A new synthesis of pteridines substituted with branched and linear alkenyl groups at C(6). The nitroso-ene reaction of 4-(alkenoylamino)-5- nitrosopyrimidines

Article abstract of DOI:10.1002/hlca.200790054

Pteridines substituted with a 1,1-, 1,2-, or 1,1,3-substituted alkenyl group (mostly (is)-configured) at C(6) were synthesized in high yields by the intramolecular nitroso-ene reaction of 4-(alkenoylamino)-2-amino-6-benzyloxy-5- nitroso- and 4-(alkenoylamino)-2,6-diamino-5-nitrosopyrimidines. Thus, the N-alkenoyl nitrosopyrimidines 4 and 5 provided the pteridines 6 and 7, respectively, characterized by a 1,2-disubstituted (E)-alkenyl substituent, the C(4)-(E)-geranoyl amide 13 led regio- and stereoselectively to the (E)-1,1,2-trisubstituted alkenyl-pteridine 16, and the C(4)-(Z) isomer 14 led to 17 possessing a 1,1-disubstituted alkenyl group. The trifluoromethylated butenoyl amide 15 possessing a less highly nucleophilic alkenoyl group reacted more slowly to give the trifluoromethylated vinylpteridine 18. Also the 4-(alkenoylamino)-2,6-diamino-5-nitrosopyrimidine 20 reacted more slowly than 4 and 5, and provided the pteridines 23; introduction of additional N-acyl groups as in 21 and 22 led to a considerably faster ene reaction. The X-ray crystal structure analysis of the nitroso amide 15 shows eight symmetrically independent molecules in the unit cell. In the crystalline state, the N,N- dimethylformamidine derivative 9 of 6 forms a centrosymmetric dimer with the 7,8-lactam group connected by intermolecular hydrogen bonds.

Full text of DOI:10.1002/hlca.200790054

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A New Synthesis of Pteridines Substituted with Branched and Linear Alkenyl
Groups at C(6). The Nitroso-Ene Reaction of 4-(Alkenoylamino)-5-
nitrosopyrimidines
by Fang-Li Zhang, W. Bernd Schweizer, Ming Xu, and Andrea Vasella*
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH Zürich, HCI, CH-8093 Zürich
Pteridines substituted with a 1,1-, 1,2-, or 1,1,3-substituted alkenyl group (mostly (E)-configured) at
C(6) were synthesized in high yields by the intramolecular nitroso-ene reaction of 4-(alkenoylamino)-2-
amino-6-benzyloxy-5-nitroso- and 4-(alkenoylamino)-2,6-diamino-5-nitrosopyrimidines. Thus, the N-
alkenoyl nitrosopyrimidines 4 and 5 provided the pteridines 6 and 7, respectively, characterized by a 1,2-
disubstituted (E)-alkenyl substituent, the C(4)-(E)-geranoyl amide 13 led regio- and stereoselectively to
the (E)-1,1,2-trisubstituted alkenyl-pteridine 16, and the C(4)-(Z) isomer 14 led to 17 possessing a 1,1-
disubstituted alkenyl group. The trifluoromethylated butenoyl amide 15 possessing a less highly
nucleophilic alkenoyl group reacted more slowly to give the trifluoromethylated vinylpteridine 18. Also
the 4-(alkenoylamino)-2,6-diamino-5-nitrosopyrimidine 20 reacted more slowly than 4 and 5, and
provided the pteridines 23; introduction of additional N-acyl groups as in 21 and 22 led to a considerably
faster ene reaction.
The X-ray crystal structure analysis of the nitroso amide 15 shows eight symmetrically independent
molecules in the unit cell. In the crystalline state, the N,N-dimethylformamidine derivative 9 of 6 forms a
centrosymmetric dimer with the 7,8-lactam group connected by intermolecular hydrogen bonds.
Introduction. – The nitroso-ene reaction [1] is a valuable method for the regio- and
stereoselective introduction of allylic nitrogen substituents, notwithstanding the debate
about its precise reaction mechanism [2]. The most useful applications of the nitroso-
ene reaction involve electron-deficient nitroso compounds, such as N-acylnitroso
derivatives [3], a-chloronitroso ethers [4], and 4-nitro-nitrosobenzene [5]. To the best
of our knowledge, nitroso-ene reactions of pyrimidines are not known, while Wanner
and Koomen [6] used the ene reaction of 2-nitrosoadenosine triacetate with cyclo-
hexene to demonstrate that the nitroso-ene reaction might be involved in the direct
damage of DNA.
We have recently described a new method for the synthesis of pteridines substituted
with a (Z)-3-hydroxyalk-1-enyl group at C(6), based on a high-yielding intramolecular
[4 þ 2] cycloaddition of N-(alka-2,4-dienoyl)-4-amino-5-nitrosopyrimidines [7]. In a
similar way, the intramolecular nitroso-ene reaction of N-(alk-2-enoyl)-4-amino-5-
nitrosopyrimidines should lead regioselectively to pteridines substituted with an
alkenyl group at C(6), with the structure of the alkenyl substituent depending on the
starting material and on the regioselectivity of the nitroso-ene reaction. We were
interested in exploring these reactions in view of the configurational complementarity
of the C(6)-1,2-disubstituted alkenyl substituents resulting from the ene reaction and
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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the [4 þ 2] cycloaddition, respectively, and considering the large number of naturally
occurring C(6)-substituted pteridines [8].
We planned to first evaluate the nitroso-ene reaction of unsaturated amides derived
from 2,4-diamino-6-(benzyloxy)-5-nitrosopyrimidine (1) [9] (Schemes 1 and 2) and of
2,4,6-triamino-5-nitrosopyrimidine (19) [10] (Scheme 3). The desired amides should be
obtained by acylation with (E)-pent-2-enoyl chloride (2), dec-2-enoyl chloride (3), the
acid chlorides 10 and 11 derived from (E)- and (Z)-geranic acid1), respectively, and
(E)-4,4,4-trifluoro-3-methylbut-2-enoyl chloride (12).
Results and Discussion. – The 4-(alkenoylamino)-5-nitrosopyrimidines 4 and 5
were obtained in a yield of 63 and 77%, respectively, by acylating a suspension of 1 in
THF with (E)-pent-2-enoyl chloride (2) and (E)-dec-2-enoyl chloride (3), respectively,
in the presence of K2CO3 (cf. [12]; Scheme 1). Purification of the amides by silica-gel
chromatography was accompanied by the progressive formation of one or several
polar, yellow, strongly blue-fluorescent products (ca. 10%), suggesting a facile ene
Scheme 1
a) 1.3 equiv. 2 or 3, 8 equiv. K2CO3, À 188, THF; 63% of 4, 77% of 5. b) Suspension in toluene, 11 mm,
1008, 3 h; ca. 98% of 6 or 7. c) 10% I2 in benzene, reflux; or 1% AcOH in toluene, reflux, 36 h; ca. 98%.
d) 1.5 equiv. Me SiCl, 1.3 equiv. LiBr, MeCN, 238; 90%. e) 1.1 equiv. t-BuOCH(NMe ) , DMF, 238; 95%
.
3
2 2
1
)
We thank Dr. Markus Gautschi, Givaudan AG, Dübendorf, for a generous gift of the two geranic
acids. For the combination of heterocycles with terpenes, see [11].

