Shifted Selectivity in Protonation Enables the Mild Deuteration of Arenes through Catalytic Amounts of Bronsted Acids in Deuterated Methanol

Article abstract of DOI:10.1021/acs.joc.0c01604

Taking advantage of the "differentiating effect"of the solvent methanol, deuterations of electron-rich aromatic systems can be carried out under mild acid catalysis and thus under far milder conditions than known so far. The exceptional functional group t

Full text of DOI:10.1021/acs.joc.0c01604

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Article
Shifted selectivity in protonation enables the mild deuteration of arenes
through catalytic amounts of Bronsted acids in deuterated methanol
Oliver Fischer, Anja Hubert, and Markus Rolf Heinrich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01604 • Publication Date (Web): 14 Aug 2020
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Page 1 of 11
The Journal of Organic Chemistry
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Shifted selectivity in protonation enables the mild deuteration
of arenes through catalytic amounts of Bronsted acids in
deuterated methanol
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Oliver Fischer, Anja Hubert, Markus R. Heinrich*
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg,
Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
Supporting Information Placeholder
protonation, so that deuteration of aromatic systems is strongly
enhanced while even highly acid-labile groups remain stable.
ABSTRACT: Taking advantage of the “differentiating effect” of
the solvent methanol, deuterations of electron-rich aromatic
systems can be carried out under mild acid catalysis, and thus under
far milder conditions than known so far. The exceptional functional
group tolerance observed under the optimized conditions, which
even includes highly acid-labile groups, results from a hitherto
unexploited shifted selectivity in protonation, and enabled a simple
and straightforward access to complex deuterium-labeled
compounds.
Results and Discussion
In preliminary studies, the conversion of 1,3,5-
trimethoxybenzene (1) to its trideuterated derivative [D3]-1 was
investigated using common acids and deuterated solvents. The
variations are summarized in Figure 1.
Figure 1. Deuteration of 1,3,5-trimethoxybenzene (1) under
various conditions
Introduction
D
H
H
Deuterated compounds play an important role in many fields of
application, among which analytical standards are certainly the
most important. Such standards may serve as reference
compounds for detection and quantification in food chemistry,
pharmacology and biochemistry.1 Moreover, the first
deuterated drug, for which the isotope exchange leads to an
improved metabolic profile, has recently been reported.2
O
O
O
O
O
O
O
O
H
solvent (1 mL)
+
+
acid (5 mol%)
rt, air
D
D
D
D
D
O
O
O
O
1
(0.1 mmol)
[D3]-1
[D2]-1
[D1]-1
Regarding the preparation of deuterated compounds, and the
deuteration of aromatic systems in particular, acid-promoted
reactions have been known for a long time.3 Due to the harsh
conditions that are typically required, research interests in this
field have recently shifted to the development of catalysts that
enable the isotope exchange on aromatic systems with a higher
functional group tolerance.4 Prominent examples include
multiple studies on iridium,5 ruthenium,6 or palladium7
catalyzed H/D exchange. More recently, novel photocatalytic
methods have been described.8 In the overall context, it is
interesting to note that a general effect, which is widely known
in analytical chemistry as the “differentiating effect” of
solvents, has so far not been exploited to its full extent for the
purpose of deuteration. By changing the solvent from water to
methanol or acetic acid, one can increase the protonating
strength of a strong acid such as hydrochloric or perchloric acid,
as the otherwise “leveling effect” of water, which turns all
strong acids into hydroxonium ions, is no longer operative.9
Consequently, the use of a suitable non-aqueous solvent could
aReaction without additional acid.
Regarding the results obtained with different solvents (Figure
1A) and acids (Figure 1B), the combinations of 5% perchloric
acid with methanol-d1 or -d4 (CH3OD or CD3OD) turned out as
the most promising. The significant improvement compared to
the use of D2O becomes obvious from two experiments
employing D2O in mixtures with CD3OD or (CD3)2SO (Figure
1A). A study using reduced amounts of deuterium source with
5, 10, 20, and 50 equivalents of CH3OD showed up to 83% of
provide
a valuable measure to improve acid-mediated
deuteration reactions, but, on the other hand, the increased
protonating strength of the acid might also lead to a lower
functional group tolerance, especially towards acid-labile
functionalities.
In this work, we show that the “differentiating effect” of
solvents can be used to achieve exceptional selectivities in
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Page 2 of 11
reaction completion for 50 equivalents of CH3OD (16.7 eq. per Particularly notable examples are the aromatic amines 12 and
1
2
3
4
5
6
7
8
exchangeable proton) in 1,4-dioxane compared to standard
conditions (see Supporting Information). This basically allows
the usage of a lower excess of deuterium source, albeit multiple
cycles would then be necessary to reach high conversion. To
maintain the simplicity and effectiveness of the present
approach, which also relies on the low cost of CD3OD and
CH3OD, the use of the deuterium source as solvent was kept for
all further investigations.
27-29, for which one could assume that deuteration should be
significantly hindered by the basicity of the amino groups,
especially since HClO4 is only present in 5 mol% relative to the
aromatic amine. Nevertheless, the deuterated derivatives were
obtained in good to high yields, thereby pointing to an altered
selectivity in protonation, which is shifted from the aromatic
amine to the aromatic core. Aliphatic amines were tolerated
either when protected as amides or when present as
hydrochlorides, as exemplified by 38 and 39.
In the next step, we evaluated how far the electron-rich
character of the arene can be reduced to still allow deuteration
under the previously optimized conditions using 5 mol% HClO4
in CD3OD (0.1 mmol scale, 220 eq. of D-source) or CH3OD (1
mmol scale, 240 eq. of D-source). Unless otherwise stated, the
substrates shown in Figures 2-5 and 7 resulted from reactions
performed at 0.1 mmol scale. Based on these studies, the
individual arenes were assigned to three groups A-C according
to conditions required for deuteration (Figures 2-5).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Group C: Deuteration at 75 °C over 1 to 7 days
OH
OH
OH
O
O
[97]
[98]
[96]
[97]
D
D
D
D
D
D
O
O
O
O
O
[97]
D
D
O
[92]
[97]
[81]
D
D
D
D
O
17
18
20
21
quant., 3 d,
quant., 3 d,
quant., 3 d,
19 quant., 3 d,
83%, 3 d,
H
O
O
O
OH
Br
[63]
CD3
O
[96]
6
D
D
D
O
D
D
D
O
O
O
[97]
Figure 2. Group A: Deuteration at room temperature over 2 to
15 hours
5
3
D
[95]
D
O
O
O
O
O
D
D
Br
[51]
[97]
[97]
[85]
CH3
OH
D
D
Bn
[97]
O
OH
O
OH
O
O
b
[97]
[97]
22
94%, 3 d,
23
24
96%, 4 d,
91% , 3 d,
25
26
23%, 2 d,
quant., 4 d,
D
D
D
D
D
D
D
D
D
D
O
OH
[97]
D
OH
[97]
[97]
[97]
D
[97]
D
Ph
[97]
O
D
[97]
D
O
O
O
O
O
HO
OH
O
O
O
O
N
[97]
[97]
[97]
[97]
[97]
D
D
D
D
D
D
D
D
H2N
N
H2N
O
[97]
D
O
5
quant., 15 h,
1
2
3
4
quant., 4 h,
Ph
92%, 4 h,
87%, 15 h,
90%, 15 h,
[97]
[97]
[97]
D
D
D
D
O
OH
27
O
28
29
92%, 2 d,
71%, 2 d,
OH
95%, 3 d,
30
90%, 2 d,
D
O
[96]
[95]
D
N
O
OH
O
H
HO
D
D
D
D
IC261
O
N
NH2
D
HO
D
D
34
quant., 1 d,
91%, 1 da
D
[96]
D
O
O
N
HCl
OH
[96]
HO
O
D
OH resveratrol
[97]
[83]
D
D
D
D
31
D
NH2
6
7
82%, 15 h,
quant., 4 h,
OH
OH
HO
H
N
85%, 3 d,
trimethoprim
84%, 3 d,
quant., 4 ha
D
D
H
[88]c
33
D
[95]
80%c, 3 d, 32
aIsolated yield from reaction performed on 1 mmol scale.
OH
D
HO
O
[87]
[98]
[13]
D
HO
O
OH
HO
D
[68]
Figure 3. Group B: Deuteration at room temperature over 5 to
9 days or at 75 °Ca in 15 hours.
O
OH
O
D
OH
OH
x H2O
[91]
OH
genistein
quant., 12 d,
quercetin
OH
O
35
haematoxylin
80%, 7 d,
36
85%, 5 d,
H
O
37
O
O
NH2
[97]
[97]
OH
[97]
[97]
[95]
[96]
[96]
D
H
N
H
N
[97]
D
D
D
D
D
O
O
D
D
D
Br
D
HO
O
D
D
[97]
[90]
O
HO
D
D
O
O
O
O
O
O
H
[96]
[75]
[97]
D
[96]
D
[97]
D
[95]
O
O
D
D
D
[97]
OH
O
NHAc
NH3Cl
8a
9
10a
11
12a
84%, 15 h,
serotonin
39
chrysin
40
melatonin
38
95%, 15 h,
32%, 9 d,
quant., 15 h,
quant., 4 d,
95%, 1 d,
quant., 3 d,
quant., 1 d,
[98]
D
[96]
Bn
aIsolated yield from reaction performed on
Dimethoxybenzoic acid was used as the starting material. The deuterated
ester was obtained. cLC/MS was used for yield and H/D-exchange
calculation.
