6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil, synthesis and transformation into annulated pyrimidinediones

Article abstract of DOI:10.1002/hlca.200890132

6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil (5) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3-d]pyrimidine-5,7-diones 7a and 7b. Rh ₂(OAc)₄ catalyzed the transformation of 5 into to a 2 : 1 (Z)/(E) mixture of 1,2-diuracilylethenes 9 (67%). Heating (Z)-9 in 12n HCl at 95° led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4-f]quinazolinetetraone 12. The Rh₂(OAc) ₄-catalyzed reaction of 5 with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran gave endo/exo-mixtures of the 2-oxabicyclo[4.1.0]heptane 13 (78%) and the 2-oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl ₃ or Me₂AlCl promoted a vinylcyclopropane - cyclopentene rearrangement, leading to the pyrano- and furanocyclopenta[1,2-d] pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2-methoxypropene was transformed into the 5-methylcyclopenta- pyrimidinedione 18 (55%). The Rh₂(OAc)₄-catalyzed reaction of 5 with thiophene gave the exo-configured 2-thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8-oxabicyclo[3.2.1]oct-2-ene 20 (73%), and the reaction with (E)-2-styrylfuran yielded a diastereoisomeric mixture of hepta-1,4,6-trien-3-ones 21 (75%) that was transformed into the (1E,4E,6E)-configured hepta-1,4,6-trien-3-one 21 (60%) at ambient temperature.

Full text of DOI:10.1002/hlca.200890132

Helvetica Chimica Acta – Vol. 91 (2008)
1201
6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil, Synthesis and
Transformation into Annulated Pyrimidinediones
by Fuyi Zhang, Anna Kulesza, Shikha Rani, Bruno Bernet, and Andrea Vasella*
Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich,
Wolfgang Pauli-Strasse 10, CH-8093 Zurich
(e-mail: vasella@org.chem.ethz.ch)
6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil (5) was prepared from the known aldehyde 3 by
hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3-
d]pyrimidine-5,7-diones 7a and 7b. Rh2(OAc)4 catalyzed the transformation of 5 into to a 2 :1 (Z)/
(E) mixture of 1,2-diuracilylethenes 9 (67%). Heating (Z)-9 in 12n HCl at 958 led to electrocyclisation,
oxidation, and deprotection to afford 73% of the pyrimido[5,4-f]quinazolinetetraone 12. The
Rh2(OAc)4-catalyzed reaction of 5 with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran gave endo/exo-
mixtures of the 2-oxabicyclo[4.1.0]heptane 13 (78%) and the 2-oxabicyclo[3.1.0]hexane 15 (86%), Their
treatment with AlCl3 or Me2AlCl promoted a vinylcyclopropane – cyclopentene rearrangement, leading
to the pyrano- and furanocyclopenta[1,2-d]pyrimidinediones 14 (88%) and 16 (51%), respectively.
Similarly, the addition product of 5 to 2-methoxypropene was transformed into the 5-methylcyclopenta-
pyrimidinedione 18 (55%). The Rh2(OAc)4-catalyzed reaction of 5 with thiophene gave the exo-
configured 2-thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8-
oxabicyclo[3.2.1]oct-2-ene 20 (73%), and the reaction with (E)-2-styrylfuran yielded a diastereoisomeric
mixture of hepta-1,4,6-trien-3-ones 21 (75%) that was transformed into the (1E,4E,6E)-configured
hepta-1,4,6-trien-3-one 21 (60%) at ambient temperature.
Introduction. – 6-Formyluridines are intermediates in the synthesis of novel
oligoribonucleotide analogues (ꢀONIBsꢁ; see [1][2] and refs. cit. there). Diazo
compounds derived from 6-formyluracils, however, have (to the best of our knowledge)
not been reported, perhaps surprisingly, considering the large number of pyrimidine
syntheses and the broad interest in 5,6-disubstituted and 6-monosubstituted pyrimidine
derivatives1) [4 – 6], and in uridine, uracil, and their derivatives and analogues [7 – 10].
The closest analogues of the envisioned vinylogous a-diazocarbonyl compounds
derived from 6-formyluracils are 6-substituted sulfoxonium ylides. Norris and Shechter
synthesized such ylides by treating 6-chloro-1,3-dimethyluracil with dimethylsulfoxo-
nium methylide [11] and used them for the synthesis of 6-cyclopropyluracils, 5,6-
methyleneuracils, and indirectly of uracils fused to seven-membered rings. Considering
the versatility of diazo compounds and particularly of stable a-diazocarbonyl
compounds [12 – 15], and more specifically their use for the synthesis of cyclopropanes
[16], for XꢀH insertions (X ¼ C, N, O, or S) [17][18], and as 1,3-dipoles [19], we
considered it worthwhile to synthesize at least one such diazo compound, characterize
1
)
Many 6-substituted uracils were synthesized from 6-chloro-1,3-dimethyluracil via nucleophilic
displacement [3].
ꢂ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 91 (2008)
it, and explore some of its transformations into known and new heterocyclic systems.
Our choice fell on the N-protected 6-(diazomethyl)uracil 5 (Scheme 1).
Results and Discussion. – The protected 6-(diazomethyl)uracil 5 was prepared in
two steps from the known carbaldehyde 3 [20] (Scheme 1). This aldehyde was first
obtained in 66% yield by formylating 1 [21], but the SeO2 oxidation of 2 [20] proved
more convenient for the preparation of larger quantities of 3, yielding 75% of 3 from 2
on a scale of 40 g. The (E)/(Z) ratio of the hydrazone 4, but not the yield (82 – 84%)
depends strongly upon the reaction conditions. A 3 :1 (E)/(Z) mixture of 4 was
obtained by using NH2NH2 · AcOH and K2CO3 in dry EtOH, and a 9 :1 mixture by
using NH2NH2 · H2O and NH2NH2 · AcOH in 96% EtOH. Pure (E)-4 was obtained by
crystallisation of (E)/(Z)-4 9 :1 from MeOH. The oxidation of (E)/(Z)-4 with freshly
prepared MnO2 in DMSO led to impure 5 that decomposed in contact with silica gel.
The analogous oxidation in CH2Cl2/DMSO 5 :1, however, proceeded cleanly, yielding
90% (on a 4-g scale) of the 6-(diazomethyl)uracil 5 as a yellow solid that was pure
according to 1H- and 13C-NMR spectroscopy, and was stored at room temperature for
several days and at 58 for several weeks without any decomposition.
Scheme 1
a) Lithium diisopropylamide (LDA), DMF, hexane/THF, ꢀ 788; 66%. b) SeO2, 1,4-dioxane/AcOH
11:1, reflux; 75%. c) NH2NH2 · H2O, NH2NH2 · AcOH, 96% EtOH, r.t.; 84%. d) MnO2, CH2Cl2/DMSO
14 :3, r.t.; 90%.
The assignment of the configuration of 4 is based on the characteristic downfield
1
shift for the H-NMR CH¼N and NH2 signals of the (E)-isomer [22] in CDCl3 or in
(D6)DMSO (Dd ¼ 0.4 – 0.9 ppm). Formation of the 6-(diazomethyl)uracil 5 is evi-
denced by the IR band at 2091 cmꢀ1 and by the diagnostic high-field shift of the 1H- and
13C-NMR signals of the diazomethyl moiety (5.33 and 44.86 ppm, resp.; cf. [23]).
Thermolysis of the 6-(diazomethyl)uracil 5 in boiling toluene gave an equilibrating
mixture 6a/6b of annulated 1H- and 2H-pyrazoles (Scheme 2; cf. [24]). Sublimating
crude 6a/6b at 1808 and 0.08 Torr resulted in 52% of 6a/6b that was demethoxymethy-
lated to 7a/7b by treatment with BCl3 in CH2Cl2 at ꢀ 788 to room temperature [21].
Prolonged treatment (10 h at room temperature) with BCl3 led to partial decom-
position before deprotection was complete, while BBr3 [25] removed both methoxy-

Helvetica Chimica Acta – Vol. 91 (2008)
1203
methyl (MOM) groups. Crystallization of the product from MeOH yielded 55% of
7a/7b [26] that dissolved readily in DMSO to give a solution of a 1:1 mixture, sharp NH
signals denoting that, under these conditions, the tautomers equilibrate slowly, if at all.
We assume that equilibration is considerably impeded by the intermolecular H-bonds
to the solvent that are evidenced by a strong downfield shift of the NH signals,
resonating at 13.95 and 13.75 ppm. The mixture 6a/6b was further characterized by
methylation with NaH and MeI in DMSO, leading to a mixture of 8a and 8b that were
separated by flash chromatography. Crystallization from 95% EtOH gave 54% of 8a
and 24% of 8b.
Scheme 2
a) Toluene, 1108; 52% of 6a/6b. b) BBr3, CH2Cl2, ꢀ 788 to r.t.; 55% of 7a/7b 1:1; 52% of (Z)-10; 58% of
(E)-10. c) NaH, MeI, DMSO; 54% of 8a and 24% of 8b. d) Rh2(OAc)4, CH2Cl2, r.t.; 45% of (Z)-9, 22%
of (E)-9. e) I2, CHCl3, visible light; 32% of (E)-9 and 10% of 11, besides 48% of (Z)-9. f) 12n HCl, 958;
73% of 12.
The structure assignment to the pyrimidine diones 8a and 8b is based on the
observation that imino C-atoms (as C(7a) in 8b) resonate ca. 10 ppm downfield relative
to corresponding enamino C-atoms [27]. Thus, C(3) of 8a resonates downfield relative
to C(3) of 8b (123.81 vs. 116.22 ppm), and C(7a) of 8b downfield to C(7a) of 8a
(130.68 vs. 119.70 ppm), whereas C(3a) of 8a and 8b resonate at a similar field (129.65
vs. 127.42 ppm). Accordingly, we assigned the 13C-NMR signals of the (very) slowly
equilibrating 1:1 mixture 7a/7b in (D6)DMSO as indicated in the Exper. Part. A rapidly
equilibrating mixture 6a/6b in CDCl3 is evidenced by a single set of broad 13C-NMR
signals. Particularly broad are the signals of C(3) at 119.01 and of C(7a) at 127.9 ppm. In
the 1H-NMR spectrum of 7a/7b, the more strongly shielded s at 7.42 ppm is assigned to
HꢀC(3) of 7a and that at 7.62 ppm to HꢀC(3) of 7b, as suggested by a comparison
with literature data [28]. The NH signals of 7a and 7b could not be assigned.

