Acylation of a 6-(methylamino)-5-nitrosopyrimidine and 1,3-dipolar cycloaddition of an 8-methylisoxanthopterin N(5)-oxide. Synthesis of C(6),N(8)-disubstituted isoxanthopterins

Article abstract of DOI:10.1002/hlca.200900009

Acylation of 2-amino-4-(benzyloxy)-6-(methylamino)-5-nitrosopyrimidine (5) with acetic anhydride or chloroacetic anhydride in the presence of 4-(dimethylamino)pyridine (DMAP) led to the C(2)-acylamino derivatives 6 and 7, respectively. In the absence of a

Full text of DOI:10.1002/hlca.200900009

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Helvetica Chimica Acta – Vol. 92 (2009)
Acylation of a 6-(Methylamino)-5-nitrosopyrimidine and 1,3-Dipolar Cyclo-
addition of an 8-Methylisoxanthopterin N(5)-Oxide. Synthesis of C(6),N(8)-
Disubstituted Isoxanthopterins
by Thomas Steinlin and Andrea Vasella*
Laboratorium fꢀr Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH Zꢀrich, HCI, CH-8093 Zꢀrich
(e-mail: vasella@org.chem.ethz.ch)
Acylation of 2-amino-4-(benzyloxy)-6-(methylamino)-5-nitrosopyrimidine (5) with acetic anhy-
dride or chloroacetic anhydride in the presence of 4-(dimethylamino)pyridine (DMAP) led to the C(2)-
acylamino derivatives 6 and 7, respectively. In the absence of a base, acetylation did not lead to a product,
while chloroacetylation led to the 6-chloropteridine 11. Chloroacetylation in the presence of Hꢀnigꢁs base
provided the pteridinone N(5)-oxide 10, suggesting that acylation of 5 is readily reversible, and that the
unfavourable equilibrium must be displaced by a follow-up reaction to trap the acylation product.
Acylation of 5 with hexadienoyl chloride, followed by intramolecular Diels – Alder reaction, provided
the pteridinone 12. A high yielding 1,3-dipolar cycloaddition of the acylnitrone 10 to electron-poor and
electron-rich dipolarophiles, followed by spontaneous N,O-bond cleavage, gave the C(6)-substituted
pteridinones 19a – 19e that were deprotected to the pteridine-4,7(3H,8H)-diones 20a – 20e. Substitution
of the 6-chloropterin 11 provided the 6-morpholinopteridine 25. Sonogashira coupling yielded the
fluorescent [(pteridin-6-yl)ethynyl]-glucopyranoside 26, 6-ethynylpteridine 28, and 6,6’-(ethynediyl)-
bispteridine 29. The alkyne 28 reacted with Me3SiCl and LiBr in MeCN to produce the bromoalkene 31.
Introduction. – We described new routes to 6-substituted pteridines based on
intramolecular Diels – Alder cycloadditions, ene-reactions, and condensations of N(6)-
acylated or N(6)-alkylated 6-amino-5-nitrosopyrimidines [1 – 4]. We also showed that
the pteridinone N(5)-oxides, resulting from the condensation of 6-amino-5-nitro-
sopyrimidines with chloroacetic acid anhydride ((ClCH2CO)2O) react as acylnitrones.
The course of their [3 þ 2] cycloaddition to acceptor-substituted dipolarophiles is
illustrated in Scheme 1 by the addition of 1 to methyl acrylate. This reaction provides 2,
resulting from a spontaneous eliminative cleavage of the N,O bond of the initially
formed isoxazolidine, and thus constitutes a new, high-yielding access to isoxantho-
pterins 2 possessing a functionalised side chain at C(6) [5]. The poor solubility of these
isoxanthopterins was assumed to result from a favourable intermolecular H-bonding of
the DADA motif involving HN(2’), N(1’), HN(8’) and O¼C(7’) of the products of type
2. This hypothesis prompts to investigate the formation and 1,3-dipolar cycloaddition of
N(8)-alkyl derivatives of 1. The simplest ones, N(8)-methylpteridinone N(5)-oxides,
should be obtained by an intramolecular condensation of 6-[(chloroacetyl)(methyl)-
amino]-5-nitrosopyrimidines. We were thus interested in the cycloaddition of N(8)-
alkylated pteridinone N(5)-oxides and the solubility of the resulting products, in the
formation of the pteridinone N-oxides by condensation of 6-[(alkyl)(chloroacetyl)-
amino]-5-nitrosopyrimidines, and in the N-acylation leading to these amides. As we had
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 92 (2009)
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assumed that the C(6)ꢀN-acylation of 6-amino-5-nitrosopyrimidines proceeds via O-
acylation of the NO group and intramolecular acyl transfer, we had to consider that it
may be affected by C(6)ꢀN-alkylation.
Scheme 1
Results and Discussion. – The synthesis of the desired N(8)-methylisoxanthopterin
N(5)-oxide 10 started by transforming the known 2-amino-6-chloro-4-(methylamino)-
pyrimidine (3) [6] into the benzyl ether 4 by treatment with benzyl alcoholate in
DMSO (Scheme 2). Nitrosation of 4 provided the 6-(methylamino)-5-nitrosopyrimi-
dine 5 that was thus obtained in a yield of 81% from 2-amino-4,6-dichloropyrimidine.
Scheme 2
a) Benzyl alcohol (BnOH), NaH, DMSO; 90%. b) NaNO2, AcOH/H2O 3 :7; 90%. c) Ac2O, 4-
(dimethylamino)pyridine (DMAP), THF; 88% of 6. Chloroacetic anhydride ((ClCH2CO)2O), DMAP,
THF; 71% of 7. d) (ClCH2CO)2O, iPr2EtN, THF; 78%. e) (ClCH2CO)2O, THF; 82%.

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Acylation of 5 required a more subtle control of reaction conditions than we had
anticipated. While Ac2O in THF did not appear to react with 5, addition of 4-
(dimethylamino)pyridine (DMAP) led to the acetamide 6. A similar DMAP promoted
treatment of 5 with (ClCH2CO)2O gave the 2-chloroacetamide 7 (77%), while
replacing DMAP by Hꢀnigꢁs base resulted in the desired 8-methylpteridin-7-one N(5)-
oxide 10 (78%). In contradistinction to the treatment of 5 with Ac2O, treatment with
(ClCH2CO)2O in THF (in the absence of an added base) gave rise to the 6-
chloropteridin-7-one 11 (82%).
That acetylation of 5 with Ac2O did not lead to the C(4)-acetamido derivative,
while the analogous chloroacetylation provided 11 is rationalised by postulating an
unfavourable equilibrium between the C(4)-acetamide or chloroacetamide and the
starting material 5 that can be shifted for the chloroacetamide by intramolecular
addition of the enolised chloroacetamide to the NO group, enolisation to generate 9,
and irreversible b-elimination to cleave the N,O bond. Hꢀnigꢁs base is assumed to
similarly shift the equilibrium by deprotonating the hydroxylamino group and, thus, via
8, promote the elimination of chloride to generate the nitrone 10. It is not clear if
DMAP acts by deprotonating the C(2)ꢀNH2 group and/or by generating an
intermediate (chloro)ketene, (chloro)acetylation of C(2)ꢀNH2 being irreversible.
Acylation of 5 at the C(4)ꢀNHMe group differs from the one of analogous
nitrosopyrimidines possessing a C(4)ꢀNH2 group that leads to amides that are
sufficiently stable to be isolated in spite of their activation by conjugation with the NO
group. This difference is explained by pointing out that the N-acyl-N-methyl amino
group can no longer form a favourable intramolecular H-bond from the acylamino NH
to the NO group [7][4]. To substantiate the hypothesis that the C(4)ꢀNHMe group is
reversibly acylated, and that the amide can be trapped by an irreversible follow-up
reaction, we treated 5 with hexadienoyl chloride (Scheme 3).
Scheme 3
i
a) Hexa-2,4-dienoyl chloride, Pr2EtN, THF; 84%.
Similarly as reported in [4], the intermediate amide reacted by a hetero-Diels –
Alder reaction and eliminative N,O bond cleavage to provide the pteridinone 12 that
was isolated in a yield of 84%.
The 4-(benzyloxy)-6-(methylamino)pyrimidine 4 is characterised by the HꢀC(5) s
at 5.06 ppm, the q at 6.47 ppm (J ¼ 4.9 Hz) and d at 2.67 ppm (J ¼ 4.8 Hz) of the
MeNH group, and by the IR NH bands at 3428, 3344, and 3201 cmꢀ1. The nitrosation of
4 to 5 was accompanied by a change from colourless to dark purple and by a change of
the chemical shift for the q (J ¼ 5.1 Hz) of the MeNH group from 6.47 to 11.12 ppm.

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The shift to lower field is due to a strong H-bond from the NH to the N¼O group.
C(2)ꢀNH2 resonate as two s, at 8.02 and 8.00 ppm. The regioselectivity of the acylation
of 5 to the C(2)ꢀN-acyl derivatives 6 and 7 is evidenced by the unchanged H,H-
coupling of the MeNH group and by a signal for HNꢀC(2) at 10.80 and 11.22 ppm,
respectively. The structure of the nitrone 10 is evidenced by a HR-MALDI mass
spectrum, elemental analysis, NH bands at 3425, 3339, and 3225 cmꢀ1, the signal of the
HꢀC(6) at 7.40 ppm, and the one of C(6) at 124.05 ppm. This signal is shifted to higher
fields by ca. 25 ppm, as compared to those of 19a – 19e due to its increased electron
density at C(6). The structure of the 6-chloropterin 11 is supported by a UV maximum
at 359 nm (log e ¼ 4.24), the HR-EI-MS signal at m/z 319.0656 for Mþ(37Cl) with 30%
intensity of the parent signal at m/z 317.0673, and by elemental analysis. The 1H-NMR
spectrum of the (Z)-allylic alcohol 12 shows a dd at 6.66 ppm for HꢀC(1’) (J ¼ 12.0 and
1.5 Hz) and a dd for HꢀC(2’) at 5.97 ppm (J ¼ 12.0 and 4.2 Hz), a m for HꢀC(3’)
between 5.19 and 5.13 ppm, a d (J ¼ 6.3 Hz) at 1.20 ppm for the Me group, and a d (J ¼
4.2 Hz) for the OH group at 4.88 ppm. In the UV spectrum, the conjugation of the
pteridine ring system and the alkenyl group is evidenced by a maximum at 376 nm
(log e ¼ 4.17).
The 1,3-dipolar cycloadditions of the nitrone 10 were performed by heating in
toluene, proceeded in yields between 79 and 90%, and yielded essentially a single
regioisomer [8] (Scheme 4). To demonstrate the expected stereoselectivity of the 1,3-
dipolar cycloaddition, we determined the configuration of the cycloadducts to diethyl
fumarate and diethyl maleate (13 and 14, resp.). The 1H-NMR spectra of 19a and 19b
in CDCl3 show considerable differences (Table 1). Presumably, the OH group in both
products forms a persistent H-bond to N(5), leading to a six-membered ring. The
coupling constant between HꢀC(3’) and the OH group is 3.3 Hz for both compounds,
as expected for a gauche configuration, suggesting that HꢀC(3’) occupies a
pseudoaxial position in both 19a and 19b. The coupling constant of 10.5 Hz between
HꢀC(2’) and HꢀC(3’) of 19a indicates a trans-diaxial configuration and the one of
5.3 Hz for 19b a cis configuration, evidencing the stereoselective cycloaddition of the
nitrone 10.
The reaction of cyclohexene (15) with 10 yielded 89% of the cis-(2-hydroxycyclo-
hexyl)pteridine 19c in 89% yield. The OH group resonates at 4.48 ppm as a dd (J ¼ 3.3,
1.0 Hz), coupling with HꢀC(2’) (4.21 ppm, br. s) and HaxꢀC(3). HꢀC(1’) gives rise to
Table 1. Configuration and Conformation of the Diesters 19a and 19b, Relevant Chemical Shifts, and
Coupling Constants in CDCl3
Substituent
19a
19b
d(H)
Jvic
d(H)
Jvic
HO
4.68
4.91
4.97
3.3
10.6
10.5, 3.3
4.78
4.16
4.92
3.3
5.3
5.3, 3.3
HꢀC(2’)
HꢀC(3’)

