A prototype solid phase synthesis of pteridines and related heterocyclic compounds

Article abstract of DOI:10.1039/b300798g

The development of a versatile solid phase synthesis of bicyclic polyaza heterocycles including pteridines, purines, and deazapurines is described. The strategy comprises the linking of a pre-formed pyrimidine through a thioether at the 2 or 4 position to a polystyrene resin, the cyclisation of the second ring, and the direct or oxidative cleavage of the product from the resin by nucleophilic substitution. This provides not only for substituent variation in the second ring, but also for variation at the site of cleavage. Limitations in the scope of the methodology are set by the intrinsic reactivity of pyrimidinyl 2- or 4-thioethers which, whilst undergoing ready nitration at C5, are surprisingly difficult to alkylate and acylate.

Full text of DOI:10.1039/b300798g

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A prototype solid phase synthesis of pteridines and related
heterocyclic compounds
Colin L. Gibson, Salvatore La Rosa and Colin J. Suckling*
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, Scotland. E-mail: c.j.suckling@strath.ac.uk
Received 23rd January 2003, Accepted 31st March 2003
First published as an Advance Article on the web 30th April 2003
The development of a versatile solid phase synthesis of bicyclic polyaza heterocycles including pteridines, purines,
and deazapurines is described. The strategy comprises the linking of a pre-formed pyrimidine through a thioether at
the 2 or 4 position to a polystyrene resin, the cyclisation of the second ring, and the direct or oxidative cleavage of
the product from the resin by nucleophilic substitution. This provides not only for substituent variation in the second
ring, but also for variation at the site of cleavage. Limitations in the scope of the methodology are set by the intrinsic
reactivity of pyrimidinyl 2- or 4-thioethers which, whilst undergoing ready nitration at C5, are surprisingly difficult to
alkylate and acylate.
Introduction
Solid phase synthesis is well established as a major contributor
to the discovery of novel biologically active compounds.
Although deriving originally from oligopeptide synthesis many
methods have now been described for the synthesis of hetero-
cyclic systems.1 Recent emphasis has been on so-called ‘trace-
Fig. 1
less linkers’ to join the desired synthetic intermediates and
products to the solid support so that cleavage can be accom-
Results and discussion
plished without leaving a residue or trace of the linker. In that
context, sulfur linkers have been attractive for heterocyclic syn-
thesis because, if placed in a position adjacent to a pyridine-like
nitrogen atom, they can be cleaved by nucleophilic aromatic
substitution. In the case of pyrimidines, thioether linkers have
been inserted, either by using thiol-substituted resins them-
selves2 or by forming a thioether with a sulfur containing
compound such as thiourea3 or a pyrimidine thiol. After the
appropriate substitution chemistry has been carried out, cleav-
age can be accomplished either by direct substitution with a
suitable amine4 or preferentially after oxidising the thioether to
a sulfone.2–4 In this way, multiply substituted pyrimidines2,3 and
aminopyridazines4 have been prepared. Alternatively, cleavage
can be carried out using Raney nickel to provide unsubstituted
derivatives as has been done with pyrimido[4,5-d]pyrimidines,
isomers of pteridines.5 Purines with a wide variety of amino
groups have also been prepared using thioether linkages.6,7
Other chemistries based upon Rink resins,8,9 tetrahydropyranyl
ethers,8,10 and silyl linkers11 have been used to prepare various
amino purines. At the outset of our studies, the only reported
solid phase synthesis of a pteridine was a non-traceless syn-
thesis of tetrahydropterins based upon Wang resin supported
amino acid chemistry.12 Recently, we have communicated the
use of 2- and 4-thioether linked solid phase methods in the
synthesis of pteridines.13 Herein we report full details of our
synthesis of pteridines together with its extension to the syn-
thesis of purines, and related heterocyclic compounds of rele-
vance to the study of pteridine biosynthesis and metabolism.
These extensions include not only additional heterocyclic sys-
tems but also further cleavage methods. In this report we are
concerned with achieving the maximum possible versatility in
terms of the heterocyclic systems accessible and the largest
possible number of points of diversity. Part of the enabling
solution phase chemistry supporting this challenge has been
described in previous papers.14,15 The aim of the study is
summarised in Fig. 1.
Solution phase chemistry underpinning the solid phase
methodology
The first syntheses of highly functionalised pterins and deaza-
purines that we developed afforded compounds with the
typical, naturally occurring ‘amino-oxo’ functionality in the
pyrimidine ring. Although some protecting group strategies,
notably involving dimethylaminoimino protecting groups, had
proved successful,15 none of these strategies readily transferred
to the solid phase. In order to develop a traceless methodology,
attention was focused on thioether linkers. The chemistry of
thioether substituted pyrimidines in the preparation of C6
functionalised pteridines and deazaguanines has already been
described.14 In preliminary work16 we investigated the synthesis
of pteridines on Merrifield resins with thioether linkers; cleav-
age was attempted using cyanogen bromide but with complex
outcomes. It was clear that the underlying heterocyclic chem-
istry of pyrimidylsulfanyl ethers was not understood well enough
for the development of a successful solid phase synthesis. The
range of available chemistry was therefore expanded in this
study through the use of 4-amino-2-benzylsulfanylpyrimidin-
6(1H )-one 1b as the model substrate (Scheme 1). Although this
compound does not react readily with C electrophiles, both it
and the analogous pyrimidine thiol 1a, smoothly undergo
nitrosation with sodium nitrite and acetic acid in DMF to form
2a and 2b in yields in excess of 75%. Similarly, reduction of the
nitroso group to the corresponding amines 3a and 3b was
achieved using sodium dithionite in aqueous methanol in 80–
97% yield. From the benzylsulfanyldiaminopyrimidine 3b it was
possible to access a number of key heterocyclic systems. Thus,
treatment with biacetyl in DMF afforded the 6,7-dimethyl-
pteridine 4b (85%). Cyclisation with methyl orthoformate and
acetic anhydride led to a new route to the 9-acetylpurine 5,17
which was hydrolysed to the corresponding purine 6 using
molar aqueous sodium hydroxide (58%). Treatment of 3b with
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1909

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Scheme
2
Reagents: i aq. DDO; ii DDO followed by Nu;
iii N-chlorobenzotriazole.
It was found that with two to three equivalents of DDO, the
thioether substrate was cleaved within two hours at room
temperature. If anhydrous conditions were not employed,
hydrolysis inevitably occurs affording 8. On the other hand,
after anhydrous oxidation without isolation of the sulfone, addi-
tion of a nitrogen nucleophile allowed the direct formation of
the 2-amino compounds required. This reaction was successful
with allylamine (7b, 79%), pyrrolidine (7c, 49%), and especially
sodium azide (7d, 49%). This 2-azidopteridine 7d was readily
reduced to the 2-aminopteridine 7a with sodium dithionite
(65%). There were practical problems associated with the puri-
fication of these products and the removal of benzylsulfinic
acid and the yields therefore cannot be considered to be opti-
mal. However such difficulties should not arise on the solid
phase.
Whilst the avoidance of the introduction of an oxo group at
C2 was a problem, the introduction of such a group at C4
would be entirely satisfactory from the point of view of syn-
thesis of pterins and guanine analogues. For this reason, the
chemistry of pyrimidine-4-sulfanyl ethers was developed in
parallel. The preparation of the sulfanyl ethers 10a and 10b
(Scheme 3) has already been described.22 As with the 2-substi-
tuted series, nitrosation (11a, 11b; 74%, 77%), reduction (12a,
12b; 74%, 90%), and cyclisation with biacetyl (13a, 13b, 84%,
77%) all took place straightforwardly. Several reagents were
investigated as cleavage reagents. Both hydrogen peroxide in
acetic acid23 and OXONE® failed to convert the thioether 13a
into a sulfone; instead the 8-N-oxide 14a was obtained, the
structure of which was suggested from its NMR spectrum
and literature comparison.24 As with the 2-thioethers, the best
results were obtained using DDO but for a short time and at
low temperature (Ϫ78 ЊC). In the absence of a stronger nucleo-
phile, the pteridinedione 7a was obtained (90%). Similarly to
the case for the 2-thioether linkage, oxidative activation fol-
lowed by addition of a nucleophile would provide an additional
point of diversity. Thus DDO oxidation of 13a followed by
addition of the nucleophile and allowing the reaction to warm
to room temperature gave good yields of a variety of 4-substi-
tuted pteridines: 7a, OH, 90%; 14, OMe, 74%; 15a, NH2,
89%; 15b, 4-chloroaniline, 84%; 15c, pyrrolidine, 92%; 15d,
3-dimethylaminopropylamine, 71%. This new process was also
applied to thioether 13b, which behaved similarly in affording
7a (89%) and 15b (87%). This cleavage reaction is thus very
effective in pteridines; the ease of reaction is consistent with the
normally found preferential reaction at C4 compared with C2.
Scheme 1 Reagents: i NaNO2–HOAc–DMF; ii Na2S2O4–aq. MeOH;
iii (MeO)3CH–Ac2O; iv aq. NaOH;
vi biacetyl–DMF.
v CNBr–ethanolic DMF;
cyanogen bromide in ethanolic DMF led directly to the 8-amino-
purine 6b (78%).18 These reactions together with those that
lead to deazaguanines described elsewhere14 provide the basis
in functional group modification chemistry and cyclisation
chemistry to approach solid phase synthesis, provided that a
suitable cleavage process can be developed.
Reactions described in the literature suggested that it would
be possible to substitute the thioether in the pteridines and pur-
ines prepared directly using a range of primary and secondary
amines.2–4 In our hands, only one such reaction using 4b as the
test compound occurred in good yield, namely ammonolysis at
180Њ in a sealed tube which afforded the pterin 7a in 90% yield.
Under milder conditions, refluxing ethanol, allylamine and pyr-
rolidine led to partial substitution (25%) and compounds 7b
and 7c were isolated and characterised. Since it had been shown
that cleavage was more successful after oxidation to the corre-
sponding sulfone, this method was investigated. It was quickly
apparent that oxidation greatly increased reactivity because,
when the test compound 4b was oxidised with m-chloro-
perbenzoic acid, the sulfone was not isolated. Instead a high
yield of the hydrolysis product, 6,7-dimethylpteridine-(1H,3H )-
2,4-dione 8 was isolated (95%). The same product was obtained
using OXONE® (78–88%).
Tetrapropylammonium per-ruthenate with N-methyl-
morpholine N-oxide19 caused substantial decomposition of the
pteridine. Seeking to expand the cleavage methodology, we
reasoned that activation of sulfur by halogenation would
provide an alternative means of introducing a nucleophile at
C-2. Accordingly, 4b was treated with 1-chlorobenzotriazole;20
cleavage duly occurred but benzotriazole itself was incorpor-
ated as the 2-substituent (9, not fully purified) (Scheme 2). This
reaction demonstrated clearly that hydrolysis could be avoided
and, if other N-chloroamines were used, additional access to
diversity might be obtained. The most generally useful
approach was found to be with dimethyldioxirane (DDO) as
oxidising agent.21 DDO was prepared freshly in anhydrous
acetone and the concentration determined by UV spectroscopy.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1910

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standardised at between 20 and 24 h at temperatures from room
temperature to 40 ЊC. Cyclisation with biacetyl required a
higher temperature of 80 ЊC. After each reaction, the resin was
washed with water and DMF and then twice successively with
water, methanol, acetone, THF, and diethyl ether. Before analy-
sis, the resin was dried under reduced pressure at 70 ЊC for 10 h.
