Synthesis of a cyclic tetrameric purine by successive cross-coupling reactions and subsequent Pd-catalyzed cyclization

Article abstract of DOI:10.1002/ejoc.200600724

The tetrameric N-benzyl-protected purine (quaterpurine) 2 was synthesized and characterized as its palladium complex [2Pd]. The synthesis commenced with the Pd-catalyzed cross-coupling of 8-zincated 9-benzyl-6-chloro-8- iodopurine (9) and 9-benzyl-6-iodopurine (11) establishing the first C-6/ C-8 bond. The sequence was repeated twice after iodo-dechlorination at C-6′ (C-6″) of the respective dimer 12 and trimer 15. The final ring closure was achieved at the tetrameric 6?-chloro-8-iodoquaterpurine 3b by a reductive intramolecular cross-coupling with hexamethylditin in the presence of Pd₂(dba)₃ and P(2-furyl)₃. The overall yield in the eight step sequence was 17 % starting from 9-benzyl-6-chloropurine (8), the immediate precursor of 11. Other strategies to combine the purine fragments, i.e. by dimer/dimer bond formation or by regioselective cross-coupling, were not successful. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600724

FULL PAPER
DOI: 10.1002/ejoc.200600724
Synthesis of a Cyclic Tetrameric Purine by Successive Cross-Coupling
Reactions and Subsequent Pd-Catalyzed Cyclization
Holger Guthmann,[a] Martin Könemann,[b] and Thorsten Bach*[a]
Keywords: Cross-coupling / Dyes / Pigments / Halogenation / Metalation / Nitrogen heterocycles
The tetrameric N-benzyl-protected purine (quaterpurine) 2
was synthesized and characterized as its palladium complex
[2·Pd]. The synthesis commenced with the Pd-catalyzed
cross-coupling of 8-zincated 9-benzyl-6-chloro-8-iodopurine
(9) and 9-benzyl-6-iodopurine (11) establishing the first C-6/
C-8 bond. The sequence was repeated twice after iodo-de-
molecular cross-coupling with hexamethylditin in the pres-
ence of Pd2(dba)3 and P(2-furyl)3. The overall yield in the
eight step sequence was 17% starting from 9-benzyl-6-chlo-
ropurine (8), the immediate precursor of 11. Other strategies
to combine the purine fragments, i.e. by dimer/dimer bond
formation or by regioselective cross-coupling, were not suc-
chlorination at C-6Ј (C-6ЈЈ) of the respective dimer 12 and cessful.
trimer 15. The final ring closure was achieved at the tetra-
meric 6ЈЈЈ-chloro-8-iodoquaterpurine 3b by a reductive intra-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Although the area of color chemistry belongs to the most
mature research fields in Organic Chemistry, the interest in
new chromophores and the need to develop new colorants
has never ceased.[1] There are numerous non-classical appli-
cations for colorants as dyes and pigments, e.g. in optical
data storage,[2] in solar energy conversion,[3] or in photody-
namic therapy.[4] In search for new chromophores, which
might be tunable by appropriate substitution, a recent re-
port by Tauer[5] attracted our attention. This article de-
scribes so-called quaterheterocycles 1 (Figure 1), which can
formally be conceived as [16]annulenes. The benzimidazole
derivative 1a exhibits in DMSO a long wavelength absorp-
tion at 393 nm (ε ≈ 10000) and shows a strong band at
349 nm (ε ≈ 60000). The benzoxazole 1b behaves similarly
but lacks the long wavelength absorption. The straightfor-
ward synthesis of compounds 1 was based on a low-yielding
cyclocondensation of 2,3-difunctionalized benzoic acids.
We envisioned tetrameric purines of the general structure
A (PG = protecting group) as highly interesting analogues
of the quaterheterocycles. If a stepwise synthesis could be
devised they would not only allow for a broad substituent
(R1–R4) variation but they would also provide an option
for protecting group(s) (PG1–PG4) removal from the purine.
The resulting heterocycle should be amenable to a re-
Figure 1. Quatercompounds 1 and general structure of tetrameric
purines A.
duction (hydrogenation) which would generate after tauto-
merization an [18]annulene. For obvious reasons the re-
duction of compounds 1 is not feasible.
As a first target the C4-symmetric N-benzyl-protected
tetrameric purine 2 was chosen (Scheme 1). The synthesis of
the compound should ideally comprise a repetitive strategy,
which should incorporate the four purine moieties success-
ively. If this was successful it would be feasible in further
work to exchange the purine building blocks at will and to
modify the substitution pattern accordingly.
In this account we report on the synthesis of compound
2 by successive cross-coupling reactions between carbon
atoms C-6 and C-8 of individual purine building blocks. We
provide full details on the preliminary experiments and on
the evolution of our synthetic strategy. It turned out that
the goal of successive cross-coupling was in this case best
achieved by addressing the electrophilic and nucleophilic
positions of the purine core separately. Attempts to apply
regioselective cross-coupling reactions to our synthetic tar-
get proved to be less rewarding.
[a] Lehrstuhl für Organische Chemie I, Technische Universität
München,
Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49-89-289-13315
E-mail: thorsten.bach@ch.tum.de
[b] BASF AG, GVP/C – A30,
67056 Ludwigshafen/Rhein, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
632
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Synthesis of a Cyclic Tetrameric Purine
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sequent chapters our successful route is being described,
which relies on a repetitive activation/cross-coupling strat-
egy.
Regioselective Cross-Coupling Attempts
Possible 6,8-dihalopurines were first evaluated as cross-
coupling substrates. In previous regioselective cross-coup-
ling experiments, 9-protected 6,8-dichloropurines have been
employed frequently.[9] The metalation of an 8-chloropu-
rine – which was required for trimer and tetramer forma-
tion – is difficult, however. On the other side of the reactiv-
ity scale, 9-protected 6,8-diiodopurines were assumed to re-
act with insufficient regioselectivity in the cross-coupling.
