Synthesis of pyrazinothienopyrimidine derivatives by the application of the intramolecular and intermolecular aza-wittig reaction/heterocyclization

Article abstract of DOI:10.1055/s-2008-1072514

Pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidine derivatives 6 were synthesized by the intermolecular aza-Wittig reaction of N-heteroaryl phosphazene derivatives with carboxylic acid chlorides. The heterocyclization occurs via imidoyl chloride intermediates derived from phosphazenes 4a,b, obtained in a one-step process from α-azidothieno[2,3-b]pyrazine carboxylic acid 3. Moreover, cyclic pyrazinothienopyrimidines were prepared, in a two-step procedure, from amides and azidothienopyrazine-α-carbonyl chloride using an intramolecular aza-Wittig heterocyclization reaction strategy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072514

PAPER
1397
Synthesis of Pyrazinothienopyrimidine Derivatives by the Application of the
Intramolecular and Intermolecular Aza-Wittig Reaction/Heterocyclization
S
ynthesis of Pyraz
e
inothienopy
r
rimidine
a
Derivative
r
s
do Blanco, José M. Quintela,* Carlos Peinador*
Departamento de Química Fundamental, Facultad de Ciencias, Universidad de A Coruña, 15071 A Coruña, Spain
Fax +34(981)167000; E-mail: jqqoqf@udc.es; E-mail: capeveqo@udc.es.
Received 23 November 2007; revised 21 January 2008
erocycles via intramolecular aza-Wittig reactions,9 in-
cluding highly efficient and regioselective synthesis of
substituted pyrazinothienopyrimidinones and bis(pyrazi-
nothienopyrimidinyl)benzenes.10 As an extension of this
Abstract: Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine derivatives 6
were synthesized by the intermolecular aza-Wittig reaction of N-
heteroaryl phosphazene derivatives with carboxylic acid chlorides.
The heterocyclization occurs via imidoyl chloride intermediates de-
rived from phosphazenes 4a,b, obtained in a one-step process from work we now report the preparation of novel N-(hetero-
a-azidothieno[2,3-b]pyrazine carboxylic acid 3. Moreover, cyclic
pyrazinothienopyrimidines were prepared, in a two-step procedure,
from amides and azidothienopyrazine-a-carbonyl chloride using an
intramolecular aza-Wittig heterocyclization reaction strategy.
aryl)phosphazenes and their employment in the synthesis
of pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines by way of
an intramolecular or intermolecular aza-Wittig reaction
followed by heterocyclization.
Key words: heterocycles, Wittig reaction, nitrogen, azides, cy-
The strategy used for the development of these com-
pounds is depicted in Scheme 1. They can be synthesized
by two different ways. Pyrazinothienopyrimidines 6 were
synthesized by the intermolecular aza-Wittig reaction of
N-heteroaryl phosphazene derivatives having secondary
amide functions with carboxylic acid chlorides followed
by heterocyclization. Cyclic pyrazinothienopyrimidines 9
were prepared in a two-step procedure from amides and
azidothienopyrazine-a-carbonyl chloride. Reaction of the
crude imides with triphenylphosphine effects an intramo-
lecular aza-Wittig reaction to afford the desired com-
pounds in good to moderate yields.
clizations
Fused pyrimidines have been the focus of great interest in
organic chemistry due to the broad spectrum of biological
properties of these compounds and their practical useful-
ness as reagents for the fine and industrial chemistry.
Compounds containing a fused pyrimidine ring play a
very important part in the biochemistry of the living cell
and have attracted attention in the past few years owing to
their wide range of biological activity, particularly in can-
cer and virus research.1 Among these heterocyclic com-
pounds, thienopyrimidines are of special significance.2 It
is known, for example, that derivatives of this family
show significant antifungal and antibacterial properties,3
whereas others possess anticonvulsant and angiotensin re-
ceptor antagonistic activities.4 We have previously report-
ed on the synthesis of novel tri- and tetracyclic ring
systems, containing the thienopyrimidine skeleton with
anti-inflammatory and antihistaminic activity.5 However,
aza-analogue compounds incorporating an S-heterocycle
fused to a pyrazine nucleus have been so far poorly uti-
lized. Among the diazines, the pyrazine motif is an impor-
tant heterocycle, as not only are these units embedded in
a variety of natural products and designed molecules
which exhibit citotoxicity against certain human cancer
cells, but they also serve as precursors to a range of related
structures.6 In addition, substituted pyrazine motifs are of-
ten to be found in compounds with applications as anti-
cancer agents, including currently marketed drugs7 and
those recently reported.8
The synthesis of N-heteroaryl phosphazene precursors
4a,b to construct the target pyrazinothienopyrimidinones
6 is summarized in Scheme 2. At first, the reaction of the
readily available heterocyclic b-enamino ester 110b with
PPh3
N3
N
N
NHR1
N
N
Cl
O
S
S
O
N
O
H
R2COCl
N
R2
Ph3P
R1
Cl
PPh3
R2
O
N
N
R2
NHR1
N
N
N
N
R1
S
O
N
S
O
– P(O)Ph3
R2
We have been interested in the preparation and the reac-
tivity of N-(heteroaryl)phosphazenes and, in previous
work, we described the facile synthesis of condensed het-
R2
N
N
N
R1
N
N
N
R1
N
N
O
S
S
O
SYNTHESIS 2008, No. 9, pp 1397–1403
x
x
.
