Application of the aza-Wittig reaction to the synthesis of pyrazinothienotriazolopyrimidinones: a new tetracyclic ring system

Article abstract of DOI:10.1016/j.tet.2007.11.059

A simple one-pot and efficient method is described for the synthesis of pyrazinothienopyrimidines 6 by domino processes involving aza-Wittig/intermolecular nucleophilic addition/intramolecular cyclization. A tandem aza-Wittig reaction of phosphazenes 7, derived from 6, with heterocumulenes (isocyanates, carbon disulfide or carbon dioxide) generates the pyrazinothienotriazolopyrimidinones 9, 11 and 12, respectively. Pyrazino[2′,3′:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H)-ones 15 and bis(pyrazinothienotriazolopyrimidinones) 17 were synthesized by the intermolecular aza-Wittig reaction of phosphazenes 7 with acyl chlorides or α,ω-dichlorides followed by heterocyclization via imidoyl chloride intermediate 16. Further S-alkylation of 11 and reaction of 6 with phosgeniminium chloride produce 2-alkylthio- and 2-N,N-dimethylaminopyrazinothienotriazolopyrimidinones 13 and 19, respectively.

Full text of DOI:10.1016/j.tet.2007.11.059

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1333e1344
www.elsevier.com/locate/tet
Application of the aza-Wittig reaction to the synthesis
of pyrazinothienotriazolopyrimidinones: a new
tetracyclic ring system
*
Gerardo Blanco, Jose M. Quintela , Carlos Peinador
*
´
Departamento de Qu´ımica Fundamental, Facultad de Ciencias, Universidad de A Coru~na, 15071 A Coru~na, Spain
Received 17 October 2007; received in revised form 5 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
A simple one-pot and efficient method is described for the synthesis of pyrazinothienopyrimidines 6 by domino processes involving aza-
Wittig/intermolecular nucleophilic addition/intramolecular cyclization. A tandem aza-Wittig reaction of phosphazenes 7, derived from 6,
with heterocumulenes (isocyanates, carbon disulfide or carbon dioxide) generates the pyrazinothienotriazolopyrimidinones 9, 11 and 12, respec-
tively. Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones 15 and bis(pyrazinothienotriazolopyrimidinones) 17 were
synthesized by the intermolecular aza-Wittig reaction of phosphazenes 7 with acyl chlorides or a,u-dichlorides followed by heterocyclization
via imidoyl chloride intermediate 16. Further S-alkylation of 11 and reaction of 6 with phosgeniminium chloride produce 2-alkylthio- and
2-N,N-dimethylaminopyrazinothienotriazolopyrimidinones 13 and 19, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
remarkable biological activities.5 We have previously reported
on the synthesis of novel tri- and tetracyclic ring systems, con-
taining the thienopyrimidine skeleton, with anti-inflammatory
and anti-histaminic activity.6 Among the diazines, the pyrazine
ring system is found in marine metabolites which exhibit mild
cytotoxicity against certain human cancer cells,7 and it is also
present in other biologically natural products.8 Besides,
substituted pyrazine motifs are often to be found in com-
pounds with applications as anti-cancer agents, including cur-
rently marketed drugs9 and those recently reported.10 On the
other hand, a large number of compounds containing the
1,2,4-triazole nucleus are responsible for a variety of biologi-
cal responses, including applications as anti-tumour and anti-
inflammatory agents.11 The introduction of a triazole and
pyrazine moieties to the thienopyrimidine system is expected
to influence the biological activities significantly. Although
there are a few examples of pyrazinothienopyrimidine scaf-
folds, no reports exist describing the synthesis of pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidines.
The aza-Wittig reaction has become one of the most
important synthetic method for constructing novel C]N,
N]N and S]N double bonds, especially in the preparation
The large number of biologically active molecules that con-
tain heterocyclic rings has made synthetic studies of new het-
erocyclic rings very attractive,1 stimulated by recent reports
that showed anti-tumour activity in a wide range of polyhetero-
cyclic compounds isolated from marine organisms.2 In this
context, nitrogen- and sulfur-containing rings are among the
most useful heterocycles and their utility has been widely
demonstrated, as a consequence of their exciting biological
properties and their role as pharmacophores of considerable
historical importance.3
Pyrimidine moiety has been widely employed in the design
of biologically active agents, and compounds containing
a fused pyrimidine have attracted attention in the past few
years owing to their wide range of biological activity, particu-
larly in cancer and virus research.4 Among its fused bicyclic,
the thienopyrimidines are of great importance because of their
* Corresponding authors.
E-mail address: capeveqo@udc.es (C. Peinador).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.059

1334
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
of nitrogen-containing heterocyclic compounds. Phospha-
zenes, nitrogen analogues of phosphorus ylides, are versatile
intermediates in modern synthetic chemistry.12 Moreover,
phosphazenes have proved to be useful building blocks for
the synthesis of functionalized imine compounds, and numer-
ous research papers and several reviews have appeared de-
scribing the general use of phosphazenes as reagents and
intermediates in organic synthesis,13 including the synthesis
of heterocyclic natural products by the aza-Wittig method.14
Recently, we have reported the synthesis of fused pyrimidines
based on the tandem aza-Wittig heterocumulene-mediated
annulation strategy.15 As a part of our continuing investiga-
tions on the aza-Wittig reaction and with the aim of designing
new polyheterocyclic systems with potential biological inter-
est, this paper reports a general method for the preparation
of derivatives of the unknown ring system pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine, which contains
the thienopyrimidine, pyrazine and 1,2,4-triazole subunits.
amino-donor nucleophile in the final step. The second way
(route B) is based on the reaction of pyrazinothienopyrimi-
dines 6 with phosgeniminium chloride.
The synthesis of pyrazothienopyrimidinones 6 and phos-
phazenes 7 from easily accessible ethyl 3-aminothieno[2,3-b]-
pyrazine-2-carboxylate 2 is summarized in Scheme 2.
Beginning with 2-chloro-3-cyanopyrazine 1, obtained follow-
ing the Johnston procedure starting from 3-cyanopyrazine,16
treatment with ethyl mercaptoacetate afforded enaminoester
2 in 98% yield. The phosphazene 3, readily prepared by the
reaction of 2 with hexachloroethaneetriphenylphosphinee
triethylamine,17 can be used as synthetic intermediate of
new substituted pyrazinothienopyrimidines 6aee by domino
processes involving aza-Wittig/intermolecular nucleophilic
addition/intramolecular cyclization.
PPh3
O
N
NH2
N
N
N
CN
Cl
N
N
O
iii
ii
i
S
S
OEt
OEt
N
3
2
1
2. Results and discussion
NHAr
NAr
C
N
S
N
NHNH2
O
The strategy used for the development of these compounds
was focused as shown in Scheme 1. The pyrazinothienopyr-
imidinones 6 appear to serve as a good building blocks for
these heterocycles. They can be synthesized from the readily
available heterocyclic b-enamino ester 2. We tried the pre-
paration of the tetracyclic fused skeletons type I and II and
bis(triazolothienotriazolopyrimidines) type III by two differ-
ent ways. The first one (route A) involves an aza-Wittig-type
reaction of phosphazenes 7, derived from pyrazinothienopyr-
imidines 6, with heterocumulenes (carbon dioxide, carbon di-
sulfide or isocyanates) or aroyl or alkanoyl chlorides to give
a 1,3,5-hexatriene or imidoyl chloride intermediate, which af-
ter subsequent intramolecular heterocyclization, generated the
functionalized 1,2,4-triazole ring with the corresponding
N
N
O
N
N
OEt
S
OEt
4
5
NHAr
NHAr
NH2
N
N
S
N
N
PPh3
N
N
N
N
N
iv
O
O
S
6a, 7a: Ar = Ph
6b, 7b: Ar = 4-CH3C6H4
6c, 7c: Ar = 4-NO2C4H4
6a-c
7a-c
Scheme 2. Synthesis of pyrazinothienopyrimidinones 6 and phosphazenes 7.
Reagents and conditions: (i) HSCH2CO2Et, Na2CO3, EtOH, reflux, 4 h; (ii)
C2Cl6, (C6H5)3P, NEt3, THF, sealed tube; (iii) (a) ArNCO, THF, room temper-
ature, 3 h; (b) NH2NH2; (iv) C2Cl6, (C6H5)3P, NEt3, toluene, 100 ꢁC, sealed
tube.
Ar
N
NHAr
X
N
PPh3
N
N
N
N
N
N
N
N
N
Pyrimido-annulation occurs via a heterocumulene moiety,
available from the reaction of the phosphazene 3 and an aro-
matic isocyanate, which, in turn, was conveniently converted,
by a one-pot procedure, into the corresponding fused hetero-
cycle 6, via initial nucleophilic addition of hydrazine to the
carbodiimide cumulenic system 4 to give the guanidine
intermediate 5 followed by intramolecular hetero conjugate
addition annulation (Scheme 2). The regioselectivity of the
reaction can be rationalized in terms that the (triphenylphos-
phoranylidene)amino derivative 5 cyclizes to give 6 across
the strong nucleophilic hydrazine group rather than the aryl-
amine one.18 The participation of carbodiimides 4 and (triphe-
nylphosphoranylidene)amino intermediates 5 in process of this
class has been confirmed experimentally.15
O
S
7
O
S
(X = NHAr, NR2, Ar,R)
I
Ar
route
X
N
NHAr
NH2
A or B
N
N
NH
N
N
N
N
N
N
O
S
O
S
6
(X = O,S)
II
Ar
N
Ar
N
N
N
S
N
O
N
O
NH2
CO2Et
N
N
N
N
linker
N
N
S
N
N
S
III
Structural elucidation of compounds 6 was accomplished
from the analytical and spectral data. The mass spectra showed
the expected molecular ion peaks and the IR spectra showed
a strong bands at n¼3344e3129 cmꢀ1, attributed to the NH
2
(linker: phenylene diamino, aryl, hetaryl)
Scheme 1. Retrosynthetic pathhway for the synthesis of pyrazinothienopyrimi-
dines I, II and III.

