An efficient one-pot three-step domino synthesis of substituted bis(pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones)

Article abstract of DOI:10.1016/j.tet.2008.09.067

A convenient and efficient one-pot three-step domino approach to bis(pyrazinothienopyrimidinones) from ethyl 3-(triphenylphosphoranylideneamino)-thieno[2,3-b]pyrazine-6-carboxylate 1 has been developed. In this method, treatment of phosphazene 1 with a mi

Full text of DOI:10.1016/j.tet.2008.09.067

Tetrahedron 64 (2008) 11136–11143
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient one-pot three-step domino synthesis of substituted
bis(pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones)
*
*
´
´
Gerardo Blanco, Antonio Fernandez-Mato, Jose M. Quintela , Carlos Peinador
Departamento de Qu´ımica Fundamental, Facultad de Ciencias, Universidad de A Corun˜a, 15071 A Coru˜na, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient one-pot three-step domino approach to bis(pyrazinothienopyrimidinones)
from ethyl 3-(triphenylphosphoranylideneamino)-thieno[2,3-b]pyrazine-6-carboxylate 1 has been de-
veloped. In this method, treatment of phosphazene 1 with a mixture of isocyanates, nitrogen, sulfur, and
oxygen bis(nucleophiles) and K2CO3 in refluxing THF regioselectively furnishes the corresponding bis
(pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones) in satisfactory to good yields. This methodology
is highly versatile and efficient for the generation of these functionalized bis(triheterocyclic) compounds
that are not readily available by other synthetic methods.
Received 1 September 2008
Received in revised form 19 September
2008
Accepted 19 September 2008
Available online 1 October 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Nitrogen heterocycles
Domino reactions
Aza-Wittig reaction
Pyrazinothienopyrimidine
1. Introduction
based structures, which appears as a serious limitation to the
strong potential coordinating properties of other heteroaromatic
Nitrogen-containing heterocyclic molecules occur in many
natural products, and are also found in fine chemicals and bi-
ologically active pharmaceuticals vital for enhancing the quality of
life.1 These structures represent a class of molecules that act as li-
gands for various biological receptors with a high degree of binding
affinity. In this context, an increasing important area of ligand de-
sign involves the synthesis and study of new bridging ligands2 and
their use as chelating ligands.3
Modern synthetic design demands high efficiency in terms of
minimization of synthetic steps, and the possibility of designing
a ‘one-pot’ sequence for the construction of complex molecules is
a major driving force for new synthetic methodologies.4 Tandem
reactions are efficient strategies in organic synthesis, since they
enable multiple transformations via a series of cascade reactions.
Consequently, they have found wide application in the preparation
of complex molecules. For example, several interesting nitrogen-
containing natural products have been synthesized using tandem,
domino, and cascade reactions.5
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.
Staudinger–Wittig/heterocumulene-mediated annelation pro-
cesses have been utilized for the synthesis of nitrogen
heterocycles.6 In the context of our ongoing studies on fused ni-
trogen-containing heterocyclic construction,7 we wish to report
a simple and efficient one-pot three-step domino process, involving
aza-Wittig/intermolecular nucleophilic addition/intramolecular
cyclization, for the preparation of bis(pyrazinothienopyrimidinone)
derivatives 5 and 6 as isosteres of pharmaceutically relevant
pyridothienopyrimidines as well as their use as appropriate 1,10-
phenantroline-like ligands toward transition metals. We
envisioned that the employment consecutively of an aryl or alkyl
isocyanate and a bifunctional reactant containing both nucleophilic
sites in such a reaction as depicted in Scheme 1 would result in the
formation of bis(N-heterocycles) compounds.
The syntheses presented in this paper rely on the following
reactions: (a) reaction of Staudinger ylide with isocyanate to afford
a carbodiimide, (b) addition of a bisnucleophile to the carbodiimide
to generate a bis amidine, and (c) lactamization of the latter with
neighboring ethyl ester group to deliver fused pyrimidones. Al-
though all the three steps are well-known the reactions are carried
out in a one-pot operation leading to complex molecules. This
three-step synthesis in a one-pot process is economically and en-
vironmentally very advantageous by the simplicity of procedure,
On the other hand, heteroaromatic nitrogen ligands have been
the focus of much work especially for their extended applications in
several important research and technological fields. The vast ma-
jority of heteroaromatic nitrogen ligands covers solely pyridine-
* Corresponding authors. Tel.: þ34 981 167000; fax: þ34 981 167065.
E-mail addresses: jqqoqf@udc.es (J.M. Quintela), capeveqo@udc.es (C. Peinador).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.067

G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
11137
N
S
N
N
N
O
O
N
S
S
N
N
S
Linker
N
N
N
N
N
N
N
O
NH
HN
R
N
Linker
O
X
N
R
X
6
R
R
5
RN=C=O
PPh3
N
N
N
R = Alkyl, aryl
CO2Et
S
Linker
HX
XH
1
X = NH, O, S
Scheme 1. Retrosynthetic analysis for the synthesis of bis(pyrazinothienopyrimidinones) 5 an 6.
reduction of isolation and purification steps, time, costs, and waste
production.
2(4H)-yl]piperazine 4a in a 73% yield (entry 1, Table 1). Pyrimido-
annulation occurs via a heterocumulene moiety, available from the
reaction of the phosphazene 1 and phenyl isocyanate, which, in
turn, was conveniently converted, by a one-pot domino procedure,
into the corresponding fused bis(heterocycle) system 4, via initial
double nucleophilic addition of piperazine to the carbodiimide
cumulenic system 2 to give the bis(guanidine) intermediate 3,
followed by intramolecular hetero conjugate addition annulation in
the presence of anhydrous potassium carbonate (Scheme 2).
We envisioned that the present domino protocol might be ap-
plied for the preparation of 4b and 4c when 4-methyl- or 4-nitro-
phenyl isocyanate instead of phenyl isocyanate is used as one of the
components (Table 1, entries 2 and 3). As demonstrated in Table 1,
the reaction is practically irrespective of the fact whether the
substituents on the benzene were electron-withdrawing or
2. Results and discussion
We first tested the reaction of ethyl 3-(triphenylphosphor-
anylideneamino)-thieno[2,3-b]pyrazine-6-carboxylate 18 with
phenyl isocyanate (Scheme 2). The reaction proceeded smoothly in
THF at room temperature. After consumption of the starting ma-
terials in 1 h, as monitored by TLC, piperazine was added to the
reaction mixture. We found that in order to facilitate the intra-
molecular annulation it was necessary the presence of a catalytic
amount of a base, and the best results were obtained employing
catalytic K2CO3 that assisted the cyclization reaction to afford
1,4-bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
PPh3
N
N
CO2Et
S
N
1
i
NAr
C
N
N
CO2Et
S
N
2
iii
ii
Ar
Ar
CO Et
N
N
EtO2C
S
HN
N
NH
N
2
N
N
N
N
S
S
S
N
N
3
N
N
EtO2C
HN
N
CO2Et
N
X
X
Linker
NH
Ar
X
X
Ar
7
O
Ar
Ar
O
S
N
S
N
S
N
N
N
N
N
N
N
N
S
N
N
N
N
N
N
O
N
O
Linker
N
4a-c
Ar
Ar
5a-o
X = NH, O, S
Linker = ethylene, 1,2-, 1,3-, and 1,4-phenylene
Scheme 2. Reagents and conditions: (i) ArNCO, THF (3 h, rt). (ii) Piperazine and K2CO3 (1 h, reflux). (iii) Bisnucleophilic reagent: HX–Linker–XH, K2CO3, reflux, 1–2 h.

