Diels - Alder additions, ene reactions, and condensations of 4-(acylamino)-5-nitrosopyrimidines - Synthesis of 8-substituted guanines and of 6-substituted pteridinones

Article abstract of DOI:10.1002/hlca.200890048

4-(Acylamino)-5-nitrosopyrimidines react either by a reductive condensation to provide 8-substituted guanines, or by a Diels - Alder cycloaddition, or an ene reaction, to provide 6-substituted pteridinones, depending on the nature of the acyl group and th

Full text of DOI:10.1002/hlca.200890048

Helvetica Chimica Acta – Vol. 91 (2008)
435
Diels – Alder Additions, Ene Reactions, and Condensations of
4-(Acylamino)-5-nitrosopyrimidines – Synthesis of 8-Substituted Guanines
and of 6-Substituted Pteridinones
by Thomas Steinlin 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)
4-(Acylamino)-5-nitrosopyrimidines react either by a reductive condensation to provide 8-
substituted guanines, or by a Diels – Alder cycloaddition, or an ene reaction, to provide 6-substituted
pteridinones, depending on the nature of the acyl group and the reaction conditions. Experimental details
are provided for the transformation of (acylamino)-nitrosopyrimidines to 8-substituted guanines, and the
scope of the reaction is further demonstrated by transforming the trifluoro acetamide 25 to the 8-
(trifluoromethyl)guanine (27), and the N,N’-bis(nitrosopyrimidinyl)-dicarboxamide 29 to the (R,R)-1,2-
di(guan-8-yl)ethane-1,2-diol (32). An intramolecular Diels – Alder reaction of the N-sorbyl (¼ N-hexa-
2,4-dienoyl) nitrosopyrimidine 10, followed by a spontaneous elimination to cleave the N,O bond of the
initial cycloaddition product provided the pteridinones 14 or 15, characterized by a (Z)- or (E)-3-
hydroxyprop-1-enyl group at C(6). Treatment of 10 with Ph3P led to the C(8)-penta-1,3-dienyl-guanine
18. The ene reaction of the N-crotonyl (¼ N-but-2-enoyl) nitrosopyrimidine 19 provided the 6-vinyl-
pteridinone 20a that dimerized readily to 21a, while treatment of 19 with Ph3P led in high yield to 8-
(prop-1-enyl)guanine (23). The structure of the dimer 21 was established by X-ray analysis of its
bis(N,N-dimethylformamidine) derivative 21b. The crystal structure of the nitroso amide 10 is
characterized by two molecules in the centrosymmetric unit cell. Intermolecular H-bonds connect the
amino group to the amide carbonyl and to N(1). The crystalline bis(purine) 30 forms a left-handed helix
with four molecules per turn and a pitch of 30.2 Š.
Introduction. – According to the modified Traube synthesis explored by Pfleiderer
and co-workers, 4-(acylamino)-5-nitrosopyrimidines are transformed into purines by
reduction of the N¼O to an amino group followed by condensation [1]. We have
communicated a simplified procedure for this transformation whereby 4-(acylamino)-
2-amino-5-nitrosopyrimidines of type 2 (Scheme 1) are treated with 2 equiv. of a
phosphine or a phosphite at elevated temperature to provide 8-substituted guanines 3
in one step [2]. The required amides are, as a rule, readily obtained by acylating the
pyrimidine 1. The convenient procedure and the high yields of the resulting guanines
prompted us to further explore the reactivity of nitroso-pyrimidines. We found that N-
(alka-2,4-dienoyl)-4-amino-5-nitrosopyrimidines 4 undergo a facile, high-yielding
intramolecular Diels – Alder cycloaddition to 5, followed by a spontaneous elimination,
leading to pteridinones 6 possessing a (Z)-3-hydroxyalk-1-enyl group at C(6) [3].
Pteridinones 9 possessing an (E)-configured alkenyl substituent at C(6) result from a
stereoselective nitroso-ene reaction of N-alk-2-enoyl derivatives 7 [4]. Similarly as for
the cycloaddition of 4, the initial product of the ene reaction is a hydroxylamine
derivative 8 that could not be observed. The ene reaction of N-alk-2-enoyl derivatives
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 1
substituted at C(2’) led to the formation of pyrimido-diazepinones that were
intercepted by a Diels – Alder cycloaddition [5].
We now provide experimental details for the synthesis of 8-substituted guanines,
and further document the scope of the method by describing the synthesis of a few
otherwise less readily accessible guanines. We also report reaction conditions that
transform alka-1,4-dienoyl and alk-1-enoyl derivatives of the amino-nitroso-pyrimidine
1 into either pteridinones or guanines.
Results and Discussion. – The alternative transformation of an N-dienoyl nitroso-
pyrimidine into either a guanine or a pteridinone was studied with the N-
(sorbylamino)-nitroso-pyrimidine 10 that was obtained in 86% yield by acylating a
suspension of 1 [6] in CH2Cl2 with sorbyl chloride in the presence of DMAP
(Scheme 2). Careful control of the temperature was essential to avoid the formation of
mixtures of the amide 10 and the pteridinone 12, besides minor products that were not
isolated.
A suspension of 10 in toluene turned into a solution at 1008, and 10 was
progressively transformed into a yellow precipitate of pteridinone 12. Pure (Z)-
configured 12 was isolated in almost quantitative yield by filtration and washing with
H2O, AcOEt, and Et2O. In an attempt to observe the primary addition product, we
followed the conversion of a solution of 10 in (D6)DMSO to 12 by 1H-NMR
spectroscopy at ambient temperature. The conversion was completed after 2 d. No
trace of the expected dihydrooxazino 11 was detected, evidencing that its trans-

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Scheme 2
a) Sorbyl chloride (¼ hexa-2,4-dienoyl chloride), 4-(dimethylamino)pyridine (DMAP), CH2Cl2; 86%.
b) Toluene; ca. 98%. c) Toluene/AcOH 99 :1; ca. 98%. d) 1n NaOH/dioxane 5 :1; 87% of 14; 92% of 15.
e) < 10À4 mbar, 3008; 29%. f ) Ph3P, o-xylene; 86%. g) LiBr, Me3SiCl, MeCN; 95%.
formation to 12 is more rapid than its formation from 10. Prolonged heating of 12 in
toluene containing 1% AcOH at 808 led to complete isomerisation to the (E)-allylic
alcohol 13, as evidenced by the change of J(1’,2’) from 12.3 to 15.9 Hz, and a strong
downfield shift of HÀC(2’) from 5.95 to 6.95 ppm. This strong downfield shift is
rationalized by the localization of HÀC(2’) of one of the rotamers of the (E)-
configured alkenyl substituent at C(6) in the deshielding cone of the C¼O group. The
influence of the configuration of 12 and 13 on the UV spectra is only minimal. The
diastereoisomers 12 and 13 were hydrolysed in boiling aqueous 1n NaOH/dioxane [7]
to the isoxanthopterine derivatives 14 and 15, respectively. Their structure follows
unambiguously from the 1H- and 13C-NMR, and from the IR data. Attempted
purification of 15 by sublimation resulted in the elimination of 1 equiv. of H2O and
formation of the pyrrole 16 (29%), by a process related to known acid-promoted
cyclisations of this type [8][9].
To transform the diene 10 into a purine, we treated its suspension in o-xylene with
Ph3P at 238. This led to disappearance of the green colour of 10 within 1 h, and
formation of a new product, as evidenced by TLC. Raising the temperature to 1458
transformed the intermediate into the blue-fluorescent (l ¼ 366 nm) 8-pentadienyl-