G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
1335
and NH2 groups, and a C]O absorption at 1682e1665 cmꢀ1
,
to react with carbon dioxide in THF. The significantly low
yield of the reaction might be due to the low solubility of
carbon dioxide in the organic solvent. The optimized results
are summarized in Table 2. S-alkylation of 11 with alkylating
reagents, such as iodomethane, benzyl chloride or chloroace-
tonitrile, in the presence of potassium carbonate, gave the
alkylthioderivatives 13aei in good yields (74e97%) (Scheme
3, Table 3).
In Scheme 3, the reaction pattern for compounds 7aec and
aromatic isocyanates, carbon dioxide and carbon disulfide is
reported, while in Tables 1e3 a complete set of reaction prod-
ucts 9aei, 11aec, 12aec and 13aei are reported. Considering
these final reported results, the first step in each reaction
sequence was the aza-Wittig-type reaction between the imino-
phosphorane 7 with the heterocumulene (aromatic isocyanate,
carbon disulfide or carbon dioxide) to provide triphenylphos-
phine oxide and a 1-azadiene cumulenic moiety, as a highly
reactive intermediate, and these reactive cumulenic systems
were cyclized to give the 1,2,4-triazole ring with the corre-
sponding amino-donor nucleophile in the final step.
while in the 1H NMR spectra, theNH and NH2 protons are found,
as a singlets, at d¼10.29e8.79 and d¼5.99e4.82, respectively,
in addition to the set of signals due to the H-7 and H-8 protons
of the pyrazine ring. The most salient features of the 1H NMR
and 13C NMR spectra are summarized under Section 4.
Due to the apparent feasibility of this reaction, and the good
yields of tricyclic compounds 6aec, we decided to extend the
heterocyclization in order to obtain new tetracyclic structures.
Compounds 6aec were converted into novel functionalized
heteroaryl phosphazenes 7aec upon reaction with triphenyl-
phosphineehexachloroethane and triethylamine. These phos-
phazenes 7, precursors of the target molecules 9, 11e15 and
17, were isolated as stable solid compounds in good yields
(75e83%).
As reported in Scheme 3, cyclization occurred when phos-
phazenes 7 react with heterocumulenes, such as isocyanates,
carbon disulfide or carbon dioxide, yielding the interesting
fused rings systems 9, 11 and 12. The phosphazenes 7aec
were first reacted with aromatic isocyanates, in THF at room
temperature, affording in few hours the cyclized products
9aei which were isolated and purified on a silica gel column
with CH2Cl2/AcOEt as eluent. On the basis of these results we
investigated the reactivity of iminophosphoranes 7aec to-
wards other heterocumulenes, as carbon dioxide or carbon
disulfide. Heating phosphazenes 7 in sealed tube at 100 ꢁC
with carbon disulfide in THF gave rise to the fused tetracyclic
ring compounds 11aec in good yields. On the other hand,
1,3-dihydro-3-arylpyrazino[20,30:4,5]thieno[3,2-d]-1,2-4-tri-
azolo[1,5-a]pyrimidin-3,10-dione compounds 12aec were ob-
tained in moderate yields when phosphazenes 7 were allowed
Table 1
Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones
9aei
Compd
Ar1
Ar2
Yield (%)
Mp (ꢁC)
9a
9b
9c
9d
9e
9f
C6H5
C6H5
C6H5
83
95
99
82
88
99
77
72
91
>300
>300
4-CH3-C6H4
4-NO2-C6H4
C6H5
C6H5
>300 (dec)
>300
>300
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-CH3-C6H4
4-NO2-C6H4
C6H5
>300 (dec)
>300
>300
9g
9h
9i
4-CH3-C6H4
4-NO2-C6H4
>300 (dec)
NHAr1
NHAr1
X
N
PPh3
N
C
ii
Table 2
Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones
11aec and 12aec
N
N
N
N
N
N
N
N
O
O
S
S
Compd
Ar1
X
Yield (%)
Mp (ꢁC)
7a-c
10a-c
11a
11b
11c
12a
12b
12c
C6H5
S
97
87
72
55
53
42
287e289
>300 (dec)
>300
i
4-CH3-C6H4
4-NO2-C6H4
C6H5
S
Ar1
N
S
X
NHAr1
O
O
O
>300
>300 (dec)
>300 (dec)
NHAr2
N
NH
N
S
C
4-CH3-C6H4
4-NO2-C6H4
N
N
N
N
N
N
N
O
S
O
11a-c: X = S
8
12a-c: X = O
Table 3
Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones
13aei
iii
Ar1
N
Ar1
N
Ar1
R
Yield (%)
Mp (ꢁC)
NHAr2
Compd
SR
N
N
13a
13b
13c
13d
13e
13f
13g
13h
13i
C6H5
C6H5
CH3
93
97
89
82
89
84
81
74
90
>300 (dec)
295e297
>300
N
N
N
O
N
N
N
N
CH2C6H5
CH2CN
CH3
C6H5
S
O
S
N
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
>300
9a-i
13a-i
CH2C6H5
CH2CN
CH3
239e240
>300
>300
Scheme 3. Synthesis of pyrazinothienotriazolopyrimidinones 9aei, 11aec,
12aec and 13aei. Reagents and conditions: (i) Ar2NCO, THF, room temper-
ature, 3e4 h; (ii) CX2, THF, 100 ꢁC, 3 h (CS2), 8 h (CO2); (iii) RX, CH3CN,
K2CO3, 60 ꢁC, 0.5e2 h.
CH2C6H5
CH2CN
277e279
>300

1336
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
NHAr
The next step of this study was the preparation of pyrazi-
no[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-
ones 15aef by an initial aza-Wittig reaction between the
phosphazenes 7 and alkanoyl or aroyl chlorides and subse-
quent intramolecular heterocyclization (Scheme 4, Table 4),
revealing the preferential reactivity of the iminophosphorane
group of compounds 7, compared to the amino moiety, to-
wards electrophilic reagents.12c Chloroimidoyl derivatives 14
are assumed to be the key intermediates in the consecutive re-
actions even though 14 could not be detected due to its high
reactivity, and these reactive intermediates were cyclized to
give the 1,2,4-triazole ring with the corresponding amino-
donor nucleophile to afford tetracyclic compounds 15 through
elimination of hydrogen chloride.
N
PPh3
+
Y
linker
Y
N
N
N
N
16a-c: Y = COCl
O
S
16d,e: Y = N=C=O
7
Ar
N
N
Ar
N
N
O
N
N
N
N
linker
N
N
N
S
S
N
O
17a-f
Scheme 5. Synthesis of bis(pyrazinothienotriazolopyrimidines) 17aef.
Ar1HN
N
NHAr1
R
Table 5
Bis(pyrazinothienotriazolopyrimidines) 17aef
N
PPh3
N
N
Cl
N
N
N
N
N
N
i
Compd
Ar
Linker
Yield (%)
Mp (ꢁC)
O
O
S
S
17a
17b
17c
17d
17e
17f
C6H5
C6H5
1,4-C6H4
1,3-C6H4
2,6-C6H3N
62
67
71
67
55
50
>300
>300
>300
14
7a-c
Ar1
N
C6H5
C6H5
R
1,4-C6H4(NH)2
1,4-C6H4(NH)2
1,3-C6H4(NH)2
250 (dec)
250 (dec)
260 (dec)
4-CH3C6H4
C6H5
N
N
N
N
N
O
S
employing phosgeniminium chloride as starting material.
N,N-Dichloromethylenedimethylammonium salts, particularly
N,N-dichloromethylenedimethylammonium chloride (Viehe’s
salt) are stable but reactive building blocks for heterocyclic
synthesis.19 We had previously used this transformation in
the preparation of fused biologically active heterocyclic ring
systems, including natural products.20 In the presented syn-
thetic approach an useful general method for the formation
of pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
4(3H)-ones 19 has been derived. On treatment with N,N-dime-
thylmethyleneiminium chloride in refluxing 1,2-dichloroethane
6aec gave directly 19 in moderate to good yields (Scheme
6, Table 6). The conversion of 6 into 19 involves an initial
nucleophilic chlorine substitution to give the chloroamidine
18, as highly reactive intermediate, which easily undergoes
ring closure across the arylamino group to the fused triazole
ring.
15a-f
Scheme 4. Synthesis of pyridothieno-1,2,4-triazolopyrimidinones 15aef.
Reagents and conditions: (i) RCOCl, THF, NEt3, room temperature, 3e8 h.
Table 4
Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones
15aef
Compd
Ar1
R
Yield (%)
Mp (ꢁC)
15a
15b
15c
15d
15e
15f
C6H5
C6H5
CH3
60
72
70
91
71
92
220 (dec)
>300
>300
C6H5
CH3
4-CH3-C6H4
4-CH3-C6H4
4-NO2-C6H4
4-NO2-C6H4
C6H5
CH3
>300
>300
>300
C6H5
We next considered the possibility to extend this design
strategy to the preparation of bis(pyrazinothienotriazolopyrimi-
dines) 17. Thus, we reacted phospazene 7 with a,u-dichlorides,
as isophthaloyl chloride, terephtaloyl chloride and 2,6-pyridi-
nedicarbonyl dichloride, or diisocyanates, as 1,3- and 1,4-phe-
nylene diisocyanate, under similar reaction conditions to those
shown in Schemes 3 and 4, which cleaning furnished the
new bis(tetraheterocyclic) compounds 17aef (Scheme 5,
Table 5). In compounds 17, two pyrazinothienotriazolopyrimi-
dine skeletons are linked via their respective C-20 carbon atoms
by a 1,3-phenylene, 1,4-phenylene, 2,6-pyridine, 1,3-phenyl-
ene diamino or 1,4-phenylene diamino chain. Isolated yields
of these interesting heterocycles ranged from moderate to
good (50e71%). Once again all new compounds showed spec-
troscopic and characterization data in accord with the proposed
structures.
ArNH
NMe2
Cl
NHAr
NH2
N
N
N
N
N
N
N
N
N
i
O
S
O
S
18
6a-c
Ar
N
NMe2
N
N
N
N
O
S
N
19a-c
Finally, it seemed possible that the 1,2,4-triazolo ring could
be alternatively derived by an efficient one-pot process
Scheme 6. Synthesis of pyridothieno-1,2,4-triazinepyrimidones 19aec.
Reagents and conditions: (i) Cl2C]NMe2Cl, CH2Cl2, reflux, 1 h.

