Efficient one-pot preparation of bis(pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-yl)benzenes based on an aza-Wittig/mediated annulation strategy

Article abstract of DOI:10.1016/j.tet.2006.12.049

Aza-Wittig mediated annulation provides a highly facile and straightforward one-pot strategy for the synthesis of bis(pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-yl)benzenes 5 and 7. A tandem aza-Wittig reaction of iminophosphorane 2 with 1,4- or 1,3-phen

Full text of DOI:10.1016/j.tet.2006.12.049

Tetrahedron 63 (2007) 2034–2041
Efficient one-pot preparation of bis(pyrazino[20,30:4,5]thieno-
[3,2-d]pyrimidin-4-yl)benzenes based on an aza–Wittig/
mediated annulation strategy
*
Gerardo Blanco, Jose M. Quintela and Carlos Peinador
*
ꢀ
Departamento de Quꢀımica Fundamental, Facultad de Ciencias, Universidad de A Corun~a, 15071 A Corun~a, Spain
Received 17 November 2006; revised 12 December 2006; accepted 15 December 2006
Available online 20 December 2006
Abstract—Aza–Wittig mediated annulation provides a highly facile and straightforward one-pot strategy for the synthesis of bis(pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4-yl)benzenes 5 and 7. A tandem aza–Wittig reaction of iminophosphorane 2 with 1,4- or 1,3-phenylene
diisocyanate, followed by intramolecular heteroconjugate addition annulation after addition of a nucleophilic reagent (amine, phenol, thio-
phenol or ROH), in presence of catalytic K2CO3 or NaOR, gives selectively the functionalized bis(pyrazinothienopyrimidinones) 5 and 7.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
marketed drugs9 and those recently reported.10 Pyrazine
ring is present in marine metabolites, which exhibit mild
cytotoxicity against certain human cancer cells,11 and it is
also present in other biologically active natural products.12
Nitrogen or sulfur-containing heterocycles have received
a great deal of interest in the medicinal, agricultural, and
material sciences and this justifies continuing efforts in the
development of new efficient and mild synthetic strategies.1
The presence of a fused pyrimidine scaffold in the framework
of various pharmacologically active compounds continues to
spur synthetic efforts regarding their acquisition.2 Structures
containing such units often play an essential role because of
their biological activity, particularly in cancer and virus
research.3 Among these heterocycles, thienopyrimidine de-
rivatives are an important class of heterocyclic compounds
in pharmaceutical discovery research.4 Anti-inflammatory,
antiallergic, antibacterial, and antifungal activities, have
been described for these compounds,5 whereas others ex-
hibited good anticonvulsant and angiotensin II or H1 receptor
antagonistic activities,6 and some of them show good anti-
tumor activity.7
On the other hand, heteroaromatic nitrogen ligands have
been the focus of much work especially for their extended ap-
plications in several important research and technological
fields.13 Thevast majority of heteroaromatic nitrogen ligands
covers solely pyridine-based structures, which appears as
a serious limitation to the strong potential coordinating
properties of other heteroaromatic structures. In this context,
an increasing important area of ligand design involves the
synthesis and study of new bridging ligands and their use
as chelating ligands.14
During the last years we reported the synthesis of substituted
heterocycles containing the pyridothienopyrimidine and
pyridazinothienopyrimidine skeletons with the aim of find-
ing compounds with anti-inflammatory, antihistaminic, and
anti-cancer activities.15 It is surprising that their isosters
pyrazinothienopyrimidines, moreover isosters of quinoxal-
inepyrimidines, have been practically ignored.16 Besides,
we have interested in the synthesis and study of new hetero-
cyclic ligands and their use in coordinationand metallosupra-
molecular chemistry.17 We previously reported the synthesis
of fused pyrimidines based on the tandem aza–Wittig
heterocumulene-mediated annulation strategy.18
Whereas pyridine annelated sulfur-containing heterocycles
have been studied extensively,8 surprisingly, aza-analogue
compounds incorporating an S-heterocycle fused to a pyr-
azine nucleus have remained relatively rare. Among the di-
azines, the pyrazine ring system is important, and substituted
pyrazine motifs are often to be found in compounds with
applications as anti-cancer agents, including currently
Keywords: Aza–Wittig reaction; Heterocumulene; Iminophosphoranes;
Bis(pyrazinothienopyrimidinones).
* Corresponding authors. Tel.: +34 981 167000; fax: +34 981 167065;
e-mail addresses: jqqoqf@udc.es; capeveqo@udc.es
In this work, we describe, as part of a program of investiga-
tion the biosignificant pyrimidine and pyrazine nuclei,
a novel, highly efficient, and regioselective synthesis of
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.049

G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
2035
substituted bis(pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4-yl)benzenes I and II, which of considerable interest as
potential biologically active compounds or pharmaceuticals
as isosters of pharmaceutically relevant pyridothienopyrimi-
dines, as well as in their use as appropriate phenanthroline-
like ligands. The focus of our research presented here is on
the strategy to synthesize these compounds via a one-pot
aza–Wittig reaction of ethoxycarbonyliminophosphorane
2 with 1,3-phenylene- or 1,4-phenylene diisocyanate and
subsequent reaction with various nucleophiles under mild
conditions (Fig. 1).
2-carboxylate 123 by a modified Kirsanov reaction of the
b-enamino ester 1 with in situ generated dichlorotriphenyl-
phosphorane, using a hexachloroethane–triphenylphosphine–
triethylamine reagent system.24
First, as shown in Scheme 1, we carried out the reaction of
1,4-phenylene diisocyanate with 2 equiv of iminophosphor-
ane 2, followed by heterocyclization on addition of second-
ary amines in the presence of a catalytic amount of K2CO3.