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reaction leading to pteridines. In keeping with this interpretation, the nitrosopyrimi-
dines 4 and 5 reacted already at room temperature, either in the solid state or in
solution, as judged by a slow progressive colour change from blue to yellow, and the
formation of a new spot on TLC. All acylated nitrosopyrimidines, therefore, had to be
stored at a temperature below 58.
On a preparative scale, suspensions of the blue nitrosopyrimidines 4 and 5 in
toluene went into solution upon heating to 1008, and were progressively transformed
into a yellow precipitate within ca. 3 h. Similarly to the facile cleavage of the N,O bond
in the primary products of the nitroso Diels – Alder reaction [7], a N,O bond cleavage of
the product of the ene reaction led in high yields to ca. 8 :2 (E/Z)-mixtures2) of the
pteridin-7(8H)-ones 6 and 7, respectively (Scheme 1). The pure (E/Z)-pteridinones 6
(from 4) and 7 (from 5) were obtained by filtration, followed by washing the solid with
H2O and Et2O. The structure of the products was confirmed by their spectroscopic data.
Thus, the constitution of (E/Z)-6 is evidenced by a high-resolution MALDI-MS, by IR
bands at 3359 and 3192 cmÀ1 (NH), a comparison of the UV spectra with those of
closely related pteridinones [7], by J(1’,2’) of the alkenyl H-atoms (15.6 Hz for (E)-6
and 12.3 Hz for (Z)-6; Table 1 in the Exper. Part), and by the 13C-NMR data (Table 2 in
the Exper. Part).
Treating a suspension of (E/Z)-6 in toluene with I2 [13] or with AcOH resulted in
the pure (E)-6 isomer that was debenzylated to the poorly soluble C(6)-(E)-prop-1-
enyl-isoxanthopterin 83) by treatment with Me3SiBr generated in situ (90%; Scheme 1).
As expected, the amidine 9 obtained by treating (E)-6 with Bredereckꢁs reagent [16]
proved much more soluble in a range of apolar solvents than 6 [17]. Crystals of 9
suitable for X-ray analysis4) were obtained by slowly concentrating a solution in
MeCN. The crystals were multiple twins with loosely bound MeCN, showing heavy and
uncorrectable overlapping of intensities reflected in a bad agreement factor (Fig. 1).
The (E)- and (Z)-geranylamides 13 and 14 and the (trifluoromethyl)butenoyla-
mide 15 were prepared similarly as 4 and 5 to explore the regioselectivity of this
nitroso-ene reaction and the effect of the nucleophilicity of the alkene (Scheme 2). The
required (E)- and (Z)-geranoyl chlorides, 10 and 11 were obtained from the
corresponding sodium salt and oxalyl chloride in the presence of pyridine5).
Beautifully blue, but poorly diffracting single crystals of 15 for X-ray analysis4)
were obtained by slow evaporation of a solution of 15 in CHCl3 (Fig. 2). The unit cell
2
)
The nitroso-ene reaction of 4 at room temperature led exclusively to the (E)-isomer, suggesting an
(E/Z) isomerisation at higher temperature. About 5% of 4 remained after two weeks.
For references about isoxanthopterin, see [14][15].
3
4
)
)
To the best of our knowledge, this is the first crystal structure of an isoxanthopterin derivative. The
crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-617876 for 9 and No. CCDC-617875 for 15. Copies of the data can be
obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ (fax:
þ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
1
5
)
The preparation of 10 from (E)-geranic acid and oxalyl chloride has been described, the H-NMR
data indicating a purity of 90% [18]. In our hands, this procedure led to substantial addition of HCl
to the dimethylethylene moiety of (E)- and (Z)-geranic acid. For the preparation of acid chlorides
from the corresponding sodium carboxylates, see [19][20].

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Fig. 1. Crystal structure of 9 · MeCN. a) ORTEP Drawing of a single molecule with co-crystallizing
MeCN (ellipsoids at the 50% level, Ph group disordered over two equally occupied positions). b)
Centrosymmetric H-bonded dimers (N ··· O 2.84 Š, H ··· O 1.99 Š). Only one position of the Ph group is
shown for clarity.
Scheme 2
a) 1.3 equiv. 10, 8 equiv. K2CO3, À 188, THF; 72% of 13. b) Soln. in CH2Cl2, 6 mm, 238, 4 d; ca. 98% of 16
or 17. c) 1.3 equiv. 11, 8 equiv. K2CO3, À 188, THF; 80% of 14. d) 1.3 equiv. 12, 8 equiv. K2CO3, À 188,
THF; 68% of 15. e) Suspension in toluene, 11 mm, 1508, 8 h in a sealed V-vial; ca. 98% of 18.

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525
parameters and the pattern of weak, but systematic reflections indicated a pseudosym-
metric arrangement of independent molecules in the crystal structure. The angles differ
by 3.98, 0.48, and 0.88 from 908 that would be required for crystallographic symmetry
¯
other than an inversion centre. The structure was solved in P1 with eight molecules in
the asymmetric unit. There are no crystallographic glide planes and translations
between the molecules, mainly differing significantly by the conformation of the Ph
ring. In all molecules, the C(4)-amido NÀH form intramolecular H-bonds to the C(5)-
nitroso O-atom (8 N ··· O distances in the range of 2.61 to 2.91 Š, H ··· O 1.78 to
1.95 Š). This is consistent with the unusual 1H-NMR chemical shift (12 – 13 ppm) of the
C(4)-amido NH group in 4, 5 and 13 – 15.
Fig. 2. Crystal structure of 15. ORTEP Drawing of a single molecule (ellipsoids at the 50% level).
The nitroso-amido groups of two molecules of 15 are related by a pseudo twofold
axis and in close contact (Fig. 3), with typical N¼O ··· N¼O distances around 2.8 Š.
No intermolecular H-bond is observed.
Fig. 3. Crystal structure of 15 showing the pseudosymmetric arrangement of eight independent molecules
in the unit cell. Note that the cell angle b is 89.68.

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The ene reactions of the (E)-configured geranoyl amide 13 led diastereoselectively
to the (E)-configured pteridinone 16. A similar regioselective H abstraction of the (Z)-
geranoyl amide 14 led to the pteridinone 17 characterized by a newly formed 1,1-
disubstituted alkenyl group (Scheme 2). Performing the ene reaction of 13 and 14
under the same conditions as the one of 4 and 5 resulted in some side-products that
were no longer formed at a lower temperature and concentration. As expected, the
strongly electron-withdrawing CF3 group of 15 led to a slower reaction. The much
higher temperature (1508) required for this ene reaction, did not, however, decrease the
yield of the resulting pteridinone 18.
1
The pteridinones 16 and 17 were easily distinguished by their H-NMR spectra.
Thus, 16 shows a triplet for HÀC(2’) and signals of three olefinically bound Me groups,
while 17 is characterized by two doublets for the exo-methylidene group CH2¼C(1’)
and the signals of two Me groups. The exo-methylidene group CH2¼C(1’) of the
pteridinone 18 resonates as a doublet and a broad singlet.
Considering the importance of 4-amino-pteridines [14], we also explored the
nitroso-ene reaction of amides derived from 2,4,6-triamino-5-nitrosopyrimidine (19;
Scheme 3), expecting a lower reactivity of the less electrophilic NO group. Mono-
Scheme 3
a) 2.5 equiv. 2, 8 equiv. K2CO3, À 188, DMF; 42% of 20 and 13% of 21. b) 3.5 equiv. 2, 10 equiv. K2CO3,
08, THF, crude 22. c) Suspension in toluene, 11 mm, 1008, 24 h; ca. 98% of 23. d) Suspension of 21 in
toluene, 11 mm, 1008, 3 h; ca. 98% of 24. e) Flash chromatography of crude 22 gave 25; 78% of 25 from
19.