In addition, synthetic access to these purines has not been
reported.[12] The easily available 6,8-dibromopurine 4 was
hence identified as the best starting material. Purine 4 was
obtained from the known 9-benzyl-6-bromopurine[13] by de-
protonation at C-8 (LDA in THF, –78 °C) and subsequent
nucleophilic bromination[14] (BrCN, –78 °C). A regioselec-
tive Negishi cross coupling[15] at position C-6 was feasible
under standard conditions (Scheme 3) to yield bromide 5.
Scheme 1. Target compound 2 and disconnection into four purine
units which need to be connected at the indicated (·) positions.
Reactivity of Purines
The retrosynthetic disconnection indicated in Scheme 1
requires a final C–C bond formation step at an appropri-
ately functionalized (X,Y) non-cyclic tetrameric purine 3
(Scheme 2). Starting from monomeric building blocks three
C–C bond forming reactions between C-6/C-8 are required.
Alternatively, one could consider the fusion of two dimeric
purines, which already bear the functional groups X and
Y or appropriate precursors thereof. The general reactivity
pattern of purines[6] in cross-coupling reactions[7] suggested
to employ the 6-position as electrophilic site and the 8-posi-
tion as nucleophilic site. Indeed, regioselective cross-coup-
ling reactions[8] at 6,8-dichlorinated purines show a prefer-
ence for a displacement at the 6-position,[9] while the 8-posi-
tion could possibly be metalated by direct metalation or
halogen–metal exchange.[10] Based on this consideration, it
was appealing to employ a 6,8-dihalopurine as monomeric
building block, which was to be subjected to a regioselective
cross-coupling with an appropriately 6-functionalized (X)
8-metalated purine. After metalation of the 8-position in
the dimer the next cross-coupling with a 6,8-dihalopurine
could be conducted leading to a trimer. Repetition of the
sequence would generate the tetrameric target 3. In this sce-
nario the individual purine building blocks could be intro-
duced at will changing the substituent at C-2 and the pro-
tecting group at N-9.
Scheme 3. Regioselective cross-coupling at position C-6 of dibro-
mopurine 4.
Further optimization reactions were not conducted.
There was no hint for the occurrence of the other re-
gioisomer. Although the outcome of this experiment is not
extremely surprising given the precedence for similar reac-
tions on 9-benzyl-6,8-dichloropurine[9a] it is to the best of
our knowledge the first example for a regioselective cross-
coupling on a 6,8-dibromopurine.
In Figure 2, starting materials are depicted, which were
to be coupled as first monomeric building block with dibro-
mide 4. The triply protected adenine 6 was readily available
from 9-benzyladenine by a twofold tert-butoxycarbonyl
(Boc) protection (Boc2O, DMAP in THF, room temp.).[16]
The bromo analogue 7 was synthesized in a similar fashion
from N-benzylated 8-bromoadenines.[17] The transforma-
tion of the NBoc2 group into a suitable leaving group for
cyclization (cf. Scheme 2, X in compound 3) was envisioned
after deprotection and diazotization. The diazotization of
9-benzyladenine and a subsequent displacement of the di-
azo group[18] were employed for the preparation of chlo-
ropurine 8.[19]
Scheme 2. Basic retrosynthetic consideration for the construction
of open chain precursor 3.
There is precedence for the generation of C-8 nucleo-
philic purines by deprotonation.[11] If deprotonated purines
could be employed in a cross-coupling, the assembly would
be even further simplified. It would be sufficient to employ
a 6-halopurine as monomeric building block and to repeat a
sequence of deprotonation/cross-coupling. In the following
section our attempts to achieve a regioselective cross-coup-
ling are described. They turned out not to offer a suitable
route for dimer, trimer, nor tetramer formation. In the sub- Figure 2. Potential precursors for a metalated purine at C-8.
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H. Guthmann, M. Könemann, T. Bach
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Attempts to deprotonate purine 6 failed, whereas the purine. This switch turned out to be an effective remedy to
chloro compound 8 could be deprotonated readily with achieve the desired cross-coupling. Dimer 12 was obtained
LDA in THF (–78 °C).[11] Transmetalation to zinc was con- in 61% yield.
ducted under standard conditions[20] employing ZnCl2 in
It was quickly shown that the conversion of dimer 12
THF. Disappointingly, subsequent cross-coupling reactions into either one of the two compounds 13 and 14 was ex-
with 6-bromopurines proceeded sluggishly under a variety tremely facile. We therefore decided to give up the regiose-
of conditions in THF as the solvent. Standard palladium lective cross-coupling strategy and we concentrated on the
catalysts commonly employed for Neghishi reactions [e.g. repetitive activation of an appropriate position. Dimer 13
PdCl2(PPh3)2, Pd(PPh3)4, PdCl2(dppf), PdCl2(o-tol)3] did was prepared in 77% yield from cross-coupling product 12
not deliver any cross-coupling product neither at ambient by treatment with N-iodosuccinimide (NIS) in refluxing
nor at elevated (45 °C) temperature. The in situ generated THF. Iodide 14 was obtained quantitatively from chloride
palladium complex formed from Pd2(dba)3 (dba: dibenzyl- 12 by the previously mentioned iodo-de-chlorination (HI in
idene acetone) and P(2-furyl)3 (tfp: tri-2-furylphosphane) H2O, 0 °C). To proceed further it was considered to conduct
turned out to be slightly more effective. At 45 °C the cross either metalation at C-8 of compound 13 with subsequent
coupling with 9-benzyl-6-bromopurine delivered 12% of the cross-coupling to 11 or repeated cross-coupling with the
desired cross-coupling product and 24% of the C-8 dimer zinc reagent derived from 9 at C-6Ј of iodide 14. Disap-
of the chloro compound 8. Attempts to further optimize pointingly, the metalation of iodide 13 failed under the con-
this result remained fruitless.