G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
1337
Table 6
Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H )-ones
19aec
4. Experimental section
4.1. General
Compd
Ar
Yield (%)
Mp (ꢁC)
19a
19b
19c
C6H5
4-CH3-C6H4
4-NO2-C6H4
87
71
60
>300
>300
>300
All reagents used were commercial grade chemicals from
freshly opened containers. Merk 60 HF254þ366 foils were
used for thin layer chromatography and Merk 60 (230e400
mesh) silica gel for flash chromatography. NMR spectra
were obtained in a Bruker Avance 500 equipped with a dual
Compounds 9, 11e13, 15, 17 and 19 were unambiguously
characterized from their spectroscopic data, mass spectromet-
ric data and elemental analyses (see Section 4). For example,
the mass spectrum of 9e shows the molecular ion peak at
m/z¼440 with 100% abundance. The IR spectrum reveals
NeH and C]O absorption bands at 3263 cmꢀ1 and
1
cryoprobe for H and 13C and a Bruker Avance 300 spectro-
meters. TMS was used as an internal reference. IR spectra
were recorded as potassium bromide disks. Mass spectrometry
experiments were carried out in a Fision VG-Quattro spec-
trometer. Melting points were measured using Stuart Scientific
SMP3 apparatus and are uncorrected. Microanalyses were
performed by the elemental analyses general service of the
1688 cmꢀ1, respectively. The H NMR spectrum of 9e shows
1
two singlets at d¼2.29 and 2.49 due to the CH3 groups, while
the NH proton resonates as a singlet at d¼9.05 ppm. The sig-
nals attributable to the H-6 and H-7 aromatic protons of the
pyrazine ring are found at d¼8.82 and 8.86 as doublets. The
13C NMR spectroscopic data for 9e show the signals of
C]O and the two CH3 at d¼157.0 ppm and 20.9 ppm and
21.5 ppm, respectively. The structure of 9i was independently
confirmed by X-ray crystal structure analysis (Fig. 1).
~
University of A Coruna.
4.2. Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate 2
To a solution of 2-chloro-3-cyanopyrazine 116 (5.00 g,
35.80 mmol) in EtOH (100 mL) were added Na2CO3
(4.24 g, 40 mmol) and ethyl thioglycolate (5.33 g, 40 mmol)
and the resultant reaction mixture was stirred at reflux temper-
ature for 4 h and poured into water (200 mL). The precipitated
product was filtered by suction, washed with water and puri-
fied by flash chromatography using CH2Cl2/AcOEt (90:10;
v/v) as eluent to give 2 (7.05 g, 90%); mp 120e121 ꢁC
(lit.15b 120e121 ꢁC).
4.3. 3-Amino-2-arylaminopyrazino[20,30:4,5]thieno-
[3,2-d]pyrimidin-4(3H )-one 6
To a solution of phosphazene 415b (3 g, 6.2 mmol) in dry
THF (60 mL) was added the appropriate isocyanate
(7.45 mmol) and the mixture was stirred at room temperature
under Ar for 3e4 h. Then, the solvent was removed under re-
duced pressure and Et2O (60 mL) was added to the precipitate
triphenylphosphine oxide. The reaction mixture was filtered
and the solvent removed. To the solution of residue prepared
above in ethanol (60 mL) was added hydrazine hydrate
(0.28 g, 7.45 mmol, 85%). The mixture was stirred for
30 min at room temperature and the resulted solid was isolated
by filtration and purified by column chromatography on silica
gel eluting with a hexaneseAcOEt gradient from 50% to
100% ethyl acetate to give 6 as a yellow solid.
Figure 1. Crystal structure of compound 9i. Solvent molecules have been omit-
ted for clarity.
3. Conclusions
In conclusion, a method based on a tandem aza-Wittig re-
action of phosphazenes 7 with heterocumulenes, as isocya-
nates, carbon disulfide and carbon dioxide, or acyl chlorides
that allows the formation of tetracyclic fused ring systems
with the biologically important pyrazine, thienopyrimidine
and 1,2,4-triazole moieties is reported. These results indicate
the importance and utility of these phosphazenes as versatile
building blocks in the preparation of complex polycyclic com-
pounds. The method utilizes easily accessible starting mate-
rials and allows mild reaction conditions, straightforward
product isolation and good yields.
4.3.1. 3-Amino-2-phenylaminopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H )-one (6a)
Yield 99%; mp: 243e245 ꢁC. IR (KBr) 3344, 3302, 3270,
3184 (NH), 1673 (C]O), 1594, 1548, 1524 cmꢀ1. H NMR
1
(CDCl3, 300 MHz) d: 4.82 (s, 2H, NH2), 7.10e7.20 (m, 1H,
ArH), 7.40e7.50 (m, 2H, ArH), 7.82e7.88 (m, 2H, ArH),
8.68 (d, 1H, J¼2.3 Hz, H-7), 8.79 (s, 1H, NH2), 8.84 (d, 1H,
J¼2.3 Hz, H-8). 13C NMR (DMSO-d6, 125 Hz) d: 114.4,
121.6, 124.0, 129.1, 138.8, 143.6, 143.9, 144.9, 148.6, 152.3,
157.4, 158.2. MS (EI) m/z 310 (Mþ, 20). Anal. Calcd for

1338
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
C14H10N6OS: C, 54.18; H, 3.25; N, 27.08; S, 10.33. Found: C,
54.10; H, 3.34; N, 26.93; S, 10.15.
4.4.2. 2-(4-Methylphenyl)amino-3-(triphenylphosphoranyl-
ideneamino)pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4(3H )-one (7b)
Yield 75%; mp: 275 ꢁC (dec). IR (KBr) 3234 (NH), 1665
4.3.2. 3-Amino-2-(4-methylphenyl)aminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H )-one (6b)
Yield 64%; mp: 255e256 ꢁC. IR (KBr) 3342, 3299, 3272,
(C]O), 1589, 1546, 1498 cmꢀ1
.
1H NMR (CDCl3,
300 MHz) d: 2.36 (s, 3H, CH3), 7.18e7.25 (m, 2H, ArH),
7.43e7.57 (m, 9H, ArH), 7.68e7.74 (m, 2H, ArH), 7.76e
7.89 (m, 6H, ArH), 8.56 (d, 1H, J¼2.3 Hz, H-7), 8.76 (d,
1H, J¼2.3 Hz, H-8), 9.65 (s, 1H, NH). 13C NMR (CDCl3,
75 Hz) d: 20.9, 119.7, 128.6, 128.7, 129.7, 130.3, 131.6,
131.8, 131.8, 132.3, 132.4, 132.7, 136.0, 141.8, 142.8, 144.4,
145.5, 150.8, 150.9, 157.5, 158.0. 31P NMR (CDCl3,
121.5 MHz) d: 22.8. MS (FAB) m/z 585 [(MH)þ, 100].
Anal. Calcd for C33H25N6OPS: C, 67.80; H, 4.31; N, 14.37;
S, 5.48. Found: C, 67.74; H, 4.25; N, 14.17; S, 5.43.
1
3129 (NH), 1665 (C]O), 1592, 1553, 1523, 1478 cmꢀ1. H
NMR (CDCl3, 300 MHz) d: 2.29 (s, 3H, CH3), 5.87 (s, 2H,
NH2), 7.17e7.20 (m, 2H, ArH), 7.79e7.82 (m, 2H, ArH),
8.80 (d, 1H, J¼2.3 Hz, H-7), 8.91 (d, 1H, J¼2.3 Hz, H-8),
9.52 (s, 1H, NH). 13C NMR (CDCl3, 75 Hz) d: 20.4, 113.4,
121.1, 128.9, 132.4, 135.6, 142.9, 143.3, 144.2, 148.1, 151.8,
156.8, 157.6. MS (FAB) m/z 325 [(MH)þ, 100]. Anal. Calcd
for C15H12N6OS: C, 55.54; H, 3.73; N, 25.91; S, 9.89. Found:
C, 55.56; H, 3.64; N, 25.77; S, 9.95.
4.4.3. 2-(4-Nitrophenyl)amino-3-(triphenylphosphoranyl-
ideneamino)pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4(3H )-one (7c)
4.3.3. 3-Amino-2-(4-nitrophenyl)aminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H )-one (6c)
Yield 73%; mp: 260 ꢁC (dec). IR (KBr) 3286, 3485 (NH),
Yield 77%; mp: >300 ꢁC. IR (KBr) 3221 (NH), 1652
1682 (C]O), 1561, 1542, 1510, 1485 cmꢀ1 1H NMR
.
(C]O), 1540, 1507, 1486 cmꢀ1
.
1H NMR (CDCl3,
(DMSO-d6, 500 MHz) d: 5.99 (s, 2H, NH2), 8.28e8.32 (m,
2H, ArH), 8.36e8.41 (m, 2H, ArH), 8.88 (d, 1H, J¼2.3 Hz,
H-7), 9.00 (d, 1H, J¼2.3 Hz, H-8), 10.29 (s, 1H, NH). 13C
NMR (DMSO-d6, 125 Hz) d: 116.2, 120.7, 125.1, 142.5, 143.7,
143.8, 145.1, 145.3, 147.9, 151.6, 157.3, 158.1. MS (FAB)
m/z 356 [(MH)þ, 40]. Anal. Calcd for C14H9N7O3S: C,
47.32; H, 2.55; N, 27.59; S, 9.02. Found: C, 47.14; H, 2.44;
N, 27.43; S, 9.15.
300 MHz) d: 7.45e7.60 (m, 9H, HAr), 7.76e7.87 (m, 6H,
HAr), 7.98e8.16 (m, 2H, ArH), 8.29e8.35 (m, 2H, ArH),
8.62 (d, 1H, J¼2.3 Hz, H-7), 8.81 (d, 1H, J¼2.3 Hz, H-8),
10.27 (s, 1H, NH). 13C NMR (CDCl3, 75 Hz) d: 118.5,
125.4, 128.7, 128.9, 130.1, 131.4, 132.0, 132.1, 132.2, 132.4,
142.1, 142.5, 143.2, 144.0, 144.4, 144.7, 158.0. 31P NMR
(CDCl3, 121.5 MHz) d: 23.4. MS (FAB) m/z 616 [(MH)þ,
70]. Anal. Calcd for C32H22N7O3PS: C, 62.43; H, 3.60;
N, 15.93; S, 5.21. Found: C, 62.25; H, 3.56; N, 15.74; S,
5.18.
4.4. 2-Arylamino-3-(triphenylphosphoranylideneamino)-
pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H )-one 7
4.5. 3-Aryl-2-arylaminopyrazino[20,30:4,5]thieno[3,2-d]-
1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one 9a. General
procedure
To
a mixture of 6 (3.2 mmol), triphenylphosphine
(4.8 mmol) and hexachloroethane (3.2 mmol) in dry toluene
(30 mL), triethylamine (16.50 mmol) was added dropwise.
The reaction mixture was heated at 100 ꢁC in a sealed tube
for 48 h. Then, the solvent was removed under reduced pres-
sure and the residue was purified by column chromatography
using a CH2Cl2eAcOEt gradient from 0% to 10% ethyl ace-
tate to give 7 as a yellow solid.
To a solution of phosphazene 7 (0.09 mmol) in dry THF
(5 mL) was added the appropriate isocyanate (0.1 mmol).
The mixture was stirred at room temperature under Ar for
3e4 h until the phosphazene had disappeared (TLC moni-
tored). Then, the precipitate obtained was isolated by filtration,
washed with THF (2 mL) and subjected to chromatography on
silica gel eluting with a CH2Cl2eAcOEt gradient from 0% to
10% ethyl acetate to give 9 as a yellow solid.
4.4.1. 2-Phenylamino-3-(triphenylphosphoranylidene-
amino)pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H )-
one (7a)
Yield 83%; mp: 285 ꢁC (dec). IR (KBr) 3257 (NH), 1660
(C]O), 1589, 1543, 1484 cmꢀ1
300 MHz) d: 7.06e7.14 (m, 1H, ArH), 7.37e7.58 (m, 11H,
ArH), 7.78e7.89 (m, 8H, ArH), 8.57 (d, 1H, J¼2.3 Hz,
H-7), 8.76 (d, 1H, J¼2.3 Hz, H-8), 9.77 (s, 1H, NH). 13C NMR
(CDCl3, 75 Hz) d: 119.5, 123.1, 128.6, 128.7, 129.2, 130.3,
131.6, 131.8, 131.9, 132.3, 132.4, 138.6, 141.9, 142.8, 144.4,
145.4, 150.6, 150.7, 158.0. 31P NMR (CDCl3, 121.5 MHz) d:
22.8. MS (EI) m/z 570 (Mþ, 55). Anal. Calcd for
C32H23N6OPS: C, 67.36; H, 4.06; N, 14.73; S, 5.62. Found:
C, 67.52; H, 3.91; N, 14.56; S, 5.62.
.
1H NMR (CDCl3,
4.5.1. 3-Phenyl-2-phenylaminopyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (9a)
Yield 83%; mp: >300 ꢁC. IR (KBr) 3458 (NH), 1684
(C]O), 1580, 1543, 1488 cmꢀ1
.
1H NMR (DMSO-d6,
300 MHz) d: 7.05e7.12 (m, 1H, ArH), 7.33e7.42 (m, 2H,
ArH), 7.67e7.79 (m, 7H, ArH), 8.82 (d, 1H, J¼2.3 Hz, H-
6), 8.85 (d, 1H, J¼2.3 Hz, H-7), 9.19 (s, 1H, NH). MS
(FAB) m/z 412 [(MH)þ, 95]. Anal. Calcd for C21H13N7OS:
C, 61.30; H, 3.18; N, 23.83; S, 7.79. Found: C, 60.98; H,
3.38; N, 23.94; S, 7.47.