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acylation of 19 to 20 proved difficult, and some 21 was always formed, even when the
(E)-pent-2-enoyl chloride (2) was slowly added using a syringe pump. The lowered
electrophilicity of the diamino-nitrosopyrimidine 20 resulted in a considerably longer
reaction time, viz. 24 h at 1008, as compared to 3 h at 1008 for 4 and 5. A second N-acyl
group, as in the 4,6-diacylated nitroso compound 21, increases the electrophilic
properties of the NO group sufficiently to perform the ene reaction under the same
conditions as for 4 and 5, leading to the pteridinones 24 in high yield (98%) as ca. 8 :2
(E/Z)-mixtures. The 2,4,6-triacylated nitrosopyrimidine 22 was formed when the
acylation was run at 08 and proved even more highly reactive; flash chromatography of
crude 22 at ambient temperature transformed most of the nitrosopyrimidine into the
(E)-configured C(6)-prop-1-enyl-pteridinone 25 that was isolated in a yield of 78%
after keeping the suspension of 22 and 25 overnight at ambient temperature.
The NMR spectra of the amino-nitroso amide 20 show two sets of signals in a 7:3
ratio, evidencing a mixture of two isomers, differing by the nature of their intra-
molecular H-bonds (Fig. 4). The major isomer is characterized by a NO ··· H2NÀC(6’)
H-bond and the minor one by a NO ··· HNÀC(4’) H-bond, suggesting the dominant
influence of the stronger conjugation between the NH2 and the NO group as compared
to the formally more pronounced H-bond donor ability of the amido group. A similar
observation was reported by Tumkevicius and co-workers [21]. The constitution of the
4-aminopteridinone 23 is evidenced by a high-resolution MALDI-MS, by broad NH
bands at 3330 and 3213 cmÀ1 in the ATR-IR spectra, a comparison of the UV spectra
with those of closely related pteridinones [22], by J(1’,2’) of the alkenyl H-atoms (15.8
Hz for (E)-23 and 11.7 Hz for (Z)-23), and by the 13C-NMR data (Table 2 in the Exper.
Part).
Fig. 4. Two H-bonded isomers of 20 and the relevant chemical shift values [ppm] of their NH groups in
(D6)DMSO
The conjugative interaction between either the N-acylamino or NH2, and the NO
substituents, and the ensuing intramolecular H-bonds also explains the observation that
the C(2) and/or C(5) signals in the 13C-NMR spectra of the nitroso amides 4, 5, and 13 –
156) were either missing, or, at best, very weak and broad in the spectra registered at
6
)
The expected weak concentration dependence of the chemical shift of C(4)ÀNH group involved in
an intramolecular H-bond, and the moderate dependence of the chemical shift of the C(2)ÀNH2
group involved in an intermolecular H-bond was confirmed for the 1H-NMR spectra (CDCl3) of the
nitroso amide 5.

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room temperature, but visible at À 308. This observation is rationalized by a hindered
rotation about the C(2)ÀNH2 and C(5)ÀNO bonds due to a vinylogous amide-like
interaction of the NH2 and NO groups. All 13C-NMR signals of the diamines 1 [12] and
20 are visible in the spectra obtained at room temperature. The conjugative interaction
between the NO and the ortho-amino group leads to a particularly favourable
intramolecularly H-bonded species.
We thank the ETH Zürich and F. Hoffmann-La Roche AG, Basel, for generous support, and Dr.
Bruno Bernet for checking the analytical data.
Experimental Part
General. See [23]. Flash chromatography (FC): Merck silica gel 60 (0.063 – 0.200 mm). UV Spectra:
MeOH, lmax (log e). FT-IR Spectra: neat (ATR), absorption in cmÀ1. HR-MALDI-MS: in 3-
hydroxypicolinic acid (3-HPA) matrix.
(E)-Pent-2-enoyl Chloride (2) and (E)-Dec-2-enoyl Chloride (3). Oxalyl chloride (21.2 ml, 0.25 mol)
was added dropwise to a soln. of the corresponding acid (0.1 mol) in toluene (40 ml) at 08. The resulting
soln. was allowed to warm to r.t. and stirred for 5 h. Distillation of the residue afforded 8.9 g (74%) of 2
(658/25 Torr) or 16.0 g (85%) of 3 (888/0.3 Torr).
(E)- and (Z)-Geranoyl Chlorides (10 and 11, resp.). An emulsion of (E)- or (Z)-geranic acid in a 5%
excess of 0.2n NaOH was stirred for 10 min at r.t, the resulting soln. was evaporated (458/15 Torr) to
dryness. The resulting off-white powder was then dried at 0.1 Torr (12 h at 408, then 2 h at 1058). A
suspension of the sodium salt of (E)- or (Z)-geranic acid (0.78 g, 4.0 mmol) in toluene (20 ml) was
treated with pyridine (49 ml, 0.6 mmol), cooled to ca. À 58, and treated dropwise with oxalyl chloride
(0.8 ml, 9.2 mmol) within 0.5 h. The ice-bath was removed, and stirring was continued for 20 min. After
filtration, the filtrate was evaporated (<208/0.5 Torr), affording 10 (0.65 g, 87%) or 11 (0.6 g, 80%).
Data of 10. 1H-NMR (300 MHz, CDCl3): 6.05 (s, HÀC(2)); 5.07 (br. t, J ¼ 5.7, HÀC(6)); 2.24 (br. s, 2
HÀC(4), 2 HÀC(5)); 2.16 (s, MeÀC(3)); 1.73, 1.64 (2s, Me2C).
Data of 11. 1H-NMR (300 MHz, CDCl3): 6.03 (s, HÀC(2)); 5.10 (br. t, J ¼ 7.2, HÀC(6)); 2.56 (t, J ꢀ
7.8, 2 HÀC(4)); 2.16 (q, J ꢀ 7.5, 2 HÀC(5)); 1.97 (s, MeÀC(3)); 1.70, 1.62 (2s, Me2C).
(E)-4,4,4-Trifluoro-3-methylbut-2-enoyl Chloride (12). A mixture of the corresponding acid (4.6 g,
30 mmol) and SOCl2 (3.3 ml, 45 mmol) was refluxed for 3 d. Distillation (1108/760 Torr) afforded 3.2 g
(63%) of 12.
General Procedure for the Preparation of the Amides 4, 5, and 13 – 15. A suspension of 1 (368 mg,
1.5 mmol) in THF (60 ml) was treated with K2CO3 (1.7 g, 12 mmol), cooled to À 188, and treated with a
soln. of the acyl chloride (1.75 mmol) in THF (5 ml) within 2 h (addition via a syringe pump), stirred for
0.5 h, diluted with CH2Cl2 (100 ml), washed with cold H2O (2 Â 50 ml) and brine (50 ml), dried
(MgSO4), and evaporated. FC (CH2Cl2/MeOH 200 :1 or 100 :1) of the green residue gave 4 (309 mg,
63%), 5 (460 mg, 77%), 13 (427 mg, 72%), 14 (474 mg, 80%), 15 (389 mg, 68%), resp., each as a blue
powder.
Data of (E)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]pent-2-enamide (4)7). UV: 204
(4.33), 263 (4.06), 351 (4.22), 650 (2.04, of a 10À3 m soln.). IR (ATR): 3372m, 3064w, 2930w, 2872w,
1708m, 1640s, 1601s, 1533s, 1498m, 1485m, 1461s, 1442s, 1386m, 1347s, 1310m, 1276s, 1248m, 1213s, 1167s,
1
1144m, 1112s, 1093s, 1031m, 977w, 901w, 865w, 834m. H-NMR (300 MHz, CDCl3): 12.80 (br. s, NH);
7.53 – 7.32 (m, 5 arom. H); 7.17 (dt, J ¼ 15.0, 6.0, HÀC(3)); 6.88, 5.95 (2 br. s, NH2); 6.09 (dt, J ¼ 15.0, 1.5,
HÀC(2)); 5.70 (s, PhCH2); 2.38 – 2.28 (m, 2 HÀC(4)); 1.14 (t, J ¼ 7.5, Me). 13C-NMR (75 MHz, CDCl3,
298 K): 165.01 (s, C¼O); 164.21 (s, C(6’)); 151.46 (d, C(3)); 145.36 (br. weak s, C(2’)); 139.08 (s, C(4’));
135.13 (s); 128.52 (2d); 128.37 (d); 128.19 (2d); 123.54 (d, C(2)); 69.57 (t, PhCH2); 25.66 (t, C(4)); 12.19
7
)
The pteridinones 6, 7, 16 – 18, and 23 – 25 show a range of decomposition temperatures between ca.
250 and 3008, whereas the nitroso compounds 4, 5, 13, 14, 20, and 21 undergo the ene reaction, with
the exception of 15.

