Efficient Flow Electrochemical Alkoxylation of Pyrrolidine-1-carbaldehyde

Article abstract of DOI:10.1055/s-0037-1611774

We report on the optimization of the alkoxylation of pyrrolidine-1-carbaldehyde by using a new electrochemical microreactor. Precise control of the reaction conditions permits the synthesis of either mono- or dialkoxylated reaction products in high yields.

Full text of DOI:10.1055/s-0037-1611774

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
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N. Amri et al.
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Efficient Flow Electrochemical Alkoxylation of Pyrrolidine-1-
carbaldehyde
Nasser Amria
Ryan A. Skiltonb
Duncan Guthrieb
Thomas Wirth*a
OR
N
CHO
N
CHO
+
ROH
0
0
0
0-0
0
0
2-8
9
9
0-0
6
6
7
H / OR
a School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
wirth@cf.ac.uk
b Vapourtec Ltd., 21 Park Farm Business Centre, Bury St Edmunds, IP28 6TS, UK
6 examples
£ 94% conversion to monoalkoxy product
£ 83% conversion to dialkoxy product
Published as part of the Cluster Electrochemical Synthesis and Catalysis
Received: 31.01.2019
Accepted after revision: 11.02.2019
Published online: 26.03.2019
distance between the electrodes in batch processes leads to
high current gradients. Some of these limitations in batch
electrochemistry can be addressed by the use of continu-
ous-flow reactors designed with small distances between
electrodes to avoid large current gradients and to minimize
or eliminate the need for supporting electrolytes.3 In addi-
tion, modifications to the electrode surface can affect the
overall reaction rate.4 The development and use of microre-
actors in continuous-flow electrosyntheses have been re-
ported by a number of organic chemists.5 Also, our group
has contributed to the development of electrochemical flow
microreactors,6 while further developments by Vapourtec
Ltd. permit the provision of commercial equipment.7
Here, we report the methoxylation of pyrrolidine-1-car-
baldehyde (1) in a reaction that is used to assess the effi-
ciency of the much-improved electrochemical microreac-
tor.7 Various factors and parameters were assessed in this
study to determine their effects on the reaction, which,
through comparison with results from the literature for this
particular methoxylation reaction,8 should permit better
control of the efficiency of the improved reactor (Scheme 1).
DOI: 10.1055/s-0037-1611774; Art ID: st-2019-b0059-c
Abstract We report on the optimization of the alkoxylation of pyrroli-
dine-1-carbaldehyde by using a new electrochemical microreactor. Pre-
cise control of the reaction conditions permits the synthesis of either
mono- or dialkoxylated reaction products in high yields.
Key words C–H activation, electrochemistry, flow chemistry, hetero-
cycles, alkoxylation, pyrrolidinecarbaldehyde
Electrochemical organic synthesis is currently receiving
renewed interest from synthetic chemists as a powerful ac-
tivation mode that permits versatile chemical transforma-
tions. The application of electrons as traceless reagents can
avoid the use of hazardous or toxic oxidizing or reducing
agents, and mild conditions can be employed for sustain-
able processes in chemistry.1 Electrochemical transforma-
tion can be powerful method for making C–C, C–X, or even
X–X bonds, which is paramount in the synthesis of new or-
ganic compounds and in modification of existing ones. The
advantages of electrochemical transformations do not stop
at the use of electrons as superior reagents to toxic or haz-
ardous chemicals, as these transformations also require
only small amounts of reacting species and can provide
highly specific reactions that avoid the formation of by-
products. In most cases, electrolysis via anionic and cationic
radical species formed from the neutral organic molecule is
carried at room temperature and atmospheric pressure, so
the reaction conditions are considered to be mild.2
As with many organic methods, organic electrochemis-
try has its own shortcomings and limitations, especially in
batch processes, as many organic solvents used for chemical
reactions have low conductivities. This necessitate the ad-
dition of supporting electrolytes and their subsequent re-
moval at the end of the reaction, while the relatively large
Scheme 1 Methoxylation of pyrrolidine-1-carbaldehyde (1) with the
Ion electrochemical microreactor (right).
