Synthesis and characterization of substituted pyrazino[2′,3′:4, 5]thieno[3,2-d]pyrimidines and related molecules

Article abstract of DOI:10.1055/s-0030-1258432

An efficient access for the synthesis of substituted pyrazino[2′, 3′:4,5]thieno[3,2-d]pyrimidines and pyrazino[2′,3′:4,5] thieno[3,2-d]-1,2,3-triazines, heteroaromatic nitrogen ligands, is reported. The title compounds were obtained by functionalization o

Full text of DOI:10.1055/s-0030-1258432

PAPER
943
Synthesis and Characterization of Substituted Pyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidines and Related Molecules
S
ynthesis of Subst
n
itute
d
Pyrazi
t
nothien
o
opyrimidine
n
s
io Fernández-Mato, Carlos Peinador,* José M. Quintela*
Departamento de Química Fundamental, Facultad de Ciencias, Universidade da Coruña, Campus A Zapateira, A Coruña 15008, Spain
Fax +34(981)167065; E-mail: carlos.peinador@udc.es; E-mail: jose.maria.quintela@udc.es
Received 14 December 2010; revised 24 January 2011
ridazinothienotriazine moieties were new antiprotozoals
Abstract: An efficient access for the synthesis of substituted
active against Philasteridis dicentrarchi, the causative
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines
and
pyrazi-
agent of scuticociliatosis in farmed turbot and Black Sea
no[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazines, heteroaromatic nitrogen
bass-bream.7 The pyrazine ring is found in the fungal me-
ligands, is reported. The title compounds were obtained by func-
tionalization of the corresponding chloro precursors, synthesized by tabolite aspergillic acid as well as in marine metabolites
reaction between 7-aminothieno[2,3-b]pyrazine-6-carbonitrile and
N,N-dimethyldichloromethyleniminium chloride (Viehe’s salt) or
sodium nitrite/hydrochloric acid, respectively. Moreover, this pro-
natural products.9 Besides, substituted pyrazine motifs are
cedure provided a convenient synthetic route to bis(pyrazi-
which exhibit mild cytotoxicity against certain human
cancer cells,8 and it is also present in other biologically
often found in compounds with applications as anticancer
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidines), functionalized molecules
agents, including currently marketed drugs10 and those re-
that are not readily available by other synthetic methods.
cently reported.11 The introduction of a pyrazine moiety to
the thienopyrimidine system is expected to influence the
biological activity significantly.
Key words: heterocycles, ligands, ring closure, antitumor agents,
fused-ring systems
On the other hand, heteroaromatic ligands have attracted
strong interest because they have found applications in
several important research and technological fields.12
Over the years, the development of aromatic azaheterocy-
cles as ligands has provided a valuable resource for re-
searchers who work in the field of metal–ligand
coordination.13 One of the most extensively studied N-
heterocyclic chelating agents is the bidentate ligand 1,10-
phenanthroline. The latter, and related N-heterocycles, are
widely employed as metal-binding components in all as-
pects of coordination chemistry, and in many of its mod-
ern applications to areas such as supramolecular
chemistry and bioinorganic chemistry.14 The vast majori-
ty of heteroaromatic nitrogen ligands are mainly pyridine-
based structures, which appears to be a serious limitation
to the strong potential coordinating properties of other
heteroaromatic structures. In this context, an increasingly
important area of ligand design involves the synthesis and
study of new bridging ligands and their use as chelating
ligands.15
Heteroaromatic rings are important constituents of drugs
and bioactive molecules. Within drug discovery there is
currently considerable interest in fragment-based ap-
proaches for the identification of novel ligands.1 Com-
pounds containing a pyrimidine ring play a very important
part in the biochemistry of the living cell and have attract-
ed attention in the past few years owing to their wide
range of biological activity, particularly in cancer and vi-
rus research.2 Their fused bicyclic analogues have also
been reported to exhibit a variety of biological activity
and constitute the backbone of several marketed drugs.
Among these fused bicyclic compounds, thienopyrim-
idines, which are well-known bioisosteres of quinazo-
lines, are of great importance because of their role as
phamacophores of considerable historical importance3
and their remarkable effects on the central nervous system
as well as a wide variety of other biological activity.4 Our
previous work on the search for novel heterocyclic com-
pounds of pharmacological interest have shown that cer-
tain tri- and tetracyclic ring systems, containing the
pyridothienopyrimidine and pyridothienotriazine skele-
tons exert acute anti-inflammatory, analgesic, and anti-
angiogenic effects. Thus, they represent a new approach
for the potential treatment of different inflammatory pa-
thologies, such as rheumatoid arthritis.5 This was the first
time that pyridothieno-1,2,3-triazine derivatives have
been identified as effective inhibitors of nitric oxide and
eicosanoid biosynthesis.6 Besides, we showed that other
analogues based on the pyridothienopyrimidine and py-
Recently, we reported the synthesis of pyrazinothieno-
pyrimidine scaffolds by domino reactions: aza-Wittig/
intermolecular nucleophilic addition/intramolecular cy-
clization.16 In this work, we describe an efficient access
for the synthesis of 5 and 11 which, as isosteres of phar-
maceutically relevant pyridothienopyrimidines and pyri-
dothienotriazines, could play an important role in the
pathophysiology of inflammation and arthritis.
Our strategy for the synthesis of these compounds was
based on the disconnection illustrated in Scheme 1. Ret-
rosynthetic pathway indicates that the most direct and ver-
satile route to ring systems 5 and 11, which present the
necessary functionality for fusion of the desired pyrimi-
dine and triazine rings, was via the easily accessible 7-
SYNTHESIS 2011, No. 6, pp 0943–0953
x
x
.
x
x
.2
0
1
1
Advanced online publication: 10.02.2011
DOI: 10.1055/s-0030-1258432; Art ID: T53410SS
© Georg Thieme Verlag Stuttgart · New York

944
A. Fernández-Mato et al.
PAPER
aminothieno[2,3-b]pyrazine-6-carbonitrile (1). Com- medium-pressure chromatography. Intermediate 2 under-
pound 1 was prepared by reaction between commercially went cyclization to the corresponding pyrazinothieno-
available 3-chloropyrazine-2-carbonitrile and sodium hy- pyrimidine 3 by reaction with dry hydrogen chloride.
drosulfide.17 The resulting thiol reacted with chloroaceto- One-pot synthesis using enaminonitrile 1 and N,N-di-
nitrile to give the thienopyrazine 1.18 In our scheme, the methyldichloromethyleniminium chloride in refluxing
conversion of 1 into 5 involves the introduction of two 1,2-dichloroethane for six hours and subsequent treatment
substituents, R and NMe2 on to the fused heterocyclic with hydrogen chloride afforded directly the chloropy-
compound. To this end, we selected a dichloromethylen- razinothienopyrimidine 3, a fruitful precursor of the ex-
iminium chloride (phosgeniminium chloride), a well- pected molecules.
