A practical one-pot procedure for the synthesis of pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidinones by a tandem aza-Wittig/heterocumulene-mediated annulation strategy

Article abstract of DOI:10.1016/j.tet.2006.09.028

A simple one-pot and efficient method is described for the synthesis of pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidinone derivatives 6 via a tandem aza-Wittig/heterocumulene-mediated annulation process. The iminophosphorane 3 reacted with aryl isocyanates, fo

Full text of DOI:10.1016/j.tet.2006.09.028

Tetrahedron 62 (2006) 11124–11135
A practical one-pot procedure for the synthesis of
pyrazino[20,30:4,5]thieno[3,2-d]pyrimidinones by a tandem
aza-Wittig/heterocumulene-mediated annulation strategy
*
Gerardo Blanco, Natalia Seguı, Jose M. Quintela, Carlos Peinador, Marcos Chas and Rosa Toba
*
´
ꢀ
´
Departamento de Quımica Fundamental, Facultad de Ciencias, Universidad de A Corun~a, 15071 A Corun~a, Spain
Received 13 July 2006; revised 6 September 2006; accepted 12 September 2006
Available online 4 October 2006
Abstract—A simple one-pot and efficient method is described for the synthesis of pyrazino[20,30:4,5]thieno[3,2-d]pyrimidinone derivatives 6
via a tandem aza-Wittig/heterocumulene-mediated annulation process. The iminophosphorane 3 reacted with aryl isocyanates, followed by
heterocyclization on addition of secondary amines to give the corresponding guanidine intermediates 5, which were cyclized in the presence
of a catalytic amount of potassium carbonate to tricyclic compounds 6. Similarly, iminophosphorane 3 reacts with phenols, thiophenol, or
ROH to give 2-aryl(alkyl)oxy(thio)pyrazino[20,30:4,5]thieno[3,2-d]pyrimidinone derivatives 7 in good yields. The corresponding carbodi-
imide 4c and guanidine-type intermediate compounds 5 could be isolated and characterized, thus confirming the suggested reaction pathway.
However, two isomeric pyrazinothienopyrimidinones 8 and 9 may be produced in the reaction of iminophosphorane 3 with aromatic
isocyanates and subsequent reaction with primary amines in the presence of a catalytic amount of potassium carbonate. The effects of
the nucleophiles and isocyanates on the regioselectivity of the cyclization have been investigated.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Following this research line and in continuation of our work
on the studies on S- and N-heterocyclic compounds, we
describe here a convenient approach to substituted pyrazino-
thienopyrimidinone derivatives I as isosteres of pharmaceu-
tically relevant pyridothienopyrimidines8 as well as their
use as appropriate 1,10-phenanthroline-like ligands toward
transition metals (Fig. 1). Derivatives I are of considerable
interest as potential biologically active compounds or phar-
maceuticals.
The development of efficient and mild methods for heterocy-
clic compound synthesis represents a broad area of organic
chemistry.1 Structures containing such units often play an
essential role because of their biological activity, particu-
larly in cancer and virus researches.2 Among these hetero-
cycles, thienopyrimidine derivatives are an important class
of heterocyclic compounds in pharmaceutical discovery
research.3 Also, some derivatives of thienodipyrimidines
have been synthesized and some of them show good anti-
tumor activity.4
In the development of strategies for the preparation of
heterocycles the aza-Wittig reaction has proved to be excep-
tionally useful and great progress has been made in the field
of heterocyclic compounds by the aza-Wittig methodology.
Whereas pyridine annelated sulfur-containing heterocycles
have been studied extensively,5 comparatively little is known
about aza-analogue systems in which an S-heterocycle is
fused to a pyrazine nucleus. During the last years, we re-
ported the synthesis of substituted heterocycles containing
the pyridothienopyrimidine and pyridazinothienopyrimi-
dine skeletons with the aim of finding compounds with
anti-inflammatory and antihistaminic activities.6 In a search
of the literature it is surprising that their isosteres pyrazino-
thienopyrimidines, moreover isosteres of quinoxalinepyri-
midines, have been practically ignored.7
O
N
N
S
S
N
EtO2C
Ph3P
Ar
N
N
N
N
Z
3
I
Z = OR, OAr, SAr, NHR, NR2
N
N
S
N
N
CN
EtO2C
SPh
H2N
Keywords: Pyrazinothienopyrimidinone; Aza-Wittig; Heterocumulene.
* Corresponding authors. Tel.: +34 981 167000; fax: +34 981 167065;
e-mail addresses: jqqoqf@udc.es; capeveqo@udc.es
Figure 1. Retrosynthetic pathway for synthesis of the pyrazinothienopyr-
imidinone derivatives I.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.028

G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
11125
NH2
Both inter- and intramolecular version of the aza-Wittig
reaction has assumed increasing importance for the specific
construction of many heterocyclic compounds, in particular
nitrogen heterocyclic compounds.9 The intramolecular
aza-Wittig reaction is a powerful tool for the synthesis of
five–seven membered nitrogen heterocycles10 and the inter-
molecular aza-Wittig reaction followed by electrocycliza-
tion, intramolecular cycloaddition, or heterocyclization,
the tandem aza-Wittig, and cyclization sequence has been
utilized for the synthesis of many important nitrogen hetero-
cycles.11
N
N
CN
N
N
O
i
ii
S
OEt
SO2Ph
1
2
N
PPh3
N
C
NAr
O
N
N
N
N
O
iii
S
S
OEt
OEt
4c Ar = 4-Me-C6H4
3
vii
iv
v
Heteroaryliminophosphoranes, derived from C-amino-
heterocycles, have proved to beveryversatile building blocks
for the construction of fused heterocondensed systems.12 In
our ongoing efforts to synthesize biologically active com-
pounds as potential therapeutic agents based on heterocycli-
zation reactions of azahexatriene compounds, we have
previously published the synthesis of fused pyrimidines
based on the tandem aza-Wittig heterocumulene-mediated
annulation strategy.13 As a continuation of our work on the
aza-Wittig-type methodology, we report here a simple, gen-
eral, and effective strategy for the preparation of substituted
derivativesof the pyrazino[20,30:4,5]thieno[3,2-d]pyrimidine
ring system employing N-heteroaryl iminophosphoranes as
a conveniently accessible precursor. Pyrimidothienopyra-
zines were obtained in a one-pot reaction of the correspond-
ing iminophosphorane of heteroaromatic b-enamino ester 2
with isocyanates, followed by heterocyclization on addition
of nucleophilic reagents HZ. Dihydropyrimido-annulation
occurs via a heterocumulene moiety, available from the reac-
tion of the iminophosphorane and an isocyanate, which on
addition of the corresponding nucleophile undergoes ring
closure by nucleophilic attack of the adjacent Z group to
give a six-membered heterocyclic ring.
Z
Z
N
N
NHAr
O
Ar
N
N
N
N
vi
O
S
S
OEt
N
5a-f
6 Z = R2N
7 Z = ArO, ArS, RO
Scheme 1. Reagents and conditions: (i) HSCH2CO2Et, Na2CO3, EtOH,
reflux; (ii) C2Cl6, PPh3, NEt3, toluene, 100 ꢁC, sealed tube; (iii)
4-MeC6H4NCO, THF, room temperature; (iv) ArNCO, THF (1–2 h, room
temperature), HZ (5 h, room temperature), K2CO3, or NaOR (1 h, reflux);
(v) secondary amine, THF, room temperature; (vi) K2CO3, acetone, reflux;
(vii) ArNCO, THF (1–2 h, room temperature), HZ (5 h, room temperature).
aza-Wittig reaction between the iminophosphorane and the
isocyanate to givethe highly reactive carbodiimideintermedi-
ates which, in turn, were conveniently converted by a one-pot
procedure into the corresponding heterocycles 6, via initial
addition of an amine to the carbodiimide cumulenic system
followed by intramolecular hetero conjugate addition annula-
tion, by simply heating in acetone in the presence of catalytic
K2CO3. The results are listed in Table 1. Similarly, imino-
phosphorane 3 reacted with isocyanates and phenol, thiophe-
nol, substituted phenols, or ROH in the presence of catalytic
K2CO3 or Na+ROꢀ to give the 2-aryl(alkyl)oxy(thioxy)pyr-
azinothienopyrimidinones 7 in satisfactory to good yields
(65–85%).
2. Preparation of pyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidinones
The starting compound for the aza-Wittig reaction and het-
erocyclization sequence was prepared from the readily avail-
able ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate 2.
The synthesis of a set of pyrazinothienopyrimidinone deriv-
atives 6 and 7 is depicted in Scheme 1.
The participation of carbodiimide 4 as an intermediate in this
process has been confirmed experimentally: the treatment
of iminophosphorane 3 with p-tolylisocyanate in dry THF
resulted in a conversion of the former into ethyl 3-(p-tolyl-
imino-methyleneamino)thieno[2,3-b]pyrazine-6-carboxylate
4c. Likewise, reaction of iminophosphorane 3 with aryl
isocyanates and secondary amines at room temperature
resulted in the formation of triphenylphosphine oxide and
The initial reaction of 3-benzenesulfonylpyrazine-2-carbo-
nitrile 114 with ethyl 2-mercaptoacetate, in the presence of
an equimolecular amount of sodiumcarbonate, gave an excel-
lent yield (97%) of pyrazine carboxylate 2. The key imino-
phosphorane 3 was obtained, in 97% yield, by a modified
Kirsanov reaction of the b-enamino ester 2 with in situ gener-
ated dichlorotriphenylphosphorane using a hexachloro-
ethane–triphenylphosphine–triethylamine reagent system.15
Reaction of iminophosphorane 3 with several aromatic isocy-
anates, followed by heterocyclization on addition of second-
ary amines in the presence of a catalytic amount of K2CO3,
resulted in the formation of triphenylphosphine oxide
and the corresponding triheterocyclic pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)ones 6a–j directly in excellent
yields (85–98%). Aniline also reacted directly with the imino-
phosphorane 3 and phenylisocyanate to afford 6k in 86%
yield. Themechanism fortheseconversions involvesaninitial
Table 1. 2-Dialkylaminopyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones 6a–6k
Compd Ar
Z
Yield (%) Mp (ꢁC)
6a
6b
6c
6d
6e
6f
6g
6h
6i
C6H5 NEt2
4-CH3O–C6H4 NEt2
92
90
91
94
93
86
98
215–216
194–196
185–187
230–231
224–225
232–233
289–290
292–293
244–245
220–221
254–255
4-CH3–C6H4
4-Cl–C6H4
4-NO2–C6H4
4-Cl–C6H4
C6H5
NEt2
NEt2
NEt2
Morpholino
Morpholino
C6H5
C6H5
C6H5
C6H5
Thiomorpholino 85
Pyrrolidino
Piperidino
C6H5NH
90
85
86
6j
6k

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G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
the corresponding guanidine-type intermediate derivatives
5a–5f in good yields (70–85%) (Table 2). It is clear that com-
pounds 5 are the key intermediates for the processes. In the
presence of anhydrous potassium carbonate, the separated
5a–f underwent intramolecular heterocyclization across the
electrophilic ester functionality to give the fused pyrimidines
6. Direct cyclization of the initially formed carbodiimide
via a 1,3-OMe migration followed by electrocyclization
(Wamhoff’s pyrimido annelation)16 was not observed.
