Synthesis and reactivity in [3 + 2] cycloadditions of isoxanthopterin N(5)-oxides - A new synthesis of 6-substituted pteridinediones

Article abstract of DOI:10.1002/hlca.200890201

Intramolecular condensation of the N-(4-amino-5-nitrosopyrimidin-4-yl)-2- chloroacetamide 2 led to the pteridinone N(5)-oxide 4, while treatment of 2 with Me₃P yielded the 8-(chloromethyl)purine 3. A high-yielding [3 + 2] dipolar cycloaddition of the N(5)-oxide 4 to electron-poor dipolarophiles, followed by spontaneous N,O-bond cleavage, gave the C(6)-substituted pteridinones 8a-8d that were deprotected to provide the pteridine-4,7(3H,8H)- diones 9a-9d, constituting a new synthesis of pterinones possessing a functionalised side chain at C(6).

Full text of DOI:10.1002/hlca.200890201

Helvetica Chimica Acta – Vol. 91 (2008)
1879
Synthesis and Reactivity in [3 þ 2] Cycloadditions of Isoxanthopterin N(5)-
Oxides – A New Synthesis of 6-Substituted Pteridinediones
by Thomas Steinlin, Tiziana Sonati, and Andrea Vasella*
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH-Zürich, HCI, CH-8093 Zürich (e-mail: vasella@org.chem.ethz.ch)
Intramolecular condensation of the N-(4-amino-5-nitrosopyrimidin-4-yl)-2-chloroacetamide 2 led to
the pteridinone N(5)-oxide 4, while treatment of 2 with Me3P yielded the 8-(chloromethyl)purine 3. A
high-yielding [3 þ 2] dipolar cycloaddition of the N(5)-oxide 4 to electron-poor dipolarophiles, followed
by spontaneous N,O-bond cleavage, gave the C(6)-substituted pteridinones 8a – 8d that were deprotected
to provide the pteridine-4,7(3H,8H)-diones 9a – 9d, constituting a new synthesis of pterinones possessing
a functionalised side chain at C(6).
Introduction. – The first pteridine N-oxides were isolated in 1963 by Pachter et al.
[1] who prepared a range of 6-substituted pteridine N(5)-oxides by condensation of
acetonyl-, phenacyl-, and a-cyanobenzylpyridinium salts with a 6-amino-5-nitrosopyr-
imidine under basic conditions. The structure of the N-oxides was established by
deoxygenating the N-oxides with Raney-Ni to the corresponding known pteridine. The
synthesis of N-oxides of lumazines1) was studied in detail by Pfleiderer et al. [2 – 4].
They observed that oxidation of lumazines occurs preferentially at N(8), and that the
regioselectivity of the oxidation depends strongly on steric factors. As illustrated by the
oxidation of 7-oxolumazine with H2O2 to produce 6,7-dioxolumazine [5] rather than
the expected N-oxide, pteridinone N-oxides are not readily available.
In 1972, Mason and Tennant described the reaction of quinoxalin-3(4H)-one N(1)-
oxides with benzyne and with aryl isocyanates [6]. Benzyne led to 2-substituted phenols
by [3 þ 2] dipolar cycloaddition and N,O-bond cleavage. A [3 þ 2] dipolar cyclo-
addition with aryl isocyanates led to secondary diarylamines by loss of CO2.
Subsequently, Kim et al. explored the 1,3-dipolar cycloaddition of benzopyrazine N-
oxides in the synthesis of annulated quinoxalines [7 – 9], while Hisano and co-workers
studied [3 þ 2] dipolar cycloadditions of aromatic N-oxides [10 – 12]. Surprisingly,
however, the reactivity of pteridine N-oxides as 1,3-dipoles was never explored.
We described a synthesis of 6-substituted pteridinones by Diels – Alder cyclo-
addition of N-dienoyl-amino(nitroso)pyrimidines and by ene reactions of N-alkenoyl
amino(nitroso)pyrimidines [13][14], while heating the same N-acylated pyrimidines
with phosphines led to 8-substituted guanines [15]. Evaluating new approaches to 6-
substituted pteridines, we have considered that the intramolecular (formal) condensa-
1
)
Lumazin ¼ pteridin-2,4(1H,3H)-dione; pterin ¼ 2-aminopteridin-4(1H)-one; isoxanthopterin ¼ 2-
aminopteridin-4,7(1H,8H)-dione.