Then, it was found that the aza–Wittig/heterocumulene-
mediated-type reaction proceeded and resulted in the forma-
tion of triphenylphosphine oxide and the correspondingly
substituted bis(pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4-yl)benzenes 5a–d in very good yields (85–95%). Pyrimido
annulation occurs via a highly reactive bis(heterocumulene)
intermediate 3. Addition of a secondary amine to the highly
reactive cumulenic system followed by intramolecular hetero-
conjugate addition annulation gives the final products via
guanidine-type intermediates 4. The results obtained are
listed in Table 1.
O
N
Z
N
O
N
Z
S
S
N
N
N
N
N
I
PPh3
NH2
N
N
N
N
N
CO2Et
CO2Et
S
S
S
2
PPh3
N
O
N
O
N
N
N
S
CO Et
2
N
S
N
N
2
Z
Z
N
N
i
N
II
Z = OR, OAr, SAr, NHR, NR2
N
C
N
N
C
N
Figure 1. Retrosynthetic pathway for synthesis of the bis(pyrazinothieno-
pyrimidinyl)benzenes I and II.
N
N
N
N
3
CO2Et
EtO2C
S
S
2. Results and discussion
Z
EtO2C
NH
S
N
It is well known that iminophosphoranes (l5-phosphazenes,
phosphine imines) are excellent sources for the construction
of imine carbon–nitrogen double bonds through an aza–
Wittig reaction in very mild reaction conditions,19 and
over the past 20 years great progress has been made in the
field of heterocyclic synthesis by the aza–Wittig methodol-
ogy.20 Especially for synthetic strategy of fused heterocycles
and biologically important heterocyclic natural products, the
aza–Wittig reaction is served as an excellent method. The
key intermediate iminophosphoranes can be prepared either
by the Staudinger reaction from organic azides21 or by
Kirsanov reaction from primary amines.22
N
N
HN
CO2Et
N
N
Z
N
S
S
4
Z
N
O
O
N
Z
S
N
N
N
N
N
N
5
Z = NR2, ArO, ArS, RO
Scheme 1. Reagents and conditions: (i) (1) 1,4-C6H4(NCO)2, THF (5 h, rt)
and (2) HZ (5 h, rt), K2CO3 or NaOR (0.5 h, reflux).
Substituted bis(pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4-yl)benzenes 5 and 7 were obtained in a one-pot reaction
of the corresponding iminophosphorane of heteroaromatic
b-enamino ester 2 with 1,4-phenylene or 1,3-phenylene
diisocyanate, followed by heterocyclization on addition of
nucleophilic reagents. Our approach is centered on the aza–
Wittig reaction of iminophosphorane with bis(heterocumu-
lenes) to give a 1,3,5-bis(hexatriene) moiety containing a
nitrogen atom at one end and cumulated double bond at
the other, which subsequently undergoes double pyrimido
annulation by addition of nucleophiles.
Table 1. Bispyrazino[20,30:4,5]thieno[3,2-d]pyrimidinones 5a–k
Compd
Z
Yielda (%)
Mp (ꢀC)
5a
5b
5c
5d
5e
5f
5g
5h
5i
Morpholino
Thiomorpholino
Piperidino
NEt2
92
95
90
85
85
83
86
91
80
83
97
>300
>300
>300
>300
>300
230 dec
230 dec
>300
290 dec
290 dec
290 dec
C6H5O
4-C(CH3)3C6H4O
4-NO2C6H4O
C6H5S
EtO
MeO
n-Butyl
5j
5k
The starting compound for the aza–Wittig reaction hetero-
cyclization sequence was prepared, in 97% yield, from
the readily available ethyl 3-aminothieno[2,3-b]pyrazine-
a
Isolated yields based on iminophosphorane 2.

2036
G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
The one-pot formation of aryloxy- and arylthioxybispyr-
azinothienopyrimidinones 5e–h was carried out by reaction
of iminophosphorane 3 with 1,4-phenylene diisocyanate,
followed by heterocyclization on addition of phenols or
thiophenols in the presence of catalytic potassium carbonate.
The reaction is practically insensitive to the presence or
absence of substituents on the phenols and, irrespective of the
fact whether the substituents on the phenols were electron-
withdrawing or electron-releasing groups, the cyclization
was completed smoothly at room temperature, the yield of
the isolated products being higher than 83%. Similarly, 1,4-
bis(2-ethoxy- or 1,4-bis(2-methoxy-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3-yl)benzenes 5i and 5j were
obtained in good yields when the reaction took place in
the presence of catalytic sodium ethoxide or sodium
methoxide, respectively. The formation of 5e–j can be ratio-
nalized in terms of an initial nucleophilic addition of
phenoxide, thiophenoxide or alkoxide to the carbodiimide
3 to give the intermediate 4, which cyclizes to affords 5
(Scheme 1).
confirmed unambiguously by an X-ray crystallographic
study carried out for the derivative 5k. Mass and spectro-
scopic data are in good agreement with the proposed struc-
tures. The FAB-mass spectra show the expected ion peaks
and the fragmentation pattern is in accord with the proposed
structures. It is worth noting that the four aromatic protons
on the benzene ring are identical and do not couple with
each other (the signals attributable to the 4-H benzene pro-
tons are found between d¼7.50–7.93, as a singlet, in the
1H NMR spectra), which suggests identical neighbors for
all the protons on the benzene ring in compounds 5. In
1
particular, the H NMR spectra of compound 5k show the
signals of NH at 5.20, as a triplet, due to coupling with the
methylene protons adjacent to the nitrogen atom, and
NCH2 at 3.60–3.70, as a multiplet, which suggests the exis-
tence of NHBu group in 5k. Moreover, when the sample was
treated with deuterated water, its NCH2 showed the signal as
triplet with disappearance of signals of NH absorption.