NH proton appears at 5.70–6.13 ppm as a broad singlet, in
addition to the set of signals due to the ethoxy group.
Also, the 13C NMR spectra showed signals between 14.3–
14.5 and 60.7–61.4 ppm due to the ethoxy groups. After het-
erocyclization, the spectra of pyrazinothienopyrimidones 6
and 7 did not include those type of signals.
Two isomeric pyrazino[20,30:4,5]thieno[3,2-d]pyrimidinones
8 and 9 may be produced in the reaction of iminophosphorane
3 with primary amines via a guanidine-type intermediate 5.
In addition, these isomeric pyrazinothienopyrimidones, 8
and 9, may be produced in the treatment of the heteroaryl-
imino-phosphorane 3 with ArNCO/RNH2 or RNCO/ArNH2
(Scheme 2).
Similarly, iminophosphorane 3 reacted with isocyanates and
phenol, thiophenol, substituted phenols, or ROH in the pres-
ence of catalytic K2CO3 or Na+ROꢀ to give the 2-aryl(alkyl)-
oxy(thioxy)pyrazinothienopyrimidinones 7 in satisfactory to
good yields (65–85%). The one-pot formation of aryloxy-
and arylthioxy pyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-
4(3H)-ones 7 (Table 3) was carried out by the reaction of
iminophosphorane 3 with phenylisocyanate, followed by
heterocyclization on addition of phenols or thiophenols in
the presence of catalytic potassium carbonate. Irrespective
of the fact whether the substituents on the phenols were
electron-withdrawing or electron-releasing groups, the
cyclization was completed smoothly at room temperature.
Meanwhile, 4-ethoxy- or 4-methoxy-pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one 7f or 7g was obtained in
satisfactory yield when the reaction took place in the pres-
ence of catalytic sodium ethoxide or sodium methoxide,
respectively. The formation of 7 can be also rationalized in
terms of an initial nucleophilic addition of phenoxide, thio-
phenoxide, or alkoxide to the carbodiimide 4 to give the
intermediate 5, which cyclizes to affords 7 (Scheme 1).
NAr
C
N
i. ArNCO
N
N
O
3
S
OEt
i. RNCO
ii. ArNH2
4
ii. RNH2
NHR
NHAr
N
NHAr
N
NHR
N
N
N
N
O
O
S
5a
OEt
S
5b
OEt
NHAr
NHR
N
N
R
N
Ar
N
N
N
N
Carbodiimide compound 4c, guanidine compounds 5a–5f,
and fused 2-substituted pyrimidinones 6 and 7 were charac-
terized from their microanalyses, spectroscopic, and mass
spectrometric data. The EI-mass spectra show the expected
molecular ion peaks in moderate to high intensity and the
fragmentation pattern is in accord with the proposed struc-
ture. The IR spectra of the guanidine-type intermediates
5a–5f showed a strong absorption at n¼3280–3320 cmꢀ1 at-
tributed to the NH group, while in the 1H NMR spectra, the
O
O
S
9
S
8
N
Scheme 2.
We decided to explore the effects of the structural variations
on isocyanates and primary amines in the ratio of the forma-
tion of compounds 8 and 9. First, a comparative study of the
one-pot procedure for the cyclization of 3 was carried out
with phenylisocyanate and substituted primary amines. The
ratio of 8:9 compounds is strongly influenced by the alkyl
substituent at the primary amine. The general conditions in
Scheme 1 are used and the results are listed in Table 4.
The results showed that the selectivity of the reaction was
found markedly dependent on the nature of the primary
amine employed. A helpful generalization is that whenever
Table 2. Guanidine-type intermediate compounds 5a–5f
Compd Ar
Z
Time Yield Mp
(ꢁC)
(h)
(%)
5a
5b
5c
5d
5e
5f
C6H5 NEt2
4-CH3O–C6H4 NEt2
3
4
5
4
1
4
70
85
84
75
80
70
106–107
194–195
194–195
155–156
182–183
160–161
4-CH3–C6H4
4-Cl–C6H4
4-NO2–C6H4
4-Cl–C6H4
NEt2
NEt2
NEt2
Morpholino
Table 4. Selectivity and yields in the reaction of 3 with phenylisocyanate
and primary amines
Entry
Compd
R
Ar
Yield (%)a
Mp (ꢁC)
Table 3. 2-Aryl(alkyl)oxypyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones 7a–7g
1
2
3
4
5
6
7
8
8a
9a
8b
9b
8c
9c
8d
9d
8e
9e
n-Butyl
n-Butyl
Benzyl
Benzyl
iso-Propyl
iso-Propyl
Cyclohexyl
Cyclohexyl
tert-Butyl
tert-Butyl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
57
19
55
44
80
0
95
0
82
0
197–198
99–101
113–115
175–176
228–230
Compd
Ar
Z
Yield (%)
Mp (ꢁC)
7a
7b
7c
7d
7e
7f
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5O
C6H5S
4-NO2–C6H4O
4-(CH3)3C–C6H4O
4-Benzyloxy-C6H4O
EtO
68
85
78
67
70
65
72
232–234
226–227
143–145
228–230
203–205
202–204
204–206
208–210
231–232
9
10
7g
MeO
a
Unoptimized yield of analytically pure isolated product.

G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
11127
Table 5. Selectivity and yields in the reaction of 3 with ArCNO and primary
amines
the primary amines are heavily substituted, that is, R¼iso-
propyl, tert-butyl, or cyclohexyl, these reactions afforded
only 8, compound 9 not being formed (Table 4, entries 5–
10). However, when the primary amine is less hindered,
e.g., R¼n-butyl or R¼benzyl, the selectivity is less satisfac-
tory, affording a 75:25 and 55:45 ratios of 8:9 compounds,
Entry
R
Ar
8/9a
Yield of isolated
products (%)
1
2
3
4
5
6
7
8
n-Butyl
n-Butyl
n-Butyl
Benzyl
Benzyl
Benzyl
C6H5
70:30
5:95
95:5
55:45
10:90
90:10 8b2: 82
8a: 57
9a: 19
9a1: 82
4-NO2–C6H4
4-CH3–C6H4
C6H5
4-NO2–C6H4
4-CH3–C6H4
C6H5
1
8a2: 89
8b: 55
respectively, ratios determined by H NMR analysis of the
mixture of reaction (Table 4, entries 1–4).
9b: 44
9b1: 85
The most important factor in the formation of products 8 and
9 can be ascribed mainly to the large difference in cycliza-
tion rates due to the steric hindrance around the Ph and R
groups.13,17 Although the carbodiimide 4 is mainly coplanar
due to the resonance effect, it is immediately obvious that the
amine would approach essentially by the opposite direction
of the COOEt group due to the steric hindrance to form the
guanidine-type intermediate 5a (Scheme 2). However, 5a
may convert to 5b through C–N single bond rotation and
this offers the opportunity that both guanidine-type interme-
diates, 5a and 5b, are suitable to cyclize: 5a for the aryl-
amine group and 5b by the alkylamino group to form 8
and 9, respectively. Steric hindrance between alkyl group
and ester group would explain the regioselectivity of the re-
action. Thus, the bulkier R group could rationalize the only
formation of the final products 8c–8e (Table 4, entries 5, 7,
and 9). In these cases, the initially formed 5a more easily
undergoes cyclization to give 8 than to divert to 5b to give
9, due the greater steric hindrance between the iso-propyl,
cyclohexyl, or tert-butyl group and the ester group in the
guanidine-type intermediate 5b. However, with n-butyl or
benzylamine, the minor steric hindrance between the alkyl
group and the ester group may convert more easily 5a to
5b with subsequent cyclization of 5a and 5b by the aryl-
amino or alkylamino group, respectively, to yield a mixture
of the pyrazinothienopyrimidines 8a/9a and 8b/9b (Table 4,
entries 1–4).
iso-Propyl
iso-Propyl
iso-Propyl
100:0
95:5
8c: 75
8c1: 81
8c2: 98
8d: 95
8d1: 84
8d2: 88
8e: 82
8e1: 93
8e2: 85
8f: 98
4-NO2–C6H4
9
4-CH3–C6H4 100:0
Cyclohexyl C6H5 100:0
10
11
12
13
14
15
16
Cyclohexyl 4-NO2–C6H4 100:0
Cyclohexyl 4-CH3–C6H4 100:0
tert-Butyl
tert-Butyl
tert-Butyl
Phenyl
C6H5
100:0
4-NO2–C6H4 100:0
4-CH3–C6H4 100:0
4-NO2–C6H4 100:0
Ratios determined by 1H NMR analysis of the mixture of compounds 8/9.
We were not able to separate the isomers 8a1, 8b1, 9a2, 9b2, and 9c1.
a
bulkier R group exerts a directing steric effect affording a
single cyclized product 8. However, entries 1–6 show the
effect of varying the NHAr group in Scheme 2, allowing
us to deduce that their relative nucleophilicity is responsible
for these changes in the selectivity of the reaction and will
affect the resulting product distribution when n-butyl or
benzylamine is employed in the one-pot reaction. The
most significant difference was observed in the reaction
with aryl isocyanates bearing electron-withdrawing groups.