x
x
.2
0
0
8
6
9
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1072514; Art ID: T18407SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines

1398
G. Blanco et al.
PAPER
1) SOCl2, reflux, 2 h
2) R1NH2, Et3N, DMAP, THF,
0 °C, 1 h; then r.t. 12 h
3) PPh3, r.t., 2 h
NH2
N3
N3
NaNO2, TFA,
KOH, Et2O, 0 °C,
15 min; then r.t., 1 h
N
N
N
N
N
N
0 °C, 10 min;
then NaN3,
0 °C, 10 min
CO2Et
CO2H
CO2Et
S
S
S
1
2
3
Cl
R2
N
R2COCl, toluene, DBU,
sealed tube, 150 °C, 24 h
PPh3
HN R1
N
R2
N
N
R1
N
N
N
HN R1
N
N
– HCl
O
– P(O)Ph3
S
S
O
N
S
O
4a R1 = Ph
4b R1 = Bn
6a–h
5
Scheme 2 Synthesis of pyrazinothienopyrimidinones 6a–h
sodium nitrite in TFA affords the azido derivative 2. The
formation of 7-azidothienopyrazine-6-carboxylate 2 was
established by IR spectroscopy; the IR spectrum of the re-
action mixture showed a strong absorption at 2102 cm–1
attributable to the N3 group. After stirring at room temper-
ature for two hours with ethanolic potassium hydroxide,
followed by reprotonation of the carboxylate salt, 7-azi-
dothieno[2,3-b]pyrazine-6-carboxylic acid (3) was isolat-
ed in 99% yield. The preparation of the required
secondary aminophosphazene precursors 4 was carried
out, in a one-step synthesis, by sequential reaction of 7-
azidothieno[2,3-b]pyrazine-6-carboxylic acid (3) with
thionyl chloride, aniline or benzylamine in the presence of
triethylamine/4-dimethylaminopyridine, and triphenyl-
phosphine. After stirring for 12 hours at room tempera-
ture, the azide derivative 3 was totally consumed, and
column chromatography of the final reaction mixture al-
lowed the isolation of 7-(triphenylphosphoranylidene-
amino)thiophene[2,3-b]pyrazine-6-carboxamides 4a
(R1 = Ph) and 4b (R1 = Bn). Phosphazene derivatives 4a
and 4b were obtained in good global yields (69% and
58%, respectively) for the conversion of 3 → 4 in a one-
pot process.
Table 1 Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 6
Product
6a
R1
R2
Yield (%) Mp (°C)
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Me
Et
73
90
81
80
82
76
79
85
214–215
6b
284–285
6c
i-Pr
Ph
205–206
6d
260–261 (dec.)
114–115
6e
Me
Et
6f
180–181 (dec.)
278–280 (dec.)
249–250 (dec.)
6g
i-Pr
Ph
6h
nothienopyrimidinones, chloroimidoyl derivatives 5 are
assumed to be the key intermediates in the consecutive re-
action even though 5 could not be detected due to its high
reactivity. Pyrimidoannulation occurs via intramolecular
attack of the corresponding amide-donor nucleophile to
give tricyclic compounds 6 through elimination of hydro-
gen chloride (Scheme 2).
Finally, the synthesis of pyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidinones 6a–h was examined by the intermolecu-
lar aza-Wittig reaction and heterocyclization. An anhy-
drous toluene solution of the corresponding phosphazene
4a or 4b and the respective acid chlorides was heated in a
sealed tube at 150 °C for 24 hours in the presence of DBU.
The products obtained from these thermal treatments were
chromatographed, thus allowing the isolation of nitrogen
heterocyclic derivatives 6a–h (Scheme 2 and Table 1).
The method proved to be general and afforded the desired
products in unoptimized yields of 73–90%.
The structural elucidation of the pyrazinothienopyrimidi-
nones 6a–h was established following their analytical and
spectral data, and confirmed by the X-ray crystal structure
determination of a monocrystal of 6b (R1 = Et; R2 = Ph).
The NH group of carboxamide derivatives 4a,b showed a
strong absorption band at 3049–3037 cm–1 in the IR spec-
tra, and it appears at d = 10.38 as a singlet, and at d = 12.06
as a triplet, respectively, in the 1H NMR spectra. After het-
erocyclization, the spectra of pyrazinothienopyrimidino-
nes 6a–h did not include these types of signals but
displayed typical absorption bands for the R2 substituent
of the pyrimidine ring. In the crystal structure of 6b the
ethyl group adopts a coplanar disposition with the pyrazi-
nothienopyrimidinone ring, whereas the dihedral angle
between the mean planes defined by the pyrazine-
thienopyrimidinone nucleus and the phenyl group is ap-
proximately 90° (Figure 1).
