Continuous-flow catalytic deuterodehalogenation carried out in propylene carbonate

Article abstract of DOI:10.1039/c8gc03192d

A selective continuous-flow (CF) deuterodehalogenation approach is described performed in propylene carbonate, which is considered as one of the greenest solvents. Various CF technologies are known for hydrodehalogenation reactions; however, they are not

Full text of DOI:10.1039/c8gc03192d

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DOI: 10.1039/C8GC03192D
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ARTICLE
Continuous-flow catalytic deuterodehalogenation carried out in
propylene carbonate
György Orsy, a Ferenc Fülöp *a,b and István M. Mándity *a,c,d
Received 00th January 20xx,
Accepted 00th January 20xx
A selective continuous-flow (CF) deuterodehalogenation approach is described performed in propylene carbonate, which is
considered as one of the greenest solvents. Various CF technologies are known for hydrodehalogenation reactions; however,
they are not directly transferable for deuteration transformations. A novel spherical activated carbon-supported palladium
catalyst has been found to be useful for the catalytic deuterodehalogenation of haloarenes. After careful reaction parameter
optimization, complete conversion was reached for bromine- and chlorine-substituted haloarenes. Nonetheless, no
deuterium exchange was observed for the fluorine substituent, while iodine-substituted compounds poisoned the catalyst.
Importantly, deuterated compounds were gained with a rate of 3 mg min-1 and the catalyst showed reasonable reusability.
Moreover, benzylic amides were deuterated too without any debenzylation side-reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
reaction occurs. The cartridge is filled with supported catalysts,
which is a crucial factor in CF hydrogenation reactions. In
addition, there is a thermostat and pressure regulator in the
system to control the temperature and pressure of the reaction.
Nowadays, such reactors are widely used in organic chemistry
laboratories.24-44 By simply changing the water in the reservoir
for heavy water and using aprotic solvents, CF deuteration
reactions can be carried out.45-48 A schematic outline of the
reactor used in this study is shown in Figure 1.
Introduction
Deuterated compounds are of considerable current interest
since they possess a wide range of biomedical, chemical and
medicinal applications.1-10 They are used in mass spectrometry
as internal standards,1,
can be applied in mechanistic
11, 12
studies,13-15 and deuterium can also be used as a protecting
16
group.4,
Most importantly, nowadays deuterium-labelled
compounds are considered as medicines of the future17, 18 and
deutetrabenazine,19, 20 the first deuterium-labelled compound,
has recently been approved by the FDA21,22 and deuterated aryl
moiety in molecules might lead to next-generation drugs due to
high therapeutic values.22 Deuterium labelling increased the
pharmacokinetic property of the parent molecule through the
kinetic isotope effect. There are deuterated drug molecules
under clinical phase trials for diseases such as Alzheimer’s
disease, cystic fibrosis, Freidreich’s ataxia, psoriasis, etc.22
The major breakthrough of continuous-flow (CF) technologies
to organic chemistry and the fine chemical industry has
appeared in the field of catalytic hydrogenation triggered by the
invention of the H-Cube® reactor.23 It consists of a pump
delivering the liquids, a built-in hydrogen generator producing
hydrogen gas from water and a catalyst cartridge, where the
H-Cube®
Electrolysis of
heavy water
D2
Catalyst
Controlled
p, T
HPLC
pump
Product
Substrate
in solvent
Figure 1. Schematic illustration of the reactor used for the dehalodeuteration
reaction
a. Institute of Pharmaceutical Chemistry University of Szeged, Eötvös u. 6, H-6720
Szeged, Hungary.
