A versatile methodology for the regioselective C8-metalation of purine bases

Article abstract of DOI:10.1021/ja5030904

Purine nucleobases are excellent ligands for metal ions, forming normally coordinative Werner-type bonds by utilizing the N donor atoms of the nucleobase skeleton. Here we show that purines such as 8-chlorocaffeine and 8-bromo-9-methyladenine react with [Pt(PPh₃)₄] under oxidative addition of the C⁸-halogen bond to the metal center. The resulting Pt^II complexes feature a C⁸-bound ylidene ligand. Protonation of the ylidene at the N^7/9-atom yields complexes bearing a protic N-heterocyclic carbene ligand derived from the purine base with an NMe,NH-substitution pattern.

Full text of DOI:10.1021/ja5030904

Communication
pubs.acs.org/JACS
A Versatile Methodology for the Regioselective C8‑Metalation of
Purine Bases
Dirk Brackemeyer, Alexandre Herve, Christian Schulte to Brinke, Mareike C. Jahnke,
́
and F. Ekkehardt Hahn*
Institut fur Anorganische und Analytische Chemie, Westfalische Wilhelms-Universitat Munster, D-48149 Munster, Germany
̈
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Purine nucleobases are excellent ligands for
metal ions, forming normally coordinative Werner-type
bonds by utilizing the N donor atoms of the nucleobase
skeleton. Here we show that purines such as 8-chloro-
caffeine and 8-bromo-9-methyladenine react with [Pt-
(PPh3)4] under oxidative addition of the C8−halogen
bond to the metal center. The resulting PtII complexes
feature a C8-bound ylidene ligand. Protonation of the
ylidene at the N7/9-atom yields complexes bearing a protic
N-heterocyclic carbene ligand derived from the purine
base with an NMe,NH-substitution pattern.
Figure 1. Purine I, 9-methyladenine II, N-alkylimidazole III, and
metalation of IV to give the NHC complex V.
Scheme 1. C−H and C−X Oxidative Addition of Neutral
ot only are purine nucleobases the building blocks for
NDNA and RNA, but at the same time they are also excellent
ligands for metal ions and provide important binding sites in
nucleic acids. A detailed understanding of the coordination
chemistry of purines is currently the subject of intensive studies1
due to the key role metal complexes play in cancer chemo-
therapy.2 Significant efforts have been directed toward nucleo-
base Pt(II) coordination compounds, with the aim to investigate
the mechanism of interaction between cis-platinum and DNA.3
Today, it is well known that the N7-position of N9-blocked but
otherwise unsubstituted purine nucleobases is the preferred
binding site for transition metal ions, including Pt(II) antitumor
agents.1a,b Almost all known complexes involving atoms of the
unsubstituted purine skeleton I (Figure 1) feature interactions
between a Lewis acidic metal ion and nitrogen donor atoms (N1,
N3, N7, or N9) of the purine bicyclus. However, substitution of
the purine skeleton, like C6-arylation, allowed the isolation of
chelate complexes with an N1-metalated purine skeleton and an
exocyclic orthometalated phenyl ring.4
We became interested in the metalation of purine nucleobases
like N9-methyladenine II at the C8-atom, which would lead to
organometallic complexes of unsubstituted purines with an
endocyclic M−C bond. The C8-metalation of II, however, poses
several challenges, like the regioselective deprotonation at the
C8-atom and the binding of a metal atom at this position.
Formation of C-metalated nucleosides and nucleotides (C2, C6,
or C8) as intermediates in metal-catalyzed C−C or C−N
coupling reactions involving the purine skeleton was described,5
but to our knowledge none of these intermediates has been
isolated and fully characterized yet.
