H/D-exchange reactions with hydride-activated catalysts

Article abstract of DOI:10.1002/jlcr.1209

A safe, user friendly and efficient method to provide high deuterium incorporation into a variety of organic substrates was developed. Systematic screening of catalysts and activators revealed that the activation of the Pd- or Rh-catalyst by NaBD₄ is essential for the H/D exchange. The feasibility has been demonstrated by the successful application of this method to bi- and tricyclic aromatic compounds as well as chiral natural products like dextrorphan or drugs like formoterol. Copyright

Full text of DOI:10.1002/jlcr.1209

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 295–299.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1209
Short Research Article
H/D-exchange reactions with hydride-activated catalystsy
VOLKER DERDAU*, JENS ATZRODT and WOLFGANG HOLLA
¨
Sanofi-Aventis Deutschland GmbH, GMPK, Isotope Chemistry and Metabolite Synthesis Frankfurt, G876, 65926 Frankfurt/Hochst, Germany
Received 27 September 2006; Revised 27 November 2006; Accepted 27 November 2006
Abstract: A safe, user friendly and efficient method to provide high deuterium incorporation into a variety of organic
substrates was developed. Systematic screening of catalysts and activators revealed that the activation of the Pd- or
Rh-catalyst by NaBD4 is essential for the H/D exchange. The feasibility has been demonstrated by the successful
application of this method to bi- and tricyclic aromatic compounds as well as chiral natural products like
dextrorphan or drugs like formoterol. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: deuterium; palladium; rhodium; heterogeneous catalysis; alkaloids; microwave
Introduction
hydride donors should be a suitable approach to
achieve high deuterium incorporation in complex
organic molecules.
Deuterium-labeled compounds are of fast-growing
interest due to the widespread application of mass
spectrometry as a specific detection and investigation
tool in pharmacological, chemical and environmental
research. Compared to conventional synthetic ap-
proaches starting from small commercially available
stable-labeled precursors, the deuterium introduction
via H/D exchange1 provides the advantage to circum-
vent a long and expensive synthesis.2
Results and discussion
In a model study with phenylbutyric acid 1 (Scheme 1)
we examined catalysts and their activation with several
hydride/deuteride-donors (Table 1) in D2O. Under the
described reaction conditions (entry 1–3), neither reflux
of 1 in D2O, addition of non-activated Pd/C in D2O nor
NaBD4 without catalyst in D2O yielded a significant
H/D-exchange. Even 5 mol% NaBD4 was already
sufficient to activate the transition metal catalyst and
to reach a high deuterium content. Surprisingly, in
most reactions the hydrogen atoms in g, b and even in
the ortho-ring position showed a higher exchange
tendency compared to the hydrogen atoms in the
a-carbonyl position. Other catalysts sources like IrCl3,
NiCl2, FeCl3, ZnBr2, Zn/DCl, PtO2, Ru/C, Rh/C or
Pt/C showed no H/D-exchange activity even after
activation with 20 mol% NaBD4. The best results with
regard to yield and deuterium incorporation were
achieved with Pd/C/NaBD4 (entry 4) or Pd salt/NaBD4
(entry 5). In situ-generated rhodium black from RhCl3
Several new methods for H/D-exchange have been
reported in the last couple of years.3 However, the
described procedures for the replacement of hydrogen
by deuterium in organic molecules are predominantly
limited to activated positions, usually require high
amounts of catalyst, the addition of acidic or basic
additives, and/or deuterium/hydrogen atmosphere
under high temperatures and pressures or even
hydrothermal conditions. Especially to improve the
heterogeneous metal-catalyzed exchange reaction we
considered a significant practical improvement could
be achieved by avoiding the handling of gaseous
reaction components. For this purpose we reasoned
that the pre-activation of the catalyst by addition of
D
D
D
D
D
D
o-Ph
α
γ
*Correspondence to: Volker Derdau, Sanofi-Aventis Deutschland
GmbH, GMPK, Isotope Chemistry and Metabolite Synthesis Frankfurt,
OH
[cat]
OH
m
p
ß
D
D
¨
G876, 65926 Frankfurt/Hochst, Germany.
O
D2O, 130˚C, 18 h
O
E-mail: volker.derdau@sanofi-aventis.com
D
x
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
1
1a
Scheme 1
Copyright # 2007 John Wiley & Sons, Ltd.