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Helvetica Chimica Acta – Vol. 91 (2008)
The RhII-promoted transformation of diazo compounds generates carbenoids that
dimerize to alkenes in the absence of carbenophiles2). Treatment of 5 with 2 mol-% of
Rh2(OAc)4 in CH2Cl2 [30 – 33] afforded a 3 :1 mixture of (Z)-9 and (E)-9.
Crystallisation from AcOEt/hexane 1:1 gave 22% of (Z)-9, and flash chromatography
of the mother liquor afforded an additional 23% of (Z)-9 and 22% of (E)-9. Both (Z)-9
and (E)-9 were deprotected with BBr3 in CH2Cl2 to the high-melting (Z)-10 (52%) and
(E)-10 (58%; both decomposing at > 2608). In contrast to (Z)-10, (E)-10 proved
particularly sensitive to air, and decomposed within a few hours at ambient temperature.
The assignment of the configurations of (Z)-9 and (E)-9 is based on the
hypsochromic and weakly hypochromic UV absorption of (Z)-9 (267 (log e 3.99) vs.
319 nm (log e 4.08) for (E)-9). Irradiation with visible light of a solution of (Z)-9 and
catalytic amounts of I2 in CHCl3 for 15 days at ambient temperature led to 32% of (E)-9
and 10% of the pyrimidoquinazolinetetraone 11 (besides 48% of unreacted (Z)-9). The
yield of the cyclisation/oxidation3) product 11 dropped to less than 5% when a boiling
solution of (Z)-9 was irradiated for 3 days. However, heating a solution of (Z)-9 in 12n
HCl to 958 gave exclusively the deprotected cyclisation/oxidation product 12 in 73%
yield. Force-field calculations suggest that 11 and 12 adopt a helical conformation; the
1,10-carbonyl groups are moved out of the plane of the benzene ring (calculated
C(10a)ꢀC(10b)ꢀC(1)ꢀO torsion angle 28.78). The helical conformation is corrobo-
rated by the crystal structure of a parent triphenylene-1,4,5,8,9,12-hexaone (torsion angle
32.78 [35]) and of angucyclinones (torsion angles 14–338 [36]), and in keeping with the
hypsochromic shift of the UV bands of 11 (246 nm) and 12 (241 nm) as compared to (Z)-
9 (267 nm). The C2 symmetry of 9 –12 is evidenced by the single set of signals in the
NMR spectra.
The addition of carbenoids to 3,4-dihydro-2H-pyran [29][30][37][38], 2,3-dihy-
drofuran [29][38 – 40], furan [31 – 33][40 – 43], and thiophene [33][40 – 45] is well
precedented. Annulated cyclopropanes resulting from these reactions, were, as a rule,
obtained as endo/exo-mixtures.
We investigated the addition of 5 to 3,4-dihydro-2H-pyran, 2,3-dihydrofuran,
thiophene, furan, and (E)-2-styrylfuran; we also explored the Lewis-acid catalyzed
vinylcyclopropane – cyclopentene rearrangement4) of the addition products.
The Rh2(OAc)4-catalyzed reaction of 5 with 3,4-dihydro-2H-pyran gave 78% of a
4 :3 endo/exo-mixture of annulated cyclopropanes 13 that were partially separated by
flash chromatography (Scheme 3). Treatment of a 4 :3 mixture endo-13/exo-13 with
AlCl3 in CH2Cl2 at 08 induced a vinylcyclopropane – cyclopentene rearrangement5)
that led, via zwitterion A, in 88% yield to the 2-oxabicyclo[4.3.0]nona-pyrimidine 14.
Similarly, the Rh2(OAc)4-catalyzed reaction of 5 with 2,3-dihydrofuran gave 86% of a
2 :1 endo/exo-mixture of annulated cyclopropanes 15, which could not be separated by
flash chromatography. Treatment of this mixture with Me2AlCl in CH2Cl2/hexane gave
the expected 2-oxabicyclo[3.3.0]octa-pyrimidine 16 (51%) besides the 5H-cyclo-
2
)
)
)
)
For the preparation of (E)- and (Z)-alkenes from cabenoids, see, e.g., [29].
For reviews, see [34].
For reviews, see [46 – 48].
For vinylcyclopropane – cyclopentene rearrangements of 2-oxabicyclo[3.1.0]hexanes and 2-oxabi-
cyclo[4.1.0]heptanes, see [49].
3
4
5

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1205
Scheme 3
a) Rh2(OAc)4, 3,4-dihydro-2H-pyran/CH2Cl2 1:3, r.t.; 78% of endo-13/exo-13 4 :3. b) AlCl3, CH2Cl2, 08;
88%. c) Rh2(OAc)4, 2,3-dihydrofuran/CH2Cl2 2 :15, r.t.; 86% of endo-15/exo-15 2 :1. d) 1m Me2AlCl in
hexane, CH2Cl2, ꢀ 788 to r.t.; 51% of 16 and 20% of 17. e) Rh2(OAc)4, 2-methoxyprop-1-ene/CH2Cl2
2 :3, r.t.; 1m Me2AlCl in toluene, CH2Cl2, ꢀ 788 to r.t.; 55%.
penta[d]pyrimidine 17 (20%). The position of the cyclopentene C¼C bond of 17 is
evidenced by a NOE of 10% for the vinyl H-atom resulting from irradiation of the
N(1)CH2 group. The formation of 17 from 16 involves the Lewis-acid catalyzed ring
opening of the oxolane ring to form an N-acylimmonium cation, followed by
deprotonation and isomerisation to the thermodynamically favoured 17 (linear
dienone system). The Rh2(OAc)4-catalyzed reaction of 5 with 2-methoxyprop-1-ene
led to a product, presumably an endo/exo-mixture of cyclopropanes, which was not
analyzed, but treated with Me2AlCl in CH2Cl2/hexane to yield 55% of the 7H-
cyclopenta[d]pyrimidine 18. The structure of 18 was established by X-ray crystal
structure analysis (Fig.)6). Comparing the structure of 17 and 18 suggests that the
degree of substitution determines the position of the cyclopentene C¼C bond of 18
(hyperconjugation and linear N-acyl dienamine system). This hypothesis is supported
6
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre
as deposition No. CCDC-671360 (18) and CCDC-671361 (20). 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).

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Helvetica Chimica Acta – Vol. 91 (2008)
Figure. X-Ray crystal structures of 18 and 20
by AM1 calculations according to which 17 and 18 are more stable by 2.69 and 1.86 kcal/
mol, respectively, than their C¼C bond isomers.
The Rh2(OAc)4-catalyzed reaction of 5 with thiophene gave selectively the exo-
configured 2-thiabicyclo[3.1.0]hex-3-ene 19 (69%; Scheme 4). Neither Me2AlCl nor
AlCl3 promoted a vinylcyclopropane – cyclopentane rearrangement, and 19 remained
unaffected by these Lewis acids. In contradistinction, the Rh2(OAc)4-catalyzed reaction
of 5 with furan led in 73% yield to the 8-oxabicyclo[3.2.1]octa-2,6-diene 207).
Apparently, Rh2(OAc)4 catalyzed the formation of the 2-oxabicyclo[3.1.0]hex-3-ene
A1 and its fragmentation to the zwitterion A2 which reacts via A3 to 20. The selective
formation of the bridged rearrangement product 20 correlates with the far higher
stability of the 2H-furanium cation A2 than of the analogous 3H-furanium cation
(DE ¼ 16.47 kcal/mol; AM1 calculation). The structure of 20 was established by X-ray
crystal structure analysis (Fig.)6).
Finally, we explored the Rh2(OAc)4-catalyzed reaction of 5 with (E)-2-styrylfuran.
It led exclusively to a mixture of diastereoisomeric hepta-1,4,6-trien-3-ones 21
1
(Scheme 4). A H-NMR spectrum of the crude product showed four ss for HꢀC(5)
of the uracil moiety, resonating at 5.75, 5.78, 6.01, and 5.96 ppm, and suggesting a ca.
50 :26 :20 :4 mixture (Z,Z,E)-21/(Z,E,E)-21/(E,E,E)-21/(E,Z,E)-21. Flash chroma-
tography (AcOEt/cyclohexane 2 :1) gave a pure sample of (Z,Z,E)-21 (6%) and a
mixture of the four diastereoisomers of 21 (69%). Keeping a solution of this mixture in
MeOH at ambient temperature for 7 d led to the complete disappearance of (Z,Z,E)-
21 in favour of (E,E,E)-21. Evaporation and crystallisation from AcOEt/hexane gave
60% of (E,E,E)-21.
7
)
For the preparation of 8-oxabicyclo[3.2.1]oct-2-enes from 2-oxabicyclo[3.1.0]hex-3-enes by
electrocyclic ring opening and 1,3-dipolar cycloaddition, see [43].

Helvetica Chimica Acta – Vol. 91 (2008)
1207
Scheme 4
a) Rh2(OAc)4, CH2Cl2, r.t.; 69% of 19; 73% of 20; 6% of (Z,Z,E)-21, and 69% of a mixture of (Z,Z,E)-
21, (Z,E,E)-21, (E,E,E)-21, and (E,Z,E)-21. b) MeOH, r.t.; 60%.
The formation of 21 is not unexpected, considering the synthesis of penta-2,4-
dienals by the reaction of carbenoids with furans [31][32][40][41]. Addition of the
carbenoid resulting from 5 to the unsubstituted C¼C bond of the furanyl moiety may
lead to the intermediate 2-oxabicyclo[3.1.0]hex-3-enes B1. Generation of a zwitterionic
species B2, corresponding to A2, via the cyclopropanes B1, or directly from styrylfuran
is not unlikely, even if no 8-oxabicyclo[3.2.1]octa-2,6-diene was obtained from
styrylfuran, since a cyclisation similar to the one of A2 may be disfavoured by the
styryl substitutent of the intermediate B2. The cyclopropane B1 may be transformed
into 21 by a (concerted) ring opening, similar to the one observed for the exo-2-
oxabicyclo[3.1.0]hex-3-enes derived from 2-methyl- and 2,5-dimethylfuran [31], with
endo-B1 leading to (Z,Z,E)-21 and exo-B1 to (E,Z,E)-21. However, the relative
proportion of C¼C bond isomers in the crude product requires that ꢁ 76% of endo-B1
be formed, and the 2-oxabicyclo[3.1.0]hex-3-enes B1 appear, therefore, rather unlikely
intermediates. We consider the 2H-furanium-2-methylide B2 to be the relevant
intermediate, and to lead to (Z,Z,E)-21 and (E,Z,E)-21. An analogous intermediate
was postulated as resulting from the addition of carbenoids to furan [31], considering
that the corresponding exo-2-oxabicyclo[3.1.0]hex-3-ene proved stable under the
reaction conditions [31][32].
The configuration of 13 – 16 was assigned on the basis of DQFCOSY, HSQC, and
HMBC spectra. The exo- and endo-isomers of 13 and 15 are easily distinguished by the