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purine 17 that was isolated in a yield of 86%. It was debenzylated in 95% yield by
treatment with in situ generated Me3SiBr, leading to the poorly soluble 8-(penta-1,3-
dienyl)guanine (18) that was filtered off, and purified by washing with H2O, Et2O, and
pentane.
1
The H-NMR spectrum of the (E)-isomer 14 in (D6)DMSO shows the Me d at
1.18 ppm (J ¼ 6.6 Hz), the alkenyl H-atom signals at 6.90 (dd, J ¼ 15.9 and 5.4 Hz) and
6.71 ppm (d, J ¼ 15.6 Hz), and the signal of the allylic H-atom at 4.31 ppm, in keeping
with a 13C q at 23.57 ppm, and ds at 143.72, 121.70, and 66.45 ppm. The Me group of the
(Z)-isomer 15 resonates at 1.22 ppm (d, J ¼ 6.6 Hz), the alkenyl H-atoms at 6.58 (dd,
J ¼ 12.3 and 1.2 Hz) and 5.89 ppm (dd, J ¼ 12.3 and 7.2 Hz), and the allylic H-atom at
5.06 ppm (m), in keeping with a 13C q at 22.64 ppm, and ds at 144.12, 119.38, and
63.04 ppm. The six ss of 14 and 15 were assigned by comparison with 12 [3]. Due to the
low solubility of 14 and 15, their high-resolution (HR)-MALDImass spectra show
[M þ H]þ and [M þ Na]þ peaks of low intensity relative to the matrix signals. In the
1H-NMR spectum of 16, the two pyrrole H-atoms resonate as ds at 6.92 and 6.27 ppm
(J ¼ 4.0 Hz). They show cross-peaks with two ds at 112.73 and 111.66 ppm in the HSQC
1
spectrum. The HSQC spectrum also reveals a q at 16.57 ppm. The corresponding H
signal is hidden by the signal of residual DMSO. The structure of 16 is further
1
evidenced by a comparison of the UV, and H- and 13C-NMR spectra with those of
closely related pyrrolocarbamides [10 – 12], by a high-resolution MALDI-MS, and by
1
elemental analysis. The H-NMR spectum of 18 shows signals at 7.45 (dd), 6.41 (dd),
6.34 (d), and 6.17 ppm (dq) with J(1’,2’) ¼ 15.6, J(2’,3’) ¼ 10.5, and J(3’,4’) ¼ 15.3 Hz,
coupling constants that are typical of pentadienes. HÀN(1) gives rise to a very broad
signal between 12 and 14 ppm.
Deep green crystals of 10 were obtained in hexane/CHCl3 at 48. Even at this low
temperature, 10 was partially transformed into a yellow precipitate of 12, indicating the
ease of the hetero-Diels – Alder cycloaddition.
The unit cell of crystalline1) 10 (Fig. 1) represents a centrosymmetric duplex
connected by four N(2)ÀH ··· O¼C(2’) and N(2)ÀH ··· N(3) H-bonds, with H ··· O and
H ··· N distances of 2.20 and 2.12 Š, respectively. The intramolecular H-bond between
the N¼O group and the amide H-atom (1.87 Š) prevents the [4 þ 2] cycloaddition of 10
in the solid state. The strength of this H-bond is also reflected in the 1H-NMR spectrum
((D6)DMSO) where NÀH resonates at 12.36 ppm.
That the transformation of the dienoyl nitrosoamide 10 into guanine 17 competes
successfully with the readily occurring Diels – Alder cycloaddition suggested that it
should not be difficult to find conditions to favour either the ene reaction of N-alkenoyl
analogues, such as 19, or their reductive condensation (Scheme 3). The amide 19 was
prepared by acylating 1 with crotonyl chloride in THF. This led initially to a yellow
1
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Center as
deposition No. CCDC-670298 for 10, CCDC-670299 for 21b, and CCDC-670300 for 30. Copies of
the data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif (or from
the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB21EZ (fax:
þ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta – Vol. 91 (2008)
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Fig. 1. Crystal structure of 10 (ORTEP drawing of the centrosymmetric dimer)
precipitate2) and, after basic aqueous workup, to the N-crotonyl-nitrosopyrimidine 19
that was isolated as a blue-green powder. It was best recrystallized in boiling EtOH, as
heating in boiling toluene effected the ene reaction that proceeded quantitatively
within 10 min. The product, however, was a dimer rather than the expected vinyl-
pteridine 20a. The HSQC spectrum of 21a showed a conspicuous 1H signal at 6.18 ppm
and a cross-peak with a C-atom resonating at 54.8 ppm, suggesting that the ene reaction
was followed by an aza-Diels – Alder reaction3) to 21a. The strong deshielding of the
signal at 6.18 ppm indicated a conformation of 21a with the tertiary HÀC(10) in the
deshielding cone of the pteridinone C¼O group. Screening of solvents showed that
performing the ene reaction in MeCN allowed isolation of the 6-vinylpteridine 20a that
was transformed into 21a upon heating in toluene.
Treatment of 20a with Bredereckꢁs reagent led to the amidine 20b that is well
soluble in a range of apolar solvents (compare [15][16]). Its solution in DMSO formed
a dimer already at room temperature, i.e., even more readily than 20a, in agreement
with a narrow HOMO/LUMO energy gap, as suggested by semiempirical calcula-
tions4) (Table).
The structure of 20a is evidenced by the HR-MALDImass spectrum, elemental
analysis, ATR-IR NH bands at 3407 and 3214 cmÀ1, and the NMR spectra
((D6)DMSO), with the alkenyl H-atom resonating at 6.89 (dd, J ¼ 17.7 and 11.1 Hz),
6.39 (dd, J ¼ 17.7 and 2.4 Hz), and 5.52 ppm (dd, J ¼ 11.1 and 2.4 Hz), in keeping with a
Filtration led to a very hygroscopic solid. Its 1H-NMR spectrum evidenced a mixture of at least two
2
)
products, presumably of 19 and the O-acylated 24.
3
4
)
For the inverse electron demand Diels – Alder reaction of similarly substituted 1-azabuta-1,3-dienes,
cf. the work of Boger et al. [13][14].
For comparison, we calculated the HOMO and LUMO energies of cyclopentadiene (De ¼
9.561 eV) and fulvene (De ¼ 8.622 eV). Comparison of these values with experimental data [17]
and with values obtained by more sophisticated calculations [18] show agreement only for the
HOMO/LUMO energy differences.
)

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Scheme 3
a) Crotonyl chloride (¼ but-2-enoyl chloride), THF; 85%. b) Toluene; ca. 96%. c) MeCN; 91%. d)
Toluene; ca. 98%. e) t-BuOCH(NMe)2, MeCN; 89%. f ) Toluene; quant. g) Ph3P, o-xylene; 80%. h)
LiBr, Me3SiCl, MeCN; 92%.
Table. LUMO and HOMO Energies and Orbital Coefficients of 20a and 20b Obtained from AM1
Calculations [19]
e [eV]
De [eV]
p-Orbital coefficientsa)
C(5)
C(6)
C(1’)
0.085
C(2’)
20a
20b
LUMO
HOMO
LUMO
HOMO
À 1.291
À 9.122
À 1.158
À 8.722
7.831
7.564
À 0.320
0.258
0.412
0.390
0.379
0.380
À 0.259
À 0.368
À 0.237
À 0.321
À 0.268
À 0.294
0.080
0.211
À 0.216
a) Figures in italics refer to favourable HOMO – LUMO interactions.
13C d at 131.56 and a t at 120.86 ppm. A single crystal1) of 21b was obtained by slowly
evaporating a solution of 21b in CH2Cl2/MeOH/toluene. The X-ray analysis confirms
the proposed structure (Fig. 2) and shows a co-crystallizing mixture of enantiomers.
The NMR spectra of 21a and 21b are very similar, and the proximity of HÀC(10) to
O¼C(7’) (2.63 Š) and to C(1)ÀOÀCH2Ph (2.15 Š), as in the crystal structure of 21b,
is indeed responsible for the strong downfield shift for HÀC(10) of 21a (6.18 ppm) and
21b (6.33 ppm). In the HMBC spectrum of 21b, the formamidinyl H-atoms show cross-
peaks with C(2’) and C(3) at 163.58 and 156.52 ppm, indicating that the assignment of
C(2) and C(8a) in [3] and [4] has to be reversed.

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Fig. 2. Crystal structure of 21b
Treating the N-crotonoyl-nitrosopyrimidine 19 with Ph3P in boiling o-xylene
yielded 80% of the purine 22 that was debenzylated with in situ generated Me3SiBr to
yield 92% of the poorly soluble 8-(prop-1-enyl)guanine (23).
The scope of the PIII-mediated condensation of vicinal (acylamino)-nitrosopyrimi-
dines was further tested by synthesizing two guanine derivatives that may not be readily
prepared by alternative methods. First, we synthesized the known 8-(trifluoromethyl)-
purines 26 and 27. 8-(Trifluoromethyl)guanine (27) had been obtained in a yield of
77% by heating pyrimidine-5,6-diamine with a mixture of (CF3CO)2O and CF3COOH
to 2608 [20], or in a yield of 46% by treating guanine with CF3I, FeSO4, and H2O2 in a
H2O/DMSO mixture [21]. The O-benzyl derivative 26 had been obtained in 29%
overall yield by chlorinating 27 with phosphorous oxychloride followed by treatment
with benzyl alcohol and NaH [22]. We prepared 26 from 1 via the nitroso amide 25
(Scheme 4), maintaining the temperature below À 208 to avoid overacylation. As 25
proved labile towards MeOH and silica, we treated the crude acylation product with
Ph3P in boiling o-xylene and obtained 26 in a yield of 81% from 1.
Scheme 4
a) (CF3CO)2O, THF. b) Ph3P, o-xylene; 81% from 1. c) LiBr, Me3SiCl, MeCN; 86%.

