Hydrogen-deuterium exchange reactions of aromatic compounds and heterocycles by NaBD4-activated rhodium, platinum and palladium catalysts

Article abstract of DOI:10.1002/chem.200901107

Conventional thermal and microwave conditions were compared for hydrogen-deuterium (H/D) exchange reactions of aminobenzoic acids catalysed by NaBD₄-activated Pd/C or RhCl₃ with D₂O as the deuterium source. We also investi

Full text of DOI:10.1002/chem.200901107

FULL PAPER
DOI: 10.1002/chem.200901107
Hydrogen–Deuterium Exchange Reactions of Aromatic Compounds and
Heterocycles by NaBD4-Activated Rhodium, Platinum and Palladium
Catalysts
Volker Derdau,* Jens Atzrodt, Jochen Zimmermann, Carsten Kroll, and
Francois Brꢀckner[a]
Abstract: Conventional thermal and
microwave conditions were compared
for hydrogen–deuterium (H/D) ex-
change reactions of aminobenzoic acids
catalysed by NaBD4-activated Pd/C or
RhCl3 with D2O as the deuterium
source. We also investigated different
NaBD4-activated metal catalysts (in-
cluding Pd/C, RhCl3 and Pt/C) under
microwave conditions for an efficient
H/D exchange of aromatic and hetero-
cyclic compounds. Even higher deuteri-
um incorporations were obtained for
Pd/C and Pt/C catalyst mixtures due to
the previously observed synergistic
effect. Finally, we have applied these
optimised conditions for one-step syn-
theses of the MS standards of several
pharmaceutically active compounds.
À
Keywords: C H activation · deute-
rium
·
hydrogen–deuterium ex-
change · microwave chemistry
Introduction
narrow isotope clusters formed by H/D exchange can be fit
for use as an internal standard for LC-MS/MS investigations
as long as the value of M0 is negligible and less than 0.5%
(to reduce cross-signal overlapping to a minimum) and a
representative mass peak is present in the mixture that can
be used as the reference mass of the internal standard (see
Figure 1). Typically, for small molecules without chlorine,
bromine or sulfur-containing functionalities, an incorpora-
tion of three to five deuterium atoms is necessary. In spite
of recent methodological improvements, H/D exchange still
often either leads to an insufficient deuterium incorporation,
results in a very broad isotope cluster, or leads to decompo-
sition of the compound. Key requirements for stable la-
belled internal standards, essential in drug development pro-
grams in the pharmaceutical industry, have not been com-
pletely addressed and there is still an unmet need for the de-
velopment of specific H/D exchange methods that provide
labelled materials with a narrow isotopologue distribution.[4]
The rapid development of tandem mass spectrometry in
combination with liquid chromatography (LC-MS/MS) and
its widespread application for the investigation of samples
originating from environmental, animal and human studies
in the life sciences has considerably increased the demand
for isotopically labelled internal standards.[1] Usually, inter-
nal standards can be prepared with very high isotope abun-
dance starting from commercially available labelled precur-
sors by conventional synthesis. However, hydrogen–deuteri-
um (H/D) exchange can be a cost- and time-efficient alter-
native approach if it can be carried out directly on the
target molecule or an advanced intermediate.[2] On the
other hand, disadvantages of H/D exchange include the
non-specific labelling of the molecule (mixtures of different
isotopomers and isotopologues[3]), leading to isotope clusters
and the potential risk of batch-to-batch variations in the
composition of these mixtures. Nonetheless, materials with
Results and Discussion
[a] Dr. V. Derdau, Dr. J. Atzrodt, Dr. J. Zimmermann, C. Kroll,
F. Brꢀckner
Based on pioneering work by Sajiki et al.,[5] we have recent-
ly developed a safe and efficient H/D exchange method
with hydride-activated Pd and Rh catalysts and D2O as the
deuterium source.[6] Compared with existing heterogeneous
transition-metal-catalysed H/D exchange methods, a small
but significant practical improvement is the avoidance of
Sanofi-Aventis Deutschland GmbH
Isotope Chemistry & Metabolite Synthesis Frankfurt
Industriepark Hçchst G876, 65926 Frankfurt am Main (Germany)
Fax : (+49)69 30517082
E-mail: volker.derdau@sanofi-aventis.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901107.
Chem. Eur. J. 2009, 15, 10397 – 10404
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10397

terium incorporation under microwave conditions, but a sys-
tematic investigation has not yet been conducted. To com-
pare conventional thermal and microwave conditions
(Table 1) and to gain more insights into the scope and limi-
Table 1. Deuteration of 2-aminobenzoic acid (1) under thermal and mi-
crowave heating conditions.
[b]
Entry Cat.
T [8C]
t [h] Yield [%]
%D[a]
Dmax
C3 C4 C5 C6
1
2
3
4
Pd/C
Pd/C
RhCl3 150
150
150, mw
2
2
2
2
61
46
42
31
76 78 86
95 93 92
0
0
0
0
D3
D3
D0
D2
24
93
0
0
24
95
RhCl3 150, mw
1
[a] Measured by H NMR spectroscopy. [b] Measured by LC-MS.
tations of this reaction, we initiated studies using NaBD4-ac-
tivated Pd/C and RhCl3 catalysts for the H/D exchange of
aminobenzoic acids 1 and 2. Besides an improved efficiency
in deuterium uptake, the selective formation of products
with the required small mass distribution pattern for internal
standard synthesis was of particular interest (see Figure 1).
To this end, we have performed H/D exchange reactions
with NaBD4-activated palladium and rhodium catalysts
under classical heating conditions and under microwave con-
ditions (at 1508C for 2 h). In both cases, an incorporation of
up to three deuterium atoms was observed for 1 with Pd/C
(Table 1, entries 1 and 2), but the H/D exchange under ther-
mal conditions was less specific, leading to a broader isotope
cluster. Compared with classical heating, an even higher
deuterium efficiency under microwave conditions was ob-
served for the RhCl3-catalysed H/D exchange of the same
substrate (Table 1, entries 3 and 4).[7] Interestingly, only the
protons at C3 and C5 were exchanged selectively, whereas
with the Pd/C catalyst high deuterium incorporation was
also obtained at the C4 position. Similarly, a higher deuteri-
um uptake under microwave conditions was observed for 2
(Table 2, entries 2 and 4), although with RhCl3 this effect
Table 2. Deuteration of 3-aminobenzoic acid (2) under thermal and mi-
crowave heating conditions.
Figure 1. A) Natural MS isotope distribution of a hydrocarbon. B) Broad
isotope cluster after an unselective H/D exchange. C) Moderately broad
isotope cluster with a representative mass peak. D) MS isotope distribu-
tion after a highly selective H/D exchange.
[b]
Entry Cat.
T [8C]
t [h] Yield [%]
%D[a]
Dmax
C2 C4 C5 C6
1
2
3
4
Pd/C 150
Pd/C 1508C, mw 2 h 57
RhCl3 150
RhCl3 150, mw
2
61
88 76 45 11 D2
97 96 95 53 D4
92 93 89 12 D3
91 92 88 12 D3
gaseous reaction components, which allows safe and easy
handling and the utilisation of automated high-throughput
devices or microwave instruments. Initial trials in our labo-
ratory have already suggested a higher efficiency of the deu-
2
2
65
67
1
[a] Measured by H NMR spectroscopy. [b] Measured by LC-MS.
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Chem. Eur. J. 2009, 15, 10397 – 10404

Hydrogen–Deuterium Exchange
FULL PAPER
was less pronounced. Again, the deuterium incorporation
was considerably higher at sites ortho to amino groups than
ortho to a carboxyl function. Thus, we concluded that the ki-
netics and equilibria of the H/D exchange reaction at each
carbon atom are largely controlled by electronic factors.