11138
G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
Table 1
only in the formation of triphenylphosphine oxide and the corre-
Bispyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 4a–c
sponding bis(heterocyclic) compounds 5i–o (Table 2, entries 9–15),
with the two pyrazinothienopyrimidinone systems linked by a 1,2-
phenylene, 1,3-phenylene, 1,4-phenylene, biphenylene, or 2,6-pyr-
idinediamine chain. Steric hindrance seems to be a limitation
to the reaction, as the reaction with 1,2-phenylenediamine and
substituted aryl isocyanates only afforded low yields of the corre-
sponding bis(pyrazinothienopyrimidines) 5j and 5k (entries 10 and
11, Table 2).
Entry
Compd
Ar
Yield (%)
Mp (ꢁC)
1
2
3
4a
4b
4c
C6H5
4-CH3–C6H4
4-NO2–C6H4
73
52
51
>300
>300
>300
Table 2
2-Dialkylaminopyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 5a–l
It is interesting to note that the reaction of Staudinger ylide 1
with alkyl isocyanates, as n-butyl or isopropyl isocyanate, followed
by addition of an primary diamine, as 1,3-propylenediamine or
phenylenediamines, is also regioselective but affords only bis(pyr-
azinothienopyrimidinones) 6a–d in moderate yields, isomeric
compounds 5 not being formed (Scheme 3, Table 3). Moreover,
more time was needed for the reaction to proceed satisfactorily.
Thus, Staudinger–Wittig reaction of phosphazene 1 with isopropyl
isocyanate and 1,3-propanediamine, in tetrahydrofuran solution at
reflux temperature for 5 h, gave bis(pyrazinothienopyrimidine) 6a
in 78% yield (entry 1, Table 3), whose formation was confirmed by
their spectroscopic data. In particular, the 1H NMR spectra of
compound 6a show the signals of NH at 5.45, as a doublet, due to
coupling with the methine proton adjacent to the nitrogen atom,
and NCH at 4.66–4.76, as a multiplet, which suggest the existence of
iPrNH group in 6a. Moreover, its NCH2 showed the signal at 4.26
(J¼7.1 Hz), as triplet, and the central methylene protons on the
propylene moiety at 2.26 (J¼7.1 Hz), as a quintuplet, in concordance
with the proposed structure. However, steric hindrance seems to be
a limitation to the intramolecular cyclization, as the reaction with
Entry
Compd
X
Linker
Ar
Yield (%)
Mp (ꢁC)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
S
S
S
O
CH2CH2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3–C6H5
C6H5
C6H5
4-CH3-C6H5
4-NO2-C6H5
C6H5
C6H5
C6H5
81
77
80
75
78
74
69
57
56
40
36
72
79
79
53
>300
>300
>300
200–201
>300
1,3-C6H4
1,4-C6H4
1,3-C6H4
1,4-C6H4
CH2CH2CH2
CH2CH2CH2
CH2CHCH3
1,2-C6H4
1,2-C6H4
1,2-C6H4
1,3-C6H4
1,4-C6H4
4,40-(C6H4)2
2,6-C6H3N
O
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
265–267
150–152
218–220
225–227
176–177
>300
9
10
11
12
13
14
15
259–260a
203–205
>300
C6H5
270–272a
a
Decomposition.
electron-releasing. Thus, replacing the phenyl in isocyanate with
tolyl or 4-nitrophenyl had a negligible effect on the enhancement of
reaction efficiency. This can be attributed to the greater steric
hindrance of substituted phenyl groups.
1,4- or 1,2-phenylenediamine afforded
a mixture of the bis
Encouraged by the aforementioned results and with the suitable
reaction conditions in hand, we next tested the feasibility of the
protocol using various nitrogen, sulfur, and oxygen bis(nucleo-
philes). Fortunately, this one-pot procedure provided a straightfor-
ward synthetic route to the pyrazinothienopyrimidine core
structure, but also generated a set of functionalized molecules that
are not readily available by other synthetic methods. Therefore, as
shown in Table 2, the phosphazene 1 was converted into the bis-
(pyrazinothienopyrimidinones) 5a–c by a domino reaction se-
quence similar to that shown in Scheme 2 employing phenyl
(pyrazinothienopyrimidines) 6b–d and the corresponding pyrazino
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 8b–d (Scheme 4).
Moreover, more time was needed for the reaction to proceed sat-
isfactorily: 9 h were necessary for 6b, 10 h for 6c, and 14 h were
needed for 6d. Thus, we found that bis(pyrazinothienopyrimidines)
6b–d were isolated and fully identified by treating phosphazene 1
with n-butyl or isopropyl isocyanate and 1,4- or 1,2-phenylenedi-
amine. The tetrahydrofuran solutions containing phosphazene 1,
alkyl isocyanate, and the appropriate phenylenediamine were
heated at reflux temperature up to total disappearance of
phosphazene. Column chromatography of the final reaction
mixtures obtained from this treatment allowed the isolation of
pure coupling bis(heterocycles) 6b–d in not very good yields. Iso-
propyl or n-butylaminopyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4(3H)-ones 8b–d were also isolated from the reaction mixtures
(entries 2–4, Table 3). The sequential treatment, in the same re-
action flask, of a tetrahydrofuran solution of phosphazene 1 with
the amino derivatives 8b–d and isopropyl isocyanate or n-butyl
isocyanate led to the corresponding linked bis(heterocycles) 6b–
d in 55–70% yield after heating at reflux temperature for 8 h.
Mass and spectroscopic data of the prepared compounds 6 are
in good agreement with the proposed structures. The IR spectra of
compounds 6 reveal, for example, N–H and C]O absorption bands
between 3434–2922 and 1690–1646 cmꢀ1, respectively. The four
aromatic protons on the benzene ring of 6b and 6c are identical and
do not couple with each other. These signals are found at 7.67 for 6b
and 7.66 for 6c as a singlet, which suggest identical neighbors for all
the protons on the benzene ring in compounds 6b,c. In particular,
the 1H NMR spectra of compound 6c show the signals of NH at 5.37,
as a doublet, due to coupling with the methine proton adjacent to
the nitrogen atom, and NCH at 4.62–4.70, as a multiplet, which
suggest the existence of NH-isopropyl group in 6c, in concordance
with the proposed structure. Indeed, consistently with that
observed in the spectroscopic and crystal data of bis(pyr-
azino[20,30:4,5]thieno[3,2-d]pyrimidin-4-yl)benzene 6b, alsoobtained
by a tandem aza-Wittig reaction of phosphazene 1 with 1,4-
isocyanate and
a,u-dithiols. In compounds 5a–c, two pyr-
azinothienopyrimidine rings are linked via their respective C2
carbon atoms by an ethylene, 1,3-phenylene, or 1,4-phenylene
dithioether chain (Table 2, entries 1–3). Bis(heterocycles) 5d and
5e, in which the two pyrazinothienopyrimidinones are linked by
a 1,3-phenylene or 1,4-phenylene diether, were prepared by a simi-
lar sequence of reactions (Table 2, entries 4 and 5).