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8-(Trifluoromethyl)guanine (27) was obtained in a yield of 86% by treating 26 with
Me3SiBr. The spectroscopic data of 26 match the data provided by Chae et al. [22], and
the data of 27 those provided by Pfleiderer and Shanshal [20]. The 13C-NMR spectrum
of 26 shows a q of the CF3 group at 118.88 ppm (J ¼ 267.8 Hz) and a q at 136.92 ppm
(J ¼ 38.8 Hz) for the vicinal 13C(8). Similarly, the 13C-NMR spectrum of 27 showed the
corresponding q at 118.67 ppm (J ¼ 267.7 Hz) and at 133.92 ppm (J ¼ 40.5 Hz).
As a second example, we selected the C2-symmetric bisguanidines 30 – 32 in view of
the tendence of guanines to form linear or cyclic associates [23 – 26]. Acylation of 1
with l-tartaryl chloride 28 [27][28] in THF provided the dicarboxamide 29 as a blue
solid that was isolated by precipitation from THF and treated with Ph3P in boiling
o-xylene to yield 81% of 30 (Scheme 5).
Scheme 5
a) 28, THF; 93%. b) Ph3P, o-xylene; 87%. c) 1. LiBr, Me3SiCl, MeCN; 82%. 2. 1n HCl/THF 1:1; ca. 98%.
Debenzylation of 30 with Me3SiCl provided 31 (82%) that was deisopropyliden-
ated by aqueous HCl in THF (Scheme 5) to provide 32 in 80% yield from 29. The
structure of the C2-symmetric 32 is evidenced by a HR-MALDImass spectrum and by
the NMR spectra ((D6)DMSO), where C(1) resonates as a d at 68.85 ppm and HÀC(1)
as a s at 5.22 ppm. A broad HN(1’) and OH band from 3350 to 2250 in the ATR-IR
spectrum evidences the formation of H-bonded aggregates in the solid state.
Single crystals1) of 30 were obtained by isothermal distillation of hexane into a
solution of 30 in CHCl3/MeOH. The crystal structure shows a left handed helix (Fig. 3)
held together by four H-bonds per purine residue, with H ··· X distances (X ¼ O or N)
of 2.08 and 2.03 (NH2 ··· OiPr), 1.93 and 1.94 (N(3’) ··· HÀN(9’)), 1.99 and 1.98
(N(9’)ÀH ··· N(3’)), and 2.04 and 1.98 Š (iPrO ··· H2N) for the short and long edge,
respectively. Four molecules form one turn of the helix with a pitch of 30.2 Š. The
projection of the purinyl residues parallel to the axes of the helix defines a rectangular
core with the dimensions of 5.7 ꢀ 8.5 Š.

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Fig. 3. Crystal structure of 30. a) Side view on the helix displaying the four intermolecular H-bonds per
purine residue. b) Top view on a helix formed by 20 molecules.
We thank the ETH-Zürich for generous support, Dr. Bruno Bernet for checking the analytical data,
and Dr. W. Bernd Schweizer for determining the crystal structures.
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 light
(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 cmÀ1 1H- and 13C-NMR spectra:
chemical shift d in ppm rel. to TMS as external standard; 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]hexa-2,4-dienamide (10). A vigorously stirred
suspension of 1 (490 mg, 2.0 mmol) and DMAP (122 mg, 1.0 mmol) in dry CH2Cl2 (30 ml) was cooled to
À 208 and treated with a precooled soln. of sorbyl chloride (0.301 ml, 2.4 mmol) in CH2Cl2 (4 ml) in one
single portion. The mixture was kept at À 158 for 12 h, diluted with sat. aq. NaHCO3 soln. (20 ml), and
extracted with CH2Cl2 (3 ꢀ 100 ml). The combined org. phases were washed with brine, dried (Na2SO4),
concentrated to 50 ml, and filtered through a pad of silica (MeOH/CH2Cl2 3 :97). After concentration to
70 ml, addition of hexane led to a precipitate of 10 (583 mg, 86%). Green powder. Rf (CH2Cl2/MeOH
9 :1) 0.65. M.p. 1308 (dec.). UV (MeOH, c ¼ 0.06 mm): 205 (4.49), 263 (4.50), 347 (4.52). VIS (DMSO,
c ¼ 0.005m): 630 (1.99). IR (ATR): 3480w, 3304w, 3204m, 2918w, 1717w, 1626s, 1603s, 1533s, 1497m, 1485s,
1455s, 1441s, 1397m, 1337s, 1331s, 1306m, 1272m, 1240s, 1202s, 1171s, 1143s, 1113s, 1055m, 1035m, 1008s,
983m, 918w, 881m, 842w, 788m, 772w, 735s, 711m, 687m, 625m, 616w. 1H-NMR (300 MHz, (D6)DMSO):
12.36 (s, HNÀC(4’)); 8.75 (s, NH2); 7.56 – 7.40 (m, 5 arom. H); 7.28 (dd, J ¼ 15.0, 6.9, HÀC(3)); 7.02 (d,
J ¼ 15.0, HÀC(2)); 6.46 – 6.28 (m, HÀC(4), HÀC(5)); 5.62 (s, PhCH2); 1.86 (d, J ¼ 5.7, Me). 13C-NMR
(75 MHz, (D6)DMSO): 166.15 (s, C¼O); 163.34 (s, C(6’)); 144.60 (d, C(3)); 140.65 (d, C(5)); 138.53 (s,
C(4’)); 135.47 (s); 130.04 (d, C(2)); 128.34 (2d); 128.29 (2d); 128.11 (d); 122.62 (d, C(4)); 68.47 (t,
PhCH2); 18.64 (q, Me); signals of C(5’) and C(2’) not visible due to coalescence. HR-MALDI-MS:
340.1401 (100, C17H18N5Oþ3 , [M þ H]þ; calc. 340.1404).
X-Ray Analysis of 10. Crystals of 10 were obtained by isothermal distillation of hexane into a soln. of
10 in CHCl3 at 48 (dimensions of the analyzed crystal: 0.28 ꢀ 0.14 ꢀ 0.02 mm; colour: green).
C17H17N5O3, Mr 339.355, triclinic, P1, a ¼ 7.5948(2), b ¼ 10.0150(3), c ¼ 11.9388(4) Š, a ¼ 108.6795(14),