From an industrial perspective, microwave systems are
simple to handle, safe and also provide the option of a
better process automation and standardisation. Due to the
higher and even more specific deuterium incorporation ob-
served, we decided to use microwave conditions (1508C,
2 h) as the standard reaction procedure for all further inves-
tigations. To understand more about the selectivity of the
pre-activated catalysts we further examined para-substituted
anilines for H/D exchange (Table 3). Two general trends
were observed. Firstly, the electronic influence of amino or
substituted amino groups on the H/D exchange of ortho-po-
sitions of compounds 3–9 was particularly pronounced. In
comparison with other functional groups present, the deute-
rium uptake at these positions was considerably higher. Sec-
ondly, RhCl3 usually gave slightly higher deuterium incorpo-
rations at aromatic centres (Table 3, entries 2, 8, 12 and 14),
but, in contrast to Pd/C, was almost ineffective for the H/D
exchange of aliphatic protons (Table 3; entries 12 and 13).
In almost all experiments (Table 3), the H/D exchange reac-
tions afforded only a small number of isotopologues, one of
which being the most abundant. In the mass spectra this was
reflected by a narrow-to-moderate mass distribution pattern
and one major mass peak.
Next, we studied palladium and rhodium catalysts in the
H/D exchange of substituted pyridines (Table 4), which are
common structural fragments of pharmaceutical drugs. 3-
Aminopyridine (10) was completely deuterated by using Pd/
C as catalyst (Table 4, entry 1) in moderate yield. Although
only very narrow mass spectrometric distribution patterns
were observed for pyridines 10 and 12, pyridines 11 and 13
gave broader clusters, as a result of incomplete H/D ex-
change of both aromatic and aliphatic protons. Pd/C gave
much better results than RhCl3 in terms of higher deuterium
incorporation. Except for pyridine 11, for which it might be
difficult to assign a representative mass spectrometric peak
as a reference mass, all other
Table 3. H/D-exchange reaction of para-substituted anilines 3–9 under microwave conditions (cat. NaBD4, pyridines 10, 12 and 13 could
1508C, 2 h, sealed vial) in deuterium oxide.
be employed as deuterated pre-
Entry
Product
Cat.
Yield [%]
%Dx
cursors for the synthesis of
more complex stable isotope-la-
belled internal MS standards.
In the course of ongoing
D0
15
0
D1
44
22
D2
39
72
D3
2
3
D4
0
0
1
2
Pd/C
RhCl3
50
33
pharmaceutical
development
programs, a series of deuterated
hetero- and bicyclic compounds
(Table 5) were required as pre-
cursors for the synthesis of
stable isotope-labelled internal
standards. Almost quantitative
deuterium incorporations and
very small isotopic clusters
were obtained for 14, 16 and 19
by applying Pd/C-catalysed H/
D exchange under standard mi-
crowave conditions (Table 5).
In contrast, the deuterium
uptake for electron-poor aro-
matic heterocycles was not suf-
ficient to use these materials as
precursors for an internal stan-
dard synthesis. Compared with
the Pd/C-catalysed exchange,
deuterium uptake catalysed by
RhCl3 was generally lower. Al-
though not very efficient in our
initial trials,[6] Pt/C was found
to be highly active in Sajikiꢂs H/
D exchange protocol[8] especial-
ly towards aromatic hydrogen
atoms. Moreover, Sajiki also re-
ported a synergistic effect when
mixing Pd/C and Pt/C together,
D0
0
33
D1
3
48
D2
90
19
D3
6
0
D4
0
0
3
4
Pd/C
RhCl3
63
74
D0
0
0
D1
2
15
D2
58
77
D3
32
8
D4
8
0
5
6
Pd/C
RhCl3
30
51
D0
0
0
D1
3
4
D2
86
89
D3
8
8
D4
3
0
7
8
Pd/C
RhCl3
80
72
D0
0
1
D1
3
6
D2
79
64
D3
17
23
D4
2
6
9
10
Pd/C
RhCl3
72
44
D0
1
0
D1
19
0
D2
67
1
D3
11
8
D4
1
75
D5
0
16
D6
0
0
11
12
Pd/C
RhCl3
67
57
D0
0
4
D1
0
9
D2
3
77
D3
7
8
D4
13
0
D5
21
0
D6
25
0
13
14
Pd/C
RhCl3
29
45
Chem. Eur. J. 2009, 15, 10397 – 10404
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V. Derdau et al.
Table 4. H/D-exchange reaction of substituted pyridines 10–13 under microwave conditions (cat. NaBD4,
1508C, 2 h, sealed vial) in deuterium oxide.
Pd/Pt/C-catalysed H/D ex-
change of 20, a phosphodiester-
ase inhibitor that was frequent-
ly used for treatment of erectile
dysfunction prior to the intro-
duction of Viagra, yielded an
internal MS standard with
seven additional mass units as
the major isotopologue. Under
the same reaction conditions,
both 21 (a compound of the
amphetamine family) and 22 (a
second-generation antidepres-
sant agent) were sufficiently
deuterated to obtain MS stand-
ards (for example, for doping
tests). Finally, the H/D ex-
change reaction of 23, a non-
Entry
Product
Cat.
Yield [%]
%Dx
D0
0
0
D1
0
0
D2
0
0
D3
1
15
D4
99
85
1
2
Pd/C
RhCl3
50
61
D0
0
3
D1
0
19
D2
0
58
D3
8
16
D4
36
4
D5
38
0
D6
15
0
3
4
Pd/C
RhCl3
44
68
D0
0
0
D1
0
0
D2
0
4
D3
9
75
D4
91
21
5
6
Pd/C
RhCl3
64
87
steroidal
anti-inflammatory
D0
0
91
D1
0
9
D2
4
0
D3
21
0
D4
39
0
D5
26
0
D6
10
0
agent that is applied for treat-
ment of rheumatoid arthritis,
yielded a convenient MS stan-
dard (major isotopologue M0 +
13) in one single reaction
step.[10]
7
8
Pd/C
RhCl3
48
30
resulting in higher deuterium incorporations compared with
those obtained with a single catalyst.[9] To increase the deu-
terium efficiency, especially for electron-poor heterocycles,
we decided to test Pt/C in single runs and also in combina-
tion with Pd/C under microwave conditions. In fact, the mix-
ture of Pd/Pt/C yielded, in most cases, a significantly higher
deuterium uptake under the same reaction conditions
(Table 5, entries 4, 8, 12 and 16).
For quinoline 14, an almost complete deuteration was
achieved by using the Pd/Pt/C catalyst mixture, and in con-
trast to Pd/C alone (Table 5, entry 1), a representative peak
at M+9 could also be identified (Table 5, entry 4). An even
more significant synergistic effect could be observed for 15
(Table 5, entry 8), 16 (Table 5, entry 12) and 17 (Table 5,
entry 16). In all cases, the poor deuterium incorporation ob-
tained with Pd/C, Pt/C or RhCl3 could be increased by using
the Pd/Pt/C catalyst mixture, resulting in the formation of
the required stable labelled precursors with a narrow mass
distribution. In contrast, no further improvement was ob-
served for furan 18 and triazole 19 using the Pd/Pt/C mix-
ture (Table 5, entries 20 and 24) than with Pd/C alone
(Table 5, entries 17 and 21). For all hetero- and bicyclic com-
pounds investigated, RhCl3 and Pt/C alone resulted in only
limited deuterium incorporations, whereas Pd/C often yield-
ed acceptable results. However, because generally the best
results were obtained with the mixture of Pd/C and Pt/C, we
have further applied this catalyst system for the preparation
of the required internal MS standards of several pharma-
ceutically active compounds by H/D exchange of the drug
material itself (Scheme 1).
Scheme 1. H/D exchange of pharmaceutically active compounds by using
NaBD4-activated Pd/Pt/C as catalyst in D2O.
