
zoic acid (m-CPBA), toxic solvents such as chloroform, as well as metal-based catalysts. Various key para-
meters were investigated in electrochemical batch or flow cells, and the optimized conditions were used
in batch and flow-cells at gram scale to synthesize noratropine in high yield and purity using a convenient
liquid–liquid extraction method without any need for chromatographic purification. Mechanistic studies
showed that the electrochemical N-demethylation proceeds by the formation of an iminium intermediate
which is converted by water as the nucleophile. The optimized method was further applied to scopola-
mine, cocaine, benzatropine, homatropine and tropacocaine, showing that this is a generic way of
N-demethylating tropane alkaloids to synthesize valuable precursors for pharmaceutical products.
Received 9th March 2020,
Accepted 7th September 2020
DOI: 10.1039/d0gc00851f
rsc.li/greenchem
demethylated to 5, 5 is alkylated with isopropyl bromide to
give N-isopropyl-noratropine 7, which is quaternized with
Introduction
Naturally occurring tropane alkaloids, such as the anticholi- methyl bromide to give 6 (Fig. 1B), with the N-isopropyl and
nergic agents atropine 1 and scopolamine 2, and the stimulant N-methyl substituents in axial and equatorial positions,
cocaine 3, are among the oldest drugs that have been used by respectively. In contrast, direct quaternization of 1 with isopro-
humans. The important characteristic of these compounds is pyl bromide leads to an isomeric mixture with the isopropyl
the presence of
a tropane ring 4 including a
tertiary group in both the axial and the equatorial positions.1,3
N-methylamine group, in their chemical structure.1 Pharmaceutical companies are currently using 7 for the prepa-
N-Demethylation of tropane alkaloids to their nortropane ration of 6.6 In a similar manner, norscopolamine 8 is used as
derivatives is a key step in the semi-synthesis of some impor- an intermediate for manufacturing the bronchodilator oxitro-
tant therapeutic agents.2,3 For example, noratropine 5 is an pium bromide 9 with N-ethyl and N-methyl substituents in the
intermediate for the synthesis of the bronchodilator ipratro- axial and equatorial positions, respectively, while the ethyl
pium bromide 6, which is in the WHO’s list of essential medi- group is located in the equatorial position, if 8 is alkylated
cines. Under the brand name of Combivent, ipratropium directly.1,7
bromide had world-wide sales of $850 million and
Despite the importance of selective N-demethylation of
$950 million in 2008 and 2009, respectively, and is among the tropane alkaloids, it has remained a challenging step for syn-
top 200 pharmaceutical products either by retail sales or pre- thetic chemists.8 Different approaches have been reported for
scriptions in the United States, in the last decade.4,5 Once 1 is N-demethylation of the tertiary amine in atropine and scopola-
mine using agents such as 2,2,2-trichloroethyl chloroformate,9
α-chloroethyl chloroformate,10 KMnO4
and photochemis-
10,11
try.12 Although these methods provide low to excellent yields
(16–100%) of 5 and 8, they use toxic solvents and chemicals
producing hazardous waste and by-products.
aDepartment of Analytical Biochemistry, Groningen Research Institute of Pharmacy,
University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands.
E-mail: h.p.permentier@rug.nl
bChemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy,
University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc00851f
The original Polonovski reaction has proven to be effective
for the N-demethylation of tertiary N-methylamines.13 Over the
past decade, modifications of the reaction based on iron cata-
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Fig. 1 (A) Structure of some naturally occurring tropane alkaloids (1–3), tropane (4), norscopolamine (8), and the semi-synthetic bronchodilator oxi-
tropium bromide (9); (B) synthesis of ipratropium bromide (6) from noratropine (5).