296 V. DERDAU ET AL.
Table 1 Optimization of H/D-exchange reaction of phenyl butyric acid 1 in D2Oa
d
Entry
Catalyst
Activator
1a [%]b
g [%D]c
b [%D]c
a [%D]c
o-Ph [%D]c
M+max
1
2
3
4
5
6
}
Pd/C (10%)
}
}
}
92
87
85
89
93
45
}
}
}
}
}
}
}
}
165
165
165
172
171
172
NaBD4
NaBD4
NaBD4
NaBD4
}
}
}
}
Pd/C (10%)
PdCl2
RhCl3
97
97
97
97
97
97
53
32
57
93
79
97
a Conditions: sealed tube with septum, 1308C, 18 h.
b Isolated yield.
c Determined by NMR.
d Determined by LC–MS.
D
13C
D
D
Pd/C, NaBD4
D2O
I
D
O
D
O
O
D
13CD3
O
13CD3
12h, 130˚C
82 %
D
O
OH
82 %
D
2
3
3a
Scheme 2
and NaBD4 (entry 6) was also active, leading, however,
to a higher level of decomposition products in this
case.4
desired final compound 9 via reduction of the nitro
group, subsequent formylation and final debenzylation
under reductive conditions. Overall the 5 step synth-
esis yielded 30% of a racemic mixture of two diaster-
eomers of [13C,D9]-formoterol 9. Under the used RP
HPLC conditions no differences in the retention times
of both diastereomers were detected.
This method was further applied to the synthesis of
racemic [13C,D9]-formoterol 9 which is used as MS
standard. (R,R)-formoterol (Foradil1), is a very potent
b2 agonist which is used as a bronchodilator in the
therapy of asthma and chronic bronchitis.5 Unfortun-
ately, the described reaction conditions for H/D-
exchange lead to decomposition and were not suitable
for the labeling of (R,R)-formoterol. However, starting
from unlabeled 1-(4-hydroxy-phenyl)-propan-2-one 2
the label was introduced by reaction with [13C,D3]-
methyl iodide followed by a palladium-catalyzed H/D-
exchange reaction in deuterium oxide to yield 3a in
82% yield (Scheme 2).
We further investigated the influence of the NaBD4-
activated Pd- or Rh-catalyzed deuteration on stereo-
genic centres and the stereoselectivity of the deuterium
incorporation. The level of deuterium introduction at
the stereocenters of (S)-ibuprofen 10 was 96% (deter-
mined by NMR). In the H/D-exchange reaction (18 h,
1308C) a significant decrease of optical purity was
found (from 99 to 56% see, Scheme 4).
To show the broad generality of the method for
labeling more complex aromatic and heteroaromatic
structures aromatic ketones (11), tetrahydroisoquino-
lines and tetrahydro-quinolines (12,13), indane (14) or
indole (15) derivatives were successfully deuterated.
However, it should be mentioned that reaction time,
temperature and catalyst need to be optimized for each
individual reaction to increase the yield and the
deuterium content of the product. All reactions were
highly reproducible with respect to deuterium incor-
poration and position.
Alternative approaches employing basic (2 N NaOD,
2 equiv. KOtBu) or acidic conditions (5 N D2SO4) for
deuteration of ketone 3 gave low yields (30–65%) mostly
due to aldol side reactions. Furthermore, the isolated
product 3a showed in these cases a broader isotope
distribution in the MS spectra.
To complete the synthesis of [13C,D9]-formoterol 9
[
13C,D8]-labeled ketone 3a was reacted with benzyl-
amine 4 under reductive conditions with platinum on
charcoal and deuterium gas to yield the racemic
secondary amine 5 (Scheme 3). Epoxide 6 was synthe-
sized according to the literature.6 Heating of a 1:1
mixture of racemic 5 and 6 without any solvent yielded
In order to reduce the reaction times and to further
increase the efficiency, work on microwave-assisted
NaBD4-activated Pd- or Rh-catalyzed deuteration has
been started. Microwave acceleration was applied for
the preparation of the deuterated MS-standard of
[
13C,D9]-aminoalcohol 7 as racemic mixture of two
diastereomers. Amino alcohol 7 was converted into the
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 295–299
DOI: 10.1002.jlcr