In regular batch operations, solid supports with small particle
sizes in the low micrometer range are used, since they offer high
catalytic activity.49-51 However, such catalysts are not suitable
for CF devices, since they can block the flow line. Thus, the
search for novel solid supports is of considerable current
interest. Recently, polymer-based spherical activated carbon
(PBSAC) was introduced as a solid support for CF catalytic
hydrogenation.52-54 This polystyrene-derived solid support
offers a high surface, which is necessary for high catalytic
b. Research Group of Stereochemistry of the Hungarian Academy of Sciences, Dóm
tér 8, H-6720 Szeged, Hungary.
c. Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University,
Hőgyes Endre u. 7, H-1092, Budapest, Hungary.
d. MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials
and Environmental Chemistry, Research Center for Natural Sciences, Hungarian
Academy of Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary
e-mail: fulop@pharm.u-szeged.hu; mandity.istvan@pharma.semmelweis-univ.hu,
mandity.istvan@ttk.mta.hu
Electronic Supplementary Information (ESI) available: general experimental set-up,
1H and 13C NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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activity. Furthermore, because of its spherical nature, it is our CF deuteration technology developed previously to perform
View Article Online
prominently compatible with CF conditions without any deuterodehalogenation reactions selectiDnOgI4: 1-b0.r1o0m39o/Ca8cGeCta0n31il9id2De
observable pressure increase in the flow line during the as a test compound. The complete reaction parameter
synthetic operation.
optimization is shown in Table 1. The starting material was
In reaction design, the appropriate choice of solvent is another dissolved in ethyl acetate (EtOAc) in a concentration of 1 mg mL-
crucial factor. A suitable solvent can enhance reaction rate, 1, utilizing 5% Pd/BaSO4 as catalyst at a temperature of 25 °C
might stabilize transition states, allows the appropriate and a pressure of 50 bar with 1 mL min-1 flow rate. No
concentration of reagents, etc. Moreover, solvents used today conversion was observed under these conditions. Increase in
should be as sustainable as possible.55 According to the recent the pressure to 100 bar provided a marginal increase in
GSK solvent selection guide, the greenest solvent today is conversion. Still, the utilization of 100 °C with 100 bar resulted
propylene carbonate (PC),56 which can be synthesized in a only in 13% conversion. To increase the performance of our
highly atom-efficient way from propylene oxide and carbon system, the catalyst was changed to charcoal-supported 5%
dioxide with prominently low energy consumption.57 PC has Pd/C. This afforded a significantly improved conversion of 48%,
already been used for several important reactions;58-63 while the deuterium incorporation value of the product was
however, its use in catalytic deuteration is practically found to be a promising 81%. Next, we turned our attention
54
unexplored.64, 65
toward the novel PBSAC supported catalyst.52,
With this
Herein we report the first CF deuterodehalogenation of catalyst 87% conversion and 92% deuterium incorporation was
aromatic compounds performed by the use of a PBSAC- observed at 100 bar pressure and 100 °C temperature. Finally,
supported Pd catalyst in PC as a prominent green solvent. In the solvent was optimized and it was changed for PC according
addition, not only ethyl acetate used traditionally was replaced to GSK solvent selection guide and CF literature results on the
by a more sustainable solvent, but a higher concentration of the suitability of PC in CF. Importantly, complete conversion was
reagents could also be achieved in PC, thus allowing higher obtained while the deuterium incorporation value was 96% at
space-time yield and lower solvent consumption.
100 bar pressure and 100 °C temperature. The effect of the
concentration of the starting material on reaction outcome was
tested too. The results revealed that without the loss of
conversion and deuterium incorporation, the concentration can
be increased to 3 mg mL-1.
Results and discussion
Hydrodehalogenation of aromatic compounds was carried out
in CF without difficulties.27, 66, 67 Thus, we aimed to implement
our CF deuteration technology developed previously to perform
deuterodehalogenation reactions selecting 4-bromoacetanilide
as a test compound. The complete reaction parameter
optimization is shown in Table 1. The starting material was
dissolved in ethyl acetate (EtOAc) in a concentration of 1 mg mL-
1, utilizing 5% Pd/BaSO4 as catalyst at a temperature of 25 °C
and a pressure of 50 bar with 1 mL min-1 flow rate. No
conversion was observed under these conditions. Increase in
the pressure to 100 bar provided a marginal increase in
conversion. Still, the utilization of 100 °C with 100 bar resulted
only in 13% conversion. To increase the performance of our
system, the catalyst was changed to charcoal-supported 5%
Pd/C. This afforded a significantly improved conversion of 48%,
while the deuterium incorporation value of the product was
Table 1. Reaction parameter optimization for CF deuterodehalogenation reaction
T
(°C)
25
p
(bar)
50
100
100
100
100
100
100
100
Conc.