lysts have been developed for the N-demethylation of tropane
Concerted N-demethylation/N-acylation strategies based on
and opiate alkaloids.2,3,6,8,14–19 These reactions are based on a palladium catalysts have been reported for atropine and opiate
multi-step process, comprising the oxidation of the tertiary alkaloids.21–24 Although these methods have been applied for
amine using m-chloroperbenzoic acid (m-CPBA) or H2O2 to the the synthesis of the semi-synthetic opiates naltrexone22 and
corresponding N-oxide, which is then isolated as the HCl salt. buprenorphine,23 the reaction is not selective for atropine,
The N-oxide salt is N-demethylated with iron-based catalysts since the hydroxyl group is dehydrated, leading to the for-
such as FeSO4·7H2O, FeCl2·4H2O, or Fe(NH4SO4)2,14,15 iron mation of apoatropine.21 In addition, application of palladium
porphyrin complex,16,17 ferrocene,8 and iron powder2 which catalysts in commercial medicines leads to cost issues due to
need to be separated from the reaction mixture by chelating the need for palladium removal below the required level of
with EDTA or TPPS (meso-tetra(4-sulfophenyl)porphyrin)14,15 or 10 ppm.3
by filtration.16–18
Organic electrosynthesis has several advantages over tra-
Recent works have focused on using greener solvents such ditional methods, such as the limited use of hazardous chemi-
as ethanol and isopropanol, instead of chloroform, in the cals, mild reaction conditions, a simple system design, scal-
N-demethylation of N-oxides.3,6,18,20 In one approach, iron ability and notably sustainability.25–27 It is thus considered to
nanoparticles have been studied as catalyst for the be a “green” alternative to widely used organic synthesis
N-dealkylation of various alkaloids reporting a yield of 85% for methods.28,29 While electrochemistry has been applied for the
the synthesis of noratropine.18 However, chloroform is still in oxidation of aliphatic amines,30–32 ferrocene-mediated oxi-
use for N-oxide formation in the first step of the reaction.18 dation of cyclohexylamines,33,34 and some phenethylamines35
Do Pham et al. studied the N-demethylation of atropine and as well as the synthesis of a wide-range of organic molecules
scopolamine using Fe(III)–TAML (tetra-amidato macrocyclic (for a detailed list see a recent review36), there is no report
ligand) as catalyst in ethanol without isolation of the N-oxide regarding its application for the N-demethylation of bicyclic
as the hydrochloride salt, reporting a yield of about 80% for tertiary amines in general and tropane alkaloids in particular.
noratropine and norscopolamine.3,6 However, this method Recently, Gul et al. reported optimized conditions for generat-
uses 50 equivalents of H2O2, which must be deactivated at the ing N-dealkylated lidocaine.37 In another study, electro-
end of the process by treatment with MnO2.3,6 A detailed com- chemical N-dealkylation of fesoterodine was reported.38
parison of these methods with respect to their advantages and However, the reported concentrations (0.1–1 mM) are far lower
disadvantages is provided in Table S1.†
than what is used in practical synthesis procedures, while only
Previous methods use either toxic organic solvents, require achieving less than 30% conversion to the N-dealkylated
powerful oxidants or necessitate chromatographic purification drugs.37,38
or filtration to remove catalysts, all of which add to the overall
In order to overcome the challenges of the available organic
cost of the procedure and increase the impact on the environ- synthesis methods, we developed a generic electrochemical
ment notably for large-scale production processes.2,3,6,8,14–19
N-demethylation strategy for tropane alkaloids that gives both
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good selectivity and yields in gram-scale synthesis. Product iso- about the electrochemical flow-cell is reported elsewhere.39
lation is straightforward using liquid–liquid extraction. The Cyclic voltammetry (CV) experiments were carried out using a
reaction proceeds at room temperature in one step without the glassy carbon electrode (1.6 mm diameter, ALS Co.) as working
need for metal-based catalysts in an ethanol or methanol/ electrode, a 100 PPI glassy carbon electrode as counter elec-
water mixture. After having established the electrochemical trode, and an Ag/AgCl reference electrode. A 5 mM solution of
synthesis reaction, we studied the mechanistic pathway compound in ethanol/water (2 : 1) including NaClO4 (0.1 M) as
showing that this reaction proceeds via the formation of an supporting electrolyte was used for CV experiments.
iminium intermediate that reacts with water to give
nortropanes.
All electrochemical measurements were performed with an
Autolab potentiostat (Metrohm AG, Herisau, Switzerland)
using NOVA software (Metrohm AG) at room temperature
under ambient atmosphere. Between each experiment, elec-
trode surfaces were washed with water and ethanol and then
dried under atmospheric conditions for both the µ-PrepCell
and home-made cells.