Conclusion
We have demonstrated that microwave-enhanced NaBD4-
activated metal-catalysed H/D exchange is a useful synthetic
method that allows access to a variety of stable isotopically
labelled compounds. Initially, activated Pd/C proved to be
the most efficient catalyst for the deuteration of several aro-
matic and heterocyclic compounds, but even better results
were obtained for Pd/C and Pt/C catalyst mixtures due to an
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Hydrogen–Deuterium Exchange
FULL PAPER
Table 5. H/D-exchange reaction of substituted quinolines 14 and 15, aminonaphthalene 16, benzothiophene
17, furan 18 and triazole 19 under microwave conditions (cat. NaBD4, 1508C, 2 h, sealed vial) in deuterium
oxide.
phase: A: water (900 mL), acetonitrile
(100 mL), trifluoroacetic acid (TFA)
(1 mL) mobile phase B: water
(100 mL), acetonitrile (900 mL), TFA
Entry Product
Cat.
Yield [%]
%Dx
(0.75 mL), flow 0.6 mLminÀ1
, detec-
D0 D1 D2 D3 D4
…
D7 D8 D9
tion UV 254 nm and UV 210 nm.
Commercially available chemicals and
solvents were used as received. Deu-
terated water (D2O) was purchased
from Aldrich. Dry Pd/C (10% on
charcoal; AB121364) was purchased
from Degussa (lot 1022260). Depend-
ing on the batch or supplier of the cat-
alyst, significant changes in catalyst re-
activity were observed. Dry Pt/C was
purchased from Hereaus (MP 60/04
Cat Box; batch K0101). The percent-
age of deuteration at each CH position
was determined by using tartaric acid
as an internal standard in 1H NMR
spectroscopy experiments.
1
2
3
4
Pd/C
RhCl3
Pt/C
86
75
53
0
0
0
0
3
17
0
0
0
8
0
5
0
0
6
47
0
0
48
0
0
54
18
0
33
29
0
10
25
0
Pd/Pt/C 46
29
59
D0 D1 D2 D3 D4 D5 D6
5
6
7
8
Pd/C
RhCl3
Pt/C
86
75
53
48
89
7
35
11
25
0
14
0
32
0
3
0
22
3
0
0
11
14
0
0
3
35
0
0
0
43
Pd/Pt/C 46
0
D0 D1 D2 D3 D4 D5 D6 D7
Typical thermal reaction conditions: A
pressure tube filled with argon was
charged with the organic compound
9
Pd/C
RhCl3
Pt/C
52
44
84
0
0
0
0
0
0
0
0
0
0
0
15
6
26
0
54
3
11
11
31
0
2
10
11
12
55
10
0
25
22
0
11
29
0
(1.00 mmol),
catalyst
(10 wt%),
Pd/Pt/C 86
80
NaBD4 (5 mol%; 98% D), and D2O
(6 mL; 99% D). The tube was sealed
and put into an oil bath and heated at
1508C for 2 h under stirring. The mix-
ture was cooled to room temperature
and acetonitrile (3 mL) was added.
The catalyst was separated by filtra-
tion and the product was isolated by
lyophilisation. Purification (if necessa-
ry) was performed by column chroma-
tography and the compounds were an-
alysed by 1H NMR spectroscopy and
LC-MS.
D0 D1 D2 D3 D4
13
14
15
16
Pd/C
RhCl3
Pt/C
95
91
82
0
76
4
50
19
60
60
40
5
28
28
8
0
6
6
2
0
2
2
Pd/Pt/C 91
4
D0 D1 D2 D3 D4 D5
17
18
19
20
Pd/C
RhCl3
Pt/C
96
95
91
0
7
19
6
11
43
31
8
11
21
29
0
0
14
0
0
53
39
0
32
39
24
[D]-1: a) 85 mg (0.61 mmol, 61%) col-
ourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.43 (brs,
1H; CO2H), 7.68 (d, J=8.5 Hz, 1H; 3-
H, 24% H), 7.61 (dd, J=8.5, 8.3 Hz,
1H; 5-H, 14% H), 7.31 (dd, J=8.5,
8.3 Hz, 1H; 4-H, 22% H), 6.90 (d, J=
8.3 Hz, 1H; 6-H, 100% H), 5.58 ppm
(brs, 2H; NH2); LC-MS (ESI): m/z
(%): 138 (1) [M0 +H]+, 139 (11), 140
(36), 141 (46), 142 (5); purity (UV,
254 nm) 97%. b) 58 mg (0.42 mmol,
42%) colourless solid; cat. RhCl3;
Pd/Pt/C 91
8
4
D0 D1 D2 D3 D4 D5 D6 D7
21
22
23
24
Pd/C
RhCl3
Pt/C
95
97
98
0
0
0
5
18
0
0
2
15
0
0
0
8
0
11
0
5
80
0
3
9
0
70
24
0
23
26
0
Pd/Pt/C 91
10
79
11
1H NMR (300 MHz, DMSO): d=12.38 (brs, 1H; CO2H), 7.68 (d, J=
8.5 Hz, 1H; 3-H, 76% H), 7.61 (dd, J=8.5, 8.3 Hz, 1H; 5-H, 76% H),
7.31 (dd, J=8.5, 8.3 Hz, 1H; 4-H, 100% H), 6.90 (d, J=8.3 Hz, 1H; 6-H,
100% H), 5.58 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%): 138 (47)
[M0 +H]+, 139 (41), 140 (10), 141 (2); purity (UV, 254 nm) 91%.
[D]-2: a) 84 mg (0.61 mmol, 61%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.14 (brs, 1H; CO2H), 8.03 (s, 1H; 2-H, 12%
H), 7.91 (d, J=8.5 Hz, 1H; 6-H, 89% H), 7.45 (dd, J=8.5, 8.3 Hz, 1H; 5-
H, 55% H), 6.91 (d, J=8.5 Hz, 1H; 4-H, 14% H), 5.58 ppm (brs, 2H;
NH2); LC-MS (ESI): m/z (%): 138 (3) [M0 +H]+, 139 (26), 140 (42), 141
(23), 142 (6); purity (UV, 254 nm) 96%; b) 89 mg (0.65 mmol, 65%) col-
ourless solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=12.14 (brs,
1H; CO2H), 8.03 (s, 1H; 2-H, 8% H), 7.91 (d, J=8.5 Hz, 1H; 6-H, 88%
H), 7.45 (dd, J=8.5, 8.3 Hz, 1H; 5-H, 11% H), 6.91 (d, J=8.5 Hz, 1H; 4-
H, 7% H), 5.58 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%): 138 (0)
[M0 +H]+, 139 (9), 140 (38), 141 (43), 142 (10); purity (UV, 254 nm)
91%.
observed synergistic effect. These conditions were success-
fully applied in a one-step deuteration of complex molecules
and pharmaceutically active compounds to give products
with a very narrow isotopologue distribution, which proved
to be applicable as deuterated MS standards.
Experimental Section
1
General methods: H (300, 500 MHz) and 13C (75, 125 MHz) NMR spec-
tra were obtained on Bruker spectrometers Avance 300 and 500 in the
solvents indicated. Column chromatography was carried out by using
Merck kieselgel 60 silica gel (particle size: 63–200). The purity of the
products was determined by an LC-MS system with a symmetry Shield
RP18 column, 3,9*150 mm with gradient program; conditions: mobile
Chem. Eur. J. 2009, 15, 10397 – 10404
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10401

V. Derdau et al.
Typical microwave reaction conditions: A pressure tube filled with argon
was charged with the organic compound (1.00 mmol), catalyst (10 wt%),
NaBD4 (5 mol%; 98% D) and D2O (6 mL; 99% D). The mixture was
stirred for approximately 30 s and the tube was sealed (note: the reaction
vessel was not closed until effervescence had stopped) and heated at
1508C for 2 h. The mixture was cooled to room temperature and acetoni-
trile (3 mL) was added. The catalyst was separated by filtration and the
product was isolated by lyophilisation. Purification (if necessary) was per-
formed by chromatography and the compounds analysed by 1H NMR
spectroscopy and LC-MS.