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Helvetica Chimica Acta – Vol. 91 (2008)
value of the vicinal couplings constants that are larger for cis- than for trans-
cyclopropanes (Table; cf. [29][31 – 33][41][50]). The O-substituent at C(1’) reduces
the values for J(1’,7’) of 13 and J(1’,6’) of 15 (cf. [51]). The endo-isomers of 13 and 15
show an allylic coupling of 1.2 – 1.5 Hz between HꢀC(5) and HꢀC(7’ or 6’), whereas
the exo isomers show at best a weak line broadening for these signals. The cis-
annulation of 14 and 16 is evidenced by J(4b,8a) of 4.5 and J(4b,7a) of 7.8 Hz,
respectively. The newly formed methylene group of 14 and 16 appears in the 1H-NMR
spectra as two dds with a geminal coupling of 17.1 and 15.0 Hz, respectively. In the
13C-NMR spectra, the d of C(4b) of 14 and 16 appears at 76.03 and 83.55 ppm,
respectively, the t of C(9) of 14 at 33.37 ppm, and the t of C(8) of 16 at 37.17 ppm.
Table. Vicinal Couplings [Hz] of the Cyclopropyl H-Atoms of 13, 15, and 19
J(1’,7’) of 13 or
J(6’,7’) of 13 or
J(1’,6’) of 13 or
J(1’,6’) of 15 and 19
J(5’,6’) of 15 and 19
J(1’,5’) of 15 and 19
endo-13
exo-13
endo-15
exo-15
exo-19
6.6
2.4
5.7
1.2
3.6
9.9
)
9.0
< 2.0
3.9
6.0
7.5
5.3
5.6
7.5
a
a) Not assigned.
The exo-orientation of the pyrimidine moiety of 19 is evidenced by small J(1’,6’)
and J(5’,6’) couplings of 3.6 – 3.9 Hz (Table; cf. [45]). These coupling contants are
larger than those of exo-15, as expected from replacing the O- by an S-atom. HexoꢀC(8)
of 20 resonates as a dd at 3.11 ppm and HendoꢀC(8) as a d at 2.31 ppm with Jgem of
18.0 Hz. The coupling of 6.0 Hz between HexoꢀC(8) and HꢀC(9), and the absence of a
coupling between HendoꢀC(8) and HꢀC(9) agree well with the HꢀCꢀCꢀH torsion
angles of ꢀ45 and 818 of the crystal structure and with the calculated coupling
constants of 6.1 and 0.9 Hz. C(1), C(8), and C(9) of 20 resonate at 72.95, 25.82, and
76.38 ppm, respectively.
The assignment of the configuration of (Z,Z,E)-21 and (E,E,E)-21 is based on
DQFCOSY, HSQC, and HMBC spectra. The two (Z)- and the (E)-configured C¼C
bonds of (Z,Z,E)-21 are evidenced by J(1’,2’) ¼ J(2’,3’) ¼ J(3’,4’) ¼ 11.4 – 11.7 Hz and
J(6’,7’) ¼ 16.2 Hz. Additionally, (Z,Z,E)-21 shows w couplings of 0.9 – 1.2 Hz between
HꢀC(5) and HꢀC(1’), between HꢀC(1’) and HꢀC(3’), and between HꢀC(2’) and
5
HꢀC(4’), and a J coupling of 1.2 Hz between HꢀC(1’) and HꢀC(4’). J(3’,4’) ¼ 15.3
and J(6’,7’) ¼ 15.9 Hz of (E,E,E)-21 evidence two (E)-configured C¼C bonds, whereas
the higher-order signal of HꢀC(1’) and HꢀC(2’) at 7.06 – 6.93 ppm allows only
estimation of the value of ca. 16 Hz for the large J(1’,2’).
We thank Dr. B. Schweizer for the determination of the X-ray structures, and the Swiss National
Science Foundation and Syngenta, Basel, for generos support.

Helvetica Chimica Acta – Vol. 91 (2008)
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Experimental Part
General. Flash chromatography (FC): Merck silica 60 (0.063 – 0.200 mm). UV Spectra: in MeOH,
lmax (log e) in nm. FT-IR Spectra: neat (ATR); in cmꢀ1. HR-MALDI-MS: in 3-hydroxypicolinic acid (3-
HPA) matrix. Force-field and semiempirical calculations were done with the programme Spartan 04
Macintosh from Wavefunction Inc., Irvine, CA.
1,3-Bis(methoxymethyl)-6-methyluracil (2) [20]. A suspension of 6-methyluracil (30 g, 0.24 mol) in
MeCN (300 ml) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 78 ml, 0.52 mol) and stirred
at r.t. for 0.5 h. The clear soln. was cooled to 08, treated dropwise with methoxymethyl chloride (MOMCl;
39.9 ml, 0.17 mol), stirred at r.t. for 3 d, and evaporated. The residue was diluted with H2O (400 ml) and
extracted with CH2Cl2 (4 Â 50 ml). The combined org. layers were washed with brine (30 ml), dried
(Na2SO4), and evaporated. FC (cyclohexane/AcOEt 2 :1) gave 2 (34.1 g, 67%). M.p. 82.5 – 83.58 ([20]:
83 – 858).
1,3-Bis(methoxymethyl)uracil-6-carbaldehyde (3) [20] a) From 1. At ꢀ 788, a soln. of 2m soln. of
LDA in hexane (4 ml, 7.95 mmol) in THF (11 ml) was treated dropwise with a soln. of 1 [21] (530 mg,
2.65 mmol) in dry THF (11 ml) over 10 min, stirred for 1 h, treated with DMF (2.2 ml, 11 mmol), stirred
for 2.5 h, treated with AcOH (1.5 ml), and allowed to warm to 238. The mixture was diluted with AcOEt
and washed with H2O. The aq. phase was extracted several times with CHCl3. The org. layers were
separately washed with sat. aq. NaHCO3 soln., H2O and brine, dried (Na2SO4), and evaporated. The
AcOEt soln. contained less pure 3. FC (hexane/AcOEt 1:1) gave 3 (400 mg, 66%).
b) From 2. According to [20], a soln. of 2 (30.0 g, 0.14 mol) in dry 1,4-dioxane/AcOH 11:1 (495 ml)
was treated with SeO2 (46.8 g, 0.42 mol), kept for 6 h at reflux, cooled to r.t., diluted with toluene, treated
with Celite, and stirred for another 0.5 h. The mixture was filtered through Celite. After evaporation of
the filtrate, the residue was treated with H2O (400 ml) and extracted with CH2Cl2 (5 Â 40 ml). The
combined org. layers were dried (Na2SO4) and evaporated. FC (cyclohexane/AcOEt 1:2) gave 3 (40.7 g,
75%). Syrup. Rf (AcOEt) 0.70.
1,3-Bis(methoxymethyl)uracil-6-carbaldehyde Hydrazone (4). a) A soln. of 3 (200 mg, 0.88 mmol) in
dry EtOH (7 ml) was treated with NH2NH2 · AcOH (81 mg, 0.88 mmol), and Na2CO3 (93 mg,
0.88 mmol) and stirred for 2 h, whereupon a precipitate was formed. After evaporation at 358, the
residue was dissolved in CHCl3 (10 ml), washed twice with sat. aq. NaHCO3 soln. and twice with H2O,
dried (Na2SO4), and evaporated to give crude (E)/(Z)-4 3 :1 (174 mg, 82%).
b) A soln. of 3 (10 g, 43.86 mmol) in 95% EtOH (600 ml) was treated with NH2NH2 · H2O (11 ml,
219.3 mmol) and NH2NH2 · AcOH (4 g, 43.86 mmol), and stirred at r.t. for 24 h. A precipitate was
gradually formed. After concentration and dilution with H2O (100 ml), the solid was filtered off and
washed with H2O and EtOH. Crystallisation of the solid ((E)/(Z)-4 9 :1; 8.9 g, 84%) from MeOH gave
pure (E)-4. White solid. Rf (AcOEt) 0.30. M.p. 193.5 – 194.68. UV: 223 (3.86), 277 (3.97), 327 (4.14). IR
(ATR): 3360w, 3181w, 3082w, 2988w, 2938w, 2831w, 1688m, 1660s, 1644s, 1601m, 1529m, 1446s, 1423s,
1373m, 1354m, 1342m, 1318m, 1265w, 1190m, 1173m, 1145m, 1119w, 1095s, 1073s, 1021m, 973w, 910s,
1
894s, 871m, 845m, 778m, 766m, 736w. H-NMR (300 MHz, CDCl3; (E)/(Z) 3 :1): (E)-isomer: 7.56 (s,
CH¼N); 6.88 (br. s, NH2); 6.00 (s, HꢀC(5)); 5.32, 5.27 (2s, 2 CH2N); 3.38, 3.35 (2s, 2 MeO); (Z)-isomer:
6.92 (s, CH¼N); 6.48 (br. s, NH2); 5.84 (s, HꢀC(5)); 5.29, 5.12 (2s, 2 CH2N); 3.385, 3.36 (2s, 2 MeO).
1H-NMR (300 MHz, (D6)DMSO; (E)/(Z) 9 :1): (E)-isomer: 8.27 (s, NH2); 7.50 (s, CH¼N); 5.89 (s,
HꢀC(5)); 5.20, 5.05 (2s, 2 NCH2O); 3.29, 3.25 (2s, 2 MeO); (Z)-isomer: 7.38 (s, NH2); 6.80 (s, CH¼N);
5.78 (s, HꢀC(5)); 5.27, 5.17 (2s, 2 NCH2O); 3.285, 3.27 (2s, 2 MeO). 13C-NMR (75 MHz, (D6)DMSO;
only (E) isomer): 161.42 (s, C(4)); 152.42 (s, C(2)); 149.85 (s, C(6)); 124.85 (d, CH¼N); 93.54 (d, C(5));
74.53, 71.47 (2t, 2 NCH2O); 56.88, 56.03 (2q, 2 MeO). HR-EI-MS: 242.1016 (Mþ, C9H14N4O4þ ; calc.
242.1015).
6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil (5). A suspension of (E)/(Z)-4 9 :1 (4.0 g,
17.2 mmol) in DMSO (150 ml) was stirred at 508 until a clear soln. was obtained. The soln. was cooled
to r.t., diluted with CH2Cl2 (700 ml), treated with MnO2 (6.0 g, 66.08 mmol), stirred at r.t. for 10 h,
treated with Celite, and stirred for another 0.5 h. After filtration through Celite (washing with CH2Cl2),
the filtrate was washed with H2O (3 Â 300 ml) and brine (300 ml), dried (Na2SO4), and evaporated. The
residue was dried under high vacuum to give crude 5 (3.57 g, 90%). Yellow solid (> 95% pure according