The reaction of phosphazenes with carboxylic acid chlo-
rides to give heterocyclic compounds has been reported
by Eguchi,11 Molina,12 Wamhoff,13 Ding,14 and Zbiral et
al.15 They have shown that upon warming or in the pres-
ence of tertiary amines, imidoyl chlorides are formed,
which react with internal nucleophiles to afford various
heterocycles. Consequently, in the formation of pyrazi-
Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrazinothienopyrimidine Derivatives
1399
Table 2 Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 9
Product
9a
X
Yield (%)
mp (°C)
144–145
219–220
189–190
CH2
58
53
54
9b
CH2CH2
CH2CH2CH2
9c
One reasonable mechanistic proposal for this sequence
begins with the formation of acyl chloride. Standard cou-
pling with the lactam to form an imide and subsequent
treatment with triphenylphosphine could afford the key
phosphazene intermediates 8, which by aza-Wittig in-
tramolecular heterocyclization reaction provide the de-
sired cyclic pyrazinothienopyrimidine products
9
(Scheme 4). When a toluene solution of the crude imide,
obtained by treatment of 3 with thionyl chloride and g-bu-
tyrolactam, was treated with triphenylphosphine for ap-
proximately six hours at room temperature, the IR spectra
of the reaction mixture showed the total disappearance of
the azide band around 2100 cm–1 associated with the N3
group. From the resulting crude material, a-amide phos-
phazene 8a was isolated by column chromatography as
the only reaction product. When a toluene solution of 8a
was heated at reflux temperature for 20 hours, it under-
went intramolecular heterocyclization to provide the ex-
pected cyclic pyrazinothienopyrimidine 9a in 99% yield.
The structural determination of phosphazene derivative
8a was achieved following their analytical and spectral
data. In the case of noncyclic amides, cyclization was not
observed due to the imide hydrolysis.16 Isolation of the
corresponding amide in the reaction mixture confirms the
imide hydrolysis and the poor reactivity to form cycliza-
tion products. The structure of 9a was independently con-
firmed by X-ray crystal structure analysis (Figure 1).
Figure 1 Crystal structures of 6b (top) and 9a (bottom). Color
labeling scheme is as follows: S (yellow), O (red) N (blue), C (gray),
H (light gray).
In an extension of this work, and since this method is not
applicable to substrates in which R1 and R2 are tethered,
we speculated that treating 7-azidothieno[2,3-b]pyrazine-
6-carboxylic acid (3) with thionyl chloride, cyclic amides,
and triphenylphosphine would lead to cyclic pyrazino-
thienopyrimidinones 9. Thus, reaction involving the cou-
pling between 7-azidothieno[2,3-b]pyrazine-6-carbonyl
chloride and cyclic amides, such as g-butyrolactam, d-
valerolactam, or e-caprolactam could allow access to
pyrazinothienopyrimidinones, a class of compounds that
are particularly challenging to synthesize using existing
technologies. Practically, these proposals worked out as
planned. In fact, in a two-step procedure lactams 7a–c
were coupled with the azido derivative 3 and cyclized to
afford pyrazinothienopyrimidinones (Scheme 3, Table 2).
At first, thionyl chloride converted the carboxylic acid
group into an acid chloride and subsequent N-acylation of
the amide in the presence of DMAP and Et3N gave the de-
sired imides, which were used directly in the cyclization
to generate the five-, six-, and seven-membered pyrazi-
nothienopyrimidines 9 by reaction with triphenylphos-
phine in toluene at 120 °C. The separation of the products
9 from triphenylphosphine oxide, the inevitable by-prod-
uct in the aza-Wittig reaction, was done by chromatogra-
phy, thus resulting in the isolation of pure cyclic
pyrazinothienopyrimidines 9a–c in acceptable yields (53–
58%).
O
X
N3
N3
SOCl2
reflux, 2 h
N
N
N
N
PPh3
– N2
N
CO2H
X
S
S
O
3
NH
O
7
DMAP, Et3N
X
N
PPh3
O
X
N
N
N
N
– P(O)PPh3
N
N
N
O
S
S
O
9
8
1) i) SOCl2, reflux, 2 h
X
Scheme 4 Proposed mechanism to cyclic pyrazinothienopyrimi-
dinones 9a–c
ii)
DMAP, Et3N, THF,
0 °C, 1 h,
X
N
N3
N
NH
7a–c
then r.t., 12 h
N
N
N
N
O
CO2H
2) PPh3, toluene, 120 °C, 20 h
In conclusion, the intermolecular aza-Wittig reaction of
N-heteroaryl phosphazene derivatives, having secondary
amide functions, with carboxylic acid chlorides followed
by heterocyclization provided an efficient synthesis of
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
via imidoyl chloride intermediates derived from N-phen-
O
S
S
9a–c
3
9a: X = CH2
9b: X = CH2CH2
9c: X = CH2CH2CH2
6
Scheme 3 Synthesis of cyclic pyrazinothienopyrimidinones 9a–c
Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York

1400
G. Blanco et al.
PAPER
and at r.t. for 1 h, the mixture was cooled in ice again, aq 2 M HCl
(50 mL) was added and then extracted with EtOAc (3 × 100 mL).