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 4
a) Dipolarophile, toluene, reflux; 90% of 19a, 89% of 19b, 89% of 19c, 79 of 19d; 85% of 19e. b)
Me3SiCl, LiBr, MeCN; 93% of 20a, 93% of 20b, 89% of 20c, 77% of 20a, 97% of 20a.
a ddd (J ¼ 12.3, 3.3, 2.2 Hz) at 3.05 ppm. Cycloaddition to 2,3-dihydrofuran (16)
resulted in the formation a 1:1 mixture (79%) of cis/trans-isomers of the (2-
hydroxytetrahydrofuran-3-yl)pteridinone 19d. The reaction of 10 with methyl propio-
late led to the fully enolized a-ketoester 19e (85%) that was crystallised from hot
(D6)DMSO. The crystal structure (Fig. 1) shows a strong intramolecular H-bond (N ···
O distance 2.58 ꢃ) that is evidenced in solution by a s at 13.76 ppm for OH. The
structure of 19e is further evidenced by a s at 6.87 ppm for HꢀC(2), a d resonating at
98.47 ppm for C(3), and a s for C(2) at 153.64 ppm. Similar to the crystal structure of

Helvetica Chimica Acta – Vol. 92 (2009)
593
the pteridine dimer 29 (compare Fig. 2), two molecules of 19e are bridged via H-bonds
to two DMSO molecules1).
Fig. 1. Crystal structure of 19e · DMSO1) showing the intra- and intermolecular H-bonds between two
molecules of 19e and two molecules of DMSO
As expected, the solubility of N(8)-methylpteridines improved dramatically:
whereas the N(8)-unsubstituted pteridines are only soluble in DMSO, their N-Me
analogues are well soluble in CH2Cl2, CHCl3, MeOH, AcOEt, THF, and dioxane.
The pteridinones 19a – 19e were debenzylated with in situ generated Me3SiBr to
yield 89 – 96% of the pteridine-4,7(3H,8H)-diones 20a – 20e. Their structures were
established on the basis of their IR, 13C- and 1H-NMR, and HR-MALDI mass spectra,
and by the similarity of the UV spectra to those of 19a – 19e (except 19d).
Deprotection of 19d by in situ generated Me3SiBr was accompanied by dehydration
and led to the 6-(2,3-dihydrofuranyl)pteridine 20d. The structure of 20d is charac-
terised by a bathochromic shift (from 341 to 379 nm) in the UV spectrum compared to
19d, a t (J ¼ 1.6 Hz) at 7.87 ppm for HꢀC(5’) showing the allylic coupling, and
corresponding resonances at 140.90 and 114.93 ppm for C(5’) and C(4’), respectively.
The pteridinediones 20a – 20e are well soluble in MeOH and in aqueous MeOH, but
not in H2O. The diethyl esters 20a and 20b are well soluble in CH2Cl2, CHCl3, and
AcOEt.
To test whether also 6-substituted pteridine 5-oxides undergo 1,3-dipolar cyclo-
additions, we synthesized the 6-phenylpteridinedione 21 (Scheme 5). Treating 5 with 2-
chloro-2-phenylacetyl chloride in the presence of Hꢀnigꢁs base yielded 82% of 21.
Heating of 21 in the presence of dipolarophiles, such as phenylmaleimide, diethyl
fumarate, or N-(cyclopent-1-enyl)morpholine led to a single strongly fluorescent
compound. In contrast to 2-phenyl-3H-indol-3-one 1-oxide that reacts with dipolaro-
philes by forming 1,3-dipolar addition products [9], 21 reacted by only forming the
deoxygenated product 22 in 82% yield; products resulting from the dipolarophiles were
not analysed. Debenzylation of 22 by in situ generated Me3SiBr gave 6-phenyl-
pteridine-4,7-dione 23 in 96% yield.
1
)
The crystallographic data have been deposited with the Cambridge Christallographic Data Centre as
deposition No. CCDC-715315 for 19e and CCDC-715316 for 29. Copies of the data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge Christallo-
graphic Data Centre, 12 Union Road, Cambridge CB21EZ (fax: þ 44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk).

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Scheme 5
i
a) 2-Chloro-2-phenylacetyl chloride, Pr2EtN, THF, 0 – 238, 1 h, 82%. b) Phenylmaleimide, toluene,
reflux, 0.5 h, 82%. c) Me3SiCl, LiBr, MeCN, 08 – r.t.; 96%.
The pteridines 21 – 23 were characterised by elemental analysis, IR, 1H- and
13C-NMR, UV, and HR-mass spectra. The UV spectra show maxima at 366, 370, and
369 nm for 21, 22, and 23, respectively, evidencing the conjugation between the
heterocycle and the Ph substituent. Similarly to 10, the 13C-NMR spectra show a s at
129.50 ppm for C(6) of the pteridine 5-oxide 21 and a s at 144.12 ppm for the pteridine
22, while 23 is characterised by a NH s at 11.19 ppm, a br. NH2 s at 7.22 ppm, and a s for
the N-Me group at 3.52 ppm.
6-Chloropterin and 2,4-diamino-6-chloropteridine were synthesised by treating
pterin 8-oxide and 2,4-diaminopteridine 8-oxide, respectively, with AcCl or phospho-
rous oxychloride [10]. The chloride was substituted by a variety of oxo- and
thionucleophiles. Treatment with amines resulted in decomposition of the starting
material. In their studies towards the synthesis of the molybdenum cofactor, Taylor
et al. used 6-chloropterin in Sonogashira cross-couplings [11 – 14]. As 6-Cl derivatives
of isoxanthopterins were not known, we subject the more highly electrophilic 6-
chloropteridine 11 to a few substitution reactions.
Heating 11 in the presence of morpholine in toluene yielded 97% of 6-
morpholinopteridine 24 (Scheme 6). The same product was obtained when the nitrone
10 was heated in the presence of morpholine. Under these conditions, the reaction time
could be reduced from 4.5 to 1.5 h. Deprotection with in situ generated Me3SiBr in
MeCN gave pteridinedione 25. Treating 11 with phenyl 2,3,6-tri-O-acetyl-4-deoxy-4-
ethynyl-1-thio-b-d-glucopyranoside [15][16] under conditions of the Sonogashira
reaction gave the 6-ethynylpteridine 26. It was isolated in 89% yield by silica-gel
i
chromatography. Recrystallisation in PrOH and toluene gave an analytically pure
sample of a strongly fluorescent product. The strong fluorescence of 26 suggested to
also prepare an ethynediyl-bridged dimer, and (trimethylsilyl)acetylene was coupled to
the 6-chloropteridine 11 to provide 27 in 92% yield. Desilylation with wet Bu4NF in
THF [17] gave the monosubstituted alkyne 28 that was treated with 6-chloropterin 11

Helvetica Chimica Acta – Vol. 92 (2009)
595
Scheme 6
a) Morpholine, toluene; 97%. b) Me3SiCl, LiBr, MeCN; 93%. c) Phenyl 2,3,6-tri-O-acetyl-4-deoxy-4-
ethynyl-1-thio-b-d-glucopyranoside, Pd(AcO)2, Ph3P, CuI, MeCN/Et3N 2 :3; 89%. d) (Trimethylsilyl)-
acetylene, Pd(AcO)2, Ph3P, CuI, MeCN/Et3N 2 :3; 92%. e) Bu3NF · 3 H2O, THF; 98% [19]. f) 11,
Pd(AcO)2, Ph3P, CuI, MeCN/Et3N 2 :3; 49% of 29, 32% of 30.
under Sonogashira conditions to yield 49% of the ethynediyl-bridged dimer 29 besides
the homodimer 30 (32%) resulting from of a Glaser coupling. The oxidative
dimerisation was avoided by effecting the transformation of 11 to 29 in one pot.
Subjecting the 6-chloropterin 11 to (trimethylsilyl)acetylene, Bu4NF · 3 H2O, and again
to 11 in the presence of CuI and Pd0 yielded exclusively the desired bispteridine 29 in an
overall yield of 47%. Crystals suitable for X-ray crystallography were obtained by
allowing a hot solution of 29 in DMSO to cool to room temperature. In the crystal
structure (Fig. 2), the two pteridine moieties are only 1.68 out of a common plane.
Similar to the crystal structure of the pteridine 19e, two molecules of 29 are bridged by
H-bonding from NH2 to two molecules of DMSO, to form bands that are stacked at a
distance of 3.51 ꢃ.

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Fig. 2. Crystal structure of 29 · 3 DMSO (ORTEP drawing of two H-bonded molecules of 29 and two
molecules of DMSO)1)
Debenzylation of 28 in the presence of Me3SiBr was accompanied by the addition
of HBr to the CꢁC bond (Scheme 7), illustrating the strongly electrophilic character of
the ethynyl derivative 28. The structure of 31 is evidenced by two H ds (J ¼ 13.4 Hz),
one for HꢀC(1’) at 7.57 ppm, and one for HꢀC(2’) at 6.92 ppm, the coupling constant
evidencing the (E)-configuration of the C¼C bond. C(1’) is resonating at 130.1 ppm,
C(2’) at 124.66 ppm, and the UV spectrum shows a maximum at 376 nm (log e ¼ 4.38).
Scheme 7
a) Me3SiCl, LiBr, MeCN; 72%.
Pteridines are used for labelling experiments in biochemistry and molecular biology
[18 – 21], since the fluorescence maxima of pteridines are well separated from those of
natural nucleosides and aromatic amino acids. The close structural relation of
pteridine-N(1) and N(8) nucleosides to pyrimidine and purine nucleosides prompted
Pfleiderer and co-workers [22] and Hawkins et al. [18] to introduce pteridine
nucleosides as fluorescent markers into oligonucleotides to study stacking effects and
oligonucleotide interactions during hybridisation and intermolecular loop formation.
The quantum yields of selected pteridines in MeOH are listed In Table 2. The
independence of the quantum yield from the presence or absence of the BnO group is
shown by comparison of 22 and 23.
The excitation and emission spectra of the monosubstituted alkyne 26 and the
disubstituted analogue 28 are very similar (Fig. 3), indicating a weak dependence of the
fluorescence on the ethynyl substituents. In the excitation and emission spectra of the
(ethynediyl)bispteridine 29, one notices a blue shift by 68 nm and a narrowing of
Stokeꢁs shift by 4 nm.

