Facilitation of displacements at the 6-position of purines by the use of 1,4-diazabicyclo[2.2.2]octane as leaving group

Article abstract of DOI:10.1039/a608207f

Reactions of 6-chloropurines with 1,4-diazabicyclo[2.2.2]octane (DABCO) give the corresponding 'DABCO-purines' 1a-d, which undergo facile displacement reactions with alkoxides in dimethyl sulfoxide to afford 6-oxy-substituted purines.

Full text of DOI:10.1039/a608207f

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Facilitation of displacements at the 6-position of purines by the use
of 1,4-diazabicyclo[2.2.2]octane as leaving group
Nicola K. Lembicz, Sharon Grant, William Clegg, Roger J. Griffin,
Sarah L. Heath and Bernard T. Golding*
Department of Chemistry, Bedson Building, The University of Newcastle upon Tyne,
Newcastle upon Tyne NE1 7RU, UK
Reactions of 6-chloropurines with 1,4-diazabicyclo-
2.2.2]octane (DABCO) give the corresponding ‘DABCO-
purines’ 1a–d, which undergo facile displacement reactions
with alkoxides in dimethyl sulfoxide to afford 6-oxy-
substituted purines.
directly from the reaction mixture. Similarly, 6-chloro- and 2,6-
[
dichloro-purine gave the corresponding ‘DABCO-purines’ 1b
and 1c,† respectively. The purines 1a–c could also be prepared
in ethanol as reaction medium, and indeed this solvent was used
to treat 2-amino-6-chloropurine 9-ribofuranoside with 2 equiv.
of DABCO (48 h, room temp.) to afford 80–90% of the deriv-
ative 1d,† which again directly precipitated from the reaction.
The structure of compound 1b was confirmed by crystal
structure analysis (see Fig. 1)‡ and shows the expected system of
For the development of inhibitors of the DNA repair protein
1
6
-O-methylguanine DNA-methyltransferase (MGMT), we
required a method for preparing 6-oxy-substituted purines.
Such compounds, in which the substituent is e.g. benzyloxy or
2
3
substituted benzyloxy, 2-thienylmethoxy or substituted
4
allyloxy, are known to be potent irreversible inactivators of
MGMT. We have found a convenient and efficient method for
preparing a variety of 6-oxy-substituted purines by employing
1
,4-diazabicyclo[2.2.2]octane (DABCO) as the leaving group in
substitution reactions at C-6 of purines.
A standard method to achieve displacements at C-6 of pur-
ines utilises a 6-chloropurine as starting material and proceeds
5
–8
via an intermediate 6-trimethylammonio species. Trimethyl-
ammonium is a better leaving group than chloride in the
addition–elimination mechanism leading to displacement of
the 6-substituent by a nucleophile. However, the production of
a 6-trimethylammoniopurine requires reaction of the corres-
ponding 6-chloropurine with trimethylamine, which is prob-
lematical, especially on a large scale, because of the volatility,
toxicity and unpleasant odour of trimethylamine. Furthermore,
the reaction of a 6-trimethylammoniopurine with a nucleophile
can display attack of the nucleophile on a methyl of the tri-
methylammonium group (S 2 displacement) competitive with

9
addition–elimination at C-6.
We have found that trimethylamine can be replaced by either
1
-azabicyclo[2.2.2]octane (quinuclidine) or 1,4-diazabicyclo-
Fig. 1 The structure of 1b showing the labelling of the independent
non-hydrogen atoms and the hydrogen bonding. All atoms, except for
C(5Ј), C(6Ј), their symmetry-equivalents and the hydrogen atoms
attached to C(2Ј) and C(3Ј), lie on crystallographic mirror planes.
[
2.2.2]octane (DABCO), with the latter being more attractive
because of its much lower cost and greater effectiveness (faster
rate of displacement compared to chloride or quinuclidine).
Thus, reaction of 1  2-amino-6-chloropurine in dimethyl sul-
foxide with 5.5 equiv. of DABCO for 12 h at room temperature
gave a 90% yield of analytically pure 2-amino-6-(1-azonia-4-aza-
bicyclo[2.2.2]oct-1-yl)purine chloride 1a,† which precipitated
‡ Crystal data for 1b: [C11
H N ]ClؒH O, M = 284.76, orthorhombic,
15 6 2
space group Pnma, a = 11.9284(10), b = 6.8762(6), c = 15.5576(13) Å,
3
U = 1276.1(2) Å , Z = 4 (all structural fragments lie on mirror planes),
–
3
D = 1.482 g cm , F (000) = 600, T = 160 K. 7559 reflections were meas-
c
ured on a Siemens SMART CCD area-detector diffractometer (Mo-Kα
–1
radiation, λ = 0.710 73 Å, µ = 0.30 mm , 2θ < 57Њ). Structure solution
was by direct methods, and refinement by full-matrix least-squares on
2
F
for all 1646 independent reflections (Rint = 0.0284), with anisotropic
displacement parameters an2d freely refined isotropic
H
atoms.
2
2
2
2
¹
Rw = {Σ[w(Fo Ϫ Fc ) ]/Σ[w(Fo ) ]} ² = 0.0827 for all data, conventional
2
2
R = 0.0309 on F values for 1538 reflections with Fo > 2σ(Fo ), goodness
2
of fit = 1.103 on F values for all data and 149 refined parameters.
Programs: Siemens SMART and SAINT control and integration
software, Siemens SHELXTL and local programs.
Atomic coordinates, thermal parameters and bond lengths and
angles have been deposited at the Cambridge Crystallographic Data
Centre (CCDC). See Instructions for Authors, J. Chem. Soc., Perkin
Trans 1, 1997, Issue 1. Any request to the CCDC for this material
should quote the full literature citation and the reference number 207/83.
†
New compounds gave analytical and spectroscopic data in accord
with their assigned structures.
J. Chem. Soc., Perkin Trans. 1, 1997
185