With the synthetic reactions apparently successfully accom-
plished, the cleavage reactions discussed above were investi-
gated. As expected, using the type-A resin, cleavage with
m-chloroperbenzoic acid (m-CPBA) in dichloromethane led
directly to the pteridinedione 8, which was isolated and fully
characterised. The cleavage took place in 25% yield from the
resin bound final product. This is equivalent to 18% yield over-
all based upon the initial loading of the resin. Direct cleavage
by ammonia and amines was also investigated:2–4,26 2-Amino
7a, 2-allylamino 7b, and 2-pyrrolidinyl 7c derivatives were all
isolated and identified but the harsh reaction conditions (sealed
tube at 180 ЊC for 7a and hot DMF for 7b and 7c) led to low
yields and substantial decomposition. Cleavage of the product
from resin type-B was investigated using DDO oxidation over
4–10 h at room temperature. Subsequent addition of a nucleo-
phile (amine or azide ion to give 7d) allowed 2-substitution to be
demonstrated. Consistent with the solution phase results, this
method was more efficient, the pteridinedione 8 being obtained in
45% yield on cleavage equivalent to 27% yield overall. Cleavage
by oxidation and subsequent addition of a nitrogen nucleophile
was also more effective than direct nucleophilic cleavage.
For linkage through 4-sulfanyl ethers, a commercially avail-
able thiol-functionalised Merrifield type resin (Novabiochem)
was used; this material was 1% cross-linked and had a loading
of 4 mmol gϪ1. Table 2 shows the results of the loading, func-
tional group modification, and cyclisation reactions success-
fully carried out under the same conditions as for the 2-sulfanyl
resin. Again consistent with the solution phase experience,
cleavage by oxidation followed by displacement with water gave
the highest yield of the pteridinedione 8; cleavage occurred in
50% yield which indicates 38% overall yield from the loaded
resin.
Scheme 3 Reagents: i NaNO2–HOAc–DMF; ii Na2S2O4–aq. MeOH;
iii biacetyl; iv OXONE®; v for 7a aq. DDO, for 14 DDO followed by
MeOH, for 15a–d DDO followed by Nu; vi (EtO)3CH–Ac2O, KOH;
vii CH3CO2H–H2O2.
In the case of purines, the diaminopyrimidine 12a was cyclised
with ethyl orthoformate and acetic anhydride and the inter-
mediate acetyl purine hydrolysed with potassium hydroxide to
afford a novel route to the 5-benzylsulfanylpurine 16 in 70%
yield.25 In this case, N-oxide formation was not a problem and
guanine itself was obtained by cleavage with hydrogen peroxide
in acetic acid (64%) using our newly developed methodology.
Conclusion
In this paper we have described the solution chemistry relevant
to the establishment of a solid phase synthesis of pteridines and
purines. We have reported new cleavage methods for 2-thio-
ethers (using 1-chlorobenzotriazole) and the potential for addi-
tional diversity through the oxidative cleavage of 4-thioethers.
These procedures have also been extended to the synthesis of
purines. Taken with the results described in previous papers13–16
the basis for the solid phase synthesis of 6-functionalised
pteridines and 7-deazaguanines has also been established.
Using the pteridinedione 8 as an example, a prototype solid
phase methodology has been developed. There are clear limit-
ations in the ability of this methodology with respect to cyclis-
ation using carbon electrophiles at C5 of pyrimidine substrates
and more work will be required to solve this problem. The
exemplification of this prototype methodology for a range of
heterocyclic products is now in hand.
Reactions on the solid phase
For linking the pyrimidine through 2-sulfanyl ethers, two
chloromethyl resins were used. Type-A was a polystyrene resi-
due cross linked with 2% divinylbenzene with a high loading of
6.05 mmol gϪ1 (courtesy Professor David Sherrington, Strath-
clyde). Type-B was a commercially available resin (Novabio-
chem) with lower cross linking (1%) and lower loading (1.94
mmol gϪ1). Although the loading and physical properties of
solid supports can be very important in the success of solid
phase synthesis, in practice, there was no significant difference
in handling between the two resins in our hands but higher
reaction yields were usually obtained with resin type-B.
The resins were loaded with 6-amino-2-sulfanylpyrimidin-
4(3H )-one by stirring in suspension in DMSO, in the presence
of potassium iodide and potassium hydroxide. The data in
Table 1 show the outcome of the sequence of reactions leading
to the dimethylpteridinedione 8 which was used as a test case.
Microanalysis was the primary analytical tool, although it was
complicated with respect to precision by samples of resin that
gained weight in air, presumably because of hygroscopy. The
sequence of transformations was conveniently carried out using
a mixed solvent system of DMF and water which made it pos-
sible to attain a reasonable degree of swelling and to use the
inorganic nitrosating and reducing agents. Reaction times were
Experimental
Instrumentation and general materials
NMR spectra were determined on a Bruker Spectrospin spec-
trometer operating at 400 MHz for 1H spectra and 100 MHz for
13C spectra. Chemical shifts are reported as ppm relative to
TMS measured from the solvent resonance. J values are given
in Hz. IR spectra were determined using a Mattson 1000 FT
spectrometer or a Nicolet Impact 400D FT spectrometer. Mass
spectra were measured on a JEOL JMS AX505 spectrometer.
Microanalyses were carried out using a Perkin-Elmer Series II
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1911

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Table 1 Solid phase synthesis using 2-sulfanyl ether linkage
Sample
Resin type
%N
Loading/ mmol gϪ1
Conversion (%)
Functional group (%)
17
18
19
20
A
B
A
B
A
B
A
B
12.27
6.46
14.7
7.71
13.01
5.68
2.91
1.53
2.62
1.37
2.32
1.02
2.11
0.93
79
96
98
94
85
72
102
96
79
96
79
90
67
65
71
64
11.84
5.21
Table 2 Solid phase synthesis using 4-sulfanyl linker
127 mmol) in water (350 mL), sodium nitrite (10.35 g, 140
mmol) and acetic acid (35 mL). Reaction time: 2 days. Yield
of 2a: 77% (16.8 g, 97.7 mmol) as a blue crystalline solid,
mp > 240 ЊC. δH(DMSO) 7.68 (1H, br s, N(6)H), 11.21 (1H, br
s, N(6)H), 12.01 (1H, br s, N(3)H), 12.53 (1H, s, S(2)H).
δC(DMSO) 140.80 (C-5), 143.02 (C-6), 159.78 (C-4), 176.87
(C-2). νmax(KBr) 3055, 2866, 1689, 1646, 1276, 1169, 768, 584,
525, 502 cmϪ1. LRMS (FAB) found: 173 (M ϩ 1).
6-Amino-2-(benzylsulfanyl)-5-nitroso-4(3H)-pyrimidinone 2b.
Obtained using a solution of 6-amino-2-(benzylsulfanyl)-
4(3H )-pyrimidinone 1b (21.5 g, 92 mmol) and sodium hydrox-
ide (5.10 g, 127 mmol) in water (350 mL), sodium nitrite (7.77 g,
113 mmol) and acetic acid (35 mL). Reaction time: 2 days. Yield
of 2b: 81% (19.5 g, 75 mmol) as an intense blue crystalline solid,
mp 185–187 ЊC. HRMS (FAB; NBA–glycerol matrix) found:
263.0586, C11H11N4O2S (M ϩ 1) requires 263.0603. δH(DMSO)
4.44 (2H, s, C(7)H2), 7.24–7.33 (3H, m, 2 × C(10)H, C(11)H),
7.41–7.48 (2H, m, 2 × C(9)H), 9.04 (1H, br s, 1 × NH2), 11.22
(1H, br s, 1 × NH2), 12.72 (1H, br s, N(3)H). δC(DMSO) 34.68
(C-7), 128.30 (C-11), 129.37 (2 × C-10), 130.13 (2 × C-9),
137.88 (C-8), 144.06 (C-5), 147.86 (C-2), 162.78 (C-6), 168.81
(C-4). νmax(KBr) 3401 (br), 3233, 3068, 1685, 1668, 1557, 1498
Loading/
mmol gϪ1
Conversion
(%)
Functional
group (%)
Sample
%N
21
22
23
24
13.25
14.67
13.35
12.65
2.37
2.09
1.91
1.81
85
95
88
85
81
71
76
104
(N᎐O), 1464, 1319, 1277, 1189 cmϪ1. λmax(MeOH) 343, 283 nm.
᎐
instrument at the University of Strathclyde. UV spectra were
determined using a Perkin-Elmer Lambda 2 spectrometer.
Melting points, when measureable, were determined on a
Reichert hot stage apparatus and are uncorrected. TLC was
carried out on silica (Merck 0.25 mm 60 F254). Column chrom-
atography was carried out using silica gel (230–400 mesh;
40–60 µm). Reagents were bought from Aldrich (Gillingham,
Dorset, UK).
6-(Benzylsulfanyl)-5-nitroso-2,4-pyrimidinediamine
11a.
Obtained using a solution of 6-(benzylsulfanyl)-2,4-pyrimidine-
diamine 10a (10 g, 43.1 mmol) and sodium hydroxide (1.7 g,
43.1 mmol) in water (80 mL), sodium nitrite (3.45 g, 50 mmol)
and acetic acid (15 mL). Reaction time: 2 days. Yield of 11a:
74% (8.35 g, 31.99 mmol) as an intense purple solid, mp 230–
233 ЊC (dec.). HRMS (FAB) found: 262.0769, C11H12N5OS
(M ϩ 1) requires 262.0763. δH(DMSO) 4.46 (2H, s, C(7)H2),
7.18–7.32 (3H, m, 2 × C(10)H, C(11)H), 7.48–7.50 (2H, m, 2 ×
C(9)H), 7.98 (1H, br s, 1 × N(2)H2), 8.07 (1H, br s, 1 × N(2)H2),
8.12 (1H, d, J = 2.8, 1 × N(4)H2), 9.71 (1H, d, J = 2.8, 1 ×
N(4)H2). δC(DMSO) 32.83 (C-7), 127.50 (C-11), 128.85 (2 ×
C-9), 129.78 (2 × C-10), 138.6 (C-8), 145.84 (C-5), 149.73 (C-4),
161.29 (C-2), 181.11 (C-6). νmax(KBr) 3484, 3310, 3147, 1666,
General method for the nitrosation at C-5 of sulfanylpyrimidines
The appropriate pyrimidine (1 eq.) was partially dissolved in a
solution of sodium hydroxide (1 eq.) in water at room temper-
ature. A solution of sodium nitrite (1.2 eq.) in water was added.
The solution was then acidified by the gradual addition of
glacial acetic acid. A white precipitate formed almost immedi-
ately, which gradually turned blue on stirring at room tem-
perature for the given time. The precipitate was collected by
filtration, and washed with water and ether to afford the corre-
sponding nitroso compound as an intensely coloured solid.
