Selective Ru(0)-catalyzed deuteration of electron-rich and electron-poor nitrogen-containing heterocycles

Article abstract of DOI:10.1021/jo300219v

A highly selective Ru₃(CO)₁₂-catalyzed deuteration method using t-BuOD as deuterium source is reported. Electron-rich and electron-poor N-heteroarenes such as indoles, azaindoles, deazapurines, benzimidazole, quinolines, isoquinolines, and pyridines were efficiently deuterated at specific positions with high selectivity; in most cases, deuterium incorporation was close to the theoretically possible values. To further increase deuteration degrees, several cycles of the reaction protocol can be carried out which gave superior deuteration degrees employing a much lower excess of deuterating agent compared to established protocols. It was proved that the same protocol can in principle be applied to tritiation reactions important for radioactive labeling of bioactive molecules.

Full text of DOI:10.1021/jo300219v

Note
pubs.acs.org/joc
Selective Ru(0)-Catalyzed Deuteration of Electron-Rich and Electron-
Poor Nitrogen-Containing Heterocycles
Birgit Groll, Michael Schnurch,* and Marko D. Mihovilovic
̈
̈
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria
S
* Supporting Information
ABSTRACT: A highly selective Ru3(CO)12-catalyzed deuter-
ation method using t-BuOD as deuterium source is reported.
Electron-rich and electron-poor N-heteroarenes such as
indoles, azaindoles, deazapurines, benzimidazole, quinolines,
isoquinolines, and pyridines were efficiently deuterated at
specific positions with high selectivity; in most cases,
deuterium incorporation was close to the theoretically possible
values. To further increase deuteration degrees, several cycles
of the reaction protocol can be carried out which gave superior
deuteration degrees employing a much lower excess of
deuterating agent compared to established protocols. It was proved that the same protocol can in principle be applied to
tritiation reactions important for radioactive labeling of bioactive molecules.
itrogen-containing heterocycles are considered to be
privileged structures because of their occurrence in many
are required;11,14 (iv) high catalyst loadings and/or expensive
or difficult to access catalysts are used;12 (v) there is a narrow
substrate scope;16 and (vi) unselective deuteration leads to
different deuteration degrees (DDs) in the different posi-
tions.11,13−15 Hence, a more economic and generally applicable
method to obtain deuterated or tritiated N-heterocycles is of
high interest. Within this paper, we disclose a protocol which
works under neutral conditions, reduces the amount of
deuteration reagent required, proceeds relatively fast, and
shows high selectivity in most cases. Unfortunately, relatively
high catalyst loading (of a commercially available catalyst) and
elevated temperatures (115 °C) are still required.
Based on a recent report indicating the capability of
Ru3(CO)12 to insert into pyridine C−H bonds even though
in an unselective manner,18 we hypothesized that successful H−
D exchange could be implemented with this catalyst by
concomitantly employing a protic deuterated solvent. Indole
and isoquinoline were chosen as first prototype systems for
electron-rich and electron-poor heterocycles. Initially, 5 mol %
of Ru3(CO)12 and 5 equiv of t-BuOD19 per exchangeable
proton were used under argon atmosphere at 115 °C.20 After 3
h, selective incorporation of deuterium into positions 1 and 3
was observed with a DD of 77% and 80%, respectively
(determined via 1H NMR), an extent very close to the
theoretically possible values when employing the specified
amount of D source21 (Table 1, entry 1). Additionally, no side
products were observed. Decreasing the reaction temperature
led to a lower DD (see the Supporting Information). Other
deuterium sources such as D2O or MeOD led only to trace
N
natural products and synthetic compounds with interesting
biological activity.1 Deuterated derivatives thereof are of high
interest for mechanistic investigations leading to a better
understanding of synthetic transformations and enabling the
development of more efficient reaction conditions.2 Various
methods for the incorporation of deuterium were reported
previously,3 and the topic was recently reviewed.4 In addition,
tritiated compounds are of increasing importance for radio-
labeling of bioactive compounds in medicinal chemistry
applications.5,6 Hence, facile, fast, and efficient protocols for
the deuteration and tritiation5,6 of indole and pyridine
derivatives are of great value. A novel method to conduct
such transformations is reported in this contribution.