G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
1339
4.5.2. 2-(4-Methylphenyl)amino-3-phenylpyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (9b)
7.62e7.66 (m, 2H, ArH), 7.98e8.03 (m, 2H, ArH),
8.30e8.35 (m, 2H, ArH), 8.85 (d, 1H, J¼2.3 Hz, H-6), 8.88
(d, 1H, J¼2.3 Hz, H-7), 9.95 (s, 1H, NH). MS (FAB) m/z
471 [(MH)þ, 10]. Anal. Calcd for C22H14N8O3S: C, 56.16;
H, 3.00; N, 23.82; S, 6.82. Found: C, 56.32; H, 3.09; N,
24.09; S, 6.64.
Yield 95%; mp: >300 ꢁC. IR (KBr) 3287 (NH), 1675
(C]O), 1575, 1524, 1511 cmꢀ1
.
1H NMR (DMSO-d6,
300 MHz) d: 2.27 (s, 3H, CH3), 7.12e7.19 (m, 2H, ArH),
7.55e7.62 (m, 2H, ArH), 7.65e7.78 (m, 5H, ArH), 8.81 (d,
1H, J¼2.3 Hz, H-6), 8.84 (d, 1H, J¼2.3 Hz, H-7), 9.08 (s,
1H, NH). MS (FAB) m/z 426 [(MH)þ, 100]. Anal. Calcd for
C22H15N7OS: C, 62.10; H, 3.55; N, 23.04; S, 7.54. Found:
C, 62.00; H, 3.48; N, 23.16; S, 7.53.
4.5.7. 3-(4-Nitrophenyl)-2-phenylaminopyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one (9g)
Yield 77%; mp: >300 ꢁC. IR (KBr) 3453 (NH), 1684
(C]O), 1580, 1529, 1492 cmꢀ1
.
1H NMR (DMSO-d6,
4.5.3. 2-(4-Nitrophenyl)amino-3-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one (9c)
Yield 99%; mp: >300 ꢁC (dec). IR (KBr) 3448 (NH), 1678
(C]O), 1568, 1507 cmꢀ1. 1H NMR (DMSO-d6, 300 MHz) d:
7.65e7.80 (m, 5H, ArH), 7.85e8.00 (m, 2H, ArH), 8.22e8.33
(m, 2H, ArH), 8.84 (d, 1H, J¼2.3 Hz, H-6), 8.87 (d, 1H, J¼
2.3 Hz, H-7), 9.98 (s, 1H, NH). MS (FAB) m/z 457 [(MH)þ,
60]. Anal. Calcd for C21H12N8O3S: C, 55.26; H, 2.65; N,
24.55; S, 7.03. Found: C, 55.38; H, 2.58; N, 24.74; S, 6.97.
500 MHz) d: 7.05e7.13 (m, 1H, ArH), 7.35e7.44 (m, 2H,
ArH), 7.65e7.73 (m, 2H, ArH), 8.06e8.14 (m, 2H, ArH),
8.55e8.62 (m, 2H, ArH), 8.83 (d, 1H, J¼2.3 Hz, H-6), 8.87 (d,
1H, J¼2.3 Hz, H-7), 9.33 (s, 1H, NH). MS (FAB) m/z 457
[(MH)þ, 100]. Anal. Calcd for C21H12N8O3S: C, 55.26; H,
2.65; N, 24.55; S, 7.03. Found: C, 55.21; H, 2.67; N, 24.50;
S, 7.15.
4.5.8. 2-(4-Methylphenyl)amino-3-(4-nitrophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (9h)
4.5.4. 2-(4-Methylphenyl)amino-3-phenylpyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (9d)
Yield 72%; mp: >300 ꢁC. IR (KBr) 3411 (NH), 1682
(C]O), 1582, 1519, 1491 cmꢀ1
.
1H NMR (DMSO-d6,
500 MHz) d: 2.28 (s, 3H, CH3), 7.17e7.23 (m, 2H, ArH),
7.55e7.60 (m, 2H, ArH), 8.06e8.11 (m, 2H, ArH),
8.52e8.61 (m, 2H, ArH), 8.83 (d, 1H, J¼2.3 Hz, H-6), 8.87
(d, 1H, J¼2.3 Hz, H-7), 9.22 (s, 1H, NH). 13C NMR
(DMSO-d6, 125 Hz) d: 20.9, 116.1, 120.2, 125.8, 129.8,
131.1, 132.7, 136.4, 136.8, 143.5, 143.8, 145.0, 148.2, 148.8,
149.1, 149.7, 152.0, 157.0. MS (FAB) m/z 471 [(MH)þ, 100].
Anal. Calcd for C22H14N8O3S: C, 56.16; H, 3.00; N, 23.82; S,
6.82. Found: C, 56.28; H, 2.90; N, 23.90; S, 6.69.
Yield 82%; mp: >300 ꢁC. IR (KBr) 3448 (NH), 1679
1
(C]O), 1581, 1563, 1514, 1488 cmꢀ1. H NMR (DMSO-d6,
500 MHz) d: 2.48 (s, 3H, CH3), 7.07e7.12 (m, 1H, ArH),
7.35e7.40 (m, 2H, ArH), 7.49e7.53 (m, 2H, ArH), 7.57e
7.61 (m, 2H, ArH), 7.67e7.71 (m, 2H, ArH), 8.83 (d, 1H,
J¼2.3 Hz, H-6), 8.85 (d, 1H, J¼2.3 Hz, H-7), 9.11 (s, 1H,
NH). MS (FAB) m/z 426 [(MH)þ, 50]. Anal. Calcd for
C22H15N7OS: C, 62.10; H, 3.55; N, 23.04; S, 7.54. Found:
C, 62.40; H, 3.65; N, 22.79; S, 7.46.
4.5.9. 3-(4-Nitrophenyl)-2-(4-nitrophenyl)aminopyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (9i)
4.5.5. 3-(4-Methylphenyl)-2-(4-methylphenyl)amino-
pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo-
[1,5-a]pyrimidin-10(3H )-one (9e)
Yield 91%; mp: >300 ꢁC (dec). IR (KBr) 3323 (NH), 1687
1
Yield 88%; mp: >300 ꢁC. IR (KBr) 3263 (NH), 1688
(C]O), 1616, 1571, 1524, 1490 cmꢀ1. H NMR (DMSO-d6,
(C]O), 1593, 1581, 1546, 1513, 1490 cmꢀ1
.
1H NMR
500 MHz) d: 7.89e7.95 (m, 2H, ArH), 8.09e8.14 (m, 2H,
ArH), 8.27e8.34 (m, 2H, ArH), 8.56e8.63 (m, 2H, ArH),
8.83 (d, 1H, J¼2.3 Hz, H-6), 8.87 (d, 1H, J¼2.3 Hz, H-7),
10.09 (s, 1H, NH). 13C NMR (DMSO-d6, 125 Hz) d: 116.2,
119.0, 125.7, 125.8, 130.9, 136.7, 143.6, 143.7, 145.2, 148.5,
148.8, 148.9, 152.0, 157.0. MS (FAB) m/z 502 [(MH)þ, 15].
Anal. Calcd for C21H11N9O5S: C, 50.30; H, 2.21; N, 25.14;
S, 6.39. Found: C, 50.18; H, 2.18; N, 25.23; S, 6.46.
(DMSO-d6, 500 MHz) d: 2.29 (s, 3H, CH3), 2.49 (s, 3H,
CH3), 7.17e7.22 (m, 2H, ArH), 7.50e7.55 (m, 2H, ArH),
7.60e7.65 (m, 4H, ArH), 8.82 (d, 1H, J¼2.3 Hz, H-6), 8.86
(d, 1H, J¼2.3 Hz, H-7), 9.05 (s, 1H, NH). 13C NMR
(DMSO-d6, 125 Hz) d: 20.9, 21.5, 115.6, 120.3, 128.5,
129.2, 129.7, 131.0, 132.6, 136.5, 140.7, 143.3, 143.9, 144.9,
148.2, 149.5, 150.4, 152.2, 157.0. MS (FAB) m/z 440 [(MH)þ,
100]. Anal. Calcd for C23H17N7OS: C, 62.86; H, 3.90; N,
22.31; S, 7.30. Found: C, 62.68; H, 3.91; N, 22.51; S, 7.29.
4.6. 3-Aryl-2-Thioxo(or 2-oxo)pyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
11 and 12
4.5.6. 3-(4-Methylphenyl)-2-(4-nitrophenyl)-
aminopyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo-
[1,5-a]pyrimidin-10(3H )-one (9f)
To a solution of phosphazene 7 (0.80 mmol) in dry THF
(5 mL) was added excess CS2 or CO2 (3.5 mmol) under Ar
at room temperature. The reaction mixture was heated at
100 ꢁC in a sealed tube for 3 h (CS2) or 8 h (CO2) (in the
Yield 99%; mp: >300 ꢁC (dec). IR (KBr) 3251 (NH), 1691
1
(C]O), 1538, 1568, 1510, 1495 cmꢀ1. H NMR (DMSO-d6,
500 MHz) d: 2.50 (s, 3H, CH3), 7.52e7.56 (m, 2H, ArH),