[D]-1: a) 63 mg (0.46 mmol, 46%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.43 (brs, 1H; CO2H), 7.68 (d, J=8.5 Hz, 1H;
3-H, 5% H), 7.61 (dd, J=8.5, 8.3 Hz, 1H; 5-H, 8% H), 7.31 (dd, J=8.5,
8.3 Hz, 1H; 4-H, 7% H), 6.90 (d, J=8.3 Hz, 1H; 6-H, 100% H),
5.58 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%): 138 (0) [M0 +H]+, 139
(1), 140 (14), 141 (77), 142 (8); purity (UV, 254 nm) 94%; b) 43 mg
(0.31 mmol, 31%) colourless solid; cat. RhCl3; 1H NMR (300 MHz,
DMSO): d=12.43 (brs, 1H; CO2H), 7.68 (d, J=8.5 Hz, 1H; 3-H, 7%
H), 7.61 (dd, J=8.5, 8.3 Hz, 1H; 5-H, 5% H), 7.31 (dd, J=8.5, 8.3 Hz,
1H; 4-H, 100% H), 6.90 (d, J=8.3 Hz, 1H; 6-H, 100% H), 5.58 ppm
(brs, 2H; NH2); LC-MS (ESI): m/z (%): 138 (1) [M0 +H]+, 139 (11), 140
(79), 141 (8), 142 (1); purity (UV, 254 nm) 91%.
[D]-2: a) 78 mg (0.57 mmol, 57%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.14 (brs, 1H; CO2H), 8.03 (s, 1H; 2-H, 3% H),
7.91 (d, J=8.5 Hz, 1H; 6-H, 47% H), 7.45 (dd, J=8.5, 8.3 Hz, 1H; 5-H,
5% H), 6.91 (d, J=8.5 Hz, 1H; 4-H, 4% H), 5.58 ppm (brs, 2H; NH2);
LC-MS (ESI): m/z (%): 138 (0) [M0 +H]+, 139 (1), 140 (9), 141 (38), 142
(53); purity (UV, 254 nm) 95%; b) 91 mg (0.67 mmol, 67%) colourless
solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=12.14 (brs, 1H;
CO2H), 8.03 (s, 1H; 2-H, 9% H), 7.91 (d, J=8.5 Hz, 1H; 6-H, 89% H),
7.45 (dd, J=8.5, 8.3 Hz, 1H; 5-H, 12% H), 6.91 (d, J=8.5 Hz, 1H; 4-H,
8% H), 5.58 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%): 138 (1) [M0 +
H]+, 139 (2), 140 (20), 141 (68), 142 (9), purity (UV, 254 nm) 87%.
[D]-3: a) 87 mg (0.50 mmol, 50%) colourless oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=7.22 (d, J=8.3 Hz, 2H; 2-H, 97% H), 6.74 ppm
(d, J=8.3 Hz, 2H; 3-H, 39% H); LC-MS (ESI): m/z (%): 173 (15) [M0 +
H]+, 174 (44), 175 (39), 176 (2); purity (UV, 254 nm) 98%; b) 57 mg
(0.33 mmol, 33%) colourless oil; cat. RhCl3; 1H NMR (300 MHz,
DMSO): d=7.22 (d, J=8.3 Hz, 2H; 2-H, 95% H), 6.74 ppm (d, J=
8.3 Hz, 2H; 3-H, 20% H); LC-MS (ESI): m/z (%): 173 (3) [M0 +H]+,
174 (22), 175 (72), 176 (3); purity (UV, 254 nm) 94%.
[D]-4: a) 88 mg (0.63 mmol, 63%) yellow oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=8.08 (d, J=7.9 Hz, 2H; 2-H, 97% H), 6.91 ppm
(d, J=7.9 Hz, 2H; 3-H, 3% H); LC-MS (ESI) m/z (%): 139 (0) [M0 +
H]+, 140 (3), 141 (90), 142 (6); purity (UV, 254 nm) 97%; b) 103 mg
(0.74 mmol, 74%) yellow oil; cat. RhCl3; 1H NMR (300 MHz, DMSO):
d=8.08 (d, J=7.9 Hz, 2H; 2-H, 85% H), 6.91 ppm (d, J=7.9 Hz, 2H; 3-
H, 71% H); LC-MS (ESI): m/z (%): 139 (33) [M0 +H]+, 140 (48), 141
(19); purity (UV, 254 nm) 91%.
[D]-5: a) 38 mg (0.30 mmol, 30%) yellow oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=6.92 (d, J=8.8 Hz, 2H; 2-H, 86% H), 6.76 (d,
J=8.8 Hz, 2H; 3-H, 3% H), 3.73 ppm (s, 3H; CH3); LC-MS (ESI): m/z
(%): 124 (0) [M0 +H]+, 125 (2), 126 (58), 127 (32), 128 (8); purity (UV,
254 nm) 96%; b) 64 mg (0.51 mmol, 51%) yellow oil; cat. RhCl3;
(1H NMR (300 MHz, DMSO): d=6.92 (d, J=8.8 Hz, 2H; 2-H, 100% H),
6.76 (d, J=8.8 Hz, 2H; 3-H, 13% H), 3.73 ppm (s, 3H; CH3); LC-MS
(ESI): m/z (%): 124 (0) [M0 +H]+, 125 (15), 126 (77), 127 (8); purity
(UV, 254 nm) 96%.
[D]-6: a) 113 mg (0.80 mmol, 80%) yellow oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=7.09 (d, J=8.3 Hz, 2H; 2-H, 81% H), 6.66 (d,
J=8.3 Hz, 2H; 3-H, 11% H), 2.45 ppm (s, 3H; CH3); LC-MS (ESI): m/z
(%): 140 (0) [M0 +H]+, 141 (3), 142 (86), 143 (8), 144 (3); purity (UV,
254 nm) 97%; b) 102 mg (0.72 mmol, 72%) yellow oil; cat. RhCl3;
1H NMR (300 MHz, DMSO): d=7.09 (d, J=8.3 Hz, 2H; 2-H, 88% H),
6.66 (d, J=8.3 Hz, 2H; 3-H, 8% H), 2.45 ppm (s, 3H; CH3); LC-MS
(ESI): m/z (%): 140 (0) [M0 +H]+, 141 (4), 142 (89), 143 (8); purity (UV,
254 nm) 95%.
[D]-7: a) 100 mg (0.72 mmol, 72%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.32 (brs, 1H; CO2H), 7.72 (d, J=8.5 Hz, 2H;
2-H, 88% H), 6.90 (d, J=8.5 Hz, 2H; 3-H, 2% H), 5.61 ppm (brs, 2H;
NH2); LC-MS (ESI): m/z (%): 138 (0) [M0 +H]+, 139 (3), 140 (79), 141
(17), 142 (2); purity (UV, 254 nm) 92%; b) 61 mg (0.44 mmol, 44%) col-
ourless solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=12.32 (brs,
1H; CO2H), 7.72 (d, J=8.5 Hz, 2H; 2-H, 81% H), 6.90 (d, J=8.5 Hz,
2H; 3-H, 11% H), 5.61 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%):
138 (1) [M0 +H]+, 139 (6), 140 (64), 141 (23), 142 (6); purity (UV,
254 nm) 94%.
[D]-8: a) 103 mg (0.67 mmol, 67%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.11 (brs, 1H; CO2H), 7.78 (d, J=8.8 Hz, 2H;
2-H, 88% H), 6.90 (d, J=8.8 Hz, 2H; 3-H, 13% H), 2.65 ppm (s, 3H;
CH3, 75% H); LC-MS (ESI): m/z (%): 152 (1) [M0 +H]+, 153 (19), 154
(67), 155 (11); purity (UV, 254 nm) 93%; b) 88 mg (0.57 mmol, 57%) col-
ourless solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=12.11 (brs,
1H; CO2H), 7.78 (d, J=8.8 Hz, 2H; 2-H, 3% H), 6.90 (d, J=8.8 Hz, 2H;
3-H, 3% H), 2.65 ppm (s, 3H; CH3, 96% H); LC-MS (ESI): m/z (%):
154 (1), 155 (8), 156 (75), 157 (16); purity (UV, 254 nm) 94%.