Transition metal catalyzed H−D/T exchange reactions are a
most attractive option. Pioneering examples for deuteration of
(hetero)arenes or alkanes were reported by the groups of
Garnett,7 Shilov,8 and Biddiscombe et al.9 using either gaseous
D2O,9 D2,10 or liquid D2O in combination with Fe, Co, Ni, Ru,
Rh, Pd, Ir, and Pt catalysts.7 Several examples for deuterations
of N-heterocycles were reported utilizing catalytic systems such
as Raney nickel,11 Pd/PVP (poly-N-vinylpyrolidone) colloid
catalyst systems,12 Crabtree’s catalyst,13 NaBD4-activated Rh,
Pt, or Pd catalysts,14 Pd or Pt metal surfaces,15 or CuI.16
Deuterium incorporation up to 95% was achieved in positions 1
and 3 of indole by heating indoles in D2O upon repetitive
application of the developed deuteration protocol.17 However,
it was not reported how many repetitive cycles had to be
applied to reach this high deuterium content.
Published protocols often suffer from certain limitations in
order to achieve high degrees of deuteration: (i) a large excess
of the deuteration reagent is required (>50 equiv);11−13 (ii)
basic or acidic additives are needed;16 (iii) long reaction times
Received: January 31, 2012
Published: April 12, 2012
© 2012 American Chemical Society
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Note
The outlined deuteration protocol can be carried out in
repetitive cycles in order to reach higher DDs. After the first
deuteration reaction, the deuteration reagent was removed, and
fresh t-BuOD and catalyst were added. Simple exchange of the
deuterium source for fresh material did not improve
deuteration grades, indicating catalyst inactivation after a
reaction cycle. The theoretical DD is 96.8% for a two-cycle
process with 5 equiv of t-BuOD in each cycle.21 This is
significantly higher compared to a single-step process using 10
equiv of deuteration reagent where a maximum of 90.9% DD
can be obtained. Two examples of this protocol were
performed (Table 2, compounds 1 and 15, conditions B). A
D-incorporation of 90% (indole) and 93% (isoquinoline) was
observed, closely approaching the theoretical value.
Table 1. Optimization of Deuteration Conditions on Indole
and Isoquinoline (Time = 3 h, Ru3(CO)12)
%D
entry
equiv per H
cat. (%)
T (°C)
indole
isoquinoline
1
2
3
4
5
6
5
5
115
115
115
115
115
115
77
76
52
63
71
83
80
24
30
60
73
85
5
2.5
5
1.25
2.5
3.75
10
5
5
5
amounts of deuterated products with indole as well as with
isoquinoline as substrate.
In an attempt to expand the methodology to aliphatic carbon
centers, we found that benzylic positions attached to an N-
heterocycle could be deuterated with high DDs (compounds
17−19) under slightly altered reaction conditions. The
capability of such systems to form a 5-membered metallacycle
intermediate after C−H activation was a critical requirement
(Scheme 1, lower part). In compounds 17 and 19, an
exchangeable pyridine position was present which was also
deuterated, but to a lesser extent compared to the benzylic
positions. This shows that on the investigated substrates
aliphatic C−H activation is preferred over aromatic (pyridine)
C−H activation. Interestingly, the 5-position on the pyridine
ring was also deuterated in compound 17, even to a higher
extent (51%) than the 6-position (22%), which was not
observed with any other pyridine derivatives.
Reactions were also carried out under microwave irradiation
(Table 2, conditions C). An excess of 10 equiv of t-BuOD per
deuteration position was identified as optimum for the
microwave-assisted protocol (see the Supporting Information
for details). Interestingly, electron-deficient compounds could
not be deuterated efficiently under these conditions even after
extensive optimization efforts (e.g., conditions C compound
15). The reason for the failure in these cases remains unclear.
In contrast, deuteration of electron-rich substrates proceeded
very well, and reaction times could be shortened to 15 min.
With the shorter microwave protocol, 5-nitroindole could be
deuterated with 45% DD, but only 25% of product was
obtained due to decomposition which required purification of
the crude material by column chromatography. Still, under
conventional heating this product was not obtained at all. For
benzimidazole, a decreased DD of 40% was obtained, and with
6-Cl-7-deazapurine no H−D exchange was observed at all, even
after 1 h in the microwave. These two substrates and the
deuterated electron-deficient compounds can be obtained using
the protocol where conventional heating is applied.