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Helvetica Chimica Acta – Vol. 91 (2008)
to 1H- and 13C-NMR spectroscopy). M.p. 93.8 – 94.88. Rf (cyclohexane/AcOEt 1:1) 0.30. UV: 227 (4.34),
250 (4.28), 317 (4.28). IR (ATR): 3091w, 2996w, 2940w, 2832w, 2091s, 1694m, 1646s, 1581s, 1448s, 1436s,
1391w, 1369w, 1335s, 1316m, 1264m, 1242w, 1198m, 1188m, 1169m, 1142w, 1109m, 1093s, 1067s, 1026m,
1016m, 968w, 909s, 888m, 801m, 774m, 752w, 735w, 716w, 661w, 647w. 1H-NMR (300 MHz, CDCl3): 5.42
(s, HꢀC(5)); 5.38, 5.26 (2s, 2 NCH2O); 5.33 (s, CH¼N2); 3.44, 3.41 (2s, 2 MeO). 13C-NMR (75 MHz,
CDCl3): 161.31 (s, C(4)); 152.55 (s, C(2)); 148.47 (s, C(6)); 91.39 (d, C(5)); 75.51, 71.98 (2t, 2 NCH2O);
57.69, 56.73 (2q, 2 MeO); 44.86 (d, CH¼N2). HR-EI-MS: 240.0855 (Mþ, C9H12N4O4þ ; calc. 240.0859).
Anal. calc. for C9H12N4O4 (240.22): C 45.00, H 5.03, N 23.32; found: C 45.00, H 4.95, N 23.13.
4,6-Bis(methoxymethyl)-pyrazolo[4,3-d]pyrimidine-5,7(1H and 2H)-dione (6a and 6b, resp.). A
soln. of 5a (500 mg, 4.13 mmol) in toluene (30 ml) was stirred at 1108 for 6 h, concentrated to 10 ml, and
cooled to r.t. The precipitate was filtered off and washed with toluene to give a slightly yellow solid
(150 mg). After evaporation of the filtrate, FC (CHCl3/MeOH 95 :5) gave additional 120 mg of a solid.
Sublimation of the combined solids at 1808/0.08 Torr gave 6a/6b (261 mg, 52%). White solid. M.p. 184.5 –
185.08. UV: 228 (3.78), 284 (3.70). IR (ATR): 3144w, 3120w, 2996w, 2934m, 2827w, 1706m, 1650s (br.),
1613m, 1605m, 1533w, 1491w, 1467w, 1449w, 1414m, 1401w, 1391w, 1369w, 1347m, 1303m, 1275s, 1198m,
1180m, 1091s, 1083s, 1038m, 964m, 946m, 916m, 904m, 879m, 800s, 783m, 752s, 695s, 666m, 634w, 621w.
1H-NMR (300 MHz, CDCl3; equilibrating mixture of 6a/6b): 12.5 (br. s, NH); 7.73 (s, HꢀC(3)); 5.52,
5.40 (2s, 2 NCH2O); 3.49, 3.42 (2s, 2 MeO). 13C-NMR (75 MHz, CDCl3, equilibrating mixture of 6a/6b):
157.10 (s, C(7)); 151.41 (s, C(5)); 127.9 (br. s, C(7a)); 127.61 (s, C(3a)); 119.01 (br. d, C(3)); 77.04, 72.58
(2t, 2 NCH2); 57.96, 56.91 (2q, 2 MeO). HR-EI-MS: 240.0855 (Mþ, C9H12N4O4þ ; calc. 240.0859). Anal.
calc. for C9H12N4O4 (240.22): C 45.00, H 5.03, N 23.32; found: C 44.94, H 4.94, N, 23.18.
Pyrazolo[4,3-d]pyrimidine-5,7(1H and 2H)-dione (7a and 7b, resp.) [26]. A soln. of 6 (110 mg,
0.46 mmol) in dry CH2Cl2 (66 ml) was cooled to ꢀ 788, treated dropwise with 1m BBr3 in CH2Cl2 (5.5 ml),
stirred for 5 h, and warmed gradually to r.t. The mixture was stirred at r.t. for 48 h, cooled to 08, and
treated with MeOH (10 ml). After evaporation and co-evaporation with MeOH (4 Â 15 ml), a
suspension of residue in MeOH (30 ml) was filtered. After evaporation of the filtrate, crystallisation from
MeOH gave 7a/7b 1:1 (38.3 mg, 55%). M.p. 265.0 – 266.08. UV: 206 (4.11), 282 (3.55). IR (ATR): 3290m,
3221m, 3132m, 3072w, 2830w, 1686s (br.), 1615m, 1454w, 1432m, 1382m, 1353w, 1304m, 1295m, 1169m,
1146m, 1072w, 1010w, 953w, 844m, 787s, 745m, 708s, 645m, 631m. 1H-NMR (300 MHz, (D6)DMSO; 7a/
7b 1:1): 13.95, 13.75 (2s, 2 NH); 11.08, 10.94, 10.85, 10.71 (4s, 4 NH); 7.62, 7.42 (2s, 2 HꢀC(3)). 13C-NMR
(75 MHz, (D6)DMSO; 7a/7b 1:1): 158.64 (s, C(7) of 7b); 154.91 (s, C(7) of 7a); 151.24 (s, C(5) of 7a and
7b); 131.26 (s, C(7a) of 7b); 129.90 (s, C(3a) of 7a); 127.18 (s, C(3a) of 7b); 125.08 (d, C(3) of 7a);
121.23 (s, C(7a) of 7a); 113.80 (d, C(3) of 7b). HR-EI-MS: 152.0334 (Mþ, C5H4N4O2þ ; calc. 152.0329).
Methylation of 6a/6b. A suspension of NaH (65% NaH in mineral oil washed with hexane, 12 mg,
0.5 mmol) in dry DMSO (2 ml) was stirred for 15 min, treated with 6a/6b (100 mg, 0.42 mmol), stirred for
45 min, treated dropwise with MeI (93 ml, 0.84 mmol), stirred for 3 h, and poured into ice-cold H2O.
After extraction with CH2Cl2, the combined org. layers were dried (Na2SO4) and evaporated. FC
(hexane/AcOEt 2 :1) and crystallisations from 95% EtOH gave 8a (57 mg, 54%) and 8b (25 mg, 24%).
Data of 1-Methylpyrazolo[4,3-d]pyrimidine-5,7(1H)-dione (8a). M.p. 116.4 – 117.48. Rf (hexane/
AcOEt 2 :3) 0.40 (UV: dull blue). IR (ATR): 3115w, 3000w, 2953w, 2938w, 2830w, 1708m, 1665s (br.),
1595m, 1548m, 1535m, 1446s, 1432s, 1416w, 1377w, 1331m, 1313s, 1262m, 1235w, 1188m, 1168m, 1154m,
1089s, 1038w, 994s, 958s, 924s, 913s, 835m, 796m, 768m, 752m, 738m, 668s, 631w, 615w. 1H-NMR
(300 MHz, CDCl3): 7.48 (s, HꢀC(3)); 5.47, 5.36 (2s, 2 NCH2O); 4.22 (s, MeN); 3.47, 3.40 (2s, 2 MeO).
13C-NMR (75 MHz, CDCl3): 154.51 (s, C(7)); 151.21 (s, C(5)); 129.65 (s, C(3a)); 123.81 (d, C(3)); 119.70
(s, C(7a)); 76.29, 72.24 (2t, 2 NCH2O); 57.66, 56.67 (2q, 2 MeO); 38.63 (q, MeN). HR-EI-MS: 254.1007
(Mþ, C10H14N4Oþ4 ; calc. 254.1015).
Data of 2-Methylpyrazolo[4,3-d]pyrimidine-5,7(2H)-dione (8b). M.p. 141.4 – 1428. Rf (hexane/
AcOEt 2 :3) 0.10 (UV: bright blue). IR (ATR): 3115w, 2936w, 2822w, 1713m, 1670s, 1603m, 1527m,
1445m, 1405m, 1303m, 1278m, 1181m, 1098s, 1081s, 937s, 906s, 752m, 699s, 660m, 606m. 1H-NMR
(300 MHz, CDCl3): 7.41 (s, HꢀC(3)); 5.51, 5.31 (2s, 2 NCH2O); 4.06 (s, MeN); 3.47, 3.38 (2s, 2 MeO).
13C-NMR (75 MHz, CDCl3): 157.24 (s, C(7)); 151.22 (s, C(5)); 130.68 (s, C(7a)); 127.42 (s, C(3a)); 116.22
(d, C(3)); 76.84, 72.23 (2t, 2 NCH2O); 57.75, 56.67 (2q, 2 MeO); 40.72 (q, MeN). HR-EI-MS: 254.1007
(Mþ, C10H14N4Oþ4 ; calc. 254.1015).

