Theophyllinylpyrimidine scaffolds undergo intramolecular cyclization reactions to form 1,3-diazepines and imidazopurines

Article abstract of DOI:10.1002/ejoc.201300360

Polyheterocyclic pyrimidinyltheophyllines have been synthesized from pyrimidine and theophylline precursors. Attempts to cyclize these reactive bis-heterocyclic systems resulted in the formation of the corresponding diazepine moieties. In addition, modifi

Full text of DOI:10.1002/ejoc.201300360

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FULL PAPER
Medicinal Chemistry
Polyheterocyclic pyrimidinyltheophyllines
have been synthesized from pyrimidine and
theophylline precursors. Attempts to
cyclize these reactive bis-heterocyclic sy-
stems resulted in the formation of the di-
azepine moiety. Modification of the reac-
tion conditions led to the formation of
imidazo[2,1-f]purines.
I. O. Lebedyeva,* V. M. Povstyanoy,
A. B. Ryabitskii, O. Panasyuk,
E. Ivahnenko, V. P. Lozova, I. Markevich,
S. Allakhverdova,
M. V. Povstyanoy ............................ 1–14
Theophyllinylpyrimidine Scaffolds Un-
dergo Intramolecular Cyclization Reac-
tions to Form 1,3-Diazepines and Imidazo-
purines
Keywords: Medicinal chemistry
/ Alk-
aloids / Nitrogen heterocycles / Fused-ring
systems / Cyclization
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I. O. Lebedyeva et al.
FULL PAPER
DOI: 10.1002/ejoc.201300360
Theophyllinylpyrimidine Scaffolds Undergo Intramolecular Cyclization
Reactions to Form 1,3-Diazepines and Imidazopurines
Iryna O. Lebedyeva,*[a] V’yacheslav M. Povstyanoy,[a] Aleksey B. Ryabitskii,[b]
Oleksandr Panasyuk,[c] Evgen Ivahnenko,[a] Vera P. Lozova,[a] Igor Markevich,[a]
Svitlana Allakhverdova,[a] and Mykhaylo V. Povstyanoy[a]
Keywords: Medicinal chemistry / Alkaloids / Nitrogen heterocycles / Fused-ring systems / Cyclization
Polyheterocyclic pyrimidinyltheophyllines have been synthe-
sized from pyrimidine and theophylline precursors. Attempts
to cyclize these reactive bis-heterocyclic systems resulted in
the formation of the corresponding diazepine moieties. In ad-
dition, modification of the reaction conditions led to the for-
mation of imidazo[2,1-f]purines.
Introduction
Purine and pyrimidine oxo derivatives are widely occur-
ring and play a crucial role in living organisms.[1] Recent
reports[2] devoted to the biological activities of both di-
hydropyrimidines (DHPM) and substituted theophyllines
demonstrate the interest of medicinal chemists towards
heterocycles of this type. Due to the broad range of applica-
tions of these heterocyclic systems, new oxo-purine and
-pyrimidine representatives are currently of particular inter-
est.[3,4]
Substituted DHPMs are represented in the pharmaceuti-
cal market by the anticancer drug Monastol[3b,5] and the
antihypertensive agents SQ 32926 and SQ 32547 (Fig-
ure 1).[6] DHPM derivatives are also found to exhibit antivi-
ral, antibacterial, and anti-inflammatory properties.[7]
The clinical pharmacodynamics and biological activities
of theophyllines considered in this work have been thor-
oughly studied in previous work.[8] Theophylline deriva-
tives, such as the pharmaceuticals Pamabrom[3a] and Di-
menhydrinate,[9] have also demonstrated antitumor[10] and
anticonvulsant effects.[11] Furthermore, theophylline is
known to be effective as an active bronchodilator in the
treatment of asthma (Figure 2.[12]
Figure 1. Pharmacologically active dihydropyrimidines.
[a] Department of Organic and Biochemical Synthesis, Kherson
National Technical University,
Berislavs’ke Highway 24, Kherson 73008, Ukraine
Fax: +38-0552-326909
E-mail: irynal@chem.ufl.edu
Homepage: http://kntu.net.ua/index.php/ukr/Fakul-teti/
Kafedri-universitetu/Himichnih-tehnologij-i-
biohimichnogo-sintezu
[b] Spoluka Chemical Company, 5 Murmanska str.,
Kiev 02660, Ukraine
Fax: +38-0445741417
Figure 2. Theophylline-based pharmaceuticals.
[c] Department of Organic Chemistry, Ukrainian State University
of Chemical Technology,
Even though the biological and medicinal properties of
both substituted theophyllines and pyrimidines are well
known, the nucleophilicity of dihydropyrimidines is less
Gagarina Ave., 8, Dnipropetrovs’k 49005, Ukraine
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300360.
2
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Theophyllinylpyrimidine Intramolecular Cyclizations
well studied.[13] The literature shows that upon reaction aryl-6-halogenomethylpyrimidin-2-ones 2. Substituent di-
with nucleophiles, 6-halogenomethylated pyrimidines un- versity in the 4-aryl-substituted pyrimidines was provided
dergo ring closure to form [3,4-d]-fused pyrroles,[13a–13d] fur- by the Biginelli reaction.[16] The high reactivity of both pre-
ans,[13a,13e] and pyridazines.[13c] The high reactivity of 2- cursors, 6-halogenomethylpyrimidinecarboxylates[13,16,17]
oxo-4-aryl-5-ethoxycarbonyl-6-halogenomethylpyrimidines
2
and 8-halogenotheophyllines[14,15,18] 1, towards nucleo-
towards nucleophiles is made possible by the halogen atom philes has already been reported and hence the alkylation
in the 6-halogenomethyl group and the 5-ethoxycarbonyl reaction was straightforward, providing high yields of the
group on the pyrimidine core.[13] The functionalization of products 3 (74–91%; Scheme 1).
8-halogenotheophylline has been well reported and it is usu-
The structures of compounds 3a–i were determined by
ally achieved either by the alkylation of potassium or so- HPLC–MS, elemental analysis, and 1H and 13C NMR spec-
dium salts at C-7[14] or by the reaction of nucleophiles with troscopy. The 1H NMR spectra of theophyllinylpyrimidines
the halogen atom at C-8.[14b,14c,15] Both approaches towards 3a–i are characterized by aromatic proton signals in the re-
theophylline derivatives have proven to be efficient and con- gion 8.15–6.89 ppm arising from substituted phenyl groups
venient.[14,15] In this work we have studied for the first time and the doublet or pseudo-singlet signals of pyrimidine
the synthesis of bis-heterocyclic scaffolds that contain 8- NHCH. The signals of the NH proton are located in the
bromotheophylline and 5- ethoxycarbonyl-DHPM units range 8.36–8.31 ppm, and the signals of the proton at the
and thus have the potential for further derivatization.
chiral C-4 pyrimidine carbon appear in the range 5.43–
A combination of the bioactive heterocyclic systems and 5.28 ppm. The signals of the methylene groups in com-
their possible further functionalization is of considerable pounds 3a–i appear at a somewhat higher field than the two
interest these days due to the novelty and therapeutic po- doublets of the chloromethyl groups of the precursors 2 and
tential of the developed heterocycles. Considering the are present at δ = 7.40–5.91 ppm. The ethoxycarbonyl
above-mentioned biological properties of theophylline and group is represented by a quartet or a multiplet signal due
pyrimidine, we expect that the tethering of a partially hy- to the CH2 group at δ = 4.14–4.11 ppm and by a triplet due
drogenated 2-oxopyrimidine cycle to a natural purine alka- to the CH3 group at δ = 1.20–1.16 ppm. The theophylline
loid theophylline would provide for an increase in their bio- residue is represented by two singlets arising from the N-
logical activity and pharmacological efficiency.[1b,7b]
methyl groups at 3.42–3.40 and 3.26–3.20 ppm. The struc-
In this work we aimed to investigate 1) the reaction of 8- ture of compound 3i was further confirmed by its NOESY,
halogenotheophylline salts with 2-oxo-4-aryl-5-ethoxy- HSQC, and HMBC spectra.
carbonyl-6-halogenomethylpyrimidines, 2) the N-function-
alization at C-8 of the newly formed bis-heterocyclic sys-
tems, and 3) the intramolecular cyclization of the 8-amino-
substituted theophyllinylpyrimidine scaffolds to form a
fused 1,3-diazepine that links the theophylline and pyrimid-
ine moieties.
Preparation of 4-Aryl-5-ethoxycarbonyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-6-yl-8-aminotheophyllines 4a–k and
(7H-Purin-7-yl)pyrimidine-5-carboxamide (5)
The precursors 3 have two electrophilic centers: 1) The
C-8 of theophylline and 2) the C-5 ester carbonyl group of
pyrimidine. It was found that the amination of bis-heterocy-
cle 3 proceeds by the substitution of the halogen atom at
C-8 of the theophylline moiety and leads to the formation
Results and Discussion
Synthesis of Halogeno-7H-Theophylline-1,2,3,4-
tetrahydropyrimidine-5-carboxylates
Reactive heterocyclic compounds 3 were prepared by alk- of 8-amino-substituted theophyllinylpyrimidines 4 (route A,
ylation of 8-halogenotheophylline potassium salts 1 with 4- Scheme 2). To confirm that the amination reaction pro-
Scheme 1. Reaction of 8-halogeno-substituted theophyllines 1 with 6-halogenomethyl-DHPMs 2.
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Scheme 2. Reaction of 8-halogeno-substituted theophyllinyl-DHMPs 3 with primary amines.
ceeded by substitution of the theophylline halogen atom, proton at δ = 7.08–6.55 ppm, together with additional sig-
the target aminotheophyllines 4 were synthesized by alkyl- nals arising from the protons of alkyl or aryl substituents.
ation of the 8-aminotheophylline potassium salt 6 with the
Monocrystals of 5 were grown from iPrOH/methanol.
corresponding 6-halogenomethylpyrimidine 2 in tBuOH/ The pyrimidinone ring of 5 adopts a “sofa” conformation
DMF (route B, Scheme 2). In both cases (routes A and B, and the planar purine fragment is rotated almost orthogo-
Scheme 2), heterocyclic amines 4 precipitated from the reac- nally to the main plane of the pyrimidine ring. In the crys-
tion mixtures soon after cooling to give yields of 68–85%. tal, molecules of 5 and water molecules are linked through
The 8-amino-substituted theophyllinylpyrimidines 4 were intermolecular hydrogen bonds into layers parallel to the
mainly synthesized by the synthetic pathway A (Scheme 2). (001) crystallographic plain.
