meta-C?H Bromination on Purine Bases by Heterogeneous Ruthenium Catalysis

Article abstract of DOI:10.1002/anie.201609014

Methods for positionally selective remote C?H functionalizations are in high demand. Herein, we disclose the first heterogeneous ruthenium catalyst for meta-selective C?H functionalizations, which enabled remote halogenations with excellent site selectivity and ample scope. The versatile heterogeneous Ru@SiO₂catalyst was broadly applicable and could be easily recovered and reused, which set the stage for the direct fluorescent labeling of purines. In contrast to palladium, rhodium, iridium, or cobalt complexes, solely the ruthenium catalysis manifold provided access to meta-halogenated purine derivatives, illustrating the unique power of ruthenium C?H activation catalysis.

Full text of DOI:10.1002/anie.201609014

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609014
German Edition: DOI: 10.1002/ange.201609014
CÀH Activation
À
meta-C H Bromination on Purine Bases by Heterogeneous
Ruthenium Catalysis
Svenja Warratz, David J. Burns, Cuiju Zhu, Korkit Korvorapun, Torben Rogge, Julius Scholz,
Christian Jooss, Dmitri Gelman, and Lutz Ackermann*
[
8]
Abstract: Methods for positionally selective remote CÀH
ruthenium-catalyzed CÀH activation, we have now devel-
[9]
functionalizations are in high demand. Herein, we disclose the
oped the first heterogeneous catalyst for meta-CÀH halo-
[10]
first heterogeneous ruthenium catalyst for meta-selective CÀH
genations, on which we report herein. Notable features of
our strategy include 1) an operationally simple heterogeneous
functionalizations, which enabled remote halogenations with
excellent site selectivity and ample scope. The versatile hetero-
[
11]
catalyst that facilitates remote CÀH halogenations, 2) effi-
cient catalyst reuse, as well as 3) the first remote CÀH
geneous Ru@SiO catalyst was broadly applicable and could
2
[
12]
be easily recovered and reused, which set the stage for the direct
fluorescent labeling of purines. In contrast to palladium,
rhodium, iridium, or cobalt complexes, solely the ruthenium
catalysis manifold provided access to meta-halogenated purine
derivatives, illustrating the unique power of ruthenium CÀH
functionalizations on nucleobases,
setting the stage for
direct fluorescent labeling diversification. It is particularly
noteworthy that the unique catalyst-guided CÀH functional-
ization selectively occurred at the remote meta-arene motif,
while the CÀH functionalization process was not governed by
[4,13]
activation catalysis.
proximity-induced ortho modification,
CÀH dissociation
[
14]
[15]
energies,
(Figure 1).
or the CÀH acidity
at the C8 position
M
ethods for the direct manipulation of otherwise unreac-
tive CÀH bonds have surfaced as transformative tools for
[
1]
molecular synthesis, with enabling applications in the
material sciences, crop protection, and the pharmaceut-
[2]
[3a]
[
3b,c]
ical industry.
have been accomplished by proximity-induced CÀH activa-
A plethora of arene CÀH functionalizations
[4]
tion through chelation assistance. In sharp contrast to ortho-
[
5]
CÀH functionalizations, remote CÀH transformations con-
[
6]
tinue to be scarce, with notable recent progress realized with
[
7]
the aid of ruthenium catalysis. Despite these considerable
[
5]
advances, ruthenium-catalyzed meta-selective CÀH func-
tionalizations have thus far been restricted to homogeneous
catalysis, rendering catalyst reuse challenging, while at the
same time leading to significant quantities of undesired metal
impurities in the target products. Within our program on
Figure 1. meta-Selective CÀH functionalization of purine derivatives
with a heterogeneous ruthenium catalyst.
[*] S. Warratz, Dr. D. J. Burns, C. Zhu, K. Korvorapun, T. Rogge,
Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
We initiated our studies by exploring reaction conditions
for the envisioned meta bromination of purine derivative 1a
[16]
(
Table 1; see also the Supporting Information, Table S1).
Among a variety of reaction conditions, DMA proved to be
the optimal solvent under an atmosphere of air. Whereas
RuCl3 hydrate (5) was identified as a viable catalyst
(entries 1–5), the user-friendly silica-derived heterogene-
J. Scholz, Prof. Dr. C. Jooss
Institut fꢀr Materialphysik
Georg-August-Universitꢁt Gçttingen
Friedrich-Hund-Platz 1, 37077 Gçttingen (Germany)
[
17]
ous catalyst Ru@SiO (6) enabled meta-CÀH halogenation
2
with excellent positional selectivity and unique catalytic
efficacy (entries 6–14). Interestingly, the heterogeneous
Ru@SiO2 catalyst (6) outperformed the homogeneous
system as revealed by meta-CÀH functionalizations at low
Prof. Dr. C. Jooss, Prof. Dr. L. Ackermann
International Center for Advanced Studies of Energy Conversion
(
ICASEC)
Georg-August University of Gçttingen (Germany)
catalyst loadings (entries 5 and 14). In stark contrast, catalysts
derived from typically used palladium, rhodium, iridium, or
cobalt complexes fell short in providing access to the desired
meta substitution pattern (entries 6–9). Similar observations
were also made with commercially available heterogeneous