1340
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
case of 12a 8 h at room temperature). The precipitate was sep-
arated by filtration, washed with THF (2 mL) and purified by
column chromatography using a hexaneseAcOEt gradient
from 70% to 100% ethyl acetate to give 11 or 12 as a yellow
solid.
4.6.5. 1,3-Dihydro-3-(4-methylphenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-3,10-dione
(12b)
Yield 53%; mp: >300 ꢁC (dec). IR (KBr) 3415 (NH), 1656
(C]O), 1593, 1579, 1557, 1518, 1593, 1579, 1557, 1518,
1
1498 cmꢀ1. H NMR (DMSO-d6, 300 MHz) d: 2.39 (s, 3H,
CH3), 7.31e7.36 (m, 2H, ArH), 7.54e7.59 (m, 2H, ArH),
8.73 (d, 1H, J¼2.3 Hz, H-6), 8.80 (d, 1H, J¼2.3 Hz, H-7).
13C NMR (DMSO-d6, 75 Hz) d: 20.8, 113.6, 126.1, 129.0,
131.4, 136.3, 142.2, 143.4, 144.3, 145.8, 151.2, 156.2. MS
(FAB) m/z 351 [(MH)þ, 100]. Anal. Calcd for
C16H10N6O2S: C, 54.85; H, 2.88; N, 23.99; S, 9.15. Found:
C, 54.73; H, 2.78; N, 23.79; S, 9.16.
4.6.1. 3-Phenyl-2-thioxopyrazino[20,30:4,5]thieno[3,2-d]-
1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (11a)
Yield 97%; mp: 287e289 ꢁC. IR (KBr) 3432 (NH), 1711
1
(C]O), 1699, 1668, 1584, 1471 cmꢀ1. H NMR (DMSO-d6,
500 MHz) d: 7.45e7.54 (m, 1H, ArH), 7.55e7.61 (m, 4H,
ArH), 8.80 (d, 1H, J¼2.3 Hz, H-6), 8.83 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (DMSO-d6, 125 Hz) d: 114.9, 129.0, 129.6,
129.7, 133.5, 143.3, 144.0, 145.0, 148.8, 150.5, 151.6,
157.2. MS (FAB) m/z 353 [(MH)þ, 100]. Anal. Calcd for
C15H8N6OS2: C, 51.12; H, 2.29; N, 23.85; S, 18.20. Found:
C, 51.13; H, 2.17; N, 23.99; S, 18.26.
4.6.6. 1,3-Dihydro-3-(4-nitrophenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-3,10-dione
(12c)
Yield 42%; mp: >300 ꢁC (dec). IR (KBr) 3427 (NH), 1671
1
(C]O), 1551, 1540, 1523, 1508 cmꢀ1. H NMR (DMSO-d6,
4.6.2. 3-(4-Methylphenyl)-2-thioxopyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one (11b)
500 MHz) d: 8.20e8.24 (m, 2H, ArH), 8.45e8.50 (m, 2H,
ArH), 8.83 (d, 1H, J¼2.3 Hz, H-6), 8.91 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (DMSO-d6, 125 Hz) d: 116.1, 124.8, 126.6,
132.8, 133.6, 139.4, 143.3, 144.1, 144.7, 146.0, 146.9, 150.9,
156.7. MS (FAB) m/z 382 [(MH)þ, 20]. Anal. Calcd for
C15H7N7O4S: C, 47.25; H, 1.85; N, 25.71; S, 8.41. Found:
C, 47.13; H, 1.77; N, 25.99; S, 8.27.
Yield 87%; mp: >300 ꢁC. IR (KBr) 3444 (NH), 1710
(C]O), 1668, 1593, 1533, 1516, 1475 cmꢀ1 1H NMR
.
(DMSO-d6, 500 MHz) d: 2.36 (s, 3H, CH3), 7.35e7.40 (m,
2H, ArH), 7.42e7.47 (m, 2H, ArH), 8.82 (d, 1H, J¼2.3 Hz,
H-6), 8.85 (d, 1H, J¼2.3 Hz, H-7). 13C NMR (DMSO-d6,
125 Hz) d: 21.3, 114.5, 128.8, 129.9, 139.0, 143.2, 143.7,
144.2, 144.8, 148.6, 150.6, 151.5, 157.1. MS (FAB) m/z 367
[(MH)þ, 100]. Anal. Calcd for C16H10N6OS2: C, 52.45; H,
2.75; N, 22.94; S, 17.50. Found: C, 52.33; H, 2.76; N,
22.89; S, 17.46.
4.7. 2-(Alkylthio)-3-arylpyrazino[20,30:4,5]thieno[3,2-d]-
1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one 13. General
procedure
A mixture of 11 (0.1 mmol), alkyl halide (0.13 mL) and
solid potassium carbonate (0.2 mmol) in CH3CN (5 mL) was
stirred for 0.5e2 h at 60 ꢁC. After cooling, the precipitate
was filtered, washed with CH3CN (1 mL) and H2O (1 mL)
and purified by column chromatography using a hexanese
AcOEt gradient from 60% to 100% ethyl acetate to give 13
as a yellow solid.
4.6.3. 3-(4-Nitrophenyl)-2-thioxopyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (11c)
Yield 72%; mp: >300 ꢁC (dec). IR (KBr) 3429 (NH), 1689
(C]O), 1580, 1522, 1504, 1489 cmꢀ1 1H NMR (CDCl3,
.
500 MHz) d: 7.88e7.92 (m, 2H, ArH), 8.52e8.56 (m, 2H,
ArH), 8.76 (d, 1H, J¼2.3 Hz, H-7), 8.84 (d, 1H, J¼2.3 Hz,
H-8). 13C NMR (CDCl3, 125 Hz) d: 115.8, 124.3, 130.5,
136.9, 140.7, 143.0, 145.4, 147.1, 148.9, 149.0, 150.7, 151.8,
157.2. MS (FAB) m/z 398 [(MH)þ, 45]. Anal. Calcd for
C15H7N7O3S2: C, 45.34; H, 1.78; N, 24.67; S, 16.14. Found:
C, 45.23; H, 1.79; N, 24.79; S, 16.17.
4.7.1. 2-(Methylthio)-3-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one (13a)
Yield 93%; mp: >300 ꢁC. IR (KBr) 1682 (C]O), 1596,
1591, 1582, 1575, 1559, 1503, 1486 cmꢀ1
.
1H NMR
(CDCl3, 500 MHz) d: 2.85 (s, 3H, CH3), 7.54e7.69 (m, 5H,
ArH), 8.72 (d, 1H, J¼2.3 Hz, H-6), 8.80 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 125 Hz) d: 14.0, 117.4, 127.2,
130.4, 130.8, 130.9, 142.5, 143.7, 144.2, 148.8, 150.1,
152.1, 156.0, 158.3. MS (FAB) m/z 367 [(MH)þ, 60]. Anal.
Calcd for C16H10N6OS2: C, 52.45; H, 2.75; N, 22.94; S,
17.50. Found: C, 52.63; H, 2.45; N, 22.75; S, 17.60.
4.6.4. 1,3-Dihydro-3-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-3,10-dione (12a)
Yield 55%; mp: >300 ꢁC. IR (KBr) 3449 (NH), 1765
(C]O), 1583, 1543, 1521, 1497, 1487 cmꢀ1 1H NMR
.
(DMSO-d6, 500 MHz) d: 7.45e7.73 (m, 5H, ArH), 8.82 (d,
1H, J¼2.3 Hz, H-6), 8.87 (d, 1H, J¼2.3 Hz, H-7). 13C NMR
(CDCl3, 125 Hz) d: 115.6, 127.4, 128.7, 129.5, 132.7, 143.4,
144.1, 144.8, 147.2, 147.6, 150.6, 156.7. MS (FAB) m/z 337
[(MH)þ, 75]. Anal. Calcd for C15H8N6O2S: C, 53.57; H,
2.40; N, 24.99; S, 9.53. Found: C, 53.29; H, 2.17; N, 25.16;
S, 9.42.
4.7.2. 2-(Benzylthio)-3-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (13b)
Yield (97%); mp: 295e297 ꢁC. IR (KBr) 1702 (C]O),
1
1587, 1538, 1525, 1503, 1485, 1454 cmꢀ1. H NMR (CDCl3,
500 MHz) d: 4.69 (s, 2H, CH2), 7.30e7.38 (m, 3H, ArH),