The combined extracts were dried (MgSO4) and the solvent re-
moved under reduced pressure to give 3, which was used in the fol-
lowing step without further purification; yield: 1.78 g (99%);
yellow-brown solid; mp 139–140 °C (dec.) (EtOAc).
yl-7-(triphenylphosphoranylideneamino)thieno[2,3-b]pyr-
azine-6-carboxamide (4a) and N-benzyl-7-(triphenylphos-
phoranylideneamino)thieno[2,3-b]pyrazine-6-carbox-
amide (4b), respectively, which were obtained in a one-
step process from 7-azidothieno[2,3-b]pyrazine-6-car-
boxylic acid (3). On the other hand, cyclic pyrazi-
nothienopyrimidines 9 were prepared in a two-step
procedure from amides and azidothienopyrazine-a-carbo-
nyl chloride using an intramolecular aza-Wittig heterocy-
clization reaction strategy. These results indicate the
importance and utility of these phosphazenes as versatile
building blocks in the preparation of complex polycyclic
compounds. Moreover, this process represents a novel re-
action sequence in the preparation of cyclic pyrazi-
nothienopyrimidinones, a class of compounds that are
particularly challenging to synthesize access using exist-
ing technologies.
IR (KBr): 3092, 2118, 1695, 1556, 1462, 1344, 1285, 1194, 1086,
1047, 988, 864, 764, 708, 510 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.75 (d, J = 2.3 Hz, 1 H), 8.76 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 142.0, 144.5, 192.4.
MS (FAB): m/z = 222 (25%).
Anal. Calcd for C7H3N5O2S: C, 38.01; H, 1.37; N, 31.66; S, 14.50.
Found: C, 37.82; H, 1.20; N, 31.42; S, 14.36.
7-(Triphenylphosphoranylideneamino)thieno[2,3-b]pyrazines
4; General Procedure
A mixture of 3 (0.2 g, 0.9 mmol) and SOCl2 (3 mL) was refluxed for
2 h. SOCl2 was removed under reduced pressure, and to the result-
ing residue was added anhyd THF (15 mL), DMAP (0.01 g, 0.09
mmol), and anhyd Et3N (0.38 mL, 2.7 mmol). After cooling in an
ice-bath, the corresponding primary amine (0.9 mmol) was added
gradually, and the mixture was stirred at 0 °C for 1 h, and at r.t. for
12 h. Next, Ph3P (0.30 g, 1.1 mmol) was added, and the mixture was
stirred at r.t for 2 h. The solvent was removed under reduced pres-
sure and the resulting material was purified by column chromatog-
raphy.
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 recorded on a Bruker Avance 300 (300 MHz and 75 MHz for
1H and 13C, respectively) or a Bruker Avance 500 spectrometer (500
MHz and 125 MHz for 1H and 13C, respectively) in CDCl3 as sol-
vent, and the chemical shifts are expressed in ppm relative to TMS
at d = 0.00 for 1H and to CDCl3 at d = 77.1 for 13C NMR spectra.
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.
N-Phenyl-7-(triphenylphosphoranylideneamino)thieno[2,3-
b]pyrazine-6-carboxamide (4a)
Silica gel (hexanes–EtOAc, 8:2); yield: 69%; yellow solid; mp 193–
194 °C (dec.) (EtOAc–hexane).
IR (KBr): 3037, 1642, 1592, 1545, 1886, 1437, 1342, 1223, 1193,
1118, 749, 717, 692, 529 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.97–7.05 (m, 1 H), 7.16–7.25 (m,
2 H), 7.33–7.60 (m, 11 H), 7.70–7.80 (m, 6 H), 7.83 (d, J = 2.3 Hz,
1 H), 8.24 (d, J = 2.3 Hz, 1 H), 12.06 (s, 1 H).
13C NMR (75 Hz, CDCl3): d = 119.8, 123.2, 128.5, 128.6, 128.7,
130.8, 131.9, 131.9, 132.2, 132.4, 132.5, 138.5, 139.0, 141.7, 143.2,
144.5, 154.9, 162.5.
Ethyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate (1) was pre-
pared according to a literature procedure.10b
Ethyl 7-Azidothieno[2,3-b]pyrazine-6-carboxylate (2)
To a suspension of 1 (2.00 g, 9 mmol) in TFA (40 mL) cooled to 0
°C was added NaNO2 (1.24 g, 18 mmol), and to this was added
gradually NaN3 (1.75 g, 27 mmol), the mixture was stirred at 0 °C
for 10 min. Then, Et2O (40 mL) was added at 0 °C, the mixture was
poured into H2O (400 mL), and the resulting suspension was ex-
tracted with Et2O (4 × 100 mL). The combined extracts were
washed with H2O (2 × 100 mL) and brine (2 × 100 mL), and dried
(MgSO4). The solvent was removed under reduced pressure and the
resulting material was purified by column chromatography on silica
gel using hexanes–EtOAc (10:1) as eluent; yield: 2.10 g (95%); pale
yellow crystals; mp 70–71 °C (Et2O–n-hexane).
31P NMR (121.5 MHz, CDCl3): d = 17.4.
MS (FAB): m/z = 531 (100%).
Anal. Calcd for C31H23N4OPS: C, 70.17; H, 4.37; N, 10.56; S, 6.04.