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(q, Me); signal of C(5’) not visibile due to coalescence. HR-MALDI-MS: 328.1404 (5, [M þ H]þ,
C16H18N5Oþ3 ; calc. 328.1404), 350.1218 (17, [M þ Na]þ, C16H17N5NaO3þ ; calc. 350.1224); low intensity of
desired peaks due to the occurence of ene reaction during measurement.
Data of (E)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]dec-2-enamide (5). UV: 208 (4.34),
263 (4.16), 352 (4.32), 648 (1.28, of a 10À3 m soln.). IR (ATR): 3329w, 3208w, 3164w, 2953w, 2924m,
2854m, 1721m, 1654m, 1639s, 1593s, 1581s, 1522s, 1497m, 1451s, 1390m, 1344s, 1286m, 1259m, 1212s,
1151s, 1112s, 1064s, 1030m, 976m, 915w, 846w. 1H-NMR (300 MHz, CDCl3): 12.96 (br. s, NH); 7.76 (br. d,
J ¼ 5.4, NH); 7.52 – 7.25 (m, 5 arom. H); 7.09 (dt, J ¼ 15.3, 6.9, HÀC(3)); 6.34 (br. d, J ¼ 3.6, NH); 6.05
(br. d, J ¼ 15.6, HÀC(2)); 5.66 (s, PhCH2); 2.30 – 2.10 (m, 2 HÀC(4)); 1.52 – 1.29 (m, 5 CH2); 0.91 – 0.86
(m, Me). 1H-NMR titration (300 MHz, CDCl3): 7.61, 6.35 (25 mm), 7.91, 6.49 (10 mm), 7.71, 6.32 (5 mm)
for C(2)ÀNH2; 12.91 (25 mm), 12.89 (10 mm), 12.85 (5 mm), 12.81 (1 mm) for C(4)ÀNH. 13C-NMR
(75 MHz, CDCl3, 298 K): 165.08 (s, C¼O); 164.31 (s, C(6’)); 150.54 (d, C(3)); 139.03 (s, C(4’)); 135.18
(s); 128.52 (2d); 128.37 (d); 128.25 (2d); 124.34 (d, C(2)); 69.42 (t, PhCH2); 32.39, 31.62, 29.06, 28.95,
27.86, 22.53 (6t); 13.99 (q, Me); signals of C(2’) and C(5’) not visibile due to coalescence. 13C-NMR
(75 MHz, CDCl3, 243 K): 171.04 (s, C(5’)); 165.39 (s, C¼O); 164.01 (s, C(6’)); 151.59 (d, C(3)); 145.78 (s,
C(2’)); 138.71 (s, C(4’)); 134.86 (s); 128.70 (5d, 5 C of Ph); 123.95 (d, C(2)); 69.84 (t, PhCH2), 32.84 (t);
32.01 (t); 29.44 (2t); 27.97 (t); 23.00 (t); 14.61 (q, Me). HR-MALDI-MS: 398.2180 (84, [M þ H]þ,
C21H28N5Oþ3 ; calc. 398.2187), 420.1995 (8, [M þ Na]þ, C21H27N5NaOþ3 ; calc. 420.2006).
Data of (E)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-3,7-dimethylocta-2,6-dienamide
(13). UV: 202 (4.21), 233 (4.11), 264 (4.19), 350 (4.36). IR (ATR): 3326w, 3155m, 2912w, 1714w,
1655m, 1628m, 1593s, 1581s, 1520s, 1496m, 1450s, 1388m, 1342s, 1290m, 1259m, 1219s, 1197s, 1148s, 1115s,
1061s, 1031m, 1003w, 969w, 933w, 891w, 864w. 1H-NMR (300 MHz, (D6)DMSO): 12.33 (br. s, NH); 8.67
(br. s, NH2); 7.55 – 7.33 (m, 5 arom. H); 6.49 (s, HÀC(2)); 5.61 (s, PhCH2); 5.10 (br. t, J ¼ 6.8, HÀC(6));
2.26 – 2.16 (m, 2 HÀC(4), 2 HÀC(5)); 2.10 (s, MeÀC(3)); 1.65, 1.60 (2s, Me2C). 13C-NMR (300 MHz,
(D6)DMSO, 298 K): 165.26 (s, C¼O); 163.48 (s, C(6’)); 160.35 (s, C(3)); 138.57 (s, C(4’)); 135.49 (s);
131.39 (s, C(7)); 128.33 (2d); 128.27 (2d); 128.10 (d); 123.14 (d, C(2)); 118.89 (d, C(6)); 68.37 (t, PhCH2);
40.46 (t, C(4)); 25.73 (t, C(5)); 25.46 (q, MeÀC(3)); 19.02, 17.61 (2q, Me2C); signals of C(2’) and C(5’) not
visibile due to coalescence. HR-MALDI-MS: 396.2025 (51, [M þ H]þ, C21H26N5O3þ ; calc. 396.2030),
418.1855 (7, [M þ Na]þ, C21H25N5NaO3þ ; calc. 418.1850).
Data of (Z)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-3,7-dimethylocta-2,6-dienamide
(14). UV: 202 (4.34), 232 (4.17), 262 (4.23), 350 (4.39). IR (ATR): 3333w, 3215m, 2973w, 1718w,
1656s, 1626m, 1584s, 1513s, 1479m, 1441s, 1389m, 1330s, 1292w, 1271m, 1232s, 1200s, 1175s, 1111s, 1079s,
1061s, 1037s, 1000w, 972w, 961w, 938w, 909m, 874w, 855w, 845w. 1H-NMR (300 MHz, (D6)DMSO): 12.35
(br. s, NH); 8.71, 8.68 (2 br. s, NH2); 7.56 – 7.38 (m, 5 arom. H); 6.56 (s, HÀC(2)); 5.62 (s, PhCH2); 5.10 (t,
J ¼ 6.9, HÀC(6)); 2.55 (br. t, J ¼ 7.2, 2 HÀC(4)); 2.11 (br. q, J ꢀ 7.2, 2 HÀC(5)); 1.97 (s, MeÀC(3)); 1.62,
1.57 (2s, Me2C). 13C-NMR (300 MHz, (D6)DMSO, 298 K): 165.17 (s, C¼O); 163.73 (s, C(6’)); 161.18 (s,
C(3)); 138.75 (s, C(4’)); 135.70 (s); 131.47 (s, C(7)); 128.49 (2d); 128.46 (2d); 128.27 (d); 123.65 (d, C(2));
119.54 (d, C(6)); 68.45 (t, PhCH2); 33.56 (t, C(4)); 26.21 (t, C(5)); 25.40 (q, MeÀC(3)); 25.25, 17.47 (2q,
Me2C); signals of C(2’) and C(5’) not visibile due to coalescence. HR-MALDI-MS: 396.2029 (54, [M þ
H]þ, C21H26N5Oþ3 ; calc. 396.2030), 418.1855 (7, [M þ Na]þ, C21H25N5NaOþ3 ; calc. 418.1850).
Data of (E)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-4,4,4-trifluoro-3-methylbut-2-en-
amide (15). M.p. 148.9 – 149.28. UV: 206 (4.39), 267 (4.14), 353 (4.36). IR (ATR): 3354w, 3321w,
3167w, 2949w, 1732w, 1653m, 1594m, 1581m, 1527m, 1496w, 1460m, 1390m, 1344s, 1299s, 1260w, 1214s,
1
1187m, 1149s, 1126s, 1103m, 1059s, 948w, 895w, 812w. H-NMR (300 MHz, CDCl3): 12.61 (br. s, NH);
7.53 – 7.31 (m, 5 arom. H); 6.73 (br. quint., J ꢀ 1.5, HÀC(2)); 6.63, 6.05 (2 br. s, NH2); 5.70 (s, PhCH2);
2.24 (d, J ¼ 1.5, Me). 13C-NMR (75 MHz, CDCl3, 298 K): 164.66 (s, C¼O); 164.18 (s, C(6’)); 144.85 (br.
2
weak s, C(2’)); 142.09 (q, J(C,F) ¼ 30.3, C(3)); 138.96 (s, C(4’)); 135.25 (s); 128.86 (2d); 128.78 (d);
128.50 (2d); 124.11 (q, 3J(C,F) ¼ 5.5, C(2)); 123.29 (q, 1J(C,F) ¼ 272.4, CF3); 70.00 (t, PhCH2); 12.84 (q,
Me); signal of C(5’) not visibile due to coalescence. 19F-NMR (282 MHz, CDCl3): À 70.93. HR-MALDI-
MS: 382.1116 (100, [M þ H]þ, C16H15F3N5O3þ ; calc. 382.1122), 404.0941 (18, [M þ Na]þ,
C16H14F3N5NaOþ3 ; calc. 404.0941). Anal. calc. for C16H14F3N5O3 (381.31): C 50.40, H 3.70, N 18.37, F
14.95; found: C 50.24, H 3.89, N 18.17, F 15.11.