1
mmol scale. b2,6-
[97]
[96]
D
O
O
O
N
N
D
D
D
D
HO
O2N
D
D
[96]
D
D
D
D
[96]
[98]
[97]
D
O
-tocopherol
quant., 15 h,
14a
15a
13
quant., 4 d,
84%, 15 h,
16a
96%, 15 h,
Figure 5 summarizes border cases, which give an impression on
the type and number of activating substituents which are at least
required for successful deuteration under the conditions of
group C. Besides a single hydroxy group, an additional weak
inductive (3-Me) or weak mesomeric (3-F) donor in the 3-
position is sufficient to give high yields and good degrees of
deuteration at 75 °C (cf. 43 and 44), which can be rationalized
by the additive substituent effects.18 Regarding the other
positions, 2-alkylation (cf. 45) turned out to be more effective
than 4-alkylation (41 and 42). Therefore, not surprisingly, the
doubly alkylated phenols 46 and 47, as well as the more
complex steroid estradiol (48) were successfully deuterated
under milder conditions than so far reported.19
Among the diverse compounds evaluated, only the aldehydes 9
and 25 turned out to be unstable. Almost all other substrates
gave yields in the range of 90% to quantitative along with
mostly high degrees of deuteration, thereby underlining the
broad applicability. Among the more complex substrates,
deuteration has already been studied for some examples.
However, those procedures either rely on the incorporation of
the isotope early in the synthesis (710, 1611), on the use of
expensive or difficultly to handle reagents (3612, 3813) or on
harsh conditions such as boiling for multiple days in D2O/acid
mixtures at temperature up to 190 °C (714, 3315 3516, 3917, 4817),
which limits these methods in their versatility and practicality.
For 34, 37 and 40 preparative direct deuteration has not yet been
described.
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The Journal of Organic Chemistry
Figure 5. Border cases of group C: Deuteration at 75°C to
95°Ca over 3-6 d.
Whereas the deuterated positions of 21, 35, and 36 show the
lowest aromatic 1H NMR shifts in the related parent compound
(6.67, 6.30/6.40, and 6.51 ppm, respectively), the inert positions
are shifted beyond the deuteration range (7.02, 6.90/7.50, and
6.99/7.70/7.80 ppm, respectively). Haematoxylin (37) also
follows this prediction model for relative regioselectivity (6.52
vs. 6.62/6.75 ppm), however, it suffers from lower reactivity
due to residual water in its commercially available form (~6%
water content).
1
2
3
4
5
6
7
8
[96]
[91]
[64]
D
D
D
F
D
D
[<6]
D
[23]
D
D
[87]
D
[72]
D
[91]
D
[37]
D
[38]
OH
OH
OH
OH
OH
41
42
44
45
quant., 6 d,
quant., 6 d,
quant., 6 d,
43
99%, 6 d,
OH
quant., 6 d,
[95]
[97]
D
D
H
D
[55]
Having observed the broad applicability of the novel
deuteration method, we turned back to the unexpected tolerance
of basic aromatic amines (cf. 27-29, Figure 4). This effect can
be explained as follows: while protonation at the amino group
generates an ammonium ion with a localized charge, the charge
resulting from protonation at the aromatic core (in the course of
deuteration) is delocalized as a cyclohexadienyl cation. The
significantly weaker ability of methanol to stabilize charges,
compared to water, is thus able to shift the selectivity towards
protonation or deuteration of the aromatic core. 9b,23 If that was
true, otherwise acid labile functional groups might be tolerated,
given that the cleavage would occur via an unfavorable,
localized charge. On the other hand, the “differentiating effect”
of aliphatic alcohols is known to maintain the protonating
strength of very strong acids, such as HClO4, more effectively,
which could also lead to an even faster cleavage of acid-labile
groups.9a-b
D
D
D
D
D
D
H
H
9
[88]
[94]
[95]
[97]
OH
quant., 6 d,
OH
quant., 6 d,
OH
HO
estradiol
48
quant., 6 d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
49a
[71]
46
47
quant., 6 d,
D
D
[78]
D
D
[90]
[22]
D
D
HO
[26]
D
D
[49]
D
D
OH
D
D
[70]
D
D
[22]
N
[43]
D
D
H
D
NH2
O
[14]
50a
51a
52a
53a
quant., 4 d,
quant., 3 d,
80%, 5 d,
95%, 4 d,
Especially of interest as a reference compound is phenol (49)
for which deuteration occurred at 95 °C. Current transition
metal free methods for deuteration include DCl (330 mol%, 140
°C), BF3•D3PO4 (360 mol%, 140 °C) or NaOD (100 mol%, 180
°C).20 The advantage over existing methods also becomes
obvious from aniline (50), which had to be treated with DCl
(100 mol%, 180 °C) or NaOD (10 mol%, 405°C) so far.21
Resultantly, we are pleased to report the first metal free
deuteration of phenol and aniline with low catalytic amounts of
acid (5 mol% HClO4) and temperatures below 100 °C. For
BINOL (53), not even any acid catalyzed deuteration has yet
been reported.22
In a first series of experiments, we evaluated the deuteration of
the glycosylated phytochemicals 54-56 (Figure 7).
Figure 7. Deuteration of glycosylated phytochemicals under
conditions of group B.
To evaluate whether easily accessible NMR data can be used to
predict the H/D exchange under the optimized conditions, the
1H NMR shifts of all exchangeable aromatic positions on the
compounds 1-48 and 54-56 (excluding heterocycles) were
summarized (Figure 6). Arenes in group D did not undergo H/D
exchange (< 10%) at 75 °C (see Supporting Information for an
overview).
OH
O
HO
H3C
[92]
D
OH
O
O
[94]a
HO
HO
OH
OH
O
O
OH
O
O
H3C
HO
D
O
O
[73]
[92]
D
54
90%,
97%a
3 d, rt
OH
[94]a
O
HO
HO
HO
O
O
O
OH
O
OH
OH
OH
OH
D
[97]
D
[73]
HO
HO
OH
56
75%,
4 w, 40 °C
O
1
[97]
OH
Figure 6. H-NMR shifts of aromatic positions accessible for
D
D
55
97%,
84%a
[97]
deuteration in CD3OD.
OH
1 d, 40 °C
aIsolated yield from reaction performed on 1 mmol scale.
High yields and high degrees of deuteration were achieved for
54 and 55 while a good yield of 75% was obtained for 56.
Remarkably, all three compounds have not yet been prepared
and isolated, but are highly useful reference compounds
regarding studies in food chemistry, where they are of interest
due to their antioxidant and potential anticancer properties.24
Especially 54 is widely used as an artificial sweetener in the
European Union.25 Control reactions in water and in the absence
of acids revealed that the optimized conditions (5 mol% HClO4
in CD3OD) are by far the most suitable to obtain 55 in high yield
and with high degrees of deuteration (see Supporting
Information). Remarkably, H/D exchange in -positions of
carbonyls, as present in 54, is much slower under the chosen
reaction conditions. This is in agreement with the earlier
observation that 3 and 6 do only show traces of deuterium
incorporation at their respective -positions.
These data show that aromatic protons with 1H NMR shifts up
to 6.7 ppm have a high probability to be deuterated under the
conditions for groups A-C described herein. The highest ppm
value for an exchangeable proton was so far observed for
positions 4 and 6 in 24 with 6.83 ppm. An illustrative example
1
for the relationship between H NMR shift and deuteration is
also 26, where H/D exchange at the 3-position (6.74 ppm)
occurred with a degree of 51%, at the 6-position (6.68 ppm)
with 63% and at the 5-position (6.59 ppm) with 95%.
Furthermore, the 1H NMR prediction model explains the
regioselectivity of the H/D exchange for 21, 35, 36 and 37.
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Table 1. Deuteration of O-silyl protected phenols.
Solvents and reagents are obtained from commercial sources
and used as received. Deuterated solvents were purchased from
1
2
3
4
5
6
7
8
D
D
O
O
O
O
O
OH
PG
Deutero GmbH. The deuterium fraction for d1-MeOD and d4-
MeOD are 99% and 99.8%, respectively. The deuterium
fraction for all deuterated solvents is >98%. If not stated
differently, the structures of the deuterated compounds were
confirmed by 1H NMR comparison (stacked plots added to the
supporting information) of the starting material with the
according deuterated compound. If heating was required, the
reactions were performed in an oil bath. 1H-NMR and 13C-NMR
spectra are recorded on a Bruker Avance 400 (1H: 400 MHz;
HClO4 (5 mol%)
(CD3OD)
PG
+
D
D
D
D
[97]
[97]
[97]
[97]
O
O
O
[D3]-57a-c
[D3]-2
57a-c
protecting
group
(PG)
ratio of silyl ether [D3]-57 to phenol [D3]-2c
3 h
5 h
(rt)a
4.8:1
46:1
160:1
30 h
(rt)a
4 h
(60 °C)a
n.a.