HPLC–MS analysis of the crude products revealed the al-
ternative reaction product, (7H-purin-7-yl)pyrimidine-5-
Synthesis of Polycyclic Theophylline-, Pyrimidine-, and 1,3-
Diazepine-Containing Heterocycles
carboxamide 5 (Scheme 2), which was isolated in 7% yield
and characterized by single-crystal X-ray diffraction analy-
sis (Figure 3). The formation of the unexpected compound
5 by rearrangement of the pyrimidine double bond as well
as amidation of the ethoxycarbonyl group at C-5 could be
explained by the electron-withdrawing nature of the theo-
phylline residue, which significantly increases the mobility
of the protons of the methylene group, in addition to the
reactivity of the ester residue towards nitrogen nucleophiles.
The annulated polyheterocyclic structures 7 and 8
(Scheme 3, Figures 4 and 5), which contain molecular frag-
ments of theophylline, pyrimidine, and 1,3-diazepine, were
synthesized by the intramolecular cyclization of 8-amino-
substituted theophyllinylpyrimidines 4. The precursors 4
were heated at reflux in tBuOH in the presence of catalytic
amounts of tBuONa for 6 h to form the novel tetracyclic
aza-heterocyclic system 7 in yields of 71–84%. The forma-
1
tion of compounds 7a–c was confirmed by H NMR spec-
troscopy. The decrease in the 1H signals of the ethoxy-
carbonyl group of DHPM as well as the signal of NH of
the residual amine at C-8 of 4 revealed the intramolecular
cyclization process. Even though the formation of the
seven-membered 1,3-diazepine ring is straightforward, we
isolated two minor reaction products. One of them was
identified as 8-amino-(7H-purin-7-yl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid 9 in 20% yield. The formation
of such an unexpected reaction product suggests an in-
creased ability of the pyrimidine C-5 ester group to undergo
hydrolysis. Another reaction product, 8 (31%), revealed the
rearrangement of the double bond of the [5,6-e]pyrimidine
backbone within the newly formed 1,3-diazepine core. Note
also that all of the three products, 1,3-diazepine-fused
Figure 3. Molecular structure of 5 determined by X-ray diffraction.
In addition to the above-described general signals, the 1H heterocycles 7, 8, and carboxylic acid 9, were obtained un-
NMR spectra of compounds 4a–k exhibit a singlet (R = der the same reaction conditions, with 1,3-diazepinylpyr-
aryl) or a triplet (R = alkyl) from the amine moiety NH imidotheophylline 7 being the major reaction product. In
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Theophyllinylpyrimidine Intramolecular Cyclizations
Scheme 3. Intramolecular cyclization of the precursors 4.
particular, we managed to cyclize those precursors 4 that
contained an aminoalkyl substituent at C-8. More rigid
aromatic systems such as 4j, in which R = NH-pTol, did not
provide the expected reaction product 7, and the starting
materials were isolated under the reaction conditions shown
in Scheme 3.
The structures of compounds 7a–c were unambiguously
determined by 1D and 2D NMR spectroscopy. The product
7b was also characterized by COSY and NOESY NMR
analyses and a single-crystal X-ray diffraction analysis con-
firmed the structure of 7a (Figure 4).
Molecule 7a consists of four heterocycles and has a “but-
terfly”-like conformation with the binding line in the seven-
membered ring N3N5C5C9 across the C9 atom and the
middle of N5–C6 bond; the angles in between the “wings”
for independent molecules A and B are 58.5(1) and 58.0(1)°,
respectively. In addition, in both molecules A and B, the
bond lengths C6–N5 in the seven-membered cycles are
1.405(7) and 1.398(7) Å, which are longer than those of C5–
N5 of 1.369(7) and 1.362(7) Å, respectively. Hence, there is
Figure 4. Perspective view of the molecular structure of 7a deter-
mined by X-ray diffraction.
a stronger conjugation of the lone pair of the N atom with with the conjugation of the lone pair of the N5 atom with
the heterocyclic π system, despite a more powerful conjuga- the C=O group [the dihedral angles between the mean
tion of the π system with the carbonyl groups, compared square
planes
N3N4C1C4C5/N5C5C6C14
and
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N5C6C7O3/N5C5C6C14 are 27.25(20)/26.85(23) and Intramolecular Recyclization of 8-Amino-Substituted
7.25(42)/7.43(48)° for independent molecules A/B, respec- Purinylpyrimidines to Form Imidazo[2,1-f]purines
tively].
For a one-pot amination and cyclization of 3 into 7, we
carried out a series of reactions in a sealed tube. Unexpec-
tedly, the condensation of 8-halogeno-substituted theo-
phyllinylpyrimidines 3 with primary amines in a sealed tube
at 170–180 °C in iPrOH for 12 h led to 8-substituted imid-
azo[2,1-f]purines 13 in yields of up to 80% (route A,
Scheme 4). The formation of 13 occurs as a result of a tan-
dem DHPM thermal ring-opening/cyclization to form the
imidazole core (Scheme 4). A change in the solvent from
iPrOH to MeOH, EtOH, nBuOH, or tBuOH did not have
an effect on the reaction. Compounds 13 were also formed
when the reaction was conducted in an open vessel in DMF
at 160 °C. HPLC–MS analysis of the crude reaction mix-
tures revealed in this case that 13 was obtained in yields of
25–40%.
The perspective view of molecule 8 is shown in Figure 5.
Molecule 8 simultaneously crystallizes in two pseudo-poly-
morphic forms that differ by the amount of solvate water
included in the crystal. The major difference between
pseudo-polymorph forms I and II is the disorder of the eth-
anol group and the arrangement of water molecules around
it. Form I has the P1 space group and contains 2.5 water
molecules per molecule of 8. Form II has the C2/c space
group and 0.15 water molecules. The molecular conforma-
tion of 8 is almost identical in the two crystal structures.
The perhydropyrimidine ring adopts a “half-chair” confor-
mation, and both crystals show similar packing motifs.
¯
Because compounds 13 are synthesized via the interme-
diate 8-amino-substituted theophyllinylpyrimidines 4, the
latter was employed as the precursor in this synthesis
(sealed tube, iPrOH, 170–180 °C, 12 h; route B, Scheme 4).
Moreover, the use of heterocycles 4 in the ring opening of
the pyrimidine to give the final products 13 (route B,
Scheme 4) allowed their isolation in slightly higher yields
than when synthesized by route A (Scheme 4).
However, we did not succeed in synthesizing the products
analogous to 7 and 13 when the aryl group in the starting
materials 3h,i (route A, Scheme 4) and 4k (route B,
Scheme 4) contained an electron-withdrawing group such
as NO2. For this purpose we employed both types of reac-
tion conditions: Heating of 3i at reflux with 2-methoxyeth-
ylamine 1) in an open vessel (iPrOH, reflux, 6 h) and 2) in
a sealed tube (iPrOH, 180 °C, 12 h). HPLC–MS data of the
crude mixture from the first reaction showed that the reac-
tion of 3i with 2-ethoxyethylamine proceeds almost equally
by the three routes to give 4k (m/z = 571.38 [M]+; 22%)
and products analogous to 7 (m/z = 525.29 [M]+; Ar = 3-
Figure 5. Molecular structure of 8 determined by X-ray diffraction. NO2C6H4; R = CH2CH2OCH3, 27%) and 13 (m/z = 425.69
Scheme 4. Synthesis of imidazo[2,1-f]theophyllines 13.
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Theophyllinylpyrimidine Intramolecular Cyclizations
[M]+; Ar = 3-NO2C6H4; R = CH2CH2OCH3, 31%), styryl substituent in trans-imidazo[2,1-f]purines 13
whereas heating the mixture in a sealed tube led to decom- (Scheme 5).[19] We were also able to confirm this mechanism
position of the reactants.
by subjecting the isolated intermediate 9 (Ar = Ph, R = Bn)
to heating at 180 °C in a sealed tube in iPrOH for 12 h.
HPLC–MS analysis of the crude reaction mixture revealed
62% of the product 13 (Ar = Ph, R = Bn; m/z = 412.19
[M]+), which supports the suggested mechanism of an intra-
molecular cyclization step in the formation of 13
(Scheme 5).
Mechanism for the Formation of Imidazo[2,1-f]purines 13
We suggest that the imidazo[2,1-f]purines 13 are formed
through a few tandem processes. The isomerization of 9
into 10 takes place as a result of the destabilizing influence
of the carboxy group in 9, which forms as a result of hydrol-
ysis of the C-5 ethoxycarbonyl group of the pyrimidine 4.
The following shift of the pyrimidine double bond towards
N-7 of the theophylline moiety leads to intermediate 10,
which then undergoes intramolecular nucleophilic attack of
The structures of compounds 13a–f were unambiguously
1
determined by 1D H and 13C NMR spectroscopy. In ad-
dition, the structure of 13b was confirmed by 2D NMR
spectroscopy (COSY, NOESY) and 13c by single-crystal X-
ray diffraction (Figure 6).
Equalization of the C–N bond lengths around the C5
the 8-amino group of theophylline on the C-6 of pyrimidine atom [in the range 1.3470(18)–1.3593(18) Å] while solving
11 (Scheme 5). Such an interaction causes ring opening of the crystal structure for 13c led to the assumption that the
the pyrimidine to give the rather unstable carboxylic acid positive charge in 13c is delocalized between the N4 and N5
intermediate 12 followed by elimination of the urea residue. atoms. The corresponding resonant structures are shown in
This explains the formation of the ethylene fragment and Figure 7.
Scheme 5. Mechanism for the formation for imidazo[2,1-f]purines 13.
Figure 6. Molecular structure of 13c determined by X-ray diffraction.
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Figure 7. Dominant resonance structures for 13c assumed from the bond lengths determined by X-ray diffraction analysis.