G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
1341
7.41e7.48 (m, 2H, ArH), 7.51e7.63 (m, 5H, ArH), 8.72 (d,
1H, J¼2.3 Hz, H-6), 8.81 (d, 1H, J¼2.3 Hz, H-7). 13C NMR
(CDCl3, 125 Hz) d: 36.3, 117.4, 127.2, 128.4, 129.0, 129.5,
130.4, 130.7, 130.9, 134.3, 142.5, 143.7, 144.2, 148.8,
149.9, 152.1, 154.9, 158.3. MS (FAB) m/z 443 [(MH)þ, 60].
Anal. Calcd for C22H14N6OS2: C, 59.71; H, 3.19; N, 18.99;
S, 14.49. Found: C, 59.52; H, 3.07; N, 18.70; S, 14.65.
128.1, 128.6, 131.1, 141.5, 143.6, 143.7, 145.4, 149.3,
151.1, 152.0, 153.0, 157.3. MS (FAB) m/z 406 [(MH)þ, 70].
Anal. Calcd for C18H11N7OS2: C, 53.32; H, 2.73; N, 24.18;
S, 15.82. Found: C, 53.14; H, 2.65; N, 23.99; S, 15.66.
4.7.7. 2-(Methylthio)-3-(4-nitrophenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(13g)
4.7.3. 2-(Cyanomethylthio)-3-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one (13c)
Yield 81%; mp: >300 ꢁC (dec). IR (KBr) 1714 (C]O),
1
1584, 1530, 1505, 1486 cmꢀ1. H NMR (CDCl3, 500 MHz)
d: 2.91 (s, 3H, CH3), 7.85e7.92 (m, 2H, ArH), 8.48e8.55
(m, 2H, ArH), 8.74 (d, 1H, J¼2.3 Hz, H-6), 8.83 (d, 1H,
J¼2.3 Hz, H-7). 13C NMR (CDCl3, 125 Hz) d: 14.2, 118.2,
125.7, 128.0, 136.1, 142.7, 143.4, 144.4, 148.5, 148.6, 149.5,
151.8, 154.6, 158.3. MS (FAB) m/z 412 [(MH)þ, 40]. Anal.
Calcd for C16H9N7O3S2: C, 46.71; H, 2.20; N, 23.83; S,
15.59. Found: C, 46.57; H, 2.31; N, 24.01; S, 15.77.
Yield (89%); mp: >300 ꢁC. IR (KBr) 1698 (C]O), 2250
1
(CN), 1582, 1539, 1507, 1488 cmꢀ1. H NMR (DMSO-d6,
300 MHz) d: 4.50 (s, 2H, CH2), 7.70e7.78 (m, 5H, ArH),
8.86 (d, 1H, J¼2.3 Hz, H-6), 8.88 (d, 1H, J¼2.3 Hz, H-7).
13C NMR (DMSO-d6, 75 Hz) d: 16.8, 115.1, 116.7, 127.8,
130.1, 130.7, 131.0, 143.1, 143.1, 144.9, 148.7, 150.5, 151.4,
152.3, 156.8. MS (FAB) m/z 392 [(MH)þ, 40]. Anal. Calcd for
C17H9N7OS2: C, 52.16; H, 2.32; N, 25.05; S, 16.38. Found: C,
52.03; H, 2.32; N, 24.87; S, 15.99.
4.7.8. 2-(Benzylthio)-3-(4-nitrophenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(13h)
4.7.4. 3-(4-Methylphenyl)-2-(methylthio)pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (13d)
Yield 74%; mp: 277e279 ꢁC (dec). IR (KBr) 1704 (C]O),
1584, 1524, 1504, 1485 cmꢀ1. 1H NMR (CDCl3, 300 MHz) d:
4.71 (s, 2H, CH2), 7.30e7.40 (m, 3H, ArH), 7.41e7.49 (m,
2H, ArH), 7.80e7.88 (m, 2H, ArH), 8.43e8.51 (m, 2H,
ArH), 8.73 (d, 1H, J¼2.3 Hz, H-6), 8.81 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 75 Hz) d: 36.7, 118.1, 125.6, 128.0,
128.6, 129.0, 129.4, 133.9, 136.1, 142.7, 143.3, 144.4, 148.5,
149.2, 151.7, 153.5, 158.2, 162.9. MS (FAB) m/z 448 [(MH)þ,
90]. Anal. Calcd for C22H13N7O3S2: C, 54.20; H, 2.69; N,
20.11; S, 13.15. Found: C, 54.09; H, 2.52; N, 19.96; S, 12.91.
Yield 82%; mp: >300 ꢁC. IR (KBr) 1691 (C]O), 1593,
1
1581, 1539, 1516, 1488 cmꢀ1. H NMR (CDCl3, 500 MHz)
d: 2.48 (s, 3H, CH3), 2.84 (s, 3H, CH3), 7.40e7.45 (m, 4H,
ArH), 8.71 (d, 1H, J¼2.3 Hz, H-6), 8.79 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 125 Hz) d: 13.9, 21.4, 117.2, 127.0,
128.2, 131.0, 141.3, 142.4, 143.7, 144.2, 148.9, 150.2, 152.2,
156.2, 158.3. MS (FAB) m/z 381 [(MH)þ, 100]. Anal. Calcd
for C17H12N6OS2: C, 53.67; H, 3.18; N, 22.09; S, 16.86.
Found: C, 53.87; H, 3.16; N, 22.01; S, 16.95.
4.7.9. 2-(Cyanomethylthio)-3-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (13i)
4.7.5. 2-(Benzylthio)-3-(4-methylphenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(13e)
Yield 90%; mp: >300 ꢁC (dec). IR (KBr) 1689 (C]O),
2252 (CN), 1585, 1523, 1505, 1489 cmꢀ1
.
1H NMR
Yield 89%; mp: 239e240 ꢁC. IR (KBr) 1706 (C]O),
(DMSO-d6, 300 MHz) d: 4.54 (s, 2H, CH2), 8.02e8.10 (m,
2H, ArH), 8.55e8.63 (m, 2H, ArH), 8.88 (d, 1H, J¼2.3 Hz,
H-6), 8.91 (d, 1H, J¼2.3 Hz, H-7). 13C NMR (DMSO-d6,
75 Hz) d: 17.1, 115.4, 116.5, 125.4, 129.1, 135.9, 142.9, 143.2,
145.0, 148.5, 148.6, 150.2, 151.3, 151.4, 156.7. MS (FAB) m/z
437 [(MH)þ, 50]. Anal. Calcd for C17H8N8O3S2: C, 46.78; H,
1.85; N, 25.68; S, 14.69. Found: C, 47.02; H, 2.12; N, 25.76;
S, 14.91.
1
1538, 1515, 1498, 1485 cmꢀ1. H NMR (CDCl3, 300 MHz)
d: 2.45 (s, 3H, CH3), 4.67 (s, 2H, CH3), 7.29e7.48 (m, 9H,
ArH), 8.70 (d, 1H, J¼2.3 Hz, H-6), 8.79 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 75 Hz) d: 21.3, 36.2, 117.1, 126.9,
128.2, 128.3, 128.9, 129.4, 130.8, 134.3, 141.1, 142.4, 143.7,
144.1, 148.8, 150.0, 152.0, 155.0, 158.2. MS (FAB) m/z 457
[(MH)þ, 100]. Anal. Calcd for C23H16N6OS2: C, 60.51; H,
3.53; N, 18.41; S, 14.05. Found: C, 60.27; H, 3.49; N,
18.24; S, 14.00.
4.8. Pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-
a]pyrimidin-10(3H )-one 15a. General procedure
4.7.6. 2-(Cyanomethylthio)-3-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (13f)
Acyl chloride (0.08 mmol) and triethylamine (0.10 mmol)
were added under argon, at room temperature, to a solution
of phosphazene 7 (0.07 mmol) in dry THF (5 mL). The solu-
tion was stirred at room temperature for 3 h (for benzoyl chlo-
ride 8 h). The precipitate was separated by filtration, washed
with THF (1 mL) and purified by column chromatography us-
ing a CH2Cl2eAcOEt gradient from 0% to 10% ethyl acetate
to give 15 as a yellow solid.
Yield 84%; mp: >300 ꢁC. IR (KBr) 1702 (C]O), 2255
(CN), 1591, 1538, 1515, 1500, 1486 cmꢀ1
.
1H NMR
(DMSO-d6, 500 MHz) d: 2.48 (s, 3H, CH3), 4.52 (s, 2H,
CH2), 7.51e7.56 (m, 2H, ArH), 7.60e7.64 (m, 2H, ArH),
8.88 (d, 1H, J¼2.3 Hz, H-6), 8.90 (d, 1H, J¼2.3 Hz, H-7).
13C NMR (DMSO-d6, 125 Hz) d: 17.3, 21.4, 115.5, 117.2,