The Ion electrochemical reactor7 demonstrated high ef-
ficiency in performing this reaction regioselectively. Many
factors were varied to achieve the highest conversion and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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optimal selectivity. For the initial optimization of the elec-
trochemical oxidation of pyrrolidine-1-carbaldehyde (1) to
2-methoxypyrrolidine-1-carbaldehyde (2), glassy carbon
(GC) was used as the anode and 304 stainless steel9 as the
cathode. The distance between the electrodes is defined by
means of a Teflon spacer (0.5 mm) containing a channel
with a total volume of 0.6 mL, resulting in an exposed elec-
trode area of 2 × 12 cm2. A 0.1 M solution of aldehyde 1 in
methanol was pumped at a flow rate of 0.5 mL/min with
0.05 M tetraethylammonium tetrafluoroborate (Et4NBF4) as
a supporting electrolyte. A current of 100 mA (1.25 F) with
a residence time of 1.2 minutes at room temperature gave
the desired product in only 75% yield (Table 1, entry 1). An
increase in the current from 100 mA to 140 mA (entries 2–
4) led to approximately 90% of product 2 together with the
2,5-dimethoxylated byproduct 3 in about 2% yield, as deter-
mined by GC. When the current was increased further, the
amount of product 2 was reduced and that of the dimethox-
ylated product 3 increased (entries 6 and 9), although the
amount of electricity that passed through the reactor was
identical due to the higher flow rate of the substrate. A sim-
ilar course of reaction was observed when the concentra-
tion of the substrate was increased to 1 M: the reaction was
incomplete, and byproduct 3 was formed (entry 10). In this
reaction, temperature did not have any impact, as the re-
sults were identical whether the reaction was performed at
room temperature, 30 °C or at 60 °C (entries 7, 11, and 12).
It was also found that the use of a graphite electrode sup-
pressed the formation of the dimethoxylated product 3 (en-
try 7). Conducting a paired electrolysis was possible in the
same equipment7 by separating the cathodic and anodic re-
actions with a Nafion membrane. Cathodic hydrogen gener-
ation was then observed with a methanolic solution of 0.05
M tetraethylammonium tetrafluoroborate, while reaction
products 2 and 3 were formed in the anodic half reaction
(entry 8). Unfortunately, better selectivity could not be ob-
tained in the paired electrolysis.
Table 1 Optimization of the Electrochemical Methoxylation of Pyrroli-
dine-1-carbaldehyde (1)
OMe
N
OMe
N
+
1
CHO
CHO
(0.1 M in
MeOH)
OMe
3
anode: glassy carbon
2
cathode: 304 stainless steel
electrode distance: 0.5 mm
volume: 0.6 mL, flow rate: 0.5 mL/min
Entry
Conditions
Conversiona to 2
(%)
Conversiona to 3
(%)
1
100 mA (1.25 F)
120 mA (1.5 F)
130 mA (1.6 F)
140 mA (1.75 F)
150 mA (1.88 F)
160 mA (2 F)
75
0
2
84
0
3
86
0
4
91
2
5
89
3
6
90
3
7
160 mA (2 F)b
160 mA (2 F) b,c
320 mA (2 F)d
1250 mA (2 F)e
1600 mA (2 F)b,g
160 mA (2 F) b,h
160 mA (2 F) b,i
640 mA (8 F)
85
0
8
80
6
9
76
12
3
10
11
12
13
14
94 (87)f
73
18
0
88
86
0
8f
83i
a Determined by GC analysis of the crude product solution.
b Graphite anode.
c Divided cell (Nafion membrane).
d Flow rate: 1.0 mL/min.
e Flow rate: 2 mL/min; cooling applied.
f Isolated yield.
g Concentration of 1: 1 M in MeOH.
h At 30 °C.
i At 60 °C.