known multiple electrophilic one carbon atom synthon,19
as the reagent of choice. The dimethylamino substituent
(i) NaSH
N
N
Cl
N
S
(ii) ClCH2CN, K2CO3
was introduced during the formation of the pyrimidine
ring, and the substituent R was introduced in the last step
by means of an aromatic nucleophilic substitution reac-
tion. The above-mentioned phosgeniminium salts are very
useful synthetic reagents that can function as Vilsmeier or
Mannich acceptors and can lead to the insertion of a one-
carbon unit bearing a dialkylamino group. This makes
them especially useful in one-step heterocyclization reac-
tions such as those considered here. In particular, cycliza-
tion reactions of aromatic ortho-aminonitriles with N,N-
dimethyldichloromethyleniminium chloride (Viehe’s
salt) provided a convenient access to a number of fused
pyrimidine derivatives, including natural products.20
CN
CN
N
NH2
1
Cl2CN+Me2Cl–
(i) Cl2CN+Me2Cl–
DCE, reflux, 6 h
(ii) HCl(g), r.t., 24 h
DCE
reflux, 6 h
N
N
S
N
CN
S
Cl
HCl (g), r.t., 24 h
Cl
N
N
N
2
N
NMe2
3
NMe2
RH, THF, reflux
RB(OH)2, K2CO3
Pd(Ph3P)4
toluene, reflux
RH, THF
reflux
N
N
N
R
S
S
S
R
R
diazotization
S
CN
N
N
N
N
N
N
N
R
N
N
N
N
N
N
N
N
N
N
N
N
S
CN
NMe2
NMe2
5m–p
5a–l
4a–e
NMe2
11
CN
R
Scheme 2 Synthesis of amide halide thienopyrazines 2 and 4, and
pyrazinothienopyrimidines 3 and 5
S
N
NH2
1
N
Viehe's salt
NMe2
The structures of compounds 2 and 3 were consistent with
their elemental analyses and spectral data. The mass spec-
5
Scheme 1 Retrosynthetic pathway for pyrazinothienopyrimidines 5 tra showed the expected molecular ion peak at m/z = 266
and pyrazinothienotriazines 11
and the IR spectrum of 2 exhibited an absorption band at
1600 cm–1 due to the imino group and presented a charac-
teristic signal at 2200 cm–1 (CN), while the decoupled 13C
For the preparation of pyrazinothienotriazines 11 we were
NMR spectrum showed one signal at d = 125.4 due to the
carbon atom in the one cyano group. In addition, IR and
13C NMR spectra of compound 3 did not include those
types of signals.
pleased to find that the intramolecular condensation of a
diazonium ion with an adjacent nucleophilic function in-
deed furnished the desired compounds in good yields.
Herein, we report the participation of 7-aminothieno[2,3-
b]pyrazine-6-carbonitrile (1) in the synthesis of triazine
compounds 11 by way of diazotization followed by in-
tramolecular condensation reaction. We considered that
this methodology would be attractive due to its concise-
ness and practical utilization of readily synthesized or
commercially available starting materials.
Phosgeniminium salts are known to undergo condensa-
tion with CH-acidic compounds such as ketones, carbox-
ylic acids and chlorides, nitriles, and amides to give amide
halides. Amide chlorides have been similarly obtained
from enamines, fulvenes, barbituric acid derivatives, and
pyridopyrimidines by reaction with dichloromethylen-
iminium salts. In addition, phosgeniminium salts do not
react with the nitrile group unless it is sufficiently activat-
ed or the salts are previously transformed into chloroimin-
ium chlorides by means of dry hydrogen chloride. Since
the amide halide intermediate 2 was isolated, the reaction
can be assumed to proceed as described in Scheme 3.21
The synthesis of pyrazinothienopyrimidines 5 is summa-
rized in Scheme 2. The conversion of 1 into 3 involves the
introduction of one additional carbon that must conserve
its electrophilic character in 3. Thus, beginning with 7-
aminothieno[2,3-b]pyrazine-6-carbonitrile (1), the pyrim-
idine ring was fused to the thiophene ring by treatment
with Viehe’s salt in refluxing 1,2-dichloroethane to give
the amide halide intermediate 2, which was isolated by
concentration of the reaction mixture and purified by
The chloride bearing group in the 7-{[chloro(dimethyl-
amino)methylene]amino}thieno[2,3-b]pyrazine-6-carbo-
Synthesis 2011, No. 6, 943–953 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Pyrazinothienopyrimidines
945
Table 2 Substituted Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines
5a–p
Cl
NH
Cl
S
N
S
CN
Cl
C
N
Time Yielda Mp
HCl (g)
Entry Compd R
(h)
(%) (°C)
N
N
N
N
>300b
NMe2
1
2
3
4
5a
5b
5c
5d
OEt
3
66
75
84
72
2
NMe2
NHBu
NEt2
SH
12
2
186–188c
140–142d
>300e
Cl
S
N
N
N
24
N
3
NMe2
5
6
5e
5f
12
24
72
70
98
69
90
80
65
182–184g
156–158g
290–292b
220–222b
198–200d
143–145f
166–168e
O
S
Scheme 3
nitrile (2) reacted readily with nucleophilic agents to give
the corresponding substituted products 4a–e in good
yields (Table 1). Similarly, pyrazinothienopyrimidine 3
also exhibited remarkable reactivity of its 4-chloro sub-
stituent toward nucleophilic agents such as alcohols, thi-
ols, and amines. Thus, aliphatic and aromatic amines and
hydrosulfide, alkoxide, or aryloxide anions afforded the
corresponding derivatives 5a–l (Table 2). Interestingly,
the aryl derivatives 5m–p can be prepared via a Suzuki–
Miyaura cross-coupling reaction between tricyclic chloro
derivative 3 and arylboronic acids using a commercially
available preformed palladium catalyst (entries 13–16).
Compound 5p could be of particular interest because biar-
yl moieties, often found in natural products and biologi-
cally active compounds, are important fragments in
medicinal chemistry.22
7
5g
5h
5i
0.5
N
8
12
3
O
S
N
N
9
10
11
5j
12
8
N
5k
Me
Br
N
N
12
5l
24
60
288–290c
NH
13
14
15
16
5m
5n
5o
12
12
10
24
71
80
88
79
223–225g
230–232g
209–211g
290 (dec.)g
Table 1 7-{[(Dimethylamino)methylene]amino}thieno[2,3-
b]pyrazine-6-carbonitriles 4a–e
Time (h) Yielda (%) Mp (°C)
MeO
Cl
Entry Compd R
1
2
4a
4b
OEt
3
3
78
79
140–142b
218–220c
O
N
N
5p
3
4
4c
2
6
75
60
199–201c
141–143c
S
a Yields refer to pure isolated products.
b Recrystallized (EtOH).
c Purified by flash chromatography (CH2Cl2–hexanes, 8:2).
d Purified by flash chromatography (CH2Cl2–EtOAc, 9:1).
e Washed with EtOH–THF.
4d
N
5
4e
3
73
279–281c
f Purified by flash chromatography (acetone–hexanes, 1:1).
g Purified by flash chromatography (CH2Cl2).
Br
NH
a Yields refer to pure isolated products.
b Recrystallized (EtOH).
compounds, two pyrazinothienopyrimidine rings are
linked via their respective C4 carbon atoms by a 1,4-phe-
nylenedisulfanyl , piperazine-1,4-diyl, propane-1,3-diyl-
diamino, or 1,4-phenylenediamino chain (Scheme 4).
Therefore, compound 3 was converted into the bis(pyrazi-
nothienopyrimidine) 6a using piperazine as the bis(nu-
cleophile) (Table 3, entry 1). Similarly, bis(heterocycle)
6b was obtained in acceptable yield (70%) using benzene-
1,4-dithiol (entry 2). Compound 3 also reacted with di-
amines, and the nature of the reaction product appeared to
depend on the diamine employed. When the reaction of 3
c Purified by flash chromatography (CH2Cl2).