ditions successfully applied to iodide 9. The failure also pre-
The bromo compound 7 offered the possibility to gener- cluded the connection of 13 and 14 employing 13 as the
ate a metalated intermediate while avoiding the presence of nucleophile and 14 as the electrophile. We shortly investi-
diisopropylamine. However, neither attempted halogen– gated, whether the alternative combination, i.e. a cross-
metal exchange reactions (BuLi, tBuLi) nor direct zincation coupling with iodide 13 as the electrophilic partner was
reactions[21] delivered the desired C-8 metalation product. possible. While 6-metalated purines were accessible[21] and
In the former reactions, decomposition occurred indicating could be coupled to trivial iodides, such as iodobenzene, the
the instability of the protecting groups towards strong lith- reaction with iodide 13 at C-8 was not feasible (Figure 3).
ium nucleophiles. A method, which had been previously
used[22] for a halogen–metal exchange/in situ zincation in
the presence of Boc groups, was not applicable to 7, either.
We speculated that the failure of the metalation was due to
the labile NBoc2 group at C-6 and decided to attempt the
metalation with a more robust substituent at C-6. The io-
dination of compound 8 at C-8 has been reported by Gund-
ersen et al.[9a] and made iodide 9 readily available
(Scheme 4).
Figure 3. Dimeric purines 13 and 14 with respective reactive sites
at C-8 and C-6Ј.
The alternative strategy, i.e. to attach the monomeric
building blocks successively to the 6-position, was evaluated
simultaneously. It eventually opened a route for the comple-
tion of the synthesis.
Completion of the Synthesis
Scheme 4. Bond formation between C-6 and C-8Ј by Negishi cross-
coupling.
In a test reaction, phenylzinc chloride (generated from
phenyllithium and zinc chloride) underwent a clean cross-
coupling with iodide 14 at carbon atom C-6Ј. The coupling
conditions were identical to the conditions found for the
transformation 11Ǟ12 [Pd2(dba)3/tfp at 45 °C in THF].
Successful Dimer Formation
Iodide 9 underwent a smooth direct metalation at C-8 The result indicated that an oxidative addition at the sub-
employing activated zinc[21] in N,N-dimethylacetamide strate was possible with the given catalyst system. The obvi-
(DMA) as the solvent. Cross-coupling attempts with 6-bro- ous way to proceed was to use the same conditions for the
mopurines, such as 10,[13] remained unsatisfactory, however. metalation as applied to 9 in the reaction 11Ǟ12 and to
Again, the best catalyst was found to be Pd2(dba)3/tfp but analogously attempt the cross-coupling with 14. Surpris-
yields of dimer 12 were disappointingly low. Iodide 11, ingly, the reaction, which had worked with the monomeric
which was easily prepared from chloride 8 by treatment iodide 11, did not work with the dimeric iodide 14. After
with aqueous HI at 0 °C (88% yield),[23] was eventually em- considerable experimentation we found that an iodine–mag-
ployed to increase the electrophilicity of the 6-substituted nesium exchange[24] was in contrast to the iodine–lithium
634
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Synthesis of a Cyclic Tetrameric Purine
FULL PAPER
exchange reaction complete and that after transmetalation trifluoroacetic acid (TFA). TFA solutions confirmed the ex-
to zinc (zinc bromide in THF) a successful cross-coupling pected highly symmetric structure in the NMR spectrum.
could be achieved [Pd2(dba)3/tfp at 45 °C in THF] upon Mass spectral analysis of the coupling product proved its
addition of lithium chloride (Scheme 5). Ideally, the lithium elemental composition as palladium complex [2·Pd]. Fur-
chloride was introduced as iPrMgBr·LiCl reagent.[25] Al- ther information about the site and coordination of palla-
though the conditions were found empirically, they can be dium could not be obtained.
rationalized in retrospective. The Grignard reagent is more
effective in the halogen–metal exchange step than butyllith-
Conclusion
ium. Lithium chloride enhances the rate of the oxidative
addition step in the catalytic cross-coupling cycle,[26] while
the use of the Pd2(dba)3/tfp as catalyst makes the transmet-
alation reasonably fast[27] and avoids hydro-de-halogenation
and substrate dimerization.
In summary, the tetrameric purine 2 was obtained from
known 9-benzyl-6-chloropurine (8) in eight synthetic steps
and in 17% overall yield as its palladium complex [2·Pd].
Key steps of the synthetic route are the consecutive Negishi
cross-coupling of the 8-zincated purine derived from 6-
chloro-8-iodopurine 9 and the ring closure by a Pd-cata-
lyzed reductive cyclization mediated by hexamethylditin.
The route is currently applied to other purines. In addition,
the spectroscopic properties of the relevant heterocycles are
investigated. Results of this study will be disclosed in due
course.
Scheme 5. Synthesis of the trimeric purines 15 and 16.
Experimental Section
With the conditions for a successful cross-coupling at di-
meric purine 14 in hand, we repeated the conversion General Remarks: All reactions involving water-sensitive chemicals
were carried out in flame-dried glassware with magnetic stirring
under argon. Common solvents [ether, ethyl acetate (EtOAc),
dichloromethane, methanol (MeOH), pentane (P) and toluene]
were distilled prior to use. Anhydrous dichloromethane, N,N-diiso-
propylamine and pyridine were distilled from CaH2, prior to use.
Relevant literature known compounds: 9-benzyl-6-bromopurine
(10),[13] iPrMgBr·LiCl,[25] and tri(2-furyl)phosphane (tfp).[28] All
other reagents were used as received. IR: Perkin–Elmer 241 FT-IR.