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Helvetica Chimica Acta – Vol. 91 (2008)
b ¼ 94.398(2), g ¼ 102.6297(13)8, V¼ 828.80(4) Š3, Z ¼ 2, Dx ¼ 1.360 Mg/m3. Intensities were measured
on a Nonius Kappa CCD diffractometer, with MoKa radiation l ¼ 0.71073 Š. Cell parameters from 10948
refl., q ¼ 0.998 – 27.4858, m ¼ 0.097 mmÀ1, T¼ 223 K. 7167 measured reflections, 3789 independent
reflections, 2428 observed reflections (>2s(I)). Refinement on F2: full-matrix least-squares refinement,
R(all) ¼ 0.0924, R(gt) ¼ 0.0542. 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.
2-Amino-4-(benzyloxy)-6-[(Z)-3-hydroxybut-1-enyl]pteridin-7(8H)-one (12). A suspension of 10
(339 mg, 1 mmol) in toluene (10 ml) was heated to 1008, affording a green soln. After 3 h at 1008, the
yellow suspension was filtered. The solid washed with H2O, AcOEt, and Et2O. Drying in vacuo gave 12
(332 mg, 98%). Yellow powder. M.p. 2428 (dec.). UV: 211 (4.59), 235 (4.14), 290 (3.82), 378 (4.27). IR
(ATR): 3420m, 3323w, 3208m, 2834w, 2737w (br.), 1802w, 1670w, 1614s, 1560s, 1538m, 1496m, 1490m,
1464m, 1428s, 1387m, 1356s, 1327m, 1307m, 1182s, 1052s, 975m, 927m, 905m. 1H-NMR (300 MHz,
(D6)DMSO): 12.40 (s, HÀN(8)); 7.53 – 7.32 (m, 5 arom. H); 7.24 (s, NH2); 6.61 (dd, J ¼ 12.3, 1.2,
HÀC(1’)); 5.95 (dd, J ¼ 12.0, 7.5, HÀC(2’)); 5.49, 5.44 (2d, J ¼ 12.6, PhCH2); 5.18 – 5.11 (m, HÀC(3’));
4.89 (d, J ¼ 4.2, OH); 1.20 (d, J ¼ 6.3, Me). 13C-NMR (100 MHz, (D6)DMSO): 164.51 (s, C(4)); 161.39 (s,
C(2)); 157.13 (s, C(7)); 150.63 (s, C(8a)); 146.08 (s, C(6)); 145.75 (d, C(2’)); 136.31 (s); 128.23 (2d); 127.77
(2d); 127.36 (d); 118.56 (d, C(1’)); 107.54 (s, C(4a)); 67.32 (t, PhCH2); 63.45 (d, C(3’)); 22.26 (q, Me). HR-
MALDI-MS: 362.1223 (82, C17H17N5NaO3þ, [M þ Na]þ; calc. 362.1229), 340.1402 (35, C17H18N5Oþ3 , [M þ
H]þ; calc. 340.1410), 322.1299 (100, C17H16N5Oþ2 , [M À OH]þ; calc. 322.1304). Anal. calc. for C17H17N5O3
(339.35): C 60.17, H 5.05, N 20.64; found: C 60.38, H 5.15, N 20.50.
2-Amino-4-(benzyloxy)-6-[(E)-3-hydroxybut-1-enyl]pteridin-7(8H)-one (13). A suspension of 12
(100 mg, 0.295 mmol) in toluene (5 ml) was treated with AcOH (50 ml) and stirred for 12 h at 808.
Filtration gave 13 (98 mg, 98%). M.p. > 2458 (dec.). UV (MeOH): 213 (4.54), 236 (4.14), 292 (3.86), 373
(4.30). IR (ATR): 3344m, 3190m, 2973m, 2888w, 2835w, 2767w, 1653s, 1614s, 1557s, 1530s, 1497s, 1480m,
1443s, 1390m, 1340s, 1304m, 1275m, 1215w, 1178m, 1084m, 1063m, 981w, 942m, 911w, 847w, 798w, 756m,
1
702m, 690w, 652w, 619w. H-NMR (300 MHz, (D6)DMSO): 12.39 (s, HÀN(8)); 7.55 – 7.35 (m, 5 arom.
H); 7.19 (s, NH2); 6.95 (dd, J ¼ 15.9, 5.4, HÀC(2’)); 6.74 (dd, J ¼ 15.9, 1.2, HÀC(1’)); 5.49 (s, PhCH2); 4.93
(br. s, OH); 4.31 (quint., J ¼ 6.3, HÀC(3’)); 1.18 (d, J ¼ 6.6, Me). 13C-NMR (75 MHz, (D6)DMSO):
164.44 (s, C(4)); 161.17 (s, C(2)); 156.94 (s, C(7)); 150.85 (s, C(8a)); 145.27 (s, C(6)); 142.47 (d, C(2’));
136.38 (s); 128.46 (2d); 128.41 (2d); 128.07 (d); 121.82 (d, C(1’)); 107.73 (s, C(4a)); 67.37 (t, PhCH2); 66.42
(d, C(3’)); 23.50 (q, Me).
2-Amino-6-[(E)-3-hydroxybut-1-enyl]pteridin-4,7(3H,8H)-dione (14). A soln. of 13 (150 mg,
0.442 mmol) in 1n aq. NaOH/dioxane 5 :1 (18 ml) was heated under reflux for 2 h, and treated with
charcoal (20 mg) for 10 min. The hot suspension was filtered, and the filtrate was added dropwise to a
boiling soln. of H2O/AcOH 6 :1 (17.5 ml). Filtration of the precipitate and washing of the solid with H2O
and EtOH gave 14 (96 mg, 87%). Yellow powder. M.p. > 3308 (dec.). IR (ATR): 3476w, 3128m, 2864m,
2772m, 1633s, 1597s, 1555s, 1476m, 1442m, 1389s, 1338m, 1258w, 1183w, 1161w, 1107w, 1056m, 916m,
1
842w, 819w, 782w, 748w, 702w, 657m. H-NMR (300 MHz, (D6)DMSO): 12.33 (s, HÀN(8)); 11.00 (s,
HÀN(3)); 7.03 (br, s, NH2); 6.90 (dd, J ¼ 15.9, 5.4, HÀC(2’)); 6.71 (d, J ¼ 15.6, HÀC(1’)); 4.93 (br. s,
OH); 4.31 (quint., J ꢁ 5.9 HÀC(3’)); 1.18 (d, J ¼ 6.6, Me). 13C-NMR (75 MHz, (D6)DMSO): 158.63 (s,
C(2)); 156.80 (s, C(7)); 154.60 (s, C(4)); 150.46 (s, C(8a)); 143.72 (d, C(2’)); 141.24 (s, C(6)); 121.70 (d,
C(1’)); 111.01 (s, C(4a)); 66.45 (d, C(3’)); 23.57 (q, Me).
2-Amino-6-[(Z)-3-hydroxybut-1-enyl]pteridin-4,7(3H,8H)-dione (15). A soln. of 13 (678 mg,
2.0 mmol) in 1n aq. NaOH/dioxane 5 :1 (72 ml) was heated under reflux for 2 h and treated with
charcoal (50 mg) for 10 min. The hot suspension was filtered, and the filtrate was added dropwise to a
boiling soln. of H2O/AcOH 6 :1 (70 ml). Filtration of the precipitate and washing of the solid with H2O
and EtOH gave 15 (458 mg, 92%). Yellow powder. M.p. > 3308 (dec.). IR (ATR): 3475w, 3128m, 2864m,
2772m, 1633s, 1597s, 1556s, 1476m, 1442m, 1407m, 1389s, 1338m, 1258w, 1183w, 1161w, 1107w, 1056m,
916m, 843w, 819w, 785w, 748w, 702w, 657m. 1H-NMR (300 MHz, (D6)DMSO): 12.35 (s, HÀN(8)); 11.11
(s, HÀN(3)); 7.02 (br. s, NH2); 6.58 (dd, J ¼ 12.3, 1.2, HÀC(1’)); 5.89 (dd, J ¼ 12.3, 7.2, HÀC(2’)); 5.09 –
5.04 (m, HÀC(3’), OH); 1.22 (d, J ¼ 6.6, Me). 13C-NMR (75 MHz, (D6)DMSO): 158.50 (s, C(2)); 157.08
(s, C(7)); 154.75 (s, C(4)); 150.48 (s, C(8a)); 144.50 (s, C(6)); 144.12 (d, C(2’)); 119.38 (d, C(1’)); 110.83 (s,