Based upon these results, we next examined the reactivity
of pyrazinothienopyrimidine 3 using various sulfur and
nitrogen bis(nucleophiles) and, fortunately, this procedure
provided a convenient synthetic route to bis(pyrazino-
thienopyrimidines) 6, functionalized molecules that are
not readily available by other synthetic methods. In these
Synthesis 2011, No. 6, 943–953 © Thieme Stuttgart · New York

946
A. Fernández-Mato et al.
PAPER
and 1,4-phenylenediamine or propane-1,3-diamine is car- function. This procedure has proven useful in the synthe-
ried out the corresponding bis(heterocycles) 6c and 6d are sis of various five- and six-membered ring nitrogen het-
obtained as crystalline solids in moderate yields (entry 3 erocycles.23 We found, in fact, that the diazotization of the
and 4). However, solubility seems to be a limitation to the key compound 7-aminothieno[2,3-b]pyrazine-6-carboni-
reaction, since the reaction with benzidine or 1,5-diami- trile (1) constituted a direct and very convenient route to
nonaphthalene afforded only pyrazinothienopyrimidines the pyrazinothienotriazine core. The synthesis of com-
7 and 8 (Figure 1). Finally, bis(pyrazinothienopyrimi- pounds 10 and 11 is outlined in Scheme 5. Diazotization
dine) 9 was obtained by reaction of chloro derivative 3 of 1 with sodium nitrite in hydrochloric acid gives a high
with tris(2-aminoethyl)amine in 60% yield.
yield (86%) of the condensed 4-chloropyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazine (10), which pro-
duced the pyrazinothieno-1,2,3-triazines 11 by halide
displacement with the appropriate nucleophile (Table 4).
The molecular formula of compounds 10 and 11 are sup-
ported by elemental analyses and mass spectra, which
gave the expected molecular ion peaks.
NMe2
N
N
N
Cl
N
S
S
N
H
R
H
R
N
S
K2CO3, THF, reflux
NMe2
N
N
N
N
3
Cl
R
N
N
N
S
S
S
N
NMe2
N
N
ii
CN
i
6a–d
N
N
N
N
N
Scheme 4 Synthesis of bis(pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimi-
dines) 6a–d
N
N
N
NH2
1
10
11a–h
Scheme 5 Synthesis of pyrazinothienotriazines 11a–h. Reagents
and conditions: (i) NaNO2, HCl; (ii) RH, THF, reflux.
Table 3 Bis(pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines) 6a–d
Entry Compd R
Time Yielda Mp
Table 4 Substituted Pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triaz-
ines 11a–h
(h)
(%) (°C)
1
2
6a
6b
48
67
70
>300b
N
S
N
Entry Compd R
Time (h) Yielda (%) Mp (°C)
1
2
11a
11b
OEt
24
48
79
81
201–203b
154–155c
18
296–298b
S
NEt2
3
4
6c
48
30
58
53
>300b
>300c
3
4
5
6
7
8
11c
11d
11e
11f
12
48
24
24
2
89
70
78
59
88
73
285 (dec.)b
223–224c
274–275d
244–246c
204–205c
254–256c
HN
NH
NH
N
6d
N
HN
a Yields refer to pure isolated products.
b Washed with EtOH–THF.
O
S
N
c Purified by flash chromatography (CH2Cl2–EtOH, 8:2).
N
H2N
11g
11h
N
N
N
S
HN
N
NH2
2
Me
N
N
N
N
N
S
7
NH
NMe2
N
a Yields refer to pure isolated products.
b Washed with EtOH–THF.
H2N
N
8
N
c Purified by flash chromatography (CH2Cl2).
d Purified by flash chromatography (EtOAc).
N
NMe2
S
N
NH
N
S
N
N
NH
N
These results indicate the importance and utility of 7-ami-
nothieno[2,3-b]pyrazine-6-carbonitrile (1) as a versatile
building block in the preparation of complex polycyclic
compounds. Moreover, this process represents a novel re-
action sequence in the preparation of bis(pyrazino-
thienopyrimidines), a class of compounds that are
particularly challenging to access using existing technol-
ogies.
N
N
Me2N
9
Me2N
Figure 1
The preparation of pyrazinothienotriazines 10 and 11 was
accomplished in good yields by intramolecular condensa-
tion of a diazonium ion with an adjacent nucleophilic
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Synthesis of Substituted Pyrazinothienopyrimidines
947
1H NMR (300 MHz, CDCl3): d = 3.35 (s, 6 H), 8.72 (d, J = 2.3 Hz,
1 H), 8.83 (d, J = 2.3 Hz, 1 H).
Pyrazinothienopyrimidines and pyrazinothienotriazines
have been tested in vitro for their potential antitumoral ac-
tivity against four standard tumoral cell lines: LLC-PK1 13C NMR (75 MHz, CDCl3): d = 37.7, 104.7, 117.6, 125.4, 142.4,
145.2.
(kidney carcinoma), NCI-H460 (human lung carcinoma),
MS (EI): m/z = 268 (19), 266 [M+, 61].
Hela 229 (human cervix carcinoma), and A2780 (human
ovary carcinoma). The results show that the compounds
are, in general, inactive. Only 4 and 5h exhibited moder-
ate in vitro antitumoral activity toward A2780, but 4 [IC50
(mM) = 13] and 5h [IC50 (mM) = 8.6] were both less active
than the reference cisplatin [IC50 (mM) = 0.47].24
Anal. Calcd for C10H8ClN5S: C, 45.20; H, 3.03; N, 26.36; S, 12.07.
Found: C, 45.31; H, 3.20; N, 26.86; S, 11.89.
4-Chloro-2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidine (3)
Method A: To a suspension of 1 (2.30 g, 13.20 mmol) in 1,2-dichlo-
roethane (100 mL) was added Viehe’s salt (3.00 g, 18.50 mmol),
and the mixture was refluxed for 6 h. A stream of dry HCl(g) was
passed through the mixture for 3 h and the mixture was allowed to
stand overnight at r.t. The solvent was removed under reduced pres-
sure and the resulting solid was recrystallized (EtOH) to afford 3
(3.17 g, 87%).
All reagents were commercial grade chemicals from freshly opened
containers. Merck 60 F254 foils were used for TLC and Merck 60
(230–400 mesh) silica gel for flash chromatography. NMR spectra
were obtained in a Bruker Avance 300 (300 MHz and 75 MHz for
1H and 13C, respectively) in CDCl3 or DMSO-d6 as solvent relative
1
to TMS at d = 0.00 ppm for H and to CDCl3 at d = 77.1 ppm for
Method B: A stream of dry HCl(g) was passed trough a soln of 2
(1.45 g, 5.46 mmol) in 1,2-dichloroethane (50 mL) for 3 h. The mix-
ture was allowed to stand overnight at r.t. The solvent was removed
under reduced pressure and the resulting solid was recrystallized
(EtOH) to afford 3 (1.42 g, 97%); mp 219–221 °C.
IR (KBr): 2923, 2862, 1570, 1494, 1404, 1163 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.34 (s, 6 H), 8.71 (d, J = 2.3 Hz,
1 H), 8.83 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 37.7, 117.6, 142.4, 143.8, 145.1,
155.6, 156.5, 159.3, 161.2.
MS (FAB): m/z (%) = 268 (13), 266 [(M + H)+, 40], 246 (9), 130
(8).
13C. IR spectra were recorded as KBr disks on a Bruker VECTOR
22 spectrophotometer. Mass spectrometry experiments were carried
out in a Thermo MAT 95 XP spectrometer. Melting points were
measured using Stuart Scientific SMP3 apparatus and are uncor-
rected. Microanalyses were performed by the elemental analyses
general service of the University of A Coruña on a Carlo Erba EA-
1108 instrument. Antitumoral activity was measured in the Plata-
forma de Screening de Fármacos USEF, University of Santiago de
Compostela (Spain).