1H and 13C NMR: Bruker AC-250, AV-360 and AMX-500. Chemi-
cal shifts are reported relative to tetramethylsilane as internal refer-
11Ǟ12 under these conditions. The cross-coupling yield
could be improved to 85%. Moreover, we applied the very
same conditions to the cross-coupling of the analogous tri-
mer 16. To this end, chloride 15 was converted into the 6ЈЈ-
iodide 16 and the iodide was subjected to the conditions of
the cross-coupling reaction. We were pleased to note, that
the cross-coupling protocol proved its generality. The tetra-
meric chloride 3a (Scheme 6) was obtained from metalated
purine 9 and from iodide 16 in full analogy to 15. The unre-
active 8-position could be easily functionalized by NIS ence. The multiplicities of the 13C NMR signals were determined
by DEPT experiments. TLC: Merck glass sheets 0.25 mm silica gel
60-F254. Detection by UV and coloration with cerium ammonium
molybdate solution (CAM). Flash chromatography: Merck silica
gel 60 (230–400 mesh) (ca. 50 g for 1 g of material to be separated),
eluent given in brackets. MS: Finnigan MAT 8200 (EI), Finnigan
MAT 95S (HRMS), Bruker Biflex III and Ultraflex 2 (MALDI),
Finnigan LTQ FT (ESI). If not indicated, all bromine and chlorine
containing compounds gave the expected mass pattern, i.e. Cl (35Cl/
37Cl = 3:1), Br (79Br/81Br = 1:1), and Br2 (81Br81Br/79Br81Br/
79Br79Br = 1:2:1). For simplicity, the intensity of only one signal,
treatment (3aǞ3b). Attempts to convert the 6ЈЈЈ-chloro-8-
iodopurine 3b into the corresponding diiodide failed. Based
on the ease, with which cross-coupling reactions at 6-chlo-
ropurines occur,[6] we speculated that the 6ЈЈЈ-chloride 3b
should be sufficiently reactive for an oxidative addition by
palladium. Indeed, the desired tetrameric purine was gener-
ated by this means. Optimization unexpectedly revealed that
quantitative amounts of palladium are required to drive the
reaction to completion (Scheme 6). Dioxane was used as
solvent and tfp as phosphane ligand. The product was not i.e. M+(35Cl), M+(81Br), or M+(79Br81Br) is provided in the analyti-
cal data.
soluble in organic solvents but could only be dissolved in
9-Benzyl-6,8-dibromopurine (4): To a solution of diisopropylamine
(1.17 mL, 850 mg, 8.39 mmol) in THF (30 mL) was added at 0 °C
butyllithium in hexane (2.5 , 3.35 mL, 8.39 mmol). The solution
was treated dropwise at –78 °C with 9-benzyl-6-bromopurine (10)
(2.02 g, 6.99 mmol) in THF (15 mL). After 2 h, BrCN (1.48 g,
14.0 mmol) in THF (5 mL) was added dropwise. The reaction was
quenched with aqueous NH4Cl (5 mL) after 1.5 h. The reaction
mixture was diluted with EtOAc (100 mL), washed with aqueous
NaCl (100 mL), dried (Na2SO4), filtered and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography (P/EtOAc, 3:1) to afford 4 (872 mg, 2.37 mmol,
34%) as a light brown solid. M.p. 98 °C. Rf = 0.63 (P/EtOAc, 1:1).
1H NMR (360 MHz, CDCl3): δ = 5.48 (s, 2 H), 7.30–7.40 (m, 5
Scheme 6. Completion of the synthesis starting from the open tet-
rameric purine 3a.
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635

H. Guthmann, M. Könemann, T. Bach
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H), 8.70 (s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 48.3 (t), heated three times with a heatgun until evolution of ethylene oc-
127.9 (d), 128.7 (d), 129.0 (d), 134.0 (s), 134.1 (s), 134.4 (s), 141.4 curred. At ambient temperature TMSCl (200 µL) was added and
(s), 151.7 (s), 152.1 (d) ppm. IR (KBr): ν = 3062 cm–1 (w, Car-H), the reaction mixture was stirred for 5 min. A solution of 9-benzyl-
˜
3028 (w, Car-H), 1586 (s), 1560 (s), 1452 (s), 1428 (s), 1368 (m), 6-chloro-8-iodopurine (9) (2.50 g, 6.76 mmol) in DMA (4.5 mL)
1347 (m), 1325 (vs), 1246 (m), 1133 (m), 920 (w), 898 (w), 854 (w), was added dropwise and the reaction mixture was heated to reflux
726 (s). MS (EI, 70 eV): m/z (%) = 368 (15) [M+(81Br79Br)], 289
(42) [M+(81Br79Br) – 79Br], 274 (15), 91 (100) [C7H7+], 77 (28)
[C6H5+], 65 (40) [C5H5+]. HRMS calcd. for C12H879Br2N4
365.9116, found 365.9108.
for 1 min. After cooling to room temperature for 2.5 h THF (4 mL)
was added. Stirring was stopped and the remaining zinc dust was
allowed to settle (1.5 h). The supernatant liquid was transferred via
syringe to a solution of Pd2(dba)3 (216 mg, 5 mol-%), tfp (216 mg,
20 mol-%) and 9-benzyl-6-iodopurine (11) (1.59 g, 4.73 mmol) in
THF (10 mL). The reaction mixture was stirred at 45 °C for 16 h
and was quenched with aqueous NH4Cl (100 mL), extracted with
dichloromethane (3ϫ100 mL), washed with brine (100 mL) and
dried (Na2SO4). After filtration the solvent was removed under re-
duced pressure and the remaining residue was purified by flash
chromatography (P/EtOAc, 4:6) to give the desired product 12
(1.30 g, 2.87 mmol, 61%) as an off-white solid. M.p. 194 °C. Rf =
9-Benzyl-8-bromo-6-phenylpurine (5): Phenyl bromide (58.0 µL,
86.0 mg, 550 µmol) was dissolved in THF (1 mL), cooled to –78 °C
and butyllithium in hexane (2.5 , 240 µL, 600 µmol) was slowly
added. After stirring for 15 min at –78 °C ZnCl2 in THF (1 ,
1.00 mL, 1.00 mmol) was added and after an additional 1 h at
–78 °C the mixture was warmed to room temp. This solution was
added to a solution of PdCl2(PPh3)2 (35 mg, 10 mol-%) and 9-ben-
zyl-6,8-dibromopurine (4) (156 mg, 424 µmol) in THF (0.5 mL).