Finally, an X-ray study of compound 5k corroborated our
earlier assignments. According to the crystal data the
benzene ring adopts a nearly anticoplanar disposition with
the three heterocyclic rings of the pyrazinothienopyrimidine
system. Thus, the anti-periplanar conformation, with the two
n-butyl substituents are opposite to each other, leads to
a more stable conformation (Fig. 2).
The participation of carbodiimide 3 and the corresponding
guanidine-type compound 4 as intermediates in this process
has been confirmed experimentally.18 In the presence of
anhydrous potassium carbonate or sodium alkoxide 4 under-
went intramolecular heterocyclization across the electro-
philic ester functionality to give the fused pyrimidinones 5.
Two isomeric bispyrazino[20,30:4,5]thieno[3,2-d]pyrimidi-
nones 5 and 6 may be produced in the reaction of iminophos-
phorane 2 with primary amines via a guanidine-type
intermediate 4 (Scheme 2). However, it is interesting to
note that the reaction of 1,4-phenylene diisocyanate with
2 equiv of iminophosphorane 3 followed by addition of an
primary amine, as n-butylamine, is regioselective to afford
only 5k in very good yield (97%), compound 6 not being
formed. These selectivity results can probably be explained
by the large difference in cyclization rates due the steric hin-
drance around the ethoxycarbonyl and the n-butyl groups.25
The structure of the prepared compounds 5 was initially de-
Figure 2. Crystal structure of compound 5k. Solvent molecules and hydro-
gen atoms have been omitted for clarity.
1
duced from H and 13C NMR spectroscopic data and then
N
C
N
N C N
N
N
N
CO2Et
EtO2C
4
S
S
N
n-BuNH2
HN
NH
NHR
RHN
N
N
N
N
N
N
N
N
N
N
N
NHR
RHN
HN
CO2Et
NH
N
EtO2C
CO2Et
N
EtO2C
S
S
N
S
S
O
O
N
N
S
S
N
NHR
O
N
S
N
N
N
R
R
N
N
N
O
N
N
N
HN
NH
N
S
RHN
5k
6
R = n-Bu
R = n-Bu
Scheme 2.

G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
2037
We next considered the possibility of extending this design
strategy to the preparation of 1,3-bis(pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4-yl)benzenes 7. Thus, we reacted
1,3-phenylene diisocyanate with heteroaryl iminophosphor-
ane 2, under similar reaction conditions, which furnished
new compounds 7 (Scheme 3). As summarized in Table 2,
isolated yields ranged from moderate to excellent (50–
96%). Once again all new compounds showed spectroscopic
and characterization data in accord with the proposed
structures.
manner.26 Studies are currently underway employing these
ligands as synthons in coordination and metallosupra-
molecular chemistry.
4. Experimental section
4.1. General
NMR spectra were recorded at 200 or 300 MHz for 1H and
50 or 75 MHz for 13C. Chemical shifts are reported in parts
per million (d) relative to an internal Me4Si. IR spectra were
recorded as potassium bromide disks. Melting points were
obtained on a Bibby SMP3 apparatus and are uncorrected.
Mass spectra were obtained on a VG-QUATTRO spectro-
meter. All reagents used were commercial grade chemicals
from freshly opened containers. The Silica gel 60 F254
used for analytical thin layer chromatography was purchased
from Merck. Microanalyses for C, H, N, and S were per-
formed by the elemental analyses general service of the
PPh3
N
N
N
CO2Et
S
2
1. 1,3-(NCO)2C6H4,THF (4h, rt.)
2. HZ (5h, rt.)
3. K2CO3 or RONa
"one-pot "
50-96 %
Z
Z
University of A Coruna. 13C NMR spectra of 5b,c,e–k,
~
and 7e,h could not be obtained due to low solubility in
ordinary solvents.
N
N
N
N
O
O
N
N
S
S
7a-j
N
N
4.2. General procedure for the synthesis of pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
(5a–d and k)
Z = OR, OAr, SAr, NR2
Scheme 3.
To a solution of iminophosphorane 3 (0.10 g, 0.21 mmol) in
dry THF (6 mL) was added 1,4-phenylene diisocyanate
(0.02 g, 0.10 mmol) at room temperature. The mixture was
stirred at room temperature for 3–5 h until the imino-
phosphorane had disappeared (TLC monitored) and it was
therefore treated with an appropriate secondary amine
(0.25 mmol). The resultant solution was stirred at room tem-
perature for 5 h. The solvent was evaporated and the residue
was solved in acetone (5 mL), a catalytic amount of K2CO3
was added, and the mixture was refluxed for 2 h. After cool-
ing, the precipitate obtained was filtered off, washed with
water and acetone, and purified by flash chromatography
on silica gel using CH2Cl2/EtOAc (85:15, v/v) as an eluent.
Table 2. Bispyrazino[20,30:4,5]thieno[3,2-d]pyrimidinones 7a–j
Compd
Z
Yielda (%)
Mp (ꢀC)
7a
7b
7c
7d
7e
7f
7g
7h
7i
Morpholino
Thiomorpholino
Piperidino
NEt2
71
96
71
92
72
52
50
82
55
57
>300
>300
217–219
280–282
>300
>300
>300
>300
230–232
275–277 dec
C6H5O
4-C(CH3)3C6H4O
4-NO2C6H4O
C6H5S
EtO
MeO
7j
a
Isolated yields based on iminophosphorane 2.