Azoles to Transition Metals
type III N-alkylazoles is rarely mentioned in the literature,6
deprotonation and C2-metalation of the related N,N′-dialkyli-
midazolium cation in IV is standard for the synthesis of
complexes V bearing N-heterocyclic carbenes (NHCs).7
Recently, the C2-metalation of N-alkylenephosphine-tethered
benzimidazoles with RuII and RhI (Scheme 1) by an oxidative
addition/reductive elimination procedure8 to give type VI
complexes was described. Subsequently, it was shown that
neutral 2-halogenoazoles such as 2-chloro-N-methylbenz-
imidazole also react with transition metal complexes
[M0(PR3)4] (M = Ni, Pd, Pt), giving initially type VII complexes
(Scheme 1).9 Protonation yields type VIII complexes bearing an
NR,NH-NHC ligand. Type VII complexes tend to dimerize via
intermolecular M−N interactions to give dinuclear species.9a,c
The C−X oxidative addition appears to be the method of
choice for the regioselective C8-metalation of N7/9-blocked and
The five-membered diaminoheterocycle of 9-methyladenine
resembles that of neutral N-alkylimidazoles III (Figure 1). While
deprotonation and regioselective C2-metalation of simple neutral
Received: March 27, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Communication
otherwise unsubstituted purine bases. C8-Halogeno-N7/9-meth-
ylpurines feature an N-methylimidazole heterocycle which is very
likely capable of oxidative addition to [Pt(PPh3)4]. In addition,
[Pt(PPh3)4] is not Lewis acidic enough for binding to the N
donors of the purine skeleton. Here we describe the reaction of
C8-chlorocaffeine and C8-bromo-N9-methyladenine with [Pt-
(PPh3)4], leading to regioselective C8-metalation of the purine
bases and formation of isolable ylidene complexes.
Scheme 2. Regioselective C8-Metalation of Caffeine
Based on the observation that the initial reaction products of
the oxidative addition of 2-halogenobenzimidazoles to Pt0 tend
to form intermolecular Pt−N interactions,9a,c we decided to start
our studies on the oxidative addition of C8-halogenated purines
with an electron-poor derivative. We were hoping to prevent
dimerization after the initial oxidative addition of the C8−X
bond. The 8-chlorocaffeine derivative 1 (8-chloro-1,3,7-
trimethyl-3,7-dihydro-1H-purine-2,8-dione) was selected for
the initial studies. A related N7,N9-dimethylated cationic
derivative of caffeine, 1,3,7,9-tetramethylxanthinium, was pre-
viously C8-metalated by the classical reaction sequence for the
synthesis of NHC complexes (C8-deprotonation followed by
metal coordination).10
8-Chlorocaffeine 1 was obtained from 8-chlorotheophylline by
N7-methylation following a published procedure.11 Reaction of 1
with [Pt(PPh3)4] led to the colorless complex [2] in 54% yield
(Scheme 2). A related Co(I) complex bearing a caffeine-derived
ylidene ligand was obtained by the acid/base reaction of caffeine
with [CoMe(PMe3)4].12 [2] was completely characterized by
NMR. The 13C{1H} NMR spectrum showed a resonance at δ
(ppm) = 150.3 (t, 2JC,P = 10.4 Hz) indicative of C8-binding of the
caffeine and coordination of the two PPh3 donors to the same Pt
atom in trans positions. The chemical shift for the C8-resonance
compares well to the chemical shift observed for the C2-atom in
Figure 2. Molecular structures of [2] in [2]·2CH2Cl2 (left) and [3]+ in
[3]BF4·0.5H2O (right) (nonrelevant H atoms and solvent molecules are
omitted for clarity, 50% probability ellipsoids). Selected bond distances
(Å) and angles (deg): for [2], Pt−Cl 2.3763(6), Pt−P1 2.3100(7), Pt−
P2 2.3101(7), Pt−C8 1.980(3), N7−C8 1.360(3), N9−C8 1.352(3),
Cl−Pt−P1 89.23(2), Cl−Pt−P2 90.94(2), Cl−Pt−C8 177.28(7), P1−
Pt−P2 179.38(2), P1−Pt−C8 88.25(7), P2−Pt−C8 91.59(7), N7−
C8−N9 110.6(2); for [3]+, Pt−Cl 2.3489(7), Pt−P1 2.3235(7), Pt−P2
2.3246(7), Pt−C8 1.967(3), N7−C8 1.342(3), N9−C8 1.373(3), Cl−
Pt−P1 89.99(3), Cl−Pt−P2 89.52(2), Cl−Pt−C8 178.72(7), P1−Pt−
P2 174.19(2), P1−Pt−C8 89.39(8), P2−Pt−C8 90.99(8), N7−C8−N9
106.1(2).
the benzimidazolin-2-ylidene complex VII (δ = 149.4, t, 2JC,P
=
9.4 Hz).9c The 31P{1H} NMR spectrum shows a resonance at δ =
1
19.3 (s, Pt satellites, JPt,P = 2795 Hz) for the two chemically
equivalent P atoms in [2], confirming their trans arrangement.