Thus, the reaction of 3 with phenylisocyanate/n-butylamine
or phenylisocyanate/benzylamine proceeded giving the
corresponding compounds 8:9 in high yields, but little selec-
tivity was observed (Table 5, entries 1 and 4), whereas, in
contrast to this, the use of 4-nitrophenylisocyanate/n-butyl-
amine and 4-nitrophenylisocyanate/benzylamine resulted
in a dramatic change in the reaction selectivity, so that after
the reaction the isomer 9 is present in the reaction mixtures
with a 95:5 and 90:10 ratios, respectively, ratios determined
by NMR spectroscopy (Table 5, entries 2 and 5). One can
assume that the powerful electron-withdrawing nitro group
decreases the electron density on nitrogen and it reduces
strongly the nucleophilicity of the NHAr group. Then, the
initially formed guanidine-type intermediate 5a does not
undergo cyclization to give 8 but then could divert conve-
niently to 5b making the cyclization mainly by the most
reactive butyl or benzylamine (Scheme 2). Moreover, for
a comparison of the method, reaction of iminophosphorane
3 with isocyanates bearing electron-releasing groups was
carried out. In this reaction the electron-releasing alkyl
groups increase the electron density on nitrogen and the ini-
tially formed 5a more easily supports cyclization to give 8
than to divert to 5b to give 9. In this manner, the p-tolyliso-
cyanate gave a very high 8-selectivity compared to that of
phenylisocyanate (Table 5, entries 3 and 6). Last, the nucleo-
philicity dependence of the NHR group on the selectivity of
the reaction was examined with phenylisocyanate/p-nitro-
aniline or p-nitrophenylisocyanate/aniline. As can be seen,
in agreement with our previous results, we found that the
reaction proceeded in high yield and with complete regio-
selectivity. In this case, guanidine intermediates 5a and 5b
(Scheme 2) are the same sterically hindered making the cycli-
zation to progress only by the strong nucleophilic amine
Though steric effects are of greatest importance in governing
the relative ratios between compounds 8 and 9 and may de-
termine, which product is formed in these processes, it is
also noteworthy that there are other electronic effects that
are of importance on the selectivity of the cyclization reac-
tion. In this manner, in an effort to explore the electronic
effects on the selectivity of the reaction, at the same time,
to achieve diversity in terms of substitution, aryl isocyanates
bearing electron-withdrawing or electron-releasing group
were also subjected to the reaction conditions with imino-
phosphorane 3 and primary amines. To the best of our
knowledge, no precedent has been reported in this way.
Armed with the results from Table 4, we examined the scope
of the one-pot tandem reaction sequence for phenylisocya-
nate, 4-nitrophenylisocyanate, and 4-methylisocyanate vary-
ing the primary amine. Interesting enough, the results from
Table 5 seem to suggest that the selectivity of the reaction
is particularly sensitive to electronic effects, as soon as the
ratio between compounds 8 and 9 was found to have a pro-
nounced dependence on the relative nucleophilicities of the
NHAr groups. Not surprisingly, the effect of nucleophilicity
of amine groups on the ratio of the formation of compounds
8c:9c, 8d:9d, and 8e:9e will not be important (Table 5,
entries 7–15). In terms of precedent discussion, this high
regioselectivity is in agreement with the explanation that the

11128
G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
group to obtain 8f (Table 5, entry 16; Ar¼phenyl, R¼4-nitro-
phenyl in Scheme 2) in excellent yield with total selectivity.
Compounds 8 and 9 were characterized from their spectral
data, and the comparison of H NMR spectra between 8
1
and 9 led us to confirm the structure of products without dif-
ficulty. In particular, in the 1H NMR spectra of 8, the corre-
sponding proton of NH displays a characteristic triplet or
doublet multiplicity due to coupling with the methylene or
methine protons adjacent to the nitrogen atom. Its chemical
shift is 3.91–4.73, more shielded than the one in PhNH of
9.18 For example, the 1H NMR spectrum of 8a shows the sig-
nals of NH at 4.27 as a triplet and NCH2 at 3.52–3.63 as
a multiplet. When the sample was treated with D2O, its
NCH2 showed the signal as a triplet with disappearance of
signals of NH absorption, which suggests the existence of
an NHBu group in 8a. The 1H NMR spectrum of compound
9a did not include the characteristic triplet corresponding to
NH–Bu proton, but shows the NCH2 signal at 4.29 as triplet
and a new singlet signal at d¼6.66 due to the NHPh group,
confirming the selective formation of pyrimido compounds
9 in this case. We were able to obtain suitable crystals of
compounds 8 and 9 for X-ray study, which corroborated
our earlier assignments (see Section 4). For example, Fig-
ures 2 and 3 show the molecular structure of compounds
8a and 9a1, respectively. Interestingly, the results revealed
a nearly coplanar disposition of the NHR group, in 8a, and
the NHAr group, in 9a1, with the three heterocyclic rings
of the pyrazinothienopyrimidine system, whereas the angle
between the NAr group in 8a (NR in 9a1) and the trihetero-
cyclic fused ring is approximately of 90ꢁ.
Figure 3. X-ray structure of compound 9a1 (50% thermal probability ellip-
soids). Hydrogen atoms have been omitted for clarity.
regioselective cyclization has been observed and explored.
Some advantages, such as the readily available reagents,
one-pot procedure in high yields, mild reaction conditions,
easy control of regioselectivity, and straightforward product
isolation, make this annulation strategy attractive and prac-
tical for these previously unreported pyrazinothienopyrimi-
dinones of considerable interest as potential biologically
active compounds as well as pharmaceuticals.
In summary, one-pot aza-Wittig/Heterocumulene-mediated
annulation methodology provides an efficient protocol for
preparing the functionalized pyrazino[20,30:4,4]thieno[3,2-
d]pyrimidinone derivatives, with variable substituents at the
pyrimidine ring, from the ethyl 3-(triphenylphosphoranyl-
ideneamino)thieno[2,3-b]pyrazine-6-carboxylate. The one-
pot sequence can be extended to secondary amines, phenols,
thiophenols, or ROH. In the case of primary amines, a highly
3. Experimental
3.1. General
NMR spectra were recorded at 200 or 300 MHz for 1H and
50 or 75 MHz for 13C. Chemical shifts are reported in parts
per million (d) relative to internal Me4Si. IR spectra were
recorded as potassium bromide disks. Melting points were
obtained on a capillary melting point apparatus and are un-
corrected. All reagents used were commercial grade chemi-
cals from freshly opened containers. Microanalyses for C, H,
N, and S were performed by the elemental analyses general
~
service of the University of A Coruna.
3.1.1. Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate
(2). To a solution of 3-benzenesulfonylpyrazine-2-carbo-
nitrile 114 (2.00 g, 8.2 mmol) in EtOH/THF (5:1, v/v)
(120 mL) was added Na2CO3 (1.06 g, 10 mmol) and the re-
sultant reaction mixture was stirred at reflux temperature for
1 h. After cooling at room temperature, was extracted with
dichloromethane (3ꢂ200 mL) and the organic extracts
were combined and dried over sodium sulfate. The methyl-
ene dichloride solution was concentrated to dryness, and the
residual material was recrystallized from ethanol to give 2
(1.80 g, 97%); mp 120–121 ꢁC (lit.7a mp 114–116 ꢁC).
3.1.2. Ethyl 3-(triphenylphosphoranylideneamino)-
thieno[2,3-b]pyrazine-6-carboxylate (3). To a mixture of
Figure 2. X-ray structure of compound 8a (30% thermal probability ellip-
soids). Hydrogen atoms have been omitted for clarity.

G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
11129
2
(1.00 g, 6.65 mmol), triphenylphosphine (2.62 g,
85%; yellow solid; mp 194–195 ꢁC; IR (KBr) n 3320
1
10 mmol), and hexachloroethane (1.37 g, 10 mmol) in dry
toluene (40 mL), triethylamine (2.4 mL, 16.50 mmol) was
added dropwise. The reaction mixture was heated at
100 ꢁC in a sealed tube for 48 h. After cooling, the precipi-
tate obtained was filtered off, washed with water, and recrys-
tallized from ethanol, to give 3 (2.00 g, 97%) as a yellow
(NH), 1635 cmꢀ1; H NMR (200 MHz, CDCl3) d 1.29 (t,
J¼6.8 Hz, 6H), 1.39 (t, J¼6.8 Hz, 3H), 3.56 (q, J¼6.8 Hz,
4H), 3.58 (s, 3H), 4.35 (q, J¼6.8 Hz, 2H), 6.35–6.45 (m,
3H), 6.66–6.70 (m, 2H), 8.47 (d, J¼2.4 Hz, 1H), 8.60 (d,
J¼2.4 Hz, 1H); MS (EI) m/z 427 (M+, 20), 354 (60), 203
(100). Anal. Calcd for C21H25N5O3S: C, 59.00; H, 5.89;
N, 16.38; S, 7.50; Found: C, 58.93; H, 5.71; N, 16.51;
S, 7.72.
solid: mp 174–176 ꢁC; IR (KBr)
n 1690 (C]O),
1175 cmꢀ1 1H NMR (200 MHz, CDCl3) d 1.44 (t,
;
J¼7.1 Hz, 3H), 4.44 (q, J¼7.1 Hz, 2H), 7.35–7.54 (m,
15H), 8.58 (d, J¼2.4 Hz, 1H), 8.62 (d, J¼2.4 Hz, 1H); 13C
NMR (50 MHz, CDCl3) d 14.7, 60.4, 128.0, 128.3, 131.2,
131.3, 132.7, 132.9, 133.5, 138.5, 138.8, 142.5, 144.9,
148.3, 155.2, 163.9. 31P NMR (81 MHz, CDCl3) d 7.37;
MS (EI) m/z 483 (M+, 55), 410 (58). Anal. Calcd for
C27H22N3O2PS: C, 67.07; H, 4.59; N, 8.69; S, 6.63. Found:
C, 67.13; H, 4.51; N, 8.57; S, 6.80.