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 91 (2008)
tion of [(chloroacetyl)amino](nitroso)pyrimidines should lead to pterinone N(5)-
oxides while treating the 6-[(chloroacetyl)amino]-5-nitrosopyrimidines with phos-
phines should lead to 8-(chloromethyl)purines. The N-oxides are acylnitrones, and
should readily undergo [3 þ 2] dipolar cycloadditions. We expected the resulting
isoxazolidines to react further by reductive scission of the N,O bond, as it was observed
for similar intermediates [6][16]. Such a b-elimination would lead to pterinones
possessing a differently functionalised 6-substituent. We report the results of this
study.
Results and Discussion. – Acylation of 4-(benzyloxy)-2,6-diamino-5-nitrosopyr-
imidine (1) [17] with chloroacetic anhydride in THF gave a blue precipitate of the
chloroacetamide 2 (Scheme 1). Treating its suspension in o-xylene in a flame-dried
Schlenk-tube with Me3P in THF yielded 62% of 8-(chloromethyl)purine 3, according
to the known reductive cyclisation of such nitrosoamides [18]. The chloromethyl
compound 3 was isolated by filtration and purified by washing with toluene and Et2O,
but it proved too highly reactive to allow purification by chromatography on silica gel.
Scheme 1
a) Chloroacetic anhydride, THF; 94%. b) Me3P, o-xylene; 62%. c) DMSO; ca. 98%. d) 2-Chloro-2-
phenylacetyl chloride, THF; 68%.
The precipitate of the chloroacetamide 2 proved poorly soluble in most organic
solvents2), except DMSO and DMF. The deep blue colour of its solution in DMSO
faded progressively, and 2 was transformed, within 24 h, to yield 98% of the acyl nitrone
4. That this transformation is not restricted to solutions in DMSO is suggested by the
transformation of the 5-nitrosopyrimidine 1 in THF to the 6-phenylpteridinone N(5)-
oxide 6. Treating a suspension of 1 with 2-chloro-2-phenylacetyl chloride led first to a
2
)
Insoluble in THF, AcOEt, MeOH, EtOH, CH2Cl2, 1,2-dichloroethane, CHCl3, hexane, pentane,
and toluene; moderatly soluble, upon heating, in acetone, MeCN, and dioxane.

Helvetica Chimica Acta – Vol. 91 (2008)
1881
greenish solution, presumably of the 5-nitrosopyrimidine 5, and then to a colourless
precipitate of nitrone 63) that was isolated in a yield of 68%.
The chloroacetamide 2 is characterised by the ClCH2 s at 4.86 ppm and, in the HR-
MALDI-MS, by a 37Cl isotope peak with 31% intensity of the 35Cl signal. The 8-
(chloromethyl)purine 3 is characterised by a [M þ 2] signal with 28% intensity of the
parent HR-MALDI-MS signal, a broad NH s at 12.77 ppm, and a sharp ClCH2 s at
4.75 ppm. C(6) of the nitrones 4 and 6 is shielded by 23 and 20 ppm, respectively, as
compared to the average chemical shift for C(6) of the pteridines 8a – 8d (cf. Scheme 2),
evidencing the higher electron density at C(6) of 4 and 6. The HꢀC(6) signal of 4 is
hidden under the Ph signals of the Bn group.
Heating a suspension of the nitrone 6 in the presence of the electron-poor
dipolarophiles 10 – 13 yielded, after filtration, the 6-substituted pteridinones 8a – 8d as
pure, poorly soluble products (Scheme 2). The isoxazole 7 could not be detected,
similarly to the dihydro-1,2-oxazines initially resulting from the Diels – Alder cyclo-
addition of N-dienoyl-amino(nitroso)pyrimidines [18]. The elimination transforming 7
into the products removes two stereogenic centers and thereby the information about
the endo/exo selectivity. The regioselectivity of the cycloaddition was predicted by
semiempirical calculations, as shown for methyl acrylate in Table 1.
The poor solubility of 8a – 8d in many common organic solvents caused significant
difficulties in separating product mixtures, and only dipolarophiles leading to single
products were considered useful. Reactions of other dipolarophiles, such as enamines,
enol ethers, alkenes, and alkynes, yielded complex mixtures and were not examined any
further.