Methods
Reagents
Atropine, scopolamine·HBr, benzatropine·mesylate, tropane, clem-
1H and 13C NMR, LC–MS, and HRMS analysis
astine
fumarate,
4-diphenylmethoxy-1-methylpiperidine·HCl,
1H and 13C NMR spectra were recorded at 500 and 126 MHz,
respectively, on a Bruker Avance 500 spectrometer. Chemical
shifts were reported in ppm relative to the solvent. A C18
reversed-phase LC column (Hypersil gold, 100 × 2.1 mm,
Thermo Scientific) was used for liquid-chromatography separ-
ation at a flow-rate of 300 µL min−1 (LC20-AD prominence,
Shimadzu). Solvent A and B were 0.1% formic acid in water
and 0.1% formic acid in acetonitrile, respectively. Mass spec-
trometry analysis was performed on a TSQ Quantum Ultra
triple quadrupole mass spectrometer (Thermo Scientific) with
electrospray ionization (ESI) in the positive mode. High resolu-
tion mass spectrometry analysis was performed on an Orbitrap
sodium carbonate (Na2CO3), sodium sulfate (Na2SO4), ammonium
hydroxide (NH4OH), and potassium cyanide (KCN) were purchased
from Sigma-Aldrich. Ultra-pure HPLC grade acetonitrile (ACN) and
dichloromethane (DCM) were purchased from Biosolve. Absolute
ethanol and methanol were purchased from either Biosolve or
VWR Chemicals. MP Ecochrom silica 32–63, 60 Å was used for
column chromatography. Tropacocaine·HCl, cocaine, and
homatropine·HBr were obtained from the Interfaculty Mass
Spectrometry Center (IMSC), University of Groningen, Groningen,
The Netherlands.
Electrochemical methods
A thin-layer electrochemical flow-cell (µ-PrepCell 2.0, Antec- Velos Pro (Thermo Scientific) with electrospray ionization (ESI)
Scientific, Zoeterwoude, The Netherlands) was used to deter- in positive mode.
mine the optimal electrode material for the electrochemical
N-dealkylation reaction. The µ-PrepCell has a 30 mm × 12 mm
Liquid–liquid extraction (LLE)
rectangular working electrode (glassy carbon, boron-doped
(a) 3-Step LLE. Upon completion of the reaction, electrodes
diamond, TiO2, stainless steel, Pt or Au) and a counter elec- were washed with methanol (15–20 mL) and the volume
trode made from a conductive polyether ether ketone (PEEK) reduced to 3–5 mL using a rotary evaporator. The solution was
polymer. It has a reaction volume of about 20 µL. Reaction basified with 15% aqueous ammonia to pH 11–12 (indicator
solutions were pumped into the flow-cell at flow-rates of paper) and extracted with 2 × 20 mL dichloromethane (DCM).
1–5 µL min−1 with a syringe pump (KD Scientific Inc., The volume was reduced to ∼5 mL and then extracted with 2 ×
Holliston, MA, USA) using a glass syringe (Hamilton, Reno, 10 mL 1 M aqueous HCl. The aqueous extract was again basi-
NV, USA). The liquid from the outlet of the flow-cell was col- fied with 15% aqueous ammonia to pH 11–12 (indicator
lected, and the fractions subjected to LC–MS analysis. Prior to paper) and extracted with 2 × 30 mL DCM.6
use and between each experiment, the µ-PrepCell was flushed
(b) 2-Step NaOH-LLE. Upon completion of the reaction,
with the corresponding reaction mixture to assure stable con- electrodes were washed with MeOH (15–20 mL) and then the
ditions. Electrochemical synthesis was performed in a home- reaction solution was dried. The residue was dissolved in
made two-electrode electrochemical cell using glassy carbon 22 mL MeOH : DCM (1 : 10) and extracted with 2 × 15 mL 1 M
with 100 pores per inch (100 PPI; Goodfellow Cambridge Ltd, HCl. The aqueous extract was basified with 5 M aqueous
UK) as both anode and cathode. A glass test tube was used as NaOH and then extracted with 2 × 30 mL DCM.
reactor. Gram-scale electrochemical synthesis of noratropine
(c) 2-Step-NH4OH-LLE. Upon completion of the reaction,
in batch-cell was performed with a stack of GC electrodes, electrodes were washed with MeOH (15–20 mL) and then the
using four anode and four cathode electrodes (Fig. S1–S3†). reaction solution was dried. The residue was dissolved in
Gram-scale electrochemical synthesis of noratropine was per- 22 mL MeOH : DCM (1 : 10) and extracted with 2 × 15 mL 1 M
formed using an 8-channel flow-cell (in series) having 704 µL HCl. The aqueous extract was basified with 15% aqueous
of total reactor volume (88 µL per channel) and 51 cm2 total NH4OH and then extracted with 2 × 30 mL DCM.