3.1.7. Ethyl 2-[N0,N0-diethyl-N00(4-methylphenyl)guani-
dino]thieno[2,3-b]pyrazine-6-carboxylate (5c). Yield
84%; yellow solid; mp 194–195 ꢁC; IR (KBr) n 3320 (NH),
1
1635; H NMR (200 MHz, CDCl3) d 1.30 (t, J¼7.3 Hz,
6H), 1.39 (t, J¼7.3 Hz, 3H), 2.15 (s, 3H), 3.57 (q, J¼
7.3 Hz, 4H), 4.35 (q, J¼7.3 Hz, 2H), 6.50 (br, 1H), 6.60–
6.67 (m, 4H), 6.78–6.89 (m, 3H), 8.47 (d, J¼2.2 Hz, 1H),
8.61 (d, J¼2.2 Hz, 1H). Anal. Calcd for C21H25N5O2S: C,
61.29; H, 6.12; N, 17.02; S, 7.79. Found: C, 61.44; H, 6.00;
N, 17.16; S, 7.62.
3.1.3. Ethyl 3-(p-tolylimino-methylenamino)thieno[2,3-
b]pyrazine-6-carboxylate (4c). To a solution of 3 (0.15 g,
0.31 mmol) in THF (3 mL) was added p-tolylisocyanate
(0.05 g, 0.37 mmol) and the mixture was stirred at room
temperature for 3–5 h. The solvent was evaporated and the
solid obtained was purified by flash chromatography using
hexane/CH2Cl2 (1:1; v/v) as eluent. Yield 53%; yellow solid;
mp 105–106 ꢁC; IR (KBr) n 2140 (C]N), 1710 (C]O),
3.1.8. Ethyl 2-[N0,N0-diethyl-N00-(4-chlorophenyl)guani-
dino]thieno[2,3-b]pyrazine-6-carboxylate (5d). Yield
75%; yellow solid; mp 155–156 ꢁC; IR (KBr) n 3280
(NH), 1710 (C]O) cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d 1.30 (t, J¼7.3 Hz, 6H), 1.39 (t, J¼7.3 Hz, 3H), 3.57 (q,
J¼7.3 Hz, 4H), 4.35 (q, J¼7.3 Hz, 2H), 5.70 (br, 1H), 6.66
(s, 2H), 6.81–6.85 (m, 2H), 8.51 (d, J¼2.4 Hz, 1H), 8.62
(d, J¼2.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 13.5,
14.4, 43.1, 60.9, 120.2, 126.8, 128.3, 139.1, 141.4, 143.1,
148.2, 152.6, 155.2; MS (EI) m/z 433/431 (M+, 11/28),
358 (39). Anal. Calcd for C20H22ClN5O2S: C, 55.61; H,
5.13; Cl, 8.21; N, 16.21; S, 7.42. Found: C, 55.43; H, 5.21;
Cl, 8.34; N, 16.39; S, 7.25.
1580, 1570, 1505 cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d 1.43 (t, J¼7.3 Hz, 3H), 2.35 (s, 3H), 4.45 (q, J¼7.3 Hz,
2H), 7.06–7.29 (m, 4H), 8.71 (d, J¼2.4 Hz, 1H), 8.66 (d,
J¼2.4 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 14.3, 21.0,
62.0, 122.2, 124.6, 129.5, 130.0, 131.6, 133.7, 135.0,
135.8, 142.3, 144.0, 154.3, 161.5. Anal. Calcd for
C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56; S, 9.48. Found:
C, 60.53; H, 4.31; N, 16.46; S, 9.31.
3.1.4. Ethyl thieno[2,3-b]pyrazine-6-carboxylates (5).
The appropriate isocyanate (0.37 mmol) was added to a solu-
tion of iminophosphorane 3 (0.15 g, 0.31 mol) in THF
(3 mL). The mixture was stirred at room temperature for
1–2 h until the iminophosphorane had disappeared (TLC
monitored) and it was therefore treated with an appropriate
amine (0.37 mmol). The resultant solution was stirred at
room temperature for 1–5 h. The solvent was evaporated,
ether (5 mL) was added, and the mixture was stirred at
room temperature for 0.5 h. The solid formed was filtered
off and purified by crystallization from ethanol or flash chro-
matography to give the corresponding compounds 5.
3.1.9. Ethyl 2-[N0,N0-diethyl-N00-(4-nitrophenylguani-
dino]thieno[2,3-b]pyrazine-6-carboxylate (5e). Yield
80%; yellow solid; mp 182–183 ꢁC; IR (KBr) n 3280
1
(NH), 1680 (C]O) cmꢀ1; H NMR (200 MHz, CDCl3,)
d 1.30 (t, J¼7.3 Hz, 6H), 1.40 (t, J¼7.3 Hz, 3H), 3.58 (q,
J¼7.3 Hz, 4H), 4.37 (q, J¼7.3 Hz, 2H), 6.63 (br, 3H), 7.75
(d, J¼9.1, 2H), 8.53 (d, J¼2.2 Hz, 1H), 8.64 (d, J¼2.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 13.6, 14.3, 43.4, 61.4,
117.8, 124.6, 140.9, 141.6, 143.4, 149.7, 154.9, 163.4;
MS (EI) m/z 442 (M+, 14), 413 (5), 369 (53), 220 (100).
Anal. Calcd for C20H22N6O4S: C, 54.29; H, 5.01;
N, 18.99; S, 7.25. Found: C, 54.43; H, 5.19; N, 18.79;
S, 7.13.
3.1.5. Ethyl 2-(N0,N0-diethyl-N00-phenylguanidino)-
thieno[2,3-b]pyrazine-6-carboxylate (5a). Yield 70%;
yellow solid; mp 106–107 ꢁC; IR (KBr) n 3320 (NH),
3.1.10. Ethyl 2-[(4-chlorophenylamino)-morpholin-1-yl-
methyleneamino]thieno[2,3-b]pyrazine-6-carboxylate
(5f). Yield 70%; yellow solid; mp 160–161 ꢁC; IR (KBr)
1635 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 1.31 (t, J¼
7.3 Hz, 6H), 1.38 (t, J¼7.3 Hz, 3H), 3.59 (q, J¼7.3 Hz,
4H), 4.35 (q, J¼7.3 Hz, 2H), 6.59–6.70 (m, 3H), 6.78–
6.89 (m, 3H), 8.47 (d, J¼2.2 Hz, 1H), 8.61 (d, J¼2.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 13.5, 14.5, 43.1, 60.7,
119.3, 122.1, 128.3, 129.2, 141.3, 142.8, 145.0, 152.7,
155.1, 163.0. MS (EI) m/z 397 (M+, 24), 324 (58). Anal.
Calcd for C20H23N5O2S: C, 60.43; H, 5.83; N, 17.62; S,
8.07. Found: C, 60.33; H, 6.01; N, 17.56; S, 8.22.
n 3300 (NH), 1700 (C]O) cmꢀ1 1H NMR (200 MHz,
;
CDCl3) d 1.38 (t, J¼7.3 Hz, 3H), 3.51–3.62 (m, 4H),
3.66–3.77 (m, 4H), 4.35 (q, J¼7.3 Hz, 2H), 6.13 (br, 1H),
6.86–7.01 (m, 4H), 8.54 (d, J¼2.2 Hz, 1H), 8.63 (d,
J¼2.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 14.4, 47.2,
61.2, 66.4, 120.6, 127.5, 128.7, 138.9, 141.7, 143.3, 152.3,
155.2, 162.8; MS (EI) m/z 447/445 (M+, 8/21), 372 (24).
Anal. Calcd for C20H20ClN5O3S: C, 53.87; H, 4.52; Cl,
7.95; N, 15.71; S, 7.19. Found: C, 53.97; H, 4.61; Cl, 8.14;
N, 15.59; S, 7.05.
3.1.6. Ethyl 2-[N0,N0-diethyl-N00-(4-methoxyphenyl)gua-
nidino]thieno[2,3-b]pyrazine-6-carboxylate (5b). Yield

11130
G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
3.2. General procedure for the synthesis of 2-dialkylyl-
amino-3-phenylpyrazino[20,30:4,5]thieno[3,2-d]pyrimi-
din-4(3H)-one 6a–6k
387/385 (M+, 7/20), 356 (100). Anal. Calcd for
C18H16ClN5OS: C, 56.03; H, 4.18; Cl, 9.19; N, 18.15; S,
8.31. Found: C, 56.14; H, 4.21; Cl, 9.33; N, 17.99; S, 8.51.
To a solution of iminophosphorane 3 (0.15 g, 0.31 mmol) in
dry THF (3 mL) was added the appropriate isocyanate
(0.37 mmol) at room temperature. The mixture was stirred
at room temperature for 1–2 h until the iminophosphorane
had disappeared (TLC monitored) and it was therefore
treated with an appropriate secondary amine or aniline
(0.37 mmol). The resultant solution was stirred at room tem-
perature for 1–5 h. The solvent was evaporated, the residue
was treated with a catalytic amount of K2CO3, acetone
(3 mL) was added, and the mixture was refluxed for 1 h.
The solvent was removed under reduced pressure, and the
residue was subjected to chromatography on silica gel elut-
ing with a hexanes/ethyl acetate gradient from 5 to 40%
ethyl acetate to give 6 as a yellow solid.
3.2.5. 2-Diethylamino-3-N-(4-nitrophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6e). Yield
93%; mp 224–225 ꢁC; IR (KBr)
n
1670 (C]O),
1520 cmꢀ1
;
1H NMR (200 MHZ, CDCl3) d 0.98 (t,
J¼7.3 Hz, 6H), 3.25 (q, J¼7.3 Hz, 4H), 7.63, 8.41 (m,
4H), 8.72 (d, J¼2.2 Hz, 1H), 8.88 (d, J¼2.2 Hz, 1H); 13C
NMR (50 MHz, CDCl3) d 12.5, 45.2, 124.5, 142.8, 143.1,
143.8, 144.2, 147.2, 149.1, 157.2, 158.7, 159.2; MS (EI)
m/z 396 (M+, 39), 367 (85). Anal. Calcd for C18H16N6O3S:
C, 54.54; H, 4.07; N, 21.20; S, 8.09. Found: C, 54.73; H,
4.01; N, 20.26; S, 8.24.