In none of the cases shown in the Table 1 was the prod-
uct obtained with full conversion without formation of by-
product 3. However, a further increase of the current to 640
mA (8 F) resulted in an 83% conversion to the dimethoxylat-
ed product 3, with only 8% of the monomethoxylated prod-
uct 2 remaining in the reaction mixture (Table 1, entry 14).
The use of a higher flow rate and a higher current led to the
generation of heat. By applying cooling to the reactor, the
temperature could be maintained at 25 °C, resulting in a
94% conversion to product 3 (87% isolated yield) at a pro-
duction rate of 1.35 g/h (Table 1, entry 10).
The selective but incomplete reaction to give product 2
(Table 1, entry 7) was further optimized by the attachment
of a sequential second electrochemical microreactor with
identical specifications. Only a few reactions have previous-
ly been carried out with two electrochemical microreactors
in line.10 Other approaches for optimization in electro-
chemical reactors have been reported through recirculating
the reaction mixture in the electrochemical reactor until
complete conversions were achieved,11 or by stacking of
electrochemical reactors in one device.12
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Table 2 Reaction of Pyrrolidine-1-carbaldehyde (1) in Two Sequential
Electrochemical Reactors
hyde reacted under the optimized conditions to give the
monomethoxylated product 12 in 67% yield. The observed
atropisomers of 12 have already been characterized.13a
2 R = Me (89%)
4 R = Et (77%)
6 R = Pr (64%)
8 R = Bu (48%)
10 R = (CH2)4Me (42%)
OR
N
+
2
3
1
(0.1 M in
MeOH)
CHO
2 reactors
160 mA (4 F)
anode: graphite
cathode: 304 stainless steel
electrode distance: 0.5 mm
OMe
12 (67%)
O
N
CHO
CHO
volume: 2 x 0.6 mL, flow rate: 0.5 mL/min
Entry
Conditions
Conversion after first Conversion after
OR
N
reactora
2 + 3 (%)
second reactora
3 R = Me (83%) + 2 (8%)
5 R = Et (51%) + 4 (26%)
7 R = Pr (35%) + 6 (24%)
9a R = Bu (27%) + 8 (29%)
11a R = (CH2)4Me (22%) + 10 (25%)
2 + 3 (%)
1 reactor
640 mA (8 F)
1
100 mA (2.5 F)
130 mA (3.2 F)
150 mA (3.76 F)
160 mA (4 F)
66 + 0
77 + 0
80 + 0
84 + 0
83 + 0
90 + 0
94 + 0
95 + 2
95 + 5
53 + 47
OR
2
Figure 1 Alkoxylations of pyrrolidine-1-carbaldehyde and morpholine-
3
4-carbaldehyde a Two reactors, 320 mA.
4
5b
120 mA (3 F)
a Determined by GC analysis of the crude product solution.
b Glassy carbon anode.
When same electrode materials of 304 stainless steel
and graphite (1 cm2) were used in a batch reaction, only a
60% conversion to 2 was observed after 160 minutes of re-
action time (10 mA, 2 F).
Four different current values were investigated in the
sequential arrangement of two electrochemical microreac-
tors. With a flow rate of 0.5 mL/min, the reaction was in-
complete after the first reactor. After optimization, almost
full conversion after the second reactor could be achieved
by using a current of 150 mA (Table 2, entry 3). When the
current was increased to 160 mA (4 F), small amounts of
the dimethoxylated product 3 were detected (entry 4). Full
conversion, however, is essential as it appears to be almost
impossible to separate the starting material 1 from product
2 chromatographically. If only one reactor is used for these
experiments, half the flow rate (0.25 mL/min) will provide
the same amount of electricity to the substrate during the
reaction (residence) time. With 2 F (80 mA) only an 80%
conversion was achieved, whereas with 4 F (160 mA), start-
ing material remained and 2 and 3 were formed with 78%
and 16% conversion, respectively.