surface area (106 mm × 3 mm open area per channel). A
(d) Gram-scale 3-step LLE. Upon completion of the reac-
planar graphite electrode with dimension of 110 mm × 45 mm tion, electrodes were washed with methanol (60–70 mL) and
was used both as anode and cathode. Detailed information the volume reduced to ∼30 mL using a rotary evaporator. The
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solution was basified with 15% aqueous ammonia to pH from any reaction mixture can be challenging. For this reason,
11–12 (indicator paper) and extracted with 3 × 100 mL di- it is important to have full conversion at the end of the reac-
chloromethane (DCM). The volume was reduced to ∼20 mL tion. Using only ethanol as solvent did not result in full con-
and then extracted with 2 × 30 mL 1 M aqueous HCl. The version. Increasing the reaction time and decreasing the
aqueous extract was again basified with 15% aqueous applied current either did not lead to complete conversion or
ammonia to pH 11–12 (indicator paper) and extracted with 3 × resulted in overoxidation, a decreased yield and a complex
100 mL DCM.6
reaction mixture of byproducts, as determined by LC–MS
The final organic extract was dried (Na2SO4), filtered and (Table 2, entries 1–5). Although increasing the applied current
the solvent removed under vacuum to give the product. The led to full conversion, analysis of the final reaction mixture by
1
yield was determined from the weight and HNMR of the iso- LC–MS showed a more complex reaction mixture including
lated product.
different overoxidized byproducts (see LC–MS chromatogram
in Fig. S5†). We then considered whether addition of water to
the reaction mixture would result in full conversion, as the
electrochemical N-demethylation of atropine is similar to the
Results and discussion
In initial experiments, an electrochemistry–liquid chromato-
graphy–mass spectrometry (EC–LC–MS) approach was used to
Table 2 Electrochemical N-demethylation of atropine to noratropine
under different conditions using a batch-cell
investigate
the
feasibility
of
the
electrochemical
N-demethylation of atropine 1 using six commercially available
flat electrodes with different materials but equal dimensions.
The electrochemical reaction of atropine was investigated
using an analytical electrochemical thin-layer flow-cell having
a reactor volume of 20 µL. Alcohols (ethanol or methanol)
were selected as solvents, since they are considered to be
among the greenest solvents.20,40 As listed in Table 1, the
electrochemical oxidation of atropine (oxidation potential of
0.95 V versus Ag/AgCl reference electrode) over carbon-based
electrodes (GC and BDD) at constant current showed higher
conversion to noratropine compared to noble-metal electrodes,
while stainless steel and titanium oxide electrodes showed no
N-demethylation or any other oxidation products at the
applied conditions (Table 1; LC–MS chromatograms in
Fig. S4†). Considering these results and the considerably lower
price of glassy carbon electrodes compared to either BDD or
noble-metal electrodes, a highly porous glassy carbon elec-
trode (100 PPI grade) was selected and a home-made electro-
chemical batch-cell was fabricated to further optimize the reac-
tion conditions (Fig. S2†).
Entry Current/time Added water
Conversionb (%) Yield (%)
1
2
3
4
5
6
7
8
6 mA/3 h
6 mA/5 h
6 mA/7 h
4 mA/6 h
8 mA/3 h
6 mA/5 h
6 mA/5 h
6 mA/3.5 h
4 mA/4.5 h
4 mA/4.5 h
4 mA/4.5 h
4 mA/4.5 h
0a
90
90
93
88
99
92
99
70b
37b
28b
25b
52b
44b
65b
67b
82c
84d
68e
80f
0a
0a
0a
0a
2.2 M (4% v/v)
11 M (20% v/v)
18.5 M (33% v/v) 99
18.5 M (33% v/v) 99
18.5 M (33% v/v) 99
18.5 M (33% v/v) 99
18.5 M (33% v/v) 99
9
10
11
12
a Absolute ethanol was used as solvent and the residual amount of
water was not measured. b Determined by LC–MS. c Isolated yield
(based on weight and 1HNMR) after silica-gel chromatography.
d Isolated yield (based on weight and 1HNMR) after 3-step LLE.
e Isolated yield (based on weight and 1HNMR) after 2-step-NaOH-LLE.
f Isolated yield (based on weight and 1HNMR) after 2-step-NH4OH-LLE.