The reactions of Staudinger ylide 1 with phenyl isocyanate and
1,3-propylenediamine or 1,2-diaminopropane provided only
bis(heterocycles) 5f–h (Table 2, entries 6–8), in which the two
pyrazinothienopyrimidine rings are linked via their respective C2
carbon atoms by a 1,3-propylene or 1,2-propylene chain, with total
selectivity. Compounds were characterized from their spectral data,
and the study of 1H NMR spectra led us to confirm the structure of
products without difficulty. In particular, in the 1H NMR spectra of
5h, the protons of the NH groups display a characteristic triplet or
doublet multiplicity depending on the coupling with the methylene
or methine protons adjacent to the nitrogen atom. Its chemical shift
is 4.31 and 5.13, more shielded than the one in PhNH of compounds
6.8 For example, the 1H NMR spectrum of 5f shows the signal of NH
at 4.31 as a triplet and NCH2 at 3.72 as a quartet. When the sample
was treated with D2O, its NCH2 showed the signal as a triplet with
disappearance of signals of NH absorption.
Likewise, reaction of phosphazene 1 with phenyl isocyanate and
aromatic primary diamines as 1,2-, 1,3-, or 1,4-phenylenediamine,
benzidine, or 2,6-diaminopyridine is regioselective and resulted

G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
11139
N
N
S
CO2Et
NR
N
C
3
+
Linker
H2N
NH2
NHR
CO2Et
S
RHN
EtO2C
S
NHR
N
RHN
N
H
N
H
N
Linker
N
N
Linker
HN
N
N
NH
EtO2C
N
N
N
CO2Et
N
7a
N
N
S
S
7b
R
N
R
N
H
N
H
R
R
Linker
N
O
O
NH
N
HN
N
N
N
N
N
N
N
N
Linker
S
S
5f-o
S
S
N
N
N
O
O
N
N
6a-d
R = Ar
R = n-butyl, isopropyl
Linker = propylene, 1,4-phenylenea
Linker = propylene, 1,2-, 1,3-, and 1,4-phenylene,
biphenylene, 2,6-pyridine
Scheme 3. Bispyrazinothienopyrimidinones 5f–o and 6a–d.
guanidine-type intermediate (Scheme 3). It seems immediately
obvious that each amine group would approach to the carbodii-
mide 2 essentially by the opposite direction of the carboxylate
group, due to the steric hindrance, to form the bisamidine 7a.
However, 7a may convert to 7b through C–N single bond rotation
and this offers the opportunity that both bisamidine in-
termediates, 7a and 7b, are suitable to cyclize: 7a for the NHR
group and 7b by the NH-linked group to form 5 and 6, re-
spectively. Steric hindrance between R and ester groups would
explain the regioselectivity of the reaction. The greater steric
hindrance between the isopropyl or n-butyl group and the ethoxy
carbonyl group in the bisamidine 7a may convert easily 7a to 7b
through C–N single bond rotation with subsequent cyclization to
afford bis(pyrazinothienopyrimidinones) 6a–d. Consequently, the
regioselectivity of the reaction seems strongly influenced by the
steric hindrance between R and ester groups. The isolation of
compounds 8b–d of the reaction mixtures could be explained by
steric hindrance of the bulkier alkyl group and could help to ex-
plain the regioselectivity of the reaction.
Table 3
2-Dialkylaminopyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 6a–d
Entry
1
Compd
R
Linker
(CH2)3
R1
Yield (%)
Mp (ꢁC)
>300
6a
8a
iPr
iPr
78
0
CH2CH2NH2
2
3
6ba
8b
nBu
nBu
1,4-C6H4
1,4-C6H4
1,2-C6H4
37
60
290b
4-NH2–C6H4
4-NH2–C6H4
2-NH2–C6H4
231–233
6c
8c
iPr
iPr
41
52
>300
266–267b
4
6d
8d
iPr
iPr
33
28
>300
250–252b
Compound 6a has also been obtained by an alternate method.6i
Decomposition.
a
b
phenylene diisocyanate followed by intramolecular hetero conju-
gate addition annulation after addition of n-butylamine as we pre-
viously reported,8 with the same compound 6b prepared using the
present protocol, the structure of compounds 6 was unambiguously
confirmed.
These selectivity results can probable be explained by the large
difference in cyclization rates due to steric hindrance around the
ethoxy carbonyl and the n-butyl or isopropyl groups on the
3. Conclusions
In conclusion, we have established a new strategy for the syn-
thesis of bis(pyrazinothienopyrimidine) derivatives based on the
domino interaction of phosphazene 1 with isocyanates and bi-
functional nucleophiles. This one-pot procedure by a tandem aza-
Wittig-heterocumulene-mediated annulation offers an attractive
synthetic route for the generation of these functionalized bis-
(triheterocyclic) compounds that are not readily available by other
synthetic methods, and can be extended to secondary amines,
phenols, or thiophenols. In the case of primary diamines a regio-
selective cyclization has been observed strongly influenced by the
steric hindrance between R and ester groups. The easy availability
of starting material, simple and convenient synthetic procedure,
and formation of functionalized bis(pyrazinothienopyrimidines)
render this method very useful in synthetic and coordination
chemistry, as well as in medicinal chemistry.
ii
R
R
R
NH
N
NH
N
HN
N
N
N
N
N
N
R1
Linker
i
N
O
1
+
N
S
O
N
S
S
N
O
8b-d
6a-d
R = n-butyl, isopropyl, R1 = 4-aminophenyl, 2-aminophenyl
Linker = ethylene, 1,2-, 1,4-phenylene
Scheme 4. Synthesis of bis(pyrazinothienopyrimidinones) 6a–d. Reagents and con-
ditions: (i) RNCO, THF, rt, 3 h; then bisnucleophilic reagent, K2CO3, reflux, 10 h. (ii)
Phosphazene (1), alkyl isocyanate, THF, rt, 1 h; then, 8b–d, reflux, 8 h.

11140
G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
4. Experimental section
(FAB) m/z 733 [(MH)þ, 40]. Anal. Calcd for C32H20N12O6S2: C, 52.46;
H, 2.75; N, 22.94; S, 8.75. Found: C, 52.68; H, 2.58; N, 22.69; S, 8.57.
4.1. General
4.2.4. 1,2-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
All reagents were commercial grade chemicals from freshly
opened containers. Merck 60 F254 foils were used for thin layer
chromatography and Merck 60 (230–400 mesh) silica gel for flash
chromatography. NMR spectra were obtained in a Bruker Avance
300 (300 MHz and 75 MHz for 1H and 13C, respectively) or a Bruker
Avance 500 (500 MHz and 125 MHz for 1H and 13C, respectively) in
CDCl3 as solvent, and the chemical shifts are expressed in parts per
pyrimidin-2(4H)-yl]ethane disulfide (5a)
Yield 81%; mp >300 ꢁC; IR (KBr)
n
¼1678 (C]O),1511,1487,1342,
1291 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
¼3.57 (s, 4H, CH2), 7.46–7.50
(m, 2H, H–Ar), 7.59–7.65 (m, 8H, H–Ar), 8.79 (d, J¼2.3 Hz, 2H, H-6),
8.85 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR spectrum could not be
obtained due to poor solubility. MS (FAB) m/z 651 [(MH)þ, 10]. Anal.