Found: C, 70.42; H, 4.18; N, 10.73; S, 6.12.
N-Benzyl-7-(triphenylphosphoranylideneamino)thieno[2,3-
b]pyrazine-6-carboxamide (4b)
Silica gel (CH2Cl2–EtOAc, 9:1); yield: 58%; yellow solid; mp 220–
221 °C (dec.) (CH2Cl2–EtOAc).
IR (KBr): 2102, 1719, 1690, 1552, 1510, 1466, 1412, 1385, 1361,
1295, 1234, 1195, 1139, 1080, 1048, 1017, 868, 848, 816, 762, 438
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.1 Hz, 3 H), 4.43 (q,
J = 7.1 Hz, 2 H), 8.67 (d, J = 2.3 Hz, 1 H), 8.70 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 14.2, 62.1, 119.3, 133.5, 141.8,
143.4, 144.1, 154.2, 160.8.
IR (KBr): 3049, 1627, 1544, 1514, 1434, 1209, 1187, 1133, 1107,
756, 690, 559, 519 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.71 (d, J = 5.9 Hz, 2 H), 7.21–
7.36 (m, 11 H), 7.41–7.49 (m, 3 H), 7.56–7.66 (m, 6 H), 7.85 (d,
J = 2.3 Hz, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 10.38 (t, J = 5.9 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 43.2, 126.9, 127.8, 128.3, 128.4,
131.1, 131.6, 131.6, 132.1, 132.3, 132.4, 138.3, 139.5, 141.4, 142.8,
144.6, 154.7, 164.6.
31P NMR (121.5 MHz, CDCl3): d = 15.6.
MS (FAB): m/z = 250 (100%).
Anal. Calcd for C9H7N5O2S: C, 43.37; H, 2.83; N, 28.10; S, 12.86.
Found: C, 43.52; H, 2.98; N, 28.29; S, 12.67.
MS (FAB): m/z = 545 (100%).
7-Azidothieno[2,3-b]pyrazine-6-carboxylic Acid (3)
To a solution of 2 (2.20 g, 9 mmol) in Et2O (100 mL) cooled to 0 °C
was added aq 2 M KOH (100 mL). After stirring at 0 °C for 15 min,
Anal. Calcd for C32H25N4OPS: C, 70.57; H, 4.63; N, 10.29; S, 5.89.
Found: C, 70.32; H, 4.48; N, 10.53; S, 5.92.
Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrazinothienopyrimidine Derivatives
1401
Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 6; Gener-
al Procedure
13C NMR (125 Hz, CDCl3): d = 125.1, 128.0, 128.9, 129.0, 129.2,
129.5, 129.8, 134.6, 137.0, 143.2, 144.2, 144.4, 148.6, 158.4, 158.6,
159.0.
A solution of the corresponding phosphazene 4 (0.1 mmol) in anhyd
toluene (10 mL) was introduced in a glass tube, and the appropriate
acid chloride (0.13 mmol) and DBU (0.2 mmol) were added. The
glass tube was sealed and the mixture was heated at 150 °C for 24
h. After cooling, the solvent was removed under reduced pressure
and the resulting material was purified by column chromatography
[silica gel (hexanes–EtOAc, 7:3)].
MS (FAB): m/z = 357 (50%).
Anal. Calcd for C20H12N4OS: C, 67.40; H, 3.39; N, 15.72; S, 9.00.
Found: C, 67.21; H, 3.52; N, 15.49; S, 9.12.
3-Benzyl-2-methylpyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6e)
Yield: 82%; white crystals; mp 114–115 °C (EtOAc–n-hexane).
2-Methyl-3-phenylypyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6a)
Yield: 73%; white crystals; mp 214–215 °C (EtOAc–n-hexane).
IR (KBr): 1668, 1562, 1540, 1514, 1454, 1386, 1337, 1185, 1140,
1095, 1045, 951, 865, 761, 721, 693, 545, 500, 438 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.74 (s, 3 H), 5.52 (s, 2 H), 7.22–
7.26 (m, 2 H), 7.31–7.38 (m, 3 H), 8.75 (d, J = 2.3 Hz, 1 H), 8.87
(d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 23.4, 47.7, 126.3, 126.7, 128.1,
128.5, 128.6, 129.1, 132.0, 134.9, 142.9, 144.0, 144.3, 158.6.
IR (KBr): 1679, 1561, 1538, 1486, 1426, 1374, 1328, 1256, 1193,
1160, 1074, 1041, 760, 696, 656, 428 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.41 (s, 3 H), 7.30–7.34 (m, 2 H),
7.54–7.63 (m, 3 H), 8.75 (d, J = 2.3 Hz, 1 H), 8.88 (d, J = 2.3 Hz, 1
H).
13C NMR (125 Hz, CDCl3): d = 24.3, 124.5, 127.7, 129.9, 130.3,
MS (FAB): m/z = 309 (70%).
137.0, 143.0, 143.9, 144.3, 148.5, 158.2, 158.5, 158.7.
Anal. Calcd for C16H12N4OS: C, 62.32; H, 3.92; N, 18.17; S, 10.40.