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597
Table 2. Quantum Yield of Selected Pteridinesa)
19a
19e
20d
19d
22
23
26
27
Q
QR
0.14
0.25
0.38
0.65
0.26
0.45
0.36
0.62
0.38
0.66
0.39
0.68
0.34
0.59
0.38
0.66
a) Q: Absolute quantum yield. QR: quantum yield relative to quinine. lex ¼ 350 nm. Emission integrated
from 380 and 520 nm. Measured in MeOH. Optical density ꢂ 0.05.
Fig. 3. Excitation and emission spectra of 26 and 28 (top), and 29 (bottom) recorded in CH2Cl2
We thank Novartis AG, Basel, for a fellowship, the ETH-Zꢀrich for financial support, Dr. Bruno
Bernet for checking the analytical data, and Anaella Dumas for the fluorescence data.
Experimental Part
General. Solvents were distilled before use. Reactions were carried out under N2, unless stated
otherwise. Qual. TLC: precoated silica-gel plates (Merck silica gel 60 F254); detection under UV
(254 nm). Flash chromatography (FC): silica gel Fluka 60 (0.04 – 0.063 mm). M.p.: uncorrected. UV

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Helvetica Chimica Acta – Vol. 92 (2009)
Spectra: lmax (log e). FT-IR Spectra: neat (ATR), absorption in cmꢀ1
.
1H- and 13C-NMR Spectra:
chemical shifts d in ppm rel. to Me4Si as external standard, and coupling constants J in Hz. HR-MALDI-
MS: in gentisic acid (¼2,5-dihydroxybenzoic acid, DHB) or 3-hydroxypropionaldehyde (3-HPA) matrix.
4-(Benzyloxy)-6-(methylamino)pyrimidine-2,4-diamine (4). A soln. of BnOH (1 ml, 9.3 mmol) in
DMSO (30 ml) was treated with 60% NaH in oil (242 mg, 6.07 mmol) and stirred for 20 min. To this
mixture was added 3 (738 mg, 4.67 mmol) in a single portion, followed by heating to 908 for 5 h. The
mixture was cooled to r.t. and poured on ice. The colourless precipitate was filtered off, and the aq.
filtrate was extracted with CH2Cl2/MeOH 19 :1 (3 ꢃ 100 ml). The combined org. layers were washed with
brine (100 ml), and the solvent was evaporated to afford 4 (967 mg, 90%). A sample for analysis was
obtained by sublimation at 1208 and < 10ꢀ3 mbar. Rf (AcOEt) 0.42. M.p. 1508. UV (MeOH, c ¼
0.09 mm): 212 (4.44), 268 (4.00). IR (ATR): 3428m, 3344m, 3201m, 2947w, 2872w, 2791w, 1650m,
1574s, 1503m, 1466s, 1453s, 1440s, 1407m, 1391m, 1353s, 1312m, 1288m, 1192s, 1093m, 1052m, 1023m,
968w, 911w, 873w, 852w, 833w, 792s, 765m, 743m, 700m, 688w. 1H-NMR (300 MHz, (D6)DMSO): 7.38 –
7.33 (m, 5 arom. H); 6.47 (q, J ¼ 4.9, NH); 5.96 (s, NH2); 5.21 (s, PhCH2); 5.06 (s, HꢀC(5)); 2.67 (d, J ¼
4.8, MeN). 13C-NMR (75 MHz, (D6)DMSO): 169.56 (br. s, C(2)); 165.78 (s, C(4)); 162.61 (s, C(6));
137.56 (s); 128.24 (2d); 127.70 (2d); 127.53 (d); 75.09 (br. d, C(5)); 65.80 (t, PhCH2); 27.52 (q, MeN). HR-
MALDI-MS: 231.1237 (100, [M þ H]þ, C12H15N4Oþ; calc. 231.1240). Anal. calc. for C12H14N4O (230.27):
C 62.59, H 6.13, N 24.33; found: C 62.67, H 6.39, N 24.39.
4-(Benzyloxy)-6-(methylamino)-5-nitrosopyrimidine-2,4-diamine (5). A suspension of 4 (1.8 g,
1.08 mmol) in AcOH/H2O 3 :7 (30 ml) was heated to 408 leading to a pale yellow soln. A soln. of NaNO2
(1.08 g, 15.6 mmol) in H2O (3.0 ml) was added dropwise leading to a purple precipitate. The formation of
brown gases indicated completion of the reaction. The precipitate was filtered off, dissolved in CH2Cl2,
and washed with sat. aq. NaHCO3 soln. The org. layer was dried (Na2SO4) and evaporated.
Recrystallisation in hexane/MeOH gave 5 (1.72 g, 90%). Purple crystals. Rf (AcOEt): 0.60. M.p. 1858.
UV (MeOH, c ¼ 0.11 mm): 207 (4.30), 232 (3.90), 329 (4.34). VIS (DMSO, c ¼ 0.005 m): 605 (2.03). IR
(ATR): 3453m, 3284w, 3238w, 3134m, 3099m, 3045m, 1641m, 1589s, 1578s, 1525s, 1495m, 1470m, 1439s,
1419s, 1385s, 1325s, 1304s, 1221w, 1177s, 1156s, 1128s, 1069m, 1052m, 1025m, 1002s, 965m, 917m, 860w,
1
844m, 793m, 762s, 731m, 721s, 704s, 684m, 620w. H-NMR (300 MHz, (D6)DMSO): 11.12 (q, J ¼ 5.1,
NH); 8.02, 8.00 (2s, NH2); 7.54 – 7.36 (m, 5 arom. H); 5.57 (s, PhCH2); 2.86 (d, J ¼ 5.1, MeN). 13C-NMR
(75 MHz, (D6)DMSO): 170.39 (s, C(2)); 163.16 (s, C(4)); 151.08 (s, C(6)); 138.74 (s, C(5)); 136.09 (s);
128.39 (4d); 128.12 (d); 67.87 (t, PhCH2); 26.28 (q, MeN). HR-MS-MALDI: 282.0961 (29, [M þ Na]þ,
C12H13NaN5Oþ2 ; calc. 282.0961), 260.1138 (100, [M þ H]þ, C12H14N5O2þ ; calc. 260.1142), 229.1076 (48,
[M ꢀ NO]þ, C12H14N4Oþ; calc. 229.1084). Anal. calc. for C12H13N5O2 · 0.25 MeOH (267.27): C 55.05, H
5.28, N 26.20; found: C 55.03, H 5.14, N 26.29.
N-[4-(Benzyloxy)-6-(methylamino)-5-nitrosopyrimidin-2-yl]acetamide (6). A soln. of 5 (520 mg,
2.01 mmol) and DMAP (268 mg, 2.2 mmol) in THF (20 ml) was cooled to 08, treated with Ac2O (375 ml,
4.0 mmol), stirred for 15 min at 08 and for 20 h at 238, diluted with sat. aq. NH4Cl soln. (20 ml), and
extracted with CH2Cl2 (3 ꢃ 30 ml). The combined org. layers were washed with H2O, dried (Na2SO4),
and evaporated. Crystallisation from EtOH gave 6 (527 mg, 88%). Rf (CH2Cl2/MeOH 9 :1) 0.68. M.p.
2048. UV (MeOH, c ¼ 0.095 mm): 210 (4.36), 251 (3.92), 315 (4.17), 354 (4.10). VIS (DMSO, c ¼
0.005 m): 646 (1.96). IR (ATR): 3212w, 3156w, 3010w, 2933w, 1677m, 1612m, 1578s, 1542m, 1499s,
1456m, 1436m, 1390m, 1366s, 1347m, 1335m, 1293s, 1240m, 1213m, 1200s, 1161s, 1134s, 1067w, 1040w,
1006s, 933w, 906w, 867w, 849m, 824w, 795m, 759m, 738m, 692m, 615w. 1H-NMR (300 MHz, (D6)DMSO):
10.99 (q, J ¼ 4.5, NHꢀC(6)); 10.80 (s, NHꢀC(2)); 7.61 – 7.37 (m, 5 arom. H); 5.70 (s, PhCH2); 2.92 (d, J ¼
4.8, MeN); 2.38 (s, AcN). 13C-NMR (75 MHz, (D6)DMSO): 171.37 (br. s, C(4)); 170.79 (s, C¼O); 158.89
(s, C(2)); 148.42 (br. s, C(6)); 139.78 (s, C(5)); 135.79 (s); 128.67 (2d); 128.45 (2d); 128.31 (d); 68.76 (t,
PhCH2); 26.99 (q, MeN); 25.90 (q, MeC¼O). HR-MALDI-MS: 324.1068 (73, [M þ Na]þ,
C14H15N5NaOþ3 ; calc. 324.1067), 302.1248 (100, [M þ H]þ, C14H16N5O3þ ; calc. 302.1248). Anal. calc. for
C14H15N5O3 (301.30): C 55.81, H 5.02, N 23.24; found: C 55.65, H 5.09, N 23.02.
N-[4-(Benzyloxy)-6-(methylamino)-5-nitrosopyrimidin-2-yl]-2-chloroacetamide (7). A soln. of 5
(260 mg, 1.0 mmol) and DMAP (146 mg, 1.2 mmol) in THF (10 ml) was cooled to 08, treated with
(ClCH2CO)2O (204 mg, 1.20 mmol), stirred for 30 min at 08 and for 1 h at 238, diluted with sat. aq. NH4Cl
soln. (10 ml), and extracted with CH2Cl2 (3 ꢃ 20 ml). The combined org. layers were washed with H2O

