Chelation-assisted rhodium hydride-catalyzed regioselective H/D exchange in arenes

Article abstract of DOI:10.1016/j.tetlet.2008.09.122

A series of air stable rhodium(III) hydride complexes are synthesized via cyclometalation of functionalized arenes, and are active catalysts for regioselective H/D exchange in various arenes via chelation-assisted C-H activation in acetone-d₆.

Full text of DOI:10.1016/j.tetlet.2008.09.122

Tetrahedron Letters 49 (2008) 6929–6932
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chelation-assisted rhodium hydride-catalyzed
regioselective H/D exchange in arenes
,
*
Shanshan Chen, Guoyong Song, Xingwei Li
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of air stable rhodium(III) hydride complexes are synthesized via cyclometalation of functional-
ized arenes, and are active catalysts for regioselective H/D exchange in various arenes via chelation-
assisted C–H activation in acetone-d6.
Received 13 August 2008
Revised 13 September 2008
Accepted 22 September 2008
Available online 25 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
H/D exchange reactions have received increasing attention in
that deuterium-labeled compounds have found extensive applica-
tions in mass spectrometry and NMR spectroscopy. In addition,
deuterium-labeled compounds are used widely as probes in reac-
tion mechanisms, drug metabolism, and structure elucidation of
biological macromolecules.1 Previously reported H/D exchange
methods include pH-dependent exchange, which is the oldest
method for this purpose, and transition metal-catalyzed H/D ex-
change. Homogeneous catalytic H/D exchange reactions are usu-
ally performed with D2 or D2O as the deuterium source owing to
their low cost and low toxicity. Deuterated solvents such as
CD3COCD3 and C6D6 are also used widely, which allow H/D ex-
change of less polar substrates. In recent years, iridium, rhodium,
C5Me5Rh(olefin)2,6 and rhodium phosphine-aryl complexes,2b have
been developed.
We recently synthesized a stable rhodium(III) hydride complex
(A) via cyclometalation of benzo[h]quinoline in acetone (Eq. (1)).
tert-Butylethylene behaves as a hydrogen acceptor to reversibly give
[Rh(PPh3)2(acetone)2]PF6, which undergoes C–H oxidative addition
to yield complex A and the analogous reactions were reported for
iridium complexes.7 Complex A was fully characterized. The hydride
resonates as a doublet of triplets at d ꢀ12.29 in the 1H NMR spec-
trum, and in the 13C{1H} NMR spectrum the Rh–C resonates as a dou-
blet of triplets (d 153.08). Single crystals of complex A were obtained
after recrystallization from methanol-d4, and the identity of A-
CD3OD was confirmed by X-ray crystallography (Fig. 1).
N
PPh3
PPh3
PPh3
D
CD3OD
acetone
acetone
PF6
acetone
H
H
O
N
N
CD3
Rh
Rh
PPh3
A-CD3OD
Rh
ð1Þ
H
H
tBuCH=CH2
acetone
-
-
PF6
PF6
-
PPh3
PPh3
56 oC, 6 h
A
and ruthenium complexes have shown great potential in C–H acti-
vation of organic substrates.2 Iridium complexes are particularly
well-known for the activation of C–H bonds, and for which reasons
iridium-mediated H/D exchange reactions make up by far the
greatest number of publications.3 In comparison, although rho-
dium catalysts have shown high activity in H/D exchange, only a
few catalyst systems, such as RhCl3,4 Rh[P(OPh)3]2(acac),5
We noted that the hydrogen of complex A could be replaced by
a deuterium (>97% D) when heated in acetone-d6 (80 °C, 3 days),
although no such reaction took place for its iridium analogue.
We reasoned that A might be an active catalyst for H/D exchange
of arenes functionalized by chelating groups since step ‘a’ in
Scheme 1 might easily occur via reversible C–H activation, and
consequently the catalytic cycle could be completed.
Initial attempts to use complex A as a catalyst for the H/D ex-
change of benzo[h]quinoline (100 °C, 6 days, acetone-d6) gave
97% deuteration at the 10-position (Eq. 2). We reasoned that
improvement could be made by using electron-rich phosphines,
since it is known that metal complexes of PMe3, PCy3, and PtBu3
* Corresponding author.
E-mail address: xli@scripps.edu (X. Li).
Current address: The Scripps Research Institute, Jupiter, FL 33458, USA.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.122