The structure of the pteridine derivatives 8a – 8d follows unambiguously from their
spectroscopic data. The alcohols 8a and 8b, giving rise to very similar analytical data,
are characterised by OH ATR-IR bands at 3413 or 3411 cmꢀ1, HR-MALDI-MS, and a d
at 5.53 ppm (J ¼ 6.0 Hz) or a s at 5.29 ppm of the OH group that slowly exchanged with
D2O. The diastereotopic H of the CH2 group resonate at 3.03 and 2.88 ppm as two dd
(J ¼ 14.4, 6.3 and 14.4, 7.5 Hz, resp.) in 8a and as two d (J ¼ 14.4 Hz) at 3.09 and
2.93 ppm in 8b. The pteridinone 8a displays an additional q at 4.49 ppm (J ꢁ 6.3 Hz) for
HꢀC(2) and 8b a Me s at 1.31 ppm. The 13C signals (Table 2 in the Exper. Part) were
assigned by comparison to known data [15]. The 1H-NMR spectrum of 8c shows ss at
13.81 and 6.80 ppm, in keeping with a s at 155.02 ppm (C(2)) and a d at 97.66 ppm
(C(3)). Most probably, the enol 8c of the a-keto ester is the more stable tautomer, as
the OH group forms a strong H-bond to N(5), as reflected by a 1H-NMR OH signal at
13.81 ppm. The UV spectrum of 8c shows a maximum at 422 nm (log e 3.45) as
compared to lmax at 342 – 344 nm for 8a, 8b, and 8d, indicating an extended chromo-
phore of 8c. The constitution of 8d is established by a HR-MALDI-MS, and by ATR-
IR, UV, and NMR spectra. The (R*,R*) configuration of 8d is suggested by the
1
reaction mechanism, but could not be unambiguously derived from the H-NMR
spectrum in (D6)DMSO.
3
)
It is not clear if these N-oxides result from nucleophilic substitution of the Cl substituent by the NO
group and deprotonation, or by addition of an enol to the NO group and elimination. A relatively
facile enolisation of the formal acylamino group is suggested by the electrophilic nature of the
amide resulting from substitution of the formal amide N-atom by a pyrimidylnitroso moiety.

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Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 2
a) Dipolarophile, toluene, 1008. b) Me3SiCl, LiBr, MeCN.
The pteridinones 8a – 8d were debenzylated with in situ generated Me3SiBr to yield
93 – 95% of the pteridine-4,7(3H,8H)-diones 9a – 9d. Their structure was established by
their ATR-IR, and 13C- and 1H-NMR spectra (disappearance of the Bn and appearance
of an additional NH signal between 10.96 and 11.36 ppm) and by the similarity of the
UV spectra to those of 8a – 8d. The very poor solubility of 9a – 9d resulted in a HR-
MALDI-MS [M þ H]þ peak of low intensity relative to the matrix signals.

Helvetica Chimica Acta – Vol. 91 (2008)
1883
Table 1. LUMO and HOMO Energies and Orbital Coefficients of 4 and 10 Obtained from AM1
Calculations [19]
E [eV]
pZ Coefficientsa)
C(1) N(2)
0.326
ꢀ 0.670
O(3)
C(4)
C(5)
4
LUMO
HOMO
LUMO
HOMO
ꢀ 1.032
ꢀ 9.285
ꢀ 0.014
ꢀ 11.073
ꢀ 0.332
0.264
0.366
ꢀ 0.1591
10
0.483
0.680
ꢀ 0.658
0.649
a) Figures in italics refer to favourable HOMO – LUMO interactions.
This transformation of the 2,6-diamino-4-(benzyloxy)-5-nitrosopyrimidine (1)
provides a facile access to a variety 6-substituted pteridines.
We thank Novartis AG, Basel, for a fellowship, the ETH-Zürich for financial support, and Dr. Bruno
Bernet for checking the analytical 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
.
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.
N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-2-chloroacetamide (2). A soln. of 1 (490 mg,
2 mmol) in THF (20 ml) was treated at 08 with a soln. of chloroacetic anhydride (410 mg, 2.4 mmol) in
THF (5 ml), stirred for 15 min at 08 and for 1 h at amb. temp., and diluted with Et2O (40 ml). The blue
precipitate was filtered off, and drying afforded 2 (606 mg, 94%). Blue powder. Rf (CH2Cl2/MeOH 9 :1)
0.58. M.p. > 1708 (dec.). UV (MeOH): 209 (4.28), 256 (4.01), 347 (4.31). IR (ATR): 3432m, 3289w,
3133m, 3100m, 2962w, 1723m, 1643m, 1585s, 1552s, 1497m, 1471s, 1451s, 1392m, 1322s, 1285s, 1212s, 1157s,
1080m, 1051s, 1029m, 943m, 914m, 872w, 850m, 832m, 800m, 762s, 722s, 696s, 627w, 619w. 1H-NMR
(300 MHz, (D6)DMSO): 12.42 (s, NH); 8.81 (s, NH2)); 7.36 – 7.56 (m, 5 arom. H); 5.63 (s, PhCH2); 4.85 (s,
CH2Cl). 13C-NMR (75 MHz, (D6)DMSO): 168.35 (s, C¼O); 163.24 (s, C(6)); 138.66 (s, C(4)); 135.5 (s);
128.50 (2d); 128.30 (2d); 127.66 (d); 68.60 (t, PhCH2); 46.38 (t, CH2Cl); signals of C(2’) and C(5’) not
visible due to coalescence. HR-MALDI-MS: 324.0664 (24, [M þ H]þ, C13H1337ClN5O3þ ; calc. 324.0671),
322.0696 (78, [M þ H]þ, C13H1335ClN5Oþ3 ; calc. 322.0701), 293.0617 (24, [M ꢀ NO]þ, C13H1237ClN4Oþ2 ;
calc. 293.0614), 291.0632 (100, [M ꢀ NO]þ, C13H1235ClN4O2þ ; calc. 291.7124).