1630, 1542 (N᎐O), 1254, 1146, 1017 cmϪ1
.
᎐
6-[(4-Methylphenyl)sulfanyl]-5-nitroso-2,4-pyrimidinediamine
11b. Obtained using a solution of 6-[(4-methylphenyl)sulfanyl]-
2,4-pyrimidinediamine 10b (10 g, 43.1 mmol) and sodium
hydroxide (1.7 g, 43.1 mmol) in water (80 mL), sodium
nitrite (3.45 g, 50 mmol) and acetic acid (15 mL). Reaction
time: 2 days. Yield of 11b: 77% (8.67 g, 33.21 mmol) as an
6-Amino-5-nitroso-2-sulfanyl-4(3H)-pyrimidinone
Obtained using solution of 6-amino-2-sulfanyl-4(3H )-
pyrimidinone 1a (18 g, 126 mmol) and sodium hydroxide (5.1 g,
2a.
a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1912

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intense purple solid, mp 180–185 ЊC (dec.). HRMS (FAB)
found: 262.0770, C11H12N5OS (M ϩ 1) requires 262.0763.
δH(DMSO) 2.36 (SH, s, C(11)H3), 7.27–7.52 (4H, m, 2 × C(8)H
and 2 × C(9)H), 7.59 (1H, br s, NH), 7.83 (1H, br s, NH), 8.15
(1H, br s, NH), 9.69 (1H, br s, NH). δC(DMSO) 21.31 (C-11),
124.76 (C-7), 130.22 (2 × C-8), 136.06 (2 × C-9), 139.37 (C-10),
145.34 (C-5), 149.44 (C-4), 161.46 (C-2), 181.69 (C-6).
130.87 (2 × C-9), 135.64 (C-10), 154.02 (C-4), 157.47 (C-2),
161.85 (C-6). νmax(KBr) 3401, 3196, 1632, 1509, 1118, 995, 810,
621 cmϪ1
.
General method for the cyclisation of di- or triaminopyrimidines
into pteridines using biacetyl
The appropriate di- or triaminopyrimidine (4 mmol) was dis-
solved in DMF (20 mL) and biacetyl (8 mmol) was added. The
solution was stirred for 5 hours at 100 ЊC, and then the solvent
was evaporated under reduced pressure. The resulting orange
oil was triturated with ether. The resulting solid was filtered and
washed with ether to yield the corresponding 6,7-dimethyl-
pteridine.
νmax(KBr) 3323, 3137, 1649, 1578, 1273, 1027 cmϪ1
.
General method for the conversion of 5-nitrosopyrimidines into
5-aminopyrimidines
A solution of sodium dithionite (20 mmol) in water (25 mL)
was added to a suspension of the appropriate 5-nitroso-
pyrimidine (10 mmol) in methanol (25 mL) at room temper-
ature. After stirring for the given time, the precipitate went
from coloured to colourless. The precipitate was collected by
filtration and washed with water, acetone and ether.
6,7-Dimethyl-2-sulfanyl-4(3H)-pteridinone 4a. Obtained
using 5,6-diamino-2-sulfanyl-4(3H )-pyrimidinone 3a (0.58 g,
3.67 mmol) in DMF (20 mL) and biacetyl (0.63 g, 7.34 mmol).
Yield of 4a: 67% (0.51 g, 2.45 mmol), mp 225–229 ЊC. HRMS
(FAB) found: 209.0498, C8H9N4OS (M ϩ 1) requires 209.0497.
δH(DMSO) 2.52 (3H, s, C(10)H3), 2.55 (3H, s, C(9)H3), 12.60
(1H, br s, N(3)H), 13.09 (1H, br s, SH). δC(DMSO) 21.87 (C-9),
22.74 (C-10), 126.12 (C-4a), 147.18 (C-6), 150.43 (C-7), 154.72
(C-8a), 159.04 (C-4), 175.54 (C-2). νmax(KBr) 3424 (NH), 1694,
5,6-Diamino-2-sulfanyl-4(3H)-pyrimidinone 3a. Obtained
using a solution of sodium dithionite (10 g, 57.5 mmol) in water
(80 mL) and 6-amino-5-nitroso-2-sulfanyl-4(3H )-pyrimidinone
2a (5 g, 29 mmol) in methanol (80 mL). Reaction time: 40 min.
Yield of 3a: 79% (3.64 g, 23 mmol) as a colourless solid,
mp > 240 ЊC. HRMS (FAB) found: 159.0341, C4H7N4OS
(M ϩ 1) requires 159.0341. δH(DMSO) 5.69 (2H, s, NH2), 11.81
(1H, br s, SH). δC(DMSO) 102.81 (C-5), 141.01 (C-6), 158.39
(C-4), 168.02 (C-2). νmax(KBr) 3403 (NH2), 3311 (NH2), 1634,
1546, 1374, 1352, 1136, 537, 455 cmϪ1
.
2-(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone
4b.
Obtained using 5,6-diamino-2-(benzylsulfanyl)-4(3H )-pyrim-
idinone 3b (1 g, 4.03 mmol) in DMF (20 mL) and biacetyl (0.7 g,
8 mmol). Yield of 4b: 85% (1.02 g, 3.44 mmol), mp > 240 ЊC.
HRMS (EI) found: 298.0889, C15H14N4OS requires 298.0888.
δH(DMSO) 2.57 (3H, s, C(14)H3), 2.60 (3H, s, C(15)H3), 4.52
(2H, s, C(9)H2), 7.24–7.47 (5H, m, 2 × C(11)H, 2 × C(12)H,
C(13)H), 12.95 (1H, br s, N(3)H). δC(DMSO) 22.17 (C-14),
23.03 (C-15), 34.28 (C-9), 127.78 (C-13), 128.92 (2 × C-11),
128.99 (C-10), 129.45 (2 × C-12), 137.18 (C-6), 151.96 (C-7),
152.99 (C-4a), 159.08 (C-8a), 159.58 (C-2), 160.71 (C-4).
1583, 1271, 1184, 552 cmϪ1
.
5,6-Diamino-2-(benzylsulfanyl)-4(3H)-pyrimidinone
3b.
Obtained using a solution of sodium dithionite (1.60 g, 9.20
mmol) in water (16 mL) and 6-amino-2-(benzylsulfanyl)-5-
nitroso-4(3H )-pyrimidinone 2b (0.42 g, 1.60 mmol) in meth-
anol (16 mL). Reaction time: 40 min. Yield of 3b: 98% (0.39 g,
1.57 mmol) as a colourless crystalline solid, mp 185–187 ЊC.
HRMS (FAB; NBA–glycerol matrix) found: 249.0810,
C11H13N4OS (M ϩ 1) requires 249.0810. δH(DMSO) 4.31 (2H, s,
C(7)H2), 5.82 (2H, br s, NH2), 7.21–7.31 (3H, m, 2 × C(10)H,
C(9)H), 7.40–7.46 (2H, m, 2 × C(9)H). δC(DMSO) 33.98 (C-7),
106.84 (C-5), 127.45 (C-11), 128.74 (2 × C-10), 129.43 (2 ×
C-9), 138.57 (C-8), 148.20 (C-6), 149.22 (C-2), 157.71 (C-4).
νmax(KBr) 3465 (br), 3366, 3346, 1654, 1626, 1521, 1495, 1465,
1355, 1221 cmϪ1. λmax(MeOH) 298 nm.
νmax(KBr) 3168, 1692 (C᎐O), 1576, 1559, 1385, 1167, 962, 823,
᎐
721, 701, 465 cmϪ1
.
4-(Benzylsulfanyl)-6,7-dimethyl-2-pteridinamine
13a.
Obtained using 6-(benzylsulfanyl)-2,4,5-pyrimidinetriamine
12a (1 g, 4.05 mmol) in DMF (20 mL) and biacetyl (0.7 g,
8 mmol). Yield of 13a: 84% (1.01 g, 3.4 mmol), mp 208–210 ЊC.
HRMS (FAB) found: 298.1136, C15H16N5S (M ϩ 1) requires
298.1126. δH(DMSO) 2.46 (3H, s, C(15)H3), 2.52 (3H, s,
C(14)H3), 4.45 (2H, s, C(9)H2), 7.22–7.31 (3H, m, C(13)H, 2 ×
C(12)H), 7.29 (2H, br s, NH2), 7.48–7.50 (2H, m, 2 × C(11)H).
δC(DMSO) 22.10 (C-15), 23.62 (C-14), 32.50 (C-9), 126.16
(C-4a), 127.42 (C-13), 128.73 (2 × C-12), 129.61 (2 × C-11),
138.23 (C-10), 148.09 (C-6), 153.30 (C-7), 161.16 (C-8a), 161.66
(C-2), 172.95 (C-4). νmax(KBr) 3467 (NH2), 3286, 1636, 1559,
6-(Benzylsulfanyl)-2,4,5-pyrimidinetriamine 12a. Obtained
using a solution of sodium dithionite (10 g, 57.5 mmol) in water
(60 mL) and 6-(benzylsulfanyl)-5-nitroso-2,4-pyrimidine-
diamine 11a (5 g, 19.1 mmol) in methanol (60 mL). Reaction
time: 1.5 hours. Yield of 12a: 74% (3.5 g, 14.2 mmol) as a
colourless crystalline solid, mp 175–177 ЊC (lit.25 177–178 ЊC).
HRMS (FAB) found: 248.0973, C11H14N5S (M ϩ 1) requires
248.0970. δH(DMSO) 4.32 (2H, s, C(7)H2), 5.43 (2H, br s, NH2),
6.0 (2H, br s, NH2), 7.18–7.29 (3H, m, 2 × C(10)H, C(11)H),
7.34–7.39 (1H, m, 2 × C(9)H). δC(DMSO) 32.76 (C-7), 112.72
(C-5), 127.01 (C-11), 128.63 (2 × C-9), 129.34 (2 × C-10),
139.73 (C-8), 150.35 (C-4), 155.70 (C-2), 157.09 (C-6).
νmax(KBr) 3402 (NH2), 3151, 1635, 1609, 1546, 1425, 897, 694
1532, 1407, 1167, 934, 643 cmϪ1
.
6,7-Dimethyl-4-[(4-methylphenyl)sulfanyl]-2-pteridinamine
13b. Obtained using 6-[(4-methylphenyl)sulfanyl]-2,4,5-pyrim-
idinetriamine 12b (1 g, 4.05 mmol) in DMF (20 mL) and
biacetyl (0.7 g, 8 mmol). Yield of 13b: 77% (0.93 g, 3.13 mmol),
mp 147–150 ЊC. HRMS (FAB) found: 298.1135, C15H16N5S (M
ϩ 1) requires 298.1126. δH(DMSO) 2.36 (3H, s, C(13)H3), 2.58
(3H, s, C(15)H3), 2.61 (3H, s, C(14)H3), 7.27–7.53 (4H, m, 2 ×
C(10)H and 2 × C(11)H), 7.49 (2H, br s, NH2). δC(DMSO)
21.32 (C-13), 22.21 (C-15), 23.65 (C-14), 123.71 (C-4a), 125.58
(C-9), 130.51 (2 × C-10), 135.52 (2 × C-11), 139.87 (C-12),
149.69 (C-6), 149.92 (C-7), 158.96 (C-8a), 162.54 (C-2), 175.98
(C-4). νmax(KBr) 3325, 3194, 1649, 1591, 1562, 1415, 1169,
cmϪ1
.