Found: C, 62.23; H, 3.77; N, 18.29; S, 10.65.
MS (FAB): m/z = 295 (100%).
Anal. Calcd for C15H10N4OS: C, 61.21; H, 3.42; N, 19.04; S, 10.89.
Found: C, 61.03; H, 3.68; N, 19.17; S, 10.67.
3-Benzyl-2-ethylpyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6f)
Yield: 76%; yellow solid; mp 180–181 °C (dec.) (EtOAc–
n-hexane).
2-Ethyl-3-phenylypyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6b)
Yield: 90%; white crystals; mp 284–285 °C (EtOAc–n-hexane).
IR (KBr): 1673, 1539, 1510, 1450, 1345, 1185, 1141, 1100, 946,
733, 695, 524, 439 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.44 (t, J = 7.4 Hz, 3 H), 2.98 (q,
J = 7.4 Hz, 2 H), 5.56 (s, 2 H), 7.22–7.27 (m, 2 H), 7.35–7.41 (m, 3
H), 8.77 (d, J = 2.3 Hz, 1 H), 8.91 (d, J = 2.3 Hz, 1 H).
13C NMR (125 Hz, CDCl3): d = 11.7, 28.7, 46.9, 124.1, 126.5,
128.0, 129.1, 135.2, 143.0, 144.1, 144.2, 148.4, 158.3, 159.1, 162.4.
IR (KBr): 1677, 1557, 1539, 1509, 1480, 1342, 1231, 1160, 1079,
870, 744, 707, 646, 499, 452, 428 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.31 (t, J = 7.4 Hz, 3 H), 2.63 (q,
J = 7.4 Hz, 2 H), 7.30–7.36 (m, 2 H), 7.53–7.65 (m, 3 H), 8.75 (d,
J = 2.3 Hz, 1 H), 8.91 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 11.8, 29.5, 124.4, 128.0, 129.8,
130.1, 136.6, 143.0, 144.1, 144.2, 148.6, 158.2, 158.8, 162.3.
MS (FAB): m/z = 323 (20%).
MS (FAB): m/z = 309 (100%).
Anal. Calcd for C17H14N4OS: C, 63.33; H, 4.38; N, 17.38; S, 9.95.
Found: C, 63.02; H, 4.25; N, 17.49; S, 9.87.
Anal. Calcd for C16H12N4OS: C, 62.32; H, 3.92; N, 18.17; S, 10.40.
Found: C, 62.05; H, 3.87; N, 18.39; S, 10.27.
3-Benzyl-2-isopropylpyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6g)
Yield: 79%; pale yellow solid; mp 278–280 °C (dec.) (EtOAc–
n-hexane).
2-Isopropyl-3-phenylypyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimi-
din-4(3H)-one (6c)
Yield: 81%; white solid; mp 205–206 °C (EtOAc–n-hexane).
IR (KBr): 1671, 1556, 1537, 1509, 1442, 1141, 1104, 947, 732, 695,
442 cm–1.
IR (KBr): 1675, 1556, 1536, 1491, 1341, 1231, 1162, 1105, 1051,
772, 739, 703, 436 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 (d, J = 6.7 Hz, 6 H), 3.26
(sept, J = 6.7 Hz, 1 H), 5.57 (s, 2 H), 7.15–7.21 (m, 2 H), 7.29–7.37
(m, 3 H), 8.73 (d, J = 2.3 Hz, 1 H), 8.90 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 21.5, 32.7, 46.5, 126.3, 127.5, 127.9,
129.1, 135.6, 142.9, 144.0, 144.1, 148.5, 159.0, 166.2.
1H NMR (300 MHz, CDCl3): d = 1.33 (d, J = 6.7 Hz, 6 H), 2.82
(sept, J = 6.7 Hz, 1 H), 7.28–7.34 (m, 2 H), 7.55–7.65 (m, 3 H), 8.74
(d, J = 2.3 Hz, 1 H), 8.92 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 21.5, 29.7, 32.9, 124.2, 128.0, 129.7,
130.1, 136.7, 142.9, 144.1, 148.8, 158.3, 158.9, 166.1.
MS (FAB): m/z = 337 (30%).
MS (FAB): m/z = 323 (100%).
Anal. Calcd for C18H16N4OS: C, 64.26; H, 4.79; N, 16.65; S, 9.53.
Found: C, 64.38; H, 4.89; N, 16.52; S, 9.26.
Anal. Calcd for C17H14N4OS: C, 63.33; H, 4.38; N, 17.38; S, 9.95.
Found: C, 63.58; H, 4.16; N, 17.55; S, 9.90.
3-Benzyl-2-phenylpyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6h)
Yield: 85%; white solid; mp 249–250 °C (dec.) (EtOAc–n-hexane).
2,3-Diphenylypyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (6d)
Yield: 80%; pale yellow solid; mp 260–261 °C (dec.) (EtOAc–
n-hexane).
IR (KBr): 1668, 1549, 1494, 1445, 1374, 1341, 1188, 1140, 1116,
1083, 1041, 869, 769, 704, 661, 515, 441 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.42 (s, 2 H), 6.93–6.99 (m, 2 H),
7.20–7.25 (m, 3 H), 7.39–7.43 (m, 4 H), 7.46–7.51 (m, 1 H), 8.74
(d, J = 2.3 Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H).
