Microwave-assisted deuterium exchange reactions for the preparation of reactive intermediates

Article abstract of DOI:10.1016/S0040-4039(02)00706-2

Deuterium labelling of a number of ketones was achieved on a preparative scale by a microwave-assisted deuterium exchange reaction with D₂O/CF₃COOD. The reaction was rapid (<15 min) and highly isotope-efficient (ca. 100%), even though deuterium incorporation can be decreased during work-up (85-90%). No exchange reaction was observed for aryl protons of aromatic ketones.

Full text of DOI:10.1016/S0040-4039(02)00706-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3789–3792
Microwave-assisted deuterium exchange reactions for the
preparation of reactive intermediates
Katalin Fodor-Csorba,a,* Giancarlo Galli,b Sa´ndor Hollyc and Eszter Ga´cs-Baitzc
aResearch Institute for Solid State Physics and Optics of the Hungarian Academy of Sciences, PO Box 49, H-1525 Budapest,
Hungary
bDipartimento di Chimica e Chimica Industriale, Universita` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
cChemical Research Center of the Hungarian Academy of Sciences, Institute for Chemistry, PO Box 17, H-1525 Budapest,
Hungary
Received 7 March 2002; revised 26 March 2002; accepted 10 April 2002
Abstract—Deuterium labelling of a number of ketones was achieved on a preparative scale by a microwave-assisted deuterium
exchange reaction with D2O/CF3COOD. The reaction was rapid (<15 min) and highly isotope-efficient (ca. 100%), even though
deuterium incorporation can be decreased during work-up (85–90%). No exchange reaction was observed for aryl protons of
aromatic ketones. © 2002 Elsevier Science Ltd. All rights reserved.
There is an ever increasing demand for the synthesis of
commercially unavailable, labelled starting materials to
be used in studies for a better understanding of e.g. the
metabolic pathways of drugs and biologically active
molecules in biological media,1 or the order and
dynamics of liquid crystals in their different
mesophases.1–3 In these latter cases, stable isotopes like
deuterium have special interest, because the labelled
compound is stable for a long time thus permitting
more detailed investigation by specialized 2H NMR and
neutron scattering techniques.
We have applied microwave-assisted deuterium
labelling to a preparative scale, i.e. a few gram scale,
for the synthesis of deuteriated ketones, aromatic or
aliphatic, that are useful intermediates for the prepara-
tion of different classes of liquid crystals in which the
deuteriated group would be directly linked to the meso-
genic core. We used D2O as the deuterium source, and
CF3COOD as a catalyst. While our test material was
2-octanone 1, other aliphatic or aromatic ketones, such
as 2-pentanone 2, 4-methyl-2-pentanone 3, 4-n-hep-
tanoylbiphenyl 4, and 1-(4-n-heptylbiphenyl)ethanone
5, were also investigated to ascertain the versatility and
selectivity of this synthetic method on different sub-
strates (Scheme 1).
For the preparation of deuterium labelled compounds
there are several possibilities using (i) chemical reac-
tions for connection of labelled segments to the non-
labelled part of the molecule, or (ii) exchange reactions
accelerated by various catalytic methods.3–5
An isotopic exchange reaction on 1 has previously been
carried out with D2O under phase transfer conditions in
the presence of t-BuOK, n-Bu4NBr and benzene with-
out microwave irradiation, but no details of the method
were described.11 According to earlier papers, the iso-
tope exchange reactions of 1–3 were carried out using
strong alkaline conditions, heating for 12 h, salting out
the test material and repeating the procedure nine or
ten times giving 100% deuteriation on the 1,1,1,3,3
positions of the ketones.11–13
Very recently, microwave-assisted deuterium labelling
reactions, which are specific and faster than similar
thermally activated reactions, have been introduced.6–10
This technique may become an increasingly effective
deuterium labelling reaction. However, to the best of
our knowledge, no attempts have been made, so far, on
microwave-assisted deuterium isotope exchange reac-
tions on a preparative scale.
* Corresponding author. Fax: +36-1-392-2215; e-mail: fodor@
szfki.hu
Scheme 1. Deuterium labelling of ketone derivatives.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00706-2