Helvetica Chimica Acta – Vol. 92 (2009)
599
and evaporated. FC (CH2Cl2/AcOEt 9 :1) gave 7/11 90 :10 (280 mg). Crystallisation from EtOH gave
pure 7 (237 mg, 71%). Rf (CH2Cl2/MeOH 9 :1) 0.73. M.p. 1638. UV (MeOH, c ¼ 0.088 mm): 209 (4.37),
226 (sh, 4.21), 250 (sh, 3.91), 318 (4.21), 344 (sh, 4.14). VIS (DMSO, c ¼ 0.005 m): 650 (1.94). IR (ATR):
3208w, 3160w, 3062w, 3014w, 2967w, 1694m, 1615m, 1576m, 1544m, 1504s, 1457m, 1441m, 1416w, 1398m,
1390m, 1370m, 1326s, 1236m, 1199s, 1154s, 1134s, 1083w, 1064w, 1001m, 919w, 901m, 874w, 858m, 792s,
772m, 755m, 737w, 696s, 622w. 1H-NMR (300 MHz, (D6)DMSO): 11.22 (s, NHꢀC(2)); 10.98 (q, J ¼ 4.9,
NHꢀC(6)); 7.61 – 7.40 (m, 5 arom. H); 5.71 (s, PhCH2); 4.82 (s, CH2Cl); 2.93 (d, J ¼ 5.0, MeN). 13C-NMR
(75 MHz, (D6)DMSO): 166.95 (s, C¼O); 158.48 (s, C(2)); 139.73 (s, C(5)); 135.47 (s); 128.66 (2d); 128.48
(2d); 128.35 (d); 68.94 (t, PhCH2); 45.66 (t, C(1)); 27.12 (q, Me); signals of C(5) and C(2) not visible due
to coalescence. HR-EI-MS: 337.0754 (5, Mþ(37Cl), C14H1437ClN5O3þ ; calc. 337.0756), 335.0779 (14,
Mþ(35Cl), C14H1435ClN5Oþ3 ; calc. 335.0785), 91.0539 (100, C7Hþ7 ). Anal. calc. for C14H14ClN5O3 (335.75):
C 50.08, H 4.20, N 20.86; found: C 50.20, H 4.23, N 20.61.
2-Amino-4-(benzyloxy)-8-methylpteridin-7(8H)-one 5-Oxide (10). A soln. of 5 (2.59 g, 10 mmol) in
THF (50 ml) was cooled to 08 and treated with EtNiPr2 (4.1 ml, 25 mmol) and (ClCH2CO)2O (1.88 g,
11 mmol). The greenish suspension was stirred for 90 min at 08 and for 60 min at 238, diluted with MeOH
(25 ml), and cooled to 08. The precipitate was filtered off, washed with MeOH, and dried, to afford 10
(1.990 g). The filtrate was evaporated, and FC (CH2Cl2/MeOH 49 :1 ! 9 :1) gave additional 10 (340 mg;
total yield 2.330 g, 78%). Rf (CH2Cl2/MeOH 9 :1) 0.49. M.p. 2288. UV (MeOH): 216 (4.52), 230 (sh, 230),
268 (4.13), 295 (sh, 3.84), 355 (4.09). IR (ATR): 3425w, 3339w, 3225w, 3090w, 1636m, 1552s, 1494m,
1443m, 1416m, 1392m, 1354s, 1223s, 1182m, 1105w, 1078w, 1041m, 909w, 872w, 814w, 786w, 747m, 734s,
1
717w, 696w, 659w, 647w. H-NMR (300 MHz, (D6)DMSO): 7.60 – 7.33 (m, 5 arom. H, NH2, HꢀC(6));
5.49 (s, PhCH2); 3.42 (s, MeN). 13C-NMR (75 MHz, (D6)DMSO): 162.20 (s, C(4)); 160.55 (s, C(2));
157.20 (s, C(7)); 153.42 (s, C(8a)); 136.07 (s); 128.28 (2d); 127.79 (d); 127.63 (2d); 124.05 (d, C(6)); 107.85
(s, C(4a)); 68.01 (t, PhCH2); 27.70 (q, MeN). HR-MALDI-MS: 322.0916 (100, [M þ Na]þ,
C14H13N5NaOþ3 ; calc. 322.0911), 300.1097 (50, [M þ H]þ, C14H14N5O3þ ; calc. 300.1091). Anal. calc. for
C14H13N5O3 (299.29): C 56.18, H 4.38, N 23.40; found: C 56.36, H 4.46, N 23.25.
2-Amino-4-(benzyloxy)-6-chloro-8-methylpteridin-7(8H)-one (11). A soln. of 5 (260 mg, 1.0 mmol)
in THF (10 ml) was cooled to 08, treated with (ClCH2CO)2O (204 mg, 1.2 mmol), stirred for 30 min at 08
and for 1 h at 238, diluted with sat. aq. NH4Cl soln. (10 ml), and extracted with CH2Cl2 (3 ꢃ 20 ml). The
combined org. layers were washed with H2O, dried (Na2SO4), and evaporated. FC (CH2Cl2/AcOEt 9 :1)
gave 11 (259 mg, 82%). Colourless crystals. Rf (CH2Cl2/MeOH 9 :1) 0.66. M.p. 2118. UV (MeOH, c ¼
0.075 mm): 214 (4.51), 232 (4.14), 282 (3.71), 349 (4.24). IR (ATR): 3482w, 3348m, 3217w, 2949w,
1681m, 1613m, 1578s, 1553s, 1525s, 1490s, 1465s, 1436s, 1411m, 1355s, 1308m, 1270w, 1226m, 1172m,
1079w, 1055m, 1036m, 1023s, 958m, 914w, 905w, 852w, 829w, 793m, 758w, 733m, 693m, 673w, 638w.
1H-NMR (300 MHz, (D6)DMSO): 7.53 – 7.37 (m, 5 arom. H, NH2); 5.48 (s, PhCH2); 3.49 (s, MeN).
13C-NMR (75 MHz, (D6)DMSO): 164.33 (s, C(4)); 161.22 (s, C(2)); 153.03 (s, C(7)); 151.45 (s, C(8a));
138.16 (s, C(6)); 135.79 (s); 128.53 (2d); 128.30 (2d); 128.10 (d); 106.55 (s, C(4a)); 67.82 (t, PhCH2); 28.52
(q, MeN). HR-EI-MS: 319.0656 (7, Mþ(37Cl), C14H1237ClN5Oþ2 ; calc. 319.0645), 317.0673 (20, Mþ(35Cl),
C14H1235ClN5Oþ2 ; calc. 317.0674), 91.0523 (100, C7H7þ ). Anal. calc. for C14H12ClN5O2 (317.73): C 52.92, H
3.81, N 22.04, Cl 11.16; found: C 52.69, H 3.94, N 21.77, Cl 11.34.
2-Amino-4-(benzyloxy)-6-[(E)-3-hydroxybut-1-enyl]-8-methylpteridin-7(8H)-one (12). A soln. of 5
(130 mg, 0.5 mmol) in THF (7 ml) was cooled to 08, treated with hexa-2,4-dienoyl choride (76 mg,
0.6 mmol) and Hꢀnigꢁs base (102 ml, 0.6 mmol), stirred for 30 min at 08 and for 2 h at 238, diluted with sat.
aq. NH4Cl soln. (10 ml), and extracted with CH2Cl2 (3 ꢃ 15 ml). The combined org. layers were washed
with H2O, dried (Na2SO4), and evaporated. FC (CH2Cl2/AcOEt 9 :1) gave 12 (149 mg, 84%). Rf (CH2Cl2/
MeOH 9 :1) 0.56. M.p. 1588. UV (MeOH, c ¼ 0.11 mm): 219 (4.31), 235 (sh, 4.09), 291 (3.79), 376 (4.17).
IR (ATR): 3569w, 3464w, 3340w, 3213w, 3031w, 2963w, 1646m, 1632m, 1558s, 1527m, 1490s, 1476s, 1432s,
1382m, 1359s, 1332m, 1308w, 1276w, 1232m, 1205m, 1112w, 1067m, 1041s, 1000w, 923w, 902w, 848w, 833w,
812w, 792m, 748w, 730m, 694w, 665w. 1H-NMR (300 MHz, (D6)DMSO): 7.54 – 7.32 (m, 5 arom. H, NH2);
6.66 (dd, J ¼ 12.0, 1.5, HꢀC(1’)); 5.97 (dd, J ¼ 12.0, 4.2, HꢀC(2’)); 5.52, 5.46 (2d, J ¼ 12.9, PhCH2); 5.19 –
5.13 (m, HꢀC(3’)); 4.88 (d, J ¼ 4.2, OH); 1.20 (d, J ¼ 6.3, Me). 13C-NMR (100 MHz, (D6)DMSO): 165.07
(s, C(4)); 161.08 (s, C(2)); 156.45 (s, C(7)); 150.61 (s, C(8a)); 145.84 (d, C(2’)); 144.12 (s, C(6)); 136.31(s);
128.29 (2d); 127.85 (d); 127.44 (2d); 119.13 (d, C(1’)); 107.85 (s, C(4a)); 67.57 (t, PhCH2); 63.49 (d, C(3’));

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Helvetica Chimica Acta – Vol. 92 (2009)
27.43 (q, MeN); 22.33 (q, Me). HR-MALDI-MS: 376.1381 (29, [M þ Na]þ, C18H17N5NaO2þ ; calc.
376.1381), 354.1562 (86, [M þ H]þ, C18H18N5O2þ ; calc. 354.1561), 353.1484 (100, Mþ, C18H17N5Oþ2 ; calc.
353.1482), 352.1405 (55, [M ꢀ H]þ, C18H16N5O2þ ; calc. 352.1405), 336.1456 (51, [M ꢀ OH]þ, C18H17N5Oþ;
calc. 336.1455), 310.1295 (83, [M ꢀ 43]þ).
Diethyl (2RS,3RS)-2-[2-Amino-4-(benzyloxy)-7,8-dihydro-8-methyl-7-oxopteridin-6-yl]-3-hydroxy-
butanedioate (19a). A suspension of 10 (300 mg, 1.0 mmol) and diethyl (E)-but-2-enedioate (13;
0.5 ml) in toluene (10 ml) was heated to reflux for 1.5 h and cooled to r.t. FC (AcOEt/hexane 1:1) gave
19a (241 mg, 89%). Colourless amorphous solid. Rf (CH2Cl2/MeOH 9 :1) 0.51. UV (MeOH, c ¼
0.084 mm): 215 (4.37), 229 (sh, 4.04), 282 (3.60), 348 (4.16). IR (ATR): 3456w, 3346w, 3229w, 2981w,
2953w, 2937w, 2872w, 1731m, 1668m, 1616m, 1582s, 1553s, 1495m, 1463m, 1437s, 1392w, 1356m, 1222s,
1
1177m, 1093m, 1065m, 1022s, 913w, 859w, 801m, 737m, 698m, 671w. H-NMR (400 MHz, (D6)DMSO):
7.59 – 7.41 (m, 5 arom. H, NH2); 5.84 (d, J ¼ 7.0, exch. OH); 5.57 (s, PhCH2); 4.76 (dd, J ¼ 8.8, 7.0,
HꢀC(3)); 4.34 (d, J ¼ 8.8, HꢀC(2)); 4.18 – 4.05 (m, 2 MeCH2O); 3.53 (s, MeN); 1.21, 1.12 (2t, J ¼ 7.1,
2 Me). 1H-NMR (400 MHz, CDCl3): 7.49 – 7.30 (m, 5 arom. H); 5.51 (s, PhCH2); 5.23 (s, NH2); 4.97 (dd,
J ¼ 10.5, 3.3, HꢀC(3)); 4.91 (d, J ¼ 10.6, HꢀC(2)); 4.68 (d, J ¼ 3.3, OH); 4.25, 4.08 (2q, J ¼ 7.1,
2 MeCH2O); 3.59 (s, MeN); 1.26, 1.08 (2t, J ¼ 7.1, 2 Me ) . 13C-NMR (75 MHz, (D6)DMSO): 171.54, 168.97
(2s, 2 C¼O); 165.11 (s, C(4’)); 161.27 (s, C(2’)); 155.97 (s, C(7’)); 151.35 (s, C(8’a)); 145.56 (s, C(6’));
136.20 (s); 128.43 (2d); 128.41 (2d); 128.13 (d); 107.43 (s, C(4’a)); 69.14 (d, C(3)); 67.71 (t, PhCH2); 60.52,
60.29 (2t, 2 MeCH2O); 52.81 (d, C(2)); 27.49 (q, MeN); 13.87, 13.81 (2q, 2 Me). HR-MALDI-MS:
510.397 (28, [M þ K]þ, C22H25KN5O7þ ; calc. 510.1386), 494.1639 (100, [M þ Na]þ, C22H25N5NaOþ7 ; calc.
494.1646).
Diethyl (2RS,3SR)-2-[2-Amino-4-(benzyloxy)-7,8-dihydro-8-methyl-7-oxopteridin-6-yl]-3-hydroxy-
butanedioate (19b). A suspension of 10 (600 mg, 2.01 mmol) and diethyl (Z)-but-2-enedioate (14;
0.5 ml) in toluene (10 ml) was heated to reflux for 1.5 h and cooled to r.t. FC (AcOEt/hexane 1:1) gave
19b (846 mg, 90%). Colourless, amorphous solid. Rf (CH2Cl2/MeOH 9 :1) 0.44. UV (MeOH, c ¼
0.075 mm): 215 (4.41), 229 (sh, 4.05), 283 (3.61), 347 (4.16). IR (ATR): 3464w, 3343w, 3228w, 2982w,
1729m, 1666m, 1615m, 1582s, 1552s, 1495m, 1463m, 1439s, 1391w, 1356m, 1224s, 1178m, 1094m, 1063m,
1025s, 860w, 801m, 739w, 698m. 1H-NMR (400 MHz, (D6)DMSO): 7.54 – 7.33 (m, 5 arom. H, NH2); 5.86
(d, J ¼ 6.9, OH); 5.51, 5.49 (2d, J ¼ 12.6, PhCH2); 4.70 (dd, J ¼ 7.8, 6.9, HꢀC(3)); 4.34 (d, J ¼ 7.8,
HꢀC(2)); 4.09 – 4.01 (m, MeCH2O); 3.96 – 3.82 (m, MeCH2O); 3.47 (s, MeN); 1.13, 0.95 (2t, J ¼ 7.1,
2 Me). 1H-NMR (400 MHz, CDCl3): 7.47 – 7.32 (m, 5 arom. H); 5.54, 5.44 (2d, J ¼ 12.4, PhCH2); 5.25 (s,
NH2); 4.92 (dd, J ¼ 5.3, 3.3, HꢀC(3)); 4.78 (d, J ¼ 3.3, OH); 4.23 – 4.15 (m, 2 MeCH2O); 4.16 (d, J ¼ 5.3,
HꢀC(2)); 3.60 (s, MeN); 1.22, 1.21 (2t, J ¼ 7.1, 2 Me ) . 13C-NMR (100 MHz, (D6)DMSO): 171.35, 168.97
(2s, 2 C¼O); 165.07 (s, C(4’)); 161.26 (s, C(2’)); 155.91 (s, C(7’)); 151.19 (s, C(8’a)); 145.02 (s, C(6’));
136.22 (s); 128.32 (2d); 128.07 (2d); 127.99 (d); 107.16 (s, C(4’a)); 69.69 (d, C(3)); 67.58 (t, PhCH2); 60.44,
60.10 (2t, 2 MeCH2O); 51.84 (d, C(2)); 27.48 (q, MeN); 13.92, 13.68 (2q, 2 Me).
2-Amino-4-(benzyloxy)-6-(cis-2-hydroxycyclohexyl)-8-methylpteridin-7(8H)-one (19c). A suspen-
sion of 10 (300 mg, 1.0 mmol) and cyclohexene (15; 3 ml) in toluene (20 ml) was boiled under reflux for
43 h and evaporated. FC (AcOEt) gave 19c (339 mg, 89%). A sample for analysis was sublimed at 1808,
< 10ꢀ3 mbar. Rf (CH2Cl2/MeOH 9 :1) 0.57. M.p. 2048. UV (MeOH, c ¼ 0.14 mm): 218 (4.30), 229 (sh,
4.16), 285 (3.80), 345 (4.25). IR (ATR): 3455w, 3292w, 3201w, 2925w, 2853w, 1663m, 1631m, 1590s, 1556s,
1495m, 1467m, 1443s, 1429s, 1351s, 1297w, 1251m, 1233m, 1218m, 1194m, 1109w, 1067m, 1024m, 1011m,
974m, 911w, 896w, 879w, 846w, 815w, 801w, 782w, 754m, 733m, 698m, 676m, 666m. 1H-NMR (400 MHz,
(D6)DMSO): 7.52 – 7.32 (m, 5 arom. H); 7.23 (s, NH2); 5.52, 5.50 (2d, J ¼ 12.6, PhCH2); 4.48 (dd, J ¼ 3.3,
1.0, exch. OH); 4.21 (br. s, HꢀC(2’)); 3.46 (s, MeN); 3.05 (ddd, J ¼ 12.3, 3.3, 2.2, HꢀC(1’)); 1.86 (qd, J ¼
12.8, 3.4, HaxꢀC(6’)); 1.78 – 1.70 (m, HeqꢀC(3’), HeqꢀC(5’)); 1.61 (dtd, J ¼ 17.6, 9.5, 4.0, HaxꢀC(4’));
1.51 – 1.48 (m, HaxꢀC(3’), HeqꢀC(6’)); 1.40 – 1.34 (m, HeqꢀC(4’)); 1.30 (qt, J ¼ 12.8, 3.5, HaxꢀC(5’)).
13C-NMR (100 MHz; (D6)DMSO): 164.74 (s, C(4)); 160.71 (s, C(2)); 155.93 (s, C(7)); 153.34 (s, C(8a));
150.92 (s, C(6)); 136.39 (s); 128.34 (2d); 127.97 (2d); 127.91 (d); 106.96 (s, C(4a)); 67.31 (t, PhCH2); 65.53
(d, C(2’)); 43.45 (d, C(1’)); 32.54 (t, C(3’)); 27.26 (q, MeN); 25.28 (t, C(6’)); 23.39 (t, C(4’)); 19.35 (t,
C(5’)). HR-MALDI-MS: 404.1700 (33, [M þ Na]þ, C20H23N5NaO3þ ; calc. 404.1693), 382.1878 (100, [M þ
H]þ, C20H24N5Oþ3 ; calc. 383.1874), 364.1772 (71, [M ꢀ OH]þ, C20H22N5O2þ ; calc. 364.1768). Anal. calc. for
C20H23N5O3 (381.43): C 62.98, H 6.08, N 18.36; found: C 62.73, H 6.17, N 18.30.