As there is only one methyl group difference between atro-
pine and noratropine, separation of these two compounds
Table 1 Electrochemical N-demethylation of atropine to noratropine using a flow-cell
Electrode material
Conversion to noratropinea
Glassy carbon (GC)
Boron-doped diamond (BDD)
Gold
Platinum
Stainless steel
Titanium oxide
26%
16%
8%
12%
0
0
a Determined by LC–MS.
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Shono-type electrochemical oxidations, which have been ceeded with good yield under all of these reaction conditions
applied for the activation and functionalization of C–H bonds (LC–MS chromatogram of final reaction mixture Fig. S7†).
adjacent to nitrogen atoms.41 It has been hypothesized that However, using LiBr as supporting electrolyte required a
water or methanol may act as a nucleophile trapping the longer reaction time to complete the conversion of atropine as
iminium intermediate produced during the electrochemical compared to other supporting electrolytes.
reaction.28,42,43 Increasing the water content of the reaction
Having studied different reaction conditions for the electro-
mixture led to full conversion and decreased the required time chemical N-demethylation of atropine, we investigated the gen-
and charge for completion of the reaction (Table 2, entries erality of this approach by applying it to other tropane
6–8), while giving a moderate yield of noratropine (44–67%). compounds (Table 4). We performed electrochemical
LC–MS analysis of the final reaction mixture still showed mul- N-demethylation of tropacocaine 10 in the home-made batch
tiple byproducts (Table 2, entry 8). Reducing the applied cell resulting in an isolated yield of 70% of nortropacocaine. It
current to 4 mA resulted in 82% isolated yield after silica-gel is noteworthy that performing the electrochemical reaction
chromatography and a less complex final reaction mixture using its salt form (tropacocaine·HCl) did not lead to any con-
with only two minor byproducts (Table 2, entry 9; LC–MS chro- version, possibly due to the acidic pH of the reaction solution
matogram Fig. S6a†).
with tropacocaine·HCl. Adding an equimolar of sodium car-
Considering the low complexity of the final reaction bonate to the reaction solution increased the pH of the solu-
mixture, based on LC–MS analysis, we tested whether the tion to about 10 leading to 95% conversion (Table S3†). The
desired product could be purified by liquid–liquid extraction facile N-demethylation reaction at basic pH is likely due to the
(LLE). As waste production and solvent consumption at the fact that the lone–pair electrons of the tertiary amine group are
final purification step of active pharmaceutical ingredients are more easily available for abstraction than under acidic con-
responsible for more than half of the overall manufacturing ditions, when the amine is largely protonated.37,38,46,47 Besides
expenses, there is a strong incentive to adopt other purification tropane alkaloids, we have applied the electrochemical
methods than chromatography.44,45 Do Pham et al. applied a N-demethylation reaction to other examples of organic com-
three step LLE approach to isolate noratropine and norscopola- pounds having N-methylpiperidine or N-methylpyrrolidine in
mine from their final reaction mixture with high purity.3,6 their chemical structures (Table S4†). Although the reaction
Three different LLE techniques were evaluated and compared proceeds with those compounds as well, the isolated yield of
to chromatographic purification to isolate noratropine from the secondary amine is lower than for the nortropanes,
the final reaction mixture obtained under the same reaction especially for N-methylpyrrolidine; the drug clemastine 14 was
conditions showing that comparable yields to chromato- mostly converted to a product which was hydroxylated on the
graphic purification can be obtained by three- or two-step LLE carbon adjacent to the nitrogen.