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K. Fodor-Csorba et al. / Tetrahedron Letters 43 (2002) 3789–3792
carbonate, evaporated and distilled at 173°C, 1.6 g,
(80%). IR (neat): 2957 (wasCH3), 2931 (wasCH2), 2874
(wsCH3), 2859 (wsCH2), 2253 (wasCD3), 2216 (wasCD2),
2176 (wsCD3), 2121 (wsCD2), 1713 (wCꢀO) cm−1. 1H
NMR (400 MHz, l ppm, CDCl3): 0.84 (t, 3H, H8), 1.56
(m, 2H, H7), 1.25–1.32 (m, 6H, H6+H5+H4), 2.12
(s+m, 0.3H, H1), 2.40 (t+m, 0.2H, H3). MS m/e: 133
(M+).
2,2,2-Trideuterio-1-phenylethanone was obtained either
in alkaline conditions14a,b,d or by heating 1-
phenylethanone at 400–410°C in deuterium oxide for 12
hours under supercritical pressure.14c
According to our investigations, the acid-catalyzed
exchange reaction on 1 with thermal activation yielded
less deuteriation even under more drastic experimental
conditions (480 min at reflux) (Table 1). Similar results
were obtained with analogous ketones such as 2 and 3.
A lower deuterium incorporation was achieved with
aromatic ketones 4 and 5, with no interference from the
aromatic protons using either power or thermal control
of the microwave reaction (Table 1). We suggest that
acid promoted enolization of the ketone takes place,
which can accelerate the exchange in the strong deuteri-
ating medium.
1,1,1,3,3-Pentadeuterio-2-pentanone 2a: 2-pentanone
(2.9 g, 33.4 mmol), heavy water 6.0 g (300.0 mmol) and
trifluoroacetic acid (4.9 g, 42.5 mmol) were irradiated in
the same reaction flask at 90°C with power control (2
min 100% and 13 min 25% of power). After cooling to
room temperature, the reaction mixture was extracted
with diethyl ether, dried over anhydrous sodium hydro-
gencarbonate and distilled at 100.0–102.4°C on 300 mm
Vigreux column. The deuteriation rate was 98%, (2.4 g.
84%). IR (neat): 3000–2800 (wasCH3, wasCH2, wsCH3,
wsCH2), 2254 (wasCD3), 2218 (wasCD2), 2181 (wsCD3),
2142 (wsCD2), 1713 (wCꢀO), 1254 (lsCD3) cm−1. 1H
NMR (400 MHz, l ppm, CDCl3): 0.93 (3H, t, C5-H3),
1.60 (2H, q, C4-H2), 2.10 (0.8H, m, C1-H3), 2.38 (0.54
H, m, C3-H2).
For high efficiency, deuterotrifluoroacetic acid and
heavy water were applied in large excess to facilitate
exchange of the protons of 2-octanone. After 15 min
irradiation, essentially quantitative deuteriation of the
carbon atoms alpha to the carbonyl group was detected
1
by H NMR. During work-up of the reaction mixture
under acidic conditions a significant decrease down to
90–85% of the deuterium content occurred. Therefore,
2-octanone-d5 1a had to be extracted very quickly and
the mixture neutralized in order to avoid the back-
exchange reaction.
The same reaction mixture was heated under reflux for
6 h at normal pressure. The reaction mixture was
worked up the same way as above. Repeated treatment
for 2 h under the same conditions using a new deu-
terium source gave 98% deuteriation on the C1 and C3
carbons, 2.2 g (75%).
In conclusion, in this work microwave-assisted deu-
terium exchange has been used on a preparative scale
and shown to be rapid, selective and isotope-efficient.
1,1,1,3,3-Pentadeuterio-4-methyl-2-pentanone 3a: 4-
methyl-2-pentanone (2.4 g, 24.00 mmol), trifluoroacetic
acid-d1 (5.9 g, 56.2 mmol) and heavy water (7.0 g, 350.0
mmol) were irradiated with the power control (as above
1a) for 15 min. The reaction mixture was extracted with
carbon tetrachloride, dried over anhydrous sodium car-
bonate, and distilled on a Vigreux column (300 mm).
Fractions boiling at 126–127°C were collected, 1.9 g
(77%).
1,1,1,3,3-Pentadeuterio-2-octanone 1a: 2-octanone (2.0
g, 15.6 mmol), CH3COOD (5 ml, 64.9 mmol) and D2O
(20.00 ml) were introduced into a tube equipped with a
mechanical stirrer, reflux condenser and placed in a
Prolabo Synthewave 402 focused microwave reactor
(600 W). The reaction mixture was irradiated for 15
min with power control at about 90°C (2 min 100% and
13 min 20%). The reaction mixture was extracted
quickly with carbon tetrachloride, washed with 5%
NaHCO3/D2O solution, dried over anhydrous sodium
The thermal treatment of the reaction mixture gave a
similar result after 9 h reflux. The work up of the
Table 1. Typical deuterium incorporation extent (D) with D2O/CF3COOD under different conditions
Substrate
Method
Power
Temperature (°C)
Time
D (%)
1
Microwave
Thermal
Thermal
Microwave
Thermal
Thermal
Microwave
Thermal
Microwave
Thermal
Thermal
Microwave
Thermal
90
–
K2CO3
80
90
15 min
480 min
120 h
15 min
480 min
120 h
15 min
540 min
20 min
1 month
24 h
20 min
540 min
1 week
96
85
Reflux
Reflux
90
Reflux
Reflux
90
Reflux
90
20
Reflux
90
Reflux
20
9912a
90
2
–
75
K2CO3
80
–
90
–
–
80
–
–
9913a,b
85
3
4
90
75
66
68
95
90
66
5
Thermal