The 1H NMR spectra of the imidazo[2,1-f]purines 13
typically show signals from the amino, aromatic, and theo-
phylline residues. The signals characterizing the products 13
[D6]DMSO was used as solvent and TMS as internal standard.
HPLC–MS was performed with a system consisting of an Agilent
1100 Series high-pressure liquid chromatograph. Mass spectra (ESI
in positive-ion mode, source voltage 6 kV) were recorded with a
are the singlet of the imidazole CH in the range 8.18–
Finnigan LCQ Deca instrument. Elemental analysis for 3a–3d, 3h,
7.31 ppm and the doublets (J = 16.4 Hz) of the trans pro-
tons of the ethenyl moiety.
4a–h, 4j, 7c, 9, 13a–d, and 13f was performed with a Perkin–Elmer
C,H,N Analyzer, and for 3e–3g, 3i, 4i, 4k, and 7b with a HEKA-
tech EuroEA combustion analyzer. X-ray diffraction analysis of a
single crystal of 7a was performed at room temperature with a
Bruker Smart Apex II diffractometer (graphite-monochromated
Mo-Kα, radiation, θmax = 25.15°). X-ray diffraction analysis of the
type I single crystal of 8 (C23H25N7O5·2.5H2O, M = 524.54) was
Conclusions
A convenient and practical method for the synthesis of
8-halogeno-substituted theophyllinylpyrimidines has been
developed. The high reactivity of the bis-heterocycles
formed allowed the straightforward formation of the corre-
sponding 8-amino-substituted derivatives, which readily un-
dergo base-catalyzed intramolecular cyclization to form
polycyclic N-heterocyclic systems containing 1,3-diazepine,
theophylline, and pyrimidine rings with potential in bio-
logical, medicinal, and materials applications. When the re-
action was performed in a sealed tube at 180 °C, imid-
azo[2,3-f]purines were isolated in high yields. The one-pot
synthesis of novel imidazo[2,3-f]purines from 8-halogen-
otheophyllinylpyrimidines is a new efficient method for the
enantiopure annulation of the arylethenylimidazole ring on
to the theophylline core. The methods developed in this
work allow the combinatorial synthesis of fused diazepino-
pyrimidotheophyllines and imidazotheophyllines in high
yields from readily available starting materials.
performed with a “Rigaku Mercury375R/M CCD” diffractometer
(graphite-monochromated Mo-Kα radiation, λ = 0.71073) at 173 K.
X-ray diffraction analysis of the type II single crystal of 8
(C23H25N7O5·0.15H2O, M = 482.20) was performed with a “Xcali-
bur 3” diffractometer (graphite-monochromated Mo-Kα radiation,
λ = 0.71073) at 298 K. X-ray diffraction analysis of single crystals
of 5 and 13c was performed with an “Xcalibur 3” diffractometer
(graphite-monochromated Mo-Kα radiation, λ = 0.71073) at 100 K.
CCDC-856085 (for 5), -800269 (for 7a), -856083 and -856084 (for
8), and 809550 (for 13c) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of Ethyl 6-[(8-Halogeno-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-7H-purin-7-yl)methyl]-1-methyl-2-oxo-4-aryl-1,2,3,4-
tetrahydropyrimidine-5-carboxylates 3a–i: DHPM 2 (0.005 mol)
was dissolved in tBuOH (15 mL) and an equimolar quantity 8-
halogenotheophylline potassium salt 1 was added to the solution
followed by the dropwise addition of DMF until the solution was
clear. The reaction mixture was then heated at reflux for 3 h. The
KBr salt that precipitated during the reaction process was sepa-
rated by decantation. The precipitate formed within 48 h was fil-
tered off, dried and purified by recrystallization from iPrOH/DMF
(3:1).
Experimental Section
All chemicals were obtained from commercial sources and used
without further purification. The potassium salt of 8-propyl-
aminotheophylline
6 was prepared following a known pro-
cedure.[14a] The melting points for 3a–3d, 3h, 4a–h, 4j, 5, 7a, 7c, 8,
9, and 13a–f were measured with an electrothermal capillary melt-
ing-point apparatus and for 3e–3g, 3i, 4i, 4k, and 7b with a Büchi
510K melting-point apparatus. The NMR spectra of 3a–3d, 3h, 4a–
h, 4j, 5, 7a, 7c, 8, 9, and 13a–f were recorded with a Varian GEM-
INI 2000 spectrometer (1H: 400 MHz, 13C: 100 MHz), and of 3e–
3g, 3i, 4i, 4k, and 7b with a Bruker Avance 400 (1H: 400 MHz, 13C:
100 MHz) spectrometer at 293 K. 13C NMR spectra were recorded
with spectral width of 30000 Hz and a number of points 128000.
Ethyl 6-[(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate (3a): White crystals; yield 1.85 g (76%), m.p.
199–200 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.10 [d,
3J(H,H) = 3.4 Hz, 1 H, NHCH], 7.35–7.27 (m, 5 H, Ar), 6.39 [d,
2
2J(H,H) = 16.6 Hz, 1 H, CH2N], 5.92 [d, J(H,H) = 16.6 Hz, 1 H,
3
3
CH2N], 5.30 [d, J(H,H) = 3.4 Hz, 1 H, NHCH], 4.14 [q, J(H,H)
= 6.9 Hz, 2 H, CH2CH3], 3.41 (s, 3 H, NCH3), 3.25 (s, 3 H, NCH3),
2.90 (s, 3 H, NCH3), 1.20 [t, 3J(H,H) = 6.9 Hz, 3 H, CH2CH3] ppm.
8
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Date: 11-06-13 17:50:10
Pages: 14
Theophyllinylpyrimidine Intramolecular Cyclizations
13C NMR (100 MHz, [D6]DMSO): δ = 169.52, 158.63, 158.13,
127.78, 114.30, 109.69, 109.10, 60.90, 55.45, 52.41, 43.67, 30.94,
155.17, 151.36, 148.86, 147.37, 142.94, 133.20, 130.85, 113.64, 29.93, 28.13, 14.38 ppm. MS (ESI): m/z = 561.3 [M]+
.
112.46, 100.39, 65.37, 57.55, 47.62, 35.28, 34.48, 32.70, 19.00 ppm.
HPLC–MS: m/z = 487.3 [M]+. C22H23ClN6O5 (486.92): calcd. C
54.27, H 4.76, N 17.26; found C 54.11, H 4.70, N 17.12.
C23H25BrN6O6 (561.40): calcd. C 49.21, H 4.49, N 14.97; found C
49.10, H 4.32, N 14.68.
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-4-(4-chlorophenyl)-1-methyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (3f): White powder; yield 2.21 g
(78%), m.p. 230–231 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
8.17 [d, 3J(H,H) = 4.0 Hz, 1 H, NHCH], 7.41 [d, 3J(H,H) = 8.5 Hz,
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate (3b): White powder; yield 2.20 g (83%), m.p.
211–212 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.16 [d,
3J(H,H) = 3.6 Hz, 1 H, NHCH], 7.36–7.25 (m, 5 H, Ar), 6.43 [d, 2 H, Ar], 7.31 [d, J(H,H) = 8.5 Hz, 2 H, Ar], 6.40 [d, J(H,H) =
3
2
2
2J(H,H) = 17.0 Hz, 1 H, CH2N], 5.91 [d, J(H,H) = 17.0 Hz, 1 H,
16.9 Hz, 1 H, CH2N], 5.93 [d, 2J(H,H) = 16.9 Hz, 1 H, CH2N],
3
3
CH2N], 5.29 [d, J(H,H) = 3.5 Hz, 1 H, NHCH], 4.12 [q, J(H,H) 5.28 [d, 3J(H,H) = 4.0 Hz, 1 H, NHCH], 4.17–4.06 (m, 2 H,
= 6.9 Hz, 2 H, CH2CH3], 3.40 (s, 3 H, NCH3), 3.23 (s, 3 H, NCH3), CH2CH3), 3.40 (s, 3 H, NCH3), 3.22 (s, 3 H, NCH3), 2.81 (s, 3 H,
2.81 (s, 3 H, NCH3), 1.18 [t, 3J(H,H) = 7.0 Hz, 3 H, CH2CH3] ppm. NCH3), 1.17 [t, 3J(H,H) = 7.08 Hz, 3 H, CH2CH3] ppm. 13C NMR
13C NMR (100 MHz, [D6]DMSO): δ = 165.43, 154.44, 154.11,
(100 MHz, [D6]DMSO): δ = 166.15, 154.28, 153.79, 150.96, 148.04,
151.05, 148.19, 145.12, 143.22, 129.11, 128.35, 128.12, 126.68, 145.60, 141.98, 132.58, 128.96, 128.58, 128.54, 109.09, 108.62,
109.63, 109.27, 96.10, 61.14, 53.21, 43.91, 31.21, 30.19, 28.40, 60.97, 52.39, 43.73, 31.09, 30.99, 29.93, 28.13, 14.36 ppm. MS
14.69 ppm. HPLC–MS: m/z = 531.2 [M]+. C22H23BrN6O5 (531.37):
(ESI): m/z = 567.3 [M]+. C22H22BrClN6O5 (565.81): calcd. C 46.70,
calcd. C 49.73, H 4.36, N 15.82; found C 49.92, H 4.22, N 15.59.
H 3.92, N 14.85; found C 47.00, H 3.80, N 14.60.