The reaction mixture was stirred at ambient temperature for 16 h
and quenched with aqueous NH4Cl (2 mL). The organic layer was
washed with water (2 mL) and aqueous NaCl (2 mL), dried
(Na2SO4), filtered and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography (P/
EtOAc, 9:1) to afford 5 (89.0 mg, 244 µmol, 58%) as a light yellow
solid. M.p. 134 °C. Rf = 0.64 (P/EtOAc, 7:3). 1H NMR (360 MHz,
CDCl3): δ = 5.52 (s, 2 H), 7.30–7.39 (m, 5 H), 7.50–7.59 (m, 3 H),
8.73–8.78 (m, 2 H), 9.01 (s, 1 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 48.1 (t), 128.3 (d), 128.9 (d), 129.2 (d), 129.4 (d), 130.2
(d), 131.7 (d), 131.7 (s), 133.5 (s), 135.2 (s), 135.5 (s), 153.0 (d),
1
0.16 (P/EtOAc, 4:6). H NMR (360 MHz, CDCl3): δ = 5.51 (s, 2
H), 6.24 (s, 2 H), 7.13 (s, 5 H), 7.28–7.40 (m, 5 H), 8.30 (s, 1 H),
8.84 (s, 1 H), 9.13 (s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ
= 47.6 (t), 48.1 (t), 127.5 (d), 127.8 (d), 127.9 (d), 128.5 (d), 128.8
(d), 129.2 (d), 131.8 (s), 132.1 (s), 134.6 (s), 136.0 (s), 145.8 (s),
147.2 (d), 149.0 (s), 151.8 (d), 152.2 (s), 152.8 (d), 153.3 (s), 153.4
(s) ppm. IR (KBr): ν = 3200–3600 cm–1 (w), 3062 (w), 1574 (vs),
˜
1558 (s), 1504 (m), 1452 (m), 1397 (w), 1339 (m), 1322 (s), 1247
(m), 1223 (w), 1152 (m), 1020 (w), 938 (w), 727 (m), 705 (m), 644
(w). MS (EI, 70 eV): m/z (%) = 452 (69) [M+], 361 (100) [M+ – Bn],
91 (95) [C7H7+]. C24H17ClN8 (452.90): calcd. C 63.65, H 3.78, N
24.74; found C 63.55, H 3.72, N 24.73.
154.0 (s), 154.2 (s) ppm. IR (KBr): ν = 3055 cm–1 (w, Car-H), 2925
˜
(w, C-H), 1582 (vs), 1555 (vs), 1496 (s), 1455 (s), 1430 (s), 1372
General Iodination Procedure with Aqueous HI: The respective 6-
(m), 1320 (s), 1235 (m), 1164 (m), 764 (m), 721 (m), 689 (m), 656 chloropurine (1 mmol) was added at 0 °C in small portions to vig-
(m). MS (EI, 70 eV): m/z (%) = 366 (31) [M(81Br)+], 364 (30)
orously stirred 57% aqueous HI (2 mL/mmol). After stirring at
[M(79Br)+], 285 (52) [M+ – Br], 91 (100) [C7H7+], 65 (14) [C5H5+]. 0 °C for 1 h the reaction mixture was carefully added to aqueous
HRMS calcd. for C18H1379BrN4 364.0324, found 364.0323.
NaHCO3 (10 mL/mmol). The aqueous layer was extracted with
dichloromethane (3ϫ10 mL/mmol), washed with aqueous NaS2O3
(10 mL/mmol) and brine (10 mL/mmol). The organic layer was
dried (Na2SO4), filtered, the solvent was removed under reduced
pressure. The procedure was repeated twice to achieve complete
iodination providing the desired 6-iodopurine.
9-Benzyl-6-chloropurine (8): To a suspension of adenine (20.6 g,
153 mmol) in DMF (400 mL) was added at 0 °C NaH (60% in
mineral oil, 6.11 g, 153 mmol). After 1 h stirring at room temp.
benzyl chloride (35.1 mL, 306 mmol) was added. After additional
stirring for 24 h the reaction was concentrated under reduced pres-
sure and H2O was added. The precipitate was filtered and washed
with H2O and Et2O. The remaining benzyladenine was dried in
vacuo. To benzyladenine (34.0 g, 151 mmol) in dry dichlorometh-
ane (500 mL) was added at 0 °C TMSCl (194 mL, 165 g, 1.51 mol).
After 10 min stirring tert-butyl nitrite (99.3 mL, 86.4 g, 755 mmol)
and benzyltriethylammonium chloride (68.9 g, 302 mmol) were
added. After 27 h stirring at ambient temperature the reaction mix-
ture was diluted with dichloromethane (300 mL), and then added
slowly to aqueous NaHCO3 (1 L). The aqueous layer was extracted
with dichloromethane (2ϫ300 mL). The combined organic layers
were washed with brine (400 mL), dried (Na2SO4), filtered and the
solvent was removed under reduced pressure. The residue was puri-
fied by flash chromatography (CH2Cl2/Et2O, 8:2) to afford 9-ben-
zyl-6-chloropurine (8)[19] (28.0 g, 115 mmol, 75%) as an off-white
solid. M.p. 86 °C (ref.[19] m.p. 86–87 °C). Rf = 0.41 (P/EtOAc, 1:1).
1H NMR (360 MHz, CDCl3): δ = 5.46 (s, 2 H), 7.27–7.42 (m, 5
H), 8.10 (s, 1 H), 8.79 (s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3):
δ = 48.0 (t), 128.0 (d), 128.9 (d), 129.3 (d), 131.3 (s), 134.4 (s), 144.9
(d), 151.1 (s), 151.8 (s), 152.3 (d) ppm. MS (EI, 70 eV): m/z (%) =
246 (23) [M(37Cl)+], 245 (32) [M(37Cl)+ – H], 244 (71) [M(35Cl)+],
243 (100) [M(35Cl)+ – H], 182 (15), 91 (74) [C7H7+], 65 (15) [C5H5+].