4.2.1. 1,4-Bis(2-(4-morpholinyl)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5a).
Yield (92%); mp >300 ꢀC; IR (KBr) n 1691 (CO), 1649,
1
3. Conclusions
1634, 1630, 1537, 1513, 1450 cmꢁ1; H NMR (300 MHz,
CDCl3) d 3.30–3.40 (m, 8H), 3.54–3.63 (m, 8H), 7.67 (s,
4H), 8.75 (d, J¼2.3 Hz, 2H), 8.90 (d, J¼2.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 49.6, 65.8, 129.4, 136.9, 142.9,
143.8, 144.3, 148.7, 157.4, 158.6, 159.1, 162.2; MS (FAB+)
m/z 653 (MH+, 40); Anal. Calcd for C30H24N10O4S2: C,
55.20; H, 3.71; N, 21.46; S, 9.83. Found: C, 55.41; H, 3.67;
N, 21.34; S, 10.03.
In summary, the present study demonstrates that the tandem
aza–Wittig-heterocumulene-mediated annulation strategy
affords a facile, efficient, and general one-pot route to
previously unreported 1,4- and 1,3-bis(pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4-yl)benzenes 5 and 7, respectively.
This one-pot procedure offers an attractive procedure for
the generation of these compounds and can be extended to
secondary amines, phenols, thiophenols or ROH. In the
case of primary amines a regioselective cyclization has
been observed. Bis-triheterocyclic compounds 5a–k and
7a–j can be useful compounds in medicinal chemistry since
the pyrazino, pyrimido, and thiophene moieties display
a broad range of biological activities and have been widely
used as pharmaceuticals. Moreover, compounds 5 and
7 can be of interest as ligands containing two tridentate bind-
ing domains arranged in a ‘angular’ or ‘stepped-parallel’
4.2.2. 1,4-Bis(4-oxo-2-(4-thiomorpholinyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5b).
Yield (95%); mp >300 ꢀC; IR (KBr) n 1678 (CO), 1537,
1453 cmꢁ1 1H NMR (300 MHz, CDCl3) d 2.40–2.55
;
(m, 8H), 3.55–3.65 (m, 8H), 7.64 (s, 4H), 8.74 (d, J¼
2.3 Hz, 2H), 8.89 (d, J¼2.3 Hz, 2H); MS (FAB+) m/z 685
(MH+, 28); Anal. Calcd for C30H24N10O2S4: C, 52.61; H,
3.53; N, 20.45; S, 18.73. Found: C, 52.52; H, 3.39; N,
20.39; S, 18.56.

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G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
4.2.3. 1,4-Bis(4-oxo-2-(1-piperidinyl)pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5c). Yield
(90%); mp >300 ꢀC; IR (KBr) n 1680 (CO), 1537,
8.71 (d, J¼2.3 Hz, 2H), 8.82 (d, J¼2.3 Hz, 2H); MS (FAB+)
m/z 779 (MH+, 30); Anal. Calcd for C42H34N8O4S2: C,
64.76; H, 4.40; N, 14.39; S, 8.23. Found: C, 64.56; H,
4.34; N, 14.57; S, 8.05.
1
1437 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.37–1.48 (m,
8H), 1.49–1.55 (m, 4H), 3.29–3.38 (m, 8H), 7.63 (s, 4H),
8.72 (d, J¼2.3 Hz, 2H), 8.87 (d, J¼2.3 Hz, 2H); MS
(FAB+) m/z 649 (MH+, 19), 281 (30); Anal. Calcd for
C32H28N10O2S2: C, 59.24; H, 4.35; N, 21.59; S, 9.89. Found:
C, 59.11; H, 4.26; N, 21.42; S, 9.76.
4.3.3. 1,4-Bis(2-(4-nitrophenoxy)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5g).
Yield (86%); mp 230 ꢀC dec; IR (KBr) n 1694 (CO), 1615,
1590, 1568, 1515 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.47–7.52 (m, 4H), 7.72 (s, 4H), 8.38–8.83 (m, 4H), 8.75
(d, J¼2.2 Hz, 2H), 8.86 (d, J¼2.2 Hz, 2H); MS (FAB+)
m/z 757 (MH+, 5); Anal. Calcd for C34H16N10O8S2: C,
53.97; H, 2.13; N, 18.51; S, 8.48. Found: C, 54.06; H,
2.24; N, 18.57; S, 8.35.
4.2.4. 1,4-Bis(2-diethylamino-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5d). Yield
(85%); mp >300 ꢀC; IR (KBr) n 1677 (CO), 1540,
1400 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 1.02 (t, J¼
7.1 Hz, 12H), 3.32 (q, J¼7.1 Hz, 8H), 7.58 (s, 4H), 8.71 (d,
J¼2.3 Hz, 2H), 8.88 (d, J¼2.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 12.6, 45.5, 129.6, 137.5, 142.7, 144.0,
144.1, 149.1, 157.8, 158.7, 159.8; MS (FAB+) m/z 625 (MH+,
5); Anal. Calcd for C30H28N10O2S2: C, 57.68; H, 4.52; N,
22.42; S, 10.27. Found: C, 57.53; H, 4.37; N, 22.38; S, 10.15.