K. Fodor-Csorba et al. / Tetrahedron Letters 43 (2002) 3789–3792
3791
reaction mixture was similar as described above. IR
(neat): 3000–2800 (wasCH3, wasCH2, wsCH3, wsCH2), 2254
(wasCD3), 2216 (wasCD2), 2169 (wsCD3), 2133 (wsCD2),
1.25–1.40 (m, 8H, 4×CH2), 1.62 (m, 2H, CH2), 2.64 (m,
1H, COCD2H), 7.27 (m, 2H, H2%, H6%), 7.54 (m, 2H,
H3%+H5%), 7.67 (m, 2H, H2%%+H6%%), 8.01 (m, 2H, H3%%+
H5%%). MS: M+=296, M+-CD2H=279.
1
1713 (wCꢀO) 1251 (lsCD3) cm−1. H NMR: (400 MHz,
l ppm, CDCl3) 0.92 (6H, d, J=6.8 Hz, C4-H, C5-H3),
2.08 (0.42H, m, C1-H3), 2.10 (1H, m, J=6.8 Hz C4-H),
2.28 (0.33H, m, C3-H2).
1H NMR spectra were recorded on a Varian XL-400
1
instrument in CDCl3 solution at room temperature. H
assignments, if necessary, were performed with the aid
of homonuclear spin-decoupling experiments. IR spec-
tra (resolution 4 cm−1) were recorded on a Nicolet
Magna 750 FT-IR spectrometer on KBr discs.
2,2-Dideuterio-4-n-heptanoylbiphenyl 4a: Trifluoroacetic
acid-d1 (11.5 g, 100 mmol) and 4-n-heptanoylbiphenyl 4
(2.7 g, 10.0 mmol) were irradiated for 15 min using the
same conditions as described under 1a. The acid was
removed by distillation and the residue was treated with
ethanol until it became neutral 2.3 g, (86%). IR (KBr):
3000–2800 (wasCH3, wasCH2, wsCH3, wsCH2), 1674
(wCꢀO), 1601 (wCArCAr), 1280 (isCD2), 839 (kCArH,
p-disubst.), 761 (kCArH, phenyl) cm−1.
Acknowledgements
The authors are thankful to the Hungarian Research
Fund OTKA for financial supports OTKA T. 030401
and OTKA T. 032667 and to Chemical Research Cen-
ter for the possibility to use Prolabo 402 equipment and
to Z. Riedl for useful advice. Partial support from the
Hungarian Academy of Sciences–Italian CNR agree-
ment is also gratefully acknowledged.
1H NMR (400 MHz, l ppm, CDCl3): 0.9 (3H, t, CH3),
1.3–1.8 (m, 4×CH2), 2.98 (m, 0.65H, CO-C(HD)2), 7.4
(m, 1H, H4%%), 7.48 (m, 2H, H3%%+H5%%), 7.62 (d, 2H,
H2%%+H6%%), 7.68 (d, 2H, H3%+H5%), 8.02 (d, 2H, H2%+
H6%).
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