The optimized conditions were then applied to the reac-
tions of pyrrolidine-1-carbaldehyde (1) with other alcohols
on a larger scale (5.5 mmol). Compounds 2, 4, 6, 8, and 10
(Figure 1) were obtained in good yields by reactions with
various alcohols. Whereas the residence time in the reac-
tors was only 2.4 minutes, the reaction time for processing
5.5 mmol of starting material was just under two hours.
The observed results relate to current efficiencies of be-
tween 21 and 45%. The monoalkoxylated formylpyrroli-
dines were obtained as mixtures of two atropisomers in an
approximately 9:1 ratio, as determined by NMR spectrosco-
py; this atropisomerism is due to restricted rotation around
the amide bond.13 Furthermore, morpholine-4-carbalde-
By applying the reaction conditions for one electro-
chemical reactor shown in Table 1, entry 12, double alkox-
ylations were possible; these were carried out on a 5.5
mmol scale to give reaction products 3, 5, and 7, as shown
in Figure 1. Whereas compound 3 was obtained as an ap-
proximately 1:2 ratio of the cis- and trans-stereoisomers,14
only one stereoisomer (not assigned) of compounds 5, 7, 9,
1
and 11 was generated, as judged by H NMR spectroscopy.
The reason for the observed stereoselectivity in the double
alkoxylation is not clear at present. With butan-1-ol or pen-
tan-1-ol as the solvent, the conductivity was very low. In
the formation of 9 and 11, the current had to be reduced to
320 mA in the two reactors to avoid voltages that were too
high.
In conclusion, we have demonstrated the efficient use of
a new electrochemical reactor for the selective mono- or di-
alkoxylation of pyrrolidine-1-carbaldehyde as an exemplar
substrate.15
Acknowledgment
We thank Vapourtec Ltd. for fruitful discussions, for the provision of
the Ion electrochemical reactors and for financial support; we also
thank the Chemistry Department, Jazan University, Saudi Arabia, for a
scholarship to N.A.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611774.
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A 0.1 M solution of aldehyde 1 in MeOH (60 mL) containing
Et4NBF4 (0.05 M) was sonicated to ensure complete dissolution
of the reactant, then pumped through one microreactor at 0.5
mL/min by using a syringe pump or the Vapourtec E series,
while a constant current of 640 mA was applied. The first 5 mL
were discarded, and the remaining reaction mixture was col-
lected for 110 min (55 mL). MeOH was removed under reduced
pressure, and the crude product was washed with H2O (50 mL),
to remove the supporting electrolyte, then extracted with
CH2Cl2 (3 × 30 mL). The organic layers were combined, dried
(MgSO4), filtered, evaporated, and dried under high vacuum.
The residue was purified by chromatography [silica gel,
hexane–EtOAc (1:1)] to give a colorless oil; yield: 629 mg (89%).
The NMR spectra showed the presence of a ~5:1 mixture of
rotamers.1H NMR (400 MHz, CDCl3):  (major) = 8.40 (s, 1 H),
4.92 (d, J = 4.8 Hz, 1 H), 3.58−3.40 (m, 2 H), 3.26 (s, 3 H),
2.13−1.79 (m, 4 H);  (minor) = 8.29 (s, 1 H), 5.37 (d, J = 4.8 Hz, 1
H), 3.58−3.40 (m, 2 H), 3.38 (s, 3 H), 2.13−1.79 (m, 4 H). 13C NMR
(101 MHz, CDCl3):  (major) = 161.4, 89.7, 54.4, 42.7, 31.8, 21.4;
 (minor) = 162.6, 85.5, 56.6, 45.2, 31.9, 22.1.
(7) For details of the Ion electrochemical reactor, see:
https://www.vapourtec.com/products/flow-reactors/ion-elec-
trochemical-reactor-features/ (accessed Mar 15, 2019).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D