2-Amino-6-(benzyloxy)-8-(chloromethyl)-9H-purine (3). A suspension of 2 (320 mg, 1.0 mmol) in
o-xylene was treated with Me3P (1m in THF, 2.2 ml, 2.2 mmol), and stirred for 2 h at 238. The colourless
precipitate was filtered off (washing with toluene and Et2O), and dried to afford 3 (178 mg, 62%). Pale
yellow powder. Rf (CH2Cl2/MeOH 9 :1) 0.42. IR (ATR): 3472w, 3316w, 3176w, 2953w, 2926w, 1727w,

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Helvetica Chimica Acta – Vol. 91 (2008)
1622s, 1579s, 1526m, 1469m, 1454m, 1398s, 1350s, 1330m, 1265s, 1154m, 1083m, 992m, 944w, 910w, 844w,
1
790w, 736m, 695m, 641w. H-NMR (300 MHz, (D6)DMSO): 12.77 (s, HꢀN(9)); 7.50 – 7.29 (m, 5 arom.
H); 6.47 (s, NH2); 5.48 (s, PhCH2); 4.75 (s, CH2Cl). 13C-NMR (100 MHz, (D6)DMSO): 159.68 (br. s,
C(2)); 159.55 (s, C(6)); 156.27 (br. s, C(4)); 145.80 (br. s, C(8)); 136.52 (s); 128.35 (2d); 128.33 (2d);
127.99 (d); 112.86 (br. s, C(5)); 66.90 (t, PhCH2); 38.52 (t, CH2Cl). HR-MALDI-MS: 292.0779 (28, [M þ
H]þ, C13H1337ClN5Oþ; calc. 292.0774), 290.0806 (100, [M þ H]þ, C13H1335ClN5Oþ; calc. 290.0803).
2-Amino-4-(benzyloxy)-pteridin-7(8H)-one 5-Oxide (4). A soln. of 2 (642 mg, 2.0 mmol) in DMSO
(10 ml) was stirred at 238 for 16 h and diluted with H2O (15 ml). The pale precipitate was filtered off,
suspended in iPrOH (15 ml), heated to reflux for 10 min, cooled to 238, and filtered. Drying in vacuo gave
4 (556 mg, 98%). Colourless solid. M.p. 2908 (dec.). UV (MeOH): 211 (4.33), 265 (3.92), 355 (3.91). IR
(ATR): 3295w, 3113w, 2774w, 1661s, 1612s, 1574s, 1574s, 1521s, 1497m, 1437m, 1399m, 1381s, 1348s,
1308m, 1279m, 1239m, 1193m, 1173m, 1111m, 1007m, 957m, 888m, 788s, 764w, 749w, 730m, 692m, 682w,
659m, 630w. 1H-NMR (300 MHz, (D6)DMSO): 12.34 (s, HꢀN(8)); 7.26 – 7.53 (m, 5 arom. H, NH2,
HꢀC(6)); 5.46 (s, PhCH2). 13C-NMR (75 MHz, (D6)DMSO): see Table 2; additionally, 136.11 (s); 128.28
(2d); 127.79 (d); 127.67 (2d); 67.81 (t, PhCH2). HR-MALDI-MS: 308.0747 (71, [M þ Na]þ,
C13H11N5NaOþ3 ; calc. 308.0754), 286.0929 (100, [M þ H]þ, C13H12N5Oþ3 ; calc. 286.0935).