(Table 2, entries 10–12, LC–MS chromatogram of final reaction
Having studied the reaction conditions, the electrochemical
mixture Fig. S6b–d†). Another four replicates of the final reac- N-demethylation of atropine was performed at the gram-scale
tion condition (Table 2, entries 9–12) were performed with using a stack of electrodes in a batch cell (Fig. S3†). As listed
another set of electrodes and reported in Table S2.†
in Table 5, good yields of noratropine were obtained by a
In order to investigate the sensitivity of the electrochemical three-step LLE method after electrochemical reaction, with
1
N-demethylation reaction to either solvent or supporting elec- high purity as examined by H-NMR analysis (1H-NMR spectra
trolyte, methanol was selected as an alternative solvent and of g-scale synthesis in ESI†), which can be used directly in sub-
four different supporting electrolytes were tested. As listed in sequent steps for the synthesis of ipratropium bromide
Table 3, the electrochemical N-demethylation of atropine pro- medicine.6
Flow synthesis is considered to be an interesting alternative
to batch cell synthesis and electrochemical flow cells have
Table 3 Electrochemical N-demethylation of atropine to noratropine
using different supporting electrolytes
been employed successfully for gram-scale synthesis.48 In
order to make a comparison between the batch-cell and flow-
cell synthesis of nortropanes in gram-scale, we used a newly
designed electrochemical flow-cell,39 which has been applied
to various electrochemical reactions.49,50 It is an 8-channel
flow-cell, with a reactor volume of 88 µL per channel using
graphite working and counter electrodes. The 8 channels of
the flow-cell were used in series with the same solvent system
as Table 5, entry 2. We performed a 2-gram scale electrosynth-
esis of noratropine. An isolated yield of 67% was obtained
after three-step LLE, which is comparable to the batch-cell syn-
thesis. A residence time of 42 min and 8 mA was found to be
the optimal conditions. Increasing the applied current for the
same residence time leads to lower yield and higher conver-
sion to byproducts while decreasing the residence time at the
Current/
time
Supporting
electrolyte
Conversiona
(%)
Yieldb
(%)
Entry
1
2
3
4
5 mA/5 h
5 mA/5 h
5 mA/5 h
5 mA/8.5 h
NaClO4
LiClO4
LiCl
99
99
83
73
80
75
99
LiBr
99, 85c
a Determined by LC–MS. b Isolated yield after 2-step-NH4OH-LLE.
c Conversion after 5 h.
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Table 4 Scope of electrochemical N-demethylation of tropane alkaloids
Tropane alkaloids
Synthesized nortropanes
Scopolamine 2b
83%c
1.01 Ve
4 mA/3 h
74%f
Cocaine 3b
60%d
1.04 Ve
4 mA/3 h
53%f
Tropacocaine 10a
73%c
1.00 Ve
4 mA/7 h
22%f
Homatropine 11b
63%c
0.97 Ve
4 mA/7 h
24%f
Benzatropine 12a
72%d
0.91 Ve
4 mA/12 h
12%f
a 0.16 mmole. b 0.2 mmole. c Isolated yield after 2-step-NH4OH-LLE. d Isolated yield after silica-gel chromatography. e Electrochemical oxidation
potential versus Ag/AgCl reference electrode (CV curves in Fig. S9†). f Faradaic efficiency (2-electron oxidation).
Table 5 Gram-scale synthesis of noratropine in a batch-cell
Entry
Current/time
Solvent
Supporting electrolyte
Yieldb (%)
Faradaic efficiency (%)
1a
2a
3a
40 mA/7 h
40 mA/6 h
40 mA/6 h
Methanol/water (2 : 1)
Methanol/water (2 : 1)
Ethanol/water (2 : 1)
LiCl
NaClO4
NaClO4
79
74
73
52%
57%
56%
a 1 g atropine in 45 mL solvent. b Isolated yield after three-step LLE.
same applied current did not lead to full conversion of atro- another advantage of the developed method avoiding a chro-
pine. It is noteworthy to mention that the ratio of the electrode matographic purification step which is a growing demand in
surface area to the reactor volume of the batch-cell in gram- the pharmaceutical industry.45
scale is calculated to be about 42 cm−1 51,52
comparable to the surface-to-volume ratio of the flow-cell39
which is about 72 cm−1
.
This number is
Analysis of byproducts and mechanistic studies
.
Analysis of the final reaction mixture by LC–MS showed two
Since a considerable amount (80–90%) of non-aqueous main byproducts with m/z of 304.1 and 561.1 next to the pro-
waste generated from the manufacturing of active pharma- duced noratropine (m/z of 290.1). Analysis of the aqueous
ceutical ingredients (APIs) are solvents, the use of green sol- extract in the first step of LLE, and the organic extract in the
vents, such as ethanol, methanol and water, is a critical second step of LLE, showed a high intensity of these two
requirement.20 Besides, the application of heterogeneous cata- byproducts compared to remaining noratropine, which con-
lysis plays a key role in developing new reaction processes to firms that the LLE method did not recover all of the products.