IR (KBr): 1666, 1533, 1487, 1442, 1339, 1175, 1126, 1070, 777,
761, 696, 544, 441 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.21–7.28 (m, 4 H), 7.29–7.32 (m,
1 H), 7.36–7.45 (m, 5 H), 8.80 (d, J = 2.3 Hz, 1 H), 8.93 (d, J = 2.3
Hz, 1 H).
Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York

1402
G. Blanco et al.
PAPER
13C NMR (75 Hz, CDCl3): d = 49.4, 125.0, 127.2, 127.5, 127.8,
128.5, 128.5, 128.7, 130.3, 134.5, 135.8, 139.8, 143.0, 144.1, 144.3,
160.0, 163.3.
IR (KBr): 1659, 1559, 1539, 1513, 1346, 1195, 1137, 1095, 781,
439 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.80–1.98 (m, 6 H), 3.23–3.33 (m,
2 H), 4.48–4.55 (m, 2 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.85 (d, J = 2.3
Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 25.0, 27.6, 29.6, 37.4, 43.4, 142.8,
144.1, 145.9, 148.2, 157.4, 158.2, 158.5, 163.6.
MS (FAB): m/z = 371 (100%).
Anal. Calcd for C21H14N4OS: C, 68.09; H, 3.81; N, 15.12; S, 8.66.
Found: C, 68.33; H, 3.64; N, 15.35; S, 8.54.
Cyclic Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidinones 9; Gener-
al Procedure
MS (FAB): m/z = 273 (100%).
Anal. Calcd for C13H12N4OS: C, 57.34; H, 4.44; N, 20.57; S, 11.77.
Found: C, 57.16; H, 4.60; N, 20.32; S, 11.94.
A mixture of 3 (0.20 g, 0.9 mmol) and SOCl2 (3 mL) was heated at
reflux temperature for 2 h. After cooling to r.t., the solvent was re-
moved under reduced pressure. The resulting solid was dissolved in
anhyd THF (8 mL), and DMAP (0.01 g, 0.09 mmol) and the corre-
sponding lactam 7a–c (0.9 mmol) were added to the solution. After
cooling to 0 °C (ice-bath), anhyd Et3N (0.38 mL, 2.7 mmol) was
added dropwise. The mixture was stirred at 0 °C for 1 h, and at r.t.
for 12 h, and the solvent was removed under reduced pressure. The
resulting solid was dissolved in CH2Cl2 (50 mL) and washed with
aq 1 M HCl (50 mL) and H2O (2 × 50 mL). The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. Then the result-
ing material was transferred to a glass tube and anhyd toluene (10
mL) and PPh3 (0.3 g, 1.1 mmol) were added. The glass tube was
sealed and the mixture was heated at 120 °C for 20 h. After cooling
to r.t. the solvent was removed under reduced pressure and the re-
sulting material was purified by silica gel chromatography
(CH2Cl2–EtOAc, 8:2) to afford the desired pyrazinothienopyrim-
idines 9.
1-{[7-(Triphenylphosphoranylideneamino)thieno[2,3-b]pyr-
azine-6-yl]carbonyl}pyrrolidin-2-one (8a)
A mixture of 3 (0.20g, 0.9 mmol) and SOCl2 (3 mL) was heated at
reflux temperature for 2 h. After cooling to r.t., the solvent was re-
moved under reduced pressure. The resulting solid was dissolved in
anhyd THF (8 mL), and DMAP (0.01 g, 0.09 mmol) and g-butyro-
lactam (0.08 g, 0.9 mmol) were added to the solution. After cooling
to 0 °C, anhyd Et3N (0.38 mL, 2.7 mmol) was added dropwise. The
mixture was stirred at 0 °C for 1 h, and at r.t. for 12 h, and Ph3P (0.3
g, 1.1 mmol) was added to the resulting material and the mixture
was stirred at r.t. for 8 h. The solvent was removed under reduced
pressure and the resulting material was purified by silica gel chro-
matography (CH2Cl2–EtOAc, 8:2) to afford the phosphazene 8a;
yield: 57%; yellow solid; mp 240–242 °C (dec.) (CH2Cl2–EtOAc).
IR (KBr): 1745, 1621, 1543, 1505, 1436, 1344, 1296, 1254, 1228,
1186, 1137, 1107, 717, 551, 532, 516, 435 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.91–2.40 (m, 4 H), 4.01 (t, J = 6.9
Hz, 2 H), 7.35–7.52 (m, 9 H), 7.68–7.79 (m, 6 H), 7.82 (d, J = 2.3
Hz, 1 H), 8.22 (d, J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 17.9, 32.8, 46.6, 128.1, 128.2, 131.3,
131.3, 131.7, 132.5, 132.6, 133.1, 138.4, 142.1, 144.5, 147.5, 155.9,
164.9, 173.0.
31P NMR (121.5 MHz, CDCl3): d = 11.5.
