A simple, efficient, and selective deuteration via a flow chemistry approach

Article abstract of DOI:10.1016/j.tetlet.2009.05.050

A simple and efficient deuteration methodology has been established for a wide variety of substrates using a continuous flow hydrogenation reactor. The described procedure is many times faster (1 mg min^-1) compared to literature methods and the

Full text of DOI:10.1016/j.tetlet.2009.05.050

Tetrahedron Letters 50 (2009) 4372–4374
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Tetrahedron Letters
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A simple, efficient, and selective deuteration via a flow chemistry approach
István M. Mándity a, Tamás A. Martinek a, Ferenc Darvas b, Ferenc Fülöp a,
*
a University of Szeged Institute of Pharmaceutical Chemistry, Eötvös u. 6, Szeged H-6720, Hungary
b ThalesNano Nanotechnology Inc., Záhony u. 7, Budapest H-1031, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient deuteration methodology has been established for a wide variety of substrates
Received 6 April 2009
Revised 4 May 2009
Accepted 15 May 2009
Available online 22 May 2009
using
a continuous flow hydrogenation reactor. The described procedure is many times faster
(1 mg minÀ1) compared to literature methods and the purity of the crude product can be as high as
99%. The deuterium source is D2O, the consumption of which is very low.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Deuteration
Flow chemistry
Heterogenous catalysis
Palladium
Reduction
Deuterium-labeled compounds are widely used as research
tools in life, environmental and materials sciences.1 They are
important, for example, as, (i) internal standards in mass
spectrometry,2 (ii) tools for the elucidation of mechanisms,3 (iii)
materials with which to investigate pharmacokinetics,4 and (iv)
compounds facilitating signal assignment and structure determi-
nation in NMR spectroscopy.5,6 Conventional techniques for the
synthesis of deuterated compounds utilize D2 gas as a deuterium
source.7 D2 is produced commercially by one of the following pro-
cedures: (i) large-scale electrolysis of D2O, (ii) fractional distillation
of liquid hydrogen, (iii) pyrolysis of UD3,8 or (iv) reactions of D2O
with sodium, iron, or magnesium.9 These methods suffer from var-
ious drawbacks on the laboratory scale such as difficulties in gas
handling, cryogenic conditions, production of radioactive waste
or a large quantity of metal sludge. Catalytic exchange methods
have also been described, but the deuterium incorporation efficien-
cies varied appreciably.10 Numerous catalytic H–D exchange reac-
tions between H2 and D2O have been reported in the literature.
However, these time-consuming methods do not produce high-
purity D2 and they also require high pressure, the use of a special
catalyst or an excess amount of a strong base or acid.11–14 Flow
chemistry approaches are commonly used in organic synthesis.15,16
Among flow chemistry techniques, the best-characterized and
most widely used reaction is heterogenous hydrogenation.17,18
The present work focuses on a time- and cost-efficient synthesis
of deuterated compounds using Pd- or Ni-catalyzed deuteration
in a continuous flow (CF) reactor combined with on-demand
pressure-controlled electrolytic D2 production. The experimental
set-up allows fine-tuning of pressure, temperature, and flow rate
(Fig. 1).
The deuterated products were characterized by HPLC, mass
spectrometry, and NMR spectroscopy (1H and 2H). The deuterium
contents were determined from the relative intensities of the 1H
NMR indicator resonances. First, the optimum conditions were
determined for the CF deuteration of unsaturated carbon–carbon
bonds with respect to the catalyst and solvent. For the Pd-cata-
lyzed test reactions, cinnamic acid was chosen (Scheme 1).
The study started with 10% Pd/C as catalyst, according to the lit-
erature,12 and methanol as solvent. The deuterium incorporation
was only 30%, and the solvent was therefore changed to aprotic
ethyl acetate, which significantly increased the incorporation of
deuterium.
Nevertheless, the deuteration level referenced to the aromatic
signals was still below optimal. The 2H NMR and MS spectra
Sample in
ethyl acetate
D2O
reservoir
Electrolysis
cell
D2
Catalyst
p, T
HPLC pump
Product
* Corresponding author. Tel.: +36 62 545 564; fax: +36 62 545 705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
Figure 1. Schematic representation of the continuous flow deuteration reactor.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.050