Helvetica Chimica Acta – Vol. 91 (2008)
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C(4a)); 63.04 (d, C(3’)); 22.64 (q, Me). HR-MALDI-MS: 272.0749 (100, C10H11N5NaOþ, [M þ Na]þ; calc.
250.0754), 250.0938 (50, C10H12N5Oþ, [M þ H]þ; calc. 250.0935).
3-Amino-9-methylpyrrolo[1,2-f]pteridine-1,6(2H,5H)-dione (16). Solid 15 (15 mg, 0.060 mmol) was
heated in a sublimation tube to 3008 under vacuum (<10À3 mbar). After 16 h, sublimed 16 (4 mg, 29%)
was obtained. M.p. > 3008 (dec.). UV (MeOH): 219 (4.19), 275 (4.23), 304 (3.81). IR (ATR): 3469w,
3310w, 3097m, 2898m, 2750m, 1642s, 1601s, 1556m, 1493m, 1400m, 1377m, 1351s, 1318m, 1259w, 1211w,
1186m, 1091w, 1037w, 1001w, 980w, 808w, 783m, 760m, 733m, 703w, 666w, 644w, 607w. 1H-NMR
(400 MHz, (D6)DMSO): 11.04 (br. s, HÀN(2), HÀN(5)); 6.92 (d, J ¼ 4.0, HÀC(7)); 6.71 (br. s, NH2);
6.27 (dq, J ¼ 4.0, 0.7, HÀC(8)); ca. 2.5 (hidden by solvent signal, Me). 13C-NMR (100 MHz, (D6)DMSO):
155.48, 155.33 (2s, C(3), C(6)); 152.74 (s, C(1)); 149.59 (s, C(4a)); 133.59 (s, C(9)); 122.92 (s, C(6a));
112.73, 111.66 (2d, C(7), C(8)); 98.37 (s, C(10a)); 16.57 (q, Me). HR-MALDI-MS: 254.0649 (25,
C10H9N5NaOþ2 , [M þ Na]þ; calc. 254.0649), 232.0824 (100, C10H10N5Oþ2 , [M þ H]þ; calc. 232.0829). Anal.
calc. for C10H9N5O2 (231.21): C 51.95, H 3.92, N 30.29; found: C 51.46, H 3.85, N 30.19.
2-Amino-6-(benzyloxy)-8-[(E,E)-penta-1,3-dienyl]purine (17). A suspension of 10 (350 mg,
1.032 mmol) in o-xylene (10 ml) was treated with Ph3P (649 mg, 2.478 mmol), warmed to 1458, and
stirred at that temp. for 20 h (colourless soln.). Evaporation and FC (MeOH/CH2Cl2 3 :97) gave 17
(273 mg, 86%). Colourless solid. Rf (CH2Cl2/MeOH 9 :1) 0.42. M.p. 2108 (dec.). UV (MeOH): 207
(4.34), 259 (4.22), 335 (4.51). IR (ATR): 3221w, 3200w, 2954w, 2925w, 1606s, 1514m, 1434s, 1338m,
1242m, 1211s, 1149m, 1063m, 1025m, 997s, 942m, 910w, 863w, 822w, 746s, 695m, 663m. 1H-NMR
(400 MHz, (D6)DMSO): 12.45 (s, HÀN(9)); 7.51 – 7.33 (m, 5 arom. H); 7.10 (dd, J ¼ 15.3, 10.2, HÀC(2’));
6.33 (s, NH2); 6.32 (d, J ¼ 15.3, HÀC(1’)); 6.26 (dd, J ¼ 14.7, 10.2, HÀC(3’)); 5.95 (dq, J ¼ 14.7, 6.9,
HÀC(4’)); 5.45 (s, PhCH2); 1.80 (d, J ¼ 6.9, Me). 13C-NMR (100 MHz, (D6)DMSO): 159.49 (s, C(6));
159.23 (s, C(2)); 156.05 (s, C(4)); 146.93 (s, C(8)); 136.67 (s); 133.77 (d, C(2’)); 133.04 (d, C(4’)); 131.13
(d, C(3’)); 128.35 (2d); 128.29 (2d); 127.90 (d); 118.57 (d, C(1’)); 114.60 (s, C(5)); 66.65 (t, PhCH2); 18.15
(q, Me). HR-MALDI-MS: 330.1338 (11, C17H17N5NaOþ, [M þ Na]þ; calc. 330.1331), 308.1509 (100,
C17H18N5Oþ, [M þ H]þ; calc. 308.1506). Anal. calc. for C17H17N5O (307.35): C 66.43, H 5.57, N 22.79;
found: C 66.17, H 5.58, N 22.56.
8-[(E,E)-Penta-1,3-dienyl]guanine (18). At 08, a suspension of 17 (200 mg, 0.651 mmol) in dry
MeCN (6 ml) was treated with anh. LiBr (72 mg, 0.847 mmol) and Me3SiCl (0.123 ml, 0.977 mmol),
warmed to 238, and stirred for 4 h. The suspension was cooled to 08, diluted with MeOH (2 ml), stirred
for 15 min, and filtered. The colourless solid was washed with H2O, Et2O, and pentane. Drying in vacuo
gave 18 (135 mg, 95%). M.p. > 2908 (dec.). UV (MeOH): 205 (4.01), 271 (4.19), 332 (4.22). IR (ATR):
3361w, 3306w, 3119m, 3038m, 2927m, 2808m, 2658m, 2559m, 1697m, 1646s, 1606s, 1542s, 1435m, 1355m,
1300m, 1265m, 1225w, 1152m, 1070w, 990m, 929w, 873m, 826w, 784m, 762m, 720w, 698w, 674w, 660w.
1H-NMR (300 MHz, (D6)DMSO): 14 – 12 (br. s, HÀN(1)); 11.65 (br. s, HÀN(9)); 7.45 (dd, J ¼ 15.3, 10.5,
HÀC(2’)); 7.26 (s, NH2); 6.41 (dd, J ¼ 15.3, 10.2, HÀC(3’)); 6.34 (d, J ¼ 15.9, HÀC(1’)); 6.17 (dq, J ¼ 15.3,
6.9, HÀC(4’)); 1.86 (br. d, J ¼ 6.9, Me). 13C-NMR (75 MHz, (D6)DMSO): 154.88 (s, C(6)); 153.04 (s,
C(2)); 150.96 (s, C(4)); 145.28 (s, C(8)); 140.08 (d, C(2’)); 138.68 (d, C(4’)); 130.58 (d, C(3’)); 112.03 (d,
C(1’)); 108.53 (s, C(5)); 18.57 (q, Me). HR-MALDI-MS: 218.1030 (100, C10H12N5Oþ, [M þ H]þ; calc.
218.1036).
N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]but-2-enamide (19). A soln. of 1 (1.150 g,
4.694 mmol) in dry THF (40 ml) was cooled to 08, treated with freshly distilled crotonyl chloride
(0.537 ml, 5.633 mmol), and stirred for 1 h at 08 and 1 h at r.t.. The green suspension was diluted with
H2O (30 ml) and extracted with CH2Cl2 (3 ꢀ 80 ml). The combined org. phases were dried (Na2SO4) and
concentrated to 50 ml. Addition of hexane led to precipitation of 19 (1.252 g, 85%). Two crystallisations
of a small sample from hot EtOH gave long green needles. Rf (CH2Cl2/MeOH 9 :1) 0.65. M.p. 1688 (dec.).
UV (MeOH, c ¼ 0.09 mm): 208 (4.34), 263 (4.17), 353 (4.31). VIS (DMSO, c ¼ 0.005m): 624 (1.99). IR
(ATR): 3486w, 3307m, 3209m, 3030w, 1721m, 1630s, 1595s, 1543s, 1500m, 1486s, 1443s, 1395m, 1352s,
1331s, 1286s, 1271m, 1202s, 1153s, 1129s, 1103s, 1058m, 1031m, 995m, 968m, 941m, 920m, 845m, 830m,
1
792m, 769w, 731m, 715m, 687m, 669m, 662m. H-NMR (300 MHz, (D6)DMSO): 12.40 (s, HNÀC(4’));
8.77, 8.72 (2s, NH2); 7.56 – 7.36 (m, 5 arom. H); 6.95 (dq, J ¼ 15.3, 6.6, HÀC(3)); 6.82 (dd, J ¼ 15.0, 1.2,
HÀC(2)); 5.62 (s, PhCH2); 1.92 (dd, J ¼ 6.6, 1.2, Me). 13C-NMR (75 MHz, (D6)DMSO): 165.47 (s,
C¼O); 163.66 (s, C(6’)); 144.79 (d, C(3)); 138.85 (s, C(4’)); 135.64 (s); 128.51 (2d), 128.45 (2d); 128.28