[D]-9: a) 50 mg (0.29 mmol, 29%) colourless solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.11 (brs, 1H; CO2H), 7.77 (d, J=7.6 Hz, 2H;
3-H, 10% H), 6.70 (d, J=7.6 Hz, 2H; 2-H, 100% H), 2.98 ppm (s, 6H;
CH3, 31% H); LC-MS (ESI): m/z (%): 166 (0) [M0 +H]+, 169 (7), 170
(13), 171 (21), 172 (25); purity (UV, 254 nm) 97%; b) 76 mg (0.45 mmol,
45%) colourless solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=
12.11 (brs, 1H; CO2H), 7.77 (d, J=7.6 Hz, 2H; 3-H, 15% H), 6.70 (d,
J=7.6 Hz, 2H; 2-H, 79% H), 2.98 ppm (s, 6H; CH3, 100% H); LC-MS
(ESI): m/z (%): 166 (4) [M0 +H]+, 167 (9), 168 (77), 169 (8); purity (UV,
254 nm) 90%.
[D]-10 x HCl: a) Addition of 2n HCl (3 mL) to the filtrate, 65 mg
(0.50 mmol, 50%) brown solid; cat. Pd/C; 1H NMR (300 MHz, DMSO):
d=7.91 (s, 1H; 2-H, 1% H), 7.82 (d, J=6.9 Hz, 1H; 6-H, 1% H), 6.99
(dd, J=6.9, 6.9 Hz, 1H; 5-H, 1% H), 6.85 (d, J=6.9 Hz, 1H; 4-H, 1%
H), 5.30 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%): 95 (0) [M0 +H]+,
98 (1), 99 (99); purity (UV, 254 nm) 97%; b) addition of 3 mL 2 N HCl
to the filtrate, 80 mg (0.61 mmol, 61%) brown solid; cat. RhCl3; 1H NMR
(300 MHz, DMSO): d=7.91 (s, 1H; 2-H, 1% H), 7.82 (d, J=6.9 Hz, 1H;
6-H, 1% H), 6.99 (dd, J=6.9, 6.9 Hz, 1H; 5-H, 20% H), 6.85 (d, 1H;
6.9 Hz, 4-H, 35% H), 5.30 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%):
95 (0) [M0 +H]+, 98 (15), 99 (85); purity (UV, 254 nm) 97%.
[D]-11: a) 54 mg (0.44 mmol, 44%) brown oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=8.25–8.19 (m, 2H; 2-H, 6-H, 1% H), 7.45 (dd,
J=6.9, 6.9 Hz, 1H; 5-H, 18% H), 7.09 (d, J=6.9 Hz, 1H; 4-H, 36% H),
2.55 (q, J=5.3 Hz, 2H; CH2CH3 25% H), 2.41 ppm (t, J=5.3 Hz, 3H;
CH2CH3 100% H); LC-MS (ESI): m/z (%): 123 (0) [M0 +H]+, 126 (8),
127 (36), 128 (38), 129 (15); purity (UV, 254 nm) 89% b) 83 mg
(0.68 mmol, 68%) brown oil; cat. RhCl3; 1H NMR (300 MHz, DMSO):
d=8.25–8.19 (m, 2H; 2-H, 6-H, 10% H), 7.45 (dd, J=6.9, 6.9 Hz, 1H; 5-
H, 85% H), 7.09 (d, J=6.9 Hz, 1H; 4-H, 90% H), 2.55 (q, J=5.3 Hz,
2H; CH2CH3, 100% H), 2.41 ppm (t, J=5.3 Hz, 3H; CH2CH3 100% H);
LC-MS (ESI): m/z (%): 123 (3) [M0 +H]+, 124 (19), 125 (58), 126 (16),
127 (4); purity (UV, 254 nm) 94%.
[D]-12·xHCl: a) Addition of 2 n HCl (3 mL) to the filtrate, 84 mg
(0.64 mmol, 64%) colourless solid; cat. Pd/C; 1H NMR (300 MHz,
DMSO): d=9.80 (brs, 1H; OH), 8.15 (d, J=6.0 Hz, 1H; 3-H, 5% H),
8.11 (d, J=5.9 Hz, 6-H, 1H; 5% H), 7.23–7.06 ppm (m, 2H; 4-H 11% H,
5-H 5% H); LC-MS (ESI): m/z (%): 96 (0) [M0 +H]+, 99 (9), 100 (91);
purity (UV, 254 nm) 96%; b) Addition of 3 mL 2 N HCl to the filtrate,
114 mg (0.87 mmol, 87%) colourless solid; cat. RhCl3; 1H NMR
(300 MHz, DMSO): d=9.80 (brs, 1H; OH), 8.15 (d, J=6.0 Hz, 1H; 3-H,
1% H), 8.11 (d, J=5.9 Hz, 1H; 6-H, 1% H), 7.23–7.06 ppm (m, 2H; 4-H
65% H, 5-H 10% H); LC-MS (ESI): m/z (%): 96 (0) [M0 +H]+, 98 (4),
99 (75), 100 (21); purity (UV, 254 nm) 96%.
[D]-13: a) 90 mg (0.48 mmol, 48%) colourless oil; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=8.25 (s, 1H; 6-H, 1% H), 7.89 (d, J=6.8 Hz, 1H;
4-H, 39% H), 6.82 (d, J=6.8 Hz, 1H; 3-H, 23% H), 3.87 ppm (s, 3H;
OMe, 36% H); LC-MS (ESI): m/z (%): 189 (0) [M0 +H]+, 191 (4), 192
(21), 193 (39), 194 (26), 195 (10); purity (UV, 254 nm) 97% b) 56 mg
10402
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10397 – 10404

Hydrogen–Deuterium Exchange
FULL PAPER
(0.30 mmol, 30%) colourless oil; cat. RhCl3; 1H NMR (300 MHz,
DMSO): d=8.25 (s, 1H; 6-H, 72% H), 7.89 (d, J=6.8 Hz, 1H; 4-H,
100% H), 6.82 (d, J=6.8 Hz, 1H; 3-H, 100% H), 3.87 ppm (s, 3H; OMe,
100% H); LC-MS (ESI): m/z (%): 96 (91) [M0 +H]+, 97 (9); purity (UV,
254 nm) 98%.
(26), 149 (11); purity (UV, 254 nm) 92%; d) 129 mg (0.86 mmol, 86%)
yellow solid; cat. mixture of Pd/C and Pt/C (ratio 2:1); 1H NMR
(300 MHz, DMSO): d=8.06 (d, J=7.5 Hz, 1H; 8-H, 1% H), 7.88 (d, J=
7.5 Hz, 1H; 5-H, 1% H), 7.39–7.32 (m, 2H; 6-H, 7-H, 1% H), 7.19 (d,
J=7.5 Hz, 1H; 4-H, 1% H), 7.06 (dd, J=7.5, 7.5 Hz, 1H; 3-H, 1% H),
6.68 (d, J=7.5 Hz, 1H; 2-H, 1% H), 5.81 ppm (brs, 2H; NH2); LC-MS
(ESI): m/z (%): 150 (11), 151 (80), 152 (9); purity (UV, 254 nm) 96%.