Finally, we investigated the possibility of using the presented
methodology for tritiation reactions based on the high
importance of radiolabeled compounds for medicinal applica-
tions.5,6 For that purpose, it is necessary to enable access to t-
BuOT. According to literature reports, CF3COOT was
employed in the synthesis of chiral methyl groups.5c We
hypothesized that CF3COOT would react with t-BuONa
leading to the more stable salts CF3COONa and t-BuOT. As
proof of principle, the corresponding reaction using commer-
cially available CF3COOD instead of CF3COOT was carried
out, and t-BuOD was formed successfully in a high DD. The so
formed t-BuOD was successfully applied in our deuteration
protocol (for details, see the Supporting Information). Since
the corresponding reaction works analogously using tritium
Lowering the catalyst loading to 1 mol % did not affect the
DD on indole; with this substrate, a DD of 37% was obtained
even without catalyst (data not shown). In the isoquinoline
series, deuteration was significantly more susceptible to changes
of catalyst loading: 2.5 mol % gave only 24% of deuterated
isoquinoline (entry 2). In general, the best results were
obtained when 5 mol % of catalyst was applied. In addition, the
amount of deuteration reagent was optimized. Increasing the
amount to 10 equiv of t-BuOD led to 85% deuteration on
isoquinoline and 83% on indole (entry 6). Further lowering the
amount of the deuterium source (entries 3−5) expectedly led
to lower DDs; however, in all cases, the observed deuterium
incorporation was close to the theoretically possible values.21
For subsequent reactions, 5 equiv of t-BuOD was as a
compromise between high deuterium incorporation and
economics.
The results of the substrate scope investigation are
summarized in Table 2. A reaction time of 30 min turned
out to be sufficient for indole and isoquinoline; however,
deuteration of substituted derivatives required longer times (up
to 3 h). Products were obtained in quantitative isolated yield
after purification in all cases (Table 2).
In the case of indoles (compounds 1−8), 7-azaindole
(compound 9) and deazapurine (compound 10) H−D
exchange takes place in β-position to the ring nitrogen,
representing the most electron-rich site. In the case of
benzimidazole, deuteration commences at position 2 (com-
pound 11). Introduction of methyl substituents into indoles in
positions 1 (compound 7) and 2 (compound 8) led to lower
DDs. In the case of nitroindoles (5- and 7-nitroindole),
decomposition and formation of a black tar was observed, and
no deuterated products were isolated. An additional N-atom in
the ring system had no significant effect on deuterium
incorporation (compounds 9 and 10).
The deuteration of electron-poor compounds (compounds
12−17) generally occurs in the α-position to the nitrogen
atom, again representing the most electron-rich site. Best
results were obtained on isoquinoline and pyridine (com-
pounds 12 and 15). 4-Aminopyridine showed significantly
lower D-incorporation, possibly due to the free amino group
competing with the ring nitrogen for complexation of the
catalyst (compound 14). Introducing a methyl group (3-
methylisoquinoline) led again to a lower DD (compound 16).
In this case, the steric bulk of the methyl group might disfavor
Ru−N complexation. Interestingly, other N-heterocycles such
as pyrimidine, pyrazole, pyridazine, and pyrrole were not
deuterated at all under these conditions. As expected,
(benzo)thiophene and (benzo)furan were not substrates for
this protocol.
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Note
Table 2. Substrate Scope of Deuterated Heterocycles
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Note
Table 2. continued
a
b
Method A: batch, T = 115 °C, time = 3 h, t-BuOD = 5 equiv/deuteration position, Ru3(CO)12 = 5 mol %. Method B: application of two cycles of
c
method A. Method C: microwave irradiation, T = 115 °C, time = 15 min, t-BuOD = 10 equiv/deuteration position, Ru3(CO)12 = 5 mol %.
d
e
Method D: batch, T = 140 °C, time = 24 h, t-BuOD = 5 equiv/deuteration position, Ru3(CO)12 = 5 mol %. Initially, the NH in these compounds
are exchanged for ND. However, in presence of small amounts of water (e.g., water in the NMR solvent) re-exchange to NH occurs.
Scheme 1. Proposed Mechanism
elaborated. DDs of above 80% could often be achieved within
15 min employing only 5 or 10 equiv of t-BuOD as deuterium
source. Additionally, it was demonstrated that DDs above 90%
can be achieved by repeating the deuteration step. In principal,
the presented methodology can also be extended to the
corresponding tritiation reactions, which is important for the
synthesis of radiolabeled compounds for medicinal applications.
EXPERIMENTAL SECTION
■
Deuteration on sp2-Systems. General Procedure for the
Preparation of Deuterated Compounds in Batch. Heteroarene
(0.5 mmol), Ru3(CO)12 (16 mg, 0.025 mmol), and t-BuOD (5
equiv/deuteration position) were added to a reaction vial with a
screw cap septum. The vial was flushed with argon several
times. The reaction mixture was then heated to 115 °C and
stirred at this temperature for 3 h. After the mixture was cooled
to rt, 10 mL of n-hexane was added, and the resulting solvent
mixture was evaporated (azeotropic distillation of t-BuOH/n-
1
hexane). Deuteration degrees were determined via H NMR.
