Dimethylpyridin-4-ylamine-catalysed alcoholysis of 2-amino-N,N,N-trimethyl-9H-purine-6-ylammonium chloride: An effective route to O6-substituted Guanine derivatives from alcohols with poor nucleophilicity

Article abstract of DOI:10.1055/s-2002-20970

Dimethylpyridin-4-ylamine (DMAP)-catalysed reactions of 2-amino-N,N,N-trimethyl-9H-purine-6-ylammonium chloride with fluoropyridine methoxides and various other alkoxides in DMSO at 60°C gave the corresponding coupling products in moderate to good yields between 20-87%. Under these reaction conditions, fluorinated O⁶-substituted Guanine derivatives have been synthesized which could not be obtained via known analogous literature procedures. The respective yields of known O⁶-substituted guanine derivatives could be significantly improved by using this method. The efficient use of DMAP as an excellent nucleophilic catalyst in the syntheses of O⁶-substituted Guanine derivatives has thus been demonstrated.

Full text of DOI:10.1055/s-2002-20970

538
PAPER
Dimethylpyridin-4-ylamine-Catalysed Alcoholysis of 2-Amino-N,N,N-
trimethyl-9H-purine-6-ylammonium Chloride: An Effective Route to O6-
Substituted Guanine Derivatives from Alcohols with Poor Nucleophilicity
An
Effective Rou
a
te to O6-Sulbstitute
fd Guanine
De
S
rivative
s
chirrmacher, Björn Wängler, Esther Schirrmacher, Thorsten August, Frank Rösch
Department of Nuclear Chemistry, Section Radiopharmaceutical Chemistry, University of Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz,
Germany
Fax +49(6131)3924510; E-mail: schirrmacher@mail.kernchemie.uni-mainz.de
Received 20 November 2001; revised 10 January 2002
respective benzyl- and hetarylmethyl alcohols was proved
Abstract: Dimethylpyridin-4-ylamine (DMAP)-catalysed reac-
to be the most suitable method by McElhinney et al.6
tions of 2-amino-N,N,N-trimethyl-9H-purine-6-ylammonium chlo-
ride with fluoropyridine methoxides and various other alkoxides in
DMSO at 60 °C gave the corresponding coupling products in mod-
erate to good yields between 20–87%. Under these reaction condi-
tions, fluorinated O6-substituted Guanine derivatives have been
synthesized which could not be obtained via known analogous liter-
ature procedures. The respective yields of known O6-substituted
guanine derivatives could be significantly improved by using this
method. The efficient use of DMAP as an excellent nucleophilic
catalyst in the syntheses of O6-substituted Guanine derivatives has
thus been demonstrated.
We applied this method to the reaction of several fluoro-
pyridine methanols, which have a decreased nucleophilic-
ity due to their electron-withdrawing N and F atoms.
Different hetaryl methanols were synthesized as shown in
Table 1. The coupling of these fluorine bearing alcohols
with the appropriate guanine precursor 1 did not give any
product even under modified conditions like increased
temperature and extended reaction time. In addition, some
other alkoxides gave only low yields, even when the
method of McElhinney et al. was applied (Scheme 1).6
Therefore, we modified this procedure and investigated
DMAP as a nucleophilic catalyst in DMSO at 60 °C.
