A convenient method for the Ru(0)-catalyzed regioselective deuteration of N-alkyl-substituted anilines

Article abstract of DOI:10.1016/j.tetlet.2014.07.071

A highly effective and operationally practical method for the regioselective deuteration of N-alkyl-substituted anilines employing Ru₃(CO)₁₂(≤1 mol %) as catalyst and D₂O as deuterium source was described. A variety of N-a

Full text of DOI:10.1016/j.tetlet.2014.07.071

Tetrahedron Letters 55 (2014) 5070–5073
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A convenient method for the Ru(0)-catalyzed regioselective
deuteration of N-alkyl-substituted anilines
Miao Zhan a, Hongxia Jiang a, Xuehai Pang b, Tao Zhang a, Ruixue Xu a, Lifeng Zhao a, Yu Liu a, Yu Gong b,
Yuanwei Chen a,b,
⇑
a State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
b Hinova Pharmaceuticals Inc, Suite 801, Building C1, #88 South KeYuan Road, Chengdu Tianfu Life Science Park, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly effective and operationally practical method for the regioselective deuteration of N-alkyl-substi-
tuted anilines employing Ru3(CO)12 (61 mol %) as catalyst and D2O as deuterium source was described. A
variety of N-alkyl-substituted anilines were efficiently deuterated (up to 98%) at the ortho and/or para
position with respect to the nitrogen at neutral conditions. Under the present conditions, deuterated ani-
lines can be easily obtained with simple extraction and evaporation. Substituents with aromatic methoxy
groups would not influence the selectivity compared to previous method.
Received 11 June 2014
Revised 8 July 2014
Accepted 21 July 2014
Available online 24 July 2014
Keywords:
H–D exchange
Ru3(CO)12
Chemoselectivity
Anilines
Ó 2014 Elsevier Ltd. All rights reserved.
D2O
Deuterium-labeled compounds have been widely used in differ-
ent branches of science including investigation of reaction mecha-
nisms and kinetics, analysis of drug metabolism, structural
elucidation of biological macromolecules, quantitative analysis of
environmental pollutants and residual pesticides, optical materi-
als, and so forth.1 Recently, deuterated drugs have drawn great
interests among pharmaceutical community.2 Consequently,
extensive researches have concentrated on the development of
diverse and selective synthetic methodologies for the preparation
of deuterium labeled compounds.3
Recently, there were many researches which focused on the
deuteration of amines employing transition metals.4 Moreover,
for the preparation of deuterium labeled anilines, a number of
H–D exchange procedures were reported, for instance, the H–D
exchange reactions catalyzed by transition metals (Pt/C–D2O–
H2,5a Pd/C–Pt/C–D2O–H2,5b NaBD4–Rh/Pt/Pd,5c Ir,6 and Rh7) or
microwave enhanced metal- and acid-catalyzed8 exchange reac-
tions. However, these methods often suffer from low deuterium-
exchange efficiency,6,7b high catalyst loadings and/or expensively
or difficultly accessible catalysts and deuterium sources.6,7 It is
worth mentioning that Mark Lautens’s group reported that anilines
were efficiently deuterated at the ortho and/or para position with
respect to the nitrogen in the presence of concd HCl (1 equiv) in
D2O under microwave irradiation at 180 °C.8c While, to achieve
high levels of deuterium incorporation, the method required a
large amount of D2O (250 equiv) due to that the concd HCl would
bring H2O into the system and also basic workup was needed.
Recently, Gröll et al., reported the capability of Ru3(CO)12 to
selectively catalyze H–D exchange of nitrogen-containing hetero-
cycles with tBuOD as deuterium source.4c Also, Chatani et al., have
reported that the treatment of 2-(1-pyrrolidinyl)pyridine with
Ru3(CO)12–CO system in 2-propanol-d8 at 140 °C showed deute-
rium incorporation at all positions.9 The studies above implied that
Ru3(CO)12 could be applied to aniline deuteration. The aim of this
investigation is to study on the regioselective deuteration of N-
alkyl-substituted anilines under neutral conditions (Scheme 1).
Initially, Ru3(CO)12 (1 mol %) as catalyst and D2O (75 equiv) as
deuterium source were used for the deuteration of N,N-dimethyl-
aniline. The reaction mixture was heated to 100 °C overnight,