24 h
(60 °C)a
n.a.
(rt)
10:1b
n.a.
a: TBS
b: TIPS
0.82:1
19:1
9
7.3:1
17:1
1.9:1
1
13C: 101 MHz) spectrometer. For H-NMR spectra CD3OD
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c: TBDPS
n.a.
58:1
2.7:1
(3.31 ppm) is used as solvent referenced to CHD2OD
(3.31 ppm). Chemical shifts are reported in parts per million
(ppm). Coupling constants are in Hertz (Hz). The following
abbreviations are used for the description of signals: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad
singlet). 13C-NMR (DEPTQ) spectra are recorded in CD3OD
using CD3OD (49.00 ppm) as standard. Chemical shifts are
given in parts per million (ppm). Protons which have been
exchanged with a deuterium atom during deuteration are
indicated with the according integral for the remaining protium
content. Masses were detected by electro spray ionization (ESI)
in a Waters ACQUITY QDa detector using Single Ion
Recording (SIR) for isotope quantification. For the calculation
of isotope percentages the natural abundance of 13C was taken
into account. Atomospheric Pressure Photoionization (APPI)
and a sector field mass analyzer was used for HRMS
measurements. Analytical TLC is carried out on Merck silica
gel plates using short wave (254 nm) UV light to visualize
components. Silica gel (Kieselgel 60, 40-63mm, Merck) is used
for flash column chromatography. The purity of isolated
substances was determined using an analytical HPLC. All
tested compounds show >95% purity. System A: Waters
XBridge C18 analytical column, 2.3 mm x 50 mm, 3.5 μm, flow
rate: 0.50 mL/min, Eluent: CH3CN in H2O + 0.1% HCO2H (0-
15 min 10%-90%, 15-18 min 90%). System B Waters XBridge
C18 analytical column, 2.1 mm x 50 mm, 3.5 μm, flow rate:
0.50 mL/min, Eluent: CH3CN in H2O + 0.1% HCO2H (0-15 min
0%-90%, 15-18 min 90%).
aDegree of H/D exchange in [D3]-57a-c and phenol [D3]-2 > 97%. bDegree
of H/D exchange 85%. cn.a.: not analyzed.
In a second series of experiments, the optimized conditions for
deuteration were applied to the O-silyl protected phenols
57a-c. Silyl groups on phenols were chosen as they have been
reported to be highly sensitive to even weak acids in water.
Arylsilyl ethers, such as tert-butyldimethylsilyl ethers (TBS),
are known to readily hydrolyse at pH 2-4 and are only
considered stable at pH > 6.26 The results obtained in the
deuteration experiments are summarized in Table 1.
Independent from the silyl group, full H/D exchange (>97%)
was observed after 5 h at room temperature with only minor
cleavage of the silyl groups, whereat the trend in stability from
TBS via TIPS to TBDPS follows known rules.26 Longer
reaction times and higher temperatures were applied to
demonstrate the stability of the silyl groups.27
Finally, experiments on the isotopic stability of the deuterated
compounds towards reverse H/D exchange were conducted for
the complex substrates 7, 34-40, 48 and 54-56 to evaluate their
usefulness as internal standards. Among the 12 compounds
studied, only [D3]-7 showed signs of D/H-exchange after 3 days
under analytically representative conditions. All other
substrates remained stable (<5 % loss in isotopic purity) over 7
days. In this context, it should be noted that, even though [D3]-
7 is susceptible towards reverse H/D-exchange, it has actually
been already used as an internal standard in the quantification
of resveratrol in red wine.14 Having now access to [D3]-piceid
([D3]-55) for the first time, stable isotope dilution assay
experiments of resveratrol derived glucosides can be
performed. This may further elucidate their role in the so called
“french paradox”, which relates to potential health benefits
resulting from the consumption of red wine.28
General Procedure A: Substrate (0.1 mmol) was dissolved in
MeOD-d4 (1 mL). If needed, d6-DMSO or CDCl3 was added as
a co-solvent. A 70% solution of HClO4 (0.005 mmol, 5 mol%,
0.42 µL) was added and the mixture was kept at the noted
temperature under argon. The degree of deuterium
incorporation (conversion achieved over the reaction conditions
and time) and yield (including recovered starting material and
all degrees of deuteration) were determined by 1H NMR
analysis of the mixture in presence of ethylene carbonate as an
internal standard (1 M in d4-MeOD, 50 µL, 50 µmol).
In conclusion, it has been shown that the shifted selectivity in
protonation observed for HClO4 in methanol can be broadly
exploited for an exceptionally mild deuteration of electron-rich
arenes. Under simple reaction conditions, the novel method
offers direct access to even complex aromatic compounds
including deuterated natural products and pharmaceuticals. For
the reaction course, and for the successful deuteration of acetal-
and silyl-protected phenols in particular, the increased tendency
to avoid localized charges in methanol can provide a plausible
explanation.
Large scale reactions:
General Procedure B: Substrate (1 mmol) was dissolved in
MeOD-d1 (10 mL). A 70% solution of HClO4 (0.05 mmol, 5
mol%, 4.2 µL) was added and the mixture was stirred at the
noted temperature under argon.
2,4,6-[D3]-1,3,5-Trimethoxybenzene ([D3]-1) was prepared
from 1,3,5-trimethoxybenzene (0.1 mmol, 16.8 mg) according
to the General Procedure A for 4 h at rt (100 µmol, 100% yield,
1
97% deuterium incorporation) according to H NMR; 93%
deuterium incorporation according to MS). 1H NMR (400 MHz,
EXPERIMENTAL SECTION
MeOD) δ 6.1 (s, 0.06H), 3.8 (s, 9H). MS (ESI, SIR) m/z (%)
General information
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172 (100%), 171 (21%), 170 (2%), 169 (0%). MS (ESI, SIR) 3,5-[D2]-1,2,4-Trimethoxybenzene([D2]-10) was prepared from
1
2
3
4
5
6
7
8
[D3]-1 (81%), [D2]-1 (17%), [D1]-1 (2%), [D0]-1 (0%).
1,2,4-trimethoxybenzene (0.1 mmol, 16.8 mg) according to the
General Procedure A for 15 h at 75 °C (100 µmol, 100% yield,
97% deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
7.0 (s, 1H), 6.7 (s, 0.03H), 6.7 (s, 0.03H), 3.8 (s, 6H), 3.8 (s,
3H).
2,4,6-[D3]-3,5-Dimethoxyphenol ([D3]-2) was prepared from
3,5-dimethoxyphenol (0.1 mmol, 15.4 mg) according to the
General Procedure A for 4 h at rt (92 µmol, 92% yield, 97%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.0 (s,
0.08H), 3.7 (s, 6H).
4,6-[D2]-2-Bromo-1,3,5-trimethoxybenzene ([D2]-11) was
prepared from 2-bromo-1,3,5-trimethoxybenzene (0.1 mmol,
24.7 mg) according to the General Procedure A for 4 d at rt (100
µmol, 100% yield, 96% deuterium incorporation). CDCl3 (1
3,5-[D2]-1-(2,4,6-trihydroxyphenyl)propan-1-one ([D2]-3) was
prepared from 1-(2,4,6-trihydroxyphenyl)propan-1-one (0.1
mmol, 18.2 mg) according to the General Procedure A for 15 h
at rt (87 µmol, 87% yield, 97% deuterium incorporation). H
NMR (400 MHz, MeOD) δ 5.8 (s, 0.06H), 3.1 (q, J = 7.3 Hz,
2H), 1.1 (t, J = 7.3 Hz, 3H).
9
1
1
mL) was used as a co-solvent. H NMR (400 MHz, MeOD) δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6.2 (s, 0.14H), 3.9 (s, 6H), 3.8 (s, 3H).
2,4,6-[D3]-3,5-Dimethoxyaniline ([D3]-12) was prepared from
3,5-dimethoxyaniline (0.1 mmol, 15.3 mg) according to the
General Procedure A for 15 h at 75 °C (84 µmol, 84% yield,
97% deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
6.0 (s, 0.05H), 6.0 (s, 0.03H), 3.7 (s, 6H).