Helvetica Chimica Acta – Vol. 91 (2008)
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Treatment of 5 with Rh2(OAc)4. A soln. of 5 (500 mg, 2.1 mmol) in dry CH2Cl2 (20 ml) was treated
with Rh2(OAc)4 (9 mg, 0.02 mmol), stirred at r.t. under Ar for 20 min, and evaporated. The residue
(crude (Z)/(E)-9 ca. 3 :1) was diluted with hexane/AcOEt 1:1 (15 ml) and stirred for 20 min. The solid
was filtered off and washed with hexane/AcOEt 1:1 to give pure (Z)-9 (101 mg). FC (cyclohexane/
AcOEt 1:1 ! 1:4 and then CH2Cl2/MeOH 10 :1) of the mother liquor gave (Z)-9 (106 mg; total yield:
45%) and (E)-9 (98 mg, 22%).
Data of (Z)-6,6’-(Ethene-1,2-diyl)bis[1,3-bis(methoxymethyl)uracil] ((Z)-9). Rf (hexane/AcOEt
2 :3) 0.40. M.p. 125.2 – 126.38. UV: 228 (4.36), 267 (3.99). IR (ATR): 3091w, 3050w, 2965w, 2938w, 2829w,
1707m, 1651s, 1616m, 1447s, 1415m, 1373m, 1339m, 1314m, 1252w, 1194m, 1170m, 1143m, 1090s, 1018m,
973w, 912m, 869m, 808w, 776m, 760w, 737w, 700w, 680w, 643w, 609w. 1H-NMR (300 MHz, CDCl3): 6.78 (s,
CH¼CH); 5.62 (s, 2 HꢀC(5)); 5.35, 5.24 (2s, 4 NCH2O); 3.46, 3.43 (2s, 4 MeO). 13C-NMR (75 MHz,
CDCl3): 161.57 (s, 2 C(4)); 152.14 (s, 2 C(2)); 148.66 (s, 2 C(6)); 128.01 (d, CH¼CH); 102.65 (d, 2 C(5));
75.83, 72.29 (2t, 4 NCH2O); 57.91, 57.32 (2q, 4 MeO). HR-EI-MS: 424.1589 (Mþ, C18H24N4O8þ ; calc.
424.1594). Anal. calc. for C18H24N4O8 (424.41; 9/10 ca. 3 :1): C 50.94, H 5.70, N 13.20; found: C 51.00, H
5.68, N 13.09.
Data of (E)-6,6’-(Ethene-1,2-diyl)bis[1,3-bis(methoxymethyl)uracil] ((E)-9). Rf (hexane/AcOEt
2 :3) 0.45. M.p. 234.5 – 235.38. UV: 228 (4.39), 319 (4.08). IR (ATR): 3075w, 2991w, 2937w, 2830w, 1697s,
1650s, 1615s, 1484w, 1437s, 1411s, 1376w, 1352m, 1320m, 1262w, 1241w, 1196m, 1174m, 1147s, 1094m,
1082s, 1023m, 992m, 965m, 922m, 913m, 875m, 861m, 777m, 738m, 699m, 670w, 638m. 1H-NMR
(300 MHz, CDCl3): 7.19 (s, CH¼CH); 6.01 (s, 2 HꢀC(5)); 5.40, 5.27 (2s, 4 NCH2O); 3.47, 3.46 (2s,
4 MeO). 13C-NMR (75 MHz, CDCl3): 161.74 (s, 2 C(4)); 152.10 (s, 2 C(2)); 149.57 (s, 2 C(6)); 128.28 (d,
CH¼CH); 101.66 (d, 2 C(5)); 75.86, 72.37 (2t, 4 NCH2O); 58.07, 57.33 (2q, 4 MeO). HR-EI-MS:
424.1584 (Mþ, C18H24N4Oþ8 ; calc. 424.1594).
(Z)-6,6’-(Ethene-1,2-diyl)diuracil ((Z)-10). Under Ar, a soln. of (Z)-9 (100 mg, 0.24 mmol) in dry
CH2Cl2 (60 ml) was cooled to ꢀ 788, treated with 1m BBr3 in CH2Cl2 (5.5 ml), stirred for 12 h, warmed
gradually to r.t., stirred for 48 h, and treated dropwise with MeOH (10 ml). The soln. was stirred at 08 for
30 min. After evaporation and co-evaporation with MeOH (3 Â 10 ml), a soln. of the residue in MeOH
was neutralized with Amberlite IR 93A (OHꢀ form) and filtered (washing with MeOH). Evaporation of
the filtrate gave (Z)-10 (30.4 mg, 52%). M.p. > 3508 (dec.). IR (ATR): 3200w (sh), 3140w, 3090w, 3030w,
2806w, 1692s, 1666s, 1496m, 1440m, 1406s, 1332w, 1265w, 1053m, 1010m, 966m, 852s, 759s, 683m, 642m,
1
615m. H-NMR (300 MHz, (D6)DMSO): 11.11 (s, 2 NH); 11.00 (s, 2 NH); 6.44 (s, CH¼CH); 5.44 (s,
2 HꢀC(5)). 13C-NMR (75 MHz, (D6)DMSO): 163.64 (s, 2 C(4)); 151.16 (s, 2 C(2)); 147.71 (s, 2 C(6));
127.57 (d, CH¼CH); 99.84 (d, 2 C(5)). HR-MALDI-MS: 271.0435 ([M þ Na]þ, C10H8N4NaO8þ ; calc.
271.0443).
(E)-6,6’-(Ethene-1,2-diyl)diuracil ((E)-10). Under Ar, a soln. of (E)-9 (100 mg, 0.24 mmol) in dry
CH2Cl2 (60 ml) was cooled to ꢀ 788, treated with 1m BBr3 in CH2Cl2 (3.54 ml), stirred for 12 h, gradually
warmed to r.t., and stirred for 48 h. After the dropwise addition of MeOH (8 ml) at 08, the mixture was
stirred at 08 for 30 min, evaporated, and co-evaporated with MeOH (3 Â 10 ml). A soln. of the residue in
MeOH (30 ml) was neutralized with Amberlite IR 93A (OHꢀ form) and filtered (washing with MeOH).
Evaporation of the filtrate gave (E)-10 (34 mg, 58%). M.p. > 2608 (dec.). IR (ATR): 3440w (br.), 3200w
(sh), 3091m, 2991m, 2807m, 1697s, 1648s (br.), 1512m, 1439s, 1409s, 1365m, 1321m, 1238w, 1061m, 1021w,
968m, 855m, 760s, 710m, 662m, 638m. 1H-NMR (300 MHz, (D6)DMSO): 11.18 (s, 2 NH); 11.01 (s,
2 NH); 7.11 (s, CH¼CH); 5.62 (s, 2 HꢀC(5)).
Isomerisation of (Z)-9. A soln. of (Z)-9 (500 mg, 1.18 mmol) in CHCl3 (200 ml) was treated with I2
(20 mg, 0.079 mmol) and irradiated with visible light (table lamp) at r.t. for 15 d. After evaporation, the
residue was suspended in cyclohexane/AcOEt 1:1 (20 ml). The solid was filtered off and washed with
cyclohexane/AcOEt 1:1 (5 ml) to give (E)-9 (160 mg, 32%). Evaporation of the filtrate and FC
(cyclohexane/AcOEt 2 :1) gave (Z)-9 (240 mg, 48%) and 11 (50 mg, 10%).
Data of 2,4,7,9-Tetrakis(methoxymethyl)pyrimido[5,4-f]quinazoline-1,3,8,10-tetraone (11). Rf (cyclo-
hexane/AcOEt 1:1) 0.30. M.p. 234.5 – 235.08. UV: 246 (4.49), 265 (sh). IR (ATR): 3109w, 2998w, 2933w,
2828w, 1732m, 1704m, 1664s (br.), 1576w, 1496m, 1482s, 1475s, 1451m, 1436m, 1415s, 1315s, 1307s, 1246w,
1201w, 1187m, 1177m, 1153m, 1145m, 1112w, 1079s, 1023s, 981m, 912s, 890s, 828m, 787m, 761w, 752m,
729w, 713m, 695m. 1H-NMR (300 MHz, CDCl3): 7.76 (s, HꢀC(5), HꢀC(6)); 5.58, 5.53 (2s, 4 NCH2O);

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Helvetica Chimica Acta – Vol. 91 (2008)
3.52, 3.45 (2s, 4 MeO). 13C-NMR (75 MHz, CDCl3): 158.62 (s, C(1), C(10)); 150.87 (s, C(3), C(8)); 137.42
(s, C(4a), C(6a)); 122.06 (d, C(5), C(6)); 114.61 (s, C(10a), C(10b)); 75.40, 73.36 (2t, 4 NCH2O); 58.09,
56.76 (2q, 4 MeO). HR-MALDI-MS: 461.1072 (10, [M þ K]þ, C18H22KN4O8þ ; calc. 461.1075), 445.1326
(31, [M þ Na]þ, C18H22N4NaO8þ ; calc. 445.1335), 423.1507 (100, [M þ H]þ, C18H23N4Oþ8 ; calc. 423.1510).
Anal. calc. for C18H22N4O8 (422.39): C 51.18, H 5.25, N 13.26; found: C 51.53, H 5.04, N 12.94.
Pyrimido[5,4-f]quinazoline-1,3,8,10-tetraone (12). A soln. of (Z)-9 (100 mg, 0.24 mmol) in 12n HCl
(1 ml) was stirred at 958 for 8 h. The precipitate was filtered off and washed with H2O (until pH 7) and
MeOH. Drying gave yellow powdered 12 (43 mg, 73%). M.p. > 3308 (dec.). UV: 203 (3.24), 241 (3.18).
IR (ATR): 3350w (sh), 3261m, 3160w, 3019m, 2829w, 1656s (br.), 1503m, 1428s, 1291m, 1223m, 1208m,
1183m, 1055m, 1004m, 961m, 890m, 853m, 780w, 757s, 640s. 1H-NMR (300 MHz, (D6)DMSO): 11.22 (s,
2 NH); 10.92 (s, 2 NH); 6.86 (s, HꢀC(5), HꢀC(6)). 13C-NMR (75 MHz, (D6)DMSO): 162.92 (s, C(1),
C(10)); 150.54 (s, C(3), C(8)); 143.39 (s, C(4a), C(6a)); 130.57 (d, C(5), C(6)); 108.68 (s, C(10a),
C(10b)). HR-MALDI-MS: 247.0465 ([M þ H]þ, C10H7N4O4þ ; calc. 247.0462).
Reaction of 5 with 3,4-Dihydro-2H-pyran. A soln. of 3,4-dihydro-2H-pyran (20 ml) in CH2Cl2
(20 ml) was treated with Rh2(OAc)4 (40 mg, 8.4 mmol), stirred at r.t. for 30 min, treated dropwise with
soln. of 5 (1.0 g, 4.16 mmol) in CH2Cl2 (40 ml), stirred at r.t. for 30 min, and evaporated. FC (CH2Cl2/
AcOEt 4 :1) gave endo-13/exo-13 4 :3 (962 mg, 78%). FC (CH2Cl2/AcOEt 8 :1) gave pure samples of
endo-13 and exo-13.
Data of endo-1,3-Bis(methoxymethyl)-6-(2-oxabicyclo[4.1.0]heptan-7-yl)uracil (endo-13). Syrup. Rf
(cyclohexane/AcOEt 1:1) 0.33. UV: 208 (3.96), 271 (3.92). IR (ATR): 2940w, 2865w, 2830w, 1710m,
1660s, 1624m, 1432s, 1386w, 1359m, 1329m, 1307m, 1282w, 1235w, 1194m, 1171w, 1148m, 1124m, 1081s,
1053m, 1026m, 983w, 963w, 940w, 913m, 879w, 831m, 801w, 773m, 735m, 706w. 1H-NMR (300 MHz,
CDCl3; assignments based on DQFCOSY, HSQC, and HMBC spectra): 5.98 (d, J ¼ 1.2, HꢀC(5)); 5.47,
5.41 (2d, J ¼ 10.8, CH2ꢀN(1)); 5.38 (s, CH2ꢀN(3)); 3.86 (t, J ꢂ 6.3, HꢀC(1’)); 3.59 (br. dt, J ¼ 10.5, 3.6,
HeqꢀC(3’)); 3.45 (s, MeOCH2ꢀN(3)); 3.41 (s, MeOCH2ꢀN(1)); 3.32 (td, J ¼ 10.8, 2.7, HaxꢀC(3’)); 2.08
(ddt, J ꢂ 14.7, 11.7, 7.2, HaxꢀC(5’)); 1.93 (br. ddt, J ꢂ 14.7, 3.0, 1.5, HeqꢀC(5’)); 1.86 (ddd, J ¼ 9.9, 6.0, 1.5,
HꢀC(7’)); 1.5 – 1.38 (m, HꢀC(6’)); 1.5 – 1.22 (m, 2 HꢀC(4’)). 13C-NMR (75 MHz, CDCl3; assignments
based on a HSQC and a HMBC spectrum): 162.27 (s, C(4)); 153.04 (s, C(2)); 151.74 (s, C(6)); 104.73 (d,
C(5)); 75.46 (t, CH2ꢀN(1)); 72.12 (t, CH2ꢀN(3)); 63.99 (t, C(3’)); 57.81 (q, MeOCH2ꢀN(3)); 57.11 (q,
MeOCH2ꢀN(1)); 53.57 (d, C(1’)); 22.43 (t, C(4’)); 20.81 (d, C(7’)); 16.82 (t, C(5’)); 15.13 (d, C(6’)). HR-
MALDI-MS: 319.1260 ([M þ Na]þ, C14H20N2NaO5þ ; calc. 319.1264). Anal. calc. for C14H20N2O5 (296.32):
C 56.75, H 6.80, N 9.45; found: C 56.72, H 6.72, N 9.25.
Data of exo-1,3-Bis(methoxymethyl)-6-(2-oxabicyclo[4.1.0]heptan-7-yl)uracil (exo-13). Syrup. Rf
(cyclohexane/AcOEt 1:1) 0.32. UV: 210 (3.99), 271 (3.99). IR (ATR): 2938w, 2860w, 2830w, 1711m,
1660s, 1623m, 1440s, 1385w, 1353m, 1337m, 1278w, 1254w, 1232w, 1195m, 1175w, 1136m, 1095m, 1082s,
1030m, 1013m, 989w, 969m, 913m, 868w, 855w, 817w, 781m, 772m, 727s, 667w, 646w, 617w. 1H-NMR
(300 MHz, CDCl3; assignments based on DQFCOSY, HSQC, and HMBC spectra): 5.47, 5.40 (2d, J ¼
10.5, CH2ꢀN(1)); 5.32 (br. s, CH2ꢀN(3)); 5.30 (br. s, HꢀC(5)); 3.63 (dd, J ¼ 7.5, 2.4, HꢀC(1’)); 3.63
(br. dt, J ꢂ 10.5, 2.7, HeqꢀC(3’)); 3.44 (s, MeOCH2ꢀN(1)); 3.40 (s, MeOCH2ꢀN(3)); 3.37 (td, J ¼ 10.5,
6.3, HaxꢀC(3’)); 2.06 – 2.00 (m, 2 HꢀC(5’), HꢀC(7’)); 1.58 – 1.51 (m, 2 HꢀC(4’), HꢀC(6’)). 13C-NMR
(75 MHz, CDCl3; assignments based on a HSQC and a HMBC spectrum): 162.35 (s, C(4)); 154.80 (s,
C(6)); 152.71 (s, C(2)); 98.18 (d, C(5)); 75.06 (t, CH2ꢀN(1)); 71.99 (t, CH2ꢀN(3)); 64.37 (t, C(3’)); 59.34
(d, C(1’)); 57.72 (q, MeOCH2ꢀN(3)); 57.02 (q, MeOCH2ꢀN(1)); 24.53 (d, C(7’)); 21.69 (t, C(4’)); 20.48
(d, C(6’)); 18.75 (t, C(5’)). HR-MALDI-MS: 319.1261 ([M þ Na]þ, C14H20N2NaO5þ ; calc. 319.1264).
cis-1,3-Bis(methoxymethyl)-4b,6,7,8,8a,9-hexahydropyrano[2’,3’:3,4]cyclopenta[1,2-d]pyrimidine-
2,4-dione (14). A soln. of endo-13/exo-13 4 :3 (500 mg, 1.69 mmol) in CH2Cl2 (25 ml) was cooled to 08,
treated with AlCl3 (675 mg, 5.06 mmol), stirred for 3 h, treated with H2O (30 ml), and extracted with
CH2Cl2 (3 Â 10 ml). The combined org. layers were neutralized with sat. NaHCO3 soln., washed with
brine, dried (Na2SO4), and evaporated. FC (cyclohexane/AcOEt 2 :1) gave 14 (442 mg, 88%). Syrup. Rf
(cyclohexane/AcOEt 2 :1) 0.23. UV: 210 (3.91), 266 (3.91). IR (ATR): 2930m, 1715s, 1666s, 1636m,
1479m, 1090s, 1055s, 916m, 897m. 1H-NMR (300 MHz, CDCl3; assignments based on DQFCOSY,
HSQC, and HMBC spectra): 5.41, 5.35 (2d, J ¼ 9.6, CH2ꢀN(3)); 5.27, 5.14 (2d, J ¼ 10.5, CH2ꢀN(1)); 4.76
(d, J ¼ 4.5, HꢀC(4b)); 3.83 (br. dt, J ꢂ 10.8, 2.1, HeqꢀC(6)); 3.44 (td, J ꢂ 11.1, 2.1, HaxꢀC(6)); 3.44 (s,