[D]-14: a) 123 mg (0.86 mmol, 86%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=8.82 (d, J=7.5 Hz, 1H; 2-H, 1% H), 8.35 (d, J=
7.5 Hz, 1H; 4-H, 1% H), 7.90 (d, J=7.5 Hz, 1H; 5-H, 27% H), 7.78 (d,
7.5 Hz, 1H; 7-H, 5% H), 7.62–7.55 (m, 2H; 3-H, 6-H, 1% H), 2.70 ppm
(s, 3H; CH3, 1% H); LC-MS (ESI): m/z (%): 144 (0) [M0 +H]+, 151 (5),
152 (47), 153 (48); purity (UV, 254 nm) 94%; b) 107 mg (0.75 mmol,
75%) yellow solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=8.82 (d,
J=7.5 Hz, 1H; 2-H, 43% H), 8.35 (d, J=7.5 Hz, 1H; 4-H, 61% H), 7.90
(d, J=7.5 Hz, 1H; 5-H, 100% H), 7.78 (d, J=7.5 Hz, 1H; 7-H, 100%
H), 7.62–7.55 (m, 2H; 3-H, 6-H, 61% H), 2.70 ppm (s, 3H; CH3, 68%
H); LC-MS (ESI): m/z (%): 144 (54) [M0 +H]+, 145 (33), 146 (10), 147
(3); purity (UV, 254 nm) 85%; c) 75 mg (0.53 mmol, 53%) yellow solid;
cat. Pt/C; 1H NMR (300 MHz, DMSO): d=8.82 (d, J=7.5 Hz, 1H; 2-H,
27% H), 8.35 (d, J=7.5 Hz, 1H; 4-H, 58% H), 7.90 (d, J=7.5 Hz, 1H;
5-H, 100% H), 7.78 (d, J=7.5 Hz, 1H; 7-H, 100% H), 7.62–7.55 (m, 2H;
3-H, 6-H, 26% H), 2.70 ppm (s, 3H; CH3, 75% H); LC-MS (ESI): m/z
(%): 144 (18) [M0 +H]+, 145 (29), 146 (25), 147 (17); purity (UV,
254 nm) 92%.d) 66 mg (0.46 mmol, 46%) yellow solid; cat. mixture of
Pd/C and Pt/C (ratio 2:1); 1H NMR (300 MHz, DMSO): d=8.82 (d, J=
7.5 Hz, 1H; 2-H, 1% H), 8.35 (d, J=7.5 Hz, 1H; 4-H, 1% H), 7.90 (d,
J=7.5 Hz, 1H; 5-H, 27% H), 7.78 (d, J=7.5 Hz, 1H; 7-H, 5% H), 7.62–
7.55 (m, 2H; 3-H, 6-H, 1% H), 2.70 ppm (s, 3H; CH3, 1% H); LC-MS
(ESI): m/z (%): 151 (6), 152 (29), 153 (59); purity (UV, 254 nm) 98%.
[D]-17: a) 143 mg (0.95 mmol, 95%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=7.78–7.72 (m, 2H; 2-H, 7-H, 78% H), 7.21 (d,
J=7.4 Hz, 1H; 3-H, 89% H), 7.01 (s, 1H; 4-H, 1% H), 6.75 (d, J=
7.4 Hz, 1H; 6-H, 65% H), 5.10 ppm (brs, 2H; NH2); LC-MS (ESI): m/z
(%): 150 (0) [M0 +H]+, 151 (50), 152 (40), 153 (8), 154 (2); purity (UV,
254 nm) 91%; b) 135 mg (0.91 mmol, 91%) yellow solid; cat. RhCl3;
1H NMR (300 MHz, DMSO): d=7.78–7.72 (m, 2H; 2-H, 7-H, 100% H),
7.21 (d, J=7.4 Hz, 1H; 3-H, 83% H), 7.01 (s, 1H; 4-H, 76% H), 6.75 (d,
J=7.4 Hz, 1H; 6-H, 100% H), 5.10 ppm (brs, 2H; NH2); LC-MS (ESI):
m/z (%): 150 (76) [M0 +H]+, 151 (19), 152 (5); purity (UV, 254 nm)
96%; c) 123 mg (0.82 mmol, 82%) yellow solid; cat. Pt/C; 1H NMR
(300 MHz, DMSO) d=7.78–7.72 (m, 2H; 2-H, 7-H, 76% H), 7.21 (d, J=
7.4 Hz, 1H; 3-H, 86% H), 7.01 (s, 1H; 4-H, 1% H), 6.75 (d, J=7.4 Hz,
1H; 6-H, 81% H), 5.10 ppm (brs, 2H; NH2); LC-MS (ESI): m/z (%):
150 (4) [M0 +H]+, 151 (60), 152 (28), 153 (6), 154 (2); purity (UV,
254 nm) 98%; d) 138 mg (0.91 mmol, 91%) yellow solid; cat. mixture of
Pd/C and Pt/C (ratio 2:1); (1H NMR (300 MHz, DMSO): d=7.78–7.72
(m, 2H; 2-H, 7-H, 57% H), 7.21 (d, J=7.4 Hz, 1H; 3-H, 64% H), 7.01
(s, 1H; 4-H, 1% H), 6.75 (d, J=7.4 Hz, 1H; 6-H, 13% H), 5.10 ppm
(brs, 2H; NH2); LC-MS (ESI): m/z (%): 151 (4), 152 (26), 153 (48), 154
(18); purity (UV, 254 nm) 98%.
[D]-15: a) 145 mg (0.84 mmol, 84%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=13.24 (brs, 1H; CO2H), 8.66 (d, J=7.5 Hz, 1H;
4-H, 78% H), 8.20–8.03 (m, 3H; 3-H, 5-H, 8-H, 70% H), 7.89 (dd, J=
7.5, 7.5 Hz, 1H; 7-H, 100% H), 7.73 ppm (dd, J=7.5, 7.5 Hz, 1H; 6-H,
100% H); LC-MS (ESI): m/z (%): 174 (48) [M0 +H]+, 175 (35), 176
(14), 177 (3); purity (UV, 254 nm) 96%; b) 160 mg (0.93 mmol, 93%)
yellow solid; cat. RhCl3; 1H NMR (300 MHz, DMSO): d=13.24 (brs,
1H; CO2H), 8.66 (d, J=7.5 Hz, 1H; 4-H, 81% H), 8.20–8.03 (m, 3H; 3-
H, 5-H, 8-H, 80% H), 7.89 (dd, J=7.5, 7.5 Hz, 1H; 7-H, 100% H),
7.73 ppm (dd, J=7.5, 7.5 Hz, 1H; 6-H, 100% H); LC-MS (ESI): m/z
(%): 174 (89) [M0 +H]+, 175 (11); purity (UV, 254 nm) 95%; c) 172 mg
(0.98 mmol, 98%) yellow solid; cat. Pt/C; 1H NMR (300 MHz, DMSO):
d=13.24 (brs, 1H; CO2H), 8.66 (d, J=7.5 Hz, 1H; 4-H, 53% H), 8.20–
8.03 (m, 3H; 3-H, 5-H, 8-H, 50% H), 7.89 (dd, J=7.5, 7.5 Hz, 1H; 7-H,
63% H), 7.73 ppm (dd, 7.5, 7.5 Hz, 1H; 6-H, 63% H); LC-MS (ESI):
m/z: 174 (7) [M0 +H]+, 175 (25), 176 (32), 177 (22), 178 (11); purity (UV,
254 nm) 97% d) 163 mg (0.91 mmol, 91%) yellow solid; cat. mixture of
Pd/C and Pt/C (ratio 2:1) ; 1H NMR (300 MHz, DMSO: d=13.24 (brs,
1H; CO2H), 8.66 (d, J=7.5 Hz, 1H; 4-H, 1% H), 8.20–8.03 (m, 3H; 3-H,
5-H, 8-H, 11% H), 7.89 (dd, J=7.5, 7.5 Hz, 1H; 7-H, 36% H), 7.73 ppm
(dd, 7.5, 7.5 Hz, 1H; 6-H, 36% H); LC-MS (ESI): m/z (%): 177 (3), 178
(14), 179 (35), 180 (43), purity (UV, 254 nm) 99%.