2,4,6-[D3]-1-(Allyloxy)-3,5-dimethoxybenzene ([D3]-4) was
prepared from 1-(allyloxy)-3,5-dimethoxybenzene (0.1 mmol,
19.4 mg) according to the General Procedure A for 15 h at rt
(90 µmol, 90% yield, 97% deuterium incorporation). 1H NMR
(400 MHz, MeOD) δ 6.1 – 6.0 (m, 1.17H), 5.4 (dq, J = 1.7, 17.3
Hz, 1H), 5.3 (dq, J = 1.5, 10.6 Hz, 1H), 4.5 (dt, J = 1.6, 5.2 Hz,
2H), 3.7 (s, 6H). The data are in accordance with those reported
in literature.29
2,4,6-[D3]-1,3-Dimethoxy-5-(4-nitrophenoxy)benzene ([D3]-
13)
was
prepared
from
1,3-dimethoxy-5-(4-
nitrophenoxy)benzene (0.1 mmol, 27.5 mg) according to the
General Procedure A for 4 d at rt (100 µmol, 100% yield, 98%
deuterium incorporation). CDCl3 (1 mL) was used as a co-
solvent. 1H NMR (400 MHz, MeOD) δ 8.2 – 8.2 (m, 2H), 7.1 –
7.0 (m, 2H), 6.4 (s, 0.02H), 6.2 (s, 0.04H), 3.8 (s, 6H). The data
are in accordance with those reported in literature.32
2,4,6-[D3]-1-(Benzyloxy)-3,5-dimethoxybenzene ([D3]-5) was
prepared from 1-(benzyloxy)-3,5-dimethoxybenzene (0.1
mmol, 24.4 mg) according to the General Procedure A for 15 h
at rt (100 µmol, 100% yield, 95% deuterium incorporation). 1H
NMR (400 MHz, MeOD) δ 7.5 – 7.2 (m, 3H), 6.2 (s, 0.09H),
6.1 (s, 0.05H), 5.0 (s, 1H), 3.7 (s, 3H). The data are in
accordance with those reported in literature.30
2,3,4,5-[D4]-N-Methyl-pyrrole ([D4]-14) was prepared from N-
methyl-pyrrole (0.1 mmol, 8.1 mg) according to the General
Procedure A for 15 h at 75 °C (84 µmol, 84% yield, 97%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.6 (s,
0.06H), 6.0 (s, 0.06H), 3.7 (s, 3H).
2,4,6-[D3]-2-(3,5-Dimethoxyphenoxy)-1-phenylethan-1-one
([D3]-6) was prepared from 2-(3,5-dimethoxyphenoxy)-1-
phenylethan-1-one (0.1 mmol, 27.2 mg) according to the
General Procedure A for 15 h at rt (82 µmol, 82% yield, 97%
deuterium incorporation). CDCl3 (1 mL) was used as a co-
2,3,4,5-[D4]-N-Benzyl-pyrrole ([D4]-15) was prepared from N-
benzyl-pyrrole (0.1 mmol, 15.7 mg) according to the General
Procedure A for 15 h at 75 °C (96 µmol, 96% yield, 96%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.4 –
7.2 (m, 3H), 7.2 – 7.1 (m, 2H), 6.7 (s, 0.05H), 6.1 (s, 0.05H),
5.1 (d, J = 0.9 Hz, 2H).
1
solvent. H NMR (400 MHz, MeOD) δ 8.0 – 8.0 (m, 2H), 7.6
(ddt, J = 1.3, 6.9, 8.0 Hz, 1H), 7.6 – 7.5 (m, 2H), 6.1 (s, 0.05H),
6.1 (s, 0.03H), 5.3 (s, 2H), 3.7 (s, 6H). The data are in
accordance with those reported in literature.31
5,7-[D2]--Tocopherol ([D2]-16) was prepared from -
tocopherol (0.1 mmol, 40.2 mg) according to the General
Procedure A for 15 h at 75 °C (100 µmol, 100% yield, 96%
deuterium incorporation). CDCl3 (0.5 mL) was used as a co-
2,4,6-[D3]-Resveratrol ([D3]-7) was prepared from resveratrol
(0.1 mmol, 28.8 mg) according to the General Procedure A for
4 h at rt (100 µmol, 100% yield, 96% deuterium incorporation)
according to 1H NMR; 93% deuterium incorporation according
1
solvent. H NMR (400 MHz, MeOD) δ 6.4 (d, J = 0.9 Hz,
1
to MS). H NMR (400 MHz, MeOD) δ 7.4 – 7.3 (m, 2H), 7.0
0.04H), 6.4 – 6.3 (m, 0.04H), 2.7 (td, J = 1.3, 6.8 Hz, 2H), 2.1
(s, 3H), 1.8 (ddq, J = 6.8, 13.5, 20.2 Hz, 2H), 1.7 – 1.0 (m, 18H),
0.9 – 0.8 (m, 13H).
(d, J = 16.3 Hz, 1H), 6.9 – 6.8 (m, 3H), 6.5 (s, 0.08H), 6.2 (s,
0.04H). HPLC (254 nm, system A) tR = 4.0 min. MS (ESI, SIR)
m/z (%) 232 (100%), 231 (21%), 230 (2%), 229 (0.2%). MS
(ESI, SIR) [D3]-7 (79%), [D2]-7 (19%), [D1]-7 (2%), [D0]-7
(0%).
3,4,5-[D3]-2,6-Dimethoxyphenol ([D3]-17) was prepared from
2,6-dimethoxyphenol (0.1 mmol, 15.5 mg) according to the
General Procedure A for 3 d at 75 °C (100 µmol, 100% yield,
1
2,4,6-[D3]-3-Methoxyphenol ([D3]-8) was prepared from 3-
methoxyphenol (0.1 mmol, 12.4 mg) according to the General
Procedure A for 15 h at 75 °C (95 µmol, 95% yield, 97%
deuterium incorporation). The deuterium incorporation and
93% (3,5-d2) / 82% (4-d) deuterium incorporation). H NMR
(400 MHz, MeOD) δ 6.8 (s, 0.19H), 6.6 – 6.6 (m, 0.16H), 3.8
(s, 6H).
4,6-[D2]-2-Methoxyphenol ([D2]-18) was prepared from 2-
methoxyphenol (0.1 mmol, 12.4 mg) according to the General
Procedure A for 3 d at 75 °C (100 µmol, 100% yield, 92% (3,5-
d2) / 81% (4-d) deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 6.9 (s, 1H), 6.9 – 6.8 (m, 1H), 3.9 (s, 3H).
1
yield were determined by H NMR analysis of the mixture in
presence of ethylene carbonate as an internal standard (1 M in
d4-MeOD, 25 µL, 25 µmol). 1H NMR (400 MHz, MeOD) δ 7.1
(s, 1H), 6.4 – 6.3 (m, 0.13H), 3.7 (s, 3H).
3,5-[D2]-2,4,6-trimethoxybenzaldehyde ([D2]-9) was prepared
from 2,4,6-trimethoxybenzaldehyde (0.1 mmol, 19.6 mg)
according to the General Procedure A for 9 d at rt (32 µmol,
32% yield, 75% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 10.3 (s, 1H), 6.3 (s, 0.49H), 4.0 (s, 3H), 4.0 (s, 6H).
2,6-[D2]-4-Methoxyphenol ([D2]-19) was prepared from 4-
methoxyphenol (0.1 mmol, 12.4 mg) according to the General
Procedure A for 3 d at 75 °C (83 µmol, 83% yield, 96%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.8 –
6.7 (m, 2.08H), 3.7 (s, 3H).
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2,4,6-[D3]-1,3-Dimethoxybenzene ([D3]-20) was prepared from
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.5 –
7.4 (m, 4H), 7.2 (ddt, J = 1.7, 6.4, 7.1 Hz, 1H), 7.2 (s, 0.07H),
6.3 (s, 0.07H).
1
2
3
4
5
6
7
8
1,3-dimethoxybenzene (0.1 mmol, 13.8 mg) according to the
General Procedure A for 3 d at 75 °C (100 µmol, 100% yield,
97% deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
7.2 (d, J = 1.3 Hz, 1H), 6.6 – 6.4 (m, 0.11H), 3.8 (s, 6H).
3,3’,5,5’-[D4]-Bis(2,4-dihydroxyphenyl)methanone ([D4]-31)
was prepared from bis(2,4-dihydroxyphenyl)methanone (0.1
mmol, 24.6 mg) according to the General Procedure A for 3 d
at 75 °C (85 µmol, 85% yield, 97% deuterium incorporation).
1H NMR (400 MHz, MeOD) δ 7.4 (s, 2H), 6.4 – 6.4 (m, 0.17H).
4,6-[D2]-1,2,3-Trimethoxybenzene ([D2]-21) was prepared
from 1,2,3-trimethoxybenzene (0.1 mmol, 16.7 mg) according
to the General Procedure A for 3 d at 75 °C (100 µmol, 100%
yield, 98% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 7.0 (s, 1H), 6.7 (s, 0.02H), 6.7 (s, 0.02H), 3.8 (s, 6H),
3.8 (s, 3H).
1,2,3,5,6,7,8-[D7]-4-Hydroxycarbazole ([D7]-32) was prepared
from 4-hydroxycarbazole (0.1 mmol, 24.6 mg) according to the
General Procedure A for 3 d at 75 °C (80 µmol, 80% yield, 88%
deuterium incorporation). 1H NMR (600 MHz, MeOD) δ 8.2 (s,
0.37H), 7.4 (s, 0.38H), 7.3 (s, 0.35H), 7.2 (s, 2.00H), 7.1 (s,
0.42H), 6.9 (t, J = 4.0, 4.0 Hz, 0.42H), 6.6 (t, J = 3.9, 3.9 Hz,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4,6-[D3]-1-Bromo-3,5-dimethoxybenzene ([D3]-22) was
prepared from 1-bromo-3,5-dimethoxybenzene (0.1 mmol, 21.7
mg) according to the General Procedure A for 3 d at 75 °C (94
µmol, 94% yield, 97% deuterium incorporation). 1H NMR (400
MHz, MeOD) δ 6.7 (s, 0.07H), 6.5 (s, 0.06H), 3.8 (s, 6H).