9-Benzyl-6-iodopurine (11): According to the General HI Iodin-
ation Procedure, iodide 11 was obtained from 9-benzyl-6-chloropu-
rine (8) (10.0 g, 44.6 mmol) as a light brown solid (13.2 g,
39.3 mmol, 88%). M.p. 142 °C (ref.[23] m.p. 152–154 °C). Rf = 0.35
(P/EtOAc, 1:1). 1H NMR (360 MHz, CDCl3): δ = 5.42 (s, 2 H),
7.28–7.37 (m, 5 H), 8.10 (s, 1 H), 8.65 (s, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 47.9 (t), 122.1 (d), 127.9 (d), 128.8 (d),
129.2 (s), 134.5 (s), 138.4 (s), 144.3 (d), 148.1 (s), 152.2 (d) ppm.
MS (EI, 70 eV): m/z (%) = 336 (7) [M+], 244 (44) [M+ – Bn], 243
(43), 209 (9) [M+ – I], 182 (10), 91 (100) [C7H7+], 65 (25) [C5H5+].
9,9Ј-Dibenzyl-6Ј-iodo-[6,8Ј]bipurine (14): According to the General
HI Iodination Procedure, iodide 14 was obtained from 6Ј-chloropu-
rine 12 (1.02 g, 2.26 mmol) as a light brown solid (1.31 g,
2.41 mmol, quant.). M.p. 144–148 °C. Rf = 0.40 (CH2Cl2/EtOAc,
1
4:6). H NMR (360 MHz, CDCl3): δ = 5.50 (s, 2 H), 6.17 (s, 2 H),
7.10–7.14 (m, 5 H), 7.28–7.35 (m, 2 H), 7.35–7.39 (m, 3 H), 8.25 (s,
1 H), 8.71 (s, 1 H), 9.12 (s, 1 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 47.6 (t), 48.0 (t), 123.7 (s), 127.5 (d), 127.8 (d), 127.9
(d), 128.5 (d), 128.8 (d), 129.2 (d), 132.3 (s), 134.6 (s), 135.9 (s),
138.6 (s), 145.9 (s), 147.0 (d), 148.3 (s), 149.6 (d), 151.8 (s), 152.7
(d), 153.3 (s) ppm. IR (KBr): ν = 3600–3200 cm–1 (s), 3059 (w, Ar-
˜
9,9Ј-Dibenzyl-6Ј-chloro-[6,8Ј]bipurine (12): Zinc dust (1.33 g,
20.3 mmol) in DMA (3 mL) and 1,2-dibromoethane (59 µL) were
H), 3031 (w), 1583 (s), 1552 (vs), 1496 (m), 1453 (s), 1396 (w), 1323
(s), 1233 (m), 1211 (m), 1133 (m), 1015 (w), 929 (w), 834 (w), 727
636
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 632–638

Synthesis of a Cyclic Tetrameric Purine
FULL PAPER
(s), 696 (m), 642 (m). MS (EI, 70 eV): m/z (%) = 544 (20) [M+],
453 (22), 361 (11), 336 (13), 91 (100) [C7H7+], 65 (15) [C5H5+].
HRMS calcd. for C24H17N8I 544.0621, found 544.0615.
ppm. 13C NMR (90.6 MHz, CDCl3): δ = 47.7 (t), 48.0 (t), 49.3 (t),
111.3 (s), 127.4 (d), 127.6 (d), 127.7 (d), 127.8 (d), 127.9 (d), 128.3
(d), 128.5 (d), 128.6 (d), 129.0 (d), 131.8 (s), 132.0 (s), 132.3 (s),
134.4 (s), 134.6 (s), 136.0 (s), 136.1 (s), 136.3 (s), 144.3 (s), 146.5
(s), 146.6 (sЈ), 150.4 (s), 150.6 (s), 151.6 (d), 152.1 (s), 152.4 (d),
152.8 (s), 153.2 (d), 153.7 (s), 154.5 (s), 154.6 (s), 154.8 (s) ppm. IR
9,9Ј,9ЈЈ-Tribenzyl-6ЈЈ-iodo-[6,8Ј,6Ј,8ЈЈ]terpurine (16): According to
the General HI Iodination Procedure, iodide 16 was obtained from
6ЈЈ-chloropurine 15 (1.02 g, 2.26 mmol) as a light brown solid
(825 mg, 1.10 mmol, 95%). M.p. 129 °C. Rf = 0.38 (CH2Cl2/
MeOH, 95:5). 1H NMR (360 MHz, [D6]DMSO): δ = 5.58 (s, 2 H),
6.03 (s, 2 H), 6.05 (s, 2 H), 6.98–7.18 (m, 10 H), 7.30–7.39 (m, 5 H),
8.78 (s, 1 H), 8.93 (s, 1 H), 9.14 (s, 1 H), 9.21 (s, 1 H) ppm. 13C
NMR (90.6 MHz, [D6]DMSO): δ = 46.6 (d), 46.9 (d), 47.1 (d),
124.1 (d), 126.8 (d), 127.0 (d), 127.4 (d), 127.5 (d), 127.9 (d), 128.2
(d), 128.3 (d), 128.6 (d), 131.4 (s), 131.9 (s), 135.8 (s), 136.0 (s),
137.7 (s), 144.5 (s), 145.7 (s), 148.6 (s), 148.9 (d), 149.2 (s), 150.4
(s), 151.4 (d), 152.6 (d), 152.7 (d), 152.8 (s), 153.8 (s) ppm. IR
(KBr): ν = 3445 cm–1 (br. m), 3062 (w), 3031 (m), 1576 (vs), 1496
˜
(m), 1452 (s), 1341 (s), 1246 (m), 1151 (m), 933 (w), 726 (s), 696
(m). MS (MALDI): m/z = 995.077 [M+ + H], 1017.064 [M+ + Na].