Key words: catalysis, coupling, fluorine, nucleophilic aromatic
substitution, pyridines
The development of new efficient methods for the synthe-
sis of O6-substituted guanines continues to receive much
attention, in part due to the fact that O6-substituted gua-
nines containing a benzyl or hetarylmethyl moiety are of
great medical interest. O6-Substituted guanines were
shown to be important synthetic targets as they effectively
inactivate O6-alkylguanine-DNA alkyltransferase (MG-
MT).1
R1-4
NaH
R1-4-OH
O
N
N
N
H2N
N
DMSO/RT-80°C
N+
H
N
N
Cl-
N
H
H2N
N
1
R5-10
There are some synthetic methods described in the litera-
ture to obtain these compounds. Displacing the halogen
with alkoxides from 2-amino-6-chloropurine at 130 °C
with the alcohol as a solvent was introduced by Bowels et
al.2 for the synthesis of O6-benzyl guanine. Annulation of
an imidazole ring to 6-(benzyloxy)-2,4,5-triaminopyrimi-
dine at 180 °C was applied by Robins et al.3 The O6-sub-
stituted guanines so far described4 have usually been
synthesized rather inefficiently by the former method
since the preparation of 2,4,5-triaminopyrimidines is very
unattractive. However, the method of Bowels et al.2 is not
useful in multistep syntheses if the starting alcohol is ei-
ther expensive or difficult to prepare. Linn et al. applied
DABCO as a catalyst for the alcoholysis reaction of 2-
amino-9-benzyl-6-chloro-9H-purine mainly with primary
and secondary alcohols.5 The reaction of 2-amino-N,N,N-
trimethyl-1H-purine-6-ammonium chloride (1) with the
O
NaH
R5-10-OH
N
N
N
H
DMSO/RT
H2N
N
low yields
Scheme 1 McElhinney’s method of preparing O6-substituted guani-
ne derivatives
DMAP is known for its excellent qualities as a catalyst in
acylation and methylation reactions7 and has never been
applied before to the syntheses of O6-substituted Guanine
derivatives. There are some indications of pyridinium
salts of Guanine and Purine derivatives reported in the lit-
erature for the syntheses of valuable intermediates in nu-
cleoside chemistry8 but not for the syntheses of O6-
(hetarylmethyl) guanines.
The reaction between 1 and several alcohols and the
mechanism of DMAP-catalysis suggested are shown in
Scheme 2. Under DMAP-catalysis, the desired com-
pounds could be obtained in yields ranging from 20–87%
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
1437-210X,E;2002,0,04,0538,0542,ftx,en;Z12701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
An Effective Route to O6-Substituted Guanine Derivatives
539
within 72 hours in DMSO at 60 °C. The trimethylammo-
nium salt 1 was first synthesized by Kilburis and Lister.9
The original synthetic route of 1 includes the low temper-
ature condensation of gaseous trimethylamine (TMA)
which is problematic owing to its high volatility and sub-
sequent reaction with 2-amino-6-chloropurine. To avoid
that critical step and to make the preparation more conve-
nient, we established a synthesis starting from commer-
cially available ethanolic TMA solution (4.2 N) and 2-
amino-6-chloropurine.
Table 1 Syntheses of Hetaryl Methanols R1–10 from Their Corre-
sponding Precursors
Entry Precursors (%)a
Lit.
YieldofCorresponding Lit.
Alcohols R1–10–OHb
1
Ref.10
-
F
F
N
N
COOH
CH2OH
2
Ref.11
Ref.11
F
F
The DMAP-intermediate 2 could be prepared directly by
the reaction of 2-amino-6-chloropurine with DMAP (2.5
equiv) in an anhydrous DMF/DMSO mixture at ambient
temperature within 72 hours. The reaction was slow and
the precipitated product could not be observed until after
48 hours of reaction time. Using the trimethylammonium
salt 1 as starting material, however, traces of the unreacted
precursor could not be removed in any way (Scheme 2).
N
COOH
N
CH2OH
3
4
Ref.12
Ref.11
Ref.14
Ref.11
N
N
F
CH2OH
F
COOH
F
F
N
N
COOH
COOH
CH2OH
CH2OH
Interestingly, the direct approach of the coupling between
the isolated DMAP-intermediate 2 and the alcohols in
DMSO within 72 hours gave lesser yields than under
DMAP catalysis only, probably because of the low solu-
bility of 2 in DMSO. Unfortunately, the purification meth-
od for the coupling products described by McElhinney et
al.,6 namely diluting the crude reaction mixture with di-
ethyl ether and subsequent washing of the resulting pre-
cipitate with water to obtain the product was not suitable
for the O6-(fluoropyridinylmethyl)guanines because of
their good solubility in diethyl ether. In the case of the oth-
er compounds, the DMAP-intermediate could not be re-
moved by McElhinney’s method either. Therefore,
purification via column chromatography was necessary.