[D]-16: a) 77 mg (0.52 mmol, 52%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=8.06 (d, J=7.5 Hz, 1H; 8-H, 79% H), 7.88 (d,
J=7.5 Hz, 1H; 5-H, 55% H), 7.39–7.32 (m, 2H; 6-H, 7-H, 48% H), 7.19
(d, J=7.5 Hz, 1H; 4-H, 59% H), 7.06 (dd, J=7.5, 7.5 Hz, 1H; 3-H, 60%
H), 6.68 (d, J=7.5 Hz, 1H; 2-H, 1% H), 5.81 ppm (brs, 2H; NH2); LC-
MS (ESI): m/z (%): 144 (0) [M0 +H]+, 148 (15), 149 (54), 150 (31);
purity (UV, 254 nm) 95%; b) 63 mg (0.44 mmol, 44%) yellow solid; cat.
RhCl3; 1H NMR (300 MHz, DMSO): d=8.06 (d, J=7.5 Hz, 1H; 8-H,
100% H), 7.88 (d, J=7.5 Hz, 1H; 5-H, 79% H), 7.39–7.32 (m, 2H; 6-H,
7-H, 87% H), 7.19 (d, J=7.5 Hz, 1H; 4-H, 79% H), 7.06 (dd, J=7.5,
7.5 Hz, 1H; 3-H, 60% H), 6.68 (d, J=7.5 Hz, 1H; 2-H, 1% H), 5.81 ppm
(brs, 2H; NH2); LC-MS (ESI): m/z (%): 145 (55), 146 (25), 147 (11), 148
(6); purity (UV, 254 nm) 90%; c) 123 mg (0.84 mmol, 84%) yellow solid;
cat. Pt/C; 1H NMR (300 MHz, DMSO): d=8.06 (d, J=7.5 Hz, 1H; 8-H,
100% H), 7.88 (d, J=7.5 Hz, 1H; 5-H, 40% H), 7.39–7.32 (m, 2H; 6-H,
7-H, 44% H), 7.19 (d, J=7.5 Hz, 1H; 4-H, 38% H), 7.06 (dd, J=7.5,
7.5 Hz, 1H; 3-H, 1% H), 6.68 (d, J=7.5 Hz, 1H; 2-H, 1% H), 5.81 ppm
(brs, 2H; NH2); LC-MS (ESI): m/z (%): 145 (10), 146 (22), 147 (29), 148
[D]-18: a) 124 mg (0.96 mmol, 96%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=12.85 (brs, 1H; CO2H), 7.83 (d, J=7.3 Hz, 1H;
5-H, 1% H), 6.52 (d, J=7.3 Hz, 1H; 4-H, 40% H), 2.33 ppm (s, 3H;
CH3, 36% H); LC-MS (ESI): m/z (%): 127 (0) [M0 +H]+, 128 (7), 129
(19), 130 (31), 131 (29), 132 (14); purity (UV, 254 nm) 97%; b) 120 mg
1
(0.95 mmol, 95%) yellow solid; cat. RhCl3; H NMR (300 MHz, DMSO):
d=12.85 (brs, 1H; CO2H), 7.83 (d, J=7.3 Hz, 1H; 5-H, 55% H), 6.52
(d, J=7.3 Hz, 1H; 4-H, 88% H), 2.33 ppm (s, 3H; CH3, 88% H); LC-
MS (ESI): m/z (%): 127 (53) [M0 +H]+, 128 (32), 129 (6); purity (UV,
254 nm) 87%; c) 116 mg (0.91 mmol, 91%) yellow solid; cat. Pt/C;
1H NMR (300 MHz, DMSO): d=12.85 (brs, 1H; CO2H), 7.83 (d, J=
7.3 Hz, 1H; 5-H, 27% H), 6.52 (d, J=7.3 Hz, 1H; 4-H, 81% H),
2.33 ppm (s, 3H; CH3, 77% H); LC-MS (ESI): m/z (%): 127 (39) [M0 +
H]+, 128 (39), 129 (11), 130 (11); purity (UV, 254 nm) 93%; d) 116 mg
(0.91 mmol, 91%) yellow solid; cat. mixture of Pd/C and Pt/C (ratio 2:1);
1H NMR (300 MHz, DMSO): d=12.85 (brs, 1H; CO2H), 7.83 (d, J=
7.3 Hz, 1H; 5-H, 1% H), 6.52 (d, J=7.3 Hz, 1H; 4-H, 56% H), 2.33 ppm
(s, 3H; CH3, 45% H); LC-MS (ESI): m/z (%): 128 (24), 129 (43), 130
(21), 131 (8), 132 (4); purity (UV, 254 nm) 96%.
[D]-19: a) 112 mg (0.95 mmol, 95%) yellow solid; cat. Pd/C; 1H NMR
(300 MHz, DMSO): d=5.79 (s, 2H; NH2), 2.22 ppm (s, 6H; CH3, 7%
H); LC-MS (ESI): m/z (%): 113 (0) [M0 +H]+, 118 (11), 119 (80), 120
(9); purity (UV, 254 nm) 97%; b) 109 mg (0.97 mmol, 97%) yellow solid;
1
cat. RhCl3; H NMR (300 MHz, DMSO): d=5.79 (s, 2H; NH2), 2.22 ppm
(s, 6H; CH3, 85% H); LC-MS (ESI): m/z (%): 113 (70) [M0 +H]+, 114
(23), 115 (5), 116 (2); purity (UV, 254 nm) 98%; c) 111 mg (0.98 mmol,
98%) yellow solid; cat. Pt/C; 1H NMR (300 MHz, DMSO): d=5.79 (s,
2H; NH2), 2.22 ppm (s, 6H; CH3, 48% H); LC-MS (ESI): m/z (%): 113
(24) [M0 +H]+, 114 (26), 115 (18), 116 (15), 117 (8); purity (UV, 254 nm)
98%; d) 107 mg (0.91 mmol, 91%) yellow solid; cat. mixture of Pd/C and
Pt/C (ratio 2:1); 1H NMR (300 MHz, DMSO): d=5.79 (s, 2H; NH2),
2.22 ppm (s, 6H; CH3, 6% H); LC-MS (ESI): m/z: 118 (10), 119 (79),
120 (11); purity (UV, 254 nm) 98%.
[D]-20 papaverine: 261 mg (0.77 mmol, 77%) colourless solid; cat. mix-
ture of Pd/C and Pt/C (ratio 2:1); 1H NMR (300 MHz, DMSO): d=8.36
(d, J=5.2 Hz, 1H; 3-H, 1% H), 7.49 (d, J=5.2 Hz, 1H; 4-H, 1% H),
7.46 (d, J=5.2 Hz, 1H; 8-H, 27% H), 7.33 (s, 1H; 5-H, 27% H), 6.98 (s,
1H; 7’-H, 1% H), 6.71–6.66 (m, 2H; 3’-H, 6’-H, 55% H), 4.44 (s, 2H; 1’-
H, 1% H), 3.98 (s, 6H; OCH3, 86% H) 3.67 ppm (s, 6H; OCH3, 55%
Chem. Eur. J. 2009, 15, 10397 – 10404
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10403

V. Derdau et al.
H); LC-MS (ESI): m/z (%): 340 (0) [M0 +H]+, 345 (11), 346 (19), 347
(25), 348 (20), 349 (14) 350 (9), 351 (2); purity (UV, 254 nm) 99%.
isotopologues with the same mass, for example, [1,1-D2]propane and
[1,2-D2]propane, see: A. D. McNaught, A. Wilkinson, IUPAC Com-
pendium of Chemical Terminology, 2nd ed., Blackwell Scientific
Publications (Eds.: A. D. McNaught, A Wilkinson), 1997.