General Procedure for the Negishi Cross-Coupling: To 9-benzyl-6-
chloro-8-iodopurine (9) (1.4 equiv.) was added iPrMgBr·LiCl[26]
(0.72  in THF, 1.4 equiv.) at –40 °C. After 15 min stirring at
–40 °C ZnBr2 (1  in THF, 1.4 equiv.) was added, the stirring was
continued for 20 min at –40 °C and then the mixture was allowed
to reach ambient temperature. The zinc reagent was transferred via
syringe to a solution of Pd2(dba)3 (5 mol-%), tfp (20 mol-%) and
the corresponding 6-iodopurine (1.0 equiv.) in THF or DMA
(10 mL/mmol). The reaction mixture was stirred at 45 °C for 16 h
and then quenched with aqueous NH4Cl (20 mL/mmol), extracted
with dichloromethane (3ϫ20 mL/mmol), washed with aqueous
NaCl (20 mL/mmol) and dried (Na2SO4). After filtration the sol-
vent was removed under reduced pressure and the remaining resi-
due was purified by flash chromatography to afford the desired
product.
(KBr): ν = 3600–3200 cm–1 (m), 3062 (w), 3030 (m), 1574 (vs), 1557
˜
(vs), 1496 (m), 1455 (s), 1328 (s), 1236 (m), 1141 (m), 1030 (w), 929
(w), 728 (s), 698 (m), 642 (w). MS (MALDI): m/z = 752.996 (100)
[M+ + H].
General Iodination Procedure with N-Iodosuccinimide (NIS): A mix-
ture of 8-hydropurine (1 equiv.) and NIS (3 equiv.) in dry THF
(10 mL/mmol) was heated at reflux for 72 h. The solvent was evap-
orated under reduced pressure and the residue was dissolved in
dichloromethane (20 mL/mmol), washed with aqueous NaS2O3
(10 mL/mmol), aqueous NaCl (10 mL/mmol) and dried (Na2SO4).
After filtration the solvent was removed under reduced pressure
and the remaining residue was purified by flash chromatography
to give the desired 8-iodopurine.
9,9Ј,9ЈЈ-Tribenzyl-6ЈЈ-chloro-[6,8Ј,6Ј,8ЈЈ]terpurine (15): According to
the General Cross-Coupling Procedure, terpurine 15 was obtained
from 9-benzyl-6-chloro-8-iodopurine (9) (1.01 g, 2.76 mmol) and
6Ј-iodopurine 14 (970 mg, 1.84 mmol) in THF as an off-white solid
(937 mg, 1.41 mmol, 77%). M.p. 133 °C. Rf = 0.25 (EtOAc/EtOH,
99:1). 1H NMR (500 MHz, CDCl3): δ = 5.50 (s, 2 H), 6.36 (s, 4 H),
7.05–7.12 (m, 5 H), 7.14–7.18 (m, 5 H), 7.26–7.36 (m, 5 H), 8.30 (s,
1 H), 8.84 (s, 1 H), 9.11 (s, 1 H), 9.18 (s, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 47.5 (t), 47.8 (t), 48.0 (t), 127.4 (d), 127.5
(d), 127.7 (d), 127.8 (d), 128.4 (d), 128.5 (d), 128.7 (d), 129.2 (d),
131.9 (s), 132.1 (s), 132.6 (s), 134.6 (s), 136.0 (s), 136.2 (s), 145.8
(s), 146.5 (s), 147.1 (s), 149.4 (s), 150.5 (s), 151.6 (d), 152.3 (s),
152.7 (d), 152.8 (d), 153.4 (s), 153.5 (s), 154.7 (s) ppm. IR (KBr):
9-Benzyl-6-chloro-8-iodopurine (9): According to the General NIS
Iodination Procedure, iodide 8 was obtained from 6-chloropurine
8 (1.96 g, 8.03 mmol) and NIS (9.03 g, 40.2 mmol) as a white solid
(3.00 g, 8.03 mmol, quant.). M.p. 136 °C (ref.[9a] m.p. 134–136 °C).
Rf = 0.68 (CH2Cl2/Et2O, 9:1). 1H NMR (360 MHz, CDCl3): δ =
5.47 (s, 2 H), 7.33 (s, 5 H), 8.71 (s, 1 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 49.7 (t), 108.0 (s), 127.9 (d), 128.6 (d), 129.0 (d), 133.8
(s), 134.3 (s), 149.4 (s), 152.1 (d), 153.1 (s) ppm. MS (EI, 70 eV):
m/z (%) = 370 (28) [M+], 243 (85) [M+ – I], 127 (25) [I+], 91 (100)
[C7H7+], 77 (35) [Ph+], 65 (42) [C5H5+], 51 (18) [C4H3+].
ν = 3600–3200 cm–1 (m), 3062 (w), 3031 (m), 2928 (w), 1654 (s),
˜
1577 (vs), 1560 (s), 1497 (m), 1453 (s), 1327 (s), 1243 (m), 1146 (m),
1030 (w), 936 (w), 727 (s), 696 (m), 642 (w). MS (MALDI): m/z =
661.053 [M+].
9,9Ј-Dibenzyl-6Ј-chloro-8-iodo-[6,8Ј]bipurine (13): According to the
General NIS Iodination Procedure, iodide 13 was obtained from
9,9Ј-dibenzyl-6Ј-chloro-[6,8Ј]bipurine (12) (1.97 g, 4.36 mmol) and
NIS (2.94 g, 16.1 mmol) as a white solid (1.94 g, 5.35 mmol, 77%).