5
6
Ref.13
Ref.15
Ref.16
Cl
Cl
N
N
c
-
N
N
F
CH2OH
F
COOH
7
8
Ref.17
Ref.19
Ref.21
Ref.18
Ref.20
-
O
S
O
S
COOCH3
CH2OH
N
N
CHO
CH2OH
CH2OH
N
N
9
S
COOCH3
S
Table 2 summarizes the results of the coupling reaction
between 1 and the hetaryl methoxides under DMAP-catal-
ysis and by using 2 directly in comparison to known pro-
cedures which we carried out separately.
N
N
c
10
-
Ref.22
S
S
Br
CHO
Br
CH2OH
In summary we have demonstrated the catalytic effect of
DMAP on the synthesis of some O6-(hetarylmethyl) gua-
nine derivatives in DMSO at a reaction temperature of
60 °C which could not be synthesized via the literature
procedure6 (in the case of fluorinated compounds) or only
gave significantly lower yields. The intermediate 2 was
synthesized directly and supports our suggested mecha-
nism of the interaction of DMAP during the coupling re-
action of alkoxides and 1. The pyridinium compound 2
could be reacted with the deprotonated alcohols under the
same reaction conditions but gave significantly lower
yields of the alcoholysis product within the same reaction
time probably due to its low solubility in DMSO. Never-
theless, compound 2 could become a useful tool for the
syntheses of O6-substituted Guanine derivatives. In par-
ticular, this reaction provides an improved synthetic path-
way for the syntheses of O6-substituted guanine
derivatives especially when alcohols with decreased nu-
cleophilicity are used.
a Carboxylic acids were all synthesized via oxidation of the corre-
sponding methylpyridines with potassium permanganate in water un-
der reflux.
b Pyridinemethanols were synthesized according to a published gen-
eral literature procedure11 and all compounds gave satisfactory spec-
troscopic data (1H, 13C and 19F NMR, FD MS).
c Commercially available.
Analytical TLC was performed using plates from Merck (Silica gel
60 F254, thickness 0.25 mm). Column chromatography was per-
formed with silica gel (Si-60, Merck). All solvents for column chro-
1
matography were p.a. grade. H, 19F and 13C NMR spectra were
recorded using a DRX 400 spectrometer (Bruker Analytik GmbH).
Chemical shifts are quoted in (ppm) downfield from TMS as an
internal standard. MS spectra were obtained on a MAT90 spectrom-
eter (Finnigan). Elemental analyses were performed with an EL2
system (Elementar vario). Melting points were determined on an
Electrothermal 9100 apparatus and are uncorrected.
Synthesis 2002, No. 4, 538–542 ISSN 0039-7881 © Thieme Stuttgart · New York

540
R. Schirrmacher et al.
PAPER
DMAP-intermediate
N
N
N
R1-10
N+
N+
O
N
N
N
R1-10-OH/NaH
DMSO, 60°C
N
N
N
N
Cl-
Cl-
DMSO/60°C
- Me3N
N
H
N
N
H
H2N
N
1
H2N
N
H2N
H
N
lower
yields
Cl
N
+ DMAP
RT
N+
R1-10-OH/NaH
DMSO, 60°C
N
N
N
N
Cl-
DMF/DMSO
N
H
H2N
N
H
H2N
N
2
Scheme 2 DMAP (0.3 equiv)-catalyzed reaction of alcohols (5.6 equiv) and 1 (1 equiv) as well as the synthesis of 2 and its direct alcoholysis
2-Amino-N,N,N-trimethyl-9H-purine-6-ylammonium Chlor-
ide (1)
13C NMR (90 °C, D2O): = 159.7, 159.2, 157.7, 146.4, 145.5,
138.1, 116.5, 107.8, 40.6.
To a stirred solution of 2-amino-6-chloropurine (0.5 g, 2.95 mmol)
in anhyd DMSO (10 mL) was added dropwise a 4.2 N ethanolic so-
lution of TMA (0.75 mL, 2.95 mmol) and the solution was stirred at
r.t. for 1 h. An additional quantity of TMA (0.75 mL, 2.95 mmol)
was added to complete the reaction. The reaction mixture was al-
lowed to stirr for 11 h. Addition of anhyd Et2O (100 mL) gave a
crude precipitate, which was filtered off, and washed with anhyd
Et2O to give the product 1 as a white solid which was dried under
vacuum (1 mbar) (0.51 g, 76%); mp 192–194 °C (Lit.9 mp 191–
193 °C).