Table 2. Selected 13C-NMR Chemical Shifts [ppm] of the Pteridin-7(8H)-ones 4, 6, 8a – 8d and the
Pteridine-4,7(3H,8H)-diones 9a – 9d in (D6)DMSO
4
68a
8b
8c
C(2’)
C(4’)
C(4a’)
C(6’)
C(7’)
C(8a’)
C(1), C(4)
C(2)
160.94
160.70
161.81
107.48
129.11
155.45
152.28
–
161.23
164.32
106.97
149.64
157.13
151.28
173.60
68.19
161.28
164.29
106.92
149.66
157.43
151.07
175.11
73.80
161.19
162.17
103.95
147.62
156.73
150.61
162.89
155.01
97.66
161.66
107.50
125.31
157.79
153.61
–
–
–
–
–
C(3)
37.33
41.39
8da)
9a
9b
9c
9da)
C(2’)
C(4’)
C(4a’)
C(6’)
C(7’)
C(8a’)
C(1), C(4)
C(2)
161.55
158.58
154.60
110.26
147.64
157.12
150.88
173.81
68.18
158.43
154.76
110.25
147.68
157.45
150.71
175.18
73.92
157.05
154.57
106.80
145.51
156.69
149.93
163.13
155.15
97.10
158.52
154.94
110.41
145.77
156.72
151.27
171.66, 169.20
69.30
51.30
164.52
107.05
147.62
156.70
151.46
171.51, 168.97
69.05
52.25
C(3)
37.32
41.49
a) Numbering according to Scheme 2.
2-Amino-4-(benzyloxy)-6-phenylpteridin-7(8H)-one 5-Oxide (6). A soln. of 1 (245 mg, 1.0 mmol) in
THF (10 ml) was cooled to 08, treated with 2-chloro-2-phenylacetyl chloride (174 ml, 1.2 mmol), and
stirred for 1 h at 08 and 2 h at 238. The white precipitate was repeatedly filtered off (washing with CH2Cl2/
MeOH 9 :1). Drying i. v. gave 6 (242 mg, 68%). Colourless solid. M.p. 2858. UV (MeOH): 209 (4.25), 247
(3.98), 270 (3.93), 367 (3.96). IR (ATR): 3492w, 3283w, 3117w, 2900w, 2798w, 1635s, 1614s, 1575s, 1518m,
1496m, 1479m, 1430m, 1395m, 1354s, 1309m, 1281w, 1261m, 1206m, 1177w, 1163m, 1100w, 1014w, 981m,
870m, 785m, 765w, 733m, 719m, 692m, 650w. 1H-NMR (300 MHz, (D6)DMSO): 12.44 (s, HꢀN(8));
7.52 – 7.33 (m, 10 arom. H, NH2); 5.45 (s, PhCH2). 13C-NMR (75 MHz, (D6)DMSO): see Table 2;

Helvetica Chimica Acta – Vol. 91 (2008)
1885
additionally, 136.09, 135.19 (2s); 130.47 – 127.35 (several d); 67.94 (t, PhCH2). HR-MALDI-MS: 384.1072
(30, [M þ Na]þ, C19H15N5NaO3þ ; calc. 384.1067), 362.1248 (100, [M þ H]þ, C19H16N5Oþ3 ; calc. 362.1248).
Anal. calc. for C19H15N5O3 · 0.167 CH2Cl2 (361.36): C 61.30, H 4.12, N 18.65; found: C 61.30, H 4.28, N
18.65.
Methyl 3-[2-Amino-4-(benzyloxy)-7,8-dihydro-7-oxopteridin-6-yl]-2-hydroxypropanoate (8a). A
suspension of 6 (300 mg, 1.05 mmol) in methyl prop-2-enoate (1 ml, 11.1 mmol) and toluene (2 ml)
was stirred for 5 h at 1008, and filtered (washing with pentane). Drying i. v. gave 8a (370 mg, 95%).
M.p. > 2608. UV (MeOH): 211 (4.48), 228 sh (4.15), 285 (3.79), 344 (4.25). IR (ATR): 3413m, 3329w,
3208m, 2899w, 2833w, 2766w, 1745m, 1666m, 1610s, 1571s, 1555s, 1499s, 1469m, 1431s, 1386s, 1356s,
1309m, 1262m, 1183s, 1147m, 1093s, 1057s, 1022m, 987m, 920m, 837w, 822w, 799m, 733m, 718m, 693m,
1
634w, 611w. H-NMR (300 MHz, (D6)DMSO): 12.36 (s, HꢀN(8’)); 7.52 – 7.35 (m, 5 arom. H); 7.13 (s,
NH2); 5.53 (d, J ¼ 6.0, OH); 5.46 (s, PhCH2); 4.49 (q, J ꢁ 6.3, HꢀC(2)); 3.52 (s, MeO); 3.03 (dd, J ¼ 14.4,
6.3, HaꢀC(3)); 2.88 (dd, J ¼ 14.1, 7.5, HbꢀC(3)). 13C-NMR (75 MHz, (D6)DMSO): see Table 2;
additionally, 136.30 (s); 128.53 (2d); 128.38 (d); 128.08 (2d); 67.38 (t, PhCH2); 51.27 (q, MeO). HR-MS-
MALDI: 394.1116 (100, [M þ Na]þ, C17H17N5NaO5þ ; calc. 394.1122).