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interlocked boat-like 6-membered rings for the DABCO sys-
tem. The free nitrogen atom of the DABCO is hydrogen-
bonded to a water molecule (the presence of which was also
indicated by elemental analysis), which acts as a bridge to a
chloride anion. The latter is bonded to the hydrogen atom at
N-9 of another purine molecule, to give continuousؒؒؒcation ؒؒؒ
anion ؒ ؒ ؒ water ؒ ؒ ؒ hydrogen-bonded chains.
Compounds 1a–d undergo facile displacement reactions with
alkoxides in dimethyl sulfoxide, with a typical example being
shown in Scheme 1. Results for 1a leading to 6-substituted
purines 2a–h† are summarised in Table 1. The order of
displacement of groups from the 6-position of purines is
100:10:5:1). The slower displacement of DABCO vs. Me N is
probably a steric effect (more crowded transition state for
3
DABCO in the addition–elimination pathway). However, we
have not observed competing attack of the alkoxide on a
DABCO methylene group, and the only disadvantage to the use
of DABCO instead of trimethylamine is the slower rate of reac-
tion of the DABCO derivatives. There are several advantages of
using DABCO over chloro and trimethylammonio moieties,
besides those already mentioned. Reactions with DABCO-
purines are easy to monitor by thin layer chromatography
(TLC) because they exhibit fluorescent spots at relatively low
R , which disappear as the reaction proceeds. Furthermore, the
f
Me N > DABCO > quinuclidine > Cl (relative rates ca.
desired product is very easy to separate from the starting
DABCO-purine, because of the latter’s greater polarity and
solubility in water. In contrast, chloropurines often have a simi-
3
lar R (TLC on silica) to the derived 6-substituted purine (e.g.
f
with C alkoxy groups), which makes separation difficult by
4
normal phase chromatography.
In a previously reported preparation of 2,4-dinitrophenyl
ethers from carbohydrates with a free hydroxy group, the
alcohol (e.g. a mixture of the anomers of 2,3,4,6-tetra-O-
acetyl--galactopyranose) was treated with 2,4-dinitro-
fluorobenzene and an excess of DABCO in dimethylform-
Scheme 1
1
0
amide. The mechanism of this reaction was not discussed,
but it seems likely that it proceeds via 1-(1-azonia-4-
azabicyclo[2.2.2]oct-1-yl)-2,4-dinitrobenzene fluoride. Indeed,
such adducts have been shown to be intermediates in reactions
Table 1 Reactions of DABCO-purine 1a with alcohols leading to
a
products 2a–h
1
1
of DABCO with 2,4-dinitrochlorobenzene and quinuclidine
1
2
with picryl chloride.
We thank ZENECA, EPSRC (for provision of an X-ray
diffractometer) and the North of England Cancer Research
Campaign for support of this research.
Reaction
ROH
time/h
Product
Yield (%)
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a
The alcohol (5.5 equiv.) was added to a stirred suspension of sodium
hydride (2.0 equiv.) in anhydrous dimethyl sulfoxide under nitrogen at
room temperature. After 1 h the DABCO-purine 1a (1 equiv.; 1  in
DMSO)wasadded and themixturewasstirred at room temperatureuntil
the reaction was complete (an aliquot was assayed by TLC and UV spec-
troscopy: shift from λmax 316 to 280 nm). The base was neutralised by
addition of glacial acetic acid and the solvent was removed in vacuo. The
residue was absorbed onto silica and the product was purified by medium
pressure chromatography (elution with 8% v/v MeOH in CH Cl ).
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Paper 6/08207F
Received 4th December 1996
Accepted 4th December 1996
2
2
1
86
J. Chem. Soc., Perkin Trans. 1, 1997