D
Conv.
(%)
0
Solvent Catalyst
(mg mL-1)
(%)
n.d.
n.d.
n.d.
81
92
96
96
97
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
PC
A
A
A
B
C
C
C
C
1
1
1
1
1
1
3
4
25
4
100
100
100
100
100
100
13
48
87
99
99
94
PC
PC
A: 5% Pd/BaSO4; B: 5% Pd/C; C: 5% Pd/PBSAC
However, the decrease in either the pressure or the
temperature resulted in lower yields (Figure 2), while the
deuterium incorporation level did not change significantly.
found to be a promising 81%. Next, we turned our attention
54
toward the novel PBSAC supported catalyst.52,
With this
catalyst 87% conversion and 92% deuterium incorporation was
observed at 100 bar pressure and 100 °C temperature. Finally,
the solvent was optimized and it was changed for PC according
to GSK solvent selection guide and CF literature results on the
suitability of PC in CF. Importantly, complete conversion was
obtained while the deuterium incorporation value was 96% at
100 bar pressure and 100 °C temperature. The effect of the
concentration of the starting material on reaction outcome was
tested too. The results revealed that without the loss of
conversion and deuterium incorporation, the concentration can
be increased to 3 mg mL-1.
Hydrodehalogenation of aromatic compounds was carried out
in CF without difficulties.27, 66, 67 Thus, we aimed to implement
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O
bromine–hydrogen exchange was surmised as described for 7;
O
View Article Online
thus a similar deuterated methanol pre-DtrOeIa: 1t0m.1e0n39t/wC8aGsCc0a3r1r9ie2Dd
out. The deuterium incorporation value, in this way, increased
to 98%.
HN
CH3
HN
D
CH3
10% Pd/PBSAC
p, T
Table 2. Results of the deuteration reaction of several bromine-substituted model
compounds
Br
Entry
1
Substrate
Product
D (%)
96
Yield (%)
96
a)
100
O
O
HN
CH3
HN
CH3
80
60
40
20
0
Br
D
1
2
COOH
COOH
2
96
97
0
20
40
60
80
100
D
Br
Pressure / bar
3
4
b)
100
80
60
40
20
0
COOH
COOH
3
4
95
95
94
Br
Br
D
D
5
6
COOH
COOH
98[a]
8
7
20
40
60
80
100
Temperature / °C
Figure 2. The effect of pressure and temperature on the reaction conversion
catalysed by PBSAC-supported 10% Pd. The effect of the pressure was measured
at 100 °C, while the effect of temperature was determined at 100 bar.
O
NH
O
NH
5
97
98
The scope of the reaction was tested first with various bromine-
substituted aromatic compounds. Benzoic acids possessing a
bromo substituent in position 4 (3), 3 (5) and 2 (7) were
examined under the optimized conditions. As shown in Table 2,
for these regioisomers complete conversions were reached
with >95% deuterium incorporation in the case of 3 and 5.
However, for 7, where the bromine is in the ortho position, only
marginal deuterium incorporation was observed. We envisaged
that intramolecular bromine–hydrogen exchange occurs due to
steric proximity of the functional groups. Thus, the starting
material was dissolved in deuterated methanol, the solution
was evaporated to dryness, and the product was utilized
immediately in the deuteration reaction. By this simple
treatment, the deuterium incorporation value increased to
97%.
Br
D
9
10
O
NH
O
NH
6
96
94
Br
D
11
12
O
NH
O
NH
7
98[a]
95
Next, a further set of test compounds, namely, aromatic amides
9, 11 and 13 were investigated possessing a bromo substituent
in position 4, 3 and 2, respectively. Excellent deuterium
incorporation and conversion were reached in all cases, except
for compound 13. Here again the same intramolecular
Br
D
13
14
[a] reached by pre-treating the staring molecule with deuterated methanol
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Ar-X
DOI: 10.1039/C8GC03192D
Ar-D
Importantly, no debenzylation was observed for compounds 9,
11 and 13. This is a significant further advantage of the method
allowing the deuteration of molecules containing the benzyl
moiety.