6-[(4-Methylphenyl)sulfanyl]-2,4,5-pyrimidinetriamine 12b.
Obtained using a solution of sodium dithionite (10 g, 57.5
mmol) in water (80 mL) and 6-[(4-methylphenyl)sulfanyl]-5-
nitroso-2,4-pyrimidinediamine 11b (8 g, 30.6 mmol) in meth-
anol (80 mL). Reaction time: 1.5 hours. Yield of 12b: 90% (6.78
g, 27.45 mmol) as a colourless crystalline solid, mp 155–157 ЊC.
HRMS (FAB) found: 248.0966, C11H14N5S (M ϩ 1) requires
148.0970. δH(DMSO) 2.25 (3H, s, C(11)H3), 7.11–7.27 (4H, m,
2 × C(8)H and 2 × C(9)H), 7.31 (2H, br s, NH2). δC(DMSO)
21.04 (C-11), 121.27 (C-5), 128.77 (C-7), 130.52 (2 × C-8),
1016, 805 cmϪ1
.
2-(Benzylsulfanyl)-1,9-dihydro-6H-purin-6-one 6a
5,6-Diamino-2-(benzylsulfanyl)-4(3H )-pyrimidinone 3b (0.5 g,
2 mmol), trimethyl orthoformate (5 mL, 4.4 mmol) and acetic
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1913

View Article Online
anhydride (5 mL) were heated to reflux for 2.5 hours. The solu-
tion was evaporated under reduced pressure, the residue dissol-
ved in sodium hydroxide solution (1 M, 10 mL) and methanol
(10 mL) and heated for 10 min on a steam bath. The pH of the
solution was brought to 3.8 with acetic acid, filtered, and
washed with water to yield the title compound 6a as a white
solid (0.3 g, 1.16 mmol, 58%), mp > 240 ЊC (lit.27 263–265 ЊC).
HRMS (FAB) found: 259.0645, C12H11N4OS (M ϩ 1) requires
259.0654. δH(DMSO) 4.44 (2H, s, C(10)H2), 7.23–7.33 (3H, m,
2 × C(13)H, C(14)H), 7.43–7.45 (2H, m, C(12)H), 8.02 (1H, s,
C(8)H), 12.77 (1H, br s, NH). δC(DMSO) 34.31 (C-10), 127.65
(C-14), 128.77 (C-4), 128.85 (2 × C-13), 129.49 (2 × C-12),
137.65 (C-11, C-4), 140.05 (C-8), 155.53 (C-6), 156.68 (C-2).
reduced pressure and the residue dissolved in the minimum
quantity of methanol and adsorbed into the top of a chroma-
tography silica gel column and eluted with ethyl acetate–
methanol (5 : 1) to yield the title compound as a yellow solid
(0.11 g, 0.48 mmol, 57%), mp > 240 ЊC. HRMS (FAB) found:
232.1208, C11H14N5O (M ϩ 1) requires 232.1198. δH(DMSO)
2.48 (3H, s, C(13)H3), 2.5 (3H, s, C(12)H3), 3.99 (2H, s, C(9)H2),
5.12 (1H, d, J = 10.2, 1 × C(11)H2), 5.22 (1H, d, J = 17.2,
1 × C(11)H2), 5.89–5.99 (1H, m, C(10)H), 6.71 (1H, br s, NH),
11.17 (1H, br s, N(3)H). δC(DMSO) 21.68 (C-12), 22.89 (C-13),
42.85 (C-9), 115.92 (C-11), 126.35 (C-6), 135.29 (C-10), 147.5
(C-4a), 152.15 (C-7), 155.6 (C-8a), 158.73 (C-2), 161.16 (C-4).
νmax(KBr) 3283 (NH), 2922 (CH), 1691 (C᎐O), 1619, 1560,
᎐
νmax(KBr) 3424 (NH), 3103, 2886, 1679 (C᎐O), 1574, 1458,
1492, 1220, 1039, 698, 620, 563 cmϪ1. λmax(MeOH) 348, 278,
᎐
1360, 1227, 962, 785, 695 cmϪ1
.
225 nm.
b) From 4b using DDO and allylamine. A solution of di-
methyldioxirane (DDO) in acetone (0.056 M, 20 mL, 1.12
mmol) was added to 2-(benzylsulfanyl)-6,7-dimethyl-4(3H )-
pteridinone 4b (0.1 g, 0.33 mmol) and stirred at room temper-
ature for 3 hours. The solution was evaporated under reduced
pressure and the yellow residue was dissolved again in DMF
(15 mL) and allylamine (50 mg, 0.87 mmol) was added. The
mixture was stirred at 80 ЊC for 40 hours, whereupon it was
evaporated to dryness under reduced pressure and purified by
silica gel column chromatography eluting with ethyl acetate–
methanol (5 : 1), to give the title compound 7b as a yellow solid
(60 mg, 0.26 mmol, 79%).
8-Amino-2-(benzylsulfanyl)-1,9-dihydro-6H-purin-6-one 6b
5,6-Diamino-2-(benzylsulfanyl)-4(3H )-pyrimidinone 3b (0.5 g,
2 mmol) was dissolved in a mixture of ethanol (10 mL) and
DMF (20 mL). To this stirring mixture, cyanic bromide (0.25 g,
2.3 mmol) was added and the reaction mixture was left stirring
overnight at room temperature. The solvents were removed
under reduced pressure and the residue was dissolved in the
minimum quantity of ethanol and absorbed on top of a chrom-
atographic silica gel column. Elution with 4 : 1 ethyl acetate–
methanol, and evaporation of the relevant fractions gave the
title compound 6b as a light green solid (0.4 g, 1.46 mmol,
73%), mp 245–247 ЊC. HRMS (FAB) found: 274.0762,
C12H12N5OS (M ϩ 1) requires 274.0763. δH(DMSO) 4.30 (2H, s,
C(10)H2), 7.01 (2H, br s, C(8)NH2), 7.20–7.30 (5H, m, 2 ×
C(12)H, 2 × C(13)H, C(14)H), 7.40 (1H, s, N(9)H), 7.42 (1H, s,
N(1)H). δC(DMSO) 35.14 (C-10), 114.32 (C-5), 127.72 (C-14),
129.16 (2 × C-12), 129.83 (2 × C-13), 139.40 (C-11), 154.07
(C-4), 158.92, 160.40, 162.84 (C-2, C-8, C-6). νmax(KBr) 3333
6,7-Dimethyl-2-(1-pyrrolidinyl)-4(3H)-pteridinone 7c from 4b
and pyrrolidine
2-(Benzylsulfanyl)-6,7-dimethyl-4(3H )-pteridinone 4b (0.5 g,
1.68 mmol) and pyrrolidine (0.59 g, 8.4 mmol) were heated
under reflux in ethanol (20 mL) at 85 ЊC for 96 hours. Then the
solution was evaporated under reduced pressure and the residue
was dissolved in the minimum quantity of methanol and
adsorbed into the top of a chromatography silica gel column
and eluted with ethyl acetate–methanol (4 : 1) to yield the title
compound 7c (0.2 g, 0.82 mmol, 49%), mp > 240 ЊC. HRMS
(FAB) found: 246.1361, C12H16N5O (M ϩ 1) requires 246.1355.
δH(DMSO) 1.92 (4H, t, J = 6.5, C(10)H2, C(11)H2), 2.47 (3H, s,
C(14)H3), 2.49 (3H, s, C(13)H3), 3.50 (4H, t, J = 6.5, C(9)H2,
C(12)H2), 11.33 (1H, br s, N(3)H). δC(DMSO) 21.68 (C-13),
22.92 (C-14), 25.20 (C-10, C-11), 47.27 (C-9, C-12), 125.31
(C-6), 146.98 (C-4a), 150.59 (C-7), 155.68 (C-8a), 158.83 (C-2),
162.21 (C-4). νmax(KBr) 3442, 3158 (NH), 2962 (CH), 1685
(NH2), 3178, 1621, 1546, 1233, 968, 701 cmϪ1
.
2-Amino-6,7-dimethyl-4(3H)-pteridinone 7a
a) From 4b using aqueous ammonia. 2-(Benzylsulfanyl)-6,7-
dimethyl-4(3H )-pteridinone 4b (0.1 g, 0.33 mmol) and conc.
NH4OH (10 mL) were placed in a sealed tube and heated at
180 ЊC for 2 hours. After cooling to room temperature, water
(20 mL) was added and the residue was filtered and washed
with water and acetone. The crude product was recrystallised
from aqueous ammonia (5 mL) to give the title compound 7a
(0.05 g, 0.26 mmol, 79%), mp > 260 ЊC. HRMS (FAB) found:
192.0878, C8H10N5O (M ϩ 1) requires 192.0885. δH(TFA) 2.88
(3H, s, C(10)H3), 2.90 (3H, s, C(9)H3). δC(TFA) 21.75 (C-10),
23.81 (C-9), 124.30 (C-4a), 148.15 (C-8a), 154.11 (C-2), 157.38
(C-6), 161.40 (C-4), 167.96 (C-7). νmax(KBr) 3264, 2847, 1689,
(C᎐O), 1605, 1560, 1520, 1398, 1271, 984, 822, 732, 518 cmϪ1
.
᎐
λmax(MeOH) 358, 286, 228 nm.
Synthesis of 2-azido-6,7-dimethyl-4(3H)-pteridinone 7d from 4b
by DDO oxidation and sodium azide
1547, 1515, 1273, 1179, 866, 686 cmϪ1
.
A solution of dimethyldioxirane (DDO) in acetone (0.1 M,
20 mL, 2 mmol) was added to 2-(benzylsulfanyl)-6,7-dimethyl-
4(3H )-pteridinone 4b (0.25 g, 0.84 mmol) and stirred for
3 hours at room temperature. The solution was evaporated
under reduced pressure, the residue was dissolved in DMF
(15 mL) and sodium azide (100 mg, 1.54 mmol) was added. The
solution was stirred for a further 15 hours at room temperature
and then the solution evaporated under reduced pressure. The
residue was dissolved in water (20 mL) and barium hydroxide
(1 mmol) was added. After stirring the solution for 10 min, it
was filtered and evaporated to yield the title compound 7d
(0.145 g, 0.67 mmol, 49%), mp > 240 ЊC. HRMS (FAB) found:
218.0784, C8H8N7O (M ϩ 1) requires 218.0790. δH(DMSO)
2.27 (3H, s, C(9)H3), 2.34 (3H, s, C(10)H3), 11.85 (1H, s,
N(3)H). δC(DMSO) 20.66 (C-9), 21.84 (C-10), 130.87 (C-6),
b) From 7d using sodium dithionite. To a suspension of
2-azido-6,7-dimethyl-4(3H )-pteridinone 7d (0.1 g, 0.46 mmol)
in methanol (7 mL) was added sodium dithionite (0.24 g,
1.38 mmol) in water (7 mL). The resulting reaction mixture was
stirred and heated at 60 ЊC overnight, and then the solvent was
removed under reduced pressure. The residue was taken in hot
methanol (5 mL) filtered and washed with water. The result-
ing crude product was recrystallised from aqueous ammonia
(5 mL) to give the required compound 7b (0.057 g, 0.3 mmol,
65%). δH(DMSO) 2.48 (3H, s, C(10)H3), 2.50 (3H, s, C(9)H3),
6.68 (2H, br s, NH2), 11.20 (1H, br s, N(3)H).