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-1-methyl-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (3c): White powder; yield 2.02 g
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-4-(4-bromophenyl)-1-methyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (3g): Yellow powder; yield 2.56 g
(84%), m.p. 234–236 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
(74%), m.p. 221–223 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
3
8.08 [d, J(H,H) = 3.6 Hz, 1 H, NHCH], 7.15–7.11 (m, 4 H, Ar), 8.17 [d, 3J(H,H) = 3.9 Hz, 1 H, NHCH], 7.54 [d, 3J(H,H) = 8.4 Hz,
6.42 [d, 2J(H,H) = 17.0 Hz, 1 H, CH2N], 5.90 [d, 2J(H,H) = 2 H, Ar], 7.25 [d, J(H,H) = 8.4 Hz, 2 H, Ar], 6.40 [d, J(H,H) =
3
2
17.0 Hz, 1 H, CH2N], 5.25 [d, 3J(H,H) = 4.1 Hz, 1 H, NHCH], 16.9 Hz, 1 H, CH2N], 5.92 [d, 2J(H,H) = 16.9 Hz, 1 H, CH2N],
4.12 [q, 3J(H,H) = 7.0 Hz, 2 H, CH2CH3], 3.40 (s, 3 H, NCH3),
5.27 [d, 3J(H,H) = 3.9 Hz, 1 H, NHCH], 4.17–4.07 (m, 2 H,
3.23 (s, 3 H, NCH3), 2.80 (s, 3 H, NCH3), 2.28 (s, 3 H, 4-CH3Ar), CH2CH3), 3.40 (s, 3 H, NCH3), 3.22 (s, 3 H, NCH3), 2.81 (s, 3 H,
3
1.18 [t, 3J(H,H) = 7.0 Hz, 3 H, CH2CH3] ppm. 13C NMR NCH3), 1.16 [t, J(H,H) = 7.0 Hz, 3 H, CH2CH3] ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 164.78, 153.77, 153.46, 150.38, 147.52,
(100 MHz, [D6]DMSO): δ = 165.14, 154.28, 153.80, 150.96, 148.04,
144.20, 139.59, 136.58, 128.96, 127.62, 125.89, 109.17, 108.61, 145.62, 142.38, 131.89, 128.92, 128.36, 121.14, 109.08, 108.56,
95.43, 60.42, 52.22, 43.22, 30.49, 29.50, 27.71, 20.72, 14.02 ppm.
HPLC–MS: m/z = 546.8 [M]+. C23H25BrN6O5 (545.40): calcd. C
50.65, H 4.62, N 15.41; found C 50.48, H 4.50, N 15.26.
60.97, 52.44, 43.73, 31.00, 29.93, 28.13, 14.36 ppm. MS (ESI): m/z
= 611.2 [M]+. C22H22Br2N6O5 (610.26): calcd. C 43.30, H 3.63, N
13.77; found C 43.48, H 3.51, N 13.48.
Ethyl 6-[(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
Ethyl 6-[(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-4-(4-methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetra- purin-7-yl)methyl]-1-methyl-2-oxo-4-(3-nitrophenyl)-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (3d): White powder; yield 2.09 g
(81%), m.p. 211–212 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
8.02 [d, 3J(H,H) = 2.8 Hz, 1 H, NHCH], 7.17 [d, 3J(H,H) = 8.4 Hz,
hydropyrimidine-5-carboxylate (3h): Yellow powder; yield 2.1 g
(79%), m.p. 191–192 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
3
8.31 [d, J(H,H) = 3.1 Hz, 1 H, NHCH], 8.16–8.11 (m, 2 H, Ar),
3
2
3
3
2 H, Ar], 6.84 [d, J(H,H) = 8.4 Hz, 2 H, Ar], 6.40 [d, J(H,H) = 7.75 [d, J(H,H) = 7.6 Hz, 1 H, Ar], 7.63 [t, J(H,H) = 7.6 Hz, 1
16.6 Hz, 1 H, CH2N], 5.92 [d, 2J(H,H) = 16.6 Hz, 1 H, CH2N], H, Ar], 6.37 [d, J(H,H) = 16.6 Hz, 1 H, CH2N], 5.96 [d, J(H,H)
2
2
5.23 [d, 3J(H,H) = 2.8 Hz, 1 H, NHCH], 4.13 [q, 3J(H,H) = 6.9 Hz,
2 H, CH2CH3], 3.75 (s, 3 H, OCH3), 3.42 (s, 3 H, NCH3), 3.26 (s,
= 16.6 Hz, 1 H, CH2N], 5.42 [d, J(H,H) = 3.1 Hz, 1 H, NHCH],
4.19–4.10 (m, 2 H, CH2CH3), 3.41 (s, 3 H, NCH3), 3.22 (s, 3 H,
3
3 H, NCH3), 2.89 (s, 3 H, NCH3), 1.20 [t, 3J(H,H) = 6.9 Hz, 3 NH3), 2.91 (s, 3 H, NCH3), 1.20 [t, 3J(H,H) = 7.0 Hz, 3 H,
H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.73,
CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.32,
158.53, 153.80, 153.26, 150.31, 146.51, 143.71, 138.09, 134.57, 153.72, 152.98, 150.27, 147.67, 146.53, 145.67, 144.67, 138.20,
127.20, 113.63, 109.01, 107.54, 95.50, 60.33, 54.92, 52.00, 42.55, 132.56, 129.96, 122.33, 121.10, 107.47, 107.05, 95.50, 60.51, 51.91,
30.21, 29.46, 27.68, 13.98 ppm. HPLC–MS: m/z = 517.3.
C23H25ClN6O6 (516.95): calcd. C 53.44, H 4.87, N 16.26; found C C22H22ClN7O7 (531.92): calcd. C 49.68, H 4.17, N 18.43; found C
42.67, 29.44, 27.63, 13.91 ppm. HPLC–MS: m/z = = 532.1 [M]+.
53.31, H 4.83, N 16.18.
49.59, H 4.10, N 18.38.
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
Ethyl 6-[(8-Bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl)methyl]-4-(4-methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetra- purin-7-yl)methyl]-1-methyl-2-oxo-4-(3-nitrophenyl)-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (3e): White powder; yield 2.25 g
(80%), m.p. 217–218 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
8.06 [d, 3J(H,H) = 3.9 Hz, 1 H, NHCH], 7.19 [d, 3J(H,H) = 8.6 Hz,
hydropyrimidine-5-carboxylate (3i): Yellow powder; yield 2.62 g
(91%), m.p. 190–192 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
3
8.31 [d, J(H,H) = 4.0 Hz, 1 H, NHCH], 8.17–8.13 (m, 2 H, Ar),
2 H, Ar], 6.89 [d, J(H,H) = 8.6 Hz, 2 H, Ar], 6.41 [d, J(H,H) = 7.77 [pseudo-d, 3J(H,H) = 7.8 Hz, 1 H, Ar], 7.67 [pseudo-t,
3
2
16.9 Hz, 1 H, CH2N], 5.91 [d, 2J(H,H) = 16.9 Hz, 1 H, CH2N], 3J(H,H) = 7.8 Hz, 1 H, Ar], 6.39 [d, 2J(H,H) = 16.9 Hz, 1 H,
5.24 [d, 3J(H,H) = 3.9 Hz, 1 H, NHCH], 4.11 [q, 3J(H,H) = 7.2 Hz,
2 H, CH2CH3], 3.73 (s, 3 H, 4-OCH3Ar), 3.40 (s, 3 H, NCH3), 3.23
CH2N], 5.95 [d, J(H,H) = 16.9 Hz, 1 H, CH2N], 5.43 [d, J(H,H)
= 4.0 Hz, 1 H, NHCH], 4.19–4.06 (m, 2 H, CH2CH2), 3.40 (s, 3
2
3
(s, 3 H, NCH3), 2.81 (s, 3 H, NCH3), 1.17 [t, 3J(H,H) = 7.08 Hz, 3 H, NCH3-pyrim), 3.20 (s, 3 H, CONCH3CO), 2.83 (s, 3 H,
H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.36,
CNCH3CO), 1.16 [t, 3J(H,H) = 7.1 Hz, 3 H, CH2CH3] ppm. 13C
159.07, 154.32, 154.00, 150.96, 148.03, 144.71, 135.12, 128.30, NMR (100 MHz, [D6]DMSO): δ = 164.98 (COOEt), 154.22 (C-6
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O30360
/KAP1
Date: 11-06-13 17:50:10
Pages: 14
I. O. Lebedyeva et al.
purine), 153.70 (C-2 pyrim.), 150.93 (C-2 purine), 148.19 (C-3 Ph), 153.70, 153.16, 152.89, 150.75, 148.41, 145.42, 142.67, 128.39,
FULL PAPER
148.06 (C-4 purine), 146.50 (C-6 pyrim.), 145.17 (C-1 Ph), 133.20
(C-6 Ph), 130.74 (C-5 Ph), 128.49 (C-8 purine), 123.01 (C-4 Ph),
121.56 (C-2 Ph), 109.03 (C-5 purine), 107.71 (C-5 pyrim.), 61.04
127.45, 126.13, 107.73, 101.59, 70.33, 60.74, 57.92, 52.79, 42.28,
40.57, 29.85, 29.28, 27.28, 13.85 ppm. HPLC–MS: m/z = 526.0
[M]+. C25H31N7O6 (525.57): calcd. C 57.13, H 5.95, N 18.66; found
(C-1, OCH2CH3-pyrim.), 52.38 (C-4 pyrim.), 43.82 (C-1, CH2-py- C 57.02, H 5.74, N 18.48.
rim.), 31.07 (NCH3 pyrim.), 29.92 (1-CH3 purine), 28.10 (1-CH3
Ethyl 6-({8-[(2-Hydroxyethyl)amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-
purine), 14.31 (C-2, OCH2CH3-pyrim.) ppm. MS (ESI): m/z =
576.3 [M]+. C22H22BrN7O7 (576.37): calcd. C 45.85, H 3.85, N
17.01; found C 45.63, H 3.66, N 16.84.
tetrahydro-7H-purin-7-yl}methyl)-1-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4c): White powder; yield 1.99 g
(78%), m.p. 186–187 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
3
Synthesis of Ethyl 6-{[1,3-Dimethyl-2,6-dioxo-8-(R-ylamino)-
1,2,3,6-tetrahydro-7H-purin-7-yl]methyl}-1-methyl-2-oxo-4-aryl-
1,2,3,4-tetrahydropyrimidine-5-carboxylates 4a–k and (Z)-4-(4-
Bromophenyl)-N-(2-hydroxyethyl)-6-{8-[(2-hydroxyethyl)amino]-1,3-
dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-ylmethylene}-1-
methyl-2-oxohexahydropyrimidine-5-carboxamide (5)
8.05 [d, J(H,H) = 3.7 Hz, 1 H, NHCH], 7.37–7.31 (m, 2 H, Ar),
3
7.29–7.25 (m, 3 H, Ar), 6.70 [t, J(H,H) = 4.9 Hz, 1 H, NHCH2],
5.87 [d, 2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.50 [d, 2J(H,H) =
3
16.8 Hz, 1 H, CH2NH], 5.20 [d, J(H,H) = 3.7 Hz, 1 H, NHCH],
4.73 [t, 3J(H,H) = 5.0 Hz, 1 H, OH], 4.18–4.06 (m, 2 H, CH2CH3),
3.52–3.45 (m, 2 H, CH2), 3.42–3.38 (m, 2 H, CH2), 3.37 (s, 3 H,
NCH3), 3.17 (s, 3 H, NCH3), 2.84 (s, 3 H, NCH3), 1.16 [t, 3J(H,H)
= 7.1 Hz, 3 H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 166.19, 163.11, 153.96, 153.31, 152.75, 150.79, 148.53, 145.48,
142.75, 128.42, 127.45, 126.08, 107.80, 101.55, 60.68, 59.52, 52.74,
45.19, 30.02, 29.33, 27.32, 13.84 ppm. HPLC–MS: m/z = 512.0
[M]+. C24H29N7O6 (511.54): calcd. C 56.35, H 5.71, N 19.17; found
C 56.42, H 5.60, N 19.03.