4.3.4. 1,4-Bis(4-oxo-2-phenylthiopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5h). Yield
(91%); mp >300 ꢀC dec; IR (KBr) n 1689 (CO), 1516,
1
1505, 1488, 1474 cmꢁ1; H NMR and 13C NMR spectra
could not be obtained due to low solubility in ordinary sol-
vents; MS (FAB+) m/z 669 (MH+, 5).
4.2.5. 1,4-Bis(2-n-butylamino-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5k). Yield
(97%); mp 290 ꢀC dec; IR (KBr) n 2956, 2933 (NH), 1677
4.4. Pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones (5i and j)
1
(CO), 1562, 1522, 1509, 1485 cmꢁ1; H NMR (300 MHz,
CDCl3) d 0.94 (t, J¼7.3 Hz, 6H), 1.28–1.44 (m, 4H), 1.49–
1.73 (m, 4H), 3.60–3.70 (m, 4H), 5.20 (t, J¼5.3 Hz, 2H),
7.67 (s, 4H), 8.72 (d, J¼2.3 Hz, 2H), 8.88 (d, J¼2.3 Hz,
2H); MS (FAB+) m/z 625 (MH+, 100); Anal. Calcd for
C30H28N10O2S2: C, 57.68; H, 4.52; N, 22.42; S, 10.27.
Found: C, 57.73; H, 4.31; N, 22.60; S, 10.11.
To a solution of iminophosphorane 3 (0.10 g, 0.21 mmol) in
dry THF (6 mL) was added 1,4-phenylene diisocyanate
(0.02 g, 0.10 mmol) at room temperature. The mixture was
stirred at room temperature for 5 h until the iminophosphor-
ane had disappeared (TLC monitored). The solvent was
evaporated, ROH (6 mL) was added to dissolve the solid
and then NaOR (0.25 mmol) was added and the resultant
mixture was stirred at room temperature for 8 h. The precip-
itate obtained was filtered off, washed water and THF, and
purified by flash chromatography on silica gel using
CH2Cl2/EtOAc (75:25, v/v) as an eluent.
4.3. Pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones (5e–h)
To a solution of iminophosphorane 3 (0.10 g, 0.21 mmol) in
dry THF (6 mL) was added 1,4-phenylene diisocyanate
(0.02 g, 0.10 mmol) at room temperature. The mixture was
stirred at room temperature for 4–5 h until the iminophos-
phorane had disappeared (TLC monitored) and after was
treated with an appropriate substituted phenol or thiophenol
(0.25 mmol), a catalytic amount of K2CO3 was added and
the resultant solution was refluxed for 8 h. After cooling,
the precipitate obtained was filtered off, washed water and
THF, and purified by flash chromatography on silica gel
with a solvent gradient of EtOAc in CH2Cl2 (10–50%) as
an eluent. Compound 5h could not be purified because of
their insolubility in ordinary solvents.
4.4.1. 1,4-Bis(2-ethoxy-4-oxopyrazino[20,30:4,5]thi-
eno[3,2-d]pyrimidin-3(4H)-yl)benzene (5i). Yield (80%);
mp 290 ꢀC dec; IR (KBr) n 1687 (CO), 1568, 1544,
1511 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 1.36 (t, J¼
7.0 Hz, 6H), 4.70 (q, J¼7.0 Hz, 4H), 7.50 (s, 4H), 8.75 (d,
J¼2.1 Hz, 2H), 8.89 (d, J¼2.1 Hz, 2H); MS (FAB+)
m/z 571 (MH+, 100); Anal. Calcd for C26H18N8O4S2: C,
54.73; H, 3.18; N, 19.64; S, 11.24. Found: C, 54.53; H,
3.00; N, 19.56; S, 11.18.
4.4.2. 1,4-Bis(2-methoxy-4-oxopyrazino[20,30:4,5]thi-
eno[3,2-d]pyrimidin-3(4H)-yl)benzene (5j). Yield (83%);
mp 290 ꢀC dec; IR (KBr) n 1683 (CO), 1573, 1543,
4.3.1. 1,4-Bis(4-oxo-2-phenoxypyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5e). Yield
(85%); mp >300 ꢀC; IR (KBr) n 1683 (CO), 1598, 1568,
1
1514 cmꢁ1; H NMR (300 MHz, CDCl3) d 4.21 (s, 6H),
7.51 (s, 4H), 8.76 (d, J¼2.2 Hz, 2H), 8.90 (d, J¼2.2 Hz,
2H); MS (FAB+) m/z 543 (MH+, 100); Anal. Calcd for
C24H14N8O4S2: C, 53.13; H, 2.60; N, 20.65; S, 11.82.
Found: C, 52.96; H, 2.47; N, 20.48; S, 11.65.
1
1506 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.25–7.65 (m,
10H), 7.93 (s, 4H), 8.87 (d, J¼2.3 Hz, 2H), 8.89 (d,
J¼2.3 Hz, 2H); MS (FAB+) m/z 667 (MH+, 37); Anal. Calcd
for C34H18N8O4S2: C, 61.25; H, 2.72; N, 16.81; S, 9.62.
Found: C, 61.36; H, 2.81; N, 16.75; S, 9.54.
4.5. Pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones (7a–d)
4.3.2. 1,4-Bis(2-(4-tert-butylphenoxy)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (5f).