No indications for dimerization of [2] were found, which we
attribute to the reduced electron density of the unsubstituted
ring-N atom due to the electron-withdrawing backbone of the
caffeine molecule in addition to steric reasons.
for all other C atoms were identified and assigned. The 31P{1H}
NMR spectrum features the resonance for the two chemically
equivalent P atoms in trans configuration slightly upfield
1
compared to that of [2] at δ = 17.4 (s, Pt satellites, JPt,P
=
2483 Hz). The upfield shift of the 31P{1H} resonance upon
protonation is in line with a decreased donor ability of the
NMe,NH-NHC ligand, and this effect was discussed in the
literature.13
Crystals of [2]·2CH2Cl2 were obtained by slow diffusion of
diethyl ether into a saturated dichloromethane (DCM) solution
of [2]. X-ray diffraction (XRD) analysis of these crystals
confirmed the formation of the trans-configured caffeine−
ylidene complex (Figure 2). The Pt atom is surrounded in a
square-planar fashion by the caffeine C8-atom, the two phosphine
donors, and a chloro ligand. Equivalent metric parameters in [2]
and VII are similar or even identical within experimental error.
An exception are the N−CNHC distances, which differ for VII by
0.07 Å (N1−C2 1.389(2) Å, N3−C2 1.319(3) Å), while they are
identical within experimental error in [2] (N7−C8 1.360(3) Å,
N9−C8 1.352(3) Å). This observation is in accord with a
reduced negative charge at the N9-atom in [2] compared to the
N3-atom in VII, with concurrent reduction of the electrostatic
interaction between N9 and C8.
Formation of cation [3]+ was also indicated by HRMS
spectrometry (ESI, positive ions), with a strong peak at m/z =
949.1969 (calcd for [3]+ 949.1967). [3]BF4 can also be obtained
by reaction of [2] with HBF4·Et2O in THF, but the direct
synthesis from 8-chlorocaffeine 1, [Pt(PPh3)4], and NH4BF4 is
more convenient, as it circumvents the isolation of [2].
The molecular structure of [3]BF4 was established by an XRD
study with crystals of [3]BF4·0.5H2O obtained by slow diffusion
of diethyl ether into a saturated DCM solution of [3]BF4.
Structure analysis confirmed the formation of the square-planar
complex cation [3]+ (Figure 2). Metric parameters of [2] and
[3]+ are rather similar. Most surprisingly, the N7/9−C8 distances
in [3]+ bearing the protic carbene ligand (N7−C8 1.342(3) Å,
N9−C8 1.373(3) Å) differ by 0.03 Å, while they are identical
within experimental error for [2]. The N7−C8−N9 angle in
cation [3]+ (106.1(2)°) is significantly smaller than in [2]
(110.6(2)°). A similar reduction of the N7−C8−N9 angle was
observed upon deprotonation of the 1,3,7,9-tetramethyl-
xanthinium cation and coordination of the resulting caffeine-
Next, 8-chlorocaffeine 1 was reacted with [Pt(PPh3)4] in
toluene in the presence of an excess of the proton source
NH4BF4. After a reaction time of 6 d, [3]BF4 bearing an N9-
protonated NMe,NH-NHC ligand was isolated as a colorless
1
solid in 63% yield (Scheme 2). H NMR confirmed the N9-
protonation of the coordinated caffeine-derived ylidene ligand (δ
= 10.89 for N9−H). The resonance for the C8-atom could not be
detected in the 13C{1H} NMR spectrum, while the resonances
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Communication
Scheme 3. Regioselective C8-Metalation of 9-Methyladenine
Figure 3. Molecular structures of [5] in [5]·2C6H6 (left) and of [6]+ in
[6]BF4·0.5CH2Cl2 (right) (nonrelevant H atoms and solvent molecules
are omitted for clarity, 50% probability ellipsoids). The asymmetric unit
of [6]BF4·0.5CH2Cl2 contains two formula units. The metric
parameters of the two cations [6]+ in the asymmetric unit are identical
within experimental error, so only one cation [6]+ is depicted here.