Methyl 3-[2-Amino-4-(benzyloxy)-7,8-dihydro-7-oxopteridin-6-yl]-2-hydroxy-2-methyl-3-propa-
noate (8b). A suspension of 6 (300 mg, 1.05 mmol) in methyl 2-methylprop-2-enoate (1 ml, 9.3 mmol)
and toluene (10 ml) was stirred for 5 h at 1008 and filtered (washing with pentane). Drying in vacuo gave
8a (384 mg, 95%). M.p. > 2608 (dec). UV (MeOH): 211 (4.31), 228 (4.13), 284 (3.78), 345 (4.21). IR
(ATR): 3411w, 3307w, 3191m, 3006w, 2936w, 2839w, 2770w, 1714m, 1689m, 1671m, 1643s, 1627s, 1577s,
1564s, 1518m, 1498s, 1443s, 1407s, 1384s, 1348s, 1305s, 1232m, 1196s, 1147s, 1112s, 1059s, 1009m, 985m,
954m, 898m, 824m, 793s, 729s, 692s, 657m, 633s. 1H-NMR (300 MHz, (D6)DMSO): 12.32 (s, HꢀN(8’));
7.50 – 7.40 (m, 5 arom. H); 7.12 (s, NH2); 5.44 (s, PhCH2); 5.29 (s, OH); 3.42 (s, MeO); 3.09, 2.93 (2d, J ¼
14.4, 2 HꢀC(3)); 1.31 (s, MeꢀC(2)). 13C-NMR (75 MHz, (D6)DMSO): see Table 2; additionally, 136.24
(s); 128.42 (2d); 128.32 (2d); 127.66 (d); 67.43 (t, PhCH2); 51.38 (q, MeO); 26.09 (q, MeꢀC(2)). HR-
MALDI-MS: 408.1274 (100, [M þ Na]þ, C18H19N5NaOþ5 ; calc. 408.1278), 386.1447 (94, [M þ H]þ,
C18H20N5Oþ5 ; calc. 386.1447).
Methyl (Z)-3-[2-Amino-4-(benzyloxy)-7,8-dihydro-7-oxopteridin-6-yl]-2-hydroxyprop-2-enoate
(8c). A suspension of 6 (300 mg, 1.05 mmol) in methyl prop-2-ynoate (1.0 ml, 11 mmol) and toluene
(10 ml) was heated to 1008 for 10 h, cooled to r.t., and filtered (washing with pentane). Drying i. v. gave
8c (359 mg, 93%). M.p. > 2008 (dec.). UV (MeOH): 209 (4.41), 230 sh (4.10), 293 (3.84), 328 (3.94), 405
(3.48), 422 (3.45). IR (ATR): 3329m, 3191m, 2953m, 2843m, 2764m, 1659s, 1614s, 1563s, 1528s, 1498s,
1471s, 1438s, 1396s, 1348s, 1283s, 1253s, 1176m, 1087m, 1065m, 1015m, 948w, 909w, 846w, 783w, 768w,
732w, 695m, 641w. 1H-NMR (300 MHz, (D6)DMSO): 13.81 (s, OH); 12.67 (s, HꢀN(8)); 7.52 – 7.34 (m, 5
arom. H, NH2); 6.80 (s, HꢀC(3)); 5.50 (s, PhCH2); 3.78 (s, MeO). 13C-NMR (75 MHz, (D6)DMSO): see
Table 2; additionally, 136.04 (s); 128.49 (2d); 128.15 (d); 127.95 (2d); 67.77 (t, PhCH2); 52.39 (q, MeO).
HR-MALDI-MS: 392.0983 (51, [M þ Na]þ, C17H15N5NaOþ5 ; calc. 392.0965), 370.1152 (100, [M þ H]þ,
C17H16N5Oþ5 ; calc. 370.1146).
Diethyl (2R*,3R*)-2-[2-Amino-4-(benzyloxy)-7,8-dihydro-7-oxopteridin-6-yl]-3-hydroxybutane-
dioate (8d). A suspension of 6 (300 mg, 1.05 mmol) in diethyl (E)-but-2-enedioate (1.0 ml, 6.0 mmol)
and toluene (10 ml) was heated to 1008 for 10 h, cooled to r.t., and filtered (washing with pentane).