Calcd for C30H18N8O2S4: C, 55.37; H, 2.79; N, 17.22; S, 19.71. Found:
C, 55.69; H, 2.95; N, 17.63; S, 19.50.
million relative to TMS at
d
¼0.00 for 1H and to CDCl3 at
¼77.1 for
d
13C. IR spectra were recorded as potassium bromide disks on
a Bruker VECTOR 22 spectrophotometer. FAB spectrometric ex-
periments were carried out in a VG Trio instrument. Melting points
were measured using Stuart Scientific SMP3 apparatus and are
uncorrected. Microanalyses were performed by the elemental
analyses general service of the University of A Corun˜a on a Carlo
Erba EA-1108 instrument.
4.2.5. 1,3-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]benzene disulfide (5b)
Yield 77%; mp >300 ꢁC; IR (KBr)
n
¼1674 (C]O), 1515, 1489,
1233 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
¼7.60–7.70 (m, 10H, H–Ar),
7.72–7.79 (m, 3H, H–Ar), 7.99 (s, 1H, H–Ar), 8.83 (d, J¼2.3 Hz, 2H, H-
6), 8.87 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
d
¼122.4, 129.6, 130.3, 130.8, 131.0, 136.0, 136.7, 141.1, 143.2, 144.2,
4.2. General procedure for the synthesis of functionalized
bis(pyrazinothienopyrimidines) 4 and 5
145.4, 148.4, 157.1, 158.2, 161.4 ppm. MS (FAB) m/z 699 [(MH)þ, 25].
Anal. Calcd for C34H18N8O2S4: C, 58.44; H, 2.60; N, 16.03; S, 18.35.
Found: C, 58.16; H, 2.22; N, 16.28; S, 18.72.
To a solution of phosphazene 1 (0.15 g, 0.31 mmol) in dry THF
(5 mL) was added the appropriate isocyanate (0.31 mmol). The
mixture was stirred at room temperature for 1–2 h until the
phosphazene had disappeared (TLC monitored) and it was there-
fore treated with piperazine or the corresponding appropriate
bisnucleophilic reagent (0.16 mmol) and a catalytic amount of
K2CO3. The resultant mixture was refluxed for 3–8 h. After cooling
to room temperature, the yellow precipitate was collected by fil-
tration and washed with water (2ꢂ3 mL) and THF (2ꢂ3 mL) or the
solvent was removed under reduced pressure. The resultant ma-
terial was subjected to chromatography on silica gel eluting with
a dichloromethane/ethyl acetate gradient from 10 to 90% ethyl
acetate to give compounds 4 or 5 as yellow solids.
4.2.6. 1,4-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]benzene disulfide (5c)
Yield 80%; mp >300 ꢁC; IR (KBr)
n
¼1675 (C]O), 1525, 1517,
1493, 1234 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
¼7.64–7.70 (m, 10H,
H–Ar), 7.74 (s, 4H, H–Ar), 8.84 (d, J¼2.3 Hz, 2H, H-6), 8.87 (d,
J¼2.3 Hz, 2H, H-7) ppm. 13C NMR spectrum could not be obtained
due to poor solubility. MS (FAB) m/z 699 [(MH)þ, 10]. Anal. Calcd for
C34H18N8O2S4: C, 58.44; H, 2.60; N, 16.03; S, 18.35. Found: C, 58.18;
H, 2.37; N, 15.81; S, 18.60.
4.2.7. 1,3-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yloxy]benzene (5d)
Yield 75%; mp 200–201 ꢁC; IR (KBr)
n
¼1691 (C]O), 1565, 1538,
4.2.1. 1,4-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]piperazine (4a)
1477, 1454, 1341, 1258 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
¼7.13 (d,
J¼2.3 Hz, 2H, H–Ar), 7.16 (d, J¼2.3 Hz, 2H, H–Ar), 7.25 (t, J¼2.3 Hz,
1H, H–Ar), 7.40–7.48 (m, 5H, H–Ar), 7.52–7.63 (m, 6H, H–Ar), 8.68
(d, J¼2.3 Hz, 2H, H-6), 8.75 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR
Yield 73%; mp >300 ꢁC; IR (KBr)
n
¼1682 (C]O), 1518, 1452,
1361, 1259 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
¼3.09 (s, 8H, NCH2),
7.35–7.41 (m, 4H, H–Ar), 7.45–7.56 (m, 6H, H–Ar), 8.72 (d, J¼2.3 Hz,
(125 MHz, CDCl3)
d
¼114.2, 119.0, 121.8, 127.8, 129.6, 129.8, 130.3,
2H, H-6), 8.86 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz,
134.2, 142.8, 143.4, 144.1, 147.3, 152.3, 155.1, 157.7, 158.1, 158.6 ppm.
MS (FAB) m/z 667 [(MH)þ, 25]. Anal. Calcd for C34H18N8O4S2: C,
61.25; H, 2.72; N, 16.81; S, 9.62. Found: C, 61.08; H, 2.53; N, 16.65; S,
9.44.
CDCl3)
d
¼48.1, 120.6, 128.3, 129.2, 129.5, 136.4, 142.7, 143.8, 144.2,
148.2, 157.7, 158.6, 159.2 ppm. MS (FAB) m/z 643 [(MH)þ, 50]. Anal.
Calcd for C32H22N10O2S2: C, 59.80; H, 3.45; N, 21.79; S, 9.98. Found:
C, 59.67; H, 3.29; N, 21.74; S, 10.36.
4.2.8. 1,4-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
4.2.2. 1,4-Bis[3-(4-methylphenyl)-4-oxopyrazino-
pyrimidin-2(4H)-yloxy]benzene (5e)
[20,30:4,5]thieno[3,2-d]pyrimidin-2(4H)-yl]piperazine (4b)
Yield 78%; mp >300 ꢁC; IR (KBr)
n
¼1683 (C]O), 1567, 1542,
Yield 52%; mp >300 ꢁC; IR (KBr)
n
¼1674 (C]O), 1588, 1523,
1488, 1341, 1265 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
¼7.41 (s, 4H, H–
1506, 1449, 1425, 1373, 1239 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
Ar), 7.51–7.57 (t, J¼7.8 Hz, 2H, H–Ar), 7.59–7.64 (t, J¼7.8 Hz, 4H, H–
Ar), 7.66–7.71 (d, J¼7.7 Hz, 4H, H–Ar), 8.87 (d, J¼2.3 Hz, 2H, H-6),
8.91 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
d
¼2.44 (s, 6H, CH3), 3.11 (s, 8H, NCH2), 7.21–7.37 (m, 8H, H–Ar), 8.71
(d, J¼2.3 Hz, 2H, H-6), 8.84 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR
(125 MHz, CDCl3)
d
¼21.4, 48.2, 120.6, 128.0, 130.2, 133.4, 139.3,
d
¼120.5, 123.3, 128.8, 129.7, 129.9, 135.2, 143.3, 144.1, 145.4, 147.8,
142.7, 143.8, 144.2, 148.1, 157.9, 158.6, 159.4 ppm. MS (FAB) m/z 671
[(MH)þ, 15]. Anal. Calcd for C34H26N10O2S2: C, 60.88; H, 3.91; N,
20.88; S, 9.56. Found: C, 60.72; H, 3.65; N, 20.57; S, 9.35.