Route A: Ethyl 6-[(8-halogeno-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydro-7H-purin-7-yl)methyl]-1-methyl-2-oxo-4-aryl-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate 3 (0.005 mol) was dissolved in
tBuOH (15 mL) and the corresponding amine (0.01 mol) was
added. The mixture was heated at reflux for 8 h. The precipitate
formed in 24 h after cooling the mixture was filtered off, dried,
and washed with hot MeOH. After evaporation of MeOH under
vacuum, the crude solid was purified by recrystallization from
MeOH/H2O (1:1) to give product 5. The precipitate formed was
purified by recrystallization from iPrOH/DMF (3:1) to give prod-
uct 4.
Ethyl 6-{[1,3-Dimethyl-2,6-dioxo-8-(propylamino)-1,2,3,6-tetra-
hydro-7H-purin-7-yl]methyl}-1-methyl-4-(4-methylphenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d): White solid; yield
1
2.12 g (83%), m.p. 217–219 °C. H NMR (400 MHz, [D6]DMSO):
δ = 8.04 [d, 3J(H,H) = 3.4 Hz, 1 H, NHCH], 7.19–7.09 (m, 4 H,
Ar), 6.57 [t, 3J(H,H) = 4.9 Hz, 1 H, NHCH2CH2CH3], 5.77 [d,
Route B: An equimolar quantity of DHPM 2 was added to the
potassium salt of 8-amino-substituted theophylline 6 (0.005 mol) in
DMF (10 mL). The reaction mixture was heated at reflux for 3 h,
then poured onto crushed ice (50 g). The precipitate formed was
filtered off, dried, and purified by recrystallization from iPrOH/
DMF (3:1) to give 4.
2
2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.49 [d, J(H,H) = 16.8 Hz, 1
H, CH2NH], 5.14 [d, 3J(H,H) = 3.4 Hz, 1 H, NHCH], 4.18–4.15
(m, 2 H, CH2CH3), 3.36 (s, 3 H, NCH3), 3.33–3.22 (m, 2 H,
NHCH2CH2CH3), 3.17 (s, 3 H, NCH3), 2.84 (s, 3 H, NCH3), 2.28
(s, 3 H, 4-CH3C6H4), 1.51–1.42 (m, 2 H, NHCH2CH2CH3), 1.16
Ethyl 6-{[1,3-Dimethyl-2,6-dioxo-8-(propylamino)-1,2,3,6-tetra-
hydro-7H-purin-7-yl]methyl}-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4a): White powder; yield 2.17 g
(85 %) (route A); 2.01 g (79 %) (route B), m.p. 255–256 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 8.14–8.08 (br. s, 1 H, NHCH),
7.34–7.28 (m, 5 H, Ar), 6.58–6.54 (br. s, 1 H, NHCH2), 5.75 [d,
3
3
[t, J(H,H) = 7.0 Hz, 3 H, CH2CH3], 0.86 [t, J(H,H) = 7.28 Hz, 3
H, NHCH2CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
166.73, 153.93, 153.26, 152.82, 150.78, 148.57, 145.17, 139.72,
136.70, 128.96, 125.97, 107.90, 101.47, 60.82, 52.50, 44.40, 40.68,
29.88, 29.31, 27.29, 22.21, 20.66, 13.90, 11.15 ppm. HPLC–MS: m/z
= 524.3 [M]+. C26H33N7O5 (523.60): calcd. C 59.64, H 6.35, N
18.73; found C 59.42, H 6.22, N 18.51.
2
2J(H,H) = 16.6 Hz, 1 H, CH2NH], 5.53 [d, J(H,H) = 16.6 Hz, 1
H, CH2NH], 5.21–5.16 (br. s, 1 H, NHCH), 4.18–4.10 (m, 2 H,
OCH2CH3), 3.39 (s, 3 H, NCH3), 3.35–3.29 (m, 1 H, NHCH2),
3.28–3.23 (m, 1 H, NHCH2), 3.19 (s, 3 H, NCH3), 2.92 (s, 3 H,
CNCH3CONH), 1.52–1.43 (m, 2 H, CH2CH2CH3), 1.19 [t,
3J(H,H) = 6.7 Hz, 3 H, OCH2CH3], 0.88 [t, 3J(H,H) = 6.9 Hz, 3
H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.94,
153.95, 152.92, 152.87, 150.68, 148.52, 145.13, 142.67, 128.28,
127.40, 126.08, 107.54, 101.44, 60.82, 52.96, 44.42, 40.65, 29.68,
29.21, 27.22, 22.24, 13.85, 11.13 ppm. HPLC–MS: m/z = 510.2
[M]+. C25H31N7O5 (509.57): calcd. C 58.93, H 6.13, N 19.24; found
C 59.09, H 6.08, N 18.99.
Ethyl 6-({8-[(2-Methoxyethyl)amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-7H-purin-7-yl}methyl)-1-methyl-4-(4-methylphenyl)-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e): White powder;
yield 2.08 g (77%), m.p. 169–170 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.06 [d, 3J(H,H) = 3.6 Hz, 1 H, NHCH], 7.15 [d,
3J(H,H) = 8.2 Hz, 2 H, C6H4], 7.12 [d, 3J(H,H) = 8.2 Hz, 2 H,
3
2
C6H4], 6.61 [t, J(H,H) = 5.3 Hz, 1 H, NHCH2], 5.84 [d, J(H,H)
= 16.7 Hz, 1 H, CH2NH], 5.54 [d, 2J(H,H) = 16.7 Hz, 1 H,
3
CH2NH], 5.12 [d, J(H,H) = 3.6 Hz, 1 H, NHCH], 4.19–4.06 (m,
2 H, CH2CH3), 3.56–3.48 (m, 2 H, CH2), 3.47–3.38 (m, 2 H, CH2),
3.37 (s, 3 H, NCH3), 3.23 (s, 3 H, OCH3), 3.17 (s, 3 H, NCH3),
2.85 (s, 3 H, NCH3), 2.28 (s, 3 H, 4-CH3Ar), 1.17 [t, 3J(H,H) =
7.1 Hz, 3 H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 166.40, 153.67, 153.14, 152.87, 150.72, 148.38, 145.26, 139.69,
136.58, 128.90, 126.02, 107.79, 101.58, 70.33, 60.70, 57.93, 52.42,
42.26, 40.51, 29.79, 29.28, 27.28, 20.72, 13.88 ppm. HPLC–MS: m/z
= 539.9 [M]+, 97.49. C26H33N7O6 (539.60): calcd. C 57.87, H 6.16,
N 18.17; found C 57.69, H 5.96, N 18.05.
Ethyl 6-({8-[(2-Methoxyethyl)amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-7H-purin-7-yl}methyl)-1-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4b): White powder; yield 2.13 g
(81%), m.p. 242–244 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
3
8.06 [d, J(H,H) = 3.5 Hz, 1 H, NHCH], 7.37–7.26 (m, 5 H, Ar),
6.57 [t, 3J(H,H) = 5.2 Hz, 1 H, NHCH2], 5.85 [d, 2J(H,H) =
16.7 Hz, 1 H, CH2NH], 5.56 [d, 2J(H,H) = 16.7 Hz, 1 H, CH2NH],
5.19 [d, 3J(H,H) = 3.5 Hz, 1 H, NHCH], 4.20–4.08 (m, 2 H,
CH2CH3), 3.57–3.49 (m, 1 H, CH2), 3.48–3.44 (m, 1 H, CH2), 3.43–
Ethyl 6-({8-[(2-Hydroxyethyl)amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-
3.39 (m, 2 H, CH2), 3.37 (s, 3 H, NCH3), 3.23 (s, 3 H, OCH3), 3.19 tetrahydro-7H-purin-7-yl}methyl)-1-methyl-4-(4-methylphenyl)-2-
(s, 3 H, NCH3), 2.88 (s, 3 H, NCH3), 1.18 [t, 3J(H,H) = 7.04 Hz, 3 oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f): White powder;
H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.32,
yield 1.79 g (68%), m.p. 253–255 °C. 1H NMR (400 MHz, [D6]-
10
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Job/Unit: O30360
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Date: 11-06-13 17:50:10
Pages: 14
Theophyllinylpyrimidine Intramolecular Cyclizations
DMSO): δ = 8.02 [d, 3J(H,H) = 3.2 Hz, 1 H, NHCH], 7.18–7.11
= 6.2 Hz, 6 H, CHCH3] ppm. 13C NMR (100 MHz, [D6]DMSO):
(m, 4 H, Ar), 6.69 [t, 3J(H,H) = 4.8 Hz, 1 H, NHCH2], 5.87 [d, δ = 167.37, 159.10, 153.78, 153.69, 153.29, 151.27, 149.14, 145.57,
2
2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.49 [d, J(H,H) = 16.8 Hz, 1
H, CH2NH], 5.15 [d, 3J(H,H) = 3.2 Hz, 1 H, NHCH], 4.73 [t,
3J(H,H) = 5.8 Hz, 1 H, CH2OH], 4.16–4.07 (m, 2 H, CH2CH3),
135.18, 127.78, 114.27, 108.52, 101.78, 61.30, 55.47, 52.59, 45.02,
41.13, 30.22, 29.71, 27.70, 22.90, 22.88, 14.32 ppm. MS (ESI): m/z
= 540.4 [M]+. C26H33N7O6 (539.60): calcd. C 57.87, H 6.16, N
3.51–3.45 (m, 2 H, NCH2 CH2 OH), 3.44–3.39 (m, 2 H, 18.17; found C 57.62, H 6.09, N 17.92.