7-Aminothieno[2,3-b]pyrazine-6-carbonitrile (1)
To a soln of 3-chloropyrazine-2-carbonitrile17 (3.82 g, 15.64 mmol)
in EtOH (100 mL) was added NaSH (20 mmol), and the mixture
was stirred at r.t. for 3 h (TLC monitoring). EtOH was evaporated
under reduced pressure, and the residue was dissolved in H2O and 2
M HCl was carefully added to neutralize the suspension. After
evaporation of the solvent, the residue was dissolved in acetone (40
mL) and ClCH2CN (1 mL, 15.64 mmol), K2CO3 (2.16 g, 15.64
mmol), and a catalytic amount of KI were added. The resulting mix-
ture was stirred at r.t. for 1 h, and then the resulting residue was sep-
arated by filtration and washed with acetone (3 × 15 mL). The
filtrate was evaporated under reduced pressure, the resulting residue
was dissolved in THF (200 mL), piperidine (1.55 mL, 15.64 mL)
was added, and the mixture was stirred at reflux temperature for 5
h. After cooling, the soln was concentrated to dryness, and the re-
sidual material was purified by column chromatography (THF–hex-
anes, 1:1) to give 1 (2.31 g, 84%); mp 205–206 °C (Lit.18 204–206
°C).
Anal. Calcd for C10H8ClN5S: C, 46.20; H, 3.03; Cl, 13.34; N, 26.36;
S, 12.07. Found: C, 46.09; H, 3.33; N, 26.54; S, 12.20.
3-Substituted {[(Dimethylamino)methylene]amino}thieno[2,3-
b]pyrazine-6-carbonitriles 4a–e; General Procedure
To a soln of 2 (0.20 g, 0.75 mmol) in THF (10 mL) was added grad-
ually the appropriate nucleophile (0.90 mmol). The mixture was
heated at reflux temperature until 2 had disappeared (TLC monitor-
ing). The soln was concentrated to dryness, and the residual materi-
al was purified by column chromatography or recrystallized.
7-{[(Dimethylamino)ethoxymethylene]amino}thieno[2,3-
b]pyrazine-6-carbonitrile (4a)
Yellow solid.
IR (KBr): 2972, 2924, 2201, 1586, 1583, 1408, 1355, 1204 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H), 2.90 (s,
6 H), 4.22 (q, J = 7.1 Hz, 2 H), 8.61 (d, J = 2.3 Hz, 1 H), 8.71 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.8, 38.0, 65.5, 88.6, 116.2,
142.4, 143.7, 154.0, 155.7, 160.1.
IR (KBr): 3328, 3231, 3204, 2197, 1643, 1566, 1529, 1351 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.80 (s, 2 H, NH2), 8.62 (d, J = 2.5
Hz, 1 H), 8.66 (d, J = 2.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 114.3, 139.5, 141.6, 144.4, 147.1,
155.5.
MS (FAB): m/z (%) = 177 [(M + H)+, 30].
MS (EI): m/z = 276.
Anal. Calcd for C7H4N4S: C, 47.72; H, 2.29; N, 31.80; S, 18.20.
Found: C, 47.49; H, 2.20; N, 32.08; S, 18.23.
Anal. Calcd for C12H13N5OS: C, 52.35; H, 4.76; N, 25.44; S, 11.65.
Found: C, 52.56; H, 4.39; N, 25.63; S, 11.79.
7-{[Chloro(dimethylamino)methylene]amino}thieno[2,3-
b]pyrazine-6-carbonitrile (2)
To a suspension of 1 (2.30 g, 13.20 mmol) in 1,2-dichloroethane
(100 mL) was added Viehe’s salt (3.00 g, 18.50 mmol), and the mix-
ture was refluxed for 6 h. After cooling, the solvent was removed
under reduced pressure and the resulting material was recrystallized
(EtOH) to give 2 (2.90 g, 80%) as yellow crystals; mp 209–211 °C.
7-{[(Dimethylamino)(morpholin-4-yl)methylene]ami-
no}thieno[2,3-b]pyrazine-6-carbonitrile (4b)
White solid.
IR (KBr): 2986, 2866, 2168, 1924, 1467, 1380, 1244, 1118, 768
cm–1.
1H NMR (300 MHz, CDCl3): d = 3.29 (s, 6 H), 3.89 (d, J = 4.8 Hz,
4 H), 3.94 (d, J = 4.8 Hz, 4 H), 8.64 (d, J = 2.3 Hz, 1 H), 8.80 (d,
J = 2.3 Hz, 1 H).
IR (KBr): 2927, 2200, 1600, 1496, 1409, 1347, 1165, 1034 cm–1.
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13C NMR (75 MHz, CDCl3): d = 37.4, 46.6, 66.7, 104.7, 142.0,
1H NMR (300 MHz, CDCl3): d = 1.51 (t, J = 7.1 Hz, 3 H), 3.36 (s,
6 H), 4.63 (q, J = 7.1 Hz, 2 H), 8.65 (d, J = 2.3 Hz, 1 H), 8.79 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.4, 37.5, 62.7, 106.0, 141.7,
143.9, 164.0.
144.1, 144.4, 155.6, 157.0, 158.9, 161.1.
MS (FAB): m/z (%) = 317 [(M + H)+ 60], 107 (20).
Anal. Calcd for C14H16N6OS: C, 53.15; H, 5.10; N, 26.56; S, 10.13.
Found: C, 53.34; H, 5.32; N, 26.79; S, 10.45.
MS (FAB): m/z (%) = 276 [(M + H)+, 100].
7-{[(Dimethylamino)(thiomorpholin-4-yl)methylene]ami-
no}thieno[2,3-b]pyrazine-6-carbonitrile (4c)
Yellow solid.
Anal. Calcd for C12H13N5OS: C, 52.35; H, 4.76; N, 25.44; S, 11.65.
Found: C, 52.66; H, 4.34; N, 25.12; S, 11.25.
IR (KBr): 2990, 2854, 2169, 1561, 1522, 1264, 1225, 768 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.77–2.81 (m, 4 H), 3.28 (s, 6 H),
4.23–4.26 (m, 4 H), 8.63 (d, J = 2.3 Hz, 1 H), 8.79 (d, J = 2.3 Hz, 1
4-(Butylamino)-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5b)
Yellow solid.
IR (KBr): 2958, 2857, 1591, 1560, 1524, 1396, 1335, 1229 cm–1.
H).
13C NMR (75 MHz, CDCl3): d = 26.9, 37.3, 49.3, 104.7, 142.1,
1H NMR (300 MHz, CDCl3): d = 1.45–1.52 (m, 3 H), 1.64–1.75 (m,
4 H), 3.30 (s, 6 H), 3.61–3.71 (m, 2 H), 4.70 (br s, 1 H, NH, ex-
changeable with D2O), 8.60 (d, J = 2.3 Hz, 1 H), 8.77 (d, J = 2.3 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 20.1, 37.4, 40.8, 105.0,
141.8, 143.5, 145.1, 153.4, 157.0, 157.4, 161.9.
144.1, 144.5, 155.6, 156.9, 158.2, 161.1.
MS (FAB): m/z (%) = 333 [(M + H)+, 70].
Anal. Calcd for C14H16N6S2: C, 50.58; H, 4.85; N, 25.28; S, 19.29.
Found: C, 50.43; H, 4.65; N, 25.17; S, 19.75.
7-{[(Dimethylamino)(4-methylpiperidin-1-yl)methylene]ami-
no}thieno[2,3-b]pyrazine-6-carbonitrile (4d)
Yellow solid.
IR (KBr): 2921, 2847, 2792, 2180, 1730, 1522, 1347, 1157 cm–1.
MS (FAB): m/z (%) = 303 [(M + H)+, 100].
Anal. Calcd for C14H18N6S: C, 55.61; H, 6.00; N, 27.79; S, 10.60.
Found: C, 55.32; H, 6.23; N, 27.51; S, 10.94.
4-(Diethylamino)-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5c)
White solid.