Helvetica Chimica Acta – Vol. 92 (2009)
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2-Amino-4-(benzyloxy)-6-(cis/trans-2-hydroxytetrahydrofuran-3-yl)-8-methylpteridin-7(8H)-one
(19d). A suspension of 10 (300 mg, 1.0 mmol) and 2,3-dihydrofuran (16; 0.8 ml) in toluene (20 ml) was
stirred at reflux for 2 h and adsorbed on silica gel. FC (AcOEt) gave 19d (290 mg, 79%). Colourless solid.
A sample for analysis was recrystallised in iPrOH. Rf (CH2Cl2/MeOH 9 :1) 0.45. M.p. 1858. UV (MeOH,
c ¼ 0.086 mm): 214 (4.49), 229 (sh, 4.17), 286 (3.81), 341 (4.26). IR (ATR): 3505w, 3342w, 3231w, 3055w,
3030w, 2947w, 2888w, 1661m, 1635m, 1581s, 1552s, 1498m, 1447s, 1392w, 1353m, 1290w, 1275w, 1236m,
1219m, 1111w, 1071w, 1025m, 1001m, 957w, 923m, 912m, 893w, 849w, 806m, 792w, 757m, 704m, 665w,
620w. 1H-NMR (400 MHz, (D6)DMSO; cis/trans 1:1; assignment based on a DQFCOSY spectrum):
7.53 – 7.32 (m, 5 arom. H); 7.27, 7.24 (2s, NH2); 5.53, 5.52, 5.51, 5.50 (4d, J ¼ 12.5, PhCH2); 3.48, 3.47 (2s,
MeN); data for trans-19d: 6.14 (d, J ¼ 5.1, OH); 5.43 (dd, J ¼ 5.1, 2.3, HꢀC(1’)); 3.99 – 3.88 (m,
2 HꢀC(4’)); 3.56 (ddd, J ¼ 8.1, 5.7, 2.3, HꢀC(2’)); 2.25 – 2.08 (m, 2 HꢀC(3’)); data for cis-19d: 5.85 (dd,
J ¼ 4.5, 0.9, OH); 5.71 (t, J ¼ 4.5, 0.5, HꢀC(1’)); 3.99 – 3.88 (m, HaꢀC(4’)); 3.77 (q, J ¼ 8.0, HbꢀC(4’));
3.50 – 3.44 (m, HꢀC(2’)); 2.71 – 2.61 (m, HaꢀC(3’)); 1.91 (dtd, J ¼ 12.1, 8.0, 4.1, HbꢀC(3’)). 13C-NMR
(100 MHz, (D6)DMSO; cis/trans 1:1; assignment based on a HSQC spectrum): 164.96 (s, C(4)); 160.96,
160.82 (2s, C(2)); 156.63, 156.25 (2s, C(7)); 151.18, 151.14 (2s, C(8a)); 149.63, 148.55 (2s, C(6)); 136.52,
136.50 (2s); 128.42 – 127.95 (several d); 107.18, 107.02 (2s, C(4a)); 67.39, 67.34 (2t, PhCH2); 27.42, 27.28 (2q,
MeN); data for trans-22d: 100.05 (d, C(1’)); 66.22 (t, C(4’)); 49.31 (d, C(2’)); 28.43 (t, C(3’)); data for cis-
22d: 96.32 (d, C(1’)); 65.28 (t, C(4’)); 48.01 (d, C(2’)); 24.18 (t, C(3’)). HR-MALDI-MS: 392.1332 (100,
[M þ Na]þ, C18H19N5NaO4þ ; calc. 392.1329). Anal. calc. for C18H19N5O4 (369.38): C 58.53, H 5.18, N
18.96; found: C 58.27, H 5.34, N 18.51.
Methyl (Z)-3-[2-Amino-4-(benzyloxy)-7,8-dihydro-8-methyl-7-oxopteridin-6-yl]-2-hydroxyprop-2-
enoate (19e). A suspension of 10 (300 mg, 1.0 mmol) and methyl prop-2-ynoate (17; 0.8 ml) in toluene
(10 ml) was stirred at 1008 for 1 h and then cooled to 08. The orange precipitate (200 mg of 19e) was
filtered off. Evaporation of the filtrate, and FC (CH2Cl2/AcOEt 9 :1) gave additional 19e (127 mg, total
yield: 85%). Orange solid. Rf (CH2Cl2/MeOH 9 :1) 0.68. M.p. 2278 (dec.). UV (MeOH, c ¼ 0.096 mm):
216 (4.34), 246 (3.84), 289 (3.75), 409 (4.18), 426 (4.18), 490 (sh, 3.39). IR (ATR): 3537w, 3505w, 3369m,
3221w, 3119w, 2954w, 1727m, 1670m, 1625m, 1585s, 1564s, 1487s, 1472s, 1453s, 1347m, 1287m, 1232s,
1113w, 1069w, 1038m, 994m, 975m, 919w, 888w, 874w, 794m, 782w, 760m, 723w, 706m, 672w, 646w.
1H-NMR (300 MHz, (D6)DMSO): 13.76 (s, OH); 7.54 – 7.37 (m, 5 arom. H, NH2); 6.87 (s, HꢀC(2)); 5.53
(s, PhCH2); 3.79 (s, MeO); 3.50 (s, MeN). 13C-NMR (100 MHz, (D6)DMSO): 163.01, 162.86 (2s, OC¼O,
C(4’)); 160.98 (s, C(2’)); 156.04 (s, C(7’)); 153.64 (s, C(2)); 150.79 (s, C(8a)); 145.10 (s, C(6)); 136.02 (s);
128.51 (2d); 128.18 (d); 127.94 (2d); 104.79 (s, C(4’a)); 98.47 (d, C(3)); 67.99 (t, PhCH2); 52.42 (q, MeO);
27.80 (q, MeN). HR-MALDI-MS: 406.1118 (44, [M þ Na]þ, C18H17N5NaO5þ ; calc. 406.1122), 384.1303
(100, [M þ H]þ, C18H18N5O5þ ; calc. 384.1303), 324.1091 (59, [M ꢀ C2H4O2 þ H]þ, C16H14N5Oþ3 ; calc.
324.1091).
X-Ray Crystal-Structure Analysis of 19e · DMSO. Cooling a hot soln. of 19e in DMSO gave yellow
single crystals of 19e · DMSO. C18H17N5O5 · C2H6OS, Mr ¼ 461.497, monoclinic, P21/n, a ¼ 14.7687(3), b ¼
7.2892(2), c ¼ 20.7070(5) ꢃ, b ¼ 98.5485(11)8, V¼ 2204.39(9) ꢃ3, Z ¼ 4, Dcalc ¼ 1.391 Mg/m3. Intensities
were measured on a Nonius Kappa CCD diffractometer, with MoKa radiation (l ¼ 0.71073 ꢃ). Cell
parameters from 16871 reflections, q ¼ 2.425 – 27.4858, m ¼ 0.194 mmꢀ1, T¼ 223 K. 9817 measured
reflections, 5031 independent reflections, 3347 observed reflections (>2s(I)). Refinement on F2: Full-
matrix least squares refinement, R(all) ¼ 0.0989, R(gt) ¼ 0.0639. All diagrams and calculations were
performed using maXus (Bruker Nonius, Delft, MacScience, Japan). The program SIR97 was used to
solve the structure and the program SHELXL-97 to refine it.
Diethyl (2RS,3RS)-2-[2-Amino-3,4,7,8-tetrahydro-8-methyl-4,7-dioxopteridin-6-yl]-3-hydroxybuta-
nedioate (20a). A suspension of 19a (150 mg, 0.32 mmol) and LiBr (69 mg, 0.80 mmol) in MeCN
(5 ml) was cooled to 08, treated with Me3SiCl (122 ml, 0.95 mmol), stirred for 15 min at 08 and for 3.5 h at
r.t., cooled to 08, diluted with MeOH (2 ml), and stored over night at ꢀ 208. The precipitate was filtered
off, washed with CH2Cl2, and dried in vacuo to afford 20a (112 mg, 93%). Amorphous solid. UV (MeOH,
c ¼ 0.094 mm): 218 (4.36), 294 (3.83), 343 (4.03). IR (ATR): 3492w, 3294w, 3136w, 2980w, 1732m, 1718m,
1685w, 1636s, 1587m, 1540s, 1524s, 1469w, 1445w, 1370m, 1342w, 1269m, 1242m, 1200w, 1180m, 1116m,
1067w, 1016m, 924w, 885w, 858w, 797m, 738w, 724w, 684w, 627w. 1H-NMR (300 MHz, (D6)DMSO): 11.24
(s, NH); 7.22 (br. s, NH2); 5.83 (d, J ¼ 7.2, OH); 4.68 (dd, J ¼ 9.0, 7.2, HꢀC(3)); 4.31 (d, J ¼ 9.3, HꢀC(2));