1
0.39H). Due to the lack of integrable protons in the H NMR,
LC/MS was used for yield calculation (average from integration
at 220 nm and 254 nm) and H/D-exchange rate (isotope
distribution analysis).
3,5-[D2]-Methyl-2,6-dimethoxybenzoate
([D2]-23)
was
prepared from 2,6-dimethoxybenzoic acid (0.1 mmol, 18.2 mg)
according to the General Procedure A for 3 d at 75 °C (91 µmol,
91% yield, 97% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 7.4 (s, 1H), 6.7 (d, J = 8.4 Hz, 0.05H), 3.8 (s, 6H).
The data are in accordance with those reported in literature.33
4,6-[D2]-Trimethoprim hydrochloride ([D2]-33) was prepared
from trimethoprim hydrochloride (0.2 mmol, 67.3 mg)
according to the General Procedure A for 3 d at 75 °C (168
µmol, 84% yield, 83% deuterium incorporation). 1H NMR (400
MHz, MeOD) δ 7.2 (s, 1H), 6.5 (s, 0.35H), 3.8 (s, 6H), 3.7 (s,
3H), 3.6 (s, 2H).
4,6-[D2]-5-Bromo-1,2,3-trimethoxybenzene ([D2]-24) was
prepared from 5-bromo-1,2,3-trimethoxybenzene (0.1 mmol,
24.6 mg) according to the General Procedure A for 4 d at 75 °C
(96 µmol, 96% yield, 85% deuterium incorporation). 1H NMR
(400 MHz, MeOD) δ 6.8 (d, J = 0.6 Hz, 0.30H), 3.8 (s, 6H), 3.8
(s, 3H).
3,5-[D2]-3-(2,4,6-Trimethoxybenzylidene)indolin-2-one ([D2]-
IC261,
[D2]-34)
was
prepared
from
3-(2,4,6-
trimethoxybenzylidene)indolin-2-one (IC261) (0.1 mmol, 31.1
mg, E/Z : 10:1) according to the General Procedure A for 1 d at
75 °C (100 µmol, 100% yield, 97% deuterium incorporation
according to 1H NMR; 95% deuterium incorporation according
to MS, E/Z : 10:1). CDCl3 (1 mL) was used as a co-solvent. 1H
NMR (400 MHz, CDCl3) δ 7.8 (s, 1H), 7.2 (td, J = 1.3, 7.6 Hz,
1H), 7.0 – 7.0 (m, 1H), 6.9 (ddd, J = 1.2, 6.6, 7.7 Hz, 2H), 6.2
(s, 0.09H), 3.9 (s, 3H), 3.8 (s, 6H). HPLC (254 nm, system A)
tR =7.5 min (E) and 7.9 min (Z). MS (ESI, SIR) m/z (%) 314
(100%), 313 (12%), 312 (0.2%). MS (ESI, SIR) [D2]-34 (91%),
[D1]-34 (9%), [D0]-34 (0%). The data are in accordance with
those reported in literature.34
2,6-[D2]-4-Hydroxy-3,5-dimethoxybenzaldehyde ([D2]-25) was
prepared from 4-hydroxy-3,5-dimethoxybenzaldehyde (0.1
mmol, 18.2 mg) according to the General Procedure A for 2 d
at 75 °C (23 µmol, 23% yield, 96% deuterium incorporation).
1H NMR (400 MHz, MeOD) δ 9.8 (s, 1H), 7.3 (d, J = 31.5 Hz,
0.08H), 3.9 (s, 6H).
3,5,6-[D3]-2-Methoxy-4-methylphenol ([D3]-26) was prepared
from 2-methoxy-4-methylphenol (0.1 mmol, 13.8 mg)
according to the General Procedure A for 4 d at 75 °C (100
µmol, 100% yield, 95% (5-d) / 63% (6-d) / 51% (3-d) deuterium
1
2,6,8-[D3]-Genistein ([D3]-35) was prepared from genistein
(0.1 mmol, 27.0 mg) according to the General Procedure A for
12 d at 75 °C (100 µmol, 100% yield, 95% (8-d) / 68% (6-d) /
incorporation). H NMR (400 MHz, MeOD) δ 6.7 (s, 0.49H),
6.7 (s, 0.37H), 6.6 – 6.6 (m, 0.05H), 3.8 (s, 3H), 2.3 (s, 3H).
2,4,6-[D3]-3-Aminophenol ([D3]-27) was prepared from 3-
aminophenol (0.1 mmol, 11.0 mg) according to the General
Procedure A for 2 d at 75 °C (92 µmol, 92% yield, 97%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.9 (s,
1H), 6.3 (d, J = 7.9 Hz, 0.03H), 6.3 (s, 0.03H), 6.2 (d, J = 8.1
Hz, 0.04H).
1
13% (2-d) deuterium incorporation) according to H NMR;
1
77% deuterium incorporation ([D2]-35) according to MS. H
NMR (400 MHz, MeOD) δ 8.2 (s, 0.87H), 7.5 – 7.4 (m, 2H),
7.0 – 6.8 (m, 2H), 6.4 (s, 0.05H), 6.3 (s, 0.32H). HPLC (254
nm, system A) tR = 5.5 min. MS (ESI, SIR) m/z (%) 273 (100%),
272 (61%), 303 (0.5%). MS (ESI, SIR) [D2]-35 (57%), [D1]-35
(39%), [D0]-35 (4%).
2,4,6-[D3]-3-(Dimethylamino)phenol ([D3]-28) was prepared
from 3-(dimethylamino)phenol (0.1 mmol, 13.7 mg) according
to the General Procedure A for 2 d at 75 °C (71 µmol, 71%
yield, 97% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 7.0 (s, 1H), 6.4 – 6.2 (m, 0.05H), 2.9 (s, 6H).
6,8-[D2]-Quercetin ([D2]-36) was prepared from quercetin (0.1
mmol, 32.2 mg) according to the General Procedure A for 5 d
at 75 °C (85 µmol, 85% yield, 98% (3-d) / 91% (5-d) deuterium
incorporation according to 1H NMR; 73% deuterium
incorporation according to MS). d6-DMSO (1 mL) was used as
a co-solvent. 1H NMR (400 MHz, MeOD) δ 7.9 (d, J = 2.2 Hz,
1H), 7.7 (dd, J = 2.2, 8.5 Hz, 1H), 7.1 (d, J = 8.5 Hz, 1H), 6.6
(s, 0.07H), 6.4 (s, 0.15H). HPLC (254 nm, system A) tR = 4.8
min. MS (ESI, SIR) m/z (%) 305 (100%), 304 (17%), 303 (6%).
MS (ESI, SIR) [D2]-36 (54%), [D1]-36 (35%), [D0]-36 (11%).
4,6-[D2]-2,5-Dimethoxybenzenamine ([D2]-29) was prepared
from 2,5-dimethoxybenzenamine (0.1 mmol, 15.3 mg)
according to the General Procedure A for 3 d at 75 °C (95 µmol,
95% yield, 97% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 6.8 (s, 1H), 6.5 (s, 0.03H), 6.3 (d, J = 8.7 Hz, 0.03H),
3.9 (s, 3H), 3.8 (s, 3H).
2,3,4,5-[D4]-N-Phenyl-pyrrole ([D4]-30) was prepared from N-
phenyl-pyrrole (0.1 mmol, 14.3 mg) according to the General
Procedure A for 2 d at 75 °C (90 µmol, 90% yield, 97%
4-[D]-Haematoxylin ([D]-37) was prepared from haematoxylin
hydrate (0.1 mmol, 30.2 mg, 94 weight%) according to the
General Procedure A for 7 d at 75 °C (80 µmol, 80% yield, 87%
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deuterium incorporation according to 1H NMR; 88% deuterium d2) / 37% (2-d) deuterium incorporation). 1H NMR (400 MHz,
incorporation according to MS). 1H NMR (400 MHz, MeOD) δ
6.7 (dd, J = 0.9, 4.0 Hz, 2H), 6.6 (s, 1H), 6.5 (d, J = 8.4 Hz,
0.13H), 4.1 – 4.0 (m, 2H), 3.7 (d, J = 11.2 Hz, 1H), 3.0 (d, J =
15.6 Hz, 1H), 2.8 (d, J = 15.7 Hz, 1H). HPLC (254 nm, system
A) tR = 0.5 min. MS (ESI, SIR) m/z (%) 302 (100%), 301 (19%),
300 (8%). MS (ESI, SIR) [D1]-37 (88%), [D0]-37 (2%).