In the case where multiple cycles were applied, the same amounts of
Ru3(CO)12 and t-BuOD were added after the evaporation step again,
and the reaction was repeated.
Because of the existence of several isotopomers by incomplete
deuteration and their interactions, signals in 13C spectra can split or
decrease in intensity. Since the assignment of the split signals to the
corresponding isotopomers is not trivial, only the chemical shift of the
most intense signal is reported, and these signals are marked with an
asterisk.
instead of deuterium, this demonstrates the principal feasibility
of tritiation reactions.
1,3-Dideutero-6-chloro-7-deazapurine (10): prepared via conven-
tional heating; amount of t-BuOD applied: 376 mg, 5 mmol = 5equiv/
D-position; 1H NMR (DMSO-d6) 6.33 (d, J = 3.13 Hz), 7.42 (s), 8.34
(s), 12.31 (s); 13C NMR (DMSO-d6): 99.7*, 117.5*, 129.2*, 151.2,
151.4*, 152.7.
A plausible mechanism of the deuteration process is
displayed in Scheme 1 for a pyridine deuteration (upper
part) as well as for the deuteration of an aliphatic position
(lower part). Initially, the catalyst is coordinated by the pyridine
nitrogen in both cases, which was already reported previously in
the literature.22 With pyridines as substrate, the metal insertion
takes place in the closest C−H bond, which is located in
position 2 since there is no possibility for the formation of a
usually favored 5-membered ruthenacycle. For the aliphatic
substrate in the lower part of Scheme 1, the insertion takes
place in the benzylic position giving rise to a favorable 5-
membered ruthenacycle.30 Then hydrogen is exchanged for
deuterium originating from the solvent (eventually via
reversible HD formation and alkoxide coordination). Finally,
reductive elimination leads to the deuterated target compound.
All of the steps are reversible, and an equilibrium of deuterated
and nondeuterated compounds is established.
In case of indole substrates, a different mechanism must be
operable since initial N-coordination of catalyst should rather
lead to insertion into the C2 C−H bond. However, insertion
takes obviously place in position 3. At this moment, we cannot
explain this unusual selectivity. Further mechanistic studies will
be carried out to elucidate this mechanism.
In conclusion, we have developed a protocol for selective
Ru(0)-catalyzed deuteration of both electron-rich and electron-
deficient N-heteroarenes as well as benzylic CH2 groups under
conventional heating; in addition, a very effective microwave-
promoted protocol for electron-rich N-heterocycles was also
1,2-Dideuterobenzimidazole (11):23 prepared via conventional
heating; amount of t-BuOD applied: 376 mg, 5 mmol = 5equiv/D-
1
position; H NMR (DMSO-d6): 7.11−7.28 (m), 7.52−7.66 (m), 8.27
(s); 13C NMR (DMSO-d6): 116.0, 122.7, 142.9*.
1,2-Dideuteropyridine (12):24 prepared via conventional heating;
amount of t-BuOD applied: 376 mg, 5 mmol = 5 equiv/D-position; 1H
NMR (CDCl3): 7.07 (d, J = 7.63 Hz), 7.46 (t, J = 7.63 Hz) 8.29−8.36
(m).
4-(Dideutero(phenyl)methyl)-1,5-dideuteropyridine (13):15 pre-
pared via conventional heating; amount of t-BuOD applied: 376 mg,
5 mmol = 5 equiv/D-position; 1H NMR (DMSO-d6): 4.00 (s), 6.89−
8.00 (m), 8.65−8.99 (m); 13C NMR (DMSO-d6): 125.0, 127.3, 129.5,
129.8, 140.4, 150.5*.
4-N,N-Dideuteroamino-1,5-dideuteropyridine (14): prepared via
conventional heating; amount of t-BuOD applied: 752 mg, 10 mmol, 5
equiv/D-position; 1H NMR (DMSO-d6) 6.03 (s), 6.49 (s), 8.00 (d, J =
5.48 Hz); 13C NMR (DMSO-d6): 110.3, 153.0, 156.0.
1,3-Dideuteroisoquinoline (15):15 prepared via conventional
heating using two subsequent steps; amount of t-BuOD applied: 2
× 376 mg, 5 mmol, 5 equiv/D-position; purification via column
chromatography (PE:EtOAc 10:1) 1H NMR (CDCl3) 7.38−8.18 (m),
8.53 (d, J = 5.67 Hz), 9.22−9.29 (m); 13C NMR (CDCl3): 120.6,
126.2, 126.7*, 127.7*, 128.9, 130.6*, 136.1, 143.3, 152.8.