2-(Allylamino)-6,7-dimethyl-4(3H)-pteridinone 7b
a) From 4b and allylamine. 2-(Benzylsulfanyl)-6,7-dimethyl-
4(3H )-pteridinone 4b (0.25 g, 0.84 mmol) and allylamine
(0.47 g, 8.4 mmol) were heated to reflux in ethanol (20 mL) at
85 ЊC for 96 hours. Then the solution was evaporated under
137.77 (C-4a), 150.72 (C-7), 151.47 (C-2), 159.2 (C-8a), 169.62
᎐
(C-4). νmax(KBr) 3385 (NH), 2134 (N᎐N), 2038, 1606, 1446,
᎐
1206, 641 cmϪ1. λmax(MeOH) 342, 266, 204 nm.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1914

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6,7-Dimethyl-2,4(1H,3H)-pteridinedione 8
NH2), 7.20–7.40 (5H, m, 2 × C(9)H, 2 × C(10)H, C(11)H).
δC(DMSO) 32.44 (C-7), 90.37 (C-5), 127.26 (C-11), 128.74
(2 × C-9), 129.29 (2 × C-10), 138.77 (C-8), 162.85 (C-4), 164.14
(C-2), 166.02 (C-6). νmax(KBr) 3440 (NH2), 3302, 1612, 1562,
a) From 4b with potassium hydrogen persulfate (OXONE®).
A solution of OXONE® (KHSO5) (0.618 g, 2 mmol) in water
(10 mL) was added at 0 ЊC to 2-(benzylsulfanyl)-6,7-dimethyl-
4(3H )-pteridinone 4b (0.3 g, 1 mmol) in methanol (10 mL). The
resulting cloudy slurry was stirred for 4 hours at room temper-
ature and evaporated to dryness under reduced pressure. The
product was separated from the salt by dissolving it in methanol
(20 mL) and filtering the salt from the solution. Evaporation of
the methanol yielded the title compound 8 (0.17 g, 0.88 mmol,
88%), mp > 260 ЊC (lit.28 > 360 ЊC). HRMS (FAB) found:
193.0725, C8H9N4O2 (M ϩ 1) requires 193.0726. δH(DMSO)
2.50 (3H, s, C(9)H3), 2.52 (3H, s, C(10)H3), 11.47 (1H, br s,
N(1)H), 11.65 (1H, br s, N(3)H). δC(DMSO) 21.56 (C-9), 22.56
(C-10), 124.14 (C-4a), 147.62 (C-6), 148.45 (C-2), 150.29
(C-8a), 158.1 (C-7), 161.44 (C-4). νmax(KBr) 3435, 3178, 3089,
1430, 1362, 787, 715 cmϪ1
.
6-[(4-Methylphenyl)sulfanyl]-2,4-pyrimidinediamine
10b.
Obtained using 4-methylbenzenethiol. Yield of 10b: 94% (1.51
g, 6.50 mmol), mp 240–242 ЊC. HRMS (EI) found: 232.0788,
C11H12N4S requires 232.0783. δH(DMSO) 2.35 (3H, s, C(11)H3),
5.08 (1H, s, C(5)H), 5.97 (2H, br s, NH2), 6.18 (2H, br s, NH2),
7.29 (2H, d, J = 7.8, 2 × C(8)H), 7.44 (2H, d, J = 7.8, 2 ×
C(9)H). δC(DMSO) 21.71 (C-11), 90.05 (C-5), 126.49 (C-7),
131.26 (2 × C-8), 136.36 (2 × C-9), 140.16 (C-10), 163.28 (C-4),
164.96 (C-2), 170.12 (C-6). νmax(KBr) 3485 (NH2), 3371, 1642,
1619, 1558, 1363, 899, 506 cmϪ1
.
1727 (C᎐O), 1690 (C᎐O), 1566, 1395, 1276, 1213, 831, 559, 441
᎐
᎐
cmϪ1. λmax(MeOH) 275, 207 nm.
4-(Benzylsulfanyl)-6,7-dimethyl-2-pteridinamine 8-oxide 14a.
A solution of OXONE® (KHSO5) (0.93 g, 3 mmol) in water
(10 mL) was added at 0 ЊC to 4-(benzylsulfanyl)-6,7-dimethyl-2-
pteridinamine 13a (0.3 g, 1 mmol) in methanol (10 mL). The
resulting cloudy slurry was stirred for 4 hours at room temper-
ature and evaporated to dryness under reduced pressure. The
product was separated from the salt by dissolving it in methanol
(20 mL) and filtering. Evaporation of the methanol yielded the
title compound 14a (0.23 g, 0.73 mmol, 73%), mp > 240 ЊC.
HRMS (FAB) found: 314.1068, C15H16N5OS (M ϩ 1) requires
314.1076. δH(DMSO) 2.53 (3H, s, C(15)H3), 2.61 (3H, s,
C(14)H3), 4.51 (2H, s, C(9)H2), 7.24–7.27 (1H, m, C(13)H),
7.30–7.34 (2H, m, 2 × C(12)H), 7.51–7.53 (2H, m, 2 × C(11)H),
7.93 (2H, br s, NH2). δC(DMSO) 22.17 (C-15), 23.58 (C-14),
32.82 (C-9), 126.00 (C-4a), 127.66 (C-13), 128.84 (2 × C-12),
129.71 (2 × C-11), 137.70 (C-10), 149.12 (C-8a), 149.88 (C-7),
158.16 (C-2), 162.41 (C-6), 176.21 (C-4).
b) From 4b with m-CPBA. A solution of m-chloroperbenzoic
acid (0.5 g, 2 mmol) in dichloromethane (15 mL) was added to
2-(benzylsulfanyl)-6,7-dimethyl-4(3H )-pteridinone 4b (0.2 g,
0.67 mmol) and the resulting mixture was stirred for 4 hours at
room temperature. The solution was evaporated under reduced
pressure and the residue was purified by silica gel column
chromatography eluting with ethyl acetate–methanol (4 : 1)
to yield the title compound 8 as a pale yellow solid (0.1 g, 0.53
mmol, 78%).
Synthesis of 2-(1H-1,2,3-benzotriazol-1-yl)-6,7-dimethyl-4(3H)-
pteridinone 9
A solution of freshly prepared 1-chlorobenzotriazole (0.31 g,
2 mmol) in methanol (10 mL) was added in portions to
2-(benzylsulfanyl)-6,7-dimethyl-4(3H )-pteridinone 4b (0.3 g,
1 mmol) in methanol (20 mL) and molecular sieves (4 Å, 200
mg) at Ϫ78 ЊC. The solution was stirred for 2 hours, while the
temperature was raised to room temperature. Evaporation of
the solvents under reduced pressure and purification by silica
gel column chromatography eluting with ethyl acetate–
methanol (4 : 1) yielded the title compound 9 together with
some impurities (0.15 g, 0.51 mmol, 25%). HRMS (FAB)
found: 294.1102, C14H12N7O (M ϩ 1) requires 294.1103.
δH(DMSO 2.59 (6H, s, C(15)H3, C(16)H3), 7.46–7.50 (1H, m,
C(11)H), 7.64–7.68 (1H, m, C(12)H), 8.12 (1H, d, J = 8.3,
C(10)H), 8.76 (1H, d, J = 8.3, C(13)H). δC(DMSO) 22.10, 23.00
(C-15, C-16), 116.27 (C-13), 119.44 (C-10), 124.86 (C-11),
128.55 (C-12), 132.23 (C-14), 146.22 (C-6), 149.4, 152.4, 155.32,
157.21 (C-8a, C-2, C-4a, C-7), 171.95 (C-4). νmax(KBr) 3413,
General method for the cleavage of the 4-benzylsulfanyl group
from 13a or the 4-[(4-methylphenyl)sulfanyl] group from 13b
using DDO oxidation and a nucleophile
4-(Benzylsulfanyl)-6,7-dimethyl-2-pteridinamine 13a or 6,7-
dimethyl-4-[(4-methylphenyl)sulfanyl]-2-pteridinamine
13b
(0.25 g, 0.84 mmol) was added to a Suba-sealed flask with a
magnetic stirring bar. The flask was immersed in an acetone–
dry ice bath, and a 0.107 M solution of DDO in acetone
(20 mL, 2.14 mmol) was added via a syringe to the stirring
solution. After 15 min, the appropriate nucleophile was added
via syringe, then the flask was removed from the dry ice bath,
and left stirring for 40 min or until it reached room temperature.
The solvent was removed under reduced pressure and the
residue was dissolved in a small amount of diethyl ether
and/or acetone and filtered to afford the required substituted
compound.
2925 (CH), 1658 (C᎐O), 1593, 1523, 1447, 1072, 949, 750, 472
᎐
cmϪ1
.
General method for the synthesis of benzylsulfanyl and (4-methyl-
phenyl)sulfanyl pyrimidines from 6-chloro-2,4-pyrimidinediamine
2-Amino-6,7-dimethyl-4(3H)-pteridinone 7a. From 13a:
Obtained using water (5 mL) as nucleophile and leaving the
reaction stirring at room temperature overnight. A pure sample
was obtained by recrystallisation from aqueous ammonia.
Yield of 7a: 90% (0.145 g, 0.76 mmol) as a yellow amorphous
solid, mp > 240 ЊC (lit.24 > 300 ЊC). HRMS (EI) found:
191.0807, C8H9N5O (Mϩ) requires 191.0807. δH(TFA) 2.88
(3H, s, C(10)H3), 2.90 (3H, s, C(9)H3). δC(TFA) 21.75 (C-10),
23.81 (C-9), 124.30 (C-4a), 148.15 (C-8a), 154.11 (C-2), 157.38
(C-6), 161.40 (C-4), 167.96 (C-7). νmax(KBr) 3263 (NH2), 2847,
To a suspension of 6-chloro-2,4-pyrimidinediamine (1 g, 6.94
mmol) and sodium hydroxide (0.35 g, 8 mmol) in ethanol
(30 mL) and water (20 mL), the appropriate thiol (1.3 g, 10.46
mmol) was added. The reaction mixture was stirred at 80 ЊC
overnight. The solution was concentrated by evaporation under
reduced pressure, and water (20 mL) was added to the residue.
The precipitate was collected by filtration, washed with water
and diethyl ether, to afford the required product as a white
solid.
2771, 1687 (C᎐O), 1547, 1517, 1389, 1270, 1179, 867, 686, 518
᎐
cmϪ1
.