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Helvetica Chimica Acta – Vol. 91 (2008)
(d); 126.24 (d, C(2)); 68.47 (t, PhCH2); 17.96 (q, Me); signals of C(5’) and C(2’) not visible due to
coalescence. HR-MALDI-MS: 336.1057 (36, C15H15N5NaOþ3 , [M þ Na]þ; calc. 336.1067), 314.1242 (64,
C15H16N5Oþ3 , [M þ H]þ; calc. 314.1248), 283.1183 (100, C15H15N4Oþ2 , [M À NO]þ; calc. 283.1190). Anal.
calc. for C15H15N5O3 (313.32): C 57.50, H 4.83, N 22.35; found: C 57.20, H 4.92, N 22.15.
2-Amino-4-(benzyloxy)-6-ethenylpteridin-7(8H)-one (20a).
A suspension of 19 (150 mg,
0.479 mmol) in MeCN (10 ml) was heated to reflux, to form a blue soln. After 90 min, the yellow
precipitate was filtered off, and washed with CH2Cl2/MeOH 9 :1. The filtrate was heated to reflux for 3 h,
and filtration was repeated. Drying of the combined solids in vacuo gave 20a (121 mg, 91%). Pale yellow
solid. M.p. > 3008 (dec.). UV (MeOH, sat. soln.): 211 (3.75), 237 (3.36), 290 (3.18), 370 (3.50). IR
(ATR): 3407m, 3334w, 3214m, 2837w, 2743w, 1811w, 1654m, 1605s, 1556s, 1536s, 1484s, 1465s, 1439s,
1410m, 1388s, 1356s, 1312m, 1293m, 1261m, 1174m, 1096m, 1072m, 1039m, 988m, 927m, 846w, 810w,
791w, 735m, 721m, 691m, 638w, 618m. 1H-NMR (300 MHz, (D6)DMSO): 12.44 (s, HÀN(8)); 7.53 – 7.33
(m, 5 arom. H); 7.26 (s, NH2); 6.89 (dd, J ¼ 17.7, 11.1, HÀC(1’)); 6.39 (dd, J ¼ 17.7, 2.4, HaÀC(2’)); 5.52
(dd, J ¼ 11.1, 2.4, HbÀC(2’)); 5.49 (s, PhCH2). 13C-NMR (75 MHz, (D6)DMSO): 164.63 (s, C(4)); 161.43
(s, C(2)); 156.93 (s, C(7)); 151.10 (s, C(8a)); 144.85 (s, C(6)); 136.31 (s); 131.56 (d, C(1’)); 128.43 (2d);
128.41 (2d); 128.07 (d); 120.86 (t, C(2’)); 107.79 (s, C(4a)); 67.42 (t, PhCH2). HR-MALDI-MS: 318.0958
(100, C15H13N5NaOþ2 , [M þ Na]þ; calc. 318.0962), 296.1137 (68, C15H14N5Oþ2 , [M þ H]þ; calc. 296.1142).
Anal. calc. for C15H13N5O2 (295.30): C 61.01, H 4.44, N 23.72; found: C 60.53, H 5.71, N 23.28.
4-(Benzyloxy)-2-{[(dimethylamino)methylidene]amino}-6-ethenylpteridin-7(8H)-one (20b). A sus-
pension of 20a (140 mg, 0.475 mmol) in MeCN (8 ml) was treated at 238 with Bredereckꢀs reagent.
Stirring the mixture for 3 h led to a yellow strongly fluorescent soln. FC (reaction mixture directly
adsorbed on silica, CH2Cl2/MeOH 19 :1) and carefull evaporation (408, 350 mbar) gave 20b (148 mg,
89%). Rf (CH2Cl2/MeOH 9 :1) 0.51. M.p. > 1608 (dec.). UV (MeOH): 209 (4.48), 266 (4.12), 378 (4.47).
IR (ATR): 3091w, 3022w, 2924w, 1860w, 1675m, 1634w, 1614w, 1577s, 1544s, 1526s, 1487m, 1461s, 1436s,
1420m, 1377s, 1354s, 1328s, 1279s, 1237m, 1203w, 1151w, 1113s, 1067w, 1017w, 998m, 985m, 953w, 928m,
896w, 884w, 859w, 814w, 796w, 748w, 727m, 693m, 669w, 623w, 616w. 1H-NMR (300 MHz, (D6)DMSO):
12.62 (br. s, HÀN(8)); 8.72 (s, HC¼N); 7.53 – 7.35 (m, 5 arom. H); 6.96 (dd, J ¼ 17.7, 11.1, HÀC(1’)); 6.47
(dd, J ¼ 17.7, 2.4, HaÀC(2’)); 5.60 (dd, J ¼ 11.1, 2.4, HbÀC(2’)); 5.83 (s, PhCH2); 3.19, 3.07 (2s, Me2N).
HR-MALDI-MS: 351.1558 (100, C18H19N3Oþ2 , [M þ H]þ; calc. 351.1564).
3-Amino-10-[2-amino-4-(benzyloxy)-7-oxo-7,8-dihydropteridin-6-yl]-1-(benzyloxy)-9,10-dihydro-
5H-pyrido[1,2-f]pteridin-6(8H)-one (21a). From 19. A suspension of 19 (50 mg, 0.160 mmol) in toluene
(5 ml) was heated to reflux for 10 min. After cooling to r.t., the yellow precipitate was filtered off and
washed with CH2Cl2/MeOH 9 :1. Drying of the residue in vacuo gave 21a (48 mg, 96%).
From 21a. A suspension of 21a (200 mg, 0.640 mmol) in toluene (10 ml) was heated to reflux for 6 h.
After cooling to r.t., the yellow precipitate was filtered off and washed with CH2Cl2/MeOH 9 :1. Drying
of the residue in vacuo gave 21a (195 mg, 98%).
Data of 21a. M.p. > 3008 (dec.). UV (MeOH, sat. soln.): 209 (4.33), 287 (3.67), 361 (3.88). IR
(ATR): 3464w, 3318w, 3200w, 2924w, 2867w, 2770w, 1666m, 1614s, 1562s, 1495s, 1453s, 1434s, 1380m,
1351s, 1331s, 1268m, 1246m, 1208w, 1156s, 1096w, 1060m, 1040w, 970w, 941w, 908w, 841w, 804w, 771w,
730m, 694m, 623w. 1H-NMR (400 MHz, (D6)DMSO): 12.34 (br. s, HÀN(8’)); 10.88 (s, HÀN(5)); 7.42 –
7.12 (m, 10 arom. H); 7.09 (br. s, C(2’)ÀNH2); 6.18 (t, J ꢁ 3.6, HÀC(10)); 5.98 (br. s, C(3)ÀNH2); 5.58 (t,
J ꢁ 2.2, HÀC(7)); 5.43 (d, J ¼ 13.4, PhCH); 5.39 (d, J ¼ 12.4, PhCH); 5.33 (d, J ¼ 13.6, PhCH); 5.13 (d,
J ¼ 12.5, PhCH); 3.37 (br. d, J ¼ 11.5, HaÀC(9)); 2.10 – 1.89 (m, HbÀC(9), 2 HÀC(8)). 13C-NMR
(100 MHz, (D6)DMSO): 164.13 (s, C(4’)); 161.29 (s, C(2’)); 159.72 (s, C(6)); 156.27 (s, C(7’)); 155.06,
155.04 (2s, C(1), C(3)); 151.10 (s, C(8a’)); 149.21 (s, C(6’)); 146.77 (s, C(4a)); 136.63 (s); 136.45 (s); 132.40
(s, C(6a)); 128.36 (2d); 127.91 (2d); 127.69 (2d); 127.43 (d); 127.16 (d); 126.25 (2d); 106.74 (s, C(4a’));
102.14 (s, C(11a)); 101.81 (d, C(7)); 66.44, 66.39 (2t, 2 PhCH2); 54.83 (d, C(10)); 22.87 (t, C(9)); 18.48 (t,
C(8)). HR-MALDI-MS (retro-Diels – Alder reaction occurred under the conditions of the measure-
.
.
ment): 591.2199 (37, C30H27N10O4þ, [M þ H]þ; calc. 591.2211), 590.2127 (36, C30H26N10Oþ4 , Mþ ; calc.
590.2133), 296.1137 (100, C15H14N5O2þ, [M/2 þ H]þ; calc. 296.1142). Anal. calc. for C30H26N10O4 (590.60):
C 61.01, H 4.44, N 23.72; found: C 60.73, H 5.50, N 23.63.
1-(Benzyloxy)-10-(4-(benzyloxy)-2-{[(dimethylamino)methylidene]amino}-7-oxo-7,8-dihydropteri-
din-6-yl)-3-{[(dimethylamino)methylidene]amino}-9,10-dihydro-5H-pyrido[1,2-f]pteridin-6(8H)-one