149.8, 156.4, 157.1, 158.9 ppm. MS (FAB) m/z 667 [(MH)þ, 20]. Anal.
Calcd for C34H18N8O4S2: C, 61.25; H, 2.72; N, 16.81; S, 9.62. Found: C,
61.07; H, 2.97; N, 16.52; S, 9.44.
4.2.3. 1,4-Bis[3-(4-nitrophenyl)-4-oxopyrazino[20,30:4,5]thieno-
4.2.9. N,N0-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
[3,2-d]pyrimidin-2(4H)-yl]piperazine (4c)
pyrimidin-2(4H)-yl]-1,3-propanediamine (5f)
Yield 51%; mp >300 ꢁC; IR (KBr)
n
¼1677 (C]O), 1522, 1507,
Yield 74%; mp 265–267 ꢁC; IR (KBr)
n
¼3305 (N–H), 1674 (C]O),
1488, 1457, 1438, 1375, 1347, 1260 cmꢀ1. 1H NMR (500 MHz, CDCl3)
1549,1519,1440,1339,1311 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
¼1.70
d
¼3.00 (s, 8H, NCH2), 7.87–7.91 (m, 4H, H–Ar), 8.41–8.45 (m, 4H, H–
(quintet, J¼6.0 Hz, 2H, NCH2CH2), 3.72 (q, J¼6.0 Hz, 4H, NCH2), 4.31
(t, J¼6.0 Hz, 2H, NH, exchangeable with D2O), 7.55–7.71 (m, 10H, H–
Ar), 8.60 (d, J¼2.3 Hz, 2H, H-6), 8.66 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C
Ar), 8.91 (d, J¼2.3 Hz, 2H, H-6), 9.01 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C
NMR spectrum could not be obtained due to poor solubility. MS

G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
11141
NMR (75 MHz, CDCl3)
d
¼29.7, 37.6, 115.0, 129.1, 129.5, 130.3, 130.9,
Ar), 8.51 (s, 2H, NH, exchangeable with D2O), 8.72 (d, J¼2.3 Hz, 2H,
H-6), 8.86 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
134.4, 142.4, 143.4, 143.9, 149.5, 153.7, 158.2, 158.3 ppm. MS (FAB)
m/z 631 [(MH)þ, 50]. Anal. Calcd for C31H22N10O2S2: C, 59.03; H,
3.52; N, 22.21; S, 10.17. Found: C, 58.92; H, 3.38; N, 22.19; S, 10.07.
d
¼117.4, 120.2, 125.1, 131.2, 133.6, 134.8, 143.1, 143.2, 143.4, 143.8,
144.9, 150.0, 150.4, 158.8, 160.3 ppm. MS (FAB) m/z 755 [(MH)þ, 15].
Anal. Calcd for C34H18N12O6S2: C, 54.11; H, 2.40; N, 22.27; S, 8.50.
Found: C, 54.52; H, 2.48; N, 22.89; S, 8.76.
4.2.10. N,N0-Bis[3-(4-methylphenyl)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-2(4H)-yl]-1,3-
propanediamine (5g)
4.2.15. 1,3-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
Yield 69%; mp 150–152 ꢁC; IR (KBr)
n
¼3340 (N–H), 1677 (C]O),
pyrimidin-2(4H)-yl]phenylenediamine (5l)
1553, 1520, 1505, 1435, 1338 cmꢀ1
.
1H NMR (500 MHz, CDCl3)
Yield 72%; mp 259–260 ꢁC (dec); IR (KBr)
n
¼3408 (N–H), 1681
d
¼1.71 (quintet, 2H, J¼6.0 Hz, NCH2CH2), 2.48 (s, 6H, CH3), 3.73 (q,
(C]O), 1517, 1479, 1434, 1340 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
J¼6.0 Hz, 4H, NCH2), 4.33 (t, J¼6.0 Hz, 2H, NH, exchangeable with
D2O), 7.43–7.49 (m, 4H, H–Ar), 7.52–7.56 (m, 4H, H–Ar), 8.61 (d,
J¼2.3 Hz, 2H, H-6), 8.67 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR
d
¼6.45 (s, 2H, NH, exchangeable with D2O), 7.00–7.17 (m, 2H, H–
Ar), 7.50–7.58 (m, 5H, H–Ar), 7.67–7.78 (m, 7H, H–Ar), 8.47 (d,
J¼2.3 Hz, 2H, H-6), 8.56 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR
(125 MHz, CDCl3)
d
¼21.5, 29.8, 31.0, 119.2, 128.1, 128.7, 130.4, 131.7,
(125 MHz, CDCl3)
d
¼112.8, 113.5, 117.5, 129.0, 129.5, 130.8, 131.2,
139.4, 140.7, 142.4, 142.6, 143.9, 144.9, 153.8 ppm. MS (FAB) m/z 659
[(MH)þ, 25]. Anal. Calcd for C33H26N10O2S2: C, 60.17; H, 3.98; N,
21.26; S, 9.74. Found: C, 60.61; H, 3.47; N, 21.78; S, 9.28.
133.8, 138.4, 141.8, 143.9, 144.3, 149.3, 150.2, 158.3, 158.6 ppm. MS
(FAB) m/z 665 [(MH)þ, 15]. Anal. Calcd for C34H20N10O2S2: C, 61.43;
H, 3.03; N, 21.07; S, 9.65. Found: C, 61.26; H, 2.72; N, 21.39; S, 9.43.
4.2.11. N,N0-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
4.2.16. 1,4-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]-1,2-propanediamine (5h)
pyrimidin-2(4H)-yl]phenylenediamine (5m)
Yield 57%; mp 218–220 ꢁC; IR (KBr)
n
¼3336 (N–H), 1672 (C]O),
Yield 79%; mp 203–205 ꢁC; IR (KBr)
n
¼3052 (N–H), 1681 (C]O),
1516, 1339 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
¼1.19 (d, J¼6.6 Hz, 3H,
1499, 1339 cmꢀ1
.
1H NMR (500 MHz, CDCl3)
d
¼6.24 (s, 2H, NH,
CH3), 3.68 (dd, J¼5.1, 7.4 Hz, 2H, NCH2), 4.53 (d, J¼8.6 Hz, 1H, NH,
exchangeable with D2O), 4.65–4.84 (m, 1H, NCH), 5.13 (t, J¼5.1 Hz,
2H, NH, exchangeable with D2O), 6.90–7.34 (m, 9H, H–Ar), 7.43–
7.52 (m, 1H, H–Ar), 8.69 (d, J¼2.3 Hz, 1H, H pyrazine), 8.72 (d,
J¼2.3 Hz, 1H, H-6), 8.79 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C NMR
exchangeable with D2O), 7.46–7.52 (m, 10H, H–Ar), 7.59 (s, 4H, H–
Ar), 8.70 (d, J¼2.3 Hz, 2H, H-6), 8.80 (d, J¼2.3 Hz, 2H, H-7) ppm. 13C
NMR (125 MHz, CDCl3)
d
¼117.4, 122.2, 128.9, 130.9, 131.2, 133.7,
133.9, 142.4, 143.9, 144.0, 149.4, 150.6, 158.6 ppm. MS (FAB) m/z 665
[(MH)þ, 55]. Anal. Calcd for C34H20N10O2S2: C, 61.43; H, 3.03; N,
21.07; S, 9.65. Found: C, 61.22; H, 2.86; N, 20.89; S, 9.88.