6-(Benzylsulfanyl)-2,4-pyrimidinediamine 10a. Obtained
using benzylthiol. Yield of 10a: 85% (1.37 g, 5.90 mmol), mp
144–146 ЊC (lit.25 146–148 ЊC). HRMS (FAB) found: 233.0871,
C11H13N4S (M ϩ 1) requires 233.0861. δH(DMSO) 4.26 (2H, s,
C(7)H2), 5.63 (1H, s, C(5)H), 6.01 (2H, s, NH2), 6.20 (2H, s,
From 13b: Obtained using water (5 mL) as nucleophile and
leaving the reaction stirring at room temperature overnight. A
pure sample was obtained by recrystallisation from aqueous
ammonia. Yield of 7a: 89% (0.142 g, 0.75 mmol) as a yellow
amorphous solid.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1915

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4-Methoxy-6,7-dimethyl-2-pteridinamine 14. Obtained using
methanol (4 mL) as nucleophile and leaving the reaction
stirring at room temperature for a further 3 hours. Yield of 14:
74% (0.127 g, 0.62 mmol) as a bright red solid, mp > 240 ЊC
(lit.29 255–257 ЊC). HRMS (FAB) found: 206.1044, C9H12N5O
(M ϩ 1) requires 206.1042. δH(DMSO) 2.50 (3H, s, C(12)H3),
2.54 (3H, s, C(11)H3), 4.03 (3H, s, C(10)H3), 7.08 (2H, s, NH2).
δC(DMSO) 22.04 (C-12), 23.45 (C-11), 54.61 (C-10), 120.15
(C-4a), 148.24 (C-6), 155.75 (C-7), 160.41, 161.20, 167.15
(C-8a, C-2, C-4). νmax(KBr) 3486, 3339, 1627, 1597, 1547, 1448,
residue was covered with water (20 mL) and then solid potas-
sium hydroxide was added until the solution was strongly basic.
The solution was boiled, treated with charcoal, and filtered.
The filtrate was neutralized with acetic acid and allowed to
cool. The precipitate was filtered, washed with water, and dried
at 70 ЊC to yield the desired purine 16 (1.1 g, 4.28 mmol, 70%),
mp 208–210 ЊC (lit.24 212–214 ЊC). HRMS (FAB) found:
258.0802, C12H12N5S (M ϩ 1) requires 258.0813. δH(DMSO)
4.55 (2H, s, C(10)H2), 6.42 (2H, s, NH2), 7.21–7.31 (3H, m,
C(14)H, 2 × C(13)H), 7.45–7.47 (2H, m, 2 × C(12)H), 7.88 (1H,
s, C(8)H), 12.51 (1H, br s, N(9)H). δC(DMSO) 31.47 (C-10),
124.04 (C-5), 127.32 (C-14), 128.73 (2 × C-13), 129.45 (C-8),
129.49 (2 × C-12), 139.08 (C-11), 152.26 (C-4), 158.37, 159.94
(C-2, C-6). νmax(KBr) 3457, 3390 (NH), 1626, 1559, 1498, 1262,
1223, 992, 821 cmϪ1
.
6,7-Dimethyl-2,4-pteridinediamine 15a. Obtained by bubbling
NH3 (gas) into the acetone solution for 5 min. Yield of
15a: 89% (0.142 g, 0.75 mmol) as an orange crystalline solid,
mp > 240 ЊC. HRMS (FAB) found: 191.1052, C8H11N6 (M ϩ 1)
requires 191.1045. δH(TFA) 2.69 (3H, s, C(10)H3), 2.72 (3H, s,
C(9)H3). δC(TFA) 23.11 (C-10), 23.46 (C-9), 121.83 (C-4a),
145.94 (C-8a), 156.49 (C-2), 158.46 (C-6, C-4), 166.88 (C-7).
νmax(KBr) 3443 (NH2), 3307, 3154, 1667, 1624, 1583, 1543,
914, 830, 703 cmϪ1
.
2-Amino-1,9-dihydro-6H-purin-6-one. 6-(Benzylsulfanyl)-9H-
purin-2-amine 16 (0.2 g, 0.78 mmol) was stirred in a solution of
acetic acid (10 mL) and hydrogen peroxide (30%, 1 mL). The
solution mixture was heated to 60 ЊC for 4 hours, and then the
solvent was evaporated under reduced pressure. The residue
was washed with water (10 mL) and dried on air to afford the
title compound (0.075 g, 0.49 mmol, 64%), mp > 260 ЊC (lit.30
365 ЊC). δH(DMSO) 6.90 (2H, br s, NH2), 8.68 (1H, s, C(8)H),
11.40 (2H, br s, N(1)H, N(9)H). δC(DMSO) 109.26 (C-5),
137.25 (C-8), 151.24 (C-4), 154.35 (C-6), 154.98 (C-2).
1447, 1342, 1232, 964, 821, 461 cmϪ1
.
N4-(4-Chlorophenyl)-6,7-dimethyl-2,4-pteridinediamine 15b.
From 13a: Obtained using 4-chloroaniline (0.127 g, 1 mmol) in
acetone (2 mL) as nucleophile. Yield of 15b: 84% (0.21 g,
0.7 mmol) as an orange solid.
From 13b: Obtained using 4-chloroaniline (0.129 g, 1 mmol)
in acetone (2 mL) as nucleophile.
νmax(KBr) 3324, 3120, 1677, 1625, 1573, 1272, 1150 cmϪ1
.
Yield of 15b: 87% (0.22 g, 0.73 mmol), mp > 240 ЊC. HRMS
(FAB) found: 301.0959, C14H14N635Cl (M ϩ 1) requires
301.0969. δH(DMSO) 2.60 (3H, s, C(15)H3), 2.63 (3H, s,
C(14)H3), 7.43 (2H, d, J = 8.8, 2 × C(11)H), 7.45 (2H, br s,
NH2), 8.06 (2H, d, J = 8.8, 2 × C(12)H), 10.26 (1H, s, N(9)H).
δC(DMSO) 21.88 (C-13), 23.28 (C-14), 119.65 (C-10), 123.61
(2 × C-11), 127.84 (C-6), 128.71 (2 × C-12), 138.04 (C-13),
152.25 (C-7), 158.45, 160.18, 160.50 (C-8a, C-2, C-4). νmax(KBr)
Solid phase reactions
Synthesis. Preparation of resin 17 (type-A and type-B) –
Loading. Merrifield resin (12 mmol) was weighed into a 50 mL
round bottom flask. To this was added potassium iodide
(0.75 eq.), potassium hydroxide (1.2 eq.) and 6-amino-2-
sulfanyl-4(3H )-pyrimidinone monohydrate 1a (2.5 eq.) fol-
lowed by DMSO (25 mL). The mixture was stirred with an
overhead stirrer with the flask being placed in a pre-heated sand
bath at 80 ЊC for 2 days. The mixture was filtered through a
sinter and the resin was washed with DMF (2 × 20 mL), water
(3 × 30 mL) and a double sequence of methanol (2 × 10 mL),
acetone (2 × 10 mL), THF (10 mL) and ether (10 mL). The
resin was dried at 70 ЊC/0.1 mmHg for 10 hours to give the
functionalised resin 17. Found resin A (6.05 mmol g Ϫ1): C
58.62, H 5.44, N 12.27, Cl 4.47, S 9.51%, corresponding to 79%
conversion, 2.91 mmol gϪ1. Found resin B (1.98 mmol gϪ1): C
74.63, H 6.57, N 6.46, S 5.33%, corresponding to 95% conver-
3478 (NH), 3096, 1687, 1589, 1554, 1490, 1090, 826, 466 cmϪ1
.
6,7-Dimethyl-4-(1-pyrrolidinyl)-2-pteridinamine 15c.
Obtained using pyrrolidine (0.12 g, 1.69 mmol) as nucleophile.
Yield of 15c: 92% (0.19 g, 0.78 mmol) as a yellow crystalline
solid. mp > 240 ЊC. HRMS (EI) found: 245.1517, C12H16N6
(Mϩ) requires 245.1514. δH(TFA) 2.21–2.34 (4H, m, 2 ×
C(11)H2), 2.78 (3H, s, C(13)H3), 2.80 (3H, s, C(12)H3), 4.10
(2H, t, J = 6.8, C(10)H2), 4.65 (2H, t, J = 6.8, C(10)H2). δC(TFA)
22.39 (C-13), 22.78 (C-12), 25.45 (1 × C-11), 28.37 (1 × C-11),
55.57 (1 × C-10), 57.35 (1 × C-10), 125.36 (C-4a), 146.68
(C-8a), 154.10 (C-2), 155.08, 156.17, 162.29 (C-6, C-4, C-7).
νmax(KBr) 3369 (NH2), 3128, 1644, 1574, 1553, 1450, 1424,
sion, 1.53 mmol gϪ1
.
Preparation of resin 18 (type-A and type-B) – Nitrosation.
Resin 17 (0.1 g) was placed in a 5 mL reaction vial containing a
spin vane. DMF (3 mL) was added followed by a solution of
sodium nitrite (5 eq.) in water (2 mL) and acetic acid (0.4 mL).
The mixture was stirred for 24 hours at room temperature to
give a green-blue resin. The mixture was filtered through a sin-
ter and the resin was washed with DMF (2 × 20 mL), water (3 ×
30 mL) and a double sequence of methanol (2 × 10 mL), acet-
one (2 × 10 mL), THF (10 mL) and ether (10 mL). The resin
was dried at 70 ЊC/0.1 mmHg for 10 hours to give the nitroso
polymer 18. Found type-A: C 57.33, H 4.83, N 14.7, S 9.38%,
corresponding to 97% conversion, 2.62 mmol gϪ1. Found type-
B: C 72.04, H 6.18, N 7.71, S 5.01%, corresponding to 93%
1342, 1313, 820 cmϪ1
.
N4-[3-(Dimethylamino)propyl]-6,7-dimethyl-2,4-pteridine-
diamine 15d. Obtained using N,N-dimethyl-1,3-propane-
diamine (0.17 g, 1.66 mmol) as nucleophile. Yield of 15d: 71%
(0.16 g, 0.6 mmol) as an amorphous white solid, mp 197–199
ЊC. HRMS (FAB) found: 276.1926, C13H22N7 (M ϩ 1) requires
276.1937. δH(DMSO) 1.70–1.77 (2H, m, C(11)H2), 2.15 (6H, s,
2 × C(14)H3), 2.30 (2H, t, J = 6.8, C(12)H2), 2.50 (6H, s,
C(15)H3, C(16)H3), 3.48 (2H, q, J = 6.8, C(10)H2), 6.41 (2H, br
s, NH2), 8.16 (1H, br s, N(9)H). δC(DMSO) 21.85 (C-16), 23.22
(C-15), 26.72 (C-11), 39.54 (C-10), 45.60 (2 × C-14), 57.71
(C-12), 120.11 (C-4a), 145.23 (C-6), 154.58 (C-7), 158.78,
160.58, 162.80 (C-8a, C-2, C-4). νmax(KBr) 3374, 1641, 1582,
conversion, 1.37 mmol gϪ1
.
Preparation of resin 19 (type-A and type-B) – Reduction.