Helvetica Chimica Acta – Vol. 91 (2008)
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MeOCH2ꢀN(3)); 3.43 (s, MeOCH2ꢀN(1)); 2.98 (dd, J ¼ 17.1, 9.3, HaꢀC(9)); 2.83 (dd, J ¼ 17.1, 7.5,
HbꢀC(9)); 2.38 – 2.27 (m, HꢀC(8a)); 1.88 (dt, J ꢂ 9.6, 4.5, 2 HꢀC(8)); 1.78 – 1.62 (m, HaxꢀC(7)); 1.53
(br. d, J ꢂ 13.2, HeqꢀC(7)). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC and a HMBC
spectrum): 159.83 (s, C(4)); 159.72 (s, C(9a)); 152.74 (s, C(2)); 114.09 (s, C(4a)); 76.09 (t, CH2ꢀN(1));
76.03 (d, C(4b)); 72.17 (t, CH2ꢀN(3)); 65.28 (t, C(6)); 57.89 (q, MeOCH2ꢀN(3)); 57.36 (q,
MeOCH2ꢀN(1)); 36.09 (d, C(8a)); 33.37 (t, C(9)); 23.73 (t, C(8)); 21.00 (t, C(7)). HR-MALDI-MS:
297.1446 ([M þ H]þ, C14H21N2O5þ ; calc. 297.1445). Anal. calc. for C14H20N2O5 (296.32): C 56.75, H 6.80, N
9.45; found: C 56.99, H 6.77, N 9.19.
endo- and exo-1,3-Bis(methoxymethyl)-6-(2-oxabicyclo[3.1.0]hex-6-yl)uracil (endo-15 and exo-15).
A soln. of 2,3-dihydrofuran (6 ml) in CH2Cl2 (15 ml) was treated with Rh2(OAc)4 (40 mg, 0.084 mmol),
stirred at r.t. for 30 min, treated dropwise with soln. of 5 (1.0 g, 3.54 mmol) in CH2Cl2 (30 ml) for 30 min,
and evaporated. FC (cyclohexane/AcOEt 1:4) gave endo-15/exo-15 2 :1 (1.01 g, 86%). UV: 207 (3.27),
271 (3.27). IR (ATR): 2942w, 2895w, 2829w, 1711m, 1659s, 1622m, 1435s, 1382w, 1341m, 1308w, 1251w,
1195m, 1164w, 1145w, 1117m, 1082s, 1062m, 1025m, 965m, 912m, 883m, 834m, 817m, 783w, 771m, 756m,
693w, 661w. Rf (cyclohexane/AcOEt 1:3) 0.35. 1H-NMR (300 MHz, CDCl3; endo-15/exo-15 2 :1): endo-
15: 5.94 (d, J ¼ 1.5, HꢀC(5)); 5.44 (s, CH2ꢀN(3)); 5.39, 5.32 (2d, J ¼ 10.9, CH2ꢀN(1)); 4.27 (t, J ¼ 5.5,
HꢀC(1’)); 4.07 (dt, J ¼ 9.5, 4.4, HaꢀC(3’)); 3.45 – 3.39 (hidden by MeO signals, HbꢀC(3’)); 3.44, 3.41 (2s,
2 MeO); 2.36 – 2.20, 2.19 – 2.10 (2m, HaꢀC(4’), HꢀC(5’)); 1.98 (ddd, J ¼ 13.1, 8.2, 4.1, HbꢀC(4’)); 1.87
(ddd, J ¼ 9.0, 5.3, 1.5, HꢀC(6’)); exo-15: 5.51, 5.35 (2d, J ¼ 10.8, CH2ꢀN(1)); 5.37 (s, CH2ꢀN(3)); 5.31 (s,
HꢀC(5)); 4.16 (dt, J ¼ 9.1, 3.1, HaꢀC(3’)); 4.00 (dd, J ¼ 5.6, 1.2, HꢀC(1’)); 3.63 (td, J ¼ 9.6, 7.8,
HbꢀC(3’)); 3.44, 3.42 (2s, 2 MeO); 2.36 – 2.20 (2 H), 2.19 – 2.10 (2m, 2 HꢀC(4’), HꢀC(6’)); 2.06 (br. dd,
J ¼ 10.3, 5.3, HꢀC(5’)). 13C-NMR (75 MHz, CDCl3; endo-15/exo-15 2 :1): endo-15: 162.22 (s, C(4));
153.63 (s, C(2)); 151.06 (s, C(6)); 103.63 (d, C(5)); 75.25 (t, CH2ꢀN(1)); 72.11 (t, CH2ꢀN(3)); 71.20 (t,
C(3’)); 63.26 (d, C(1’)); 57.78 (q, MeOCH2ꢀN(3)); 57.04 (q, MeOCH2ꢀN(1)); 26.18 (t, C(4’)); 24.60 (d,
C(6’)); 23.56 (d, C(5’)); exo-15: 162.11 (s, C(4)); 152.95 (s, C(6)); 152.65 (s, C(2)); 98.67 (d, C(5)); 74.99 (t,
CH2ꢀN(1)); 72.03 (t, CH2ꢀN(3)); 67.45 (t, C(3’)); 66.67 (d, C(1’)); 57.78 (q, MeOCH2ꢀN(3)); 57.04 (q,
MeOCH2ꢀN(1)); 27.75 (t, C(4’)); 24.66 (d, C(6’)); 22.02 (d, C(5’)). HR-ESI-MS: 305.1114 ([M þ Na]þ,
C13H18N2NaOþ5 ; calc. 305.1113). 282.0868 (Mþ, C13H18N2Oþ5 ; calc. 282.1216). Anal. calc. for C13H18N2O5
(282.3): C 55.31, H 6.43, N 9.92; found: C 54.89, H 6.43, N 9.72.
Lewis Acid-Catalyzed Rearrangement of endo-15/exo-15. A soln. of endo-15/exo-15 2 :1 (200 mg,
0.71 mmol) in CH2Cl2 (5 ml) was cooled to ꢀ 788, treated with 1m Me2AlCl in hexane (1.42 ml), stirred
for 10 h, warmed gradually to r.t., and stirred for 24 h. The mixture was diluted with H2O, neutralized
with sat. NaHCO3 soln., and extracted with CH2Cl2 (3 Â 10 ml). The combined org. layer were washed
with brine, dried (Na2SO4), and evaporated. FC (AcOEt/acetone/cyclohexane 1:1:0.5) gave 16 (101 mg,
51%) and 17 (40 mg, 20%). HR-ESI-MS: 305.1108 ([M þ Na]þ, C13H18N2NaO5þ ; calc. 305.1113). Anal.
calc. for C13H18N2O5 (282.30): C 55.31, H 6.43, N 9.92; found: C 54.89, H 6.43, N 9.72.
Data of cis-1,3-Bis(methoxymethyl)-6,7,7a,8-tetrahydro-1H-furo[2’,3’:3,4]cyclopenta[1,2-d]pyrimi-
dine-2,4-dione (16). Syrup. Rf (AcOEt/acetone/cyclohexane 1:1:0.5) 0.42. UV: 210 (3.92), 263 (3.86).
IR (ATR): 2942w, 2830w, 1714m, 1663s, 1472s, 1392w, 1351m, 1330m, 1281w, 1175m, 1120m, 1075s,
1029m, 989m, 951m, 913s, 860m, 798w, 770m, 727w, 705w, 647w. 1H-NMR (300 MHz, CDCl3; assignments
based on DQFCOSY, HSQC, and HMBC spectra): 5.37, 5.32 (2d, J ¼ 9.3, CH2ꢀN(3)); 5.365 (d, J ¼ 7.8,
HꢀC(4b)); 5.18, 5.12 (2d, J ¼ 10.8, CH2ꢀN(1)); 3.86 (ddd, J ¼ 9.0, 6.6, 3.9, HaꢀC(6)); 3.65 (td, J ꢂ 6.0,
5.4, HbꢀC(6)); 3.41 (s, MeOCH2ꢀN(3)); 3.38 (s, MeOCH2ꢀN(1)); 3.23 – 3.06 (m, HꢀC(7a), HaꢀC(8));
2.71 (dd, J ¼ 15.0, 2.1, HbꢀC(8)); 2.20 – 2.07 (m, HaꢀC(7)); 1.73 – 1.68 (m, HbꢀC(7)). 13C-NMR
(75 MHz, CDCl3; assignments based on a HSQC and a HMBC spectrum): 159.87 (s, C(4)); 156.43 (s,
C(8a)); 152.83 (s, C(2)); 111.51 (s, C(4a)); 83.55 (d, C(4b)); 75.70 (t, CH2ꢀN(1)); 72.09 (t, CH2ꢀN(3));
66.60 (t, C(6)); 57.83 (q, MeOCH2ꢀN(3)); 57.18 (q, MeOCH2ꢀN(1)); 38.68 (d, C(7a)); 37.17 (t, C(8));
34.35 (t, C(7)). HR-MALDI-MS: 305.1107 (96, [M þ Na]þ, C13H18N2NaO5þ ; calc. 305.1113), 283.1285
(100, [M þ H]þ, C13H19N2Oþ5 ; calc. 283.1294).
Data of 6-(2-Hydroxyethyl)-1,3-bis(methoxymethyl)cyclopenta[d]pyrimidine-2,4(5H)-dione (17).
Solid. Rf (AcOEt/acetone/cyclohexane 1:1:0.5) 0.30. M.p. 101 – 1028. UV: 215 (4.03), 233 (4.06), 309
(3.85). IR (ATR): 3432w, 2937w, 2828w, 1687s, 1643s, 1547m, 1487s, 1469s, 1446m, 1433m, 1383m, 1363m,
1341m, 1322m, 1272m, 1240m, 1223m, 1188m, 1174m, 1148m, 1126m, 1093s, 1069s, 1041m, 1010s, 952m,