3.2.6. 3-N-(4-Chlorophenyl)-2-(4-morpholinyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6f). Yield
86%; mp 232–233 ꢁC; IR (KBr)
n 1670 (C]O),
1
3.2.1. 2-Diethylamino-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (6a). Yield 92%; mp
1520 cmꢀ1; H NMR (200 MHz, CDCl3) d 3.23–3.32 (m,
4H), 3.50–3.54 (m, 4H), 7.40, 7.54 (m, 4H), 8.72 (d,
J¼2.2 Hz, 1H), 8.87 (d, J¼2.2 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d 49.4, 65.8, 120.0, 129.5, 129.7, 134.8,
135.1, 142.7, 143.7, 144.2, 148.5, 157.4, 158.5, 159.1; MS
(EI) m/z 401/399 (M+, 36/100), 313 (57). Anal. Calcd for
C18H14ClN5O2S: C, 54.07; H, 3.53; Cl, 8.87; N, 17.51; S,
8.02. Found: C, 54.13; H, 3.41; Cl, 9.08; N, 17.46; S, 7.91.
215–216 ꢁC; IR (KBr) n 1685 (C]O), 1530 cmꢀ1 1H
;
NMR (200 MHz, CDCl3) d 0.92 (t, 6H, J¼7.3 Hz, 6H),
3.25 (q, J¼7.3 Hz, 4H), 7.35–7.58 (m, 5H), 8.69 (d, J¼
2.2 Hz, 1H), 8.85 (d, J¼2.2 Hz, 1H); 13C NMR (50 MHz,
CDCl3) d 12.5, 45.3, 128.5, 128.6, 129.2, 137.6, 142.5,
143.8, 148.9, 158.0, 158.7, 159.9; MS (EI) m/z 351 (M+,
20), 322 (100). Anal. Calcd for C18H17N5OS: C, 61.52; H,
4.88; N, 19.93; S, 9.12. Found: C, 61.43; H, 4.81; N, 20.06;
S, 9.31.
3.2.7. 2-(4-Morpholinyl)-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (6g). Yield 98%; mp
289–290 ꢁC; IR (KBr) n 1701 (C]O), 1520, 1490,
1
3.2.2. 2-Diethylamino-3-N-(4-methoxyphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6b). Yield
1265 cmꢀ1; H NMR (300 MHz, CDCl3) d 3.26–3.36 (m,
4H), 3.40–3.50 (m, 4H), 7.41–7.62 (m, 5H), 8.71 (d,
J¼2.4 Hz, 1H), 8.86 (d, J¼2.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 49.4, 65.8, 119.9, 128.4, 128.9, 129.3,
136.7, 142.6, 144.0, 148.5, 157.6, 158.5, 159.3; MS (EI)
m/z 365 (M+, 5), 279 (10), 77 (100). Anal. Calcd for
C18H15N5O2S: C, 59.16; H, 4.14; N, 19.17; S, 8.78. Found:
C, 58.97; H, 4.20; N, 19.01; S, 8.62.
90%; mp 194–196 ꢁC; IR (KBr)
n 1690 (C]O),
1525 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 0.95 (t, J¼
7.3 Hz, 6H), 3.26 (q, J¼7.3 Hz, 4H), 3.87 (s, 3H), 7.03–
7.29 (m, 4H), 8.68 (d, J¼2.4 Hz, 1H), 8.84 (d, J¼2.4 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 12.6, 45.3, 55.5, 114.5,
118.3, 129.5, 130.1, 142.4, 143.8, 144.2, 148.9, 158.3,
158.6, 159.4, 160.2; MS (EI) m/z 381 (M+, 13), 352 (46).
Anal. Calcd for C19H19N5O2S: C, 59.82; H, 5.02; N,
18.36; S, 8.41. Found: C, 60.03; H, 5.01; N, 18.26; S, 8.31.
3.2.8. 3-N-Phenyl-2-(4-thiomorpholinyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6h). Yield
85%; mp 292–293 ꢁC; IR (KBr) n 1702 (C]O), 1530,
3.2.3. 2-Diethylamino-3-N-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6c). Yield
1449, 1383 cmꢀ1 1H NMR (300 MHz, CDCl3) d 2.30–
;
2.40 (m, 4H), 3.50–3.70 (m, 4H), 7.30–7.65 (m, 5H), 8.71
(d, J¼2.4 Hz, 1H), 8.86 (d, J¼2.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 26.4, 51.9, 120.1, 128.7, 128.8, 129.4,
137.0, 142.6, 144.1, 148.4, 158.4, 159.4; MS (EI) m/z 397
(M+, 4), 279 (25), 203 (15). Anal. Calcd for C18H15N5OS2:
C, 56.67; H, 3.96; N, 18.36; S, 16.81. Found: C, 56.43; H,
4.03; N, 18.36; S, 16.77.
91%; mp 185–187 ꢁC; IR (KBr)
n 1670 (C]O),
1520 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 0.93 (t, J¼
6.8 Hz, 6H), 2.43 (s, 3H), 3.26 (q, J¼6.8 Hz, 4H), 7.25–
7.33 (m, 4H), 8.68 (d, J¼2.4 Hz, 1H), 8.84 (d, J¼2.4 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 12.6, 21.2, 45.3, 128.2,
129.9, 134.9, 138.5, 142.4, 143.8, 144.1, 148.9, 158.2,
158.7, 160.1; MS (EI) m/z 365 (M+, 22), 336 (100). Anal.
Calcd for C19H19N5OS: C, 62.44; H, 5.24; N, 19.16; S,
8.77. Found: C, 62.63; H, 5.21; N, 19.26; S, 8.61.
3.2.9. 3-N-Phenyl-2-(1-pyrrolidinyl)pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (6i). Yield 90%; mp
244–245 ꢁC; IR (KBr) n 1703 (C]O), 1570, 1443,
1
3.2.4. 2-Diethylamino-3-N-(4-chlorophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6d). Yield
1348 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.70–1.82 (m,
4H), 3.16–3.25 (m, 4H), 7.35–7.57 (m, 5H), 8.66 (d,
J¼2.4 Hz, 1H), 8.81 (d, J¼2.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 25.4, 50.6, 128.7, 129.2, 137.2, 142.2,
143.8, 144.2, 150.0, 155.3, 158.9, 159.7; MS (EI) m/z 349
(M+, 20), 294 (13), 77 (100). Anal. Calcd for
C18H15N5OS: C, 61.87; H, 4.33; N, 20.04; S, 9.18. Found:
C, 61.73; H, 4.34; N, 19.91; S, 9.07.
94%; mp 230–231 ꢁC; IR (KBr) n 1680 (C]O), 1530 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 0.96 (t, J¼6.8 Hz, 6H), 3.25
(q, J¼6.8 Hz, 4H), 7.30–7.52 (m, 4H), 8.70 (d, J¼2.4 Hz,
1H), 8.85 (d, J¼2.4 Hz, 1H); 13C NMR (50 MHz, CDCl3)
d 12.5, 45.3, 118.5, 129.5, 129.9, 134.5, 135.9, 142.4,
142.6, 144.0, 149.0, 157.8, 158.7, 159.9; MS (EI) m/z

G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
11131
3.2.10. 3-N-Phenyl-2-(1-piperidinyl)pyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (6j). Yield 85%; mp
220–221 ꢁC; IR (KBr) n 1700 (C]O), 1602, 1547, 1520,
for C20H12N4OS2: C, 61.84; H, 3.11; N, 14.42; S, 16.51.
Found: C, 61.72; H, 2.99; N, 14.39; S, 16.45.
1
1390 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.20–1.50 (m,
3.3.3. 2-(4-Nitrophenoxy)-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (7c). Yield 78%; mp
143–145 ꢁC; IR (KBr) n 1699 (C]O), 1569, 1538, 1524,
6H), 3.10–3.40 (m, 4H), 7.30–7.56 (m, 5H), 8.66 (d,
J¼2.4 Hz, 1H), 8.82 (d, J¼2.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 23.9, 24.8, 50.4, 119.2, 128.4, 128.5,
129.1, 137.4, 142.5, 143.9, 144.0, 148.8, 158.6, 158.7,
159.6; MS (EI) m/z 363 (M+, 20). Anal. Calcd for
C19H17N5OS: C, 62.79; H, 4.71; N, 19.27; S, 8.82. Found:
C, 62.63; H, 4.63; N, 19.16; S, 8.78.
1487, 1345, 1260, 1218 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 7.40–7.49 (m, 4H), 7.53–7.65 (m, 3H), 8.28–
8.50 (m, 2H), 8.72 (d, J¼2.3 Hz, 1H), 8.82 (d, J¼2.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 121.9, 125.6, 127.8,
129.8, 129.9, 133.9, 143.1, 144.3; MS (FAB) m/z 418
(MH+, 50), 371 (19), 279 (100). Anal. Calcd for
C20H11N5O4S: C, 57.55; H, 2.66; N, 16.78; S, 7.68. Found:
C, 57.45; H, 2.82; N, 16.73; S, 7.52.
3.2.11. 2-Phenyl-3-N-phenylaminopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (6k). Yield 86%; mp
254–255 ꢁC; IR (KBr) n 3404 (NH), 1682 (C]O), 1595,
1556, 1537, 1516 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
3.3.4. 3-(4-tert-Butylphenoxy)-2-N-phenylpyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7d). Yield
67%; mp 228–230 ꢁC; IR (KBr) n 1690 (C]O), 1567,
d 6.24 (s, 1H), 7.08–7.13 (m, 1H), 7.31–7.37 (m, 2H),
7.47–7.57 (m, 4H), 7.59–7.71 (m, 3H), 8.65 (d, J¼2.3 Hz,
1H), 8.79 (d, J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 117.2, 120.8, 124.4, 128.8, 129.0, 130.6, 131.0, 133.7,
137.2, 142.4, 143.8, 149.3, 150.3, 158.3, 158.4; MS (EI)
m/z 371 (M+, 55). Anal. Calcd for C20H13N5OS: C, 64.68;
H, 3.53; N, 18.86; S, 8.63. Found: C, 64.49; H, 3.53; N,
18.66; S, 8.65.
1
1542, 1503, 1354, 1268, 1215 cmꢀ1; H NMR (300 MHz,
CDCl3) d 1.33 (s, 9H), 7.13–7.16 (m, 2H), 7.40–7.45 (m,
4H), 7.50–7.63 (m, 3H), 8.70 (d, J¼2.1 Hz, 1H), 8.81 (d,
J¼2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 31.4, 120.3,
127.7, 126.7, 127.9, 129.4, 134.5, 142.8, 144.1; MS (EI)
m/z 348 (M+, 45), 294 (43). Anal. Calcd for C24H20N4O2S:
C, 67.27; H, 4.70; N, 13.07; S, 7.48. Found: C, 67.11; H,
4.53; N, 12.95; S, 7.33.