IR (KBr): 3041, 2975, 2929, 1537, 1352, 1080 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 6.32 Hz, 3 H), 1.25–
1.34 (m, 2 H), 1.78–1.86 (m, 3 H), 3.04–3.28 (m, 2 H), 3.28 (s, 6 H),
4.67–4.73 (m, 2 H), 8.61 (d, J = 2.3 Hz, 1 H), 8.77 (d, J = 2.3 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 21.7, 29.6, 31.3, 34.1, 37.3, 46.8,
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7.0 Hz, 6 H), 3.38 (s,
6 H), 3.80 (q, J = 7.0 Hz, 4 H), 8.63 (d, J = 2.3 Hz, 1 H), 8.79 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 37.3, 43.6, 126.3, 141.8,
143.8, 144.5, 154.8, 157.1, 157.3, 161.2.
104.9, 141.8, 143.8, 144.6, 155.1, 157.0, 158.4, 161.2.
MS (FAB): m/z (%) = 329 [(M + H)+, 100].
Anal. Calcd for C16H20N6S: C, 58.51; H, 6.14; N, 25.59; S, 9.76.
Found: C, 58.75; H, 6.36; N, 25.44; S, 9.45.
MS (FAB): m/z (%) = 303 [(M + H)+, 100].
7-{[(4-Bromophenylamino)(dimethylamino)methylene]ami-
no}thieno[2,3-b]pyrazine-6-carbonitrile (4e)
Garnet solid.
Anal. Calcd for C14H18N6S: C, 55.61; H, 6.00; N, 27.79; S, 10.60.
Found: C, 55.44; H, 6.18; N, 27.94; S, 10.44.
IR (KBr): 3279, 2928, 2166, 1615, 1547, 1441, 1391, 1169 cm–1.
2-(Dimethylamino)-4-mercaptopyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidine (5d)
1H NMR (300 MHz, CDCl3): d = 3.36 (s, 6 H), 6.63 (s, 1 H, NH),
7.56 (d, J = 8.8 Hz, 2 H), 7.68 (d, J = 8.8 Hz, 2 H), 8.70 (d, J = 2.3
Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H).
Yellow solid.
IR (KBr): 3066, 2927, 2796, 1657, 1489, 1407, 1148, 989 cm–1.
13C NMR (75 MHz, CDCl3): d = 37.9, 105.4, 117.0, 123.3, 129.0,
131.1, 132.1, 137.5, 142.4, 144.4, 155.3, 157.6, 161.8, 168.0.
1H NMR (300 MHz, DMSO-d6): d = 3.34 (s, 6 H), 8.89 (d, J = 2.3
Hz, 1 H), 8.96 (d, J = 2.3 Hz, 1 H).
MS (FAB): m/z (%) = 403 [(M + H)+, 60], 401 (58), 322 (45).
13C NMR (75 MHz, DMSO-d6): d = 37.3, 55.4, 60.2, 120.1, 143.4,
143.7, 146.7, 155.8, 158.2, 158.4, 160.9.
Anal. Calcd for C16H13BrN6S: C, 47.89; H, 3.27; N, 20.94; S, 7.99.
Found: C, 47.31; H, 3.03; N, 21.12; S, 7.65.
MS (FAB): m/z (%) = 264 [(M + H)+, 20], 219 (10), 176 (30).
Anal. Calcd for C10H9N5S2: C, 45.61; H, 3.44; N, 26.59; S, 24.35.
Found: C, 45.56; H, 3.32; N, 26.67; S, 24.45.
4-Substituted 2-(Dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidines 5; General Procedure
To a soln of 3 (0.10 g, 0.37 mmol) in THF (15 mL) was added grad-
ually the appropriate nucleophile (0.44 mmol). The mixture was
heated at reflux temperature until 3 had disappeared (TLC monitor-
ing). The soln was concentrated to dryness, and the residual materi-
al was purified by column chromatography or recrystallized.
2-(Dimethylamino)-4-phenoxypyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidine (5e)
Yellow solid.
IR (KBr): 3046, 2925, 1693, 1581, 1545, 1405, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.14 (s, 6 H), 7.28–7.33 (m, 3 H),
7.42–7.47 (m, 2 H), 8.68 (d, J = 2.3 Hz, 1 H), 8.82 (d, J = 2.3 Hz, 1
2-(Dimethylamino)-4-ethoxypyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidine (5a)
Yellow solid.
IR (KBr): 2986, 2933, 2792, 1583, 1528, 1408, 1334 cm–1.
H).
13C NMR spectrum could not be obtained due to poor solubility.
MS (FAB): m/z (%) = 323 [(M + H)+, 85], 191 (70), 136 (68).
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Synthesis of Substituted Pyrazinothienopyrimidines
IR (KBr): 3040, 2952, 2856, 1535, 1383, 1115, 943 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.97 (d, J = 6.38 Hz, 3 H), 1.24–
1.37 (m, 2 H), 1.76–1.80 (m, 3 H), 3.02–3.12 (m, 2 H), 3.27 (s, 6 H),
4.65–4.71 (m, 2 H), 8.59 (d, J = 2.3 Hz, 1 H), 8.76 (d, J = 2.3 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 21.7, 31.3, 34.1, 46.7, 104.8,
141.8, 143.8, 144.6, 155.1, 156.9, 158.3, 161.2.
MS (FAB): m/z (%) = 329 [(M + H)+, 100].
949
Anal. Calcd for C16H13N5OS: C, 59.43; H, 4.05; N, 21.61; S, 9.92.
Found: C, 59.11; H, 4.32; N, 21.90; S, 9.75.
2-(Dimethylamino)-4-(phenylthio)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5f)
Orange solid.
IR (KBr): 2920, 2851, 1676, 1646, 1516, 1162 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.10 (s, 6 H), 7.46–7.48 (m, 3 H),
7.67–7.71 (m, 2 H), 8.67 (d, J = 2.3 Hz, 1 H), 8.79 (d, J = 2.3 Hz, 1
Anal. Calcd for C16H20N6S: C, 58.51; H, 6.14; N, 25.59; S, 9.76.
Found: C, 58.75; H, 6.45; N, 25.37; S, 9.43.
H).
13C NMR (75 MHz, CDCl3): d = 37.1, 127.1, 129.0, 129.7, 136.0,
142.0, 144.6, 153.9, 160.6.
MS (FAB): m/z (%) = 340 [(M + H)+, 100].
2-(Dimethylamino)-4-(4-methylpiperazin-1-yl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5k)
White solid.
IR (KBr): 3051, 2848, 2761, 1523, 1175, 965 cm–1.
Anal. Calcd C16H13N5S2: C, 56.61; H, 3.86; N, 20.63; S, 18.89.
Found: C, 56.83; H, 3.76; N, 20.42; S, 18.99.
1H NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H), 2.58 (t, J = 4.80 Hz,
4 H), 3.29 (s, 6 H), 3.96 (t, J = 4.80 Hz, 4 H), 8.62 (d, J = 2.3 Hz, 1
H), 8.78 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 37.4, 46.0, 46.1, 54.9, 104.8,
141.9, 144.0, 144.6, 155.4, 157.0, 158.6, 161.1.
2-(Dimethylamino)-4-(pyrrolidin-1-yl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5g)
White solid.
IR (KBr): 3051, 2937, 2856, 1556, 1535, 1400, 1208 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04–2.07 (m, 4 H), 3.27 (s, 6 H),
3.88–3.91 (m, 4 H), 8.59 (d, J = 2.3 Hz, 1 H), 8.76 (d, J = 2.3 Hz, 1
MS (FAB): m/z (%) = 330 [(M + H)+, 100], 259 (42).
Anal. Calcd for C15H19N7S: C, 54.69; H, 5.81; N, 29.76; S, 9.73.
Found: C, 54, 74; H, 5.99; N, 29.82; S, 9.45.
H).
13C NMR (75 MHz, CDCl3): d = 25.3, 37.2, 47.5, 105.1, 141.6,
143.4, 144.5, 154.1, 156.6, 157.3, 161.4.
MS (FAB): m/z (%) = 301 [(M + H)+, 100].