FD-MS: m/z (%) = 256.7 (100), 255.7 (81), 169.5 (24.07), 122.6
(38).
Anal. Calcd for C12H14ClN7 (291.7): C 49.40, H 4.84, N 33.61.
Found C 49.21, H 4.62, N 33.72.
6-Fluoropyridin-2-ylmethanol; Typical Procedure11
To a suspension of 6-fluoropyridine-2-carboxylic acid10 (2.1 g, 15
mmol) in benzene (80 mL) was added Et3N (1.59 g, 15.8 mmol) at
r.t. After the solution was clear, ethyl chloroformate (1.71 g, 15.8
mmol) was added. The mixture was stirred for 1 h at r.t. The precip-
itated triethylammonium chloride was filtered off and the filtrate
was evaporated to dryness to give the mixed anhydride. THF (50
mL) was added to the residue and the mixture was added dropwise
to a suspension of LiAlH4 (0.6 g, 15.8 mmol) in THF (20 mL) at –
78 °C. The resulting mixture was stirred for 30 min at the same tem-
perature, passed into a sat. aq NH4Cl solution (60 mL) and was ex-
tracted with Et2O (150 mL). The organic phase was dried (Na2SO4),
evaporated under vacuum, and purified via column chromatography
on silica gel (EtOAc–n-hexane, 75:25, Rf 0.7). The product was ob-
tained as a white slurry (0.9 g, 47%).
1H NMR (D2O): = 8.11 (s, 1 H), 3.63 (s, 9 H).
13C NMR (D2O): = 158.86, 157.96, 152.46, 143.36, 115.90,
54.39.
FD-MS: m/z (%) = 326 (6), 208 (42), 193 (100), 179 (70).
1-(2-Amino-9H-purine-6-yl)-4-dimethylaminopyridinium
Chloride (2)
A suspension of 2-amino-6-chloropurine (0.5 g, 2.95 mmol) in
DMF (10 mL) was heated to 70 °C under stirring. DMSO was added
dropwise (about 1 mL) until a clear solution was obtained. DMAP
(0.7 g, 5.91 mmol) was added and the mixture was allowed to cool
to r.t. The solution turned yellow and remained clear for 48 h before
a yellow solid started to precpitate. After 72 h the crude product was
filtered off, washed first with DMSO (10 mL), then with Et2O (20
mL), and was dried under vacuum (1 mbar) for 24 h to yield 2 as a
yellow solid (0.35 g). A second fraction was obtained via dilution
of the remaining DMSO filtrate with Et2O (5 mL). Isolation of the
crude product by filtration and workup as described above gave an
additional amount of product (0.12 g). The total yield was 49%
(0.47 g); mp >350 °C (dec.).
1H NMR (DMSO-d6): = 7.8 (dd, 1 H, J = 16.0, 8.0 Hz), 7.35 (m,
1 H), 6.9 (dd, 1 H, J = 8.0, 3.0 Hz), 5.4 (s, 1 H), 4.5 (s, 2 H).
13C NMR (DMSO-d6): = 163.64, 161.55, 141.57, 117.92, 107.5,
63.68.
19F NMR (DMSO-d6): = –69.38 (d).
FD-MS: m/z (%) = 128.7 (100%).
Anal. Calcd for C6H6FNO (127.1): C 56.69, H 4.76, N 11.02.
Found: C 56.64, H 4.70, N 11.12.
1H NMR (90 °C, D2O): = 9.6 (d, 2 H), 8.7 (s, 1 H), 7.4 (d, 2 H),
3.9 (s, 6 H).
O6-(Hetarylmethyl) Guanines from 1 and Alcohols Using
DMAP as a Catalyst; General Procedure
1H NMR (100 °C, DMSO-d6): = 9.6 (d, 2 H), 8.05 (s, 1H), 7.9 (s,
1H), 7.2 (d, 2 H), 6.4 (s, 2 H), 3.4 (s, 6 H).
1H NMR spectra were not well enough resolved to give coupling
constants.