Selected bond distances (Å) and angles (deg): for [5], Pt−Br 2.4987(3),
Pt−P1 2.3183(6), Pt−P2 2.3131(6), Pt−C8 1.996(2), N7−C8
1.323(3), N9−C8 1.385(3), Br−Pt−P1 88.16(2), Br−Pt−P2
91.12(2), Br−Pt−C8 177.88(7), P1−Pt−P2 179.07(2), P1−Pt−C8
89.79(7), P2−Pt−C8 90.93(7), N7−C8−N9 111.7(2); for [6]+, Pt1−
Br1 2.4678(7), Pt1−P1 2.3086(15), Pt1−P2 2.3174(15), Pt1−C8
1.979(6), N7−C8 1.327(7), N9−C8 1.359(7), Br1−Pt1−P1 89.45(4),
Br1−Pt1−P2 88.86(4), Brl−Pt1−C8 178.68(16), P1−Pt1−P2
174.60(5), P1−Pt1−C8 91.80(16), P2−Pt1−C8 89.93(16), N7−C8−
N9 107.0(5).
derived ylidene ligand to Ag(I) and Rh(I).10b Generally, the
metric parameters found for the caffeine−ylidene ligand in [3]+
compare well with the metric parameters observed in type VIII
complexes, and this allows to conclude that the carbon-bound
ligand in [3]+ behaves overall as a classical protic NHC ligand.
After demonstrating that purine derivatives such as 8-
chlorocaffeine 1 can be converted into protic NHC ligands by
an oxidative addition reaction without prior alkylation of both N
atoms of the five-membered heterocycle, we turned to the C8-
metalation of adenine. 9-Methyladenine was prepared together
with 3-methyladenine by N-alkylation of adenine with methyl
iodide.14 Chromatographic separation of the isomers and
reaction of 9-methyladenine with N-bromosuccinimide in
acetonitrile gave 8-bromo-9-methyladenine 4 as a beige powder
(Scheme 3).15 4 was reacted with [Pt(PPh3)4] in toluene to give
[5] as an off-white powder in 68% yield. Formation of [5] was
confirmed by NMR. The 1H NMR spectrum features the
expected resonances for the adenine-derived ylidene and the
phenyl groups. More information can be drawn from the
13C{1H} NMR spectrum, showing the resonance for the C8-atom
at δ = 149.9, downfield shifted when compared to the C8-
Reaction of 4 with [Pt(PPh3)4] in the presence of the proton
acid NH4BF4 yielded [6]BF4 bearing a protic NR,NH-NHC
ligand derived from 9-methyladenine. [6]BF4 was identified by
the typical resonance for the carbene C8-atom at δ = 155.2 in the
1H,13C-HMBC NMR spectrum. The chemical shift of this
resonance corresponds well with chemical shifts observed for
protic (benz)imidazolin-2-ylidenes coordinated to Pt(II).9a,16 In
addition, the 1H NMR spectrum features a resonance at δ = 12.57
for the N7−H proton. Only one resonance at δ = 16.5 (s, Pt
1
satellites, JPt,P = 2484 Hz) was observed in the 31P{1H} NMR
spectrum, indicating the trans arrangement of the phosphine
donors.
The conclusions drawn from NMR were confirmed by an
XRD study with crystals of composition [6]BF4·0.5CH2Cl2
obtained by slow evaporation of the solvent from a DCM
solution of [6]BF4. The structure analysis shows complex cation
[6]+ surrounded in a slightly distorted square-planar coordina-
tion geometry by the 9-methyladenine-derived carbene ligand,
the two phosphine donors in trans positions, and a bromo ligand
(Figure 3). All bond distances involving the Pt atom in cation
[6]+ are slightly shorter than comparable distances in the neutral
complex [5] bearing the unprotonated adenine-derived ylidene
ligand. This is very likely to result from the different charges in
[5] and [6]+. The bond parameters within the five-membered
heterocycle in [5] and [6]+ also differ slightly. Upon N7-
protonation of [5] to [6]+, the N7/9−C8 distances become more
equal (N7−C8 1.327(7) Å, N9−C8 1.359(7) Å), and the
difference between the two N7/9−C8 distances is reduced from
0.06 Å for [5] to 0.03 Å for [6]+. As previously observed with the
caffeine-derived NHC ligands, the N7−C8−N9 angle in [5]
(111.7(2)°) shrinks upon protonation of the free ring-nitrogen
atom N7 to 107.0(5)° in [6]+, in accord with the expectations for
a protic NHC ligand.17
resonance for 4 at δ = 127.0. The 31P{1H} NMR spectrum
1
features only one resonance at δ = 18.0 (s, Pt satellites, JPt,P
=
2801 Hz), indicative for the arrangement of two phosphine
ligands in trans positions. In addition, an intensive peak at m/z =
948.1344 (calcd for [5+H]+ 948.1348) was detected in the
HRMS spectrum, and microanalytical data also confirmed the
formation of a complex with the composition of [5].