Yield (83%); mp 230 ꢀC dec; IR (KBr) n 1698 (CO), 1568,
To a solution of iminophosphorane 3 (0.15 g, 0.31 mmol) in
dry THF (3 mL) was added 1,3-phenylene diisocyanate
(0.37 mmol) at room temperature. The mixture was stirred at
room temperature for 1–5 h until the iminophosphorane had
1
1544, 1505 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.34 (s,
18H), 7.16–7.22 (m, 4H), 7.40–7.47 (m, 4H), 7.67 (s, 4H),

G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
2039
disappeared (TLC monitored) and it was therefore treated
with an appropriate secondary amine. The resultant solution
wasstirredatroom temperaturefor5 h. Thesolventwasevap-
orated and the residue was solved in acetone (3 mL), a cata-
lytic amount of K2CO3 was added, the mixture was refluxed
for 0.5 h. The solvent was removed under reduced pressure,
and the solid obtained was purified by flash chromatography
on silica gel using CH2Cl2/EtOAc (75:25, v/v) as an eluent.
(0.37 mmol) at room temperature. The mixture was stirred
at room temperature for 1–5 h until the iminophosphorane
had disappeared (TLC monitored) and it was therefore
treated with an appropriate secondary amine. The resultant
solution was stirred at room temperature for 5 h. The solvent
was evaporated and the residue was solved in acetone
(3 mL), a catalytic amount of K2CO3 was added, the mixture
was refluxed for 0.5 h. The solvent was removed under re-
duced pressure, and the solid obtained was purified by flash
chromatography on silica gel with a solvent gradient of
EtOAc in CH2Cl2 (10–60%) as an eluent. Compound 7h
could not be purified because of its insolubility in ordinary
solvents.
4.5.1. 1,3-Bis(2-(4-morpholinyl)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7a).
Yield (71%); mp >300 ꢀC; IR (KBr) n 1697 (CO), 1534,
1530, 1484 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 3.30–
;
3.70 (m, 16H), 7.45–7.50 (m, 2H), 7.70–7.79 (m, 2H), 8.74
(d, J¼2.3 Hz, 2H), 8.89 (d, J¼2.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 49.7, 65.9, 119.6, 127.8, 130.1, 131.5,
137.3, 142.9, 143.8, 144.3, 148.8, 157.5, 158.5, 159.3; MS
(FAB+) m/z 653 (MH+, 100); Anal. Calcd for
C30H24N10O4S2: C, 55.20; H, 3.71; N, 21.46; S, 9.83. Found:
C, 55.20; H, 3.76; N, 21.32; S, 9.70.
4.6.1. 1,3-Bis(4-oxo-2-phenoxypyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7e). Yield
(50%); mp >300 ꢀC; IR (KBr) n 1701 (CO), 1566,
1
1485 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.00–7.50 (m,
10H), 7.60–7.70 (m, 3H), 7.80–7.85 (m, 1H), 8.71 (d, J¼
2.3 Hz, 2H), 8.81 (d, J¼2.3 Hz, 2H); MS (FAB+) m/z 667
(MH+, 100); Anal. Calcd for C34H18N8O4S2: C, 61.25; H,
2.72; N, 16.81; S, 9.62. Found: C, 61.08; H, 2.57; N, 17.00;
S, 9.61.
4.5.2. 1,3-Bis(4-oxo-2-(4-thiomorpholinyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7b).
Yield (92%); mp >300 ꢀC; IR (KBr) n 1694 (CO), 1550,
1536, 1532, 1452 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
4.6.2. 1,3-Bis(2-(4-tert-butylphenoxy)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7f).
Yield (40%); mp >300 ꢀC; IR (KBr) n 1688 (CO), 1573,
d 2.30–2.60 (m, 8H), 3.70–3.75 (m, 8H), 7.37–7.42 (m,
2H), 7.70–7.73 (m, 1H), 7.74–7.79 (m, 1H), 8.74 (d, J¼
2.3 Hz, 2H), 8.89 (d, J¼2.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 26.6, 52.2, 119.7, 127.9, 130.3, 132.5, 137.7,
142.9, 143.7, 144.3, 148.8, 158.2, 158.5, 159.4; MS (FAB+)
m/z 685 (MH+, 25); Anal. Calcd for C30H24N10O2S4: C,
52.61; H, 3.53; N, 20.45; S, 18.73. Found: C, 52.47; H,
3.75; N, 20.40; S, 18.80.
1564, 1543, 1521 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 1.35 (s, 18H), 6.95–7.15 (m, 2H), 7.30–7.55 (m, 5H),
7.60–7.70 (m, 4H), 7.79–7.83 (m, 1H), 8.73 (d, J¼2.3 Hz,
2H), 8.84 (d, J¼2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 31.5, 120.3, 121.3, 126.7, 128.3, 129.2, 130.6, 135.4,
142.9, 143.5, 144.2, 147.6, 149.1, 149.3, 155.2, 158.3,
158.4; MS (FAB+) m/z 779 (MH+, 100); Anal. Calcd for
C42H34N8O4S2: C, 64.76; H, 4.40; N, 14.39; S, 8.23. Found:
C, 64.67; H, 4.29; N, 14.20; S, 8.16.
4.5.3. 1,3-Bis(4-oxo-2-(1-piperidinyl)pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7c). Yield
(72%); mp 217–219 ꢀC; IR (KBr) n 1687 (CO), 1537, 1532,
1524, 1485 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 1.29–1.40
(m, 4H), 1.40–1.55 (m, 8H), 3.30–3.45 (m, 8H), 7.37–7.45
(m, 2H), 7.65–7.75 (m, 2H), 8.71 (d, J¼2.3 Hz, 2H), 8.87
(d, J¼2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 24.0,
24.9, 50.7, 127.5, 129.7, 131.6, 131.7, 137.9, 142.6, 143.9,
144.0, 149.1, 158.5, 159.6; MS (FAB+) m/z 649 (MH+, 100);
Anal. Calcd for C32H28N10O2S2: C, 59.24; H, 4.35; N, 21.59;
S, 9.89. Found: C, 59.37; H, 4.31; N, 21.44; S, 9.87.