Helvetica Chimica Acta – Vol. 91 (2008)
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(21b). A suspension of 20b (100 mg, 0.286 mmol) in toluene (7 ml) was heated to 608 and stirred for 6 h.
Evaporation gave 21b (100 mg, quant.). Rf (CH2Cl2/MeOH 9 :1) 0.36. M.p. 199 – 2008 (dec.). UV
(MeOH): 207 (4.57), 344 (4.34). IR (ATR): 3180w, 2925w, 1681m, 1618m, 1582s, 1547s, 1432s, 1374s,
1349s, 1318s, 1238m, 1166m, 1155m, 1111m, 1093m, 1062m, 1017w, 984w, 951w, 907w, 880w, 851w, 809w,
779w, 740w, 725m, 692m, 661w, 622w. 1H-NMR (400 MHz, (D6)DMSO): 12.33 (br. s, HÀN(8’)); 11.05 (s,
HÀN(5)); 8.68, 8.30 (2s, 2 HC¼N); 7.43 – 7.09 (m, 10 arom. H); 6.33 (t, J ꢁ 3.8, HÀC(10)); 5.68 (d, J ꢁ
4.8, HÀC(7)); 5.51 (d, J ¼ 13.9, PhCH); 5.46 (d, J ꢁ 13.0, PhCH); 5.42 (d, J ꢁ 15.2, PhCH); 5.18 (d, J ¼
12.7, PhCH); 3.18, 3.06, 3.01, 2.91 (4s, 2 Me2N); 2.47 – 2.42 (m, HaÀC(9)); 2.15 – 1.91 (m, HbÀC(9), 2
HÀC(8)). 13C-NMR (100 MHz, (D6)DMSO): 164.42 (s, C(4’)); 163.58 (s, C(2’)); 159.19 (s, C(6)); 159.11,
157.03 (2d, 2 HC¼N); 156.52 (s, C(3)); 156.04 (s, C(7’)); 154.03 (s, C(1)); 152.16 (s, C(6’)); 150.76 (s,
C(8a’)); 146.38 (s, C(4a)); 136.97 (s); 136.69 (s); 132.08 (s, C(6a)); 128.39 (2d); 127.93 (2d); 127.36 (d);
127.14 (2d); 127.07 (d); 125.93 (2d); 108.95 (s, C(4a’)); 105.76 (s, C(11a)); 102.92 (d, C(7)); 66.70, 66.60
(2t, 2 PhCH2); 55.26 (d, C(10)); 40.67, 40.07, 34.64, 34.14 (4q, 2 Me2N); 22.61 (t, C(9)); 18.36 (t, C(8)).
HR-MALDI-MS: 701.3043 (60, C36H37N12Oþ4 , [M þ H]þ; calc. 701.3055); 351.1547 (100, C18H19N6Oþ2 , [M/
2 þ H]þ; calc. 351.1564). Retro-Diels – Alder reaction occurred under the conditions of the measurement.
Anal. calc. for C36H36N12O4 (700.76): C 61.70, H 5.18, N 23.99; found: C 61.57, H 5.24, N 23.71.
X-Ray Analysis of 21b. Crystals of 21b were obtained by slow evaporation of a soln. of 21b in a
mixture of CH2Cl2/MeOH/toluene (dimensions of the analyzed crystal: cube 0.36 ꢀ 0.18 ꢀ 0.10 mm;
colour: amber). 2(C36H36N12O4) · 1.66 MeOH · 1.34 CH2Cl2, Mr 1568.49, triclinic, P1, a ¼ 14.4432(3), b ¼
14.9092(4), c ¼ 20.0995(5) Š, a ¼ 72.2602(12), b ¼ 88.0190(14), g ¼ 78.4158(8)8, V¼ 4036.7(2) Š3, Z ¼ 2,
Dx ¼ 1.29 Mg/m3. Intensities were measured on a Nonius Kappa CCD diffractometer, with MoKa
radiation l ¼ 0.71073 Š, Cell parameters from 163419 refl., q ¼ 2.425 – 25.6828, m ¼ 0.185 mmÀ1, T¼
223 K. 28458 measured reflections, 14997 independent reflections, 10742 observed reflections
(>2s(I)). Refinement on F2: full-matrix least squares refinement, R(all) ¼ 0.1737, R(gt) ¼ 0.1412.
Crystal cut from a block with multiple non-merohedral twins. The measured crystal gave rise to
overlapping peaks (poor agreement of equivalent reflections). A mixture of disordered CH2Cl2 and
MeOH is present. 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.
2-Amino-6-(benzyloxy)-8-[(E)-prop-1-enyl]purine (22). A suspension of 19 (400 mg, 1.278 mmol)
in o-xylene (15 ml) was treated with Ph3P (803 mg, 3.066 mmol), heated to 1458 for 24 h, and allowed to
cool to r.t. FC (directly adsorbed on silica gel; CH2Cl2/MeOH 19 :1) gave 22 (287 mg, 80%). Rf (CH2Cl2/
MeOH 9 :1) 0.48. M.p. 2208. UV (MeOH): 215 (4.42), 309 (4.33). IR (ATR): 3480w, 3294w, 3186m,
3033w, 2962w, 1664w, 1618s, 1576s, 1482s, 1454m, 1439m, 1415s, 1395s, 1348s, 1322m, 1303m, 1263s,
1211m, 1153s, 1077m, 1005m, 994m, 950s, 907m, 843w, 789m, 752m, 714w, 695m, 674m. 1H-NMR
(300 MHz, (D6)DMSO): 12.42 (s, HÀN(9)); 7.51 – 7.34 (m, 5 arom. H); 6.60 (dq, J ¼ 16.2, 6.6, HÀC(2’));
6.32 (s, NH2); 6.27 (dq, J ¼ 16.2, 1.5, HÀC(1’)); 5.46 (s, PhCH2); 1.87 (dd, J ¼ 6.6, 1.5, Me). 13C-NMR
(75 MHz, (D6)DMSO): 159.48 (s, C(6)); 159.29 (s, C(2)) 156.06 (s, C(4)); 146.79 (s, C(8)); 136.75 (s);
131.58 (d, C(2’)); 128.39 (2d), 128.33 (2d); 127.93 (d); 121.27 (d, C(1’)); 114.06 (s, C(5)); 66.63 (t, PhCH2);
18.19 (q, Me). HR-MALDI-MS: 304.1170 (9, C15H15N5NaOþ, [M þ Na]þ; calc. 304.1174), 282.1344 (100,
C15H16N5Oþ, [M þ H]þ; calc. 282.1349). Anal. calc. for C15H15N5O (281.32): C 64.04, H 5.37, N 24.89;
found: C 63.78, H 5.60, N 24.81.
8-[(E)-Prop-1-enyl]guanine (23). A suspension of 22 (100 mg, 0.356 mmol) and anh. LiBr (36 mg,
0.427 mmol) in dry MeCN (5 ml) was treated with Me3SiCl (67 ml, 0.534 mmol), stirred for 12 h, cooled
to 08, treated with MeOH (1 ml), and stirred for 15 min. The colourless precipitate was filtered off, and
drying in vacuo afforded 23 (62 mg, 92%). M.p. > 3508 (dec.). UV (MeOH): 209 (4.13), 259 (4.03), 336
(4.27). IR (ATR): 3312m, 3165m, 2714m, 2628m, 2566m, 1677s, 1647s, 1612s, 1559s, 1453m, 1436m,
1366m, 1244w, 1137w, 1075w, 1016w, 959m, 859w, 765m, 671w. 1H-NMR (300 MHz, (D6)DMSO): 11.85
(s, HÀN(9)); 7.43 (s, NH2); 4.11 (dq, J ¼ 16.2, 7.2, HÀC(2’)); 6.39 (dq, J ¼ 16.2, 1.8, HÀC(1’)); 1.98 (dd,
J ¼ 6.9, 1.8, Me); HÀN(1) not visible. 13C-NMR (75 MHz, (D6)DMSO): 155.08 (s, C(6)); 152.66 (s, C(2));
150.16 (s, C(4)); 144.59 (s, C(8)); 141.25 (d, C(2’)); 114.50 (d, C(1’)); 107.10 (s, C(5)); 18.73 (q, Me). HR-
MALDI-MS: 192.0883 (100, C8H10N5Oþ, [M þ H]þ; calc.192.0880).