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Helvetica Chimica Acta – Vol. 92 (2009)
4.10, 4.01 (2q, J ¼ 6.9, 2 MeCH2O); 3.43 (s, MeN); 1.19, 1.08 (2t, J ¼ 6.9, 2 Me). 13C-NMR (100 MHz,
(D6)DMSO): 171.69, 169.19 (2s, 2 C¼O); 158.69 (s, C(2’)); 156.00 (s, C(7’)); 154.59 (s, C(4’)); 151.14 (s,
C(8’a)); 143.50 (s, C(6’)); 110.83 (s, C(4’a)); 69.34 (d, C(3)); 60.45, 60.26 (2t, MeCH2O); 51.96 (d, C(2));
27.95 (q, MeN); 13.89, 13.85 (2q, 2 Me). HR-MALDI-MS: 404.1170 (22, [M þ Na]þ, C15H19N5NaO7þ ;
calc. 404.1177), 388.1431 (100, [M þ Li]þ, C15H19LiN5O7þ ; calc. 388.1431), 382.1349 (17, [M þ H]þ,
C15H20N5Oþ7 ; calc. 382.1357).
Diethyl (2RS,3SR)-2-[2-Amino-3,4,7,8-tetrahydro-8-methyl-4,7-dioxopteridin-6-yl]-3-hydroxybuta-
nedioate (20b). A suspension of 19b (300 mg, 0.64 mmol) and LiBr (138 mg, 1.59 mmol) in MeCN
(10 ml) was cooled to 08, treated with Me3SiCl (241 ml, 1.91 mmol), stirred for 15 min at 08 and 3 h at r.t.,
and cooled to 08. The precipitate was filtered off, washed with cold MeCN, and dried in vacuo to afford
20b (225 mg, 93%). Amorphous solid. UV (MeOH, c ¼ 1.0 mm): 219 (4.33), 294 (3.86), 342 (4.08). IR
(ATR): 3347w, 3332w, 3193w, 3159w, 2982w, 2940w, 2903w, 1744m, 1721m, 1633s, 1587m, 1545s, 1522s,
1466m, 1445m, 1404m, 1364m, 1274m, 1263m, 1219s, 1195m, 1180m, 1116m, 1093m, 1082m, 1026s, 853m,
1
802m, 729m, 629s. H-NMR (400 MHz, (D6)DMSO): 11.26 (s, NH); 7.35 (br. s, NH2); 5.83 (d, J ¼ 6.7,
OH); 4.71 (dd, J ¼ 7.9, 6.7, Hꢀ(3)); 4.29 (d, J ¼ 8.0, HꢀC(2)); 4.06 (qd, J ¼ 7.1, 1.0, MeCH2O); 4.00 (qd,
J ¼ 7.0, 2.3, MeCH2O); 3.43 (s, MeN); 1.14, 1.06 (2t, J ¼ 7.1, 2 Me ) . 13C-NMR (100 MHz, (D6)DMSO):
171.49, 169.04 (2s, 2 C¼O); 158.50 (s, C(2’)); 155.84 (s, C(7’)); 154.58 (s, C(4’)); 151.03 (s, C(8’a)); 143.02
(s, C(6’)); 110.59 (s, C(4’a)); 69.80 (d, C(3)); 60.33, 60.17 (2t, 2 MeCH2O); 51.67 (d, C(2)); 27.92 (q,
MeN); 13.96, 13.70 (2q, 2 Me). HR-MALDI-MS: 404.1175 (30, [M þ Na]þ, C15H19N5NaO7þ ; calc.
404.1177), 388.1438 (100, [M þ Li]þ, C15H19LiN5Oþ7 ; calc. 388.1431), 382.1349 (20, [M þ H]þ,
C15H20N5Oþ7 ; calc. 382.1357).
2-Amino-6-(cis-2-hydroxycyclohexyl)-8-methylpteridin-4,7(3H,8H)-dione (20c). A suspension of
19c (227 mg, 0.60 mmol) and LiBr (129 mg, 1.49 mmol) in MeCN (7 ml) was cooled to 08, treated with
Me3SiCl (227 ml, 1.79 mmol), stirred for 15 min at 08 and for 6 h at r.t., cooled to 08, diluted with MeOH
(2 ml), and stirred for 15 min. The precipitate was filtered off. Crystallization from H2O/PrOH 1:1 gave
20c (154 mg, 89%). UV (MeOH, c ¼ 0.070 mm): 218 (4.38), 296 (3.91), 343 (4.07). IR (ATR): 3367w,
3295w, 3200w, 3152w, 2927w, 2850w, 1682m, 1629s, 1584m, 1537s, 1514s, 1445m, 1359m, 1297w, 1273w,
1226w, 1196w, 1136w, 1111w, 1071w, 1056w, 1028w, 1010w, 972w, 948w, 920w, 893w, 848w, 821w, 802m,
788w, 726w, 712w, 659w, 622w. 1H-NMR (400 MHz; (D6)DMSO): 11.13 (s, NH); 7.07 (s, NH2); 4.64 (dd,
J ¼ 2.7, 1.0, OH); 4.18 (br. s, HꢀC(2’)); 3.43 (s, MeN); 3.00 (ddd, J ¼ 12.3, 3.4, 2.1, HꢀC(1’)); 1.84 (qd, J ¼
12.8, 3.4, HaxꢀC(6’)); 1.78 – 1.72 (m, HeqꢀC(3’), HeqꢀC(5’)); 1.64 (qt, J ¼ 12.7, 3.4, HaxꢀC(4’)); 1.52 – 1.47
(m, HaxꢀC(3’), HeqꢀC(6’)); 1.44 – 1.35 (m, HeqꢀC(4’)); 1.31 (qt, J ¼ 12.8, 3.6, HaxꢀC(5’)). 13C-NMR
(100 MHz, (D6)DMSO): 158.85 (s, C(2)); 155.93 (s, C(7)); 154.15 (s, C(4)); 151.51 (s, C(8a)); 150.50 (s,
C(6)); 110.18 (s, C(4a)); 65.69 (d, C(2’)); 43.02 (d, C(1’)); 32.62 (t, C(3’)); 27.80 (q, MeN); 25.49 (t, C(6’));
23.49 (t, C(4’)); 19.43 (t, C(5’)). HR-MALDI-MS: 314.1225 (100, [M þ Na]þ, C13H17N5NaO3þ ; calc.
314.1224), 292.1404 (70, [M þ H]þ, C13H18N5O3þ ; calc. 292.1404), 274.1298 (93, [M ꢀ OH]þ, C13H16N5Oþ2 ;
calc. 274.1299).
2-Amino-6-(2,3-dihydrofuran-4-yl)-8-methylpteridine-4,7(3H,8H)-dione (20d). A suspension of 19d
(130 mg, 0.352 mmol) and LiBr (76 mg, 0.881 mmol) in MeCN (5 ml) was cooled to 08, treated with
Me3SiCl (134 ml, 1.057 mmol), stirred for 15 min at 08 and for 4 h at r.t., diluted with MeOH (2 ml), and
stirred for 15 min. The precipitate was filtered off, washed with CH2Cl2/MeOH 9 :1, and dried in vacuo to
afford 20d (75 mg, 76%). Red-brown solid. UV (MeOH, c ¼ 0.13 mm): 218 (4.24), 242 (sh, 3.71), 323
(4.73), 379 (4.09). IR (ATR): 3369w, 3177m, 3115w, 2908w, 2726w, 1672m, 1638s, 1588s, 1548s, 1501s,
1451m, 1383m, 1322m, 1266m, 1253m, 1171w, 1148m, 1123s, 1042m, 1011m, 979w, 933w, 909m, 890w,
879m, 867w, 824w, 796m, 787w, 775w, 727w, 625w. 1H-NMR (400 MHz, (D6)DMSO): 11.18 (s, NH); 7.87
(t, J ¼ 1.6, HꢀC(5’)); 7.11 (s, NH2); 4.41 (t, J ¼ 9.6, 2 HꢀC(4’)); 3.50 (s, MeN); 2.96 (td, J ¼ 9.6, 1.6,
2 HꢀC(3’)). 13C-NMR (100 MHz, (D6)DMSO): 158.98 (s, C(2)); 155.17 (s, C(7)); 153.63 (s, C(4));
150.19 (s, C(8a)); 148.82 (s, C(6)); 140.90 (d, C(5’)); 114.93 (s, C(4’)); 111.52 (s, C(4a)); 69.82 (t, C(2’));
29.88 (t, C(3’)); 27.90 (q, MeN). HR-MALDI-MS: 284.0749 (71, [M þ Na]þ, C11H11NaN5O3þ ; calc.
284.0754), 268.1017 (64, [M þ Li]þ, C11H11LiN5O3þ ; calc. 268.1016), 262.0933 (100, [M þ H]þ,
C11H12N5Oþ3 ; calc. 268.1016).
Methyl (Z)-3-[2-Amino-3,4,7,8-tetrahydro-8-methyl-4,7-dioxopteridin-6-yl]-2-hydroxyprop-2-enoate
(20e). A suspension of 19e (50 mg, 0.13 mmol) and LiBr (28 mg, 0.33 mmol) in MeCN (3 ml) was cooled