Drying i.v. gave 8d (465 mg, 97%). M.p. 1908 (dec). UV (MeOH): 213 (4.42), 226 (4.42), 262 (3.79), 274
(3.75), 342 (4.25). IR (ATR): 3330w, 3209m, 2981w, 2934w, 2904w, 2835w, 2734w, 1732s, 1670s, 1626s,
1552s, 1498s, 1469m, 1395m, 1355s, 1326m, 1306m, 1271m, 1202s, 1183s, 1153s, 1089m, 1063s, 1022s, 990m,
1
970m, 928m, 869m, 832m, 799m, 731s, 693s, 653m, 624m. H-NMR (300 MHz, (D6)DMSO): 12.53 (s,
HꢀN(8)); 7.53 – 7.35 (m, 5 arom. H); 7.26 (s, NH2); 5.85 (d, J ¼ 6.9, OH); 5.48 (s, PhCH2); 4.68 (dd, J ¼
9.0, 6.9, HꢀC(3)); 4.22 (d, J ¼ 9.0, HꢀC(2)); 4.10 – 3.98 (m, 2 MeCH2O); 1.15 (t, J ¼ 7.1, Me); 1.06 (t, J ¼
6.9, Me). 13C-NMR (75 MHz, (D6)DMSO): see Table 2; additionally, 136.18 (s); 128.47 (2d); 128.37 (2d);
128.10 (d); 67.50 (t, PhCH2); 60.46, 60.23 (2t, 2 MeCH2O); 13.83, 13.77 (2q, 2 Me). HR-ESI-MS: 480.1489
(100, [M þ Na]þ, C21H24N5NaOþ7 ; calc. 480.1490).
Methyl 3-(2-Amino-3,4,7,8-tetrahydro-4,7-dioxopteridin-6-yl)-2-hydroxypropanoate (9a). A suspen-
sion of 8a (100 mg, 0.27 mmol) and LiBr (59 mg, 0.67 mmol) in MeCN (5 ml) was cooled to 08, treated
with Me3SiCl (104 ml, 0.81 mmol), and stirred for 10 min at 08 and for 20 h at amb. temp. The suspension

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Helvetica Chimica Acta – Vol. 91 (2008)
was diluted with MeOH (3 ml), stirred for 15 min, filtered (washing with MeOH and pentane). Drying in
vacuo gave 9a (71 mg, 93%). M.p. > 2008 (dec). UV (MeOH): 214 (4.30), 292 (3.87), 340 (3.99). IR
(ATR): 3314w, 3131m, 2844m, 2760m, 1731w, 1627s, 1567s, 1479m, 1439m, 1390m, 1265m, 1230m, 1202m,
1
1153w, 1087m, 1064m, 1033m, 889w, 851w, 789w, 712w, 667m, 609w. H-NMR (300 MHz, (D6)DMSO):
12.28 (s, HꢀN(8’)); 10.96 (s, HꢀN(3’)); 6.99 (s, NH2); 6 – 5 (br. s, OH); 4.53 (dd, J ¼ 6.0, 7.5, HꢀC(2));
3.60 (s, MeO); 2.96 (dd, J ¼ 13.8, 6.3, HaꢀC(3)); 2.87 (dd, J ¼ 14.1, 7.8, HbꢀC(3)). 13C-NMR (75 MHz,
(D6)DMSO): see Table 2; additionally, 51.36 (q, MeO). HR-MS-MALDI: 304.0652 (89, [M þ Na]þ,
C10H11N5NaOþ5 ; calc. 304.0653 ), 288.0917 (100, [M þ Li]þ, C10H11LiN5Oþ5 ; calc. 288.0915).
Methyl 3-(2-Amino-3,4,7,8-tetrahydro-4,7-dioxopteridin-6-yl)-2-hydroxy-2-methylpropanoate (9b).
A suspension of 8b (130 mg, 0.34 mmol) and LiBr (73 mg, 0.84 mmol) in MeCN (5 ml) was cooled to
08, treated with Me3SiCl (129 ml, 1.01 mmol), and stirred for 10 min at 08 and for 19 h at 238. The
suspension was diluted with MeOH (3 ml), stirred for 15 min, and filtered (washing with MeOH and
pentane). Drying in vacuo gave 9b (94 mg, 95%). UV (MeOH): 215 (4.33), 230 sh (3.98), 292 (3.91), 342
(4.05). IR (ATR): 3323w, 3155w, 2845w, 2771w, 1708m, 1680m, 1631s, 1602s, 1562s, 1475m, 1454m, 1393m,
1373m, 1313m, 1282w, 1225m, 1179m, 1114m, 957w, 900w, 863w, 821w, 791w, 704m, 679w, 639w, 610w.