6930
S. Chen et al. / Tetrahedron Letters 49 (2008) 6929–6932
N
N
A-F, 3 mol%
ð2Þ
CD3COCD3, 100 o
C
D
Screening of these catalysts was performed using benzo[h]quin-
oline (Eq. 2), and all these catalysts were applied with 3 mol %
loading in J-Young NMR tubes in acetone-d6 at 100 °C. The results
are given in Table 1. Electron-donating phosphine ligands were
Table 1
Screening of catalysts for H/D exchange of benzo[h]quinoline
Catalyst
Solvent
Time (d)
D%a
Figure 1. Molecular structure of compound A-CD3OD. Selected bond distances (Å)
and angles (°): C(1)–Rh(1) 1.9782(19), N(1)–Rh(1) 2.1788(17), O(1)–Rh(1)
2.2157(15), P(1)–Rh(1) 2.3396(5), P(2)–Rh(1) 2.3517(5), C(1)–Rh(1)–N(1)
81.39(8), C(1)–Rh(1)–O(1) 178.20(7), C(1)–Rh(1)–P(1) 87.83(5), N(1)–Rh(1)–P(1)
93.29 (4), O(1)–Rh(1)–P(1) 93.23(4), C(1)–Rh(1)–P(2) 85.76(5), P(1)–Rh(1)–P(2)
170.282(18).
A
A
B
C
D
D
E
F
CD3COCD3
CD3COCD3+CD3OD
CD3COCD3
CD3COCD3
CD3COCD3
CD3COCD3+D2O
CD3COCD3
CD3COCD3
6
6
6
3
1.5
2
3
7
2
97
93
97
98
97
90
98
94
15
Rh(PPh3)3Cl
CD3COCD3
are usually more active toward CꢀH activation.8–11 Thus, we syn-
thesized rhodium hydride complexes A–F (Fig. 2).
a
% Deuterium incorporation.
CD3
CD3
PPh3
O
D
N
Rh
N
PPh3
CD3COCD2H
C
H
a
b
N
CD3
CD3
PPh3
C
D
O
H
N
Rh
CD3COCD3
PHPh3
Scheme 1. A simplified mechanism for H/D exchange of N-functionalized arenes.
PPh3
PPh3
P
OMe
OMe
3
N
N
O
H
N
O
O
-
Rh
P
PF6
-
Rh
Rh
-
PF6
PF6
H
H
PPh3
PPh3
3
A
B
C
PPh2Bn
PPh2Me
P
OMe
3
N
N
N
O
H
O
-
O
-
PF6
Rh
Rh
Rh
P
PF6
-
PF6
H
H
OMe
PPh2Bn
PPh2Me
3
D
E
F
Figure 2. Rhodium hydride catalysts A–F.