Helvetica Chimica Acta – Vol. 92 (2009)
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to 08, treated with Me3SiCl (50 ml, 0.39 mmol), stirred for 15 min at 08 and for 4 h at r.t., cooled to 08,
diluted with MeOH (2 ml), and stirred for 30 min. The precipitate was filtered off, washed with CH2Cl2/
MeOH 9 :1, and dried in vacuo to afford 20e (37 mg, 97%). UV (MeOH, c ¼ 0.13 mm): 220 (4.34), 268
(3.71), 309 (3.78), 408 (4.21), 425 (4.20), 489 (3.43). IR (ATR): 3319w, (br.) 3183m, 2953w, 1718m, 1630s,
1583s, 1552s, 1504s, 1435s, 1360m, 1263s, 1212s, 1106m, 1071w, 985w, 968w, 924w, 868w, 828w, 775m, 758m,
711m, 619w. 1H-NMR (400 MHz, (D6)DMSO): 13.85 (s, OH); 11.49 (s, NH); 7.40 (s, NH2); 6.81 (s,
HꢀC(3)); 3.79 (s, MeO); 3.47 (s, MeN). 13C-NMR (100 MHz, (D6)DMSO): 163.09 (s, C¼O); 157.47 (s,
C(2’)); 155.99 (s, C(7’)); 154.21 (s, C(4’)); 153.43 (s, C(2)); 150.25 (s, C(8’a)); 143.45 (s, C(6’)); 107.82 (s,
C(4’a)); 98.22 (d, C(3)); 52.32 (q, MeO); 28.21 (q, MeN). HR-MALDI-MS: 294.0625 (100, [M þ H]þ,
C11H12N5Oþ5 ; calc. 294.0833).
2-Amino-4-(benzyloxy)-8-methyl-6-phenylpteridin-7(8H)-one 5-Oxide (21). A soln. of 5 (520 mg,
2.01 mmol) and EtNiPr2 (862 ml, 5.00 mmol) in THF (20 ml) was cooled to 08, treated with 2-chloro-2-
phenylacetyl chloride (349 ml, 2.40 mmol), stirred for 30 min at 08 and for 30 min at r.t., diluted with sat.
aq. NaHCO3 soln., and extracted with CH2Cl2 (3 ꢃ 30 ml). The combined org. layers were washed with
brine, dried (Na2SO4), and evaporated. FC (CH2Cl2/AcOEt 9 :1) gave 21 (612 mg, 82%). Crystalisation
from iPrOH gave yellow crystals. Rf (CH2Cl2/MeOH 9 :1) 0.63. M.p. 2408. UV (MeOH): 217 (4.46), 244
(sh, 4.20), 269 (4.14), 366 (4.19). IR (ATR): 3458w, 3326w, 3210w, 3115w, 3066w, 3014w, 1660m, 1634m,
1555s, 1499m, 1482s, 1465m, 1453s, 1441s, 1421s, 1359s, 1312m, 1288m, 1243s, 1194m, 1140m, 1107w,
1077w, 1044m, 1025m, 999w, 987w, 954w, 921w, 904w, 853w, 826w, 785s, 763m, 739m, 724m, 688m, 674m,
650m, 617w. 1H-NMR (400 MHz, (D6)DMSO): 7.55 – 7.29 (m, 10 arom. H, NH2); 5.47 (s, PhCH2); 3.57 (s,
MeN). 13C-NMR (100 MHz, (D6)DMSO): 162.34 (s, C(4)); 160.24 (s, C(2)); 156.97 (s, C(7)); 152.33 (s,
C(8a)); 136.05, 134.03 (2s); 129.50 (s, C(6)); 130.55, 128.47, 28.26, 127.76, 127.68, 127.38 (several d); 107.88
(s, C(4a)); 68.14 (t, PhCH2); 28.39 (q, MeN). HR-MALDI-MS: 398.1217 (100, [M þ Na]þ,
C20H17N5NaOþ3 ; 398.1224), 376.1400 (62, [M þ H]þ, C20H18N5O3þ ; calc. 376.1404). Anal. calc. for
C20H17N5O3 (375.39): C 63.99, H 4.56, N 18.66; found: C 64.11, H 4.72, N 18.51.
2-Amino-4-(benzyloxy)-8-methyl-6-phenylpteridin-7(8H)-one (22). A suspension of 21 (120 mg,
0.32 mmol) in toluene (5 ml) was treated with N-phenylmaleimide (83 mg, 0.480 mmol), kept at reflux
for 1 h, and evaporated. FC (hexane/AcOEt 3 :2) gave 22 (95 mg, 82%). A sample for analysis was
crystallized from EtOH. Rf (CH2Cl2/MeOH 9 :1) 0.76. M.p. 1788. UV (MeOH): 219 (4.32), 241 (4.08),
292 (3.76), 370 (4.28). IR (ATR): 3494w, 3455w, 3335m, 3221w, 3048w, 1663m, 1624m, 1556s, 1522m,
1478s, 1472s, 1455s, 1439s, 1394m, 1356s, 1315m, 1292m, 1256m, 1228s, 1184m, 1115w, 1094m, 1059w,
1037m, 1020s, 956m, 924w, 900m, 851w, 834w, 802m, 754m, 746s, 726m, 699m, 686s, 647m. 1H-NMR
(400 MHz, (D6)DMSO): 8.13 – 8.10 (m, 2 arom. H); 7.54 – 7.32 (m, 8 arom. H, NH2); 5.55 (s, PhCH2); 3.54
(s, Me). 13C-NMR (100 MHz, (D6)DMSO): 165.35 (s, C(4)); 161.15 (s, C(2)); 156.05 (s, C(7)); 151.21 (s,
C(8a)); 144.12 (s, C(6)); 136.35, 136.12 (2s); 128.98, 128.54, 128.40, 128.27, 128.03, 127.72 (several d);
108.25 (s, C(4a)); 67.56 (t, PhCH2); 27.62 (q, MeN). HR-MALDI-MS: 360.1454 (100, [M þ H]þ,
C20H18N5Oþ2 ; calc. 360.1455). Anal. calc. for C20H17N5O2 (359.39): C 66.84, H 4.77, N 19.49; found: C
67.00, H 4.90, N 19.44.
2-Amino-8-methyl-6-phenylpteridin-4,7(3H,8H)-dione (23).
A suspension of 22 (160 mg,
0.45 mmol) and LiBr (50 mg, 0.58 mmol) in MeCN (7 ml) was cooled to 08, treated with Me3SiCl
(86 ml, 0.67 mmol), stirred for 15 min at 08 and for 16 h at r.t., diluted with MeOH (2 ml), and stirred for
15 min. The precipitate was filtered off. Recrystallisation in PrOH gave 23 (117 mg, 97%). Yellow
crystals. Rf (CH2Cl2/MeOH 9 :1) 0.35. M.p. > 3708 (dec.). UV (MeOH, c ¼ 0.12 mm): 224 (4.35), 240 (sh,
4.12), 302 (4.00), 369 (4.33). IR (ATR): 3413w, 3338w, 3184w, 3106m, 2924w, 2839w, 2760w, 1678m,
1664m, 1627s, 1595s, 1555m, 1505s, 1485s, 1442s, 1397m, 1386m, 1336m, 1287m, 1252w, 1216w, 1181w,
1152w, 1105w, 1074w, 1050w, 1021m, 1010m, 929w, 913w, 861w, 838m, 803m, 748w, 732m, 686m, 652w,
625w. 1H-NMR (400 MHz, (D6)DMSO): 11.19 (s, HꢀN(3)); 8.20 – 8.17 (m, 2 arom. H); 7.44 – 7.36 (m, 3
arom. H); 7.22 (br. s, NH2); 3.52 (s, MeN). 13C-NMR (100 MHz, (D6)DMSO): 159.01 (s, C(2)); 155.90 (s,
C(7)); 154.41 (s, C(4)); 150.98 (s, C(8a)); 141.85 (s, C(6)); 136.34 (s); 128.60 (d); 128.22 (2d); 127.67 (2d);
111.59 (s, C(4a)); 28.10 (q, MeN). HR-MALDI-MS: 308.0541 (15, [M þ K]þ, C13H11KN5O2þ ; calc.
308.0544), 292.0800 (49, [M þ Na]þ, C13H11N5NaO2þ ; calc. 292.0805), 270.0984 (100, [M þ H]þ,
C13H12N5Oþ2 ; calc. 270.0984). Anal. calc. for C13H11N5O2 (269.26): C 57.99, H 4.12, N 26.01; found: C
57.89, H 4.25, N 25.82.

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2-Amino-4-(benzyloxy)-8-methyl-6-(morpholin-4-yl)pteridin-7(8H)-one (24). From 11. A suspen-
sion of 11 (50 mg, 0.16 mmol) in toluene (5 ml) was treated with freshly distilled morpholine (0.3 ml),
kept for 4.5 h at reflux, cooled to r.t., and evaporated. FC (AcOEt/hexane 2 :3) gave 24 (56 mg, 97%).
From 10. A suspension of 10 (300 mg, 1.0 mmol) in toluene (10 ml) was treated with freshly distilled
morpholine (1.0 ml), kept for 1.5 h at reflux, cooled to r.t., and evaporated. FC (AcOEt/hexane 2 :3) gave
24 (359 mg, 98%). A sample for analysis was sublimed at 1608, < 10ꢀ3 mbar. Colourless solid. Rf
(CH2Cl2/MeOH 9 :1) 0.60. M.p. 1728. UV (MeOH, c ¼ 0.10 mm): 215 (4.33), 243 (4.06), 299 (3.95), 362
(4.21). IR (ATR): 3439w, 3344m, 3233w, 3031w, 2970w, 2900w, 2857w, 1661m, 1640s, 1564s, 1550s, 1497m,
1443s, 1433s, 1406m, 1393s, 1354s, 1302m, 1242s, 1225s, 1178m, 1107s, 1063m, 1037s, 1028s, 1000m, 965m,
1
949w, 893m, 854m, 789m, 734m, 694m, 651w. H-NMR (300 MHz, (D6)DMSO): 7.50 – 7.30 (m, 5 arom.
H); 6.84 (s, H2NꢀC(2)); 5.49 (s, PhCH2); 3.69 (t, J ¼ 4.5, H2ꢀC(3’)); 3.55 (t, J ¼ 4.5, H2ꢀC(2’)); 3.48 (s,
MeN). 13C-NMR (75 MHz, (D6)DMSO): 163.42 (s, C(4)); 158.80 (s, C(2)); 153.23 (s, C(7)); 148.90 (s,
C(8a)); 146.96 (s, C(6)); 136.83 (s); 128.37 (2d); 127.91 (2d); 127.82 (d); 105.60 (s, C(4a)); 66.90 (t,
PhCH2); 65.87 (t, 2 CH2O); 47.25 (t, 2 CH2N); 28.52 (q, MeN). HR-MALDI-MS: 369.1667 (100, [M þ
H]þ, C18H20N6O3þ ; calc. 369.1670). Anal. calc. for C18H20N6O3 (368.39): C 58.69, H 5.47, N 22.81; found:
C 58.96, H 5.63, N 22.59.
2-Amino-8-methyl-6-(morpholin-4-yl)pteridin-4,7(3H,8H)-dione (25). A suspension of 24 (60 mg,
0.16 mmol) and LiBr (21 mg, 0.24 mmol) in MeCN (5 ml) was cooled to 08, treated with Me3SiCl (41 ml,
0.36 mmol), stirred for 15 min at 08 and for 8 h at r.t., cooled to 08, diluted with MeOH (2 ml), and stirred
for 15 min. The precipitate was filtered, washed with CH2Cl2/MeOH 9 :1, and dried in vacuo to give 25
(42 mg, 93%). Colourless solid. UV (MeOH, c ¼ 0.13 mm): 213 (4.40), 318 (4.12), 357 (4.15). IR (ATR):
3576w, 3446w, 3359w, 3186m, 2933w, 2896w, 2757w, 1655s, 1606s, 1561m, 1551s, 1519s, 1453m, 1441m,
1392m, 1366m, 1328m, 1296w, 1281w, 1248s, 1214w, 1169w, 1107s, 1070w, 1052w, 1034w, 1023m, 981m,
941w, 899m, 867m, 822w, 788m, 776w, 731w, 666w. 1H-NMR (400 MHz, (D6)DMSO): 10.98 (s, HꢀN(3));
6.75 (s, NH2); 3.69 (br. t, J ¼ 4.7, 2 CH2O); 3.50 (br. t, J ¼ 4.7, 2 CH2N); 3.45 (s, MeN). 13C-NMR
(100 MHz, (D6)DMSO): 158.86 (s, C(2)); 152.87 (s, C(7)); 152.27 (s, C(4)); 147.38 (s, C(8a)); 146.40 (s,
C(6)); 108.50 (s, C(4a)); 65.90 (t, 2 CH2O); 47.28 (t, 2 CH2N); 28.16 (q, MeN). HR-MALDI-MS:
301.1017 (25, [M þ Na]þ, C11H14N6NaO3þ ; calc. 301.1020), 279.1197 (100, [M þ H]þ, C11H15N6Oþ3 ; calc.
279.1200).
Phenyl 2,3,6-Tri-O-acetyl-4-{2-[2-amino-4-(benzyloxy)-7,8-dihydro-7-oxopteridin-6-yl]ethynyl}-4-
deoxy-1-thio-b-d-glucopyranosid (26). A suspension of 11 (50 mg, 0.16 mmol), phenyl 2,3,6-tri-O-
acetyl-4-deoxy-4-ethynyl-1-thio-b-d-glucopyranoside (96 mg, 0.24 mmol), Pd(OAc)2 (4.3 mg,
0.02 mmol), CuI (6.0 mg, 0.03 mmol), and Ph3P (10 mg, 0.04 mmol) in MeCN (2 ml) was treated with
Et3N (3 ml) and stirred for 5.5 h at 238. The soln. was diluted with CHCl3 (10 ml) and filtered through a
pad of Celite. Evaporation and FC (AcOEt/Hexane 1:1 ! 4 :1) gave 26 (94 mg, 87%). A sample for
i
analysis was recrystallised in PrOH and toluene. Cream coloured solid. Rf (CH2Cl2/MeOH 9 :1) 0.56.
M.p. 2248. UV (MeOH, c ¼ 0.088 mm): 218 (4.48), 242 (4.23), 286 (sh, 3.67), 379 (4.38). IR (ATR):
3516w, 3405m, 3058w, 2949w, 2880w, 2236w, 1736s, 1666m, 1601m, 1573s, 1555s, 1522m, 1479m, 1422m,
1399w, 1369m, 1355m, 1315w, 1289m, 1226s, 1216s, 1143w, 1121w, 1071m, 1036s, 1012s, 913m, 879w, 856m,
800m, 754m, 742m, 722w, 703m, 689m, 642w, 621w. 1H-NMR (400 MHz, (D6)DMSO): 7.60 (s, NH2);
7.53 – 7.30 (m, 10 arom. H); 5.48 (s, PhCH2); 5.45 (dd, J ¼ 10.8, 9.2, HꢀC(3)); 5.31 (d, J ¼ 10.0, HꢀC(1));
4.78 (dd, J ¼ 10.0, 9.2, HꢀC(2)); 4.41 – 4.36 (m, HaꢀC(6)); 4.28 – 4.21 (m, HꢀC(5), HbꢀC(6)); 3.44 (s,
MeN); 3.28 (dd, J ¼ 10.8, 10.2, HꢀC(4)); 2.04, 2.02, 2.01 (3s, AcO). 13C-NMR (100 MHz, (D6)DMSO):
170.00, 169.19, 169.17 (3s, 3 C¼O); 164.94 (s, C(4’)); 161.61 (s, C(2’)); 156.10 (s, C(7’)); 151.32 (s, C(8’a));
135.97 (s); 132.51 (s, C(6’)); 130.96 (s); 130.67 (2d); 129.02 (2d); 128.71 (2d); 128.43 (2d); 128.25 (d);
127.45 (d); 108.92 (s, C(4’a)); 88.03 (s, C ꢁ CꢀC(4)); 83.43 (d, C(1)); 81.24 (s, C ꢁ CꢀC(4)); 75.07 (d,
C(5)); 72.43 (d, C(3)); 70.10 (d, C(2)); 67.99 (t, PhCH2); 63.84 (t, C(6)); 36.23 (d, C(4)); 27.64 (q, MeN);
20.52, 20.44, 20.35 (3q, 3 MeC¼O). HR-MALDI-MS: 710.1897 (100, [M þ Na]þ, C34H33N5NaO9Sþ; calc.
710.1891), 688.2081 (65, [M þ H]þ, C34H34N5O9Sþ; calc. 688.2072). Anal. calc. for C34H33N5O9S · 0.1
toluene (696.94): C 59.85, H 4.89, N 10.03; found: C 59.83, H 4.93, N 10.00.
2-Amino-4-(benzyloxy)-8-methyl-6-[2-(trimethylsilyl)ethynyl]pteridin-7(8H)-one (27). A suspen-
sion of 11 (500 mg, 1.58 mmol), (trimethylsilyl)acetylene (337 ml, 2.37 mmol), Pd(OAc)2 (42 mg,
0.19 mmol), CuI (60 mg, 0.32 mmol), and Ph3P (99 mg, 0.38 mmol) in MeCN (12 ml) was treated with