4-[(4-Bromophenyl)amino]-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5l)
Garnet solid.
IR (KBr): 3016, 2920, 1693, 1373, 1237, 1104 cm–1.
Anal. Calcd for C14H16N6S: C, 55.98; H, 5.37; N, 27.98; S, 10.67.
Found: C, 55.93; H, 5.33; N, 27.79; S, 10.95.
1H NMR (300 MHz, CDCl3): d = 3.30 (s, 6 H), 6.50 (s, 1 H, NH, ex-
changeable with D2O), 7.50–7.65 (m, 4 H), 8.66 (d, J = 2.3 Hz, 1
H), 8.82 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 37.7, 123.1, 131.9, 142.2, 144.1,
155.1.
2-(Dimethylamino)-4-(morpholin-4-yl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5h)
Yellow solid.
IR (KBr): 2888, 1643, 1537, 1170, 1070 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.31 (s, 6 H), 3.89 (t, J = 4.8 Hz,
4 H), 3.91 (t, J = 4.8 Hz, 4 H), 8.64 (d, J = 2.3 Hz, 1 H), 8.80 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 37.4, 46.6, 66.7, 142.1, 144.1,
155.6, 157.0, 158.9, 161.2.
MS (FAB): m/z (%) = 317 [(M + H)+, 100].
MS (FAB): m/z (%) = 403 (95), 401 [(M + H)+, 100].
Anal. Calcd for C16H13BrN6S: C, 47.89; H, 3.27; N, 30.94. S, 7.99.
Found: C, 47.99; H, 3.11; N, 30.59; S, 8.20.
4-Substituted 2-(Dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidines 5m–p; General Procedure
To a soln of 3 (0.10 g, 0.37 mmol) in anhyd toluene (5 mL) were
added the appropriate boronic acid (0.56 mmol), K2CO3 (64 mg,
0.47 mmol), and Pd(PPh3)4 (11 mg, 0.0094 mmol). The mixture was
heated at 100 °C under argon until 3 had disappeared (TLC moni-
toring). After cooling, the resulting precipitate was filtered off, the
soln was concentrated to dryness, and the residual material was pu-
rified by column chromatography.
Anal. Calcd for C14H16N6OS: C, 53.15; H, 5.10; N, 26.56; S, 10.13.
Found: C, 53.34; H, 5.11; N, 26.23; S, 10.15.
2-(Dimethylamino)-4-(thiomorpholin-4-yl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5i)
Yellow solid.
IR (KBr): 3048, 2987, 2849, 1552, 1398, 1175 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.80 (d, J = 5.0 Hz, 4 H), 3.34 (s,
6 H), 4.25 (d, J = 5.0 Hz, 4 H), 8.63 (d, J = 2.3 Hz, 1 H), 8.79 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.9, 37.4, 49.9, 66.7, 104.7,
142.1, 144.5, 155.6, 157.0, 158.9, 161.2.
2-(Dimethylamino)-4-phenylpyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidine (5m)
White solid.
IR (KBr): 2851, 2793, 2193, 1584, 1505, 1444, 1337 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.43 (s, 6 H), 7.58–7.61 (m, 3 H),
8.17–8.20 (m, 2 H), 8.70 (d, J = 2.3 Hz, 1 H), 8.85 (d, J = 2.3 Hz, 1
MS (FAB): m/z (%) = 333 [(M + H)+, 100], 259 (15), 149 (29).
H).
Anal. Calcd for C14H16N6S2: C, 50.58; H, 4.85; N, 25.28; S, 19.29.
Found. C, 50.66; H, 4.83; N, 25.46; S, 19.05.
13C NMR (CDCl3): d = 37.6, 128.4, 128.9, 130.8, 137.6, 142.1,
144.3, 144.7, 156.3, 159.3, 161.1, 161.8.
MS (FAB): m/z (%) = 308 [(M + H)+, 100].
2-(Dimethylamino)-4-(4-methylpiperidin-1-yl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5j)
Yellow solid.
Anal. Calcd for C16H13N5S: C, 62.52; H, 4.26; N, 22.78; S, 10.43.
Found: C, 62.66; H, 4.20; N, 22.99; S, 10.15.
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2-(Dimethylamino)-4-(4-methoxyphenyl)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5n)
White solid.
IR (KBr): 3013, 2927, 1608, 1463, 1405, 1265, 1172, 838 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.35 (s, 6 H), 3.76 (s, 3 H), 6.76–
6.78 (m, 4 H), 8.71 (d, J = 2.3 Hz, 1 H), 8.84 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 37.5, 55.4, 114.3, 130.1, 142.1,
144.6, 146.0, 161.8.
MS (FAB): m/z (%) = 338 [(M + H)+, 100].
1H NMR (300 MHz, DMSO-d6): d = 3.35 (s, 12 H), 8.30 (s, 4 H),
8.65 (d, J = 2.3 Hz, 2 H), 8.68 (d, J = 2.3 Hz, 2 H).
13C NMR spectrum could not be obtained due to poor solubility.
MS (FAB): m/z (%) = 601 [(M + H)+, 60].
Anal. Calcd for C26H20N10S4: C, 51.98; H, 3.36; N, 23.31; S, 21.35.
Found: C, 51.65; H, 3.40; N, 23.50; S, 21.45.
1,4-Bis{[2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidin-4-yl]amino}benzene (6c)
Yellow solid.
IR (KBr): 2963, 2865, 1640, 1493, 1359, 1164, 955 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.37 (s, 12 H), 6.89 (s, 2 H,
NH, exchangeable with D2O), 8.49 (s, 4 H), 8.73 (d, J = 2.3 Hz, 2
H), 8.76 (d, J = 2.3 Hz, 2 H).
Anal. Calcd for C17H15N5OS: C, 60.52; H, 4.48; N, 20.76; O, 4.74;
S, 9.50. Found: C, 60.19; H, 4.41; N, 20.72; S, 9.75.
4-(4-Chlorophenyl)-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5o)
White solid.
IR (KBr): 3053, 2960, 1557, 1525, 1404, 1337, 1172, 762 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.43 (s, 6 H), 7.53–7.55 (m, 2 H),
8.04–8.16 (m, 2 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1
13C NMR spectrum could not be obtained due to poor solubility.
MS (ESI): m/z = 567.
Anal. Calcd for C26H22N12S2: C, 55.11; H, 3.91; N, 29.66; S, 11.32.
Found: C, 55.36; H, 4.02; N, 29.45; S, 11.07.
H).
13C NMR (75 MHz, CDCl3): d = 37.6, 126.4, 128.6, 130.1, 130.8,
N,N¢-Bis[2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidin-4-yl]propane-1,3-diamine (6d)
Yellow solid.
IR (KBr): 3270, 2923, 2194, 1583, 1559, 1400, 1341, 1167 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.22–1.26 (m, 2 H), 3.35 (s, 12
H), 3.73–3.75 (m, 4 H), 6.98 (br s, 2 H, NH, exchangeable with
D2O), 8.78 (d, J = 2.3 Hz, 2 H), 8.84 (d, J = 2.3 Hz, 2 H).
135.1, 139.4, 142.2, 144.1, 144.9, 156.6, 159.6, 161.7.
MS (FAB): m/z (%) = 345 (37), 342 [(M + H)+, 100].
Anal. Calcd C16H12ClN5S: C, 56.22; H, 3.54; N, 10.37; S, 9.38.
Found: C, 56.01; H, 3.84; N, 10.44; S, 9.55.
4-(Biphenyl-4-yl)-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (5p)
13C NMR spectrum could not be obtained due to poor solubility.
MS (FAB): m/z (%) = 533 [(M + H)+, 30], 345 (15), 192 (100).