(75 MHz, CDCl3)
d
¼18.5, 47.1, 48.0, 115.5, 115.6, 127.9, 128.3, 128.6,
128.7,129.5,130.1,130.6,130.7,133.4,133.7,142.1,143.8,143.9,149.6,
149.7, 153.5, 153.8, 158.3, 158.4, 158.5 ppm. MS (FAB) m/z 631
[(MH)þ, 50]. Anal. Calcd for C31H22N10O2S2: C, 59.03; H, 3.52; N,
22.21; S, 10.17. Found: C, 58.69; H, 3.25; N, 22.49; S, 9.79.
4.2.17. 4,40-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]biphenylenediamine (5n)
Yield 79%; mp >300 ꢁC; IR (KBr)
n
¼3412 (N–H), 1681 (C]O),
1598, 1537, 1487, 1338 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d¼6.37 (s,
4.2.12. 1,2-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]-1,2-phenylenediamine (5i)
2H, NH, exchangeable with D2O), 7.19–7.25 (m, 2H, H–Ar), 7.43–7.49
(m, 4H, H–Ar), 7.65–7.69 (m, 4H, H–Ar), 7.70–7.73 (m, 4H, H–Ar),
8.02–8.08 (m, 4H, H–Ar), 8.78 (d, J¼2.3 Hz, 2H, H-6), 8.92 (d,
Yield 56%; mp 225–227 ꢁC; IR (KBr)
n
¼3280 (N–H), 1667 (C]O),
1601, 1537, 1518, 1484, 1444, 1337 cmꢀ1. 1H NMR (300 MHz, CDCl3)
¼7.12–7.19 (m, 2H, H–Ar), 7.38–7.45 (m, 4H, H–Ar), 7.65–7.74 (m, 6H,
J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
¼117.4, 121.3,
d
d
128.9, 129.4, 129.7, 130.1, 133.9, 137.2, 142.0, 142.7, 143.9, 144.2,
149.5, 150.4, 158.6, 158.7 ppm. MS (FAB) m/z 741 [(MH)þ, 40]. Anal.
Calcd for C40H24N10O2S2: C, 64.85; H, 3.27; N, 18.91; S, 8.66. Found:
C, 64.42; H, 3.56; N, 18.50; S, 8.45.
H–Ar), 7.85–7.90 (m, 2H, H–Ar), 7.94 (s, 2H, NH, exchangeable with
D2O), 8.66 (d, J¼2.3 Hz, 2H, H-6), 8.80 (d, J¼2.3 Hz, 2H, H-7) ppm. 13
C
NMR (75 MHz, CDCl3)
d
¼115.9, 121.2, 124.4, 129.1, 131.4, 133.0, 135.2,
137.8,142.7, 143.5,144.3,150.9,151.2,158.8, 160.2 ppm. MS (FAB) m/z
665 [(MH)þ, 70]. Anal. Calcd for C34H20N10O2S2: C, 61.43; H, 3.03; N,
21.07; S, 9.65. Found: C, 61.17; H, 3.32; N, 21.21; S, 9.43.
4.2.18. 2,6-Bis[4-oxo-3-phenyl-pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-2(4H)-yl]diaminopyridine (5o)
Yield 53%; mp 270–272 ꢁC (dec); IR (KBr)
n
¼3387 (N–H), 1689
4.2.13. 1,2-Bis[3-(4-methylphenyl)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-2(4H)-yl]-
phenylenediamine (5j)
(C]O), 1549, 1488, 1455, 1337 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
d
¼6.66 (s, 2H, NH, exchangeable with D2O), 7.40–7.48 (m, 4H, H–
Ar), 7.65–7.74 (m, 6H, H–Ar), 8.03 (t, J¼7.7 Hz, 1H, H–Py), 8.51 (d,
J¼7.7 Hz, 2H, H–Py), 8.75 (d, J¼2.3 Hz, 2H, H-6), 8.90 (d, J¼2.3 Hz,
Yield 40%; mp 176–177 ꢁC; IR (KBr)
n
¼3327 (N–H), 1680 (C]O),
1633, 1600, 1518, 1451, 1342 cmꢀ1
.
1H NMR (500 MHz, CDCl3)
2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
d
¼109.4, 118.5, 128.8,
d
¼2.35 (s, 6H, CH3), 7.18–7.24 (m, 4H, H–Ar), 7.55–7.60 (m, 4H, H–
130.8, 131.2, 133.5, 141.7, 142.8, 143.8, 144.2, 148.9, 149.0, 158.3,
158.6 ppm. MS (FAB) m/z 666 [(MH)þ, 20]. Anal. Calcd for
C33H19N11O2S2: C, 59.54; H, 2.88; N, 23.14; S, 9.63. Found: C, 59.79;
H, 2.65; N, 23.46; S, 9.82.
Ar), 7.63–7.69 (m, 2H, H–Ar), 7.81 (s, 2H, NH, exchangeable with
D2O), 7.84–7.91 (m, 2H, H–Ar), 8.65 (d, J¼2.3 Hz, 2H, H-6), 8.79 (d,
J¼2.3 Hz, 2H, H-7) ppm. 13C NMR (125 MHz, CDCl3)
¼20.9, 115.6,
d
121.4, 129.6, 131.4, 133.0, 134.1, 135.1, 142.7, 143.6, 144.3, 151.0, 151.4,
158.8, 160.2 ppm. MS (FAB) m/z 693 [(MH)þ, 10]. Anal. Calcd for
C36H24N10O2S2: C, 62.41; H, 3.49; N, 20.22; S, 9.26. Found: C, 62.79;
H, 3.28; N, 20.59; S, 9.54.
4.3. General procedure for the synthesis of functionalized
bis(pyrazinothienopyrimidines) 6
To a solution of phosphazene 1 (0.15 g, 0.31 mmol) in dry THF
(5 mL) was added the appropriate alkyl isocyanate (0.37 mmol).
The mixture was stirred at reflux temperature for 8 h until the
phosphazene had disappeared (TLC monitored) and it was there-
fore treated with the corresponding appropriate bisnucleophilic
reagent (0.16 mmol) and a catalytic amount of K2CO3. The resultant
mixture was refluxed for 5–14 h. After cooling, the solvent was
4.2.14. 1,2-Bis[3-(4-nitrophenyl)-4-oxopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-2(4H)-yl]-
phenylenediamine (5k)
Yield 36%; mp >300 ꢁC; IR (KBr)
1603, 1520, 1452, 1329 cmꢀ1
7.72 (m, 2H, H–Ar), 7.86–7.97 (m, 6H, H–Ar), 8.28–8.35 (m, 4H, H–
n
¼3353 (N–H), 1638 (C]O),
.
1H NMR (500 MHz, CDCl3)
d
¼7.64–

11142
G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
removed under reduced pressure, and the residue was subjected to
chromatography on silica gel eluting with a dichloromethane/ethyl
acetate gradient from 0 to 100% ethyl acetate to give compounds
6a–d and 8b–d as yellow solids.