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Pd(0)
To further broaden the scope of the developed
deuterodehalogenation reaction, aromatic compounds with
other halogen substituents were also tested (Table 3).
Ar Pd
D
Ar Pd
X
DX
D2
D
Ar Pd
Table 3. Results of the deuteration reaction with substrates possessing chloro,
iodo and fluoro substituents
D
X
Scheme 1. Proposed mechanism for the catalytic deuterodehalogenation
Entry
1
Substrate
Product
D (%)
96
Yield (%)
O
O
In the context of green chemistry criteria, catalyst recycling is
an important issue. Therefore, the robustness of the reaction
was tested too (Figure 3). The deuterodehalogenation reaction
of 1 was repeated multiple times with the same catalyst bed. In
the first 6 cycles, the conversion value did not change
significantly. However, from run 7 on, considerable decreases in
the catalytic activity were observed. Thus, the catalyst used in
the CF deuterodehalogenation reaction proved to be
moderately robust.71
HN
CH3
HN
CH3
96
Cl
D
2
O
15
O
HN
CH3
HN
CH3
The catalyst recycling data were utilized for a careful design of
the large scale reaction. Since the catalyst activity did not
decrease significantly until 5 cycles and one cycle was carried
out with 100 mg of compound 1, it was planned that after the
pumping of 500 mg of 1 through the system, the catalyst
cartridge will be replaced with new one. In total a CF
deuterodehalogenation reaction was carried out with 1.5 g of
compound 1. The product (2) was isolated with 95% yield and
the data showed 96% deuterium incorporation.
2
n.d.
30
I
D
2
O
16
O
HN
CH3
HN
CH3
3
n.d.
0
O
O
HN
CH3
D
HN
CH3
F
10% Pd/PBSAC
100 bar, 100 °C
2
17
Br
D
In the reaction of chlorine-substituted acetanilide 15, full
conversion was achieved with a high deuterium incorporation
value. Surprisingly, the corresponding iodine-substituted
derivative (16) gave only a mere 30% conversion. However, by
repeating the reaction with the catalyst used in the first trial, no
conversion was observed. Obviously, compound 16 poisons the
catalyst. Compound 17 was selected to test the effect of the
fluorine substituent. The results show that the fluorine
substituent remained intact and no conversion was observed.
These results can be explained by the proposed mechanism of
the reaction (Scheme 1).68 A key step is the oxidative addition
of the aryl halide to a Pd(0) species. According to literature
results this reaction is not proceeding for aryl fluorides,69 of
which supports our observation for fluorinated compounds. The
poisoning of the catalyst in case of iodinated compounds can be
explained by the elimination of the iodide ion. According to
literature results iodide ion are known to poison the Pd
catalyst.70
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9
10
Number of cycles
Figure 3. Robustness of the CF deuterodehalogenation investigated in the reaction
of 1. The same reaction was repeated 10 times on the same catalyst.
Conclusions
In conclusion, we have developed the first CF
deuterodehalogenation reaction induced by palladium.
Surprisingly, the conditions described previously for CF
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hydrodehalogenations were not suitable for deuteration. Harsh
reaction conditions (100 bar and 100 °C), a novel spherical N-benzylbenzamide-3-2H (12)
support (PBSAC) and PC as solvent were necessary to obtain White crystals; m.p. 104.1-106.2 °C
View Article Online
DOI: 10.1039/C8GC03192D
complete conversions with concomitant >95% deuterium 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=5.3, 1H), 7.87-7.92 (m,
incorporations. Importantly, PC allowed the use of an increased 2H), 7.44-7.56 (m, 2H), 7.19-7.28 (m, 1H) 7.28-7.37 (m, 4H), 4.49
(3 times higher) concentration of the reactants with (d, J=5.3, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.2, 139.7,
considerably faster reactions. Test compounds possessing 134.3, 131.1, 128.3, 128.2, 128.0, 127.2, 127.1, 127.1, 126.7,
bromine substituents in different positions provided excellent 42.6.