IR (KBr): 3036, 2920, 2850, 2352, 1554, 1403, 1169, 766 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.45 (s, 6 H), 7.42–7.53 (m, 3 H),
7.72 (d, J = 7.7 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 8.28 (d, J = 8.4
Hz, 2 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H).
Anal. Calcd for C23H24N12S2: C, 51.86; H, 4.54; N, 31.56; S, 12.04.
Found: C, 51.78; H, 4.67; N, 31.23; S, 12.32.
13C RMN (75 MHz, CDCl3): d = 37.6, 127.2, 127.6, 127.9, 128.9,
4-[(4¢-Aminobiphenyl-4-yl)amino]-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (7)
Yellow solid.
136.4, 140.2, 142.1, 143.7, 144.3, 144.8, 156.3, 160.7, 161.8.
MS (FAB): m/z (%) = 384 [(M + H)+, 20], 345 (15), 191 (70).
Anal. Calcd for C22H17N5S: C, 68.91; H, 4.47; N, 18.26; S, 8.36.
Found: C, 68.81; H, 4.37; N, 18.37; S, 8.45.
IR (KBr): 3042, 2539, 1585, 1490, 1167, 817 cm–1.
1H NMR (3000 MHz, DMSO-d6): d = 3.23 (s, 6 H), 7.11–7.15 (m,
4 H), 7.64–7.68 (m, 2 H), 7.94–7.97 (m, 2 H), 8.80 (d, J = 2.3 Hz, 1
H), 8.87 (d, J = 2.3 Hz, 1 H), 9.69 (s, 1 H, NH, exchangeable with
D2O).
13C NMR spectrum could not be obtained due to poor solubility.
MS (FAB): m/z (%) = 414 [(M + H)+, 45], 276 (35).
Bis[pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines] 6a–d and
Compounds 7–9; General Procedure
To a soln of 3 (0.20 g, 0.74 mmol) in THF (25 mL) were added the
appropriate bis(nucleophile) (0.32 mmol) and a catalytic amount of
K2CO3. The mixture was heated at reflux temperature until 3 had
disappeared (TLC monitoring). The soln was concentrated to dry-
ness, and the residual material was purified by column chromatog-
raphy or recrystallized.
Anal. Calcd for C22H19N7S: C, 63.90; H, 4.63; N, 23.71; S, 7.75.
Found: C, 63.80; H, 4.54; N, 24.04; S, 7.62.
4-(5-Amino-1-naphthylamino)-2-(dimethylamino)pyrazi-
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (8)
Yellow solid.
IR (KBr): 3347, 2920, 2851, 1681, 1528, 1373, 774 cm–1.
1,4-Bis[2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyri-
midin-4-yl]piperazine (6a)
Yellow solid.
IR (KBr): 2988, 2895, 2856, 1561, 1538, 1457, 1238 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.09 (s, 6 H), 5.84 (s, 2 H,
NH2, exchangeable with D2O), 6.85 (d, J = 7.1 Hz, 1 H), 7.17–7.22
(m, 1 H), 7.44 (d, J = 7.4 Hz, 1 H), 7.50 (d, J = 7.1 Hz, 1 H), 7.93–
7.97 (m, 1 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.72 (d, J = 2.3 Hz, 1 H),
8.82 (d, J = 2.3 Hz, 1 H), 9.72 (s, 1 H, NH, exchangeable with
D2O).
13C NMR (75 MHz, DMSO-d6): d = 37.1, 104.4, 108.3, 111.1,
122.3, 123.3, 123.9, 126.0, 127.6, 132.4, 133.8, 142.6, 143.9, 145.0,
145.6, 154.6, 157.6, 158.1, 161.6.
1H NMR (300 MHz, DMSO-d6): d = 2.63–2.65 (s, 8 H), 3.34 (s, 12
H), 8.92 (d, J = 2.3 Hz, 2 H), 8.99 (d, J = 2.3 Hz, 2 H).
13C NMR spectrum could not be obtained due to poor solubility.
MS (ESI): m/z = 545.
Anal. Calcd for C24H24N12S2: C, 52.95; H, 4.44; N, 30.86; S, 11.77.
Found: C, 52.76; H, 4.12; N, 30.78; S, 11.97.
1,4-Bis{[2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidin-4-yl]sulfanyl}benzene (6b)
MS (FAB): m/z (%) = 388 [(M + H)+, 50], 276 (100).
IR (KBr): 2911, 2845, 1612, 1508, 1398, 1156, 788 cm–1.
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PAPER
Synthesis of Substituted Pyrazinothienopyrimidines
IR (KBr): 3060, 2974, 2931, 2868, 1560, 1489, 1151 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.45 (t, J = 6.8 Hz, 6 H), 3.96 (q,
J = 6.8 Hz, 4 H), 8.80 (d, J = 2.3 Hz, 1 H), 8.98 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 44.1, 99.9, 143.7, 145.5,
152.4, 156.1.
MS (FAB): m/z (%) = 261 [(M + H)+, 100], 233 (21).
951
Anal. Calcd for C20H17N7S: C, 62.00; H, 4.42; N, 25.30; S, 8.28.
Found: C, 61.97; H, 4.75; N, 25.21; S, 8.07.
N,N¢-Bis[2-(dimethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidin-4-yl]tris(2-aminoethyl)amine (9)
Yellow solid.
IR (KBr): 3290, 3167, 2960, 2176, 1588, 1446, 1384, 1323, 1064
cm–1.
Anal. Calcd for C11H12N6S: C, 50.75; H, 4.65; N, 32.28; S, 12.32.
Found: C, 50.97; H, 4.44; N, 32.12; S, 12.47.
1H NMR (300 MHz, CDCl3): d = 1.63 (br s, 2 H, NH2, exchange-
able with D2O), 2.43 (t, J = 5.9 Hz, 4 H), 2.55 (t, J = 5.6 Hz, 2 H),
2.70–2.83 (m, 2 H), 2.89–2.95 (m, 4 H), 3.24 (s, 12 H), 6.50 (t,
J = 4.1 Hz, 2 H, NH, exchangeable with D2O), 8.48 (d, J = 2.3 Hz,
2 H), 8.69 (d, J = 2.3 Hz, 2 H).
4-(Pyrrolidin-1-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-tria-
zine (11c)
Yellow solid.
IR (KBr): 3052, 2964, 2872, 1564, 1520, 1317, 1163 cm–1.
13C NMR spectrum could not be obtained due to poor solubility.
1H NMR (300 MHz, CDCl3): d = 2.16–2.19 (m, 4 H), 3.98–4.05 (m,
4 H), 8.74 (d, J = 2.3 Hz, 1 H), 8.93 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 45.9, 46.0, 54.7, 115.7, 142.8,
143.8, 145.7, 147.6, 153.0, 156.0.
MS (FAB): m/z (%) = 605 [(M + H)+, 30).
Anal. Calcd for C26H32N14S2: C, 51.64; H, 5.33; N, 32.43; S, 10.60.
Found: C, 51.52; H, 5.47; N, 32.64; S, 10.37.
MS (FAB): m/z = 259 [(M + H)+, 100], 231 (17), 136 (18).
4-Chloropyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazine (10)
To an ice-cooled soln of 1 (0.90 g, 5.10 mmol) in HCl–AcOH (1:1,
100 mL) was added dropwise a soln NaNO2 (0.70 g, 10.20 mmol)
in H2O (5 mL). The mixture was stirred at the same temperature for
2 h, and then poured into H2O (75 mL). The resulting solid was fil-
tered off, washed with H2O (pH 7), and subjected to chromatogra-
phy (silica gel, CH2Cl2) to give 10 (0.97 g, 86%) as yellow crystals;
mp 182–183 °C.
IR (KBr): 1535, 1512, 1309, 1070, 1045, 866, 822, 439 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.96 (d, J = 2.3 Hz, 1 H), 9.14 (d,
J = 2.3 Hz, 1 H).