Crystals of [5]·2C6H6 were obtained by slow evaporation of
the solvents from a benzene/DCM solution of [5] at ambient
temperature. The XRD structure analysis (Figure 3) with these
crystals confirmed the overall composition and geometry of [5]
as indicated from the spectroscopic data. While the majority of
comparable metric parameters of [2] and [5] are almost
identical, the N7/9−C8 distances in [5] differ by 0.06 Å, with
the short separation found for the N7−C8 bond (1.323(3) Å)
and a longer separation found for the N9−C8 bond (1.385(3)
Å). This could be the result of an enhanced accumulation of
negative charge at the N7-atom of [5] leading to a stronger
electrostatic interaction between N7 and C8 due to the less
electron-withdrawing ligand backbone compared to the caffeine-
derived ligand in [2]. As was observed for [2], the N7−C8−N9
angle in [5] (111.7(2)°) is larger than in classical benzannulated
NHC ligands.
Only one report on the molecular structure of a C8-metalated
N9-blocked adenine has appeared so far.18 An ethylenediamine-
tethered adenine was observed to react with a Ru(III) complex to
give a C8-metalated RuII complex. No proposal for the formation
of this complex and for the reduction of RuIII to RuII during the
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Journal of the American Chemical Society
Communication
(4) (a) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.; Jung,
Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 1132. (b) Chamala, R. R.;
Parrish, D.; Pradhan, P.; Lakshman, M. K. J. Org. Chem. 2013, 78, 7423.
reaction has been put forward. Based on subsequent inves-
tigations, it can be assumed that the reaction proceeds by
oxidative addition of the C8−H bond to Ru(II) followed by
reductive elimination of a proton from the formed hydride
complex. This proton or protons from the solvent can then
protonate the N7-atom of the adenine moiety. The chelating
diamine tether is essential for the observed reactivity, and in the
absence of the tether, the typical metal coordination at the N7-
atom of the nucleobase occurs.19 Related reactivity was observed
during the reaction of phosphine-tethered neutral benz-
imidazoles with Ru(II)8a and Rh(I)8b (Scheme 1).
We present a facile, straightforward method for the regio-
selective C8-metalation of N7- or N9-blocked but otherwise
unsubstituted purine bases by oxidative addition of the C8−
halogen bond to Pt0 complexes. Both electron-deficient 8-
chlorocaffeine and 8-bromo-9-methyladenine react in the
oxidative addition reaction to give, in the absence of a proton
source, the ylidene complexes with an unsubstituted ring-
nitrogen atom. In the presence of a proton source, complexes
bearing NMe,NH-NHC ligands are obtained from both the
caffeine- and the adenine-derived ligand precursors. The
oxidative addition reaction is not affected by basic functionalities
of the purine bases. C8-Metalation of adenine with selected
metals in the absence of a proton source gives access to stable
ylidene complexes, which possibly can be further metalated
instead of protonated at the ring-nitrogen N7-atom.20 Such
double metalation might lead to interesting building blocks for
supramolecular structures and even to novel base-pairings via
metal−nitrogen interactions. In addition, the use of water-
soluble phosphine complexes possibly enables oxidative addition
in water and subsequent incorporation of the metalated adenine
into DNA, thereby generating DNA regioselectively metalated at
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ASSOCIATED CONTENT
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Experimental details for the synthesis of all compounds and X-ray
crystallographic files (in CIF format) for [2]·2CH2Cl2, [3]BF4·
0.5H2O, [5]·2C6H6, and [6]BF4·0.5CH2Cl2. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
fehahn@uni-muenster.de
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Deutsche Forschungsgemeinschaft (SFB
858) for financial support.
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