I. M. Mándity et al. / Tetrahedron Letters 50 (2009) 4372–4374
4373
D
O
Table 2
O
Deuteration of selected compounds containing a carbon–carbon multiple bond
catalyst, solvent, 50 atm
flow rate: 1 mL min-1, RT
OH
OH
Entry
1
Substrate
Product
Da (%)
Yieldb (%)
D
D
Ph
O
Ph
O
99
99
Ph
Ph
Scheme 1. Deuteration of cinnamic acid.
D
D
D
Table 1
Optimization of the reaction conditions
Me
2
3
97
93
98
97
Me
Ph
O
Ph
Ph
O
Entry
Catalyst
Solvent
D content (%)
D
D
1
2
3
10% Pd/C
10% Pd/C
Methanol
30
70
95
Ph
Ethyl acetate
Ethyl acetate
Ph
Ph
5% Pd/BaSO4
D
D
O
O
revealed that the phenyl ring was partially saturated with deute-
rium also, thereby biasing the apparent degree of deuteration.
The regioselectivity of the reaction could be improved using the
less active catalyst (5%) Pd/BaSO4 in ethyl acetate (Table 1), which
consequently further elevated the apparent deuterium incorpora-
tion ratio observed on the aliphatic carbons. These values are
highly competitive as compared with the literature methods men-
tioned above.12,13 A pressure in the 40–60 atm range and flow rate
in the range 0.7–2 mL minÀ1 did not influence the yield or the
degree of deuterium incorporation. It is important to note that
the reactions were carried out in a single run and the products
were analyzed without any further purification. On the basis of
the promising results obtained with cinnamic acid, the deuteration
of various unsaturated substrates was performed in the CF system
with ethyl acetate as solvent and 5% Pd/BaSO4 as catalyst at room
temperature (Table 2). The substrates were selected to include a
range of functional groups so as to establish the performance of
the CF deuteration methodology. The selection covered foldamer
(unnatural folding systems) building blocks also, as the incorpora-
tion of deuterium offers new possibilities for the elucidation of the
structures of these intriguing substances, where bacterial labeling
is not possible.19–21 The successful deuteration (high yield/high
D%) of these compounds supports the view that the proposed
experimental CF deuteration set-up is generally applicable in deu-
terium labeling tasks for carbon–carbon multiple bonds. The deu-
terium incorporation for entries 4–8 in Table 2, is cis-selective.
The relative configurations have not been determined as yet.
Another approach with which to introduce deuterium into mol-
ecules through simple chemistry is deuteration of a nitrile group.
In accordance with the reaction conditions described in the litera-
ture, Raney nickel catalyst was applied at atmospheric pressure
and a temperature of 80 °C.17 In this case, H2O contamination
NH Me
D
D
NH Me
4
96
98
H
H
N
N
Me
Me
O
O
O
O
D
NH Me
NH Me
5
96
99
D
H
H
N
N
Me
Me
O
O
O
O
NH Me
D
D
NH Me
6
7
95
97
98
99
95
98
H
H
N
N
Me
Me
O
O
O
O
Me
Me
Me
Me
NH
D
D
NH
H
H
N
N
O
O
D
Boc
OH
Boc
OH
NH
NH
D
8
O
O
a
Deuterium content in %.
Isolated yield.
b
Table 3
Deuteration of selected nitrile derivatives
Entry
1
Substrate
Product
Da (%)
Yieldb (%)
85
D D
D
D
CN
C1 89
C2 33
2
1
NH2
D D
MeO
MeO
D
D
CN
MeO
MeO
2
2
C1 90
C2 17
70
1
NH2
a
Deuterium content in %.
Isolated yield.
b

4374
I. M. Mándity et al. / Tetrahedron Letters 50 (2009) 4372–4374
(Raney nickel is stored under water in the laboratory) was
minimized by soaking the catalyst in D2O for 24 h before placing
it in the CF reactor. The solvent was dry ethyl acetate. The CF
deuteration was successful on the selected model compounds even
with the initial conditions (Table 3) and the yields and degrees of
deuteration were higher than those previously reported.12 How-
ever, it should be noted that by-products arising from amine addi-
tion to the imine intermediates cannot be eliminated, which
explains the lower yields observed in this reaction.17 On the other
hand, these by-products could be easily removed by HPLC purifica-
tion. These results indicate that CF deuteration can be extended to
compounds containing a CN group.
be
found,
in
the
online
version,
at
doi:10.1016/
j.tetlet.2009.05.050.
References and notes
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In conclusion, we have established deuteration procedures for a
wide variety of substrates in a CF hydrogenation reactor. We
emphasize that the synthesis is magnitudes faster (1 mg minÀ1
)
than literature methods and the purity of the crude product can
be as high as 99%. The only exception is nitrile reduction, where
the purification is straightforward. The D2O consumption is very
low (4.41
l
L minÀ1), which represents much higher deuterium
efficiency than in earlier methods. The proposed method is conve-
nient, cost- and time-efficient, environmentally friendly, and safe.
15. Csajági, C.; Borcsek, B.; Niesz, K.; Kovács, I.; Székelyhidi, Z.; Bajkó, Z.; Ürge, L.;
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Acknowledgments
16. Continuous flow reactors: www.thalesnano.com, www.syrris.com.
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18. Continuous flow hydrogenation instruments: www.thalesnano.com,
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J. J.; Gellman, S. H. Nature 1997, 387, 381.
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We thank the Hungarian Research Foundation (NF69316,
T049407) for financial support. T.A.M. acknowledges the award
of a János Bolyai Fellowship from the HAS.
Supplementary data
Supplementary data (general experimental procedures, 1H
NMR, 2H NMR, and MS spectra) associated with this article can
21. Mándity, I. M.; Wéber, E.; Martinek, T. A.; Olajos, G.; Tóth, G. K.; Vass, E.; Fülöp,
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