MeOD) δ 7.2 (td, J = 8.2, 8.2, 6.9 Hz, 1H), 6.6 (s, 0.09H), 6.6 –
6.5 (m, 0.63H).
1
2
3
4
5
6
7
8
4,6-[D2]-o-Cresol ([D2]-45) was prepared from o-cresol (0.1
mmol, 10.8 mg) according to the General Procedure A for 6 d
at 75 °C (100 µmol, 100% yield, 64% (4-d) / 38% (2-d)
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.0 (s,
1H), 6.6 (dt, J = 7.6, 0.7, 0.7 Hz, 0.04H), 6.6 – 6.6 (m, 0.28H),
6.6 (dq, J = 8.1, 0.6, 0.6, 0.6 Hz, 0.13H), 2.3 (s, 3H).
2,4,6-[D3]-Melatonin ([D3]-38) was prepared from melatonin
(0.1 mmol, 23.2 mg) according to the General Procedure A for
1 d at 75 °C (100 µmol, 100% yield, 97% deuterium
incorporation according to 1H NMR; 98% deuterium
incorporation according to MS). 1H NMR (400 MHz, MeOD) δ
7.2 (s, 1H), 7.1 – 7.0 (m, 0.06H), 6.8 (d, J = 8.8 Hz, 0.03H), 3.8
(s, 3H), 3.5 (t, J = 7.3 Hz, 2H), 3.0 – 2.8 (m, 2H), 1.9 (s, 3H).
HPLC (254 nm, system A) tR = 3.5 min. MS (ESI, SIR) m/z (%)
234 (100%), 233 (5%), 232 (0.1%), 231 (0.0%). MS (ESI, SIR)
[D3]-38 (95%), [D2]-38 (5%), [D1]-38 (0%), [D0]-38 (0%).
2,6-[D2]-3,4-Dimethylphenol ([D2]-46) was prepared from 3,4-
dimethylphenol (0.1 mmol, 12.2 mg) according to the General
Procedure A for 6 d at 75 °C (100 µmol, 100% yield, 95%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.5 (p,
J = 0.7 Hz, 0.03H), 6.4 (p, J = 0.7 Hz, 0.07H), 2.2 (s, 3H).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4,6-[D3]-3,5-Dimethylphenol ([D3]-47) was prepared from
3,5-dimethylphenol (0.1 mmol, 12.2 mg) according to the
General Procedure A for 6 d at 75 °C (100 µmol, 100% yield,
97% deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
6.9 (s, 1H), 6.6 (s, 0.05H), 6.5 (d, J = 8.1 Hz, 0.06H), 2.2 (t, J =
0.4 Hz, 3H), 2.2 (d, J = 0.6 Hz, 3H).
2,4,6-[D3]-Serotonin hydrochloride ([D3]-39) was prepared
from serotonin-HCl (0.086 mmol, 18.2 mg) according to the
General Procedure A for 1 d at 75 °C (81 µmol, 95% yield, 95%
(4-d, 6-d) / 90% (2-d) deuterium incorporation according to 1H
NMR; 93% deuterium incorporation according to MS). The
deuterium incorporation and yield was determined by 1H NMR
analysis of the mixture in presence of ethylene carbonate as an
2,4-[D2]-Estradiol ([D2]-48) was prepared from estradiol (0.1
mmol, 27.2 mg) according to the General Procedure A for 6 d
at 75 °C (100 µmol, 100% yield, 71% (4-d) / 55% (2-d)
deuterium incorporation according to 1H NMR; 62% deuterium
incorporation according to MS). CDCl3 (1 mL) was used as a
1
internal standard (1 M in d4-MeOD, 21.4 µL, 21.4 µmol). H
NMR (400 MHz, MeOD) δ 7.2 (s, 1H), 7.1 (d, J = 0.8 Hz,
0.10H), 7.0 (d, J = 0.6 Hz, 0.05H), 6.7 (d, J = 8.7 Hz, 0.05H),
3.2 (t, J = 7.3 Hz, 2H), 3.1 (ddd, J = 0.9, 7.1, 7.9 Hz, 2H). HPLC
(254 nm, system A) tR = 0.5 min. MS (ESI, SIR) m/z (%) 180
(100%), 179 (22%), 178 (3%), 177 (0.0%). MS (ESI, SIR) [D3]-
39 (79%), [D2]-39 (18%), [D1]-39 (2%), [D0]-39 (0%).
1
co-solvent. H NMR (400 MHz, MeOD) δ 7.1 – 7.1 (m, 1H),
6.6 (d, J = 8.5 Hz, 0.49H), 6.5 (t, J = 1.2 Hz, 0.31H), 3.7 (t, J =
8.6 Hz, 1H), 3.0 – 2.7 (m, 2H), 2.3 (dtd, J = 2.6, 4.2, 13.3 Hz,
1H), 2.1 (td, J = 4.3, 11.1 Hz, 1H), 2.0 (dtd, J = 5.7, 9.3, 13.2
Hz, 1H), 2.0 – 1.9 (m, 1H), 1.9 – 1.8 (m, 1H), 1.8 – 1.6 (m, 1H),
1.6 – 1.3 (m, 3H), 1.2 – 1.1 (m, 3H), 0.8 (d, J = 0.6 Hz, 3H).
HPLC (254 nm, system A) tR = 6.9 min. MS (ESI, SIR) m/z (%)
256 (100%), 257 (82%), 255 (25%). MS (ESI, SIR) [D2]-48
(38%), [D1]-48 (49%), [D0]-48 (13%).
6,8-[D2]-Chrysin ([D2]-40) was prepared from chrysin (0.1
mmol, 25.4 mg) according to the General Procedure A for 3 d
at 75 °C (100 µmol, 100% yield, 97% deuterium incorporation
according to 1H NMR; 87% deuterium incorporation according
to MS). d6-DMSO (1 mL) and CDCl3 (1 mL) were used as co-
solvents. 1H NMR (400 MHz, MeOD) δ 8.0 – 8.0 (m, 2H), 7.6
– 7.5 (m, 3H), 6.8 (s, 1H), 6.5 (s, 0.03H), 6.3 (s, 0.03H). HPLC
(254 nm, system A) tR = 7.2 min. MS (ESI, SIR) m/z (%) 257
(100%), 256 (29%), 255 (2%). MS (ESI, SIR) [D2]-40 (76%),
[D1]-40 (23%), [D0]-40 (1%).
2,4,6-[D3]-Phenol ([D3]-49) was prepared from phenol (0.1
mmol, 9.4 mg) according to the General Procedure A for 3 d at
95 °C (100 µmol, 100% yield, 95% (4-d) / 88% (2,6-d2)
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.2 (t,
J = 1.7, 1.7 Hz, 1H), 6.8 (d, J = 7.4 Hz, 0.02H), 6.8 (d, J = 8.6
Hz, 0.12H).
2,4,6-[D3]-Aniline ([D3]-50) was prepared from aniline (0.1
mmol, 9.3 mg) according to the General Procedure A for 3 d at
95 °C (100 µmol, 100% yield, 90% (4-d) / 70% (2,6-d2)
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.1 (d,
J = 4.0 Hz, 2H), 6.8 (d, J = 8.4 Hz, 1H), 6.7 (td, J = 7.4, 7.4, 1.1
Hz, 0.70H).
4,6-[D2]-p-Cresol ([D3]-41) was prepared from p-cresol (0.1
mmol, 10.8 mg) according to the General Procedure A for 6 d
at 75 °C (100 µmol, 100% yield, 5% deuterium incorporation).
1H NMR (400 MHz, MeOD) δ 7.0 – 6.9 (m, 2H), 6.7 – 6.6 (m,
1.78H), 2.2 (d, J = 0.7 Hz, 3H).
2,6-[D2]-4-(tert-Butyl)phenol ([D2]-42) was prepared from 4-
(tert-butyl)phenol (0.1 mmol, 15.0 mg) according to the
General Procedure A for 6 d at 75 °C (100 µmol, 100% yield,
23% deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
7.2 – 7.2 (m, 2H), 6.8 – 6.7 (m, 1.66H), 1.3 (s, 12H).
2,4,6-[D3]-Anisole ([D3]-51) was prepared from anisole (0.1
mmol, 10.8 mg) according to the General Procedure A for 5 d
at 95 °C (80 µmol, 80% yield, 22% deuterium incorporation).
1H NMR (400 MHz, MeOD) δ 7.3 – 7.2 (m, 1H), 7.0 – 6.9 (m,
2.43H), 3.8 (s, 3H).
2,4,6-[D3]-m-Cresol ([D3]-43) was prepared from m-cresol (0.1
mmol, 10.8 mg) according to the General Procedure A for 6 d
at 75 °C (100 µmol, 100% yield, 96% (4-d) / 87% (2-d) / 72%
(6-d) deuterium incorporation). 1H NMR (400 MHz, MeOD) δ
7.0 (tdt, J = 3.3, 3.3, 1.5, 0.8, 0.8 Hz, 1H), 7.0 – 6.9 (m, 1H),
6.7 (d, J = 8.0 Hz, 0.62H), 6.8 – 6.7 (m, 0.36H), 2.2 (d, J = 0.7
Hz, 3H).