ruthenium catalysts (entries 11 and 12).
Prof. Dr. D. Gelman
Institute of Chemistry, The Hebrew University
Edmond Safra Campus, 91904 Jerusalem (Israel)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201609014.
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1
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Table 1: Optimization studies for the meta-selective bromination of
[
a]
purines.
Entry
[TM]
–
2a [%]
3a [%]
4a [%]
1
2
3
4
5
6
7
8
9
–
49
41
77
25
–
–
–
–
–
2
2
4
–
–
–
–
–
–
–
–
–
–
–
–
39
–
–
–
–
6
–
–
[RuCl (p-cymene)]2
2
Ru (CO)
3
12
RuCl ·3H O (5)
5 (5 mol%)
Pd(OAc)2
[Cp*RhCl2]2
[Cp*IrCl2]2
Cp*CoI (CO)
RuO2
Ru/Al O3
Ru(OH) ·Fe O
4
Ru@SiO (6)
3
2
2
10
11
12
13
14
–
<5
5
[
[
b]
b]
–
–
–
–
2
3
3
70
68
2
6 (5 mol%)
[a] Reaction conditions: 1a (0.25 mmol), NBS (0.50 mmol), [TM]
(
10 mol%), DMA (0.50 mL), 808C, 20 h, under air. Yields of isolated
1
products are given. [b] Conversion determined by H NMR analysis using
,3,5-trimethoxybenzene as the internal standard. Cp*=pentamethyl-
1
Scheme 1. a) Remote homogeneous meta-CÀH bromination of purines
cyclopentadienyl, DMA=N,N-dimethylacetamide, NBS=N-bromo-
succinimide.
1. b) Remote meta-CÀH functionalization in the presence of D O.
2
ization. These investigations revealed a shift in the nature and
oxidation state of the ruthenium active sites (Figure 2).
Finally, the remarkable synthetic utility of our remote
nucleobase meta-CÀH functionalization was demonstrated by
With optimized catalytic reaction conditions for remote
purine functionalization in hand, we explored their versatility
in meta-CÀH functionalization (Scheme 1). Several nucleo-
[
19]
base derivatives 1 were identified as viable substrates for the
meta-selective bromination approach with catalyst 5, selec-
tively proceeding at the benzenoid moiety in a remote fashion
introducing a pyrene fluorescent label in a user-friendly
fashion (Scheme 3), highlighting the potential for the fluo-
[
20]
rescent labeling of nucleobases.
(
Scheme 1a). It is noteworthy that kinetic studies revealed
In conclusion, we have reported on the first remote CÀH
a first-order dependence of the reaction rate on the concen-
tration of the ruthenium complex
observe significant H/D exchange when employing isotopi-
cally labeled D O as the cosolvent.
functionalization on aryl-substituted purines, which was based
on the use of a heterogeneous ruthenium catalyst that enabled
meta-CÀH brominations with broad scope and excellent
[16,18]
whereas we did not
[
16]
Furthermore, the
positional selectivity. The versatile ruthenium catalyst could
be easily recovered and reused, and sets the stage for novel
strategies for direct nucleobase fluorescent labeling. In
contrast to palladium, rhodium, iridium, or cobalt complexes,
2
efficacy of the remote CÀH bromination was not affected
[
16]
by the addition of 2,6-di-tert-butylpyridine.
Thereafter, we explored the scope of the remote purine
CÀH halogenation with heterogeneous catalyst 6 (Sche-
me 2a). The silica-supported catalyst Ru@SiO2 (6) was
found to be broadly applicable for the CÀH functionalization
of nucleobases 1 with excellent levels of meta selectivity.
Moreover, the heterogeneous catalyst was not restricted to
purine bases, but also enabled the efficient meta-CÀH
bromination of diversely substituted arenes 7 by heteroarene
assistance (Scheme 2b). Importantly, the practical utility of
the heterogeneous catalyst was reflected by its facile recovery
[
16]
and reuse (Scheme 2c).
Given the unique selectivity features of the recyclable
heterogeneous catalyst 6, we intended to delineate its
structural properties. To this end, we performed detailed
[
16]
XPS and SEM
studies of the catalyst nanomaterial
(
< 100 nm) prior to and after remote meta-CÀH functional-
Figure 2. XPS studies of heterogeneous catalyst 6.
2
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Scheme 3. meta-CÀH labeling of purine bases 1 with a fluorescent tag.
Acknowledgements
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
(
FP7 2007–2013/ERC Grant agreement No. 307535), the
Chinese Scholarship Program (fellowship to C.Z.), the DFG
SFB 1073 C01), and the DAAD (fellowship to K.K.) is
(
gratefully acknowledged. Furthermore, we thank Dr. Klaus
Simon (University of Gçttingen) for ICP-MS analyses.
Conflict of interest
The authors declare no conflict of interest.
Keywords: CÀH activation · heterogeneous catalysis ·
meta selectivity · nucleobases · ruthenium
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Final Article published: && &&, &&&&
4
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Communications
CÀH Activation
S. Warratz, D. J. Burns, C. Zhu,
K. Korvorapun, T. Rogge, J. Scholz,
C. Jooss, D. Gelman,
L. Ackermann*
&&& — &&&
meta-CÀH Bromination on Purine Bases
Remote control: A reusable heterogene-
ous ruthenium complex was developed
for meta-CÀH functionalization reactions
tionally selective CÀH halogenation reac-
by Heterogeneous Ruthenium Catalysis
tions and diversification with a fluores-
cent label were thus accomplished.
on purine derivatives. Chemo- and posi-
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