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Helvetica Chimica Acta – Vol. 90 (2007)
X-Ray Analysis of 154). Slow evaporation of a soln. of 15 in CHCl3 gave suitable single crystals for X-
ray analysis (dimensions: 0.24 Â 0.2 Â 0.04 mm; colour: dark blue). C16H14F3N5O3, Mr 381.314, triclinic,
¯
P1, a ¼ 13.1447(2), b ¼ 13.4048(2), c ¼ 38.5360(5) Š, a ¼ 86.0982(6), b ¼ 89.5773(5), g ¼ 89.2288(5)8,
V¼ 6773.6(2) Š3; Z ¼ 16, Z’ ¼ 8, Dcalc. ¼ 1.496 Mg/m3. Intensities were measured on a Nonius Kappa
CCD diffractometer, with MoKa radiation l ¼ 0.71073 Š, Cell parameters from 38829 reflections, q ¼
0.998 – 26.3738, m ¼ 0.128 mmÀ1, T¼ 223 K. 38829 measured reflections, 25068 independent reflections,
8976 observed reflections (>2s(I)). Refinement on F2: Full-matrix least-squares refinement, R(all) ¼
0.2165, R(gt) ¼ 0.0860. Pseudo a-centering and pseudo-inversion centre at 0.0, 0.25, 0.25 with relatively
week k þ l ¼ odd reflections but refinement in monoclinic space group does not give satisfactory results.
All diagrams and calculations were performed using maXus (Bruker Nonius, Delft & MacScience,
Japan). The programme SIR97 was used to solve the structure and the programme SHELXL-97 to refine it.
Preparation of the Pteridin-7(8H)-ones 6, 7, and 18. A suspension of 4 (72 mg, 0.22 mmol), 5
(87.5 mg, 0.22 mmol), or 15 (84 mg, 0.22 mmol) in toluene (20 ml) was heated at the indicated temp. and
time, affording a blue soln. upon heating and the desired product as yellow precipitate. 4, 5 (1008, 3 h), 15
(1508, 8 h). The suspension was concentrated, followed by filtration, to give a yellow powder, which was
successively washed with H2O and Et2O. Drying i.v. gave (E/Z)-6 (67 mg), (E/Z)-7 (82 mg), and 18
(78.5 mg) in a yield of ca. 98%, resp. Heating (E/Z)-6 under reflux in benzene containing 10% I2 for 36 h,
or in toluene with 1% AcOH for 36 h, gave pure (E)-6.
Preparation of the Pteridin-7(8H)-ones 16 and 17. A soln. of 13 or 14 (43.5 mg, 0.11 mmol) in CH2Cl2
(10 ml) was stirred at 238 for 4 d. The suspension of the resulting precipitate was concentrated to a small
volume. Filtration gave 16 as yellow powder and 17 as light-brown powder. Drying i.v. gave 16 (40 mg)
and 17 (41 mg) in a yield of ca. 98%, resp.
Data of 2-Amino-6-[(E/Z)-prop-1-enyl]-4-(benzyloxy)pteridin-7(8H)-one (6). UV: 211 (4.21), 291
(3.57), 370 (3.90). IR (ATR): 3359m, 3192m, 2905w, 2844w, 2778w, 1652s, 1614s, 1560s, 1532s, 1495s,
1446s, 1391s, 1348s, 1310m, 1293m, 1220w, 1186m, 1104w, 1082m, 1068m, 1028w, 1005w, 978m, 956m,
1
937w, 913m, 898m, 852m, 832w, 815w. H-NMR (300 MHz, (D6)DMSO; (E)/(Z) 83 :17): see Table 1;
additionally, 7.00 – 6.88 (m, 0.83 H), 6.10 – 6.04 (m, 0.17 H) (HÀC(2’)); 6.71 (d, J ¼ 12.3, 0.17 H), 6.64 (d,
J ¼ 15.6, 0.83 H) (HÀC(1’)); 2.17 (d, J ¼ 7.8, 0.51 H), 1.87 (d, J ¼ 6.9,, 2.49 H) (Me(3’)). 13C-NMR
(125 MHz, (D6)DMSO; only signals of the the (E)-isomer observed): see Table 2; additionally, 136.36
(s); 133.58 (d); 128.47 (2d); 128.41 (2d); 128.06 (d, C(1’)); 125.93 (d, C(2’)); 67.38 (t, PhCH2); 18.66 (q,
Me). HR-MALDI-MS: 310.1297 (82, [M þ H]þ, C16H16N5Oþ2 ; calc. 310.1299), 332.1113 (100, [M þ Na]þ,
C16H15N5NaOþ2 ; calc. 332.1118).
Data of 2-Amino-6-[(E/Z)-oct-1-enyl]-4-(benzyloxy)pteridin-7(8H)-one (7). UV: 210 (4.21), 288
(3.77), 375 (3.94). IR (ATR): 3360w, 3189m, 3065w, 3032w, 2951w, 2919m, 2848m, 2767w, 1791w, 1650s,
1614s, 1557s, 1529s, 1496s, 1480m, 1443s, 1390m, 1342s, 1306m, 1216w, 1179m, 1086m, 1068m, 1029w,
1
Table 1. Selected H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Pteridin-7(8H)-
ones 6, 7, and 16 – 18 i n (D)DMSO
6
6
7
16
17
18
HÀN(8)
H2NÀC(2)
Ph
HEÀC(1’)
HZÀC(1’)
HEÀC(2’)
HZÀC(2’)
H2C¼C(1’)
PhCH2
12.37
12.37
12.30
7.13
7.51 – 7.33
–
–
6.97
–
–
5.50
–
12.36
7.22
7.51 – 7.31
–
–
–
–
6.48, 5.51
5.49
–
12.68
7.44
7.51 – 7.31
–
–
–
–
7.01, 6.39
5.51
–
7.18, 7.16
7.50 – 7.33
6.64
7.14, 7.11
7.52 – 7.34
6.61
6.71
6.68
7.00 – 6.88
6.10 – 6.04
–
5.48
15.6
7.00 – 6.92
5.99 – 5.93
–
5.48
15.8
J(1’,2’)E
J(1’,2’)Z
12.3
11.8
–
–
–