NCH2CH2OH), 3.36 (s, 3 H, NCH3), 3.17 (s, 3 H, NCH3), 2.83 (s,
Ethyl 6-{[8-(Benzylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
3
3 H, NCH3), 2.28 (s, 3 H, 4-CH3Ar), 1.16 [t, J(H,H) = 7.0 Hz, 3
hydro-7H-purin-7-yl]methyl}-4-(4-methoxyphenyl)-1-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4j): White powder;
yield 2.35 g (80%), m.p. 176–178 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.09 [d, 3J(H,H) = 3.5 Hz, 1 H, NHCH], 7.36–7.24
(m, 5 H, Ar), 7.18 [d, 3J(H,H) = 8.4 Hz, 2 H, C5H4Me], 7.09 [t,
H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.25,
153.97, 153.31, 152.77, 150.78, 148.52, 145.27, 139.76, 136.61,
128.94, 126.00, 107.95, 101.55, 60.66, 59.52, 52.40, 45.19, 40.59,
29.97, 29.31, 27.31, 20.68, 13.89 ppm. HPLC–MS: m/z = 526.0
[M]+. C25H31N7O6 (525.27): calcd. C 57.13, H 5.95, N 18.66; found
C 57.29, H 5.72, N 18.53.
3
3J(H,H) = 5.0 Hz, 1 H, NHCH2], 6.86 [d, J(H,H) = 8.4 Hz, 2 H,
C5H4Me], 5.83 [d, 2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.57 [d,
2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.07 [d, 3J(H,H) = 3.5 Hz, 1 H,
NHCH], 4.62 [q, 2J(H,H) = 6.0 Hz, 1 H, NHCH2Ar], 4.48 [q,
2J(H,H) = 6.0 Hz, 1 H, NHCH2Ar], 4.03–3.95 (m, 2 H, CH2CH3),
3.73 (s, 3 H, 4-OCH3Ar), 3.36 (s, 3 H, NCH3), 3.18 (s, 3 H, NCH3),
2.86 (s, 3 H, NCH3), 1.06 [t, 3J(H,H) = 7.0 Hz, 3 H CH2CH3] ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 166.63, 158.55, 153.67,
153.30, 152.93, 150.76, 148.38, 145.30, 138.55, 134.71, 128.24,
127.34, 127.10, 126.96, 113.77, 108.04, 101.77, 60.70, 55.04, 52.23,
48.17, 40.65, 30.00, 29.35, 27.32, 13.77 ppm. HPLC–MS: m/z =
588.3 [M]+. C30H33N7O6 (587.64): calcd. C 61.32, H 5.66, N 16.68;
found C 61.14, H 5.47, N 16.59.
Ethyl 6-({1,3-Dimethyl-8-[(4-methylphenyl)amino]-2,6-dioxo-1,2,3,6-
tetrahydro-7H-purin-7-yl}methyl)-1-methyl-4-(4-methylphenyl)-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g): White powder;
yield 2.06 g (72 %), m.p. 252–253 °C. 1H NMR (400 MHz, [D6-
DMSO): δ = 9.09 (s, 1 H, NH), 8.01 [d, 3J(H,H) = 2.4 Hz, 1 H,
3
3
NHCH], 7.27 [d, J(H,H) = 8.2 Hz, 2 H, Ar], 7.09 [d, J(H,H) =
7.9 Hz, 2 H, Ar], 7.05 [d, 3J(H,H) = 8.2 Hz, 2 H, Ar], 6.95 [d,
3J(H,H) = 7.9 Hz, 2 H, Ar], 5.87 [d, 2J(H,H) = 16.6 Hz, 1 H,
CH2NH], 5.62 [d, 2J(H,H) = 16.6 Hz, 1 H, CH2NH], 5.16 [d,
3J(H,H) = 2.4 Hz, 1 H, NHCH], 4.24–4.15 (m, 2 H, CH2CH3),
3.45 (s, 3 H, NCH3), 3.23 (s, 3 H, NH3), 2.92 (s, 3 H, NCH3), 2.29
(s, 3 H, 4-CH3Ar), 2.25 (s, 3 H, 4-CH3Ar), 1.21 [t, 3J(H,H) =
7.1 Hz, 3 H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 167.78, 153.26, 152.67, 150.62, 149.48, 147.78, 144.42, 139.54,
136.52, 136.50, 130.75, 129.01, 128.80, 125.97, 117.87, 107.90,
101.54, 95.50, 61.15, 52.84, 41.31, 29.52, 29.39, 27.38, 20.73, 20.44,
13.87 ppm. HPLC–MS: m/z = 570.2 [M]–. C30H33N7O5 (571.64):
calcd. C 63.04, H 5.82, N 17.15; found C 62.78, H 5.68, N 17.01.
Ethyl 6-({8-[(2-Methoxyethyl)amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-7H-purin-7-yl}methyl)-4-(3-nitrophenyl)-1-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4k): Yellow crystals;
yield 2.37 g (83%), m.p. 231–232 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.32 [d, 3J(H,H) = 4.0 Hz, 1 H, NHCH], 8.18–8.14
3
(m, 2 H, Ar), 7.78 [d, J(H,H) = 7.7 Hz, 1 H, Ar], 7.65 [pseudo-t,
3J(H,H) = 8.3 Hz, 1 H, Ar], 6.67 [t, 3J(H,H) = 4.3 Hz, 1 H,
2
NHCH2CH2], 5.81 [d, J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.61 [d,
Ethyl 6-({8-[(4-Hydroxyphenyl)amino]-1,3-dimethyl-2,6-dioxo-
1,2,3,6-tetrahydro-7H-purin-7-yl}methyl)-1-methyl-4-(4-methyl-
phenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4h): Pink
2J(H,H) = 16.8 Hz, 1 H, CH2NH], 5.32 [d, 3J(H,H) = 4.0 Hz, 1 H,
3
NHCH], 4.15 [q, J(H,H) = 7.0 Hz, 2 H, CH2CH3], 3.58–3.38 (m,
4 H, CH2CH2), 3.36 (s, 3 H, NCH3), 3.23 (s, 3 H, NCH3), 3.16 (s,
3 H. OCH3), 2.87 (s, 3 H, NCH3), 1.17 [t, 3J(H,H) = 7.0 Hz, 3
H CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.50,
154.18, 153.53, 153.31, 151.25, 148.94, 148.21, 147.17, 145.28,
133.26, 130.67, 123.00, 121.68, 106.95, 102.01, 70.80, 61.33, 58.36,
52.50, 42.64, 40.91, 30.44, 29.71, 27.68, 14.18 ppm. MS (ESI): m/z
= 571.4 [M]+. C25H30N8O8 (570.57): calcd. C 52.63, H 5.30, N
19.64; found C 52.77, H 5.16, N 19.39.
1
powder; yield 1.95 g (68%), m.p. 275–277 °C. H NMR (400 MHz,
[D6]DMSO): δ = 9.17 (s, 1 H, OH), 8.89 (s, 1 H, NH), 8.02 [d,
3J(H,H) = 3.6 Hz, 1 H, NHCH], 7.23 [d, J(H,H) = 8.1 Hz, 2 H,
3
Ar], 7.12 [d, 3J(H,H) = 7.4 Hz, 2 H, Ar], 7.05 [d, 3J(H,H) = 7.4 Hz,
3
2
2 H, Ar], 6.71 [d, J(H,H) = 8.1 Hz, 2 H, Ar], 5.86 [d, J(H,H) =
16.8 Hz, 1 H, CH2NH], 5.58 [d, 2J(H,H) = 16.8 Hz, 1 H, CH2NH],
5.15 [d, 3J(H,H) = 3.6 Hz, 1 H, NHCH], 4.22–4.09 (m, 2 H,
CH2CH3), 3.39 (s, 3 H, NCH3), 3.20 (s, 3 H, NCH3), 2.88 (s, 3 H,
NCH3), 2.25 (s, 3 H, 4-CH3Ar), 1.19 [t, 3J(H,H) = 6.8 Hz, 3 H,
CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 167.43,
153.11, 152.97, 152.80, 150.71, 150.15, 147.99, 144.73, 139.58,
136.62, 130.64, 128.89, 125.97, 119.99, 115.18, 107.98, 101.46,
61.08, 52.68, 41.24, 30.65, 29.72, 29.43, 27.39, 20.72, 13.88 ppm.
HPLC–MS: m/z = 574.2 [M]+. C29H31N7O6 (573.61): calcd. C
60.72, H 5.45, N 17.09; found C 60.79, H 5.36, N 16.99.
(Z)-4-(4-Bromophenyl)-N-(2-hydroxyethyl)-6-({8-[(2-hydroxyethyl)-
amino]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl}methylene)-1-methyl-2-oxohexahydropyrimidine-5-carboxamide
(5): White powder; yield 0.21 g (7%), m.p. 238–239 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.14–8.09 (br. s, 1 H, NHCH), 7.69
[d, 3J(H,H) = 3.88 Hz, 2 H, Ar], 7.63–7.52 (br. s, 1 H, CONHCH2),
7.19–7.11 (m, 3 H, Ar; CNHCH2), 6.05–6.01 (br. s, 1 H, ArCHCH),
5.73 (s, 1 H, CCHN), 4.93–4.83 (br. s, 1 H, ArCHCH), 4.63–4.56
(m, 2 H, 2 OH), 3.53–3.40 (m, 4 H, 2 CH2), 3.16 (s, 6 H, 2 CH3),
3.09 (s, 3 H, CH3), 3.06–2.99 (m, 4 H, 2 CH2) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 168.31, 154.07, 152.05, 151.10, 141.28,
141.25, 141.17, 131.13, 130.82, 128.15, 127.82, 127.78, 121.1, 99.85,
59.51, 59.08, 45.56, 44.82, 41.75, 30.45, 29.22, 27.04 ppm. HPLC–
MS: m/z = 605.2 [M]+.