4.6.3. 1,3-Bis(2-(4-nitrophenoxy)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7g).
Yield (50%); mp >300 ꢀC; IR (KBr) n 1699 (CO), 1569,
1541, 1521, 1487 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.55–7.65 (m, 4H), 7.65–7.73 (m, 3H), 7.86–7.91 (m,
1H), 8.32–8.42 (m, 4H), 8.77 (d, J¼2.3 Hz, 2H), 8.87 (d,
J¼2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 115.6,
121.1, 125.7, 126.2, 128.4, 129.5, 131.1, 135.0, 143.1,
143.3, 144.7, 145.7, 147.1, 153.9, 155.8, 158.3; MS
(FAB+) m/z 757 (MH+, 15), 341 (25); Anal. Calcd for
C34H16N10O8S2: C, 53.97; H, 2.13; N, 18.51; S, 8.48. Found:
C, 54.08; H, 2.27; N, 18.60; S, 8.61.
4.5.4. 1,3-Bis(2-diethylamino-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7d). Yield
(52%); mp 280–282 ꢀC; IR (KBr) n 1696 (CO), 1539, 1521,
1
1472 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.00–1.07 (m,
12H), 3.20–3.51 (m, 8H), 7.33–7.38 (m, 2H), 7.62–7.68
(m, 1H), 7.70–7.72 (m, 1H), 8.71 (d, J¼2.3 Hz, 2H), 8.87
(d, J¼2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 12.7,
45.4, 127.7, 129.9, 131.6, 138.2, 142.6, 144.0, 144.1, 149.2,
157.7, 158.6, 159.8; MS (FAB+) m/z 625 (MH+, 100); Anal.
Calcd for C30H28N10O2S2: C, 57.68; H, 4.52; N, 22.42; S,
10.27. Found: C, 57.62; H, 4.50; N, 22.31; S, 10.28.
4.6.4. 1,3-Bis(4-oxo-2-phenylthiopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7h). Yield
(82%); mp >300 ꢀC; IR (KBr) n 1692 (CO), 1545, 1515,
1
1493, 1482 cmꢁ1; H NMR and 13C NMR spectra could
not be obtained due to low solubility in ordinary solvents;
MS (FAB+) m/z 699 (MH+, 15).
4.7. Pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones (7i and j)
4.6. Pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones (7e–h)
To a solution of iminophosphorane 3 (0.15 g, 0.31 mmol) in
dry THF (3 mL) was added 1,3-phenylene diisocyanate
(0.37 mmol) at room temperature. The mixture was stirred
To a solution of iminophosphorane 3 (0.15 g, 0.31 mmol) in
dry THF (3 mL) was added 1,3-phenylene diisocyanate

2040
G. Blanco et al. / Tetrahedron 63 (2007) 2034–2041
Nat. Prod. Rep. 1997, 14, 413; (e) Neusch€utz, K.; Velker, J.;
Neier, R. Synthesis 1998, 227; (f) Palacios, F.; Gil, M. J.;
at room temperature for 1–5 h until the iminophosphorane
had disappeared (TLC monitored) and it was therefore
treated with an appropriate secondary amine. The resultant
solution was stirred at room temperature for 5 h. The solvent
was evaporated and the residue was solved in acetone
(3 mL), a catalytic amount of K2CO3 was added, the mixture
was refluxed for 0.5 h. The solvent was removed under
reduced pressure, and the solid obtained was purified by
flash chromatography using CH2Cl2/AcOEt2 (75:25, v/v)
as an eluent.
ꢀ
ꢀ
Martınez, E.; Rodrıguez, M. Tetrahedron Lett. 1999, 40,
2411; (g) Renslo, A. R.; Danheiser, R. L. J. Org. Chem.
1998, 63, 7840.
2. (a) Ganjgee, A.; Adair, O.; Queener, S. F. J. Med. Chem. 2003,
46, 5074 and references cited therein; (b) Ding, M.-W.; Huang,
N.-Y.; He, H.-W. Synthesis 2005, 1601 and references cited
therein.
ꢀ
3. (a) Wnuk, S. F.; Lewandowska, E.; Companioni, D. R.; Garcıa,
P. I., Jr.; Secrist, J. A., III. Org. Biomol. Chem. 2004, 2, 120; (b)
Cushman, M.; Sambaiah, T.; Jin, G.; Illarionov, B.; Fischer, M.;
Bacher, A. J. Org. Chem. 2004, 69, 601; (c) Haraguchi, K.;
Kubota, Y.; Tanaka, H. J. Org. Chem. 2004, 69, 1831; (d)
Depecker, G.; Patino, N.; Giorgio, C. D.; Terreux, R.; Cabrol-
Bass, D.; Bailly, C.; Aubertin, A.-M.; Condom, R. Org.