Helvetica Chimica Acta – Vol. 90 (2007)
531
Table 2. Selected 13C-NMR Chemical Shifts [ppm] of the Pteridin-7(8H)-ones 6, 7, 16 – 18, and 23 – 25 in
(D6)DMSO
6
7
16a)
17a)
18
23
24
25
C(2)
C(4)
C(4a)
C(6)
C(7)
C(8a)
150.73
164.39
107.58
145.73
156.83
161.08
150.75
164.38
107.62
145.33
156.87
161.07
150.56
164.47
107.07
147.90
156.71
161.27
150.80
164.68
107.21
144.12
156.77
161.60
150.90
164.66
107.43
139.47
156.14
161.91
148.61
161.80
106.44
142.59
157.32
160.49
149.74
163.50
108.02
145.02
156.96
161.17
151.45
161.38
113.78
147.07
156.56
157.25
a) Assignments based on a HSQC and a HMBC spectrum.
976m, 949m, 913s, 848m, 815w. 1H-NMR (500 MHz, (D6)DMSO; (E)/(Z) 78 :22): see Table 1;
additionally, 7.00 – 6.92 (m, 0.78 H), 5.99 – 5.93 (m, 0.22 H) (HÀC(2’)); 6.68 (d, J ¼ 11.8, 0.22 H), 6.61
(d, J ¼ 15.8, 0.78 H) (HÀC(1’)); 2.73 (q, J ¼ 7.6, 0.44 H), 2.21 (q, J ¼ 6.5,, 1.56 H) (CH2(3’)); 1.45 – 1.15
(m, 4 CH2); 0.86 (t, J ¼ 6.8, 2.34 H), 0.80 (t, J ¼ 6.8, 0.66 H) (Me(8’)). 13C-NMR (125 MHz, (D6)DMSO;
only signals of the (E)-isomer observed): see Table 2; additionally, 138.50 (s); 136.38 (d, C(1’)); 128.46
(2d); 128.39 (2d); 128.06 (d); 124.59 (d, C(2’)); 67.35 (t, PhCH2); 32.67 (t, C(3’)); 31.06 (t, C(4’)); 28.31 (2t,
C(5’), C(6’)); 22.02 (t, C(7’)); 13.91 (q, C(8’)). HR-MALDI-MS: 380.2075 (100, [M þ H]þ, C21H26N5O2þ ;
calc. 380.2081), 402.1906 (6, [M þ Na]þ, C21H25N5NaO2þ ; calc. 402.1900).
Data of 2-Amino-4-(benzyloxy)-6-[(E)-1,5-dimethylhexa-1,4-dienyl]pteridin-7(8H)-one (16). UV:
211 (4.32), 256 (3.57), 293 (3.60), 363 (4.10). IR (ATR): 3461m, 3298w, 3282w, 3184m, 2962w, 2908w,
2761w, 1797w, 1654s, 1631s, 1619s, 1560s, 1531s, 1489m, 1470m, 1457m, 1439s, 1398m, 1349s, 1323m,
1295m, 1218w, 1177m, 1110w, 1087m, 1044m, 978w, 950m, 915s, 862w, 833m, 800m. 1H-NMR (300 MHz,
(D6)DMSO): see Table 1; additionally, 6.97 (br. t, J ꢀ 6.8, HÀC(2’)); 5.15 (br. t, J ꢀ 6.4, HÀC(4’)); 2.90
(br. t, J ꢀ 7.1, CH2(3’)); 1.97 (s, MeÀC(1)); 1.67, 1.63 (2s, Me2C). 13C-NMR (100 MHz, (D6)DMSO): see
Table 2; additionally: 136.54 (s); 134.47 (d, C(2’)); 132.20 (s, C(1’)); 131.61 (s, C(5’)); 128.40 (2d); 128.05
(2d); 127.96 (d); 121.88 (d, C(4’)); 67.17 (t, PhCH2); 27.81 (t, C(3’)); 25.42 (q, MeÀC(1)); 17.66, 14.22 (2q,
Me2C). HR-MALDI-MS: 378.1917 (100, [M þ H]þ, C21H24N5O2þ ; calc. 378.1925), 400.1739 (5, [M þ
Na]þ, C21H23N5NaOþ2 ; calc. 400.1744).
Data of 2-Amino-4-(benzyloxy)-6-[5-methyl-1-methylidenehex-4-enyl]pteridin-7(8H)-one (17). UV:
211 (4.57), 292 (3.70), 363 (4.31). IR (ATR): 3338m, 3190m, 2965w, 2910m, 2850m, 2778m, 1647s, 1620s,
1607s, 1561s, 1531s, 1480s, 1454m, 1438s, 1387s, 1345s, 1304m, 1218w, 1188s, 1102m, 1083m, 1046m, 1027m,
982m, 962m, 929m, 909m, 893m, 842m, 827m, 812w. 1H-NMR (300 MHz, (D6)DMSO): see Table 1;
additionally, 6.48 (d, J ¼ 2.7, CH¼C(1’)); 5.51 (CH’¼C(1’), overlapping with the PhCH2 signal); 5.10 (br.
t, J ꢀ 7.1, H ÀC(4’)); 2.48 (CH2(2’), overlapping with the DMSO signal); 2.12 (br. q, J ꢀ 6.9, CH2(3’));
1.59, 1.46 (2s, Me2C). 13C-NMR (125 MHz, (D6)DMSO): see Table 2; additionally, 145.85 (s, C(1’));
136.52 (s); 130.89 (s, C(5’)); 128.34 (2d); 127.89 (d); 127.79 (2d); 124.19 (d, C(4’)); 120.05 (t, CH2¼C(1’));
67.19 (t, PhCH2); 34.81 (t, C(2’)); 27.30 (t, C(3’)); 25.45, 17.42 (2q, Me2C). HR-MALDI-MS: 378.1916
(100, [M þ H]þ, C21H24N5O2þ ; calc. 378.1925), 400.1744 (10, [M þ Na]þ, C21H23N5NaOþ2 ; calc. 400.1744).
Data of 2-Amino-4-(benzyloxy)-6-[1-(trifluoromethyl)ethenyl]pteridin-7(8H)-one (18). UV: 211
(4.44), 287 (3.52), 366 (4.19). IR (ATR): 3464w, 3319w, 3198w, 3144w, 2836w, 2732w, 1969w, 1813w,
1662w, 1611s, 1567s, 1542m, 1490m, 1465m, 1449m, 1430s, 1394m, 1370m, 1353s, 1318m, 1308m, 1251w,
1
1187m, 1163s, 1137s, 1094m, 1078m, 1030m, 983m, 926m, 875w, 834w, 822w, 813w. H-NMR (300 MHz,
(D6)DMSO): see Table 1; additionally, 7.01 (d, J ¼ 1.5, CH¼C(1’)); 6.39 (br. s, CH’¼C(1’)). 13C-NMR
(75 MHz, (D6)DMSO): see Table 2; additionally, 136.16 (s); 133.08 (q, 2J(C,F) ¼ 27.9, C(1’)); 128.20 (2d);
127.74 (d); 127.48 (2d); 126.44 (d, 3J(C,F) ¼ 6.0, C(2’)); 122.44 (q , 1J(C,F) ¼ 272.3, CF3); 67.23 (t, PhCH2).
19F-NMR (282 MHz, (D6)DMSO): À 61.85. HR-MALDI-MS: 364.1011 (100, [M þ H]þ, C16H13F3N5Oþ2 ;
calc. 364.1016), 386.0837 (33, [M þ Na]þ, C16H12F3N5NaO2þ ; calc. 386.0835).