[D]-21: 100 mg (0.67 mmol, 67%) colourless oil; cat. mixture of Pd/C
1
and Pt/C (ratio 2:1); H NMR (300 MHz, DMSO): d=7.26 (d, J=7.5 Hz,
[4] For recent publications on this topic, see: DCl: A. Martins, M. Lau-
tens, Org. Lett. 2008, 10, 4351–4353; Rh: T. Maegawa, Y. Fujiwara,
Y. Inagaki, H. Esaki, Y. Monguchi, H. Sajiki, Angew. Chem. 2008,
120, 5474–5477; Angew. Chem. Int. Ed. 2008, 47, 5394–5397; Pd:
a) H. Esaki, N. Ito, S. Sakai, T. Maegawa, Y. Monguchi, H. Sajiki,
Tetrahedron 2006, 62, 10954–10961; b) B. Kerler, J. Pol, K. Harto-
nen, M. T. Soederstroem, H. T. Koskela, M.-L. Riekkola, J. Super-
crit. Fluids 2007, 39, 381–388; Ir: a) J. R. Heys, J. Labelled Compd.
Radiopharm. 2007, 50, 770–778; b) J. Zhou, J. F. Hartwig, Angew.
Chem. 2008, 120, 5867–5871; Angew. Chem. Int. Ed. 2008, 47, 5783–
5787; c) A. Trꢃff, G. N. Nilsson, K. J. Szabo, L. Eriksson, J. Organo-
met. Chem. 2007, 692, 5529–5531; d) J. A. Brown, S. Irvine, A. R.
Kennedy, W. J. Kerr, S. Andersson, G. N. Nilsson, Chem. Commun.
2008, 1115–1117; Ru: a) M. H. G. Prechtl, M. Hoelscher, Y. Ben-
David, N. Theyssen, R. Loschen, D. Milstein, W. Leitner, Angew.
Chem. 2007, 119, 2319–2322; Angew. Chem. Int. Ed. 2007, 46, 2269–
2272; b) K. Ishibashi, S. Matsubara, Chem. Lett. 2007, 36, 724–725.
[5] a) H. Sajiki, T. Kurita, H. Esaki, F. Aoki, T. Maegawa, K. Hirota,
Org. Lett. 2004, 6, 3521–3523; b) H. Sajiki, F. Aoki, H. Esaki, T.
Maegawa, K. Hirota, Org. Lett. 2004, 6, 1485–1487; c) H. Esaki, F.
Aoki, M. Umemura, M. Kato, T. Maegawa, Y. Monguchi, H. Sajiki,
Chem. Eur. J. 2007, 13, 4052–4063; d) T. Kurita, K. Hattori, S. Seki,
T. Mizumoto, F. Aoki, Y. Yamada, K. Ikawa, T. Maegawa, Y. Mon-
guchi, H. Sajiki, Chem. Eur. J. 2008, 14, 664–673.
2H; 3-H, 33% H), 7.20–7.17 (m, 3H; 2-H, 4-H, 16/67% H), 2.81 (dd, J=
6.1, 6.9 Hz, 1H; 3’-H, 1% H), 2.56 (d, J=7.2 Hz, 2H; 1’-H, 1% H), 1.55
(dd, J=6.9, 7.2 Hz, 2H; 2’-H, 1% H), 1.15 ppm (d, J=6.9 Hz, 3H; 4’-H,
1% H); LC-MS (ESI): m/z (%): 150 (0) [M0 +H]+, 159 (3), 160 (11), 161
(29), 162 (38); 163 (17), 164 (2); purity (UV, 254 nm) 92%.
[D]-22 l-tryptophan: 173 mg (0.85 mmol, 85%) colourless solid; cat. mix-
1
ture of Pd/C and Pt/C (ratio 2:1); H NMR (300 MHz, DMSO): d=11.42
(brs, 1H; CO2H), 7.62 (d, J=8.0 Hz, 1H; 4-H, 55% H), 7.44 (s, 1H; 2-H,
27% H), 7.33 (d, J=7.6 Hz, 1H; 7-H, 53% H), 7.07 (dd, J=7.6, 8.0 Hz,
1H; 6-H, 86% H), 6.98 (dd, J=7.8/8.0 Hz, 1H; 5-H, 89% H), 4.15 (d,
J=7.6 Hz, 1H; 2’-H, 1% H), 3.67 (brs, 2H; NH2), 3.11 ppm (d, J=
7.6 Hz, 2H; 1’-H, 1% H); LC-MS (ESI): m/z: 205 (0) [M0 +H]+, 208 (3),
209 (53), 210 (38), 211 (6); purity (UV, 254 nm) 97%.
[D]-23 mefenamic acid: 186 mg (0.73 mmol, 73%) colourless solid; cat.
mixture of Pd/C and Pt/C (ratio 2:1); 1H NMR (300 MHz, DMSO): d=
13.24 (brs, 1H; CO2H), 7.63 (dd, J=7.5, 7.4 Hz, 1H; 4-H, 1% H), 7.54
(d, J=7.4 Hz, 1H; 6-H, 1% H), 7.36 (dd, J=7.5, 7.5 Hz, 1H; 5-H, 1%
H), 7.06 (d, J=7.5 Hz, 1H; 3-H, 1% H), 6.92 (dd, J=7.5, 7.5 Hz, 5’-H,
1% H), 6.82–6.77 (m, 4’-H, 6’-H, 1% H), 2.23 (s, 3H; CH3, 2% H),
2.15 ppm (s, 3H; CH3, 2% H); LC-MS (ESI): m/z (%): 242 (0) [M0 +H]+
, 253 (3), 254 (16), 255 (72), 256 (9); purity (UV, 254 nm) 98%.
[6] a) V. Derdau, J. Atzrodt, Synlett 2006, 1918–1922; b) V. Derdau, J.
Atzrodt, W. Holla, J. Labelled Compd. Radiopharm. 2007, 50, 1276–
1286.
Acknowledgements
[7] An advantage of RhCl3 can be the higher reproducibility observed.
With commercial catalysts on charcoal/silica or alumina the catalyst
activity can strongly vary depending on the supplier or even the
batch.
We want to thank Dr. John Allen (Sanofi-Aventis, F) and Dr. John Her-
bert (Sanofi-Aventis, UK) for critical discussions and corrections of this
manuscript.
[8] a) H. Sajiki, N. Ito, H. Esaki, T. Maesawa, T. Maegawa, K. Hirota,
Tetrahedron Lett. 2005, 46, 6995–6998; b) M. Yamamoto, K.
Oshima, S. Matsubara, Heterocycles 2006, 67, 353–359; c) N. Ito, H.
Esaki, T. Maesawa, E. Imamiya, T. Maegawa, H. Sajiki, Bull. Chem.
Soc. Jpn. 2008, 81, 278–286.
[9] a) N. Ito, T. Watahiki, T. Maesawa, T. Maegawa, H. Sajiki, Adv.
Synth. Catal. 2006, 348, 1025–1028; b) N. Ito, T. Watahiki, T. Maesa-
wa, T. Maegawa, H. Sajiki, Synthesis 2008, 1467–1478.
[1] a) E. Stovkis, H. Rosing, J. H. Beijnen, Rapid Commun. Mass Spec-
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[2] For a recent review, see: J. Atzrodt, V. Derdau, T. Fey, J. Zimmer-
mann, Angew. Chem. 2007, 119, 7890–7911; Angew. Chem. Int. Ed.
2007, 46, 7744–7765, and references therein.
[10] The yields reported are isolated yields. Low to moderate yields were
found for reactions with significant decomposition and/or low solu-
bility of the product in acetonitrile/water/methanol mixtures.
[3] Isotopologues are compounds with the same chemical structure that
differ only in their isotope composition (for example, [1,2-
D2]propane and [1,2,3-D3]propane). The term isotopomer indicates
Received: April 27, 2009
Published online: August 13, 2009
10404
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10397 – 10404