1342
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
4.8.1. 2-Methyl-3-phenylpyrazino[20,30:4,5]thieno[3,2-d]-
1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (15a)
2.52 (s, 3H, CH3), 8.06e8.11 (m, 2H, ArH), 8.56e8.61 (m,
2H, ArH), 8.89 (d, 1H, J¼2.3 Hz, H-6), 8.92 (d, 1H,
J¼2.3 Hz, H-7). 13C NMR (DMSO-d6, 125 Hz) d: 17.1,
120.3, 130.5, 134.6, 142.2, 148.4, 148.5, 150.3, 153.4, 154.3,
155.1, 156.7, 157.1, 162.0. MS (FAB) m/z 380 [(MH)þ, 40].
Anal. Calcd for C16H9N7O3S: C, 50.66; H, 2.39; N, 25.85;
S, 8.45. Found: C, 50.36; H, 2.33; N, 25.91; S, 8.22.
Yield 60%; mp: 220 ꢁC (dec). IR (KBr) 1698 (C]O),
1586, 1490 cmꢀ1 1H NMR (CDCl3, 300 MHz) d: 2.30 (s,
.
3H, CH3), 7.33e7.50 (m, 5H, ArH), 8.83 (d, 1H, J¼2.3 Hz,
H-6), 8.98 (d, 1H, J¼2.3 Hz, H-7). 13C NMR (CDCl3,
125 Hz) d: 12.3, 117.1, 127.4, 130.6, 130.7, 131.4, 142.4,
143.7, 144.3, 149.5, 149.6, 151.6, 152.6, 158.3. MS (FAB)
m/z 335 [(MH)þ, 90]. Anal. Calcd for C16H10N6OS: C,
57.48; H, 3.01; N, 25.14; S, 9.59. Found: C, 57.60; H, 3.09;
N, 25.35; S, 9.58.
4.8.6. 3-(4-Nitrophenyl)-2-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one (15f)
Yield 92%; mp: >300 ꢁC. IR (KBr) 1713 (C]O), 1583,
1556, 1541, 1524, 1487, 1449 cmꢀ1 1H NMR (CDCl3,
.
4.8.2. 2,3-Diphenylpyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-
triazolo[1,5-a]pyrimidin-10(3H )-one (15b)
500 MHz) d: 7.46e7.52 (m, 2H, ArH), 7.58e7.63 (m, 3H,
ArH), 7.72e7.76 (m, 2H, ArH), 8.43e8.48 (m, 2H, ArH),
8.78 (d, 1H, J¼2.3 Hz, H-6), 8.87 (d, 1H, J¼2.3 Hz, H-7).
13C NMR (CDCl3, 125 Hz) d: 118.2, 123.5, 125.6, 128.5,
129.3, 129.4, 132.5, 137.5, 142.8, 143.4, 144.5, 148.2, 149.1,
149.3, 151.6, 152.4, 158.4. MS (FAB) m/z 442 [(MH)þ, 20].
Anal. Calcd for C21H11N7O3S: C, 57.14; H, 2.51; N, 22.21;
S, 7.26. Found: C, 57.25; H, 2.62; N, 22.02; S, 7.07.
Yield 72%; mp: >300 ꢁC. IR (KBr) 1712 (C]O), 1578,
1539, 1486 cmꢀ1
.
1H NMR (DMSO-d6, 500 MHz) d:
7.47e7.52 (m, 2H, ArH), 7.51e7.59 (m, 3H, ArH), 7.64e
7.66 (m, 5H, ArH), 8.89 (d, 1H, J¼2.3 Hz, H-6), 8.92 (d,
1H, J¼2.3 Hz, H-7). 13C NMR (DMSO-d6, 125 Hz) d:
115.2, 125.2, 129.0, 129.4, 129.6, 130.4, 130.8, 132.2, 133.1,
143.6, 143.8, 145.5, 149.9, 151.2, 152.4, 152.7, 157.4. MS
(FAB) m/z 397 [(MH)þ, 70]. Anal. Calcd for C21H12N6OS:
C, 63.62; H, 3.05; N, 21.20; S, 8.09. Found: C, 63.46; H,
2.85; N, 21.19; S, 8.04.
4.9. Bis(pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo-
[1,5-a]pyrimidin-10(3H )-ones) 17. General procedure
Diacyl
chloride
(0.05 mmol)
and
triethylamine
4.8.3. 2-Methyl-3-(4-methylphenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(15c)
(0.26 mmol) were added under argon, at room temperature,
to a solution of phosphazene 7 (0.10 mmol) in dry THF
(5 mL). The reaction mixture was heated at 150 ꢁC in a sealed
tube for 3 h. The precipitate was separated by filtration,
washed with THF (1 mL) and purified by column chromatog-
raphy using a CH2Cl2eAcOEt gradient from 0% to 10% ethyl
acetate to give 17 as a yellow solid.
Yield 70%; mp: >300 ꢁC (dec). IR (KBr) 1699 (C]O),
1
1595, 1542, 1517, 1493 cmꢀ1. H NMR (CDCl3, 500 MHz)
d: 2.50 (s, 3H, CH3), 2.52 (s, 3H, CH3), 7.33e7.50 (m, 4H,
ArH), 8.71 (d, 1H, J¼2.3 Hz, H-6), 8.80 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 125 Hz) d: 12.2, 21.4, 117.0, 127.1,
128.7, 131.1, 141.1, 142.4, 143.8, 144.3, 149.5, 149.8, 151.8,
152.6, 158.4. MS (ESI) m/z 349 [(MH)þ, 10]. Anal. Calcd for
C17H12N6OS: C, 58.61; H, 3.47; N, 24.12; S, 9.20. Found: C,
58.44; H, 3.47; N, 24.26; S, 9.15.
4.9.1. 1,4-Bis(100-oxo-30-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-yl)benzene
(17a)
Yield 62%; mp: >300 ꢁC (dec). IR (KBr) 1705 (C]O),
1582, 1537, 1465, 1432 cmꢀ1. H NMR (CDCl3, 500 MHz)
1
4.8.4. 3-(4-Methylphenyl)-2-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(15d)
d: 7.61e7.66 (m, 10H, HAr), 7.67 (s, 4H, HAr), 8.74 (d,
2H, J¼2.3 Hz, H-5), 8.82 (d, 2H, J¼2.3 Hz, H-6). 13C NMR
(CDCl3, 125 Hz) d: 127.7, 127.9, 129.4, 129.7, 129.8, 130.6,
130.8, 137.9, 139.5, 142.4, 144.2, 144.3, 144.4, 149.5,
154.8. MS (FAB) m/z 715 [(MH)þ, 10]. Anal. Calcd for
C36H18N12O2S2: C, 60.50; H, 2.54; N, 23.52; S, 8.97. Found:
C, 60.70; H, 2.48; N, 23.63; S, 9.06.
Yield 91%; mp: >300 ꢁC. IR (KBr) 1714 (C]O), 1592,
1
1578, 1540, 1515, 1487 cmꢀ1. H NMR (CDCl3, 300 MHz)
d: 2.47 (s, 3H, CH3), 7.30e7.45 (m, 6H, ArH), 7.48e7.56
(m, 1H, ArH), 7.59e7.65 (m, 2H, ArH), 8.72 (d, 1H,
J¼2.3 Hz, H-6), 8.82 (d, 1H, J¼2.3 Hz, H-7). 13C NMR
(CDCl3, 75 Hz) d: 21.3, 117.1, 124.3, 127.4, 128.8, 129.4,
129.7, 130.9, 131.8, 140.6, 142.4, 143.8, 144.2, 149.5, 150.2,
152.3, 152.7, 158.4. MS (FAB) m/z 411 [(MH)þ, 100]. Anal.
Calcd for C22H14N6OS: C, 64.38; H, 3.44; N, 20.48; S, 7.81.
Found: C, 64.43; H, 3.31; N, 20.36; S, 7.55.
4.9.2. 1,3-Bis(100-oxo-30-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-yl)benzene
(17b)
Yield 67%; mp: >300 ꢁC (dec). IR (KBr) 1695 (C]O),
1599, 1584, 1522, 1496, 1485, 1443 cmꢀ1
.
1H NMR
(CDCl3, 500 MHz) d: 7.37e7.47 (m, 5H, HAr), 7.57e7.63
(m, 6H, ArH), 7.71e7.75 (m, 2H, HAr), 7.81e7.84 (m, 1H,
HAr), 8.74 (d, 2H, J¼2.3 Hz, H-5), 8.83 (d, 2H, J¼2.3 Hz,
H-6). 13C NMR (CDCl3, 125 Hz) d: 117.5, 125.4, 127.7,
129.6, 130.1, 130.7, 130.9, 131.8, 132.4, 142.6, 143.6, 144.4,
149.5, 149.9, 150.7, 152.5, 158.4. MS (FABþ) m/z 715
4.8.5. 2-Methyl-3-(4-nitrophenyl)pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-one
(15e)
Yield 71%; mp: >300 ꢁC. IR (KBr) 1713 (C]O), 1581,
1
1527, 1505, 1488 cmꢀ1. H NMR (DMSO-d6, 500 MHz) d:

G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
1343
[(MHþ), 15]. Anal. Calcd for C36H18N12O2S2: C, 60.50; H,
2.54; N, 23.52; S, 8.97. Found: C, 60.38; H, 2.34; N, 23.69;
S, 8.79.
4.10. 3-Aryl-2-(N,N-dimethylamino)-pyrazino[20,30:4,5]-
thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-
one 19
4.9.3. 2,6-Bis(100-oxo-30-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-yl)pyridine
(17c)
To a solution of 7 (0.08 mmol) in CH2Cl2 (3 mL) was
added N,N-dichloromethylenedimethylammonium chloride
(Viehe’s salt) (0.10 mol). The reaction mixture was heated at
reflux temperature for 1 h. Then, the solvent was removed un-
der reduced pressure and the residue was purified by column
chromatography using a CH2Cl2eAcOEt gradient from 20%
to 30% ethyl acetate to give 19 as a yellow solid.
Yield 71%; mp: >300 ꢁC (dec). IR (KBr) 1686 (C]O),
1581, 1488, 1456, 1448, 1436 cmꢀ1 1H NMR (CDCl3,
.
500 MHz) d: 7.14e7.20 (m, 4H, ArH), 7.39e7.48 (m, 6H,
ArH), 8.12e8.19 (m, 1H, ArH), 8.32e8.38 (m, 2H, ArH),
8.75 (d, 2H, J¼2.3 Hz, H-5), 8.84 (d, 2H, J¼2.3 Hz, H-6).
13C NMR (CDCl3, 125 Hz) d: 117.4, 127.3, 127.6, 129.6,
130.0, 132.0, 139.0, 142.7, 143.5, 144.5, 144.6, 149.2, 149.8,
149.8, 152.6, 158.5. MS (FABþ) m/z 716 [(MH)þ, 10]. Anal.
Calcd for C35H17N13O2S2: C, 58.73; H, 2.39; N, 25.44; S,
8.96. Found: C, 58.90; H, 2.44; N, 25.53; S, 9.15.
4.10.1. 2-(N,N-Dimethylamino)-3-phenylpyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-one (19a)
Yield 87%; mp: >300 ꢁC. IR (KBr) 1684 (C]O), 1580,
1
1546, 1522, 1491 cmꢀ1. H NMR (CDCl3, 300 MHz) d: 2.87
(s, 6H, CH3), 7.52e7.64 (m, 5H, ArH), 8.66 (d, 1H, J¼
2.3 Hz, H-6), 8.75 (d, 1H, J¼2.3 Hz, H-7). 13C NMR
(CDCl3, 75 Hz) d: 40.2, 117.6, 124.0, 127.2, 130.0, 130.4,
132.8, 142.1, 143.7, 148.0, 149.5, 152.3, 155.2, 158.0. MS
(FAB) m/z 364 [(MH)þ, 100]. Anal. Calcd for C17H13N7OS:
C, 56.19; H, 3.61; N, 26.98; S, 8.82. Found: C, 56.00; H,
3.54; N, 27.17; S, 8.77.
4.9.4. 1,3-Bis(100-oxo-30-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-yl)-
phenylene diamine (17d)
Yield 67%; mp: 250 ꢁC (dec). IR (KBr) 3272 (NH), 1669
(C]O), 1595, 1574, 1539, 1514, 1486, 1446, 1339 cmꢀ1
.
1H NMR (CDCl3, 300 MHz) d: 5.66 (s, 2H, NH), 7.05e7.12
(m, 4H, HAr), 7.45e7.52 (m, 6H, HAr), 7.81 (s, 4H, HAr),
8.57 (d, 2H, J¼2.3 Hz, H-5), 8.75 (d, 2H, J¼2.3 Hz, H-6).
13C NMR spectrum could not be obtained due to poor solubil-
ity. MS (FAB) m/z 745 [(MH)þ, 10]. Anal. Calcd for
C36H20N14O2S2: C, 58.06; H, 2.71; N, 26.33; S, 8.61. Found:
C, 58.00; H, 2.68; N, 26.24; S, 8.57.
4.10.2. 2-(N,N-Dimethylamino)-3-(4-methylphenyl)-
pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]-
pyrimidin-10(3H )-one (19b)
Yield 71%; mp: >300 ꢁC. IR (KBr) 1694 (C]O), 1596,
1
1573, 1540, 1515, 1492 cmꢀ1. H NMR (CDCl3, 300 MHz)
d: 2.47 (s, 3H, CH3), 2.90 (s, 6H, CH3), 7.36e7.50 (m, 4H,
ArH), 8.66 (d, 1H, J¼2.3 Hz, H-6), 8.76 (d, 1H, J¼2.3 Hz,
H-7). 13C NMR (CDCl3, 75 Hz) d: 21.3, 40.2, 117.5, 127.0,
130.2, 130.9, 140.4, 142.1, 143.7, 143.9, 148.0, 149.7, 152.3,
155.3, 158.0. MS (FAB) m/z 378 [(MH)þ, 100]. Anal. Calcd
for C18H15N7OS: C, 57.28; H, 4.01; N, 25.98; S, 8.50. Found:
C, 57.09; H, 3.87; N, 25.79; S, 8.32.
4.9.5. 1,4-Bis{100-oxo-30-(400-methylphenyl)-pyrazino-
[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-
10(3H )-yl}phenylene diamine (17e)
Yield 55%; mp: 250 ꢁC (dec). IR (KBr) 3341 (NH), 1685
(C]O), 1591, 1578, 1512, 1493, 1443, 1387 cmꢀ1 1H
.
NMR (CDCl3, 300 MHz) d: 2.52 (s, 6H, CH3), 5.99 (s, 2H,
NH), 6.70e6.73 (m, 4H, HAr), 7.35e7.38 (m, 4H, HAr),
7.50 (s, 4H, HAr), 8.69 (d, 2H, J¼2.3 Hz, H-5), 8.78 (d, 2H,
J¼2.3 Hz, H-6). A 13C NMR spectrum could not be obtained
due to poor solubility. MS (FAB) m/z 773 [(MH)þ, 20]. Anal.
Calcd for C38H24N14O2S2: C, 59.06; H, 3.13; N, 25.37; S,
8.30. Found: C, 58.98; H, 3.28; N, 25.24; S, 8.47.
4.10.3. 2-(N,N-Dimethylamino)-3-(4-nitrophenyl)-
pyrazino[20,30:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]-
pyrimidin-10(3H )-one (19c)
Yield 60%; mp: >300 ꢁC. IR (KBr) 1679 (C]O), 1580,
1533, 1502 cmꢀ1. 1H NMR (CDCl3, 300 MHz) d: 2.94 (s, 6H,
CH3), 7.92e7.99 (m, 2H, ArH), 8.48e8.56 (m, 2H, ArH),
8.70 (d, 1H, J¼2.3 Hz, H-6), 8.79 (d, 1H, J¼2.3 Hz, H-7). 13
C
4.9.6. 1,3-Bis(100-oxo-30-phenylpyrazino[20,30:4,5]thieno-
[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-10(3H )-yl)-
phenylene diamine (17f)
Yield 50%; mp: 260 ꢁC (dec). IR (KBr) 3271 (NH), 1673
(C]O), 1630, 1544, 1486, 1450, 1339 cmꢀ1 1H NMR
.
NMR (CDCl3, 75 Hz) d: 40.6, 118.6, 125.7, 127.7, 138.1,
142.4, 143.5, 144.0, 147.7, 148.0, 148.8, 152.0, 154.8, 158.0.
MS (FAB) m/z 409 [(MH)þ, 85]. Anal. Calcd for
C17H12N8O3S: C, 50.00; H, 2.96; N, 27.44; S, 7.85. Found: C,
49.81; H, 2.88; N, 27.25; S, 8.03.
(CDCl3, 300 MHz) d: 5.14 (s, 2H, NH), 7.37e7.45 (m, 4H,
HAr), 7.79e7.88 (m, 10H, HAr), 8.58 (d, 2H, J¼2.3 Hz,
H-5), 8.77 (d, 2H, J¼2.3 Hz, H-6). 13C NMR spectrum could
not be obtained due to poor solubility. MS (FAB) m/z 745
[(MH)þ, 15]. Anal. Calcd for C36H20N14O2S2: C, 58.06; H,
2.71; N, 26.33; S, 8.61. Found: C, 57.90; H, 2.78; N, 26.34;
S, 8.67.
5. Crystallographic material
Crystallographic data (excluding structural factors) for 9i
have been deposited in the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 664177.
Copies of the data may be obtained, free of charge, on

1344
G. Blanco et al. / Tetrahedron 64 (2008) 1333e1344
L. M.; Rioja, I.; Terencio, M. C.; Ubeda, A.; Alcaraz, M. J.; Riguera,
R. J. Med. Chem. 1999, 42, 4720.
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK (fax: þ44 1223 33603 or e-mail: deposit@ccdc.cam.
ac.uk).
7. Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5, 2433.
8. (a) Pettit, G. R.; Tan, R.; Xu, J.; Ichihara, Y.; Williams, M. D.; Boyd,
M. R. J. Nat. Prod. 1998, 61, 995; (b) Immamura, N.; Nishijima, M.;
Takadera, T.; Adachi, K.; Sakai, M.; Sano, H. J. Antibiot. 1997, 50, 8.
9. (a) Baker, D. C.; Hand, E. S.; Plowman, J.; Rampal, J. B.; Safavy, A.;
Haugwitz, R. D.; Narayanan, V. L. Anti-Cancer Drug Des. 1987, 2,
297; (b) For a recent review, see: Pawar, V. G.; De Borggraeve, W. H.
Synthesis 2006, 2799.
Acknowledgements
We thank to MCyT and FEDER (Grants BQU 2003-00574
and CTQ2006-04728) and the Xunta de Galicia, Spain (Grants
PGI-DIT04PXIC10307PN and PGIDIT06PXIB103224PR) for
financial support. G.B. acknowledges a predoctoral fellowship
10. For a recent example, see: Burns, C. J.; Wilks, A. F.; Bu, X. Worldwide
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F. E.; Yap, M. C. H.; Zhu, Y. U.S. Patent 20,020,019,370, 2002 (Chem.
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~
from the University of A Coruna.
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