1H-NMR (400 MHz, (D6)DMSO): 12.24 (s, HꢀN(8’)); 11.00 (s, HꢀN(3’)); 7.04 (br. s, NH2); 5.37 (br. s,
OH); 3.60 (s, MeO); 3.02, 2.95 (2d, J ¼ 14.1, 2 HꢀC(3)); 1.33 (s, Me). 13C-NMR (100 MHz, (D6)DMSO):
see Table 2; additionally, 51.60 (q, MeO); 25.88 (q, Me). HR-MS-MALDI: 318.0809 (87, [M þ Na]þ,
C11H13N5NaOþ5 ; calc. 318.0809), 302.1072 (63, [M þ Li]þ, C11H13LiN5O5þ ; calc. 302.1072), 296.0989 (100,
[M þ H]þ, C11H14N5Oþ5 ; calc. 296.0989).
Methyl 3-(2-Amino-3,4,7,8-tetrahydro-4,7-dioxopteridin-6-yl)-2-hydroxyprop-2-enoate (9c). A sus-
pension of 8c (100 mg, 0.26 mmol) and LiBr (56 mg, 0.67 mmol) in MeCN (5 ml) was cooled to 08,
treated with Me3SiCl (104 ml, 0.81 mmol), and stirred for 10 min at 08 and for 21 h at 238. The suspension
was diluted with MeOH (3 ml), stirred for 15 min, and filtered (washing with MeOH and pentane).
Drying in vacuo gave 9c (71 mg, 94%). UV (MeOH): 213 (4.11), 293 (3.53), 307 (3.52) 406 (3.71), 420
(3.70). IR (ATR): 3312m, 3135m, 2957m, 2846m, 2747m, 1637s, 1582s, 1546s, 1473m, 1435m, 1381s, 1275s,
1
1247s, 1178s, 1105m, 1023w, 975m, 936w, 874w, 824w, 824w, 791w, 775m, 761m, 712w, 680m. H-NMR
(300 MHz, (D6)DMSO): 13.82 (br. s, OH); 11.61 (s, HꢀN(8’)); 11.36 (s, HꢀN(3’)); 7.19 (br. s, NH2); 6.75
(s, H-C(3)); 3.79 (s, MeO). 13C-NMR (75 MHz, (D6)DMSO): see Table 2; additionally, 52.29 (q, MeO).
HR-MS-MALDI: 280.0609 (30, [M þ H]þ, C10H10N5O5þ ; calc. 280.0672).
Diethyl (2R*,3R*)-2-(2-Amino-3,4,7,8-tetrahydro-4,7-dioxopteridin-6-yl)-3-hydroxybutanedioate
(9d). A suspension of 8d (100 mg, 0.22 mmol) and LiBr (48 mg, 0.55 mmol) in MeCN (5 ml) was
cooled to 08, treated with Me3SiCl (84 ml, 0.66 mmol), and stirred for 10 min at 08 and for 20 h at 238. The
suspension was diluted with MeOH (3 ml), and filtered (washing with MeOH and pentane). Drying in
vacuo gave 9d (75 mg, 93%). M.p. > 2708 (dec.). UV (MeOH): 214 (4.23), 292 (3.77), 340 (3.89). IR
(ATR): 3433w, 3318w, 3147w, 2984w, 2876m, 2757m, 1738m, 1629s, 1572s, 1538m, 1475w, 1391m, 1370m,
1340w, 1303w, 1278m, 1255m, 1228w, 1201m, 1182m, 1164m, 1114w, 1094w, 1048m, 1020m, 967w, 882m,
852m, 817w, 777w, 734w, 704w, 675m, 650w, 612w. 1H-NMR (300 MHz, (D6)DMSO): 12.43 (s, HꢀN(8’));
11.04 (s, HꢀN(3’)); 7.07 (br. s, NH2); 5.86 (br. s, OH); 4.66 (d, J ¼ 9.3, HꢀC(3)); 4.27 (d, J ¼ 9.3,
HꢀC(2)); 4.09, 4.03 (2q, J ¼ 6.9, 2 MeCH2O); 1.18, 1.08 (2t, J ¼ 7.2, 2 Me). 13C-NMR (75 MHz,
(D6)DMSO): see Table 2; additionally, 60.43, 60.23 (2t, 2 MeCH2O); 13.87, 13.83 (2q, 2 Me). HR-
MALDI-MS: 390.1019 (100, [M þ Na]þ, C14H17N5NaO7þ ; calc. 390.1020), 374.1283 (66, [M þ Li]þ,
C14H17LiN5Oþ7 ; calc. 374.1283).
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Received July 8, 2008