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Helvetica Chimica Acta – Vol. 91 (2008)
941m, 914s, 885m, 874m, 804m, 767s, 756m, 697m, 675m. 1H-NMR (300 MHz, CDCl3; assignments based
on DQFCOSY, HSQC, and HMBC spectra): 6.50 (s, irrad. at 5.33 ! NOE of 10%, HꢀC(7)); 5.41 (s,
CH2ꢀN(3)); 5.33 (s, irrad. at 6.50 ! NOE of 2%, CH2ꢀN(1)); 3.89 (q, J ¼ 6.3, CH2OH); 3.45 (s,
H2C(5)); 3.43 (s, MeOCH2ꢀN(3)); 3.40 (s, MeOCH2ꢀN(1)); 2.79 (t, J ¼ 6.3, CH2CH2OH); 2.04 (br. s,
OH). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC and a HMBC spectrum): 160.26 (s,
C(6)); 159.01 (s, C(4)); 155.22 (s, C(7a)); 153.13 (s, C(2)); 120.96 (d, C(7)); 109.93 (s, C(4a)); 75.78 (t,
CH2ꢀN(1)); 72.08 (t, CH2ꢀN(3)); 61.28 (t, CH2OH); 57.59 (q, MeOCH2ꢀN(3)); 56.92 (q,
MeOCH2ꢀN(1)); 39.36 (t, C(5)); 34.61 (t, CH2CH2OH). HR-MALDI-MS: 305.1106 (100, [M þ Na]þ,
C13H18N2NaOþ5 ; calc. 305.1113), 283.1285 (76, [M þ H]þ, C13H19N2O5þ ; calc. 283.1294), 251.1021 (97, [M
– CH2OH]þ, C12H15N2Oþ4 ; calc. 251.2580). Anal. calc. for C13H18N2O5 (282.30): C 55.31, H 6.43, N 9.92;
found: C 55.40, H 6.44, N 9.85.
1,3-Bis(methoxymethyl)-5-methylcyclopenta[d]pyrimidine-2,4-(7 H)-dione (18). A soln. of 2-meth-
oxyprop-1-ene (20 ml) in CH2Cl2 (10 ml) was treated with Rh2(OAc)4 (40 mg, 0.084 mmol), stirred at r.t.
for 30 min, treated dropwise with a soln. of 5 (1.0 g, 4.3 mmol) in CH2Cl2 (20 ml), stirred for 30 min and
evaporated. A soln. of the residue in CH2Cl2 (25 ml) was cooled to ꢀ 788, treated with 1m Me2AlCl in
toluene (7.05 ml), and stirred for 10 h at ꢀ 788 and for 24 h at r.t. Evaporation and FC (AcOEt/
cyclohexane 5 :1) gave 18 (0.57 g, 55%). Colourless crystals. Rf (AcOEt/cyclohexane 5 :1) 0.72. M.p.
124.7 – 125.08. UV: 214 (3.84), 243 (3.90), 312 (3.45). IR (ATR): 2953w, 2892w, 2835w, 1702m, 1659s,
1582m, 1522w, 1493m, 1475m, 1445m, 1428w, 1413m, 1397w, 1368m, 1327w, 1305m, 1260w, 1237w, 1199m,
1176m, 1138m, 1117m, 1091s, 1070s, 1033m, 1008m, 983m, 956w, 922s, 909s, 877w, 779m, 757m, 740m,
1
701m, 650m, 621s. H-NMR (300 MHz, CDCl3; assignments based on DQFCOSY, HSQC, and HMBC
spectra): 5.69 (br. sext., J ¼ 1.8, HꢀC(6)); 5.43 (s, CH2ꢀN(3)); 5.29 (s, CH2ꢀN(1)); 3.46 (s,
MeOCH2ꢀN(3)); 3.41 (s, MeOCH2ꢀN(1)); 3.39 (br. quint., J ¼ 2.1, 2 HꢀC(7)); 2.24 (br. q, J ¼ 2.1,
Me). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC and a HMBC spectrum): 159.29 (s,
C(4)); 157.63 (s, C(7a)); 152.33 (s, C(2)); 139.40 (s, C(5)); 118.63 (d, C(6)); 116.44 (s, C(4a)); 76.05 (t,
CH2ꢀN(1)); 72.11 (t, CH2ꢀN(3)); 57.68 (q, MeOCH2ꢀN(3)); 57.09 (q, MeOCH2ꢀN(1)); 37.05 (t, C(7));
15.09 (q, Me). HR-ESI-MS: 275.1003 ([M þ Na]þ, C12H16N2NaO4þ ; calc. 275.1008). Anal. calc. for
C12H16N2O4 (252.27): C 57.13, H 6.39, N 11.10; found: C 57.25, H 6.36, N 10.96.
X-Ray Analysis of 186). Slow evaporation of a soln. of 18 in MeOH gave a single crystal suitable for
X-ray-analysis (0.36 Â 0.08 Â 0.04 mm; colourless). C12H16N2O4 (252.270): monoclinic P21; a ¼ 4.3736(3),
b ¼ 18.3636(11), c ¼ 14.9891(12) Š, b ¼ 94.117(4)8, V¼ 1200.74(15) Š3; Z ¼ 4, Dcalc ¼ 1.396 Mg/m3.
Intensities were measured on a Nonius Kappa CCD diffractometer, with MoKa radiation (l ¼
0.71073 Š, q ¼ 2.167 – 24.7138, m ¼ 0.106 mmꢀ1) at 223 K. Of the total 7129 reflections 2026 are
independent and 1573 were observed. R ¼ 0.1535, Rw ¼ 0.3799.
exo-1,3-Bis(methoxymethyl)-6-(2-thiabicyclo[3.1.0]hex-3-en-6-yl)uracil (19). A soln. of thiophene
(10 ml) and Rh2(OAc)4 (40 mg, 0.084 mmol) in CH2Cl2 (10 ml) was stirred at r.t. for 30 min, treated
dropwise with a soln. of 5 (1.0 g, 4.16 mmol) in CH2Cl2 (20 ml), stirred for 2 h, and evaporated. FC
(AcOEt/cyclohexane 2 :1) gave 19 (0.85 g, 69%). Syrup. Rf (AcOEt/cyclohexane 2 :1) 0.40. UV: 203
(4.01), 266 (3.99), 295 (3.91). IR (ATR): 3169w, 3019w, 2923w, 1713w, 1598w, 1495w, 1424w, 1331w, 1155s,
1120s, 1053m, 1032s, 1007s, 918m, 813s, 773m, 708m, 679s. 1H-NMR (300 MHz, CDCl3; assignments
based on DQFCOSY, HSQC, and HMBC spectra): 6.20 (dd, J ¼ 6.0, 1.5, HꢀC(3’)); 5.91 (dd, J ¼ 5.7, 3.0,
HꢀC(4’)); 5.39, 5.31 (2d, J ¼ 10.5, CH2ꢀN(1)); 5.34, 5.30 (2d, J ¼ 10.8, CH2ꢀN(3)); 5.30 (s, HꢀC(5));
3.40 (s, MeOCH2ꢀN(1)); 3.39 (s, MeOCH2ꢀN(3)); 3.27 (ddd, J ¼ 7.5, 3.6, 1.5, HꢀC(1’)); 2.96 (br. dt, J ꢂ
7.2, 3.0, HꢀC(5’)); 1.52 (t, J ¼ 3.9, HꢀC(6’)). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC
and a HMBC spectrum): 161.93 (s, C(4)); 155.46 (s, C(6)); 152.46 (s, C(2)); 128.27 (d, C(3’)); 122.72 (d,
C(4’)); 97.16 (d, C(5)); 74.95 (t, CH2ꢀN(1)); 71.99 (t, CH2ꢀN(3)); 57.71 (q, MeOCH2ꢀN(3)); 56.98 (q,
MeOCH2ꢀN(1)); 38.75 (d, C(5’)); 34.62 (d, C(1’)); 23.05 (d, C(6’)). HR-MALDI-MS: 319.0726 (100,
[M þ Na]þ, C13H16N2NaO4þ ; calc. 319.0728), 297.0905 (21, [M þ H]þ, C13H17N2O4Sþ; calc. 297.0909).
4,6-Bis(methoxymethyl)-12-oxa-4,6-diazatricyclo[7.2.1.02,7]dodeca-2(7),10-diene-3,5-dione (20). A
soln. of furan (10 ml) and Rh2(OAc)4 (30 mg, 0.063 mmol) in CH2Cl2 (10 ml) was stirred at r.t. for
30 min, treated dropwise with a soln. of 5 (1.0 g, 4.16 mmol) in CH2Cl2 (20 ml), stirred at r.t for 2 h, and
evaporated. FC (AcOEt/cyclohexane 2 :1) gave 20 (917 mg, 73%). Colourless crystals. Rf (AcOEt/
cyclohexane 2 :1) 0.22. M.p. 122.0 – 122.58. UV: 219 (4.01), 279 (3.82). IR (ATR): 2972w, 2940w, 2826w,