To a stirred solution of the heterocyclic alcohol (Tables 1, 14.5
mmol) in DMSO (3–5 mL) was carefully added NaH (0.2 g, 5.7
mmol, 60% w/w on mineral oil) and the stirring was continued for
45 min. 2-Amino-N,N,N-trimethyl-9H-purine-6-ylammonium
chloride (1; 0.5 g, 2.6 mmol) and DMAP (104 mg, 0.85 mmol) were
added and the mixture was heated to 60 °C for 72 h. HOAc (0.44
Synthesis 2002, No. 4, 538–542 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Effective Route to O6-Substituted Guanine Derivatives
541
mL) was added, the mixture was adsorbed on silica gel (3 g), dried
under vacuum (1 10–3 bar), loaded on a silica gel column, and pu-
rified via flash chromatography (detailed TLC-conditions and
chemical yields are shown in Table 2).
References
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O6-(Hetarylmethyl) Guanines from 2 and Alcohols; General
Procedure
The synthesis was carried out as described above. Instead of 1, com-
pound 2 (0.66 g, 2.6 mmol) was used directly. Workup was the same
as described above (detailed TLC-conditions and chemical yields
are shown in Table 2).
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Table 2 Yields of O6-(Hetarylmethyl) Guanine Derivatives 2 via Different Methodsa
Entryb Coupling Products Yield Yield Yield Rfd 1H NMR (DMSO-d6),
13C NMR (DMSO-d6),
19F NMR
(DMSO-d6) (M+, 100%)
FD-MS m/z
Guanine (Gu)
(%)e (%)f (%)c
1
2
3
4
80
66
60
20
40
34
15
10
0
0
0
0
0.31 12.5 (s, 1 H), 8.25 m, 1 H), 164.7, 162.3, 159.8,
7.8 (s, 1 H), 7.4 (m, 1 H), 7.2 148.0, 141.0, 138.0,
(s, 1 H), 6.3 (s, 2 H), 5.5 (s, 2 120.6, 108.0, 107.6, 64.7
H)
–69.18
–69.5
–68.5
–69.3
260.7
260.7
260.7
260.7
N
O
Gu
F
0.35 12.5 (s, 1 H), 8.4 (m, 1 H),
8.1 (m, 1 H), 7.75 (s, 1 H),
164.7, 162.3, 159.8,
154.8, 153.7, 148.4,
F
O
7.1 (dd, 1 H), 6.25 (s, 2 H), 143.3, 134.7,109.8, 109.4,
N
5.4 (s, 2 H)
63.7
Gu
0.39 12.5 (s, 1 H), 7.9 (m, 1 H),
161.5, 159.8, 159.7,
7.8 (s, 1 H), 7.4 (d, 1 H), 7.1 154.8, 153.7, 143.2,
(d, 1 H), 6.3 (s, 2 H), 5.4 (s, 2 134.7, 113.6, 109.9,
O
N
H)
108.6, 66.4
Gu
F
0.33 12.5 (s, 1 H), 8.2 (d, 1 H),
8.17 (m, 1 H), 7.8 (s, 1 H),
7.4 (m, 1 H), 6.35 (s, 2 H),
5.45 (s, 2 H)
162.5, 159.8, 159.6,
155.65, 155.65, 147.5,
142.3, 122.5, 119.2,
118.9, 60.8
O
N
Gu
F
5
6
85
85
60
62
10
58
0.41
-
-
-
-
-
-
N
O
Gu
Cl
0.40
-
-
Cl
O
N
Gu
7
8
72
83
68
87
42
40
35
39
32
40
28
14
0.30
0.30
0.34
0.39
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
O
O
N
Gu
S
O
N
Gu
9
S
O
N
Gu
10
S
Br
O
Gu
a All alcoholysis reactions were carried out in DMSO at 60 °C with DMAP as catalyst.
b The spectroscopic data (1H, 13C NMR and FD-MS) of all the products listed under entries 5–10 were in accordance with the literature data.
c Yields refer to the reactions carried out according to the method of McElhinney et al.6
d Solvent system: benzene–MeOH (4:1).
e Yields via in situ generation of 2.
f Yields via direct use of 2.
Synthesis 2002, No. 4, 538–542 ISSN 0039-7881 © Thieme Stuttgart · New York

542
R. Schirrmacher et al.
PAPER
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Synthesis 2002, No. 4, 538–542 ISSN 0039-7881 © Thieme Stuttgart · New York