9,10-Dihydropyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrrolo[1,2-a]py-
rimidin-6(8H)-one (9a)
Yield: 58%; brown crystals; mp: 144–145 °C (CH2Cl2–EtOAc).
IR (KBr): 1674, 1589, 1484, 1436, 1177, 1118, 997, 765, 751, 720,
693, 535, 505, 441 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.35–2.48 (dt, J = 7.4, 8.0 Hz, 2
H), 3.36 (t, J = 8.0 Hz, 2 H), 4.35 (t, J = 7.4 Hz, 2 H), 8.74 (d, J = 2.3
Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H).
MS (FAB): m/z = 523 (20%).
13C NMR (125 Hz, CDCl3): d = 19.9, 32.4, 47.3, 123.9, 142.9,
Anal. Calcd for C29H23N4O2PS: C, 66.65; H, 4.44; N, 10.72; S, 6.14.
Found: C, 66.72; H, 4.38; N, 10.73; S, 6.01.
143.9, 144.3, 150.2, 157.5, 158.0, 163.4.
MS (FAB): m/z = 245 (30%).
Anal. Calcd for C11H8N4OS: C, 54.09; H, 3.30; N, 22.94; S, 13.13.
Found: C, 53.82; H, 3.56; N, 22.83; S, 13.24.
X-ray Crystallographic Data for Compounds 6b and 9a
The crystal and molecular structure of 6b and 9a were determined
by X-ray diffraction studies.17,18 Crystals were mounted on a glass
fiber and transferred to the cold gas stream of the diffractometer
Bruker Smart APEX. Data were recorded with Mo-Ka radiation
(l = 0.71073 Å) in w-scan mode. The structures were solved by the
direct method and refined anisotropically on F2. Methyl groups
were refined using rigid groups and other hydrogens were refined
using a riding method.
8,9,10,11-Tetrahydro-6H-pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyri-
do[1,2-a]pyrimidin-6-one (9b)
Yield: 53%; pale yellow solid; mp 219–220 °C (CH2Cl2–EtOAc).
IR (KBr): 1667, 1556, 1537, 1507, 1345, 1191, 1143, 1091, 762,
440 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96–2.15 (m, 4 H), 3.21 (t, J = 6.6
Hz, 2 H), 4.20 (t, J = 6.6 Hz, 2 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.85 (d,
J = 2.3 Hz, 1 H).
13C NMR (75 Hz, CDCl3): d = 19.1, 21.9, 31.8, 43.1, 123.2, 142.7,
144.0, 144.2, 148.3, 158.1, 158.6, 158.8.
Compound 6b
Suitable crystal for an X-ray diffraction analysis was grown from
EtOH. Yellow prism, FW = 308.36; orthorhombic, space group P,
a = 7.527(5) Å, b = 19.500(5) Å, c = 19.602(5) Å; V = 2877(2) Å3;
Z = 8; Dcalcd = 1.424 mg m–3, F(000) = 1280; T = 298 (2) K.
MS (FAB): m/z = 259 (100%).
Anal. Calcd for C12H10N4OS: C, 55.80; H, 3.90; N, 21.69; S, 12.41.
Found: C, 55.72; H, 4.18; N, 21.63; S, 12.54.
Compound 9a
Suitable crystal for an X-ray diffraction analysis was grown from
EtOH. Yellow prism, F = 244.27; monoclinic, space group P2(1)/c,
a = 7.7222(8) Å, b = 10.4362(11) Å, c = 12.5784(13) Å;
b = 93.577(2)°; V = 1011.72(18) Å3; Z = 4; Dcalcd = 1.604 mg m–3,
F(000) = 504; T = 298 (2) K.
9,10,11,12-Tetrahydropyrazino[2¢¢,3¢¢:4¢,5¢]thieno[3¢,2¢:4,5]py-
rimido[1,2-a]azepin-6(8H)-one (9c)
Yield: 54%; orange solid; mp 189–190 °C (CH2Cl2–EtOAc).
Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrazinothienopyrimidine Derivatives
1403
(6) (a) Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5,
2433. (b) Pettit, G. R.; Tan, R.; Xu, J.; Ichihara, Y.;
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Acknowledgment
This work was supported by the Xunta de Galicia (Spain) and
FEDER (Project PGIDIT06PXIB103224PR). One of us (G.B.)
thanks University of A Coruña for a predoctoral fellowship.
(7) (a) Baker, D. C.; Hand, E. S.; Plowman, J.; Rampal, J. B.;
Safavy, A.; Haugwitz, R. D.; Narayanan, V. L. Anticancer
Drug Des. 1987, 2, 297. (b) For a recent review, see: Pawar,
V. G.; De Borggraeve, W. H. Synthesis 2006, 2799.
(8) For a recent example, see: Burns, C. J.; Wilks, A. F.; Bu, X.
WO Patent 2005054230, 2005; Chem. Abstr. 2005, 143,
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(9) For reviews, see: (a) Palacios, F.; Alonso, C.; Aparicio, D.;
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523. (b) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso, C.;
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(c) Eguchi, S. Top. Heterocycl. Chem. 2006, 6, 113.
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Synthesis 2008, No. 9, 1397–1403 © Thieme Stuttgart · New York