Ethyl 6-{[8-(Isopropylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydro-7H-purin-7-yl]methyl}-4-(4-methoxyphenyl)-1-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4i): White powder;
yield 1.99 g (74%), m.p. 207–208 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.04 [d, 3J(H,H) = 3.8 Hz, 1 H, NHCH], 7.19 [d,
3J(H,H) = 8.6 Hz, 2 H, Ar], 6.89 [d, J(H,H) = 8.6 Hz, 2 H, Ar],
6.55 [d, J(H,H) = 7.2 Hz, 1 H, CNHCH(CH3)2], 5.74 [d, J(H,H)
3
3
2
= 16.8 Hz, 1 H, CH2NH], 5.46 [d, 2J(H,H) = 16.8 Hz, 1 H, Synthesis of 8-Aryl-6-alkyl-2,4,11-trimethyl-8,12-dihydro-2H-pyr-
CH2NH], 5.15 [d, J(H,H) = 3.8 Hz, 1 H, NHCH], 4.21–4.08 (m, imido[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-1,3,7,10(4H,6H,9H,11H)-
3
2 H, CH2CH3), 3.99–3.90 [m, 1 H, CH(CH3)2], 3.73 (s, 3 H, 4-
OCH3Ar), 3.36 (s, 3 H, NCH3), 3.17 (s, 3 H, NCH3), 2.84 (s, 3 H, 10,10a-dihydro-1H-pyrimido[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-
NCH3), 1.17 [t, 3J(H,H) = 7.0 Hz, 3 H, CH2CH3], 1.12 [t, 3J(H,H)
2,4,8,11(3H,7H,9H,12H)-tetraone (8), and 6-{[8-(Benzylamino)-1,3-
tetrones 7a–c, 12-(2-Hydroxyethyl)-1,3,7-trimethyl-10-(p-tolyl)-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O30360
/KAP1
Date: 11-06-13 17:50:10
Pages: 14
I. O. Lebedyeva et al.
FULL PAPER
dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl]methyl}-1-
methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic 200 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.04–8.01 (br. s, 1
9H,12H)-tetraone (8): White crystals; yield 0.74 g (31%), m.p. 198–
1
Acid (9): A catalytic amount of tBuONa was added to a solution
of compound 4 (0.005 mol) in tBuOH (15 mL). The reaction mix-
ture was heated at reflux for 6 h. After completion of the reaction,
tBuONa was separated by decantation and the precipitate formed
in 48 h after cooling the reaction mixture was filtered and purified
by recrystallization from MeOH/DMF (3:1) to give product 7
(from 4a, 4d, and 4e). The undissolved in the MeOH/DMF (3:1)
mixture, purinylpyrimidinecarboxylic acid 9, was filtered off and
purified by recrystallization from DMF. The filtrate was evaporated
and the residue recrystallized from EtOH to give 8 (from 4f).
H, NHCH], 7.16–7.10 (m, 4 H, Ar], 6.70 (s, 1 H, CHCO], 5.0–4.96
(br. s, 1 H, CHN], 4.77 [t, J = 5.52 Hz, 1 H, NHCH], 4.15–4.04
3
(m, 2 H, CH2CH2OH], 3.62–3.56 (m, 3 H, CH2CH2OH], 3.38 (s, 3
H, NCNCH3CO], 3.16 (s, 3 H, CONCH3CO], 3.10 (s, 3 H,
CNCH3 CONH], 2.27 (s, 3 H, 4-CH3Ar] ppm. 13 C NMR
(100 MHz, [D6]DMSO): δ = 171.28, 158.36, 156.23, 155.49, 151.07,
150.30, 143.68, 141.29, 134.25, 133.84, 130.52, 108.73, 100.42,
63.07, 54.43, 54.37, 49.75, 34.82, 34.43, 32.40, 25.68 ppm. HPLC–
MS: m/z = 480.2 [M]+.
6-{[8-(Benzylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl]methyl}-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
imidine-5-carboxylic Acid (9): White powder; yield 0.53 g (20%),
1,3,7-Trimethyl-10-phenyl-12-propyl-9,10-dihydro-1H-pyrimido-
[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-2,4,8,11(3H,6H,7H,12H)-tetra-
one (7a): White powder; yield 1.95 g (84%), m.p. 190–192 °C. 1H
1
m.p. Ͻ305 °C. H NMR (400 MHz, [D6]DMSO): δ = 11.16–11.08
NMR (400 MHz, [D6]DMSO): δ = 8.07 (s, 1 H, NHCH), 7.27–7.23 (br. s, 1 H, COOH), 7.56–7.48 (br. s, 1 H, NH), 7.34 [d, 3J(H,H) =
3
(m, 3 H, Ar), 7.10 [d, J(H,H) = 6.9 Hz, 2 H, Ar], 5.45 [d, 2J(H,H)
7.6 Hz, 2 H, Ar], 7.31–7.14 (m, 8 H, Ar), 5.78–5.68 (br. s, 1 H,
= 15.9 Hz, 1 H, CH2N], 5.33–5.31 (br. s, 1 H, NHCH), 5.16 [d, CHNH), 5.50 [d, 2J(H,H) = 14.9 Hz, 2 H, CH2NH], 5.16–5.10 (br.
2J(H,H) = 15.9 Hz, 1 H, CH2N], 3.96–3.90 (m, 2 H, CH2CH2CH3), s, 1 H, NHBn), 4.66–4.58 (m, 1 H, CH2N), 4.27 [d, 2J(H,H) =
3.37 (s, 3 H, NCH3), 3.32 (s, 3 H, NCH3), 3.23 (s, 3 H, NCH3),
1.66–1.60 (m, 2 H, CH2CH2CH3), 0.82 [t, J(H,H) = 6.9 Hz, 3 H,
13.7 Hz, 1 H, CH2N], 3.33 (s, 3 H, NCH3), 3.19 (s, 3 H, NCH3),
3
2.88 (s, 3 H, NCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
CH2CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.94, 169.16, 153.78, 153.28, 152.98, 150.67, 148.33, 144.80, 142.50,
153.95, 152.33, 150.62, 147.22, 146.57, 144.36, 142.83, 128.45, 138.56, 128.30, 128.27, 128.18, 127.27, 126.81, 126.15, 108.36,
128.42, 127.35, 125.88, 125.62, 69.76, 53.01, 48.74, 40.47, 30.22, 101.71, 95.61, 52.88, 48.18, 46.05, 42.70, 29.64, 29.26, 27.25 ppm.
29.55, 27.47, 20.97, 11.08 ppm. HPLC–MS: m/z = 464.3 [M]+.
HPLC–MS: m/z = 530.3 [M]+. C27H27N7O5 (529.56): calcd. C
61.24, H 5.14, N 18.51; found C 60.97, H 4.98, N 18.4.
1,3,7-Trimethyl-12-propyl-10-(p-tolyl)-9,10-dihydro-1H-pyrimido-
[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-2,4,8,11(3H,6H,7H,12H)-tetra-
one (7b): White powder; yield 1.88 g (79%), m.p. 201–202 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 8.03 [d, 3J(H,H) = 3.6 Hz, 1 H,
Synthesis of 8-Substituted 1,3-Dimethyl-7-[(E)-2-arylethenyl]-1H-
imidazo[2,1-f]purine-2,4(3H,8H)-diones 13a–f
Route A: The corresponding amine (0.01 mol) was added to com-
pound 3 (0.005 mol) in iPrOH (15 mL). The reaction was heated
at 180 °C for 12 h in a sealed tube. The precipitate formed in 48 h
after cooling the reaction mixture was filtered off, thoroughly
washed with 50% acetone, and purified by double recrystallization
from 2-PrOH/DMF (1:3).
3
3
NHCH], 7.07 [d, J(H,H) = 8.0 Hz, 2 H, Ar], 6.97 [d, J(H,H) =
8.0 Hz, 2 H, Ar], 5.44 [d, 2J(H,H) = 15.9 Hz, 1 H, CH2N], 5.28 [d,
2
3J(H,H) = 3.6 Hz, 1 H, NHCH], 5.14 [d, J(H,H) = 15.9 Hz, 1 H,
CH2N], 4.0–3.87 (m, 2 H, NCH2CH2), 3.38 (s, 3 H, CONCH3CO),
3.32 (s, 3 H, NCH3-pyrim.), 3.22 (s, 3 H, NCNCH3CO), 2.22 (s, 3
H, Ph-CH3), 1.71–1.56 (m, 2 H, CH2CH3), 0.83 [t, 3J(H,H) =
7.4 Hz, 3 H CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 163.56 (C-7), 154.53 (C-1 purine), 152.97 (C-10), 151.17 (C-3
purine), 147.73 (C-5a), 147.10 (C-4a purine), 144.88 (C-11a),
140.44 (C-1 Ph), 137.09 (C-4 Ph), 129.55 (C-3b, C-5 Ph), 125.99
(C-2, C-6 Ph), 108.06 (C-7a), 103.09 (C-13a), 53.07 (C-8), 49.16 (C-
1 Alk), 39.8 (C-12), 30.64 (2-CH3), 29.99 (1-CH3 pyrim.), 27.89 (4-
CH3), 21.36 (C-2 Alk), 20.97 (CH3 Ar), 11.45 (C-3 Alk) ppm.
HPLC–MS: m/z = 478.3 [M]+. C24H27N7O4 (477.53): calcd. C
60.37, H 5.70, N 20.53; found C 60.49, H 5.52, N 20.28.
Route B: Compound 4 (0.005 mol) in iPrOH (15 mL) was heated
in a sealed tube at 180 °C for 12 h. The isolation and purification
of the precipitate formed were performed as described in method
A.