H/D-EXCHANGE REACTIONS
297
O
Ph
NH2
D
D
D
D
4
H
BnN
BnO
O
D
Pt/C, D2
59 %
6
NO
D
D
13 CD3
13 CD3
neat, 90˚C
99 %
D
O
D
O
D
D
3a
5
Bn
OH
Bn
D
D
OH
D
D
N
D
D
PtO2, D2
99%
N
D
D
13 CD3
O
13 CD3
BnO
D
BnO
D
O
D
D
NO2
NH2
7
8
OH
H
D
D
H
N
1.HCOOH, 70%
2.Pd/C, D2,76%
D
D
13 CD3
HO
D
O
D
HN
O
9
Scheme 3
O
H
OH
O
D
OH
Pd/C
NaBD4
[96]
α
α
D2O
80 %
α
M+max
+
(S) : (R)
(S)-Ibuprofen, 10
99 %ee
78 : 22 M0 + 10
O
[25]
[82]
[70]
[57]
HO
[98]
[75]
[74]
[25]
[44]
[56]
NH
[92]
HO
N
H
[37]
[46]
[97]
[74]
[31]
11 (77 %)
12 (86 %)
13 (73 %)
[43]
[56]
[97]
[92]
[73]
[68]
[97]
[18]
[32]
[66]
[71]
NH2
OH
[92]
[91]
[99]
N
[69]
H
14 (34 %)
15 (83 %)
16 (63%)
Scheme 4
dextrorphan 18 (Scheme 5), a compound which is
frequently used for enzyme inhibition studies within
pharmaceutical drug development. Starting from read-
ily available dextromethorphan 17 the exchange oc-
curred predominantly at the aliphatic positions and
after purification the deuterated dextrormethorphan
(M0+9) was obtained in 87% yield. Finally, the O-methyl
group was removed with HBr and after work up the
deuterated dextrorphan 18 (M0+9) was obtained in
67% yield.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 295–299
DOI: 10.1002.jlcr

298 V. DERDAU ET AL.
30
1. Pd/C (10%)
NaBD4,D2O
92
50
93
N
90
N
98
140˚C, 2 h
(87%)
microwave
sealed tube
HO
O
HBr
HBr
2.HBr (48%),
reflux, 2 h
(67%)
15
17
18
Scheme 5 Synthesis of a MS standard of dextrorphan 18; MS-spectra of a LC–MS co-injection of dextrorphan and dextrorphan
MS standard 18 in the ratio of 3:1 (right side).
labeling yields. An example was given for the successful
Method
application of the microwave-assisted NaBD4-activated
Pd- catalyzed deuteration.
Typical thermal reaction conditions
Into a pressure tube filled with argon was placed
Acknowledgements
We want to thank Silvia Weber for experimental and
1.00 mmol of the organic compound, 10 weight-%
catalyst, 5 mol% NaBD4 (98% D), and 3 ml D2O (99%
Gerald Scholz for analytical support.
D). The mixture was heated to 508C and the tube was
sealed. Then the reaction mixture was heated to 1308C
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method to provide high deuterium incorporation into
a wide variety of substrates employing a catalyst
system consisting of Pd/C or a Pd or Rh salt and an
activator like NaBD4. The pre-activation of the catalyst
by hydride/deuteride donors is essential for high
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DOI: 10.1002.jlcr