Resin 18 (0.15 g) was placed in a 5 mL reaction vial containing
a spin vane. DMF (2 mL) was added followed by a solution of
sodium hydrosulfide (5 eq.) in water (2 mL). The mixture was
stirred for 20 hours at 40 ЊC to give a yellow resin. The mixture
was filtered through a sinter and the resin was washed with
DMF (2 × 20 mL), water (3 × 30 mL) and a double sequence of
methanol (2 × 10 mL), acetone (2 × 10 mL), THF (10 mL) and
ether (10 mL). The resin was dried (70 ЊC at 0.1 mmHg) for
1439, 1338, 1220, 977, 822, 469 cmϪ1
.
6-(Benzylsulfanyl)-9H-purin-2-amine 16. 6-(Benzylsulfanyl)-
2,4,5-pyrimidinetriamine 12a (1.5 g, 6.07 mmol) was suspended
in a 1 : 1 mixture (20 mL) of ethyl orthoformate and acetic
anhydride. The solution was heated at reflux for 2–3 hours, and
the excess solvent was removed under reduced pressure. The
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1916

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10 hours to give the diamino polymer 19. Found type-A (hygro-
scopic) C 55.06, H 5.25, N 13.01, S 10.67%, corresponding to
85% conversion, 2.32 mmol gϪ1. Found type-B (hygroscopic): C
73.97, H 6.23, N 5.69, S 6.31%, corresponding to 72% conver-
Cleavage. 7a from resin 24 using DDO and water. Resin 24
(0.3 g, 0.54 mmol) was suspended in an acetone solution of
dimethyldioxirane (0.105 M, 25 mL, 2.62 mmol) at room tem-
perature and stirred for 5 hours. Afterwards, the acetone solu-
tion was carefully removed from the flask and a further 25 mL
of DDO solution in acetone was added. This was stirred at
room temperature for 7 hours and then water (2 mL) was
added. The solution was kept stirring for 5 hours at 40 ЊC, and
then it was filtered, washing the resin extensively with methanol
(30 mL) and conc aqueous ammonia (10 mL). All the filtrates
were reunited, evaporated under reduced pressure, and the resi-
due dissolved in conc. aqueous ammonia (10 mL). The title
compound 7a crystallised from the solution to give a yellow
solid (52 mg, 0.27 mmol, 50%), mp > 260 ЊC. δH(TFA) 2.89 (3H,
s, C(10)H3), 2.91 (3H, s, C(9)H3). δC(TFA) 21.75 (C-10), 23.81
(C-9), 124.30 (C-4a), 148.15 (C-8a), 154.11 (C-2), 157.38 (C-6),
161.40 (C-4), 167.96 (C-7). νmax(KBr) 3265, 2842, 1689, 1547,
sion, 1.02 mmol gϪ1
.
Preparation of resin 20 (type-A and type-B) – Cyclisation.
Resin 19 (0.12 g) was placed in a 5 mL reaction vial containing
a spin vane. DMF (4 mL) was added followed by biacetyl
(5 eq.). The mixture was stirred for 18 hours in a sand bath at
80 ЊC to give a dark brown resin. The mixture was filtered
through a sinter and the resin was washed with DMF (2 ×
20 mL), water (3 × 30 mL) and a double sequence of methanol
(2 × 10 mL), acetone (2 × 10 mL), THF (10 mL) and ether
(10 mL). The resin was dried (70 ЊC/0.1 mmHg) for 10 hours to
give polymer 20. Found type-A (hygroscopic): C 63.53,
H 5.68, N 11.84, S 8.55%, corresponding to 101% conversion,
2.11 mmol gϪ1. Found type-B (hygroscopic): C 79.23, H 6.54,
N 5.21, S 5.67%, corresponding to 96% conversion, 0.93
1519, 1389, 1179, 686, 517 cmϪ1
.
mmol gϪ1
.
7b from cleavage of resin 20 (type-A) using allylamine. Resin
20 (type-A, 0.2 g, 0.42 mmol) and allylamine (3 mL) were
stirred in DMF (20 mL) at 100 ЊC for 72 hours. Then the resin
was filtered off and washed with DMF (5 mL), water (5 mL)
and methanol (5 mL). All the filtrates were reunited, evaporated
under reduced pressure and purified by silica gel column
chromatography eluting with ethyl acetate–methanol (5 : 1)
(6 mg, 26 µmol, 6%), mp > 240 ЊC. δH(DMSO) 2.48 (3H,
s, C(13)H3), 2.49 (3H, s, C(12)H3), 3.99 (2H, s, C(9)H2),
5.12 (1H, d, J = 10.2, 1 × C(11)H2), 5.22 (1H, d, J = 17.2,
1 × C(11)H2), 5.90–5.97 (1H, m, C(10)H), 6.72 (1H, br s, NH),
11.17 (1H, br s, N(3)H). δC(DMSO) 21.69 (C-12), 22.91 (C-13),
42.83 (C-9), 115.93 (C-11), 135.28 (C-10), 152.16 (C-7), 161.12
(C-4).
7b from cleavage of resin 20 (type-B) using DDO and
allylamine. A solution of dimethyldioxirane (DDO) in acetone
(0.09 M, 15 mL, 1.35 mmol) was added to the resin 20 (type-B,
0.3 g, 0.28 mmol) and stirred at room temperature for 3 hours.
Then the acetone solution was carefully removed and a further
15 mL of the same solution were added. The resin was stirred
for a further 5 hours, filtered and washed with acetone (10 mL),
THF (10 mL) and ether (10 mL). After, the resin was suspended
in DMF (10 mL), THF (5 mL) and allylamine (0.3 mL) were
added. The mixture was stirred at 50 ЊC for 24 hours. Then, the
resin was filtered off and washed with DMF (5 mL), water
(5 mL) and methanol (5 mL). All the filtrates were reunited,
evaporated under reduced pressure and purified by silica gel
column chromatography eluting with ethyl acetate–methanol
5 : 1 to give the title compound as a yellow solid (22 mg,
95 µmol, 34%), mp > 240 ЊC. δH(DMSO) 2.48 (3H, s, C(13)H3),
2.49 (3H, s, C(12)H3), 3.99 (2H, s, C(9)H2), 5.12 (1H, d,
J = 10.2, 1 × C(11)H2), 5.22 (1H, d, J = 17.2, 1 × C(11)H2),
5.90–5.97 (1H, m, C(10)H), 6.72 (1H, br s, NH), 11.17 (1H, br s,
N(3)H). δC(DMSO) 21.68 (C-12), 22.89 (C-13), 42.84 (C-9),
115.92 (C-11), 126.35 (C-6), 135.29 (C-10), 147.5 (C-4a), 152.15
(C-7), 155.6 (C-8a), 158.73 (C-2), 161.16 (C-4).
7c from cleavage of resin 20 (type-A) with pyrrolidine. Resin
20 (type-A, 0.2 g, 0.42 mmol) and pyrrolidine (3 mL) were
stirred in DMF (20 mL) at 100 ЊC for 72 hours. Then the resin
was filtered off and washed with DMF (5 mL), water (5 mL)
and methanol (5 mL). All the filtrates were reunited, evaporated
under reduced pressure and purified by silica gel column
chromatography eluting with ethyl acetate–methanol 5 : 1
(5 mg, 20 µmol, 5%), mp > 240 ЊC. The compound was identi-
fied by TLC analysis with an authentic sample.
7c from cleavage of resin 20 (type-B) using DDO and pyrrol-
idine. A solution of dimethyldioxirane (DDO) in acetone
(0.048 M, 15 mL, 0.72 mmol) and THF (7 mL) was added to
the resin 20 (type-B, 0.3 g, 0.28 mmol) and stirred at room
temperature for 3 hours. Then the acetone solution was care-
fully removed and a further 15 mL of the same solution were
added. The resin was stirred for a further 5 hours, then filtered
Preparation of resin 21 – Loading. A mercapto-functionalised
Merrifield-type resin (Novabiochem, 2 g, 4 mmol gϪ1, 8 mmol)
was weighed into a 100 mL round bottom flask equipped with
an overhead stirrer and nitrogen inlet. To this was added potas-
sium iodide (1 g, 6 mmol), potassium hydroxide (0.45 g,
8 mmol) and 2,4-diamino-6-chloropyrimidine (2.9 g, 20 mmol)
followed by DMSO (40 mL). The mixture was stirred with an
overhead stirrer with the flask being placed in a pre-heated sand
bath at 80 ЊC for 2 days. The mixture was filtered through a
sinter and the resin was washed with DMSO (2 × 20 mL), water
(3 × 30 mL) and a double sequence of methanol (2 × 10 mL),
acetone (2 × 10 mL), THF (10 mL) and ether (10 mL). The
resin was dried at 70 ЊC/0.1 mmHg for 10 hours to give the
functionalised resin 21. Found: C 69.32, H 6.28, N 13.25,
S 7.75%, corresponding to 84% conversion, 2.37 mmol gϪ1
.
Preparation of resin 22 – Nitrosation. Resin 21 (0.2 g,
0.47 mmol) was placed in a 5 mL reaction vial containing a spin
vane. DMF (3 mL) was added followed by a solution of sodium
nitrite (0.1 g, 1.45 mmol) in water (2 mL) and acetic acid
(0.4 mL). The mixture was stirred for 24 hours at room temper-
ature to give a green-blue resin. The mixture was filtered
through a sinter and the resin was washed with DMF (2 ×
20 mL), water (3 × 30 mL) and a double sequence of methanol
(2 × 10 mL), acetone (2 × 10 mL), THF (10 mL) and ether
(10 mL). The resin was dried at 70 ЊC/0.1 mmHg for 10 hours to
give the nitroso polymer 22. Found: C 68.45, H 5.99, N 14.67,
S 7.45%, corresponding to 95% conversion, 2.09 mmol gϪ1
.
Preparation of resin 23 – Reduction. Resin 22 (0.2 g, 0.42
mmol) was placed in a 5 mL reaction vial containing a spin
vane. DMF (3 mL) was added followed by a solution of sodium
hydrosulfide (0.36 g, 2.1 mmol) in water (2 mL). The mixture
was stirred for 20 hours at 40 ЊC to give a yellow resin. The
mixture was filtered through a sinter and the resin was washed
with DMF (2 × 20 mL), water (3 × 30 mL) and a double
sequence of methanol (2 × 10 mL), acetone (2 × 10 mL), THF
(10 mL) and ether (10 mL). The resin was dried (70 ЊC/
0.1 mmHg) for 10 hours to give the diamino polymer 23. Found
(hygroscopic) C 66.88, H 6.23, N 13.35, S 6.88%, corresponding
to 88% conversion, 1.91 mmol gϪ1
.
Preparation of resin 24 – Cyclisation. Resin 23 (0.12 g,
0.23 mmol) was placed in a 5 mL reaction vial containing a
spin vane. DMF (4 mL) was added followed by biacetyl (0.1 g,
1.16 mmol). The mixture was stirred for 18 hours in a sand bath
at 80 ЊC to give a dark brown resin. The mixture was filtered
through a sinter and the resin was washed with DMF (2 ×
20 mL), water (3 × 30 mL) and a double sequence of methanol
(2 × 10 mL), acetone (2 × 10 mL), THF (10 mL) and ether
(10 mL). The resin was dried (70 ЊC/0.1 mmHg) for 10 hours to
give polymer 24.