1,3-Dimethyl-7-[(E)-2-phenylethenyl]-8-propyl-1H-imidazo[2,1-f]-
purine-2,4(3H,8H)-dione (13a): White powder; yield 1.43 g (79%)
(route A); 1.49 g (82 %) (route B), m.p. 265–267 °C. 1H NMR
3
(400 MHz, [D6]DMSO): δ = 8.04 (s, 1 H, NCH), 7.65 [d, J(H,H)
= 7.6 Hz, 2 H, C6H5], 7.44–7.34 (m, 3 H, Ar), 7.33–7.28 (m, 1 H,
CH), 7.19 [d, 3J(H,H) = 16.4 Hz, 1 H, C6H5CHCH], 4.23 [t,
3J(H,H) = 5.4 Hz, 2 H, NCH2], 3.46 (s, 3 H, NCH3), 3.25 (s, 3 H,
12-(2-Methoxyethyl)-1,3,7-trimethyl-10-(p-tolyl)-9,10-dihydro-1H-
pyrimido[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-2,4,8,11(3H,6H,
7H,12H)-tetraone (7c): White powder; yield 1.75 g (71 %), m.p.
258–259 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 7.87 [d,
3J(H,H) = 2.84 Hz, 1 H, NHCH]; 7.05 [d, 3J(H,H) = 7.84 Hz, 2 H,
Ar], 6.97 [d, 3J(H,H) = 7.84 Hz, 2 H, Ar], 5.48 [d, 2J(H,H) =
3
NCH3), 1.84–1.75 (m, 2 H, NCH2CH2), 0.89 [t, J(H,H) = 7.2 Hz,
3 H, CH2CH3] ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
152.88, 151.33, 151.08, 147.59, 138.30, 130.94, 130.63, 128.55,
127.99, 126.60, 113.46, 103.23, 98.66, 44.55, 29.78, 27.34, 22.43,
10.76 ppm. HPLC–MS: m/z = 364.2 [M]+. C20H21N5O2 (363.42):
calcd. C 66.10, H 5.82, N 19.27; found C 65.97, H 5.77, N 19.18.
3
15.88 Hz, 1 H, CH2N], 5.31 [d, J(H,H) = 2.84 Hz, 1 H, NHCH],
5.06 [d, 2J(H,H) = 15.88 Hz, 1 H, CH2N], 4.30–4.22 (m, 1 H, CH2),
4.19–4.11 (m, 1 H, CH2), 3.52 [t, 3J(H,H) = 5.8 Hz, 2 H, CH2],
3.41 (s, 3 H, OCH3), 3.34 (s, 3 H, NCH3), 3.26 (s, 3 H, NCH3),
3.10 (s, 3 H, NCH3), 2.25 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 162.96, 153.97, 152.30, 150.61, 147.21, 146.52,
144.68, 139.87, 136.47, 128.96, 125.49, 107.43, 102.66, 95.46, 68.98,
57.97, 52.54, 46.03, 30.20, 29.52, 27.44, 20.65 ppm. HPLC–MS: m/z
= 494.3 [M]+. C24H27N7O5 (493.53): calcd. C 58.41, H 5.51, N
19.87; found C 58.11, H 5.34, N 19.69.
8-(2-Methoxyethyl)-1,3-dimethyl-7-[(E)-2-phenylethenyl]-1H-imid-
azo[2,1-f]purine-2,4(3H,8H)-dione (13b): White powder; yield 1.38 g
(73 %) (route A); 1.56 g (82 %) (route B), m.p. 215–216 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 7.99 (s, 1 H, NCH), 7.60 [d,
3J(H,H) = 7.5 Hz, 2 H, Ar], 7.38 [t, 3J(H,H) = 7.4 Hz, 2 H, Ar],
3
7.36–7.26 (m, 2 H Ar; CHCH), 7.17 [d, J(H,H) = 16.4 Hz, 1 H,
C6H5CHCH], 4.42 [t, 3J(H,H) = 4.9 Hz, 2 H, CH2CH2], 3.71 [t,
3J(H,H) = 4.9 Hz, 2 H, CH2CH2], 3.45 (s, 3 H, OCH3), 3.26 (s, 6
H, 2 NCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.80,
151.18, 151.02, 147.52, 136.35, 130.90, 130.61, 128.55, 127.91,
12-(2-Hydroxyethyl)-1,3,7-trimethyl-10-(p-tolyl)-10,10a-dihydro-
1H-pyrimido[5Ј,4Ј:5,6][1,3]diazepino[2,1-f]purine-2,4,8,11(3H,7H,
12
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Job/Unit: O30360
/KAP1
Date: 11-06-13 17:50:10
Pages: 14
Theophyllinylpyrimidine Intramolecular Cyclizations
126.52, 113.66, 103.13, 98.69, 69.80, 58.14, 42.82, 29.80, 27.37 ppm.
HPLC–MS: m/z = 380.0 [M]+. C20H21N5O3 (379.42): calcd. C
63.31, H 5.58, N 18.46; found C 63.47, H 5.44, N 18.35.
Acknowledgments
The authors are thankful to Professor Dr. Heiko Ihmels and Dr.
Thomas Paululat (University of Siegen, Germany) for their help in
performing microanalytical measurements, Professor Dr. Alexan-
der N. Chernega, Dr. Eduard B. Rusanov (Institute of Organic
Chemistry of Ukraine), Professor Dr. Oleg V. Shishkin, and Dr.
Roman I. Zubatyuk (STC “Institute for Single Crystals”) for per-
forming the single-crystal X-ray diffraction measurements. This
work was supported by the Ministry of Education, Science, Youth
and Sports of Ukraine (grant number 0111U001128).
8-(2-Hydroxyethyl)-1,3-dimethyl-7-[(E)-2-phenylethenyl]-1H-imid-
azo[2,1-f]purine-2,4(3H,8H)-dione (13c): White powder; yield 1.3 g
(71 %) (route A); 1.41 g (77 %) (route B), m.p. 238–239 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 7.96 (s, 1 H, NCH), 7.58 [d,
3J(H,H) = 7.5 Hz, 2 H, Ar], 7.38 [t, 3J(H,H) = 7.4 Hz, 2 H, Ar],
3
7.34–7.25 (m, 2 H, Ar; CHCH), 7.16 [d, J(H,H) = 16.4 Hz, 1 H,
C6H5CHCH], 5.01 [t, 3J(H,H) = 5.6 Hz, 1 H, OH], 4.27 [t, 3J(H,H)
= 5.1 Hz, 2 H, CH2CH2OH], 3.75 [t, 3J(H,H) = 5.2 Hz, 2 H,
CH2CH2OH], 3.43 (s, 3 H, NCH3), 3.24 (s, 3 H, NCH3) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 152.75, 151.15, 151.00, 147.53,
136.38, 131.09, 130.40, 128.52, 127.86, 126.48, 113.90, 102.99,
98.60, 59.22, 45.71, 29.78, 27.36 ppm. HPLC–MS: m/z = 366.0
[M]+.
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1,3-Dimethyl-8-(4-methylphenyl)-7-[(E)-2-(4-methylphenyl)ethenyl]-
1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (13d): White powder;
yield 1.45 g (68 %) (route A); 1.26 g (63 %) (route B), m.p. 180–
182 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.18 (s, 1 H, NCH),
3
3
7.50 [d, J(H,H) = 8.2 Hz, 2 H, Ar], 7.46 [d, J(H,H) = 8.2 Hz, 2
H, Ar], 7.28 [d, 3J(H,H) = 7.9 Hz, 2 H, Ar], 7.20 [d, 3J(H,H) =
16.4 Hz, 1 H, CHCH], 7.15 [d, 3J(H,H) = 7.9 Hz, 2 H, Ar], 6.64
3
[d, J(H,H) = 16.5 Hz, 1 H, CHCH], 3.39 (s, 3 H, NCH3), 3.28 (s,
3 H, NCH3), 2.45 (s, 3 H, 4-CH3Ar), 2.29 (s, 3 H, 4-CH3Ar) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 152.97, 151.27, 151.05,
147.26, 138.79, 137.71, 133.25, 130.89, 130.83, 130.77, 130.29,
129.31, 126.84, 126.26, 112.45, 104.28, 95.35, 29.81, 27.47, 20.87,
20.80 ppm. HPLC–MS: m/z = 426.2 [M]+. C25H23N5O2 (425.49):
calcd. C 70.57, H 5.45, N 16.46; found C 70.34, H 5.36, N 16.29.
8-(4-Hydroxyphenyl)-1,3-dimethyl-7-[(E)-2-(4-methylphenyl)eth-
enyl]-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (13e): Red powder;
yield 1.5 g (70 %) (route A); 1.71 g (80 %) (route B), m.p. 287–
1
288 °C. H NMR (400 MHz, [D6]DMSO): δ = 10.05 (s, 1 H, OH),
8.02 (s, 1 H, NCH), 7.46–6.87 (m, 9 H, Ar, CHCH), 6.56 [d,
3J(H,H) = 16.4 Hz, 1 H, CHCH], 3.34 (s, 3 H, NCH3), 3.24 (s, 3
H, NCH3), 2.28 (s, 3 H, 4-CH3Ar) ppm. 13C NMR (100 MHz, [D6]
DMSO): δ = 158.00, 152.78, 151.12, 150.90, 147.33, 137.49, 133.19,
130.93, 130.41, 129.18, 128.42, 126.11, 124.25, 116.17,
112.35,103.86, 98.73, 29.75, 27.41, 20.92 ppm. HPLC–MS: m/z =
428.3 [M]+. C24H21N5O3 (427.47): calcd. C 67.44, H 4.95, N 16.38;
found C 67.18, H 4.76, N 16.17.
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3 H, Ar; CHCH), 6.99 [d, J(H,H) = 16.4 Hz, 1 H, CHCH], 6.92
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147.49, 136.40, 130.92, 130.66, 128.84, 128.61, 127.88, 127.66,
126.76, 114.03, 102.88, 102.88, 99.98, 55.11, 45.92, 29.82,
27.38 ppm. HPLC–MS: m/z = 442.3 [M]+. C25H23N5O3 (441.49):
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compounds, COSY, HMBC, and HSQC spectra of 3i and 7b,
NOESY spectrum of 13b.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Pages: 14
I. O. Lebedyeva et al.
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Published Online: ᭿
R. O. De Souza, E. T. Penha, H. M. S. Milagre, S. J. Garden,
14
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