and deuterium incorporation reached to 94% at the ortho and para
positions (Table 1, entry 1). Delightfully, further reduction of the
R1
R2
R1
R2
N
N
D
R3
D
Ru3(CO)12, D2O
R3
R1=Alkyl
D
R2=Alkyl,H
⇑
Corresponding author. Tel.: +86 18602831330; fax: +86 02885058465.
E-mail address: ywchen@scu.edu.cn (Y. Chen).
Scheme 1. Ru3(CO)12 catalyzed deuteration of N-alkyl-substituted anilines.
http://dx.doi.org/10.1016/j.tetlet.2014.07.071
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. Zhan et al. / Tetrahedron Letters 55 (2014) 5070–5073
5071
Table 1
Optimization of deuteration conditions on N,N-dimethylaniline
Table 2
Deuteration of various anilines catalyzed by Ru3(CO)12 in D2Oa
Entry
Catalyst
Amount (mol %)
T (°C)
D contenta (%)
Entry
D content (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
None
Ru3(CO)12
Fe3(CO)12
10% Pd/C
10% Ph/C
20% Ru/C
HCl
1
100
100
100
100
100
100
100
100
80
100
100
100
100
100
94
94
95
91
94b
98c
96d
0
68
77
87
32
54
38
N
0.5
0.25
0.1
0.25
0.25
0.25
0
D
D
95
1
95
93
93
D
95
N
0.25
1
D
98
D
10e
10e
5e
2
3
100
N
a
Unless otherwise mentioned, the reaction was conducted with 1 mmol of N,N-
D
D
dimethylaniline in 1.5 mL D2O at 100 °C overnight. The D content was calculated on
95
the basis of 1H NMR spectrum.
b
6 h.
c
After repeating the labeling procedure once with fresh Ru3(CO)12 and D2O.
Toluene as co-solvent.
Wt %.
D
d
95
e
N
D
D
24
4
96
92
catalyst amount to 0.25 mol % resulted in high deuterium content
(Table 1, entry 3). Moreover, 0.1 mol % of Ru3(CO)12 still allowed
high deuteration degree (91%, Table 1, entry 4). Reducing the reac-
tion time to 6 h also led to 94% of deuterium incorporation when
0.25 mol % of the catalyst was used (Table 1, entry 5). Additionally,
nearly complete deuteration (98%, Table 1, entry 6) could be
achieved by repeating the labeling procedure once. Toluene as
co-solvent maintained the efficiency of the deuteration process
(Table 1, entry 7). As expected, H–D exchange of N,N-dimethylan-
iline was not observed without catalyst (Table 1, entry 8). Decreas-
ing the temperature led to a lower deuteration degree (Table 1,
entry 9). However, other zero-valent catalysts gave lower deute-
rium efficiency (Table 1, entries 10–13). Stoichiometric amounts
of 37% concd HCl, which was used for the regioselective deutera-
tion of anilines under microwave irradiation,8 allow only 38% of
deuterium incorporation at 100 °C (Table 1, entry 14). Therefore,
the optimized conditions were obtained by using 0.25 mol % of
Ru3(CO)12 in D2O (75 equiv) and heating to 100 °C for 12 h.
A variety of substituted anilines were subjected to the opti-
mized conditions to evaluate the scope of the reaction (Table 2).
Spectrographically pure labeled anilines were obtained through
simple extraction and evaporation, and no further purification pro-
cess was required. Tertiary anilines with the electron-donating
group were efficiently deuterated (Table 2, entries 1–3 and 6–8).
However, when steric hindered substituent is on the aniline nitro-
gen, the degree of deuterium incorporation is diminished ortho to
the nitrogen (Table 2, entry 4). An attempt to deuterate the 1-phe-
nylpyrrolidine was less satisfactory at this condition because of
steric hindrance, however 96% of deuterium incorporation was
achieved by further optimizing the temperature from 100 °C to
120 °C (Table 2, entry 5). The presence of phenols slightly reduced
the degrees of deuterium incorporation.10
D
94
N
D
D
5c
96
D
96
N
D
88
D
87.5
6
91
90
O
D
87.5
N
D
D
89
7d
O
N
D
95.5
D
O
8d
93
91
O
N
D
D
91
96
9
However, substrates with the electron-withdrawing group (Br,
CN, carbonyl, ester, and NO2) could not be labeled even at 140 °C
probably due to low activity of the substrates and/or the weak
interaction between anilines and the catalyst. To our delight, ani-
lines with weak electron-withdrawing group in meta-position
were efficiently deuterated (Table 2, entries 9 and 10).
In the case of secondary anilines, elevated temperature and high
loading of the catalyst (1 mol %) were needed to achieve high
degree of deuterium incorporation and the substituent effects were
similar to those of tertiary anilines (Table 2, entries 12–15).
Cl
D
91
N
D
D
96
97
10
94
F
D
96
(continued on next page)