4.3.6. 1,2-Bis[(2-isopropyl)-4-oxopyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-3(4H)-yl]benzene (6d)
Eluted with CH2Cl2/EtOAc (20:80). Yield 33%; mp >300 ꢁC; IR
(KBr)
n
¼3434, 3403, 3338 (NH), 1680 (C]O), 1542, 1521, 1455,
1338 cmꢀ1
.
1H NMR (500 MHz, CDCl3)
d
¼1.19 (d, J¼6.5 Hz, 12H,
4.3.1. 1,3-Bis[2-isopropylamino-4-oxopyrazino[20,30:4,5]thieno-
[3,2-d]pyrimidin-3(4H)-yl]propane (6a)
CH3), 4.35–4.50 (m, 2H, CH), 5.46 (d, J¼7.7 Hz, 2H, NH, exchange-
able with D2O), 7.50–7.58 (m, 2H, H–Ar), 7.81–7.89 (m, 2H, H–Ar),
8.63 (d, J¼2.3 Hz, 2H, H-7), 8.78 (d, J¼2.3 Hz, 2H, H-8) ppm. 13C
Eluted with CH2Cl2/EtOAc (40:60). Yield 78%; mp >300 ꢁC; IR
(KBr)
n
¼3393 (N–H), 1646 (C]O), 1545, 1489, 1347, 1301 cmꢀ1
.
NMR (125 MHz, CDCl3)
d¼21.5, 22.5, 44.6, 113.5, 131.9, 133.0, 134.1,
1H NMR (500 MHz, CDCl3)
d
¼1.38 (d, J¼6.5 Hz, 12H, CH3), 2.26
142.5, 143.9, 144.2, 151.7, 152.9, 159.0, 159.9 ppm. MS (FAB) m/z 597
[(MH)þ, 20]. Anal. Calcd for C28H24N10O2S2: C, 56.36; H, 4.05; N,
23.47; S, 10.75. Found: C, 55.72; H, 4.42; N, 23.79; S, 11.17.
(quintet, J¼6.5 Hz, 2H, NCH2CH2), 4.26 (t, J¼6.5 Hz, 4H, NCH2),
4.66–4.76 (m, 1H, CH), 5.45 (d, J¼7.6 Hz, 2H, NH, exchangeable
with D2O), 8.67 (d, J¼2.3 Hz, 2H, H-7), 8.82 (d, J¼2.3 Hz, 2H, H-
8) ppm. 13C NMR (125 MHz, CDCl3)
d¼22.8, 26.7, 40.0, 44.6, 114.1,
4.3.7. 3-N-(2-Aminophenyl)-2-isopropylaminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8d)
142.4, 142.8, 144.0, 144.1, 150.5, 152.3, 158.7, 159.6 ppm. MS (FAB)
m/z 563 [(MH)þ, 35]. Anal. Calcd for C25H26N10O2S2: C, 53.36; H,
4.66; N, 24.89; S, 11.40. Found: C, 53.62; H, 4.38; N, 25.19; S,
11.27.
Eluted with CH2Cl2. Yield 28%; mp 250–252 ꢁC (dec); IR (KBr)
n
¼3404, 3338 (N–H), 1668 (C]O), 1541, 1520, 1499, 1338. 1H NMR
(500 MHz, CDCl3)
d
¼1.20 (d, J¼6.5 Hz, 6H, CH3), 3.76 (s, 2H, NH2,
NH, exchangeable with D2O), 4.42 (d, J¼8.1 Hz, 1H, NH, exchange-
able with D2O), 4.50–4.65 (m, 1H, CH), 6.94–7.02 (m, 2H, H–Ar),
7.09–7.16 (m, 1H, H–Ar), 7.33–7.42 (m, 1H, H–Ar), 8.69 (d, J¼2.3 Hz,
2H, H-7), 8.85 (d, J¼2.3 Hz, 2H, H-8) ppm. 13C NMR (125 MHz,
4.3.2. 1,4-Bis[2-n-butylamino-4-oxopyrazino[20,30:4,5]thieno-
[3,2-d]pyrimidin-3(4H)-yl]-benzene (6b)
Eluted with CH2Cl2/EtOAc (80:20). Yield 37%; mp 290 ꢁC (dec),
mp 290 ꢁC (dec).6i Its spectroscopic data were identical to those
reported in the literature.6i
CDCl3)
d
¼22.7, 44.0, 114.8, 117.9, 118.9, 120.2, 129.2, 131.5, 142.3,
143.4, 143.9, 144.1, 150.7, 152.7, 158.3, 158.7 ppm. MS (FAB) m/z 353
[(MH)þ, 40]. Anal. Calcd for C17H16N6OS: C, 57.94; H, 4.58; N, 23.85;
S, 9.10. Found: C, 57.61; H, 4.29; N, 23.99; S, 8.87.
4.3.3. 3-N-(4-Aminophenyl)-2-n-butylaminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8b)
Eluted with CH2Cl2/EtOAc (40:60). Yield 60%; mp 231–233 ꢁC; IR
4.4. General procedure for the synthesis of functionalized
bis(pyrazinothienopyrimidines) 6 from derivatives 8b–d
(KBr)
(500 MHz, CDCl3)
n
¼3056, 2956 (N–H), 1676 (C]O), 1556, 1514, 1436. 1H NMR
d
¼0.89 (t, J¼7.3 Hz, 3H, CH3), 1.25–1.34 (m, 2H,
NCH2CH2CH2), 1.46–1.54 (m, 2H, NCH2CH2), 3.54–3.60 (dt, J¼5.1,
7.1 Hz, 2H, NCH2), 4.06 (s, 2H, NH2, exchangeable with D2O), 4.48 (t,
J¼5.1 Hz,1H, NH, exchangeable with D2O), 6.82–6.86 (m, 2H, H–Ar),
7.05–7.09 (m, 2H, H–Ar), 8.65 (d, J¼2.3 Hz, 2H, H-7), 8.81 (d,
To a solution of phosphazene 1 (0.15 g, 0.31 mmol) in dry THF
(5 mL) was added the appropriate alkyl isocyanate (0.31 mmol).
The mixture was stirred at reflux temperature for 8 h until the
phosphazene had disappeared (TLC monitored) and it was there-
fore treated with the corresponding appropriate nucleophilic re-
agents 8b–d (0.31 mmol) and a catalytic amount of K2CO3. The
resultant mixture was refluxed for 8 h. After cooling, the solvent
was removed under reduced pressure, and the residue was sub-
jected to flash chromatography on silica gel eluting with
a dichloromethane/ethyl acetate gradient to give 6b (70% yield), 6c
(66% yield), and 6d (55% yield) as yellow solids.
J¼2.3 Hz, 2H, H-8) ppm. 13C NMR (125 MHz, CDCl3)
¼13.9, 20.1,
d
31.3, 42.1, 115.4, 116.6, 123.5, 129.4, 142.3, 143.7, 144.3, 148.3, 150.1,
154.3, 158.7, 159.3 ppm. MS (FAB) m/z 367 [(MH)þ, 20]. Anal. Calcd
for C18H18N6OS: C, 59.00; H, 4.95; N, 22.93; S, 8.75. Found: C, 59.34;
H, 4.71; N, 23.19; S, 8.97.