Found: C 70.06, H 6.21, N 12.65, S 7.01%, corresponding to
104% conversion, 1.81 mmol gϪ1
.
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1917

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and washed with acetone (10 mL), THF (10 mL) and ether
(10 mL). Afterwards, the resin was suspended in DMF (10 mL)
and THF (5 mL) and pyrrolidine (0.3 mL) was added. The
mixture was stirred at 50 ЊC for 24 hours. Then, the resin was
filtered off and washed with DMF (5 mL), water (5 mL) and
methanol (5 mL). All the filtrates were reunited, evaporated
under reduced pressure and purified by silica gel column
chromatography eluting with ethyl acetate–methanol 5 : 1 to
give the title compound as a yellow solid (30 mg, 0.12 mmol,
43%). mp > 240 ЊC. δH(DMSO) 1.92 (4H, t, J = 6.5, C(10)H2,
C(11)H2), 2.48 (3H, s, C(14)H3), 2.50 (3H, s, C(13)H3), 3.50
(4H, t, J = 6.5, C(9)H2, C(12)H2), 11.34 (1H, br s, N(3)H).
Acknowledgements
We thank Dr Adam McCluskey for important preliminary
work. This research was supported by an EU TMR Network
‘Pteridines’ EUFMRXCT980204.
References
1 J. C. H. M. Wijkmans and R. P. Beckett, Drug Discovery Today,
2002, 7, 126–132; R. G. Franzen, J. Comb. Chem., 2000, 2, 195–214;
B. A. Bunin, J. M. Dener and D. A. Livingston, Annu. Rep. Med.
Chem., 1999, 34, 267–286.
2 L. M Gayo and M. J. Suto, Tetrahedron Lett., 1997, 38, 211–214.
3 D. Obrecht, C. Abrecht, A. Grieder and J. M. Villalgordo,
Helv. Chim. Acta, 1997, 80, 65–72.
νmax(KBr) 3440, 3159 (NH), 2962 (CH), 1685 (C᎐O), 1605,
᎐
1559, 1520, 1396, 1270, 984, 821, 732 cmϪ1. λmax(MeOH) 358,
286, 228 nm.
4 I. Parrot, C.-G. Wermuth and M. Hilbert, Tetrahedron Lett., 1999,
40, 7975–7978.
7d from cleavage of resin 20 (type-B) using DDO and sodium
azide. A solution of dimethyldioxirane (DDO) in acetone
(0.048 M, 15 mL, 0.72 mmol) and THF (7 mL) was added to
the resin 20 (type-B, 0.3 g, 0.28 mmol) and stirred at room
temperature for 3 hours. Then the acetone solution was care-
fully removed and a further 15 mL of the same solution were
added. The resin was stirred for a further 5 hours, then filtered
and washed with acetone (10 mL), THF (10 mL) and ether
(10 mL). Afterwards, the resin was suspended in DMF (10 mL)
and THF (5 mL), and sodium azide (0.1 g, 1.54 mmol) was
added. The mixture was stirred at 50 ЊC for 24 hours. Then, the
resin was filtered off and washed with DMF (5 mL), water
(5 mL) and MeOH (5 mL). All the filtrates were reunited,
evaporated under reduced pressure and re-dissolved in ethanol.
The salt was filtered off the solution and the filtrate evapor-
ated to yield the title compound (25 mg, 0.115 mmol, 41%), mp
> 240 ЊC. δH(DMSO) 2.30 (3H, s, C(9)H3), 2.35 (3H, s,
C(10)H3), 11.90 (1H, s, N(3)H). νmax(KBr) 3380 (NH), 2137
5 S. K. Srivastava, W. Haq and P. M. S. Chauhan, Bioorg. Med. Chem.
Lett., 1999, 9, 965–966.
6 V. Brun, M. Legraverend and D. S. Grierson, Tetrahedron Lett.,
2001, 42, 8161–8164.
7 V. Brun, M. Legraverend and D. S. Grierson, Tetrahedron Lett.,
2001, 42, 8165–8167.
8 T. C. Norman, N. S. Gray, J. T. Koh and P. G. Schultz, J. Am. Chem.
Soc., 1996, 118, 7430–7431.
9 H. Rink, Tetrahedron Lett., 1987, 28, 3787–3790.
10 N. S. Gray, L. Wodicka, A.-M. Thunnissen, T. C. Norman, S. Kwon,
F. O. M. D. Herman Espinoza, G. Barnes, S. LeClerc, L. Meijer,
S.-H. Kim, D. J. Lockhart and P. G. Schultz, Science, 1998, 281,
533–538.
11 K. Kim and B. Wang, Chem. Commun., 2001, 2268–2269.
12 A. D. Baxter, E. A. Boyd, P. B. Cox, V. Loh Jr., C. Monteils and
A. Proud, Tetrahedron Lett., 2000, 41, 8177–8181.
13 C. L. Gibson, S. La Rosa and C. J. Suckling, Tetrahedron Lett., 2003,
44, 1267–1270.
14 D. Guiney, C. L. Gibson and C. J. Suckling, Org. Biomol. Chem.,
2003, 665–675; S. La Rosa, P. Boyle, C. L. Gibson, K. Ohta and
C. J. Suckling, J. Chem. Soc. (paper in preparation); S. La Rosa,
P. H. Boyle, C. L. Gibson, D. Guiney and C. J. Suckling, Chem. Biol.
Pteridines Folates, Proc. Int. Symp. Pteridines Folates, 12th, 2002,
25–29; D. Guiney, P. H. Boyle, C. L. Gibson, S. La Rosa and
C. J. Suckling, Chem. Biol. Pteridines Folates, Proc. Int. Symp.
Pteridines Folates, 12th, 31–35; C. L. Gibson, P. H. Boyle, D. Guiney,
S. La Rosa and C. J. Suckling, Chem. Biol. Pteridines Folates,
Proc. Int. Symp. Pteridines Folates, 12th, 421–425.
15 C. L. Gibson, A. Lang, K. Ohta, M. J. Rice and C. J. Suckling,
J. Chem. Soc., Perkin Trans. 1, 1999, 163–169.
16 A. McCluskey, C. L. Gibson, and C. J. Suckling, Solid Phase
Synthesis and Combinatorial Chemical Libraries, Mayflower Press,
Kingswinford, 2001, 359–360.
17 L. Goldman, J. W. Marsico and A. L. Gazzola, Chem. Commun.,
1956, 21, 599–600.
18 J. Lee, A. Doucette, N. S. Wilson and J. Lord, Tetrahedron Lett.,
2001, 42, 2635–2638.
19 K. R. Guertin and A. S. Kende, Tetrahedron Lett., 1993, 34, 5369–
5372.
Ϫ1
᎐
(N᎐N), 2041, 1605, 1448, 1206, 641 cm . λmax(MeOH) 342,
᎐
266, 205 nm.
8 from cleavage of resin 20 (type-A) with m-CPBA. Resin 20
(type-A, 0.10 g, 0.21 mmol) was suspended in dichloromethane
(15 mL) and m-chloroperbenzoic acid (0.15 g, 0.6 mmol) was
added. The mixture was stirred for 20 hours at room temper-
ature and then the resin was filtered off and washed with di-
chloromethane (10 mL) and methanol (10 mL). All the filtrates
were reunited, evaporated under reduced pressure, dissolved
in ethyl acetate and absorbed into the top of a silica gel
column and eluted with ethyl acetate (10 mg, 52 µmol, 25%),
mp > 260 ЊC. δH(DMSO) 2.50 (3H, s, C(9)H3), 2.52 (3H, s,
C(10)H3), 11.47 (1H, br s, N(1)H), 11.65 (1H, br s, N(3)H).
δC(DMSO) 22.05 (C-9), 23.05 (C-10), 124.64 (C-4a), 148.12
(C-6), 148.94 (C-2), 150.78 (C-8a), 158.58 (C-7), 161.94 (C-4).
λmax(MeOH) 275, 207 nm.
20 W. D. Kingsbury and C. R. Johnson, Chem. Commun., 1969, 365–
365.
8 from cleavage of resin 20 (type-B) with DDO. Resin 20
(type-B, 0.5 g, 0.46 mmol) was suspended in an acetone solu-
tion of dimethyldioxirane (0.11 M, 25 mL, 2.75 mmol) at room
temperature and stirred for 5 hours. After, the acetone solution
was carefully removed from the flask and a further 25 mL of
DDO was added. This was stirred at room temperature for 7
hours and then water (2 mL) was added. The solution was kept
stirring for 5 hours at 40 ЊC, and then it was filtered, washing
the resin extensively with methanol. All the filtrates were
reunited, evaporated and purified by flash silica gel column
21 W. Adam, J. Bialas and L. Hadjiarapoglou, Chem. Ber., 1991, 124,
2377–2377.
22 R. Soyka and W. Pfleiderer, Pteridines, 1990, 63; R. Soyka,
W. P fleiderer and R. Prewo, Helv. Chim. Acta, 1990, 73, 808.
23 Y. Tominaga, Y. Honkawa, M. Hara and A. Hosomi, J. Heterocycl.
Chem., 1990, 27, 775–783.
24 H. Yamamoto, W. Hutzenlaub and W. Pfleiderer, Chem. Ber., 1973,
106, 3175–3193.
25 G. D. Daves, C. W. Noell, R. K. Robins, H. C. Koppel and
A. G. Beaman, J. Am. Chem. Soc., 1960, 82, 2633–2640.
26 T. Sugimoto, S. Matsuura and T. Nagatsu, Bull. Chem. Soc. Jpn.,
1980, 53, 2344–2347.
27 B. R. Baker and J. L. Hendrickson, J. Pharm. Sci., 1967, 56, 955–
959.
28 W. Pfleiderer and W. Hutzenlaub, Chem. Ber., 1973, 106, 3149–3174.
29 B. Roth, J. M. Smith and M. E. Hultquist, J. Am. Chem. Soc., 1951,
73, 2869–2871.
30 Kazakevich. El’Tekov, Russ. J. Phys. Chem. (Transl. of Zh. Fiz.
Khim.), 1987, 61, 233–234.
chromatography (ethyl acetate
ethyl acetate–methanol
4 : 1) (40 mg, 0.21 mmol, 45%), mp > 260 ЊC. δH(DMSO) 2.50
(3H, s, C(9)H3), 2.52 (3H, s, C(10)H3), 11.47 (1H, br s, N(1)H),
11.65 (1H, br s, N(3)H). δC(DMSO) 21.59 (C-9), 22.57 (C-10),
124.18 (C-4a), 147.66 (C-6), 148.50 (C-2), 150.29 (C-8a), 158.16
(C-7), 161.57 (C-4). νmax(KBr) 3436, 3174, 3089, 1725 (C᎐O),
᎐
1689 (C᎐O), 1569, 1396, 1286, 831, 563 cmϪ1. λmax(MeOH) 275,
᎐
207 nm.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 0 9 – 1 9 1 8
1918