1,3,6,8-[D4]-Carbazole ([D4]-52) was prepared from carbazole
(0.1 mmol, 16.7 mg) according to the General Procedure A for
4 d at 95 °C (95 µmol, 95% yield, 43% (1,8-d2) / 78% (3,6-d2)
deuterium incorporation). CDCl3 (1 mL) was used as a co-
solvent. H NMR (400 MHz, MeOD) δ 8.1 – 8.0 (m, 2H), 7.4
(dd, J = 8.2, 0.8 Hz, 1.26H), 7.4 – 7.3 (m, 2H), 7.2 (ddd, J = 7.9,
1
7.0, 1.0 Hz, 0.44H).
2,4,6-[D3]-3-Fluorophenol ([D3]-44) was prepared from 3-
fluorophenol (0.1 mmol, 11.2 mg) according to the General
Procedure A for 6 d at 75 °C (99 µmol, 99% yield, 91% (4,6-
3,3’,7,7’,8,8’-[D4]-1,1'-Binaphthyl-2,2'-diol ([D6]-53) was
prepared from 1,1'-binaphthyl-2,2'-diol (0.1 mmol, 28.6 mg)
according to the General Procedure A for 4 d at 95 °C (100
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Page 8 of 11
µmol, 100% yield, 14% (1,1’-d2) / 26% (7,7’-d2) / 49% (8,8’-
experiment a 1HNMR of the reaction mixture was recorded after
1
2
3
4
5
6
7
8
d2) deuterium incorporation). CDCl3 (1 mL) was used as a co-
solvent. 1H NMR (400 MHz, MeOD) δ 7.9 (d, J = 8.9 Hz, 2H),
7.9 – 7.8 (m, 2H), 7.3 (d, J = 8.9 Hz, 1.68H), 7.3 – 7.2 (m,
1.39H), 7.2 (tdd, J = 6.8, 6.8, 3.2, 1.4 Hz, 1.93H), 7.1 – 7.0 (m,
1.08H).
either 4 h at 60 °C (88 µmol, 88% yield, 95% deuterium
incorporation) or 24 h at 60 °C (66 µmol, 66% yield, 97%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 6.0 (s,
0.15H), 3.7 (s, 6H), 1.3 – 1.2 (m, 3H), 1.1 (s, 9H), 1.1 – 1.1 (m,
9H). The data are in accordance with those reported in
literature.36
6,8-[D2]-Neohesperidine dihydrochalcone ([D2]-54) was
prepared from neohesperidine dihydrochalcone (0.1 mmol, 61.2
mg) according to the General Procedure A for 3 d at rt (90 µmol,
90% yield, 92% deuterium incorporation according to 1H NMR;
59% deuterium incorporation according to MS). d6-DMSO (1
2,4,6-[D3]-tert-Butyl(3,5-dimethoxyphenoxy)diphenylsilane
([D3]-57c)
was
prepared
from
tert-butyl(3,5-dimethoxyphenoxy)diphenylsilane (0.1 mmol,
39.3 mg) according to the General Procedure A. A 1HNMR of
the reaction mixture was recorded after either 5 h at rt (100
µmol, 100% yield, 97% deuterium incorporation) 30 h at rt (98
µmol, 98% yield, 97% deuterium incorporation). In a second
experiment a 1HNMR of the reaction mixture was recorded after
either 4 h at 60 °C (94 µmol, 94% yield, 97% deuterium
incorporation) or 24 h at 60 °C (73 µmol, 73% yield, 97%
deuterium incorporation). 1H NMR (400 MHz, MeOD) δ 7.7 –
7.7 (m, 4H), 7.5 – 7.3 (m, 6H), 6.0 (s, 0.02H), 5.9 (s, 0.04H),
3.5 (s, 6H), 1.1 (s, 9H). The data are in accordance with those
reported in literature.37
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mL) was used as a co-solvent. H NMR (400 MHz, MeOD) δ
6.8 (d, J = 8.2 Hz, 1H), 6.7 (d, J = 2.1 Hz, 1H), 6.7 (dd, J = 2.1,
8.2 Hz, 1H), 6.1 (s, 0.15H), 5.3 (d, J = 1.7 Hz, 1H), 5.0 (d, J =
7.4 Hz, 1H), 4.0 – 3.9 (m, 3H), 3.8 (s, 3H), 3.8 – 3.6 (m, 4H),
3.5 – 3.4 (m, 3H), 3.3 – 3.3 (m, 2H), 2.8 (dd, J = 6.9, 8.7 Hz,
2H), 1.3 (d, J = 6.2 Hz, 3H). HPLC (254 nm, system A) tR = 5.5
min. MS (ESI, SIR) m/z (%) [M-Rha]+ 307 (100%), 306 (94%),
305 (46%). MS (ESI, SIR) [D2]-54 (35%), [D1]-54 (44%), [D0]-
54 (21%).
2,4,6-[D3]-Piceid ([D3]-55) was prepared from piceid (0.1
mmol, 39.0 mg) according to the General Procedure A for 1 d
at 40 °C (97 µmol, 97% yield, 97% deuterium incorporation
according to 1H NMR; 93% deuterium incorporation according
Large scale reactions:
2,4,6-[D3]-Resveratrol ([D3]-7) was prepared from resveratrol
(1.0 mmol, 288 mg) according to the General Procedure B for
4 h at rt. The solvent was partly removed in vacuo, then, EtOAc
and sat. NaHCO3 (aq.) was added and the reaction mixture
extracted with EtOAc (3x). The organic phases were combined,
dried over Na2SO4 and the solvent was removed in vacuo to
obtain the clean product as a yellowish solid (0.99 mmol, 231
mg, 100% yield, 97% deuterium incorporation, starting material
1
to MS). H NMR (400 MHz, MeOD) δ 7.5 – 7.3 (m, 2H), 7.0
(d, J = 16.3 Hz, 1H), 6.9 (d, J = 16.3 Hz, 1H), 6.8 – 6.7 (m, 2H),
6.7 – 6.6 (m, 0.05H), 6.5 (s, 0.07H), 4.0 (dd, J = 2.2, 12.1 Hz,
1H), 3.7 (dd, J = 5.8, 12.1 Hz, 1H), 3.6 – 3.4 (m, 4H). HPLC
(254 nm, system A) tR = 2.8 min. MS (ESI, SIR) m/z (%) [M-
Glc]+ 232 (100%), 231 (25%), 230 (3%), 229 (0.0%). MS (ESI,
SIR) [D3]-55 (79%), [D2]-55 (20%), [D1]-55 (1%), [D0]-55
(0%).
1
recovered). H NMR (400 MHz, MeOD) δ 7.4 – 7.3 (m, 2H),
7.0 (d, J = 16.3 Hz, 1H), 6.9 – 6.8 (m, 3H), 6.5 (s, 0.08H), 6.2
(s, 0.05H). 13C NMR (101 MHz, MeOD) δ 158.1, 157.0, 139.7,
128.0, 127.4, 125.5, 115.1. HPLC (254 nm, system A): tR= 6.5
min, purity: >95%. HRMS (ESI) m/z: [M - H]- Calcd for
6,8-[D2]-Hesperidine ([D2]-56) was prepared from hesperidine
(0.1 mmol, 61.0 mg) according to the General Procedure A for
4 weeks at 40 °C (75 µmol, 75% yield, 73% deuterium
incorporation according to 1H NMR; 67% deuterium
incorporation according to MS). 1H NMR (400 MHz, MeOD) δ
7.0 – 6.8 (m, 3H), 6.1 (dd, J = 1.2, 5.4 Hz, 0.54H), 5.4 (td, J =
4.2, 7.3 Hz, 1H), 4.9 (dd, J = 4.0, 7.5 Hz, 1H), 4.5 (d, J = 1.7
Hz, 1H), 3.8 – 3.8 (m, 1H), 3.8 (s, 3H), 3.7 (ddd, J = 1.7, 3.5,
9.3 Hz, 1H), 3.6 – 3.4 (m, 4H), 3.3 – 3.1 (m, 5H), 1.1 (dd, J =
3.0, 6.2 Hz, 3H). HPLC (254 nm, system A) tR = 4.1 min. MS
(ESI, SIR) m/z (%) [M-Rut]+ 305 (100%), 304 (72%), 303
(33%). MS (ESI, SIR) [D2]-56 (45%), [D1]-56 (41%), [D0]-56
(14%).
-
C14H8D3O3 : 230.0892; Found 230.0902.