1-Deutero-3-methylisoquinoline (16): prepared via conventional
heating; amount of t-BuOD applied: 188 mg, 2.5 mmol, = 5 equiv/D-
position; 1H NMR (CDCl3) 2.69 (s), 7.41−7.56 (m), 7.89 (d, J = 8.02
Hz), 9.15 (s); 13C NMR (CDCl3): 24.4, 118.6, 126.1, 126.4, 127.0,
127.6, 130.4, 136.7, 151.8, 152.1.
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Note
1
General Procedure for the Preparation of Deuterated
Compounds in the Microwave. Heteroarene (0.5 mmol),
Ru3(CO)12 (16 mg, 0.025 mmol), and t-BuOD (10 equiv/deuteration
position) were added to a microwave vial. The vial was sealed and
subsequently flushed with argon. The reaction mixture was then
heated in a Biotage Initiator Sixty microwave to 115 °C for 15 min.
The temperature was measured by an external IR-sensor. After the
mixture was cooled to rt, 10 mL of n-hexane was added (azeotropic
distillation of t-BuOH/n-hexane), and the resulting solvent mixture
BuOD applied: 940 mg, 12.5 mmol, = 5 equiv/D-position; H NMR
(CDCl3) 1.96 (s), 4.26 (s), 4.50−4.63 (m), 6.41−6.55 (m), 7.05−7.38
(m), 7.83−8.02 (m); 13C NMR (CDCl3): 17.2, 133.1, 116.7, 127.4,
128.1, 128.8, 137.0*, 140.2, 145.7*, 156.9.
N-(Dideutero(phenyl)methyl)-N-deutero-1-methyl-1H-benzo[d]-
imidazol-2-amine (18):31 prepared via conventional heating; amount
of t-BuOD applied; 564 mg, 7.5 mmol, = 5 equiv/D-position; 1H
NMR (CDCl3) 3.38 (s), 4.60−4.71 (m), 4.78−4.95 (m), 5.26 (s),
6.82−7.65 (m); 13C NMR (CDCl3): 28.4, 107.3, 116.4, 119.8, 121.4,
127.7, 128.1, 128.8*, 135.3, 138.8*, 142.3, 154.7.
1
was evaporated. Deuteration degrees were determined via H NMR.
1,3-Dideuteroindole (1):25 prepared via microwave protocol;
amount of t-BuOD applied 752 mg, 10 mmol = 10 equiv/D-position;
1H NMR (CDCl3) 6.53 (d, J = 2.93 Hz), 7.01−7.36 (m), 7.57−7.70
(m); deuterium NMR (CHCl3) 6.53 (s), 8.16 (s); 13C NMR (CDCl3)
102.9*, 111.4*, 120.1, 121.0*, 122.2, 124.3*, 128.0*, 136.0*.
1,3-Dideutero-5-nitroindole (2): prepared via microwave protocol;
amount of t-BuOD applied: 752 mg, 10 mmol = 10 equiv/D-position;
1H NMR (CDCl3) 6.69−6.79 (m), 7.31−7.52 (m), 8.12 (dd, J = 9.00
Hz, J = 2.35 Hz), 8.62 (d, J = 2.15 Hz); 13C NMR (CDCl3): 105.5*,
111.4, 118.1, 118.4*, 127.6, 127.7*, 139.1, 142.3*.
2-(1,1-Dideutero-2-phenylethyl)-6-deutero-3-methylpyridine
(19):32 prepared via conventional heating; amount of t-BuOD applied:
564 mg, 7.5 mmol = 5 equiv/D-position; 1H NMR (CDCl3) 2.46 (s),
3.06 (s), 6.95−7.44 (m), 8.44 (d, J = 3.91 Hz); 13C NMR (CDCl3):
19.0, 35.3*, 121.6*, 126.2, 128.8, 128.9, 131.5, 137.9, 142.3, 147.1*,
159.8.
Synthesis of t-BuOD via CF3COOD. A mixture of sodium tert-
butoxide (480 mg, 5 mmol) and CF3COOD (575 mg, 5 mmol) was
stirred at room temperature for 1 h. The product was purified via
Kugelrohr distillation and obtained in 31% yield (147 mg).