meet the target of green chemistry.53 The concept of catalyst The peak with m/z of 304.1 was therefore isolated using silica
immobilization and reuse, which has been recently defined as gel chromatography and characterized by 1H and 13C NMR and
a new “key green chemistry research area” by big pharmaceutical was confirmed to be N-formyl-noratropine which was also
companies,54 is addressed by our newly developed method reported elsewhere as a byproduct of atropine demethyl-
using a cheap glassy carbon electrode for a prolonged period ation.3,6 Interestingly, all of the other examined tropanes (com-
of time for different batches of the reaction in gram-scale. pounds 10–12), except scopolamine, showed equivalent bypro-
Finally, the purification of the synthesized noratropanes using ducts: analysis of the final reaction mixtures by LC–MS ana-
a convenient LLE technique in high yields and purity is lysis showed for every compound a peak of M − 14 as the nor-
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Fig. 2 Proposed mechanism for the electrochemical N-demethylation of tropane alkaloids via the formation of an iminium intermediate reacting
with water (route a), and predicted route for trapping the iminium intermediate with cyanide (route c).
tropane product, a peak of M + 14 as the N-formyl-nortropane assium cyanide as a source of cyanide ions to trap the
product and a peak at [M] + [M − 14] − 5 as a probable dimer iminium intermediate (Fig. 2, route c). LC–MS analysis of the
byproduct. In order to confirm the dimer structure, the electro- outlet of the cell (Fig. S8†) showed that, besides intact atropine
chemical reaction was performed by tropane 4 as starting com- at m/z = 290.1 (M) and noratropine at m/z = 276.1 (M − 14), a
pound. As expected, a byproduct with m/z of 233.1 was pro- new compound at m/z = 315.1 (M + 25) was produced during
duced. The byproduct was isolated and purified from the reac- the reaction. This compound (N-nitrilo-noratropine, VI-1,
tion mixture and its structure confirmed by 1H-NMR, 13C-NMR Fig. 2) can be formed by the addition of a CN− group (26 Da)
and HRMS as a quaternary amine, compound V-4 (Fig. 2).
to an iminium intermediate and abstraction of a hydrogen
A basic understanding of the mechanistic pathways of the atom, supporting a reaction mechanism during which an
catalytic reactions facilitates the improvement of catalytic pro- iminium intermediate is generated by a two-electron oxidation
cesses providing the opportunity for the rational design of the reaction at the anode. N-Nitrilo-noratropine was synthesized in
catalytic systems.53 The high dissociation energy of the C–N a home-made electrochemical cell and characterized by 1H
bond and the intrinsic stability of amines makes cleavage of and 13C NMR. Dimer formation during the electrochemical
the C–N bond challenging for synthetic chemists.55 Generally, reaction can be explained by this mechanism as well, since the
two types of C–N bond cleavage by transition-metal catalysts produced noratropine, a secondary amine, can act as a nucleo-
(such as iron-based catalysts) have been studied broadly: (a) phile and react with the iminium intermediate resulting in a
the oxidative addition of transition-metal catalysts to the C–N tertiary diamine (compound IV, Fig. 2) which undergoes a two
bond and, (2) the formation of intermediate imine or iminium electron electrochemical oxidation reaction to form an amidi-
species.56 The latter mechanism has also been proposed for nium structure. The produced formaldehyde from the
the Shono-type electrochemical oxidation,57,58 which provides removed methyl group was detected by LC–MS using a simple
a route to activate and functionalize C–H bonds in the vicinity derivatization method, where acetylacetone reacts with formal-
of a nitrogen atom. Shono-type oxidations proceed by the dehyde in the presence of ammonium acetate to form the
initial formation of a nitrogen-centered radical via direct elec- cyclized 3,5-diacetyl-1,4-dihydrolutidine product (m/z of
tron transfer to the electrode, followed by a sequence of ET/PT/ 194.1),62,63 which can be easily detected by LC–MS analysis
ET (electron/proton/electron transfer) steps leading to an (Fig. S12†). In theory, only 2 F mol−1 electricity is required for
iminium intermediate, which can be trapped with water or
alcoholic solvents.28,42,43 Therefore, we hypothesized that the N-demethylation of atropine at gram scale was calculated to
a
two-electron oxidation reaction.47 The electrochemical
electrochemical N-demethylation of tropane alkaloids on require 2.6 F mol−1
glassy carbon electrodes may also proceed via the formation of
an iminium intermediate, which subsequently reacts with
water to form nortropanes, as depicted in Fig. 2 (route a).
.