M.p. 236 °C. Rf = 0.65 (CH2Cl2/EtOAc, 1:1). 1H NMR (360 MHz,
CDCl3): δ = 5.53 (s, 2 H), 6.22 (s, 2 H), 7.12 (s, 5 H), 7.30–7.35 (m,
5 H), 8.85 (s, 1 H), 9.05 (s, 1 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 48.1 (t), 49.3 (t), 111.7 (s), 127.5 (d), 127.8 (d), 127.9
(d), 128.5 (d), 128.6 (d), 128.9 (d), 131.8 (s), 134.3 (s), 134.4 (s),
135.9 (s), 144.2 (s), 148.7 (s), 151.6 (d), 152.4 (s) 152.9 (d), 153.4
9,9Ј,9ЈЈ,9ЈЈЈ-Tetrabenzyl-6ЈЈЈ-chloro-[6,8Ј,6Ј,8ЈЈ,6ЈЈ,8ЈЈЈ]quaterpurine
(3a): According to the General Cross-Coupling Procedure, quater-
purine 3a was obtained from 9-benzyl-6-chloro-8-iodopurine (9)
(184 mg, 498 µmol) and 6ЈЈ-iodopurine 16 (250 mg, 333 µmol) in
DMA as a light brown solid (132 mg, 152 µmol, 46%). M.p.
160 °C. Rf = 0.25 (CH2Cl2/EtOAc/MeOH, 49:50:1). 1H NMR
(500 MHz, CDCl3): δ = 5.53 (s, 2 H), 6.36 (s, 2 H), 6.48 (s, 2 H),
3
3
6.55 (s, 2 H), 6.81 (d, J = 7.1 Hz, 2 H), 6.89 (t, J = 7.1 Hz, 2 H),
6.97 (t, 3J = 7.1 Hz, 1 H), 7.12–7.21 (m, 10 H), 7.34–7.37 (m, 2 H),
7.39–7.43 (m, 3 H), 8.39 (s, 1 H), 8.58 (s, 1 H), 9.14 (s, 1 H), 9.18
(s, 1 H), 9.21 (s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 47.6
(t), 47.9 (t), 48.0 (t), 48.6 (t), 127.1 (d), 127.4 (d), 127.6 (d), 127.8
(d), 128.0 (d), 128.3 (d), 128.5 (d), 128.6 (d), 128.9 (d), 129.3 (d),
131.9 (s), 132.5 (s) 134.5 (s), 136.1 (s), 136.2 (s), 136.4 (s), 145.8 (s),
146.2 (s), 146.5 (s), 147.4 (d), 150.0 (s), 150.8 (s), 151.1 (s), 151.5
(d), 152.2 (d), 152.5 (d), 153.6 (s), 153.7 (d), 154.5 (s), 155.0 (s)
(s), 154.5 (s) ppm. IR (KBr): ν = 3600–3300 cm–1 (m), 3032 (m),
˜
1581 (vs), 1496 (s), 1466 (s), 1452 (vs), 1413 (s), 1350 (s), 1310 (s),
1250 (s), 1153 (s), 1029 (w), 945 (m), 859 (w), 720 (s), 649 (m), 602
(w), 571 (w), 536 (w). MS (EI, 70 eV): m/z (%) = 578 (7) [M+], 451
(41) [M+ – I], 91 (100) [C7H7+]. C24H16ClIN8 (578.80): calcd. C
49.80, H 2.79, N 19.36; found C 50.08, H 2.74, N 19.16.
9,9Ј,9ЈЈ,9ЈЈЈ-Tetrabenzyl-6ЈЈЈ-chloro-8-iodo-[6,8Ј,6Ј,8ЈЈ,6ЈЈ,8ЈЈЈ]quat-
erpurine (3b): According to the General NIS Iodination Procedure,
iodide 3b was obtained from purine 3a (88 mg, 101 µmol) and NIS
(68 mg, 303 µmol) as a light brown solid (59.4 mg, 59.3 µmol,
59%). M.p. 177 °C. Rf = 0.25 (EtOAc/EtOH, 95:5). 1H NMR
(360 MHz, CDCl3): δ = 5.51 (s, 2 H), 6.24 (s, 2 H), 6.40 (s, 2 H),
6.49 (s, 2 H), 6.92–7.02 (m, 5 H), 7.10–7.18 (m, 10 H), 7.28–7.38
ppm. IR (KBr): ν = 3445 cm–1 (m br.), 3062 (w), 3031 (m), 1575
˜
(vs), 1496 (m), 1455 (s), 1328 (s), 1236 (m), 1141 (m), 1030 (w), 929
(w), 728 (s), 698 (m), 643 (w). MS (MALDI): m/z = 869.45 [M+
+
H], 891.45 [M+ + Na].
9-Benzyl-[6,8Ј]cyclotretrapurine (2·Pd): Purine 3b (50.0 mg,
(m, 5 H), 8.68 (s, 1 H), 9.04 (s, 1 H), 9.16 (s, 1 H), 9.22 (s, 1 H) 50.3 µmol), Pd2(dba)3 (23.0 mg, 50.3 µmol), tfp (46.0 mg,
Eur. J. Org. Chem. 2007, 632–638
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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637

H. Guthmann, M. Könemann, T. Bach
FULL PAPER
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200 µmol) and Me3SnSnMe3 (20.8 µL, 106 µmol) were stirred at
85 °C in 1,4-dioxane (20 mL) for 2 d. The reaction mixture was
filtered and washed with Et2O. The residue was dissolved in TFA
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9.86 (s, 4 H) ppm. 13C NMR (90.6 MHz, [D]TFA): δ = 53.1 (d),
128.6 (s), 130.5 (d), 131.4 (d), 131.7 (d), 135.7 (s), 144.0 (s), 146.4
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Acknowledgments
This work has been generously supported by the BASF AG (Lud-
wigshafen). We thank Drs. R. Müller-Mall and H. Reichelt for
valuable discussions and their continuing interest in this research.
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ˇ
Received: August 17, 2006
Published Online: November 29, 2006
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ˇ
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