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Helvetica Chimica Acta – Vol. 90 (2007)
2-Amino-6-[(E)-prop-1-enyl]pteridine-4,7(3H,8H)-dione (8). A soln. of anh. LiBr (7.3 mg,
0.083 mmol) in MeCN (1 ml) was treated with Me3SiCl (12.5 ml, 0.1 mmol), stirred at 238 under Ar for
5 min, and treated with dry (E)-6 (20 mg, 0.064 mmol). The resulting suspension was stirred at 238 for
12 h, cooled to 08, and treated with MeOH (0.5 ml). The suspension was filtered. The solid was washed
with H2O and dried i.v. to afford 8 (12.7 mg, 90%). Light yellow powder. UV: 214 (4.22), 302 (3.73), 369
(3.99). IR (ATR): 3323w, 3122m, 2961w, 2912w, 2849w, 2770w, 1697m, 1666s, 1641s, 1601s, 1581s, 1518m,
1474m, 1443m, 1374m, 1342m, 1317w, 1287w, 1252w, 1186w, 1156w, 1111w, 966m, 937w, 901m, 819w.
1H-NMR (300 MHz, (D6)DMSO): 12.29, 10.96 (2 br. s, 2 NH); 6.97 (br. s, NH2); 6.97 – 6.85 (m,
HÀC(2’)); 6.60 (dq, J ¼ 15.0, 1.8, HÀC(1’)); 1.88 (dd, J ¼ 6.9, 1.8, Me). 13C-NMR (125 MHz,
(D6)DMSO): 158.55 (s, C(6)); 156.57 (s, C(4)); 154.45 (s, C(8a)); 150.26 (s, C(7)); 143.89 (s, C(2));
132.09 (d, C(2’)); 125.97 (d, C(1’)); 110.80 (s, C(4a)); 18.54 (q, Me). HR-MALDI-MS: 220.0833 (35,
[M þ H]þ, C9H10N5Oþ2 ; calc. 220.0829), 242.0645 (24, [M þ Na]þ, C9H9N5NaOþ2 ; calc. 242.0648).
4-(Benzyloxy)-2-{[(dimethylamino)methylidene]amino}-6-[(E)-prop-2-enyl]pteridin-7(8H)-one
(9). A suspension of (E)-6 (110 mg, 0.36 mmol) in DMF (15 ml) was treated at 238 with Bredereckꢁs
reagent (83.2 ml, 0.4 mmol) and stirred for 3 h, leading progressively to a red-brown soln. DMF was
distilled off at 258/0.3 Torr. Drying of the residue i.v. gave 9 (124.3 mg, 95%). Red-brown solid. UV: 209
(4.42), 267 (4.04), 378 (4.43). IR (ATR): 3500 – 2000w (br.), 3038w, 2925m, 1660m, 1625m, 1579s, 1550s,
1515m, 1498m, 1484m, 1433s, 1420s, 1381s, 1351s, 1336s, 1321s, 1278s, 1234m, 1215m, 1153m, 1114s,
1048m, 998w, 974m, 944m, 913m, 895m, 849m, 832w, 803m. 1H-NMR (300 MHz, (D6)DMSO): 12.56 (br.
s, NH); 8.70 (s, HC¼N); 7.52 – 7.33 (m, 5 arom. H); 7.09 – 6.89 (m, HÀC(2’)); 6.71 (dq, J ¼ 15.6, 1.8,
HÀC(1’)); 5.56 (s, PhCH2); 3.17, 3.06 (2s, Me2N); 1.91 (br. d, J ¼ 6.9, Me). 13C-NMR (75 MHz, CD2Cl2):
164.53 (s, C(8a)); 164.46 (s, C(4)); 159.46 (d, HC¼N); 157.17 (s, C(2)); 149.86 (s, C(7)); 149.20 (s, C(6));
136.96 (d, C(2’)); 136.73 (s); 128.72 (2d); 128.50 (d); 128.23 (2d); 125.83 (d, C(1’)); 111.14 (s, C(4a));
68.94 (t, PhCH2); 41.64, 35.45 (2q, Me2N); 19.35 (q, Me). HR-MALDI-MS: 365.1717 (100, [M þ H]þ,
C19H21N6Oþ2 ; calc. 365.1721), 387.1533 (52, [M þ Na]þ, C19H20N6NaOþ2 ; calc. 387.1540).
X-Ray Analysis of 94). Slow evaporation of a soln. of 9 in MeCN gave crystals suitable for X-ray
analysis (dimensions: cube 0.4 Â 0.2 Â 0.06 mm; color: amber). C19H20N6O2 · MeCN, Mr 405.462, triclinic,
¯
P1, a ¼ 4.6804 (5), b ¼ 13.789 (2), c ¼ 17.642(2) Š, a ¼ 79.920 (6), b ¼ 87.846 (6), g ¼ 83.811 (6)8, V¼
1114.3 (2) Š3, Z ¼ 2, Dcalc. ¼ 1.208 Mg/m3, Intensities were measured on a Nonius Kappa CCD
diffractometer, with MoKa radiation l ¼ 0.71073 Š, cell parameters from 5500 reflections, q ¼ 2.910 –
22.9868, m ¼ 0.082 mmÀ1, T¼ 213 K, 5500 measured reflections, 3019 independent reflections, 2176
observed reflections. Refinement on F2: full-matrix least-squares refinement, R(all) ¼ 0.2525, R(gt) ¼
0.2237. Crystals lose solvent rapidly at r.t. Crystals composed of multiple twins (>4). Cell selection
manually. Overlap correction for twinning not possible leading to bad agreement factors. All calculations
were performed using maXus (Bruker Nonius, Delft & MacScience, Japan). The programme SIR97 was
used to solve the structure and the programme SHELXL-97 to refine it.
Acylation of 19. A soln. of 19 (308 mg, 2.0 mmol) in DMF (30 ml) was treated with K2CO3 (2.2 g,
16.0 mmol), cooled to À 188, treated with a soln. of 2 (0.57 ml, 5.0 mmol) in THF (5 ml) within 4 h
(addition via a syringe pump), and stirred for 0.5 h. DMF was distilled off at 258/0.3 Torr. A soln. of the
residue in CH2Cl2 (100 ml) was washed with cold H2O (2 Â 50 ml) and brine (50 ml), dried (MgSO4), and
evaporated. FC (CH2Cl2/MeOH 100 :1 ! 50 :1) gave 20 (200 mg, 42%) as a green powder and 21 (81 mg,
13%) as a blue powder.
Data of (E)-N-(2,6-Diamino-5-nitrosopyrimidin-4-yl)pent-2-enamide (20). UV: 220 (4.32), 265
(4.14), 341 (4.36), 562 (1.87, of a 10À3 m soln.). IR (ATR): 3333m, 3186w, 2974w, 2940w, 2887w, 1688m,
1663m, 1616s, 1511m, 1486s, 1462s, 1392w, 1347m, 1321m, 1288s, 1256m, 1183s, 1128s, 1087m, 1055m,
1001w, 979m, 969m, 885w, 856w, 821w. 1H-NMR (300 MHz, (D6)DMSO, 7:3 mixture): 12.98 (s, 0.3 H),
10.58 (s, 0.7 H) (NHÀC(4’); 9.91, 8.13 (2 br. d, J ¼ 3.6, 1.4 H), 8.58, 7.95 (2 br. s, 0.6 H) (NH2ÀC(6’)); 7.95,
7.85 (2 br. s, 1.4 H), 8.02, 7.80 (2 br. s, 0.6 H) (NH2ÀC(2’)); 7.01 – 6.93 (m, HÀC(3)); 6.83 (br. d, J ¼ 15.9,
HÀC(2)); 2.25 (q, J ¼ 7.5, CH2(4)); 1.05 (t, J ¼ 7.5, Me). 13C-NMR (100 MHz, (D6)DMSO; 7:3 mixture):
165.99, 163.85 (2s, C¼O); 165.93, 163.51 (2s, C(5’)); 164.41, 162.43 (2s, C(4’)); 150.23, 145.44 (2s, C(2’));
150.18, 149.31 (2d, C(3)); 138.24, 136.57 (2s, C(6’)); 124.34, 123.64 (2d, C(2)); 24.95, 24.79 (2t, C(4));
12.27, 12.18 (2q, Me). HR-MALDI-MS: 237.1091 (100, [M þ H]þ, C9H13N6O2þ ; calc. 237.1095), 259.0916
(33, [M þ Na]þ, C9H12N6NaOþ2 ; calc. 259.0914).