3.3. General procedure for the synthesis of 3-aryloxy-2-
phenylpyrazino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one 7a–7e
3.3.5. 3-(4-Benzyloxyphenoxy)-2-N-phenylpyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7e). Yield
70%; mp 203–205 ꢁC; IR (KBr) n 1660 (C]O), 1568,
1547, 1535, 1520, 1497, 1446, 1354, 1195 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 5.06 (s, 2H), 6.90–7.20 (m, 4H),
7.25–7.80 (m, 10H), 8.69 (d, J¼2.1 Hz, 1H), 8.81 (d,
J¼2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 70.4, 115.7,
122.0, 127.5, 127.9, 128.1, 128.6, 129.5, 129.7, 142.8,
144.0; MS (FAB) m/z 479 (MH+, 24), 279 (52). Anal. Calcd
for C27H18N4O3S: C, 67.77; H, 3.79; N, 11.71; S, 6.70.
Found: C, 67.52; H, 3.61; N, 11.65; S, 6.58.
To a solution of iminophosphorane 3 (0.15 g, 0.31 mmol) in
dry THF (3 mL) was added phenylisocyanate (0.37 mmol) at
room temperature. The mixture was stirred at room tempera-
ture for 1–2 h until the iminophosphorane had disappeared
(TLC monitored) and after treating with an appropriate
substituted phenol or thiophenol (0.37 mmol), a catalytic
amount of K2CO3 was added and the resultant solution was
refluxed for 1 h. The solvent was evaporated under reduced
pressure, the solid residue was treated with ether (5 mL),
and the mixture was stirred at room temperature for 0.5 h.
The solid formed was filtered off and purified by chromato-
graphy on silica gel eluting with a dichloromethane/
ethyl acetate gradient from 10 to 30% ethyl acetate to give
7 as a yellow solid.
3.3.6. 3-Alkoxy-2-phenylpyrazino[20,30:4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one 7f and 7g. To a solution of imino-
phosphorane 3 (0.15 g, 0.31 mmol) in THF (3 mL) was
added the appropriate isocyanate (0.37 mmol) at room tem-
perature. The mixture was stirred at room temperature for
1–2 h until the iminophosphorane had disappeared (TLC
monitored). The solvent was evaporated, ROH (4 mL) was
added to dissolve the solid, and then NaOR (0.40 mmol)
was added and the resultant mixture was stirred at room tem-
perature for 1 h. The solvent was removed under reduced
pressure, and the residue was subjected to chromatography
on silica gel eluting with a dichloromethane/ethyl acetate
90:10 (v/v).
3.3.1. 3-N-Phenyl-2-phenoxypyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (7a). Yield 68%; mp
232–234 ꢁC; IR (KBr) n 1687 (C]O), 1600, 1564, 1534,
1505, 1487 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.18–
;
7.32 (m, 3H), 7.37–7.50 (m, 4H), 7.51–7.65 (m, 3H), 8.69
(d, J¼2.1 Hz, 1H), 8.80 (d, J¼2.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 121.0, 126.3, 127.9, 129.5, 129.7,
129.8, 142.8, 144.1; MS (FAB) m/z 373 (MH+, 98), 279
(13). Anal. Calcd for C20H12N4O2S: C, 64.50; H, 3.25; N,
15.04; S, 8.61. Found: C, 64.42; H, 3.11; N, 14.95; S, 8.56.
Compound 7f: yield 65%; yellow solid; mp 202–204 ꢁC; IR
(KBr) n 1692 (C]O), 1563, 1541, 1515, 1373, 1335,
3.3.2. 3-N-Phenyl-2-phenylthiopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (7b). Yield 85%; mp
226–227 ꢁC; IR (KBr) n 1677 (C]O), 1516, 1493, 1340,
1196 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.30 (t,
;
J¼7.1 Hz, 3H), 4.65 (q, J¼7.1 Hz, 2H), 7.28–7.33 (m,
2H), 7.48–7.60 (m, 3H), 8.73 (d, J¼2.3 Hz, 1H), 8.88 (d,
J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.0, 66.0,
127.9, 129.2, 129.4, 142.7, 144.1; MS (EI) m/z 324 (M+,
44). Anal. Calcd for C16H12N4O2S: C, 59.25; H, 3.73;
N, 17.27; S, 9.89. Found: C, 59.13; H, 3.61; N, 17.12;
S, 9.79.
1233, 1182 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.43–
;
7.55 (m, 5H), 7.57–7.70 (m, 5H), 8.65 (d, J¼2.2 Hz, 1H),
8.76 (d, J¼2.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 127.8, 128.9, 129.4, 130.1, 130.2, 130.6, 135.4, 143.0,
143.9; MS (FAB) m/z 389 (MH+, 100), 279 (16). Anal. Calcd

11132
G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
Compound 7g: yield 72%; yellow solid; mp 204–206 ꢁC; IR
(KBr) n 1693 (C]O), 1569, 1543, 1517, 1487, 1449, 1353,
7.20–7.35 (m, 5H), 7.35–7.45 (m, 2H), 7.50–7.70 (m, 3H),
8.69 (d, J¼2.3 Hz, 1H), 8.83 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 46.3, 127.4, 127.7, 128.6, 128.8,
130.5, 130.9, 133.9, 137.5, 142.3, 143.9, 150.1, 153.4,
158.6, 158.7; MS (EI) m/z 385 (M+, 5), 279 (3), 106 (25),
91 (100). Anal. Calcd for C21H15N5OS: C, 65.44; H, 3.92;
N, 18.17; S, 8.32; Found: C, 65.30; H, 4.01; N, 18.07; S,
8.16.
1
1265, 1194 cmꢀ1; H NMR (300 MHz, CDCl3) d 4.14 (s,
3H), 7.25–7.35 (m, 2H), 7.45–7.65 (m, 3H), 8.73 (d,
J¼2.3 Hz, 1H), 8.88 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 56.8, 127.9, 129.3, 129.5, 134.3,
142.7, 143.6, 144.1, 147.7, 156.8, 158.3, 158.7; MS (FAB)
m/z 311 (MH+, 68). Anal. Calcd for C15H10N4O2S: C,
58.05; H, 3.25; N, 18.05; S, 10.33. Found: C, 57.93; H,
3.38; N, 18.12; S, 10.19.
3.4.4. 3-N-Benzyl-2-phenylaminopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (9b). Yield 44%; mp
175–176 ꢁC; IR (KBr) n 3311 (NH), 1655 (C]O), 1595,
3.4. General procedure for the synthesis of pyrazino-
thienopyrimidinones 8 and 9
;
1536, 1461, 1455, 1446 cmꢀ1 1H NMR (300 MHz,
CDCl3) d 5.55 (s, 2H), 6.73 (s, 1H, NH), 7.05–7.15 (m,
1H), 7.30–7.55 (m, 9H), 8.66 (d, J¼2.3 Hz, 1H), 8.76 (d,
J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 45.5, 121.0,
124.5, 126.8, 129.0, 129.1, 129.8, 134.0, 137.6, 142.4,
143.9, 149.2, 150.9, 158.7, 159.1; MS (EI) m/z 385 (M+,
25), 294 (15). Anal. Calcd for C21H15N5OS: C, 65.44; H,
3.92; N, 18.17; S, 8.32. Found: C, 65.33; H, 4.01; N,
18.05; S, 8.15.
The appropriate isocyanate (phenyl-, 4-nitrophenyl-, or
4-methylphenylisocyanate) (0.37 mmol) was added to a so-
lution of iminophosphorane 3 (0.15 g, 0.31 mmol) in THF
(3 mL) at room temperature. The mixture was stirred at
room temperature for 1–2 h until the iminophosphorane
had disappeared (TLC monitored) and it was then treated
with the appropriate primary amine (0.37 mmol). The resul-
tant solution was stirred at room temperature for 5 h. The
solvent was evaporated, the solid residue was treated with
a catalytic amount of K2CO3, acetone (3 mL) was added,
and the mixture was refluxed for 1 h. The solvent was evap-
orated under reduced pressure, and the residue was subjected
to chromatography on silica gel eluting with a hexanes/ethyl
acetate gradient from 5 to 40% ethyl acetate to give 8/9 as
a yellow solid.
3.4.5. 2-Isopropylamino-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (8c). Yield 80%; mp
228–230 ꢁC; IR (KBr) n 3416 (NH), 1679 (C]O), 1545,
1522, 1508, 1485 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 1.15 (d, J¼6.5 Hz, 6H), 4.11 (d, J¼7.7 Hz, 1H, NH),
4.47–4.62 (m, 1H), 7.33–7.35 (m, 2H), 7.54–7.65 (m, 3H),
8.65 (d, J¼2.3 Hz, 1H), 8.80 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 22.7, 44.0, 115.2, 128.6, 130.2, 130.8,
134.0, 142.2, 143.7, 144.1, 150.2, 152.7, 158.5, 158.7; MS
(EI) m/z 337 (M+, 40), 294 (100). Anal. Calcd for
C17H15N5OS: C, 60.52; H, 4.48; N, 20.76; S, 9.50. Found:
C, 60.48; H, 4.55; N, 20.56; S, 9.41.
3.4.1. 2-n-Butylamino-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (8a). Yield 57%; mp
197–198 ꢁC; IR (KBr) n 3435 (NH), 1676 (C]O), 1589,
1
1564, 1548, 1530, 1523, 1486 cmꢀ1; H NMR (300 MHz,
CDCl3) d 0.88 (t, J¼7.3 Hz, 3H), 1.20–1.35 (m, 2H),
1.42–1.56 (m, 2H), 3.52–3.63 (m, 2H), 4.27 (t, J¼5.0 Hz,
1H, NH), 7.32–7.40 (m, 2H), 7.53–7.69 (m, 3H), 8.67 (d,
J¼2.3 Hz, 1H), 8.81 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 13.7, 19.9, 31.1, 40.0, 128.6, 130.6,
130.8, 134.0, 142.2, 143.7, 144.0, 150.2, 153.5, 158.5,
158.6; MS (EI) m/z 351 (M+, 25), 294 (85). Anal. Calcd
for C18H17N5OS: C, 61.52; H, 4.88; N, 19.93; S, 9.12.
Found: C, 61.37; H, 4.95; N, 19.92; S, 8.92.