Helvetica Chimica Acta – Vol. 92 (2009)
605
Et3N (18 ml) and stirred for 8 h at 238. The soln. was diluted with CHCl3 (50 ml) and filtered through a
pad of Celite. Evaporation and FC (AcOEt/CH2Cl2 1:4) gave 27 (550 mg, 92%). Cream coloured solid. A
i
sample for analysis was recrystallised in PrOH. Rf (CH2Cl2/MeOH 9 :1) 0.69. M.p. > 3008 (dec.). UV
(MeOH, c ¼ 0.092 mm): 220 (4.37), 242 (4.14), 260 (sh, 3.88), 290 (sh, 3.73), 384 (4.39). IR (ATR):
3520w, 3275w, 3188w, 3135w, 2955w, 2152w, 1661m, 1619m, 1597m, 1558s, 1522m, 1466s, 1439s, 1355m,
1320m, 1276s, 1249m, 1227m, 1091w, 1065w, 1037w, 984w, 910w, 883w, 838s, 798m, 759m, 747m, 736m,
697m, 624w. 1H-NMR (300 MHz, (D6)DMSO): 7.45 (br. s, NH2); 7.53 – 7.37 (m, 5 arom. H); 5.48 (s,
PhCH2); 3.34 (s, MeN); 0.22 (s, Me3Si). 13C-NMR (100 MHz, (D6)DMSO): 164.97 (s, C(4)); 161.63 (s,
C(2)); 156.07 (s, C(7)); 151.33 (s, C(8a)); 135.92 (s); 131.07 (s, C(6)); 128.81 (2d); 128.44 (2d); 128.28 (d);
109.07 (s, C(4a)); 101.51 (s, C ꢁ CꢀC(6)); 98.66 (s, C ꢁ CꢀC(6)); 68.02 (t, PhCH2); 27.59 (q, MeN);
ꢀ 0.41 (q, Me3Si). HR-MALDI-MS: 402.1348 (19, [M þ Na]þ, C19H21N5NaO2Siþ; calc. 402.1357),
380.1529 (100, [M þ H]þ, C19H22N5O2Siþ; calc. 380.1537). Anal. calc. for C19H21N5O2Si (379.49): C 60.14,
H 5.58, N 18.45; found: C 60.14, H 5.65, N 18.61.
2-Amino-4-(benzyloxy)-6-ethynyl-8-methylpteridin-7(8H)-one (28). A soln. of 27 (240 mg,
0.78 mmol) in THF (10 ml) was treated with Bu4NF · 3 H2O (74 mg, 0.23 mmol), stirred for 30 min,
and adsorbed on silica gel. FC (AcOEt/CH2Cl2 1:4 ! 2 :3) gave 28 (233 mg, 98%). Rf (CH2Cl2/MeOH
9 :1) 0.53. M.p. 2018. UV (MeOH, c ¼ 0.12 mm): 218 (4.35), 240 (4.07), 286 (3.34), 375 (4.30). IR (ATR):
3434m, 3284m, 3181m, 2953w, 2114w, 1672m, 1626m, 1583m, 1567s, 1550s, 1479s, 1453s, 1435s, 1356s,
1326m, 1312m, 1270m, 1237s, 1215s, 1125m, 1057m, 1038s, 981m, 909w, 838w, 799m, 777w, 739m, 726m,
1
700m, 658m, 646m, 618w. H-NMR (400 MHz, (D6)DMSO): 7.61 (s, NH2); 7.53 – 7.35 (m, 5 arom. H);
5.48 (s, PhCH2); 4.45 (s, C ꢁ CH); 3.45 (s, MeN). 13C-NMR (100 MHz, (D6)DMSO): 164.96 (s, C(4));
161.67 (s, C(2)); 156.24 (s, C(7)); 151.36 (s, C(8a)); 135.95 (s); 130.97 (s, C(6)); 128.63 (2d); 128.42 (2d);
128.22 (d); 108.97 (s, C(4a)); 84.44 (s, C ꢁ CH); 80.32 (d, C ꢁ CH); 67.98 (t, PhCH2); 27.61 (q, MeN). HR-
MALDI-MS: 330.0961 (34, [M þ Na]þ, C16H13N5NaO2þ ; calc. 330.0961), 308.1144 (100, [M þ H]þ,
C16H14N5Oþ2 ; calc. 308.1142). Anal. calc. for C16H13N5O2 · 0.46 CH2Cl2 (346.38): C 57.06, H 4.05, N 20.21;
found: C 57.03, H 4.17, N 20.17.
6,6’-(Ethyne-1,2-diyl)bis[2-amino-4-(benzyloxy)-8-methylpteridin-7(8H)-one] (29). From 11 and 28.
A suspension of 11 (70 mg, 0.29 mmol), 28 (108 mg, 0.34 mmol), Pd(OAc)2 (6 mg, 0.03 mmol), CuI
(9 mg, 0.05 mmol), and Ph3P (14 mg, 0.06 mmol) in MeCN (4 ml) was treated with Et3N (6 ml), stirred
for 7 h at 238, diluted with CHCl3 (10 ml), and filtered through a pad of Celite. Evaporation and FC
(CH2Cl2/MeOH 49 :1 ! 9 :1) gave 29 (63 mg, 47%).
From 11 and Me3SiꢀC ꢁ CH. A suspension of 11 (250 mg, 0.79 mmol), (trimethylsilyl)acetylene
(169 ml, 1.18 mmol), Pd(OAc)2 (42 mg, 0.19 mmol), CuI (60 mg, 0.32 mmol), and Ph3P (99 mg,
0.38 mmol) in MeCN (8 ml) was treated with Et3N (12 ml), stirred for 7 h at 238, treated with Bu4NF ·
3 H2O (75 mg, 0.24 mmol), stirred for 30 min, treated with 11 (250 mg, 0.79 mmol), and stirred
overnight. The soln. was diluted with CHCl3 (20 ml), and filtered through a pad of Celite. Evaporation
and FC (CH2Cl2/MeOH 49 :1 ! 9 :1) gave 29 (253 mg, 55%). Rf (CH2Cl2/MeOH 9 :1) 0.44. UV (MeOH,
sat. soln.): 212, 237 (sh), 369 (sh), 438, 458 (sh). IR (ATR): 3462w, 3340m, 3328m, 3217w, 2953w, 2200w,
1660m, 1619m, 1567s, 1547s, 1485s, 1462s, 1429s, 1391m, 1360m, 1337m, 1305m, 1260m, 1218s, 1097m,
1060m, 1001m, 912w, 881w, 812w, 799m, 773w, 757w, 734m, 702w, 621w. 1H-NMR (300 MHz,
(D6)DMSO): 7.72 (br. s, NH2); 7.55 – 7.39 (m, 5 arom. H); 5.50 (s, PhCH2); 3.46 (s, MeN). HR-ESI-
MS: 627.1626 (28, [M þ K]þ, C30H24KN10O4þ ; calc. 627.1614), 611.1884 (100, [M þ Na]þ, C30H24N10NaOþ4 ;
calc. 611.1874), 589.2051 (19, [M þ H]þ, C30H25N10O4þ ; calc. 589.2055).
X-Ray Crystal Structure Analysis of 29 · 3 DMSO. Cooling a hot soln. of 29 in DMSO gave single
crystals. C30H30N10O4 · 3 C2H6OS, Mr ¼ 822.987, monoclinic, P2/c, a ¼ 18.2346(7), b ¼ 14.4849(6), c ¼
15.0548(5) ꢃ, b ¼ 90.801(2)8, V¼ 3976.0(3) ꢃ3, Z ¼ 4, Dcalc ¼ 1.375 Mg/m3. Intensities were measured
on a Nonius Kappa CCD diffractometer, with MoKa radiation (l ¼ 0.71073 ꢃ). Cell parameters from
55443 reflections, q ¼ 2.425 – 27.0288, m ¼ 0.247 mmꢀ1, T¼ 203 K. 23841 measured reflections, 6996
independent reflections, 4579 observed reflections (>2s(I)). Refinement on F2: full-matrix least squares
refinement, R(all) ¼ 0.1105, R(gt) ¼ 0.0673. All diagrams and calculations were performed using maXus
(Bruker Nonius, Delft, MacScience, Japan). The program SIR97 was used to solve the structure and the
program SHELXL-97 to refine it.

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Helvetica Chimica Acta – Vol. 92 (2009)
2-Amino-6-[(E)-2-bromoethenyl]-8-methylpteridin-4,7(3H,8H)-dione (31). A suspension of 28
(100 mg, 0.33 mmol) and LiBr (42 mg, 0.489 mmol) in MeCN (5ml) was cooled to 08, treated with
Me3SiCl (83 ml, 0.641 mmol), stirred for 15 min at 08 and for 13 h at r.t., cooled to 08, diluted with MeOH
(2 ml), and stirred for 15 min. The precipitate was filtered off, washed with cold MeCN, and dried in
vacuo to afford 31 (70 mg, 72%). UV (MeOH, c ¼ 0.099 mm): 222 (4.42), 238 (sh, 4.22), 303 (4.01), 376
(4.38). IR (ATR): 3551w, 3341w, 3184m, 3118m, 2931w, 2756w, 1655s, 1643s, 1602s, 1551m, 1519s, 1458m,
11392m, 1386m, 1335m, 1277m, 1227w, 1202w, 1071m, 971w, 943m, 873m, 846m, 818m, 788m, 764w, 743w,
729w, 678w, 626m. 1H-NMR (400 MHz, (D6)DMSO): 11.25 (s, NH); 8 – 6.5 (br. s, NH2); 7.57 (d, J ¼ 13.4,
HꢀC(2’)); 6.92 (d, J ¼ 13.4, HꢀC(1’)); 3.46 (s, MeN). 13C-NMR (100 MHz, (D6)DMSO; assignment
based on a HMBC spectrum): 158.72 (s, C(2)); 155.57 (s, C(7)); 154.50 (s, C(4)); 150.76 (s, C(8a)); 138.95
(s, C(6)); 130.10 (d, C(1’)); 124.66 (d, C(2’)); 111.94 (s, C(4a)); 27.80 (q, MeN).
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Received January 9, 2009