Helvetica Chimica Acta – Vol. 90 (2007)
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Data of 5-Nitroso-4,6-bis{[(E)-pent-2-enoyl]amino}pyrimidine (21). UV: not measured, due to the
rapid ene reaction in solution. IR (ATR): 3331w, 3188m, 2966w, 2933w, 2872w, 1722w, 1682m, 1663s,
1632s, 1610s, 1528s, 1464s, 1419m, 1386w, 1334m, 1310s, 1282s, 1245m, 1172s, 1114s, 1090m, 1066m, 1014m,
977m, 919w, 887w, 857w, 842w. 1H-NMR (300 MHz, CDCl3): 12.64 (br. s, NH); 10.23 (br. s, NH); 7.24 –
7.15 (m, HÀC(3’), HÀC(3’’)); 7.08, 6.95 (2 br. s, NH2); 6.35 (d, J ¼ 15.3, HÀC(2’)); 6.14 (d, J ¼ 16.2,
HÀC(2’’)); 2.34 (br. s, 2 CH2); 1.14 (d, J ¼ 6.3, 2 Me). 13C-NMR (75 MHz, (D6)DMSO): the rapid ene
reaction of a sat. soln. of 21 in DMSO prevented the measurement of a 13C-NMR spectrum. HR-
MALDI-MS (low intensity of the desired peaks): 319.1523 (14, [M þ H]þ, C14H19N6O3þ ; calc. 319.1513),
341.1340 (45, [M þ Na]þ, C14H18N6NaO3þ ; calc. 341.1333).
Preparation of the Pteridin-7(8H)-ones 23 and 24. A suspension of 20 (52 mg, 0.22 mmol) or 21
(70 mg, 0.22 mmol) in toluene (20 ml) was heated at 1008 for the indicated time, to afford a greenish-blue
soln. upon heating and the desired product as yellow precipitate. The suspension was concetrated to a
small volume and filtered to give a yellow powder, which was successively washed with H2O and Et2O.
Drying of the residue i.v. gave (E/Z)-23 (24 h, 48 mg, 98%) and (E/Z)-24 (3 h, 65 mg, 98%), resp.
Data of 2,4-Diamino-6-[(E/Z)-prop-1-enyl]pteridin-7(8H)-one (23). UV: 211 (4.36), 245 (4.03), 267
(4.04), 299 (3.68), 382 (4.21). IR (ATR): 3438w, 3330w, 3213w, 2843w, 2766w, 2720w, 1834w, 1611s, 1562s,
1530m, 1476m, 1458s, 1397m, 1374w, 1329m, 1298w, 1251w, 1198w, 1172w, 1154w, 1065w, 1016w, 966w,
1
937m, 856w, 818w. H-NMR (400 MHz, (D6)DMSO; (E)/(Z) 81:19): 11.94 (br. s, NH); 7.06 – 6.95 (dq,
J ¼ 15.8, 6.9, 0.81 H), 6.07 – 6.01 (dq, J ¼ 11.7, 7.2, 0.19 H) (HÀC(2’)); 6.88 (br. s, NH2); 6.67 (br. dq, J ¼
15.6, 1.5, HÀC(1’), relative signal of (Z)-isomer not observed due to overlapping); 6.40, 6.35 (2 br. s,
NH2); 2.13 (d, J ¼ 7.2, 0.57 H), 1.89 (d, J ¼ 6.9, 2.43 H) (Me). 13C-NMR (75 MHz, (D6)DMSO; only
signals of the (E)-isomer observed): see Table 2; additionally, 131.89 (d, C(2’)); 124.98 (d, C(1’)); 18.67
(q, Me). HR-MALDI-MS: 219.0983 (100, [M þ H]þ, C9H11N6Oþ; calc. 219.0989), 241.0804 (1, [M þ
Na]þ, C9H10N6NaOþ; calc. 241.0808).
Data of 2-Amino-4-{[(E)-pent-2-enoyl]amino}-6-[(E/Z)-prop-1-enyl]pteridin-7(8H)-one (24). UV:
213 (4.35), 251 (4.18), 319 (3.76), 381 (4.19). IR (ATR): 3317m, 3201m, 2965w, 2931w, 2904w, 2880w,
2847w, 2764w, 2726w, 1668s, 1626s, 1561s, 1473s, 1389m, 1346m, 1288m, 1246m, 1193m, 1119m, 1073w,
1051w, 972m, 933w, 904w, 855w, 828w. 1H-NMR (300 MHz, (D6)DMSO; (E)/(Z) 78 :22): 12.44, 9.65 (2
br. s, 2 NH); 7.14 (br. s, NH2); 7.15 (dq, J ¼ 15.6, 6.9, 0.78 H), 6.17 (dq, J ¼ 11.7, 7.5, 0.22 H) (CH¼CHMe);
6.97 (dt, J ¼ 15.3, 6.0, CH¼CHEt); 6.87 (dt, J ¼ 15.3, 1.5, CH¼CHEt); 6.70 (dq, J ¼ 15.6, 1.8, 0.78 H,
CH¼CHMe; the signals of the (Z)-isomer hidden due to overlapping); 2.26 (quint., J ¼ 6.0, CH2); 2.13
(dd, J ¼ 7.5, 1.8, 2.34 H), 1.92 (dd, J ¼ 6.9, 1.8, 0.66 H) (¼CHMe); 1.05 (t, J ¼ 7.5, Me). 13C-NMR
(75 MHz, (D6)DMSO; only signals of the (E)-isomer were observed): see Table 2; additionally, 154.77 (s,
C¼O); 148.84 (d, CH¼CHEt); 134.58 (d, CH¼CHMe); 124.75 (d, CH¼CHMe); 123.23 (d,
CH¼CHEt); 24.88 (t, CH2); 18.78 (q, CH¼CHMe); 12.40 (q, CH2Me). HR-MALDI-MS: 301.1406
(100, [M þ H]þ, C14H17N6O2þ ; calc. 301.1408), 323.1230 (15, [M þ Na]þ, C14H16N6NaOþ2 ; calc. 323.1227).
Anal. calc. for C14H16N6O2 · 0.5 H2O (309.32): C 54.36, H 5.54, N 27.17; found: C 54.87, H 5.51, N 27.14.
Preparation of 2,4-Bis{[(E)-pent-2-enoyl]amino}-6-[(E)-prop-1-enyl]pteridin-7(8H)-one (25). A
suspension of 19 (154 mg, 1.0 mmol) in THF (30 ml) was treated with K2CO3 (1.4 g, 10 mmol), cooled to
08, treated with the a soln. of 2 (0.4 ml, 3.5 mmol) in THF (5 ml) within 2 h (addition via a syringe pump),
stirred for 10 h at 0 – 58, diluted with CH2Cl2 (100 ml), washed with cold H2O (2 Â 50 ml) and brine
(50 ml), dried (MgSO4), and evaporated. FC (CH2Cl2/AcOEt 1:2) gave a yellowish-green soln., which
was concentrated to ca. 10 ml, whereupon 25 precipitated. Upon stirring at 238 overnight, the colour of
the supernatant liquor disappeared almost completely. Filtration and drying of the solid gave 25 (296 mg,
78%). Yellow powder. UV: 217 (4.53), 239 (4.47), 315 (3.97), 380 (4.25). IR (ATR): 3372w, 3310w,
3206w, 2964w, 2912w, 2880w, 2835w, 2768w, 1718m, 1670s, 1638s, 1614s, 1552s, 1538s, 1499m, 1463w, 1418s,
1393m, 1336m, 1294m, 1245m, 1186s, 1156m, 1109m, 1060w, 1020w, 966m, 918w, 846w. 1H-NMR
(300 MHz, (D6)DMSO, 333 K): 12.52 (br. s, NH); 7.26 (2 br. s, 2 NH); 6.95 (dt, J ¼ 15.3, 6.9, 2 ¼CHEt);
6.82 (dq, J ¼ 15.6, 6.9, ¼CHMe); 6.67 (dq, J ¼ 15.6, 1.5, CH¼CHMe); 6.17 (dt, J ¼ 15.3, 1.5, 2
CH¼CHEt); 2.20 (dq, J ¼ 1.5, 7.2, 2 CH2); 1.88 (dd, J ¼ 1.5, 6.9, ¼CHMe); 0.98 (t, J ¼ 7.2, 2 CH2Me).
13C-NMR (75 MHz, (D6)DMSO): see Table 2; additionally, 167.43 (s, 2 C¼O); 150.41 (d, 2 CH¼CHEt);
135.10 (d, CH¼CHMe); 124.24 (d, CH¼CHMe); 122.85 (d, 2 CH¼CHEt); 24.85 (t, 2 CH2Me); 18.60 (q,

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Helvetica Chimica Acta – Vol. 90 (2007)
Me); 12.31 (q, 2 CH2Me). HR-MALDI-MS: 383.1821 (38, [M þ H]þ, C19H23N6O3þ ; calc. 383.1826),
405.1641 (34, [M þ Na]þ, C19H22N6NaO3þ ; calc. 405.1646).
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Received November 21, 2006