Conclusions
C–N bond cleavage in the form of N-dealkylation, a
common in vivo metabolic pathway for most of the amine-con- We introduce an efficient, straightforward and green electro-
taining drugs catalyzed by Cytochrome P450 (CYP) enzymes, chemical N-demethylation strategy for tropane alkaloids based
also proceeds via iminium intermediate formation59,60 which on oxidation on a glassy-carbon electrode. Using a commer-
can be trapped by a nucleophile such as cyanide.61 In order to cially available flow cell (µ-PrepCell) and a home-made electro-
investigate the mechanism, we added an excess amount of pot- chemical batch cell, we screened a number of parameters. The
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optimized conditions were applied to a set of tropane alka- 11 M. J. Van Der Meer and H. K. L. Hundt, J. Pharm.
loids, with a focus on atropine and scopolamine. Compared to Pharmacol., 1983, 35, 408–408.
other iron-based catalytic methods, our electrochemical pro- 12 J. A. Ripper, R. T. Tiekink and P. J. Scammells, Bioorg. Med.
cedure proved to be generally applicable for producing nortro- Chem. Lett., 2001, 11, 443–445.
pane derivatives in good to high yields with high purity at 13 D. Grierson, Org. React., 2004, 39, 85–295.
gram-scale without any need for chromatographic purification. 14 K. McCamley, J. A. Ripper, R. D. Singer and
The method is a convenient, one-step process using a water–
ethanol/methanol co-solvent system avoiding multi-step pro- 15 S. Thavaneswaran and P. J. Scammells, Bioorg. Med. Chem.
cesses, need for hazardous oxidizing agents such as H2O2 or Lett., 2006, 16, 2868–2871.
m-CPBA, toxic solvents such as chloroform or metal-based cat- 16 Z. Dong and P. J. Scammells, J. Org. Chem., 2007, 72, 9881–
alysts. Other advantageous features of our approach comprise 9885.
the use of an open-flask electrochemical reactor under 17 G. Kok, T. D. Ashton and P. J. Scammells, Adv. Synth.
ambient conditions and a low-cost porous glassy carbon elec- Catal., 2009, 351, 283–286.
trode, which can be used for a prolonged period of time. We 18 J. K. Awalt, R. Lam, B. Kellam, B. Graham, P. J. Scammells
P. J. Scammells, J. Org. Chem., 2003, 68, 9847–9850.
show that alternatively an electrochemical flow reactor can be
used for gram-scale synthesis of nortropanes.
and R. D. Singer, Green Chem., 2017, 19, 2587–2594.
19 J. K. Awalt, P. J. Scammells and R. D. Singer, ACS
Sustainable Chem. Eng., 2018, 6, 10052–10057.
20 R. K. Henderson, C. Jiménez-González, D. J. C. Constable,
S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood,
S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854–
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Conflicts of interest
There are no conflicts to declare.
21 R. J. Carroll, H. Leisch, E. Scocchera, T. Hudlicky and
D. P. Cox, Adv. Synth. Catal., 2008, 350, 2984–2992.
22 A. MacHara, D. P. Cox and T. Hudlicky, Adv. Synth. Catal.,
2012, 354, 2713–2718.
Acknowledgements
This work is part of the Open Technology Programme of 23 A. MacHara, L. Werner, M. A. Endoma-Arias,
Toegepaste en Technische Wetenschappen (TTW) with project
number 15230 which is financed by the Netherlands
D. P. Cox and T. Hudlicky, Adv. Synth. Catal., 2012, 354,
613–626.
Organisation for Scientific Research (NWO). The authors 24 B. Gutmann, P. Elsner, D. P. Cox, U. Weigl, D. M. Roberge
thank Prof. Dr Timothy Noël and Dr Gabriele Laudadio from
the Micro Flow Chemistry & Synthetic Methodology group of
and C. O. Kappe, ACS Sustainable Chem. Eng., 2016, 4,
6048–6061.
the Eindhoven University of Technology, The Netherlands, for 25 O. Hammerich and B. Speiser, Organic electrochemistry:
providing the electrochemical flow cell.
revised and expanded, CRC Press, 2015.
26 E. J. Horn, B. R. Rosen and P. S. Baran, ACS Cent. Sci., 2016,
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27 H. J. Schäfer, C. R. Chim., 2011, 14, 745–765.
28 M. D. Kärkäs, Chem. Soc. Rev., 2018, 47, 5786–5865.
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