Helvetica Chimica Acta – Vol. 91 (2008)
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1692m, 1645s, 1585w, 1519w, 1462s, 1445s, 1428m, 1415m, 1390w, 1363m, 1334m, 1321m, 1280w, 1268m,
1250w, 1223m, 1211w, 1175s, 1110s, 1094s, 1070s, 1054s, 1020m, 1008m, 978s, 963m, 943m, 903s, 879m,
831m, 820m, 777s, 760m, 721s, 700s, 655m, 621s. 1H-NMR (300 MHz, CDCl3; assignments based on
DQFCOSY, HSQC, and HMBC spectra): 6.61 (dd, J ¼ 5.7, 1.5, HꢀC(11)); 6.03 (dd, J ¼ 5.7, 1.5,
HꢀC(10)); 5.49 (d, J ¼ 1.5, HꢀC(1)); 5.39, 5.35 (2d, J ¼ 9.3, CH2ꢀN(4)); 5.24, 5.19 (2d, J ¼ 10.8,
CH2ꢀN(6)); 5.10 (dd, J ¼ 6.0, 1.5, HꢀC(9)); 3.42 (s, MeOCH2ꢀN(4)); 3.37 (s, MeOCH2ꢀN(6)); 3.11
,
(dd, J ¼ 18.0, 6.0, HexoꢀC(8)); 2.31 (d, J ¼ 18.0, HendoꢀC(8)). 13C-NMR (75 MHz, CDCl3; assignments
based on a HSQC and a HMBC spectrum): 159.82 (s, C(3)); 152.30 (s, C(5)); 145.63 (s, C(7)); 138.00 (d,
C(11)); 127.73 (d, C(10)); 113.79 (s, C(2)); 76.38 (d, C(9)); 73.77 (t, CH2ꢀN(6)); 72.95 (d, C(1)); 72.12 (t,
CH2ꢀN(4)); 57.86 (q, MeOCH2ꢀN(4)); 57.14 (q, MeOCH2ꢀN(6)); 25.82 (t, C(8)). HR-ESI-MS:
303.0952 ([M þ Na]þ, C13H16N2NaOþ5 ; calc. 303.0957). Anal. calc. for C13H16N2O5 (280.28): C 55.71, H
5.75, N 9.99; found: C 55.72, H 5.78, N 9.99.
X-Ray Analysis of 206). Slow evaporation of a soln. of 20 in MeOH gave a single crystal suitable for
X-ray-analysis (0.34 Â 0.2 Â 0.08 mm; colourless). C13H16N2O5 (280.280), orthorhombic Pc21b; a ¼
4.6614(2), b ¼ 16.1141(8), c ¼ 17.3301(8), V¼ 1301.74(10) Š3; Z ¼ 4, Dcalc ¼ 1.430 Mg/m3. Intensities
were measured on a Nonius Kappa CCD diffractometer, with MoKa radiation (l ¼ 0.71073 Š, q ¼
2.425 – 27.4858, m ¼ 0.111 mmꢀ1) at 223 K. Of the total 2797 reflections 2583 are independent and 2243
were observed. R ¼ 0.0542, Rw ¼ 0.1336.
Reaction of 5 with (E)-2-Styrylfuran. A soln. of (E)-2-styrylfuran (0.85 g, 4.99 mmol) in CH2Cl2
(20 ml) was treated with Rh2(OAc)4 (40 mg, 0.084 mmol), stirred at r.t. for 30 min, treated dropwise with
a soln. of 5 (1.0 g, 4.16 mmol) in CH2Cl2 (20 ml), stirred at r.t. for 1 h, and evaporated. A 1H-NMR
spectrum of the crude product suggested a 50 :26 :20 :4 mixture (Z,Z,E)-21/(Z,E,E)-21/(E,E,E)-21/
(E,Z,E)-21. FC (AcOEt/cyclohexane 2 :1) gave pure (Z,Z,E)-21 (100 mg, 6%) and a mixture of all four
isomers of 21 (1.6 g, 69%).
Data of 1,3-Bis(methoxymethyl)-6-[(1Z,3Z,6E)-5-oxo-7-phenylhepta-1,3,6-trien-1-yl]uracil
((Z,Z,E)-21). Yellow solid. Rf (AcOEt/cyclohexane 3 :1) 0.70. M.p. 164.08 (dec.). UV: 202 (4.34), 228
(4.25), 332 (4.47). IR (ATR): 3089w, 2981w, 2920w, 2828w, 1712m, 1662s, 1619s, 1590m, 1573m, 1494w,
1449m, 1433m, 1423m, 1413m, 1389m, 1360m, 1342m, 1323m, 1253m, 1228m, 1192s, 1170m, 1142m, 1093s,
1076s, 1048m, 1017m, 999m, 975m, 966m, 906s, 872m, 858s, 791m, 776s, 734m, 696m, 680m, 642m, 611m.
1H-NMR (300 MHz, CDCl3; assignments based on DQFCOSY, HSQC, and HMBC spectra): 7.85 (td,
J ¼ 11.7, 1.2, HꢀC(2’)); 7.64 (d, J ¼ 16.2, HꢀC(7’)); 7.59 (dd, J ¼ 7.8, 3.9, HꢀC(3) and HꢀC(5) of Ph);
7.45 – 7.39 (m, HꢀC(2), HꢀC(4) and HꢀC(6) of Ph); 6.90 (td, J ¼ 11.7, 1.2, HꢀC(3’)); 6.87 (d, J ¼ 16.2,
HꢀC(6’)); 6.65 (dq, J ¼ 11.7, 1.2, HꢀC(1’)); 6.56 (dt, J ¼ 11.4, 1.2, HꢀC(4’)); 5.75 (d, J ¼ 0.9, HꢀC(5));
5.41 (s, CH2ꢀN(3)); 5.19 (s, CH2ꢀN(1)); 3.48 (s, MeOCH2ꢀN(3)); 3.45 (s, MeOCH2ꢀN(1)). 13C-NMR
(75 MHz, CDCl3; assignments based on a HSQC and HMBC spectrum): 189.76 (s, C(5’)); 161.66 (s,
C(4)); 152.30 (s, C(2)); 148.75 (s, C(6)); 144.10 (d, C(7’)); 135.36 (d, C(3’)); 134.21 (s, C(1) of Ph); 133.74
(d, C(2’)); 130.74 (d, C(4) of Ph); 129.26 (d, C(4’)); 128.89 (d, C(3) and C(5) of Ph); 128.37 (d, C(2) and
C(6) of Ph); 127.04 (d, C(6’)); 126.18 (d, C(1’)); 104.63 (d, C(5)); 75.86 (t, CH2ꢀN(1)); 72.22 (t,
CH2ꢀN(3)); 57.99 (q, MeOCH2ꢀN(3)); 57.22 (q, MeOCH2ꢀN(1)). HR-MALDI-MS: 421.1160 (18,
[M þ K]þ, C21H22KN2Oþ5 ; calc. 421.1166), 405.1418 (100, [M þ Na]þ, C21H22N2NaOþ5 ; calc. 405.1426),
383.1598 (70, [M þ H]þ, C21H23N2O5þ ; calc. 383.1607).
1,3-Bis(methoxymethyl)-6-[(1E,3E,6E)-5-oxo-7-phenylhepta-1,3,6-trien-1-yl]uracil ((E,E,E)-21). A
soln. of a mixture (Z,Z,E)-21/(Z,E,E)-21/(E,E,E)-21/(E,Z,E)-21 (1.6 g, 4.19 mmol) in MeOH (30 ml)
was stirred at r.t. for 7 d when TLC (AcOEt/cyclohexane 3 :1) evidenced the complete disappearance of
(Z,Z,E)-21. Evaporation and crystallization from cyclohexane/AcOEt 5 :1 gave (E,E,E)-21 (1.10 g,
60%). Yellow solid. M.p. 170.0 – 170.48. Rf (AcOEt/cyclohexane 3 :1) 0.68. UV: 202 (4.41), 340 (4.47). IR
(ATR): 3086w, 2982w, 2826w, 1704m, 1660s, 1645s, 1620s, 1575s, 1495w, 1433s, 1390m, 1361m, 1343m,
1320m, 1268m, 1254m, 1191m, 1172m, 1143m, 1093s, 1072s, 1021m, 1001s, 967m, 909s, 885m, 870m, 864m,
848m, 777m, 749m, 679m, 667m, 642m, 612m. 1H-NMR (300 MHz, CDCl3; assignments based on a
DQFCOSY, a HSQC and a HMBC spectrum): 7.72 (d, J ¼ 15.9, HꢀC(7’)); 7.61 (dd, J ¼ 6.6, 3.6, HꢀC(2)
and HꢀC(6) of Ph); 7.48 – 7.38 (m, HꢀC(3), HꢀC(4) and HꢀC(5) of Ph, HꢀC(3’)); 7.06 – 6.93 (m,
HꢀC(1’), HꢀC(2’)); 6.99 (d, J ¼ 15.9, HꢀC(6’)); 6.78 (d, J ¼ 15.3, HꢀC(4’)); 6.01 (br. s, HꢀC(5)); 5.40
(s, CH2ꢀN(3)); 5.28 (s, CH2ꢀN(1)); 3.48 (s, MeOCH2ꢀN(1)); 3.46 (s, MeOCH2ꢀN(3)). 13C-NMR

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Helvetica Chimica Acta – Vol. 91 (2008)
(75 MHz, CDCl3): 188.26 (s, C(5’)); 162.07 (s, C(4)); 152.46 (s, C(2)); 150.79 (s, C(6)); 144.31 (d, C(7’));
139.83 (d, C(3’)); 136.30 (d, C(2’)); 134.40 (s, C(1) of Ph); 133.20 (d, C(4’)); 130.87 (d, C(4) of Ph); 129.30
(d, C(1’)); 129.02 (d, C(2) and C(6) of Ph); 128.49 (d, C(3) and C(5) of Ph); 125.09 (d, C(6’)); 100.24 (d,
C(5)); 75.71 (t, CH2ꢀN(1)); 72.24 (t, CH2ꢀN(3)); 57.91 (q, MeOCH2ꢀN(3)); 57.12 (q, MeOCH2ꢀN(1)).
HR-MALDI-MS: 421.1160 (26, [M þ K]þ, C21H22KN2Oþ5 ; calc. 421.1166), 405.1425 (81, [M þ Na]þ,
C21H22N2NaOþ5 ; calc. 405.1426), 383.1599 (100, [M þ H]þ, C21H23N2O5þ ; calc. 383.1607). Anal. calc. for
C21H22N2O-5 (382.42): C 65.96, H 5.80, N 7.33; found: C 65.67, H 5.88, N 7.28.
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Received March 18, 2008