Biomol. Chem. 2004, 2, 74; (e) Rabow, A. A.; Shoemaker,
R. H.; Sausville, E. A.; Covell, D. J. J. Med. Chem. 2002, 45,
818; (f) Carraro, F.; Naldini, A.; Pucci, A.; Locatelli, G. A.;
Maga, G.; Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli,
F.; Brullo, Ch.; Fossa, P.; Menozzi, G.; Mosti, L.; Modugno,
M.; Tintori, C.; Menetti, F.; Botta, M. J. Med. Chem. 2006,
49, 1549 and references cited therein; (g) Koch, U.; Attenni,
B.; Malancona, S.; Colarusso, S.; Conte, I.; Di Filippo, M.;
Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.;
Tomei, L.; De Francesco, R.; Altamura, S.; Matassa, V. G.;
Narjes, F. J. Med. Chem. 2006, 49, 1693 and references cited
therein; (h) Santana, L.; Teijeira, M.; Uriarte, E.; Balzarini,
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E. J. Clin. Virol. 2004, 30, 115.
4.7.1. 1,3-Bis(2-ethoxy-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7i). Yield
(55%); mp 230–232 ꢀC dec; IR (KBr) n 1695 (CO), 1683,
1568, 1543, 1540, 1521 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 1.37 (t, J¼7.0 Hz, 6H), 4.69 (q, J¼7.0 Hz, 4H),
7.32–7.35 (m, 1H), 7.45–7.50 (m, 2H), 7.70–7.77 (m, 1H),
8.74 (d, J¼2.3 Hz, 2H), 8.88 (d, J¼2.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 14.0, 66.4, 128.4, 128.6, 129.0, 130.1,
132.0, 132.2, 135.2, 142.8, 143.6, 144.2, 156.0, 158.3; MS
(FAB+) m/z 571 (MH+, 45), 279 (100); Anal. Calcd for
C26H18N8O4S2: C, 54.73; H, 3.18; N, 19.64; S, 11.24.
Found: C, 55.02; H, 3.20; N, 19.51; S, 11.28.
4.7.2. 1,3-Bis(2-methoxy-4-oxopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-3(4H)-yl)benzene (7j). Yield
(55%); mp 275–277 ꢀC dec; IR (KBr) n 1689 (CO), 1571,
1544, 1521, 1513 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 4.22 (s, 6H), 7.36–7.38 (m, 1H), 7.50–7.54 (m, 2H),
7.75–7.79 (m, 1H), 8.77 (d, J¼2.3 Hz, 2H), 8.92 (d,
J¼2.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 57.2, 120.3,
128.4, 129.2, 130.4, 135.1, 142.9, 143.6, 144.3, 147.9,
156.5, 158.4, 158.6; MS (FAB+) m/z 543 (MH+, 60); Anal.
Calcd for C24H14N8O4S2: C, 53.13; H, 2.60; N, 20.65; S,
11.82. Found: C, 53.08; H, 2.59; N, 20.65; S, 11.69.
4. (a) Shishoo, C. J.; Shirsath, V. S.; Rathod, I. S.; Yande, V. D.
Eur. J. Med. Chem. 2000, 35, 351; (b) Walter, H. WO
9911631, 1999; Chem. Abstr. 1999, 130, 237580e; (c) Walter,
H. WO 9914202, 1999; Chem. Abstr. 1999, 130, 252368k; (d)
Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar,
R. H. Eur. J. Med. Chem. 2003, 38, 89.
5. (a) Aboulwafa, O. M.; Ismail, K. A.; Koreish, E. A. Farmaco
1992, 47, 631; (b) See Ref. 4c; Chem. Abstr. 1999, 130,
252368k; (c) Leitsner, S.; Wagner, G.; Guetschow, M.; Glusa,
E. Pharmazie 1986, 41, 54; (d) Hozien, Z. A.; Atta, F. M.;
Hassan, K. M.; Abdel-Wahah, A. A.; Ahmed, S. A. Synth.
Commun. 1996, 26, 3733.
5. Crystallographic material
Crystallographic data (excluding structural factors) for 5k
have been deposited in the Cambridge Crystallographic
Data Center as supplementary publication number CCDC
627137. Copies of the data may be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44 1223 33603 or e-mail: deposit@ccdc.
cam.ac.uk).
6. (a) See Ref. 4a; (b) Santagati, M.; Modica, M.; Santagati, A.;
Russo, F.; Spampinato, S. Pharmazie 1996, 51, 7.
7. (a) Cheng, C. C. Structural Aspects of Antineoplastic Agents. A
New Approach; Ellis, G. P., West, G. B., Eds.; Progress in
Medicinal Chemistry; Elsevier: Amsterdam, 1988; Vol. 25,
pp 35–83; (b) Skelton, V.; Bavetsias, V.; Jackman, A. WO
0050417, 2000; Chem. Abstr. 2000, 133, 207917q.
Acknowledgements
8. (a) Jones, G. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A.,
Eds.; Pergamon: Oxford, 1996; Vol. 5; (b) Friedrichsen, W.
Comprehensive Heterocyclic Chemistry; Bird, W.,
Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984;
p 1002; (c) Jones, G. Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Boulton, A. J., McKillop, A.,
Eds.; Pergamon: Oxford, 1984; Vol. 2.
The authors are grateful to MCyT (Spain, Grant BQU2003-
00574) and the Xunta de Galicia (Spain, Grant PGI-DIT04P-
XIC10307PN) for financial support. G.B. acknowledges
~
a predoctoral fellowship from the University of A Coruna.
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15. (a) Quintela, J. M.; Peinador, C.; Gonzalez, L. M.; Rioja, I.;
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Quintela, J. M.; Peinador, C.; Gonzalez, L.; Iglesias, R.;
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Med. Chem. 2003, 38, 265; (d) Rioja, I.; Ubeda, A.;
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Terencio, M. C.; Guillen, I.; Riguera, R.; Quintela, J. M.;
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18. (a) Vazquez, D.; Peinador, C.; Quintela, J. M. Tetrahedron
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