S. Chen et al. / Tetrahedron Letters 49 (2008) 6929–6932
6931
found to be crucial, and catalysts C, D, and E were more active than
A or B. The catalytic activity of complex F was very low, possibly
because of the introduction of more sterically congested ligands.
We conclude that catalysts D and E are the best choice for this
reaction. D2O and CD3OD are also used widely as deuterium
sources for the deuteration of non-labile H atoms.2a Rhodium(III)
hydride complexes A–F, however, are sparingly soluble in CD3OD
and are insoluble in D2O. Catalysis was thus attempted using
CD3COCD3/D2O or CD3COCD3/CD3OD in a 20/1 ratio to provide
extra sources of active deuterium, but only lower yields were
obtained. Therefore, complex D was retained for reactions of other
substrates (Eq. 3), and the results are given in Table 2.
All the substrates under study can potentially undergo chela-
tion-assisted CꢀH activation and deuteration took place predomi-
nantly at carbon atoms involved in CꢀH activation. In addition, the
2-position of pyridines could also be deuterated at up to 20% level.
Importantly, the deuterium incorporation is reasonably regioselec-
tive for the substrates in entries 1–9, particularly for benzo[h]quin-
oline, which afforded high conversion in a short reaction time.
Heys and coworkers have reported the H/D exchange reactions of
benzo[h]quinoline and 2-phenylpyridine at the same positions,
but the level of deuteration was rather low.12 Kerr reported effi-
cient deuteration of 2-phenylpyridine using iridium carbene cata-
lysts and deuterium gas.10 The phenyl group of entries 2 and 8
received nearly quantitative deuteration at the ortho positions only
after a long reaction time, and this is because two C–H bonds need
to be activated. The pyrimidine unit of 5-(pyridine-2-yl)pyrimidine
complex D, 3 mol%
N
C
N
C
ð3Þ
CD3COCD3, 100 o
C
D
H
Table 2
Selective H/D exchange of arenes
Entry
Substrate
D position
Time (d)
1.5
Dinc
%
Time (d)
Dinc %
1
a: 5% b: 98%
a
D
N
b
N
D
D
a
2
2
a: 64% b: 12%
8
a: 95% b: 9%
N
N
N
a
D
b
D
3
4
2
2
a: 16% b: 60%
a: 12% b: 90%
6
3
a: 15% b: 96%
a: 12% b: 96%
a
D
b
D
N
OCH
3
OCH
3
N
a
D
b
D
N
5
6
2
2
a: 13% b: 67%
6
6
a: 20% b: 95%
a
D
N
N
b
N
N
N
D
D
c
N
N
a: 51% b:62% c:11%
a: 31% b:97% c: 14%
N
N
N
a
b
D
D
D
b
N
N
N
N
7
2
a: 24% b: 68% c: 45%
9
a: 21% b:85% c:47%
D
c
b
D
N
a
D
N
D
a
O
O
8
9
2
2
2
2
a: 65% b: 6%
a: 24% b: 73% c: 71%
a: 84% b: 25%
33%
7
4
a: 94% b: 16%
N
N
a
D
b
D
D
a
D
b
D
c
N
H CO
N
3
a: 9% b: 95% c: 94%
H CO
3
N
N
H
c
D
D
D
b
10
11
N
N
a
O
b
D
O
O
O
D
8
81%

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S. Chen et al. / Tetrahedron Letters 49 (2008) 6929–6932
(entry 7) is more acidic at the 2-position, such that three positions
were deuterated, which prolonged the reaction time. In entries 10
and 11, the oxygen atoms are rather poor directing groups, and the
deuteration took place predominantly at the more acidic methyl
group in acetophenone. We also analyzed the extent of deuterium
incorporation of most substrates after 2 days, and the results are
listed in Table 2, during which time the extent of deuterium incor-
poration achieved was 60–70% and the regioselectivity is reason-
ably high. In fact, the rate of deuterium exchange is very low
when approaching the end of the reaction because of the lower
concentration of the deuterium source.
In conclusion, we have synthesized a series of rhodium hydride
complexes and explored their activity in H/D exchange reactions
using acetone-d6 as a deuterium source. They showed reasonable
regioselectivity for substrates demonstrating nitrogen chelation-
assistance. Rhodium complexes with stronger electron-donating
phosphine groups tend to give higher catalytic activity. Develop-
ment of other catalytic reactions using these rhodium hydrides is
currently in progress in our laboratory.
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Acknowledgment
We thank the School of Physical and Mathematical Sciences,
Nanyang Technological University, for financial support.