Anal. Calcd for C11H10N6S: C, 51.15; H, 3.90; N, 32.54; S, 12.41.
Found: C, 51.53; H, 3.77; N, 32.59; S, 12.11.
4-(Piperidin-1-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazine
(11d)
White solid.
IR (KBr): 3053, 3000, 2940, 2856, 1552, 1488, 1354 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.82 (s, 6 H), 4.10 (s, 4 H), 8.80
(d, J = 2.3 Hz, 1 H), 8.97 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.4, 26.1, 47.6, 115.5, 143.7,
145.5, 147.5, 152.8, 156.0.
13C NMR (300 MHz, CDCl3): 132.4, 141.9, 144.8, 147.1, 149.6,
154.4, 157.8.
MS (FAB): m/z (%) = 225 (17), 223 [(M + H)+, 50], 188 (36), 159
MS (FAB): m/z (%) = 273 [(M + H)+, 100], 245 (32), 109 (31).
Anal. Calcd for C12H12N6S: C, 52.95; H, 4.44; N, 30.86; S, 11.77.
Found: C, 53.26; H, 4.64; N, 30.50; S, 11.60.
(100), 132 (11).
Anal. Calcd for C7H2ClN5S: C, 37.60; H, 0.90; N, 31.31; S, 14.34.
Found: C, 37.12; H, 0.58; N, 31.13; S, 14.65.
4-(Morpholin-4-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-tria-
zine (11e)
Yellow solid.
IR (KBr): 3060, 2979, 2922, 2872, 1964, 1666, 1543 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.82–3.85 (m, 4 H), 4.04–4.07
(m, 4 H), 9.00 (d, J = 2.3 Hz, 1 H), 9.12 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 31.2, 36.2, 46.3, 66.3, 116.2,
142.3, 144.8, 147.0, 147.7, 153.6, 156.2, 162.8.
4-Substituted Pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazines
11; General Procedure
To a soln of 10 (0.15 g, 0.67 mmol) in THF (15 mL) was added
gradually the appropriate nucleophile (1.60 mmol). The mixture
was stirred at reflux temperature until 10 had disappeared (TLC
monitoring). The precipitated solid was filtered off, washed with
THF, and purified by column chromatography (silica gel) or recrys-
tallized.
MS (FAB): m/z (%) = 275 [(M + H)+, 96], 247 (17), 137 (66).
4-Ethoxypyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazine (11a)
Yellow solid.
IR (KBr): 3056, 2983, 2936, 1548, 1522, 1330 cm–1.
Anal. Calcd for C11H10N6OS: C, 48.17; H, 3.67; N, 30.64; S, 11.69.
Found: C, 48.62; H, 3.24; N, 30.45; S, 11.65.
1H NMR (300 MHz, CDCl3): d = 1.60 (t, J = 7.1 Hz, 3 H), 4.95 (q,
J = 7.1 Hz, 2 H), 8.85 (d, J = 2.3 Hz, 1 H), 9.03 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.3, 65.5, 120.0, 142.5, 143.9,
145.9, 157.6, 160.2.
4-(Thiomorpholin-4-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-
triazine (11f)
Orange solid.
IR (KBr): 3010, 2980, 2953, 2878, 1522, 1488, 1282 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.87–2.89 (m, 4 H), 4.37–4.39 (m,
4 H), 9.01 (d, J = 2.3 Hz, 1 H), 9.12 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.9, 49.4, 79.1, 79.4, 79.7, 116.3,
142.2, 144.8, 147.0, 147.7, 153.6, 156.2.
MS (FAB): m/z (%) = 234 [(M + H)+, 100], 206 (7).
Anal. Calcd for C9H7N5OS: C, 46.34; H, 3.02; N, 30.03; S, 12.32.
Found: C, 46.11; H, 3.50; N, 29.75; S, 12.12.
MS (FAB): m/z (%) = 291 [(M + H)+, 100], 263 (14), 136 (32).
4-(Diethylamino)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-1,2,3-triazine
(11b)
Anal. Calcd for C11H10N6S2: C, 45.50; H, 3.47; N, 28.94; S, 22.09.
Found: C, 45.18; H, 3.63; N, 28.94; S, 22.25.
White solid.
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952
A. Fernández-Mato et al.
PAPER
properties and biological activity of thienopyridines, see:
4-(4-Methylpiperidin-1-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-
1,2,3-triazine (11g)
Yellow solid.
IR (KBr): 3001, 2952, 2858, 1556, 1472, 1342, 965 cm–1.
1H NMR (300 MHz, CDCl3): 1.02 (s, 3 H), 1.36–1.41 (m, 2 H),
1.91–1.95 (m, 3 H), 3.27–3.36 (m, 2 H), 4.90–4.96 (m, 2 H), 8.80
(d, J = 2.3 Hz, 1 H), 8.99 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): 21.6, 31.1, 34.2, 46.8, 115.6, 143.0,
143.8, 145.6, 147.5, 152.9, 156.0.
(e) Backhite, E. A.-G. Phosphorus, Sulfur Silicon Relat.
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Alfonso, A.; Botana, L. M.; Riguera, R. Eur. J. Med. Chem.
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Bioorg. Med. Chem. 1998, 6, 1911.
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Nieto, S.; Quintela, J. M.; Fernndez, A.; Medina, M. A.;
Quesada, A. R. Mol. Cancer Ther. 2007, 6, 2675. (b) Rioja,
I.; Ubeda, A.; Terencio, M. C.; Guillén, I.; Riguera, R.;
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Eur. J. Pharmacol. 2000, 397, 207. (c) Quintela, J. M.;
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42, 4720.
EM (FAB): m/z (%) = 287 [(M + H)+, 80], 137 (72), 107 (25).
Anal. Calcd for C13H14N6S: C, 54.53; H, 4.93; N, 29.35; S, 11.20.
Found. C, 54.67; H, 4.79; N, 29.10; S, 11.44.
4-(4-Methylpiperazin-1-yl)pyrazino[2¢,3¢:4,5]thieno[3,2-d]-
1,2,3-triazine (11h)
Yellow solid.
IR (KBr): 3009, 2888, 2773, 1549, 1519, 1194, 1142, 996, 847
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.38 (s, 3 H), 2.64 (t, J = 5.0 Hz,
4 H), 4.16 (t, J = 5.0 Hz, 4 H), 8.80 (d, J = 2.3 Hz, 1 H), 8.98 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 45.9, 46.0, 54.7, 115.7, 142.8,
143.8, 145.7, 147.6, 153.0, 156.0.
(7) Quintela, J. M.; Peinador, C.; González, L.; Iglesias, R.;
Paramá, A.; Alvarez, F.; Sanmartín, M.; Riguera, R. Eur. J.
Med. Chem. 2003, 38, 265.
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(b) Immamura, N.; Nishijima, M.; Takadera, T.; Adachi, K.;
Sakai, M.; Sano, H. J. Antibiot. 1997, 50, 8.
MS (FAB): m/z (%) = 288 [(M + H)+, 60].
Anal. Calcd for C12H13N7S: C, 50.16; H, 4.56; N, 34.12; S, 11.16.
Found: C, 50.35; H, 4.30; N, 34.01; S, 11.34.
(10) (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,
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WO 2005,054,230, 2005; Chem. Abstr. 2005, 143, 60004o.
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3129. (c) Fache, F.; Schulz, E.; Thommasino, M. L.;
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Acknowledgment
This work was supported by Ministerio de Ciencia y Tecnología
(Spain) and FEDER (project CTQ2007-63839). A.F.-M. acknow-
ledges predoctoral fellowships from the Xunta de Galicia (Spain).
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Synthesis of Substituted Pyrazinothienopyrimidines
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