results, except the 2-bromo-substituted compounds. In these
cases, deuteromethanol pre-treatment was necessary, due to N-benzylbenzamide-2-2H (14)
intramolecular halogen–hydrogen exchange. Importantly, White crystals; m.p. 104.1-106.2 °C
molecules containing the benzyl group were deuterated too 1H NMR (400 MHz, DMSO-d6) δ 9.05 (t, J=5.3, 1H), 7.88 (d, J=7.4,
without any trace of debenzylation. Chloro-substituted 1H), 7.43-7.56 (m, 3H), 7.19-7.28 (m, 1H) 7.28-7.37 (m, 4H), 4.48
derivatives also provided excellent results. However, the iodine (d, J=5.3, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.4, 139.8,
substituent poisoned the catalyst, while the fluorine substituent 134.3, 131.4, 128.5, 128.4, 128.3, 127.3, 127.3, 127.0, 126.9
remained intact. Thus, selective deuteration can be performed 42.6.
in the presence of a fluorine substituent. The catalyst under
these harsh reaction conditions showed moderate reusability.
Conflicts of interest
There are no conflicts to declare.
Experimental section
NMR characterization of products
N-(phenyl-4-2H)acetamide (2)
Acknowledgements
White crystals; m.p. 110.2-111.8 °C (data is in agreement with
the literature reference: 110-112 °C)72
1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.56 (d, J=8.2 Hz,
2H), 7.27 (d, J=8.2 Hz, 2H), 2.03 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 168.3, 139.3, 128.6, 123.0, 118.9, 24.0.
We are grateful to the Hungarian Research Foundation (OTKA
No. K 115731). The financial support of the GINOP-2.3.2-15-
2016-00014 project is acknowledged.
Notes and references
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Biomol. Chem., 2008, 6, 3048-3051.
Benzoic-4-2H acid (4)
White crystals; m.p. 119.1-121.4 °C (data is in agreement with
the literature reference: 119-121 °C)72
1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=7.5 Hz, 2H), 7.50 (d,
J=7.5 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 167.4, 132.9,
130.8, 129.3, 128.6.
5. A. K. L. Yuen, O. Lafon, T. Charpentier, M. Roy, F. Brunet, P.
Berthault, D. Sakellariou, B. Robert, S. Rimsky, F. Pillon, J.-C.
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Comp. Radiopharm., 2001, 44, 529-539.
Benzoic-3-2H acid (6)
White crystals; m.p. 119.6-121.3 °C (data is in agreement with
the literature reference: 121 °C)73
1H NMR (400 MHz, DMSO-d6) δ 7.91-7.95 (m, 2H), 7.58-7.62 (m,
1H), 7.47 (t, J=8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ
167.3, 132.9, 130.7, 129.3, 128.6.
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Science, 2004, 305, 495-499.
Benzoic-2-2H acid (8)
White crystals; m.p. 119.3-121.1 °C (data is in agreement with
the literature reference: 121 °C)73
1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=7.3, 1H), 7.58-7.65 (m,
1H), 7.47-7.54 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 167.3,
132.9, 130.6, 129.2, 128.6.
N-benzylbenzamide-4-2H (10)
White crystals; m.p. 104.1-106.2 °C (compound is known,74 but
m.p. not published)
1H NMR (400 MHz, DMSO-d6) δ 9.02 (t, J=5.3, 1H), 7.90 (d, J=7.4,
2H), 7.47 (d, J=7.4, 2H), 7.19-7.28 (m, 1H) 7.28-7.37 (m, 4H),
4.49 (d, J=5.3, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.2, 139.7,
134.3, 130.9, 128.3, 128.2, 127.2, 127.1, 126.7, 42.6.
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Green Chemistry
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DOI: 10.1039/C8GC03192D
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