6,8-[D2]-Neohesperidine dihydrochalcone ([D2]-54) was
prepared from neohesperidine dihydrochalcone (1 mmol, 612
mg) according to the General Procedure B for 3 d at rt. d6-
DMSO (1 mL) was used as a co-solvent. After 3 d, the reaction
was stopped by addition of one drop of sat. NaHCO3 (aq.). After
subsequent syringe filtration and reduction of the solvent in
vacuo, the clean product was obtained as a white powder (0.97
mmol, 598 mg, 97% yield, 94% deuterium incorporation,
starting material recovered). 1H NMR (400 MHz, MeOD) δ 6.8
(d, J = 8.2 Hz, 1H), 6.7 (d, J = 2.1 Hz, 1H), 6.7 (dd, J = 2.1, 8.2
Hz, 1H), 6.1 (s, 0.13H), 5.3 (d, J = 1.7 Hz, 1H), 5.0 (d, J = 7.4
Hz, 1H), 4.0 – 3.9 (m, 3H), 3.8 (s, 3H), 3.8 – 3.6 (m, 4H), 3.5 –
3.4 (m, 3H), 3.3 – 3.3 (m, 2H), 2.8 (dd, J = 6.9, 8.7 Hz, 2H), 1.3
(d, J = 6.2 Hz, 3H). 13C NMR (101 MHz, MeOD) δ 205.5,
163.9, 163.2, 146.0, 145.9, 134.6, 119.1, 115.1, 111.4, 105.4,
101.0, 97.9, 94.8, 77.7, 77.4, 76.7, 72.5, 70.8, 70.7, 69.8, 68.5,
60.9, 55.1, 45.9, 30.0, 16.8. HPLC (254 nm, system A): tR= 4.9
min, purity: >95%. HRMS (ESI) m/z: [M + H]+ molecular
weight could not be calculated due to fragmentation. m/z (%)
615.2253 (100%), 616.2287 (35%), 617.2311 (5%).
2,4,6-[D3]-tert-Butyl(3,5-dimethoxyphenoxy)dimethylsilane
([D3]-57a)
was
prepared
from
tert-butyl(3,5-dimethoxyphenoxy)dimethylsilane (0.1 mmol,
26.8 mg) according to the General Procedure A. A 1HNMR of
the reaction mixture was recorded after either 3 h (91 µmol,
91% yield, 95% deuterium incorporation), 5 h (83 µmol, 83%
yield, 95% deuterium incorporation) or 30 h at rt (45 µmol, 45%
yield, 97% deuterium incorporation). 1H NMR (400 MHz,
MeOD) δ 6.0 (s, 0.15H), 3.7 (s, 6H), 1.0 (s, 8H), 0.2 (s, 6H).
The data are in accordance with those reported in literature.35
2,4,6-[D3]-(3,5-Dimethoxyphenoxy)triisopropylsilane ([D3]-
57b)
was
prepared
from
2,4,6-[D3]-Piceid ([D3]-55) was prepared from piceid (1 mmol,
390 mg) according to the General Procedure B for 1 d at 40 °C.
The solvent was removed in vacuo and residue was purified by
trituration with CH3CN to obtain the product as a white powder
(0.84 mmol, 347 mg, 84 % yield, 95% purity, 97% deuterium
incorporation, starting material recovered). The product can
(3,5-dimethoxyphenoxy)triisopropylsilane (0.1 mmol, 31.1
1
mg) according to the General Procedure A. A HNMR of the
reaction mixture was recorded after either 5 h at rt (98 µmol,
98% yield, 97% deuterium incorporation), 30 h at rt (95 µmol,
95% yield, 97% deuterium incorporation). In a second
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1
The Journal of Organic Chemistry
additionally be purified via preparative HPLC (CH3CN:H2O –
5:9585:15 over 15 min) to obtain the clean product as a white
Notes
A patent application has been filed related to the content of the
present manuscript.
2
powder (>>95% purity, 97% deuterium incorporation). 1H
NMR (400 MHz, MeOD) δ 7.5 – 7.3 (m, 2H), 7.0 (d, J = 16.3
Hz, 1H), 6.9 (d, J = 16.3 Hz, 1H), 6.8 – 6.7 (m, 2H), 6.7 – 6.6
(m, 0.03H), 6.5 (s, 0.04H), 4.0 (dd, J = 2.2, 12.1 Hz, 1H), 3.7
(dd, J = 5.8, 12.1 Hz, 1H), 3.6 – 3.4 (m, 4H). 13C NMR (101
MHz, MeOD) δ 159.0, 158.1, 157.1, 139.8, 128.9, 128.5, 127.5,
125.1, 115.0, 101.0, 76.8, 73.5, 70.0, 61.2, 26.3. HPLC (254
nm, system B): tR= 6.7 min, purity: >95%. HRMS (ESI) m/z:
3
4
5
6
7
8
ACKNOWLEDGMENT
O.F., and A.H. thank the GRK1910 and the Graduate School
Molecular Science for support of this work. O.F. thanks Hendrik
Lepper for his assistance in the laboratory.
REFERENCES
9
[M + H]+ Calcd for C20H18D3O8 : 394.1576; Found 394.1585.
+
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C6H4)(CO) 2 (Ir–Ir) and Related Complexes. Synthesis 2019, 51,
2409–2429. (e) Valero, M.; Kruissink, T.; Blass, J.; Weck, R.;
Güssregen, S.; Plowright, A. T.; Derdau, V. C−H Functionalization
– Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen
Isotope Exchange Competition Reactions. Angew. Chem. Int. Ed.
2020, 59, 5626–5631. (f) Valero, M.; Bouzouita, D.; Palazzolo, A.;
Atzrodt, J.; Dugave, C.; Tricard, S.; Feuillastre, S.; Pieters, G.;
Chaudret, B.; Derdau, V. NHC‐Stabilized Iridium Nanoparticles as
Catalysts in Hydrogen Isotope Exchange Reactions of Anilines.
Ang. Chem. Int. Ed. 2020, 59, 3517–3522.
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3,5-[D2]-3-(2,4,6-Trimethoxybenzylidene)indolin-2-one ([D2]-
IC261,
[D2]-34)
was
prepared
from
3-(2,4,6-
trimethoxybenzylidene)indolin-2-one (IC261) (1 mmol, 311
mg, E/Z : 10:1) according to the General Procedure B for 1 d at
75 °C (100 µmol, 100% yield, 97% deuterium incorporation).
CDCl3 (1 mL) was used as a co-solvent. After 1 d, the reaction
was stopped by addition of one drop of sat. NaHCO3 (aq.). After
subsequent syringe filtration and reduction of the solvent in
vacuo, the clean product was obtained as a yellow powder (0.91
mmol, 285 mg, 91% yield, 96% deuterium incorporation, E/Z :
10:1, starting material recovered). 1H NMR (400 MHz, CDCl3)
δ 7.8 (s, 1H), 7.2 (td, J = 1.3, 7.6 Hz, 1H), 7.0 – 7.0 (m, 1H), 6.9
(ddd, J = 1.2, 6.6, 7.7 Hz, 2H), 6.2 (s, 0.09H), 3.9 (s, 3H), 3.8
(s, 6H). 13C NMR (101 MHz, CDCl3) δ 170.6, 163.0, 159.7,
140.7, 129.0, 128.4, 124.4, 121.4, 109.3, 90.3, 55.5. HPLC (254
nm, system A): tR= 7.4 min (E) and 7.8 min (Z), purity: >95%.
+
HRMS (ESI) m/z: [M + H]+ Calcd for C18H16D2NO4 :
314.1356; Found 314.1351. The data are in accordance with
those reported in literature.34
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Synthesis, kinetic data, stability assay, alternative deuteration
procedures, dependence of 1H NMR shift and proton
exchangeability
AUTHOR INFORMATION
Corresponding Author
Markus R. Heinrich – Department of Chemistry and Pharmacy,
Pharmaceutical
Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen,
Germany; ORCID: 0000-0001-7113-2025; Email:
Chemistry,
Friedrich-Alexander-Universität
markus.heinrich@fau.de
Authors
Oliver Fischer – Department of Chemistry and Pharmacy,
Phamaceutical Chemistry, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen,
Germany; ORCID: 0000-0002-2101-6939
Anja Hubert – Department of Chemistry and Pharmacy,
Pharmceutical
Chemistry,
Friedrich-Alexander-Universität
Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen,
Germany.
Author Contributions
(6) (a) Pieters, G.; Taglang, C.; Bonnefille, E.; Gutmann, T.;
Puente, C.; Berthet, J.-C.; Dugave, C.; Chaudret, B.; Rousseau, B.
Regioselective and Stereospecific Deuteration of Bioactive Aza
Compounds by the Use of Ruthenium Nanoparticles. Angew.
Chem. Int. Ed. 2014, 53, 230–234. (b) Hale, L. V. A.; Szymczak,
O. F. performed the research, designed, synthesized, analyzed the
data, and wrote the manuscript. A. H. performed the research and
synthesized. M. R. H. designed the research, analyzed the data, and
wrote the manuscript.
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OH
OH
OH
OH
HClO4
(5 mol%)
D
O
O
HO
HO
HO
HO
[97]
O
O
OH
D
D
OH [97]
[97]
CH3O or CD3O
D
D
40 °C, 1 d
OH
OH
97% (NMR)
facile procedure
broad scope
high atom efficiency
cheap and green reagents
metal-free
84% (isol., 1 mmol)
3]-piceid
55 examples
piceid
D
[
+
(71%-quant.)
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