4.3.4. 1,4-Bis[(2-isopropyl)-4-oxopyrazino[20,30:4,5]thieno-
[3,2-d]pyrimidin-3(4H)-yl]-benzene (6c)
Eluted with CH2Cl2/EtOAc (30:70). Yield 41%; mp >300 ꢁC; IR
¼2922 (NH), 1690 (C]O), 1545, 1464, 1379 cmꢀ1
.
1H NMR
Acknowledgements
(KBr)
(500 MHz, CDCl3)
n
d
¼1.17 (d, J¼6.5 Hz, 12H, CH3), 4.62–4.70 (m, 2H,
We gratefully acknowledge financial support from the Xunta de
Galicia and Feder (Project PGIDIT06PXIB103224PR).
CH), 5.37 (d, J¼7.6 Hz, 2H, NH, exchangeable with D2O), 7.66 (s, 4H,
H–Ar), 8.71 (d, J¼2.3 Hz, 2H, H-7), 8.87 (d, J¼2.3 Hz, 2H, H-8) ppm.
13C NMR spectrum could not be obtained due to poor solubility. MS
(FAB) m/z 597 [(MH)þ, 10]. Anal. Calcd for C28H24N10O2S2: C, 56.36;
H, 4.05; N, 23.47; S, 10.75. Found: C, 56.07; H, 3.78; N, 23.79; S,
10.52.
References and notes
1. (a) Undheim, K.; Benneche, T. In Advances in Heterocyclic Chemistry; Gilchrist, T. L.
, Gribble, G. W., Eds.; Pergamon: Oxford, 1999; vol. 11, p 21; (b) Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Per-
gamon: Oxford, 1996; (c) Conchon, E.; Anizon, F.; Aboba, B.; Prudhomme, M. J.
Med. Chem. 2007, 50, 4669; (d) Kiriazis, A.; Buffer, T.; Jantti, S.; Lang, H.; Yli-
Kauhaluama, J. J. Comb. Chem. 2007, 9, 263; (e) Ife, R. J.; Brown, T. H.; Blurton, P.;
Keeling, D. J.; Leach, C. A.; Meeson, M. L.; Parsons, M. E.; Theobald, J. J. Med. Chem.
1995, 38, 2763.
2. (a) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382; (b) Branowska,
D.; Rykowski, A.; Wysocki, W. Tetrahedron Lett. 2005, 46, 6223; (c) Landreau, C.;
Deniaud, D.; Meslin, J. C. J. Org. Chem. 2003, 68, 4912; (d) Acharya, A. N.; Ostresh,
J. M.; Houghten, R. A. J. Comb. Chem. 2002, 4, 214.
3. (a) Encyclopedia of Supramolecular Chemistry; Atwood, J. L., Steed, J. W., Eds.; Marcel
Dekker: NewYork, NY, 2004; (b) Steed, J. W.;Atwood, J. L. SupramolecularChemistry;
John Wiley&Sons: New York, NY, 2000; (c) Lehn, J.-M. Supramolecular Chemistry:
Concepts and Prospectives; VCH: Weinheim,1995; (d) Steel, P. J. Acc. Chem. Res. 2005,
38, 243; (e) Heterocyclic Supramolecules I, Topics in Heterocyclic Chemistry; Matsu-
moto, K., Ed.; Springer: Berlin, Heidelberg, 2008; Vol. 17.
4. (a) Xiang, J.; Zheng, L.; Chen, F.; Dang, Q.; Bai, X. Org. Lett. 2007, 9, 765 and
references cited therein; (b) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev.
1996, 96, 195; (c) Denmark, S. E.; Thorarenson, A. Chem. Rev. 1996, 96, 137.
4.3.5. 3-N-(4-Aminophenyl)-2-isopropylaminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (8c)
Eluted with CH2Cl2. Yield 52%; mp 266–267 ꢁC (dec); IR (KBr)
n
¼3408, 3363 (N–H), 1682 (C]O), 1611, 1542, 1517, 1343. 1H NMR
(500 MHz, CDCl3)
d
¼1.17 (d, J¼6.5 Hz, 6H, CH3), 4.02 (s, 2H, NH2,
NH, exchangeable with D2O), 4.32 (d, J¼8.1 Hz, 1H, NH, exchange-
able with D2O), 4.48–4.62 (m, 1H, CH), 6.80–6.88 (m, 2H, H–Ar),
7.02–7.10 (m, 2H, H–Ar), 8.65 (d, J¼2.3 Hz, 2H, H-7), 8.81 (d,
J¼2.3 Hz, 2H, H-8) ppm. 13C NMR (125 MHz, CDCl3)
¼22.8, 43.9,
d
115.2, 116.6, 123.5, 129.4, 142.2, 143.7, 144.3, 148.2, 150.2, 153.5,
158.7, 159.3 ppm. MS (FAB) m/z 353 [(MH)þ, 70]. Anal. Calcd for
C17H16N6OS: C, 57.94; H, 4.58; N, 23.85; S, 9.10. Found: C, 57.74; H,
4.79; N, 23.70; S, 8.91.

G. Blanco et al. / Tetrahedron 64 (2008) 11136–11143
11143
5. For some relevant recent examples, see: (a) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong,
T.; Liu, Q. Angew. Chem., Int. Ed. 2007, 46, 1726; (b) Chapman, C. J.; Frost, C. G.
Synthesis 2007, 1 and references cited therein; (c) Elliot, G. I.; Velcicky, J.; Ishi-
kawa, H.; Li, Y.; Boger, D. L. Angew. Chem., Int. Ed. 2006, 45, 620 For previous
examples of aza-Wittig reactions in domino or cascade processes, see: (d) Pal-
acios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J. M. Tetrahedron
2007, 63, 523 and references cited therein; (e) Eguchi, S. Arkivoc 2005, 98; (f)
Fresneda, P. M.; Molina, P. Synlett 2004, 1.
Wamhoff, H.; Soha´r, P. J. Organomet. Chem. 2001, 634, 122; (e) Jin, J.; Weinrd, S. M.
J. Am. Chem. Soc. 1997, 119, 5773; (f) Noguchi, M.; Okada, H.; Watenabe, M.;
Okuda, K.; Nakamura, O. Tetrahedron 1996, 52, 6581; (g) Saito, T.; Tsuda, K.
Tetrahedron Lett. 1996, 37, 9071; (h) Nitta, M.; Iino, Y.; Kamata, K. J. Chem. Soc.,
Perkin Trans. 1 1994, 2721; (i) Blanco, G.; Quintela, J. M.; Peinador, C. Tetrahedron
2007, 63, 2034; (j) Quintela, J. M.; Alvarez-Sarande´s, R.; Peinador, C. Tetrahedron
1998, 54, 8107.
7. Blanco, G.; Quintela, J. M.; Peinador, C. Tetrahedron 2008, 64, 1333 and references
´
6. See, for example: (a) Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999,
64, 2540; (b) Okawa, T.; Eguchi, S. Synlett 1994, 555; (c) Ding, M.-W.; Xu, S.-Z.;
Zhao, J.-F. J. Org. Chem. 2004, 69, 8366; (d) Tu´ ro´s, G.; Csa´mpai, A.; Czugler, M.;
cited therein.
8. Blanco, G.; Seguı´, N.; Quintela, J. M.; Peinador, C.; Chas, M.; Toba, R. Tetrahedron
2006, 62, 11124.