5072
M. Zhan et al. / Tetrahedron Letters 55 (2014) 5070–5073
Table 2 (continued)
N
Yieldb (%)
D
D
Entry
D content (%)
90
0.25 mol % Ru3(CO)12
D2O/ Toluene, 120 oC
N
D
98
N
11e
96
O
D
96
N
NH
D
D
97
D
D
97
1. conc HCl (1 equiv)
O
D2O, 180 oC, wave
12c
13c
14c
94
µ
D
2. basic workup
59.5
D
97
O
96
D
D
H
N
Scheme 2. Ru3(CO)12 catalyzed deuteration of N-alkyl-substituted anilines.
99
91
D
96
pure labeled anilines. This exchange method also showed high
selectivity to substrates with aromatic methoxy groups when
compared to the existing methods. It is envisaged that this meth-
odology can also be extended to the tritium-labeling of pharma-
ceutically interesting molecules for medicinal applications.
NH
D
D
98
94
O
D
96
Representative procedure for deuteration reactions
NH
N,N-Dimethylaniline (2 mmol) and Ru3(CO)12 (3.2 mg,
0.005 mmol) in D2O (3 mL) were stirred at 100 °C in a sealed tube
under a N2 atmosphere for 12 h. After the mixture was cooled to
room temperature, water (10 ml) was added, and then extracted
with diethyl ether (2 Â 10 mL). The organic layer was washed with
brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate
was concentrated to afford N,N-dimethylaniline-d3. The total incor-
poration yield was determined by 1H NMR spectroscopy relative to
the intensity of a nonexchangeable proton in the molecule and
confirmed by 2H NMR and mass spectrometry.
D
D
94
96
15c
90
Cl
D
96
a
Unless otherwise noted, the reaction was conducted with 1 mmol of the sub-
strate and 0.25 mol % of Ru3(CO)12 in 1.5 mL D2O at 100 °C overnight. The D content
was calculated on the basis of 1H NMR spectrum.
b
Isolated yield.
c
1 mol % of Ru3(CO)12 was used at 120 °C.
d
Toluene as co-solvent.
140 °C.
e
Supplementary data
Supplementary data (general procedures and 1H, 2H and 13C
NMR spectra of all compounds) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.07.071.
Unfortunately, deuteration of primary anilines failed, maybe due to
the catalyst poisoning.
Compared to established methods, it showed special selectivity
to substrates with aromatic methoxy groups as depicted in
Scheme 2. As reported, microwave mediated H-D exchange of
anilines often suffers from selectivity problems.8
References and notes
To gather further insight into our novel Ru3(CO)12-catalyzed
deuteration of N-alkyl-substituted anilines, radical scavenger, such
as 1,1-diphenylethylene11 (1 equiv), was employed in the reaction.
The deuteration of N,N-dimethylaniline was immune to the radical
scavenger, which could indicate that the exchange reaction did not
involve in radical intermediates. In addition, toluene as co-solvent
did not affect the deuterium efficiency (96%, Table 1, entry 6),
which indicated that the catalyst may bond to the nitrogen of
the aniline rather than the aromatic ring to some extent. To review
the existing method for the labeling of anilines, the use of a variety
of Brønsted and Lewis acids in D2O under microwave irradiation
afforded considerable amounts of deuteration (15–58%),8c which
was proposed to occur via electrophilic aromatic substitution upon
deuterium ions and so was our method.
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