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Helvetica Chimica Acta – Vol. 91 (2008)
2-Amino-6-(benzyloxy)-8-(trifluoromethyl)purine (26). A soln. of 1 (490 mg, 2.0 mmol) in dry THF
(20 ml) at À 408 was treated with (CF3CO)2O (0.340 ml, 2.4 mmol). Over 2 h, the temp. was raised to
À 208. The mixture was diluted with H2O (30 ml), and extracted with CH2Cl2 (3 ꢀ 80 ml). The combined
org. phases were dried (Na2SO4) and evaporated to yield crude 25 (652 mg) as a blue solid. A suspension
of crude 25 in o-xylene (20 ml) was treated with Ph3P (1.257 g, 4.8 mmol), heated to 1458, and stirred for
8 h. Evaporation and FC (CH2Cl2/MeOH 96 :4) gave 26 (501 mg, 81%). Colourless solid. Rf (CH2Cl2/
MeOH 9 :1) 0.39. M.p. 214.3 – 215.88. UV (MeOH): 214 (4.39), 246 (3.84), 290 (4.07). IR (ATR): 3467w,
3444w, 3303w, 3173w, 2650w, 1637m, 1592s, 1533m, 1484m, 1470m, 1438m, 1399m, 1349m, 1298m, 1274m,
1195m, 1154s, 1143s, 1050w, 981m, 959m, 909w, 842m, 790w, 781w, 745m, 726m, 697m. 1H-NMR
(300 MHz, (D6)DMSO): 13.78 (s, HÀN(9)); 7.53 – 7.32 (m, 5 arom. H); 6.82 (s, NH2); 5.51 (s, PhCH2).
13C-NMR (75 MHz, (D6)DMSO): 160.84 (s, C(6)); 160.01 (s, C(2)); 155.16 (s, C(4)); 136.92 (q, J ¼ 38.8,
C(8)); 136.00 (s); 128.46 (2d), 128.26 (2d); 128.01 (d); 118.88 (q, J ¼ 267.8, CF3); 113.62 (s, C(5)); 67.14 (t,
PhCH2). 19F-NMR (300 MHz, (D6)DMSO): À 62.09 (s, CF3). HR-MALDI-MS: 310.0910 (100,
C13H11F3N5Oþ, [M þ H]þ; calc.: 310.0910).
8-(Trifluoromethyl)guanine (27). A suspension of 26 (200 mg, 0.647 mmol) in dry MeCN (8 ml) was
treated at 248 with anh. LiBr (72 mg, 0.841 mmol) and Me3SiCl (0.125 ml, 0.971 mmol), stirred for 4 h,
and treated with MeOH (2 ml). After evaporation, the colourless residue was crystallized from hot H2O
to afford 27 (122 mg, 86%). M.p. > 3508 (dec.). UV (MeOH): 205 (4.10), 257 (4.10). IR (ATR): 3319w,
3152m, 3047m, 2938w, 2719w, 1687s, 1634s, 1561m, 1519m, 1449m, 1357m, 1286m, 1176s, 1140s, 1039w,
978m, 865m, 773m, 760w, 736w, 695w, 665w. 1H-NMR (300 MHz, (D6)DMSO): 13.69 (s, HÀN(9)); 10.78
(s, HÀN(1)); 6.57 (s, NH2). 13C-NMR (75 MHz, (D6)DMSO): 156.31 (s, C(6)); 154.39 (s, C(2)); 152.73 (s,
C(4)); 133.92 (q, J ¼ 40.5, C(8)); 118.67 (q, J ¼ 267.7, CF3); 116.11 (s, C(5)). 19F-NMR (300 MHz,
(D6)DMSO): À 61.87 (s, CF3). HR-MALDI-MS: 242.0259 (100, C6H4F3N5NaOþ, [M þ Na]þ; calc.
242.0266), 220.0443 (78, C6H5F3N5Oþ, [M þ H]þ; calc. 220.0440).
(4R,5R)-N,N’-Bis[2-amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-2,2-dimethyl-1,3-dioxolane-4,5-
dicarboxamide (29). A soln. of 1 (1.150 g, 4.694 mmol) in dry THF (30 ml) at 08 was treated with l-2,2-
dimethyl-1,3-dioxolane-4,5-dicarbonyl dichloride (28; 0.380 ml, 2.347 mmol), stirred for 1 h at 08, and for
1 h at r.t. The soln. was treated with Et3N (1.308 ml, 9.388 mmol), filtered, and the solid residue washed
with MeOH (5 ml). The filtrate was diluted with hexane (70 ml) and cooled to 48. After 12 h, the gel-like
precipitate was filtered off to afford 29 (1.412 g, 93%) after drying in vacuo. Blue powder. Rf (CH2Cl2/
MeOH 9 :1) 0.46. M.p. 1728 (dec.). VIS (DMSO, c ¼ 0.005m): 639 (2.27). IR (ATR): 3305w, 3204m,
3131w, 1740m, 1634m, 1596s, 1516s, 1456s, 1396m, 1340s, 1279m, 1257s, 1241s, 1229s, 1210m, 1143s, 1077s,
969w, 929w, 908w, 860m, 795m, 746m, 718w, 699m. 1H-NMR (300 MHz, (D6)DMSO): 12.99 (s,
HNC¼O); 8.80, 8.76 (2s, NH2); 7.57 – 7.37 (m, 5 arom. H); 5.64 (s, PhCH2); 4.94 (s, HÀC(4)); 1.66 (s,
Me). 13C-NMR (75 MHz, (D6)DMSO): 169.15 (s, 2 C¼O); 164.10 (s, 2 C(6’)); 139.27 (s, 2 C(4’)); 135.66
(2s); 128.54 (4d); 128.46 (4d); 128.30 (2d); 113.54 (s, C(2)); 78.04 (d, 2 C(4), C(5)); 68.49 (t, 2 PhCH2);
26.40 (q, 2 Me); signals of 2 C(5’) and 2 C(2’) not visible due to coalescence. HR-MALDI-MS: 343.2029
(100, C29H27N10O8À, [M À H]À; calc. 643.2019).
(4R,5R)-4,5-Bis[2-amino-6-(benzyloxy)-9H-purin-8-yl]-2,2-dimethyl-1,3-dioxolane (30). A suspen-
sion of 29 (644 mg, 1 mmol) in o-xylene (20 ml) was treated with Ph3P (1.257 g, 4.8 mmol), and heated to
1008 for 6 h. After evaporation, FC (CH2Cl2/MeOH 20 :1) gave 30 (506 mg, 87%). Colourless solid. Rf
(CH2Cl2/MeOH 9 :1) 0.34. M.p. 2048. UV (MeOH): 212 (4.55), 247 (4.27), 288 (4.35). IR (ATR): 3472w,
3362w, 3204w, 3064w, 2987w, 1623s, 1580s, 1467m, 1454m, 1409s, 1352m, 1323m, 1257m, 1239m, 1219m,
1153m, 1081s, 1045m, 1018m, 980m, 952w, 900w, 844m, 810w, 789m, 733m, 694m, 666w. 1H-NMR
(300 MHz, (D6)DMSO): 12.89 (s, HÀN(9’)); 7.48 – 7.30 (m, 5 arom. H); 6.39 (s, NH2); 5.51 (s, HÀC(4));
5.43 (s, PhCH2); 1.47 (s, Me). 13C-NMR (75 MHz, (D6)DMSO): 159.80 (s, 2 C(6’)); 159.74 (s, 2 C(2’));
155.99 (s, 2 C(4’)); 145.34 (s, 2 C(8’)); 136.54 (2s); 128.60 (4d); 128.34 (4d); 128.01 (2d); 113.36 (s, C(5’));
111.09 (s, C(2)); 74.59 (d, 2 C(4), C(5)); 66.77 (t, 2 PhCH2); 26.57 (q, Me2C). HR-MALDI-MS: 603.2172
(60, C29H28N10NaOþ4 , [M þ Na]þ; calc. 603.2193), 581.2361 (100, C29H29N10Oþ4 , [M þ H]þ; calc. 581.2368).
Anal. calc. for C29H28N10O4 · 0.75 MeOH: C 59.10, H 5.17, N 23.17; found: C 58.89, H 5.17, N 23.17.
X-Ray Analysis of 30. Isothermal distillation of hexane into a soln. of 30 in CHCl3/MeOH gave
single crystals (dimensions of the analyzed colourless crystal: 0.33 ꢀ 0.22 ꢀ 0.12 mm). 2(C29H28N10O4) ·
CHCl3 · MeOH, Mr 1312.638, orthorhombic, P212121, a ¼ 13.4060(2), b ¼ 15.9895(2), c ¼ 30.2057(4) Š,

Helvetica Chimica Acta – Vol. 91 (2008)
449
V¼ 6474.8(2) Š3, Z ¼ 4, Dx ¼ 1.347 Mg/m3. Intensities were measured on a Nonius Kappa CCD
diffractometer, with MoKa radiation l ¼ 0.71073 Š, Cell parameters from 42184 refl., q ¼ 0.998 –
25.0288, m ¼ 0.213 mmÀ1, T¼ 223 K. 11017 measured reflections, 10984 independent reflections, 9552
observed reflections (>2s(I)). Refinement on F2: full-matrix least-squares refinement, R(all) ¼ 0.0944,
R(gt) ¼ 0.0819. The structure contains two molecules of CHCl3 and disordered MeOH in the asymmetric
unit. 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.
(4R,5R)-4,5-Di(guanin-8-yl)-2,2-dimethyl-1,3-dioxolane (31). A suspension of 30 (200 mg,
0.345 mmol) and LiBr (78 mg, 0.896 mmol) in dry MeCN (5 ml) was treated with TMSCl (130 ml,
1.035 mmol) and stirred for 20 h. The suspension was cooled to 08, diluted with MeOH (1 ml), and stirred
for 15 min. The colourless precipitate was filtered off, and washed with H2O, Et2O, and CH2Cl2/MeOH
9 :1. Drying in vacuo gave 31 (113 mg, 82%). M.p. > 2608 (dec.). UV (MeOH): 202 (4.29), 255 (4.15). IR
(ATR): 3322s (br.), 3176m (br.), 2933w, 2762w, 1676s, 1629s, 1593s, 1507m, 1436m, 1348m, 1218m,
1
1159m, 1092m, 998w, 888w, 777m, 725w, 689m. H-NMR (300 MHz, (D6)DMSO): 10.74 (s, HÀN(9’));
6.54 (s, NH2); 5.44 (s, HÀC(4)); 1.49 (s, Me); HÀN(1’) not visible. 13C-NMR (75 MHz, (D6)DMSO):
155.70 (s, 2 C(6’)); 153.42 (s, 2 C(2’)); 153.02 (s, 2 C(4’)); 144.4 (br. s, 2 C(8’)); 114.4 (br. s, 2 C(5’)); 110.98
(s, C(2)); 74.51 (2d, C(4), C(5)); 26.59 (q, Me2C). HR-MALDI-MS: 439.0993 (51, C15H16KN10Oþ4 , [M þ
K]þ; calc. 439.0993), 423.1250 (100, C15H16N10NaOþ4 , [M þ Na]þ; calc. 423.1254), 401.1429 (87,
C15H17N10Oþ4 , [M þ H]þ; calc. 401.1429).
(1R,2R)-1,2-Di(guanin-8-yl)ethane-1,2-diol (32). A suspension of 31 (50 mg, 0.114 mmol) in THF
(5 ml) was treated with 1n aq. HCl (5 ml) and stirred for 20 h. THF was removed under reduced pressure,
and the aq. suspension was lyophilized. M.p. > 2508 (dec.). UV (MeOH): 204 (4.15), 259 (4.05). IR
(ATR): 3353m, 3160m, 2854m, 2731m, 2550m, 1692s, 1649s, 1614s, 1543s, 1434w, 1369s, 1263w, 1228m,
1
1153m, 1111m, 1054m, 1003w, 914w, 858w, 766m, 732w, 688w, 665w. H-NMR (500 MHz, (D6)DMSO):
11.56 (s, HÀN(9’)); 7.16 (s, NH2); 5.22 (s, HÀC(1)); HÀN(1’) and HOÀC(1) not visible. 13C-NMR
(125 MHz, (D6)DMSO): 154.16 (s, C(6’)); 153.27 (s, C(2’)); 150.40 (s, C(4’)); 149.21 (s, C(8’)); 108.83 (s,
C(5’)); 68.85 (d, C(1)). HR-MALDI-MS: 383.0938 (25, C12H12N10NaOþ4 , [M þ Na]þ; calc. 383.0941),
361.1117 (100, C12H13N10Oþ4 , [M þ H]þ; calc. 361.1116).
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Received December 11, 2008