3.4.6. 2-Cyclohexylylamino-3-N-phenylpyrazino[20,30:
4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8d). Yield 95%;
mp 208–210 ꢁC; IR (KBr) n 3271 (NH), 1685 (C]O),
1
1532, 1517, 1487, 1479, 1452 cmꢀ1; H NMR (300 MHz,
CDCl3) d 1.00–1.13 (m, 3H), 1.31–1.49 (m, 5H), 1.88–
1.92 (m, 2H), 4.20–4.28 (m, 2H), 7.30–7.32 (m, 2H),
7.47–7.60 (m, 3H), 8.59 (d, J¼2.3 Hz, 1H), 8.75 (d,
J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 23.9, 25.2,
32.4, 49.6, 114.9, 128.4, 130.1, 130.6, 133.9, 142.0, 143.5,
143.8, 150.1, 152.6, 158.3, 158.5; MS (EI) m/z 377 (M+,
10), 294 (95). Anal. Calcd for C20H19N5OS: C, 63.64; H,
5.07; N, 18.55; S, 8.49; Found: C, 63.56; H, 4.97; N,
18.49; S, 8.47.
3.4.2. 3-N-n-Butyl-2-phenylaminopyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (9a). Yield 19%; mp
99–101 ꢁC dec; IR (KBr) n 3354 (NH), 1674 (C]O),
1657, 1537, 1523, 1494, 1472, 1456, 1444 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 1.04 (t, J¼7.3 Hz, 3H), 1.45–1.60
(m, 2H), 1.80–1.95 (m, 2H), 4.29 (t, J¼7.7 Hz, 2H), 6.66
(s, 1H, NH), 7.14–7.23 (m, 1H), 7.40–7.50 (m, 2H), 7.63–
7.72 (d, 2H), 8.79 (d, J¼2.3 Hz, 1H), 8.86 (d, J¼2.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 13.7, 20.3, 29.8, 41.9,
121.6, 124.8, 129.3, 137.8, 142.4, 143.8, 150.6, 158.7; MS
(EI) m/z 351 (M+, 25), 294 (45). Anal. Calcd for
C18H17N5OS: C, 61.52; H, 4.88; N, 19.93; S, 9.12. Found:
C, 61.34; H, 4.99; N, 19.83; S, 8.95.
3.4.7. 2-tert-Butylamino-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (8e). Yield 82%; mp
231–232 ꢁC; IR (KBr) n 3432 (NH), 1683 (C]O), 1561,
1545, 1521, 1485 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 1.48 (s, 9H), 4.12 (s, 1H, NH), 7.33–7.37 (m, 2H), 7.61–
7.64 (m, 3H), 8.66 (d, J¼2.3 Hz, 1H), 8.85 (d, J¼2.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 28.9, 53.2, 128.6,
130.3, 130.9, 143.6, 145.0; MS (EI) m/z 351 (M+, 5), 294
(30). Anal. Calcd for C18H17N5OS: C, 61.52; H, 4.88; N,
19.93; S, 9.12. Found: C, 61.49; H, 4.73; N, 20.06; S, 9.25.
3.4.3. 2-Benzylamino-3-N-phenylpyrazino[20,30:4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (8b). Yield 55%; mp
113–115 ꢁC; IR (KBr) n 3249 (NH), 1681 (C]O), 1552,
3.4.8. 3-N-n-Butyl-2-(4-nitrophenylamino)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (9a1). Yield
82%; mp 234–235 ꢁC; IR (KBr) n 3423 (NH), 1676
1522, 1493, 1339 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 4.63 (t, J¼5.3 Hz, 1H, NH), 4.83 (d, J¼5.3 Hz, 2H),

G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
11133
(C]O), 1538, 1502, 1404 cmꢀ1
;
1H NMR (300 MHz,
C17H14N6O3S: C, 53.40; H, 3.69; N, 21.98; S, 8.39. Found:
C, 53.49; H, 3.53; N, 21.76; S, 8.25.
CDCl3) d 1.06 (t, J¼7.3 Hz, 3H), 1.48–1.63 (m, 2H),
1.80–1.96 (m, 2H), 4.34 (t, J¼7.7 Hz, 2H), 7.03 (s, 1H,
NH), 7.30–7.37 (m, 2H), 7.87–7.99 (m, 2H), 8.71 (d,
J¼2.3 Hz, 1H), 8.84 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 13.7, 20.2, 30.1, 42.1, 120.1, 125.3,
142.7, 143.5, 144.2, 158.3; MS (EI) m/z 396 (M+, 15),
339 (25). Anal. Calcd for C18H16N6O3S: C, 54.54; H,
4.07; N, 21.20; S, 8.09. Found: C, 54.31; H, 4.21; N,
21.45; S, 8.14.
3.4.13. 2-Isopropylamino-3-N-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8c2). Yield
98%; mp 217–219 ꢁC; IR (KBr) n 3414 (NH), 1676
(C]O), 1665, 1552, 1547, 1522, 1507, 1482, 1466, 1422,
1
1409 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.16 (d, J¼
6.5 Hz, 6H), 2.46 (s, 3H), 4.18 (d, J¼7.9 Hz, 1H, NH),
4.45–4.75 (m, 1H), 7.17–7.25 (m, 2H), 7.40–7.45 (m, 2H),
8.65 (d, J¼2.3 Hz, 1H), 8.81 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 21.3, 22.7, 43.9, 115.2, 128.2, 131.2,
132.5, 140.5, 142.2, 143.7, 144.1, 150.2, 152.9, 158.6,
158.8; MS (EI) m/z 351 (M+, 40), 308 (100), 91 (25).
Anal. Calcd for C18H17N5OS: C, 61.52; H, 4.88; N, 19.93;
S, 9.12. Found: C, 61.45; H, 4.97; N, 20.03; S, 9.17.
3.4.9. 2-n-Butylamino-3-N-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8a2). Yield
89%; mp 163–165 ꢁC; IR (KBr) n 3256 (NH), 1611
(C]O), 1562, 1524, 1509, 1480, 1464, 1435 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 0.88 (t, J¼7.3 Hz, 3H), 1.22–
1.34 (m, 2H), 1.44–1.54 (m, 2H), 2.45 (s, 3H), 3.53–3.60
(m, 2H), 4.35 (t, J¼5.1 Hz, 1H, NH), 7.21–7.23 (m, 2H),
7.39–7.42 (m, 2H), 8.65 (d, J¼2.3 Hz, 1H), 8.80 (d,
J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 13.7, 19.9,
21.3, 31.1, 42.0, 115.3, 128.2, 131.2, 131.5, 140.5, 142.1,
143.7, 144.1, 150.1, 153.6, 158.5, 158.7; MS (EI) m/z 365
(M+, 10), 308 (30). Anal. Calcd for C19H19N5OS: C,
62.44; H, 5.24; N, 19.16; S, 8.77. Found: C, 62.51; H,
5.39; N, 19.02; S, 8.75.
3.4.14. 2-Cyclohexylylamino-3-N-(4-nitrophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8d1). Yield
84%; mp 246–248 ꢁC; IR (KBr) n 3429 (NH), 1690
(C]O), 1547, 1530, 1346 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 1.06–1.24 (m, 3H), 1.35–1.50 (m, 3H), 1.73–
1.92 (m, 2H), 1.99–2.04 (m, 2H), 3.97 (d, J¼8.0 Hz, 1H,
NH), 4.25–4.38 (m, 1H), 7.57–7.65 (m, 2H), 8.48–8.56
(m, 2H), 8.71 (d, J¼2.3 Hz, 1H), 8.86 (d, J¼2.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 24.3, 25.3, 32.8, 50.4,
126.1, 130.4, 140.0, 142.5, 144.1, 148.8, 150.6, 151.7; MS
(EI) m/z 422 (M+, 5), 339 (30), 203 (30), 123 (30), 99
(52). Anal. Calcd for C20H18N6O3S: C, 56.86; H, 4.29; N,
19.89; S, 7.59. Found: C, 56.69; H, 4.13; N, 19.76; S, 7.46.
3.4.10. 3-N-Benzylamino-2-(4-nitrophenylamino)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (9b1). Yield
85%; mp 113–115 ꢁC; IR (KBr) n 3393 (NH), 1676
(C]O), 1610, 1541, 1503, 1464, 1413 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 5.61 (s, 2H), 7.01 (s, 1H, NH), 7.42–
7.57 (m, 5H), 7.58–7.65 (m, 2H), 8.21–8.28 (m, 2H), 8.74
(d, J¼2.3 Hz, 1H), 8.86 (d, J¼2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 45.8, 119.7, 125.3, 127.0, 130.0,
130.2, 133.7, 142.8, 144.3; MS (EI) m/z 430 (M+, 10), 279
(3), 91 (20). Anal. Calcd for C21H14N6O3S: C, 58.60; H,
3.28; N, 19.52; S, 7.45. Found: C, 58.58; H, 3.39; N,
19.43; S, 7.39.
3.4.15. 2-Cyclohexylylamino-3-N-(4-methylphenyl)pyr-
azino[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8d2).
Yield 88%; mp 233–235 ꢁC; IR (KBr) n 3416 (NH), 1686
(C]O), 1546, 1532, 1520, 1485, 1347 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 1.00–1.23 (m, 3H), 1.36–1.65 (m,
5H), 1.90–2.05 (m, 2H), 2.48 (s, 3H), 4.20–4.35 (m, 2H),
7.19–7.26 (m, 2H), 7.39–7.47 (m, 2H), 8.67 (d, J¼2.3 Hz,
1H), 8.82 (d, J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 21.3, 24.2, 25.4, 32.8, 49.9, 115.2, 128.2, 131.3, 131.5,
140.5, 142.2, 143.6, 144.1, 150.2, 153.0, 158.6, 158.9; MS
(EI) m/z 391 (M+, 10), 308 (100). Anal. Calcd for
C21H21N5OS: C, 64.43; H, 5.41; N, 17.89; S, 8.19. Found:
C, 64.33; H, 5.42; N, 17.69; S, 8.12.