1,3-Dideutero-5-methoxyindole (3): prepared via microwave
protocol; amount of t-BuOD applied: 752 mg, 10 mmol = 10equiv/
ASSOCIATED CONTENT
■
1
D-position; H NMR (CDCl3) 3.99 (s), 6.62 (d, J = 2.54 Hz), 7.01
S
* Supporting Information
Reaction optimization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(dd, J = 8.70 Hz, J = 2.45 Hz), 7.20−7.42 (m), 8.17 (s); 13C NMR
(CDCl3) 56.1, 102.4*, 102.5*, 112.1*, 112.5, 125.2*, 128.4*, 131.2*,
154.3.
1,3-Dideutero-5-chloroindole (4):26 prepared via microwave
protocol; amount of t-BuOD applied: 752 mg, 10 mmol = 10
equiv/D-position; purification via column chromatography (PE:EtOAc
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mschnuerch@ioc.tuwien.ac.at.
1
5:1); H NMR (CDCl3) 6.47 (d, J = 3.13 Hz), 7.06−7.24 (m), 7.61
(d, J = 1.76 Hz), 8.03 (s); 13C NMR (CDCl3): 102.6*, 112.3, 120.3,
122.5, 125.6*, 125.8*, 129.1*, 134.2*
Notes
1,3-Dideutero-6-chloroindole (5): prepared via microwave proto-
col; amount of t-BuOD applied: 752 mg, 10 mmol = 10 equiv/D-
The authors declare no competing financial interest.
1
position; H NMR (CDCl3) 6.56 (d, J = 2.93 Hz), 7.07−7.23 (m),
ACKNOWLEDGMENTS
7.37 (d, J = 1.76 Hz), 7.58 (d, J = 8.41), 8.05 (s); 13C NMR (CDCl3):
103.0*, 111.2*, 120.8*, 121.8, 125.0*, 126.6*, 128.1, 136.4*.
1,3-Dideutero-7-Chloroindole (6): prepared via microwave proto-
col; amount of t-BuOD applied: 752 mg, 10 mmol = 10 equiv/D-
position; purification via column chromatography (PE:EtOAc 5:1); 1H
NMR (CDCl3) 6.62 (d, J = 3.13 Hz), 7.01−7.32 (m), 7.23 (d, J = 3.33
Hz), 8.34 (s); 13C NMR (CDCl3): 104.0*, 116.9, 119.6, 120.9, 121.6,
125.0*, 129.5*, 133.4*.
■
Funding for this research by the Austrian Science Fund (FWF,
project P21202-N17) is gratefully acknowledged
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■
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Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 5837−
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1
equiv/D-position; H NMR (CDCl3) 2.44 (s), 6.26 (m), 7.10−7.34
(m), 7.50−7.66 (m); 13C NMR (CDCl3): 14.0, 100.7, 110.5, 119.9,
121.2, 129.4, 135.4, 136.3.
1,3-Dideutero-7-azaindole (9):29 prepared via microwave protocol;
amount of t-BuOD applied: 752 mg, 10 mmol =10 equiv/D-position;
1
purification via column chromatography (PE:EtOAc 10:1); H NMR
(CDCl3) 6.49 (d, J = 3.52 Hz), 7.01−7.17 (m), 7.38 (s), 7.96 (d, J =
7.83 Hz), 8.35 (d, J = 3.91 Hz), 12.02 (s); 13C NMR (CDCl3): 100.5*,
115.7, 120.6*, 125.4*, 129.1, 142.2, 148.8.
Deuteration on sp3-Systems. General Procedure. Substrate
(0.5 mmol), Ru3(CO)12 (16 mg, 0.025 mmol), and t-BuOD (5 equiv/
deuteration position) were added to a reaction vial with a screw cap
septum. The vial was flushed with argon several times. The reaction
mixture was then heated to 140 °C and stirred at this temperature for
24 h. After the mixture was cooled to rt, 10 mL of n-hexane was added,
and the resulting solvent mixture was evaporated (azeotropic
distillation of t-BuOH/n-hexane). Deuteration degrees were deter-
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mined via H NMR.
N-(Dideutero(phenyl)methyl)-N,5,6-trideutero-3-methylpyridin-
2-amine (17):30 prepared via conventional heating; amount of t-
4436
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exchangeable position. For details, see the Supporting Information.
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proton = 90.9%, 5 equiv = 83.3%, 3.75 equiv = 78.9%, two cycles 5
equiv each = 96.8%. For calculations, see the Supporting Information.
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