3.4.11. 2-Benzylamino-3-N-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8b2). Yield
82%; mp 218–220 ꢁC; IR (KBr) n 3336 (NH), 1685
(C]O), 1553, 1522, 1509, 1452, 1343 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 2.43 (s, 3H), 4.73 (t, J¼5.2 Hz, 1H,
NH), 4.83 (d, J¼5.2 Hz, 2H), 7.20–7.35 (m, 7H), 7.36–
7.44 (m, 2H), 8.68 (d, J¼2.3 Hz, 1H), 8.81 (d, J¼2.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 21.3, 46.2, 115.9,
127.4, 127.6, 128.2, 128.7, 131.0, 131.6, 137.5, 140.7,
142.3, 143.8, 144.1, 150.0, 153.6, 158.6, 158.8; MS (EI)
m/z 399 (M+, 20), 91 (35). Anal. Calcd for C22H17N5OS:
C, 66.15; H, 4.29; N, 17.53; S, 8.03. Found: C, 66.24; H,
4.08; N, 17.64; S, 8.17.
3.4.16. 2-tert-Butylamino-3-N-(4-nitrophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8e1). Yield
93%; mp 227–229 ꢁC; IR (KBr) n 3415 (NH), 1690
(C]O), 1596, 1556, 1545, 1523, 1518, 1484 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 1.50 (s, 9H), 3.99 (s, 1H, NH),
7.58–7.61 (m, 2H), 7.48–7.51 (m, 2H), 8.68 (d, J¼2.3 Hz,
1H), 8.86 (d, J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 29.0, 53.8, 126.0, 130.4, 140.3, 142.6, 143.9, 144.1,
148.7, 150.3, 151.0, 158.4, 158.7; MS (EI) m/z 396 (M+,
15), 339 (90). Anal. Calcd for C18H16N6O3S: C, 54.54; H,
4.07; N, 21.20; S, 8.09. Found: C, 54.43; H, 4.19; N,
21.14; S, 8.19.
3.4.12. 2-Isopropylamino-3-N-(4-nitrophenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8c1). Yield
81%; mp>300 ꢁC; IR (KBr) n 3350 (NH), 1685 (C]O),
1545, 1520, 1480, 1390 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 1.21 (d, J¼6.5 Hz, 6H), 3.91 (d, J¼7.8 Hz, 1H,
NH), 4.45–4.70 (m, 1H), 7.58–7.65 (m, 2H), 8.50–8.56
(m, 2H), 8.71 (d, J¼2.3 Hz, 1H), 8.86 (d, J¼2.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 22.8, 44.5, 115.1, 126.1,
130.4, 139.9, 142.5, 144.1, 148.8, 151.7; MS (EI) m/z 382
(M+, 63), 339 (100), 324 (17), 203 (33). Anal. Calcd for
3.4.17. 2-tert-Butylamino-3-N-(4-methylphenyl)pyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8e2). Yield
85%; mp 224–226 ꢁC; IR (KBr) n 3428 (NH), 1681
(C]O), 1557, 1545, 1520, 1484, 1456 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 1.45 (s, 9H), 2.43 (s, 3H), 4.29 (s,

11134
G. Blanco et al. / Tetrahedron 62 (2006) 11124–11135
3. (a) Shishoo, C. J.; Shirsath, V. S.; Rathod, I. S.; Yande, V. D.
Eur. J. Med. Chem. 2000, 35, 351; (b) Walter, H. WO
9911631, 1999; Chem. Abstr. 1999, 130, 237580e; (c) Walter,
H. WO 9914202, 1999; Chem. Abstr. 1999, 130, 252368k;
(d) Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar,
R. H. Eur. J. Med. Chem. 2003, 38, 89.
4. (a) Stratmann, J. Chem.-Ztg. 1991, 115, 59; (b) Clark, J.;
Hitiris, G. J. Chem. Soc., Perkin Trans. 1 1984, 2005; (c)
Gewald, K.; Martin, A. J. Prakt. Chem./Chem.-Ztg. 1981,
323, 843.
5. Sherman, A. R. Bicyclic 5-6 Systems. Two Heteroatoms 1:1. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Elsevier
Science: UK, 1996; Vol. 7, p 167.
ꢀ
6. (a) Quintela, J. M.; Peinador, C.; Gonzalez, L. M.; Rioja, I.;
Terencio, M. C.; Ubeda, A.; Alcaraz, M. J.; Riguera, R.
1H, NH), 7.18–7.21 (m, 2H), 7.33–7.41 (m, 2H), 8.62 (d, J¼
2.3 Hz, 1H), 8.81 (d, J¼2.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 21.2, 28.8, 53.0, 115.1, 128.1, 131.4, 140.3,
142.2, 143.4, 144.2, 149.8, 152.2, 158.4, 158.9; MS (EI)
m/z 365 (M+, 10), 308 (50). Anal. Calcd for C19H19N5OS:
C, 62.44; H, 5.24; N, 19.16; S, 8.77. Found: C, 62.49; H,
5.39; N, 19.13; S, 8.91.
3.4.18. 3-N-(4-Nitrophenyl)-2-phenylaminopyrazino-
[20,30:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8f). Yield
98%; mp 254–256 ꢁC; IR (KBr) n 3380 (NH), 1609
(C]O), 1572, 1542, 1537, 1520, 1503, 1492, 1487, 1455,
1
1413 cmꢀ1; H NMR (300 MHz, CDCl3) d 6.54 (s, 1H,
NH), 7.49–7.52 (m, 2H), 7.68–7.79 (m, 3H), 7.81–7.84
(m, 2H), 8.24–8.27 (m, 2H), 8.75 (d, J¼2.3 Hz, 1H), 8.90
(d, J¼2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 119.7,
125.2, 128.8, 131.2, 131.4, 133.3, 142.9, 143.1, 143.4,
143.6, 144.3, 148.6, 149.0, 158.1, 158.4; MS (EI) m/z 416
(M+, 100), 370 (20). Anal. Calcd for C20H12N6O3S: C,
57.69; H, 2.90; N, 20.18; S, 7.70. Found: C, 57.50; H,
2.78; N, 20.33; S, 7.82.
ꢀ
J. Med. Chem. 1999, 42, 4720; (b) Quintela, J. M.; Gonzalez,
L.; Devesa, I.; Ferrandiz, M. L.; Alcaraz, M. J.; Riguera, R.
ꢀ
Bioorg. Med. Chem. 2003, 11, 863 and references cited
ꢀ
therein.; (c) Quintela, J. M.; Peinador, C.; Gonzzalez, L.;
Iglesias, R.; Parama, A.; Alvarez, F.; Sanmartın, M.; Riguera,
ꢀ
ꢀ
´
R. Eur. J. Med. Chem. 2003, 38, 265 and references cited
ꢀ
therein; (d) Rioja, I.; Ubeda, A.; Terencio, M. C.; Guillen, I.;
Riguera, R.; Quintela, J. M.; Peinador, C.; Gonzalez, L.;
ꢀ
4. Crystallographic material
Alcaraz, M. J. Eur. J. Pharmacol. 2000, 397, 207.
7. To our knowledge, there is only two reports on the pyridothieno-
pyridazine system, see: (a) Schneller, S. W.; Clough, F. W.;
Hardee, L. E. J. Heterocycl. Chem. 1975, 12, 513; (b) Badr,
M. Z. A.; Mahgoub, S. A.; Atta, F. M.; Moustafa, O. S.
J. Indian Chem. Soc. 1997, 74, 30.
8. (a) Cheng, C. C. Progress in Medicinal Chemistry; Elli, G. P.,
West, G. B., Eds.; Elsevier: Amsterdam, 1989; p 35; (b)
Leitsner, S.; Wagner, M.; Guetscharo, M.; Glosa, E.
Pharmazie 1986, 41, 54; (c) Bousquet, E.; Guerrera, F.;
Siracusa, N. A.; Caruso, A.; Roxas, M. A. Farmaco 1984, 39,
110; (d) Chaykosky, M.; Lin, M.; Rosowsky, A.; Modest,
E. J. J. Med. Chem. 1973, 10, 188.
Crystallographic data (excluding structural factors) for
8a, 8c1, and 9a1 have been deposited in the Cambridge
Crystallographic Data Center as supplementary publication
numbers CCDC 614690, CCDC 614691, and CCDC
614692 for 8a, 8c1, and 9a1, respectively. Copies of the
data may be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
+44 1223 33603 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
We thank MCyT (Spain, Grant BQU2003-00574) and the
Xunta de Galicia Spain, Grant PGI-DIT04PXIC10307PN)
for financial support.
9. For recent reviews on heterocyclic synthesis by the aza-
Wittig reaction, see: (a) Fresneda, P. M.; Molina, P. Synlett
2004, 1; (b) Eguchi, S.; Okano, T.; Okawa, T. Recent
Research Developments in Organic Chemistry; Pandalai,
S. G., Ed.; Transworld Research Network; Wiley: 1997;
Vol. 1, p 337; (c) Molina, P.; Vilaplana, M. J. Synthesis
1994, 1197; (d) Eguchi, S.; Matsushita, Y.; Yamashita, K.
Org. Prep. Proced. Int. 1992, 24, 209; (e) Wamhoff, H.;
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€
Richardt, G.; Stolben, S. Advances in Heterocyclic
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10. (a) Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun.
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´
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Synlett 1992, 295; (c) Molina, P.; Dıaz, I.; Tarraga, A.
Tetrahedron 1995, 51, 5617; (d) Eguchi, S.; Yamashita, K.;
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56, 1535; (g) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara,
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ꢀ
(d) Quintela, J. M.; Alvarez-Sarandes, R.; Peinador, C.
´
ꢀ
ꢀ
11. For some references, see: (a) Molina, P.; Alajarın, M.; Sanchez-
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Tetrahedron 1998, 54, 8107.
14. Sato, N.; Matsui, N. J. Heterocycl. Chem. 1992, 29, 1689.
15. This iminophosphorane synthesis is known as the Appel
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Halstenberg, M. Organophosphorous Reagents in Organic
Synthesis; Cadogan, J. I. G., Ed.; Academic: London, 1979;
p 378; and often used in recent literatures, for example (a)
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T.; Kawase, M.; Eguchi, S. Synthesis 1998, 1185.
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Reviews on Heteroatom Chemistry; Oae, S., Ed.; MYU:
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ꢀ
13. (a) Vazquez, D.; Peinador, C.; Quintela, J. M. Tetrahedron
2004, 60, 275; (b) Alvarez-Sarandes, R.; Peinador, C.;
ꢀ
ꢀ