A new approach to pyrazino[2,1-b]quinazolines and pyrazino[1,2-a]thieno[3, 2-d] pyrimidines

Article abstract of DOI:10.1055/s-2007-966025

The reaction of [2-(chloromethyl)-4-oxo-3,4-dihydroquinazolin-3-yl] acetonitrile and 2-(chloromethyl)-3-(2-oxopropyl)quinazolin-4(3H)-one with aliphatic primary amines was shown to yield 2-alkyl-3-(alkylimino)-1,2,3,4- tetrahydro-6H-pyrazino[2,1-b]quinazo

Full text of DOI:10.1055/s-2007-966025

PAPER
1503
A New Approach to Pyrazino[2,1-b]quinazolines and Pyrazino[1,2-a]thi-
eno[3,2-d]pyrimidines
P
yrazino[2,1-
b
v
]quinazoline
e
s
tlana N. Kulik,a Alexander S. Kobko,b Andrey A. Tolmachev,a Anton V. Tverdokhlebov,*b Oleg V. Shishkin,c
Alexander N. Chernegad
a
Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
b
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
STC ‘Institute for Single Crystals’ NAS, 60 Lenina ave., 310001 Khar’kov, Ukraine
c
d
Institute of Organic Chemistry NAS, Murmanska str. 5, 02094 Kiev, Ukraine
Received 13 February 2007; revised 20 March 2007
(Figure 1). Hence, except for a few instances,7,12 the ma-
jority of the pyrazinoquinazolines described are the 3-oxo
derivatives of type 1. Moreover the known methods8–10
are inapplicable for the preparation of hetero analogues of
Abstract: The reaction of [2-(chloromethyl)-4-oxo-3,4-dihydro-
quinazolin-3-yl]acetonitrile and 2-(chloromethyl)-3-(2-oxopro-
pyl)quinazolin-4(3H)-one with aliphatic primary amines was
shown to yield 2-alkyl-3-(alkylimino)-1,2,3,4-tetrahydro-6H-
pyrazino[2,1-b]quinazolin-6-ones and 2-alkyl-3-methyl-1,2-dihy- 1, for example the thieno-annulated bioisosteres 2. To the
dro-6H-pyrazino[2,1-b]quinazolin-6-ones,
starting materials were prepared by alkylation of 2-(chlorometh-
yl)quinazolin-4(3H)-one with chloroacetonitrile or chloroacetone.
respectively.
The
best of our knowledge only three derivatives of the pyrazi-
no[1,2-a]thieno[2,3-d]pyrimidine framework 2 have been
reported to date.13 Hence it would be relevant to elaborate
an alternative approach to the pyrazino[2,1-b]quinazoline
system providing substituent diversity at position 3 and,
simultaneously, being suitable for the preparation of
thieno analogues. Our recent results in the field are report-
ed herein.
Furthermore
2-alkyl-3-(alkylimino)-1,2,3,4,7,8,9,10-octahydro-
6H-[1]benzothieno[2,3-d]pyrazino[1,2-a]pyrimidin-6-ones and 8-
alkyl-2,3,7-trimethyl-8,9-dihydro-4H-pyrazino[1,2-a]thieno[2,3-
d]pyrimidin-4-ones were obtained through the same sequence start-
ing from the appropriate 2-(chloromethyl)thieno[2,3-d]pyrimidin-
4(3H)-ones.
Key words: alkylations, heterocycles, nitriles, pyrazines, ring clo-
sure
O
R
O
O
4
N5
N
3
N
N
S
N
N
The pyrazino[2,1-b]quinazoline system has been shown
to be the core of a number of fungal metabolites such as
glyantripine,1 fumiquinazolines,2 fiscalines,3 alantrypi-
none,4 and spiroquinazoline.5 These natural compounds
are useful in cancer chemotherapy and their biological
properties have been assigned to the pyrazinoquinazoline
pharmacophore. Thus, several synthetic pyrazino[2,1-
b]quinazoline derivatives have exhibited a comparable
level of activity.6 Furthermore, certain pyrazinoquinazo-
lines have been claimed to be sedatives.7 To date three
general approaches to this system have been developed:
(1) double cyclization of tripeptide analogues containing
the anthranilic acid moiety as the central amino acid resi-
due;6a,8 (2) N-acylation of piperazin-2-one derivatives
with 2-azidobenzoyl chloride and further Staudinger aza-
Wittig reaction sequence;8d,9 and (3) the reaction of piper-
azine-derived imino esters with anthranilic acid or its de-
rivatives.10 Additionally, a few less common approaches
have been reported.11 However, in most of these methods
readily available amino acids are used as building blocks
for the preparation of the key precursors.8–10 Therefore the
substitution pattern at the C3–C4–N5 moiety of pyrazino-
quinazoline is derived from the appropriate amino acid
1
2
Figure 1 R = H, alkyl
The readily available 2-(chloromethyl)quinazolin-4(3H)-
one (3)11b and related thienopyrimidine 713a were chosen
as the starting materials. Their alkylation with chloroace-
tonitrile afforded compounds 4 and 8 in good yields
(Scheme 1). Although quinazolin-4(3H)-ones are known
to undergo alkylation predominantly at N314 a few in-
stances of N1- and O-alkylation have been reported.15
Therefore, to confirm without doubt the position of the cy-
anomethyl group in compounds 4 and 8 an X-ray crystal-
lographic study was carried out for derivative 8
(Figure 2). It indicated clearly that alkylation had pro-
ceeded at N3.
Treatment of the chloronitriles 4 and 8 with excess ammo-
nia or primary amines was found to give the target pyrazi-
noquinazolines 6a–d and their thieno analogues 9a–d.
Apparently the products 6 and 9 are formed through re-
amination of the initial adducts, e.g. 5. The structure of the
amidinium salts 6 and 9 was confirmed by H and 13C
1
NMR data. First of all the absence of nitrile absorption
both in IR and 13C NMR (d = 115.8 for the starting mate-
rials 4 and 8) spectra of compounds 6 and 9 indicated
clearly that ring closure had taken place with its participa-
SYNTHESIS 2007, No. 10, pp 1503–1508
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966025; Art ID: Z03507SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

1504
S. N. Kulik et al.
PAPER
O
O
N
NH
Cl
60%
CN
N
CN
N
Cl
4
Cl
3
R-NH2
O
O
N
R
N
NH
R
R-NH2
N
N
⋅HCl
N
– NH3
N
R
N
70–80%
6a–d
5
O
N
O
N
O
R
N
Cl
CN
71%
NH
N
CN
N
R-NH2
69–84%
⋅HCl
R
N
S
S
S
N
Cl
Cl
9a–d
7
8
Scheme 1 a R = H; b R = Me; c R = Et; d R = Bn
and carbon atoms were observed at the usual values and
were in good agreement with the structures of 6 and 9.
Continuing our research, we attempted to extend the
scope of the method by changing the nature of electro-
philic group attached to N3 of compounds 4 and 8. For
this purpose the quinazoline 3 and thienopyrimidine 13
were alkylated with chloroacetone to give derivatives 10
and 14 in 50–70% yields (Scheme 2). Similarly to the pre-
vious case, the alkylation occurred smoothly and selec-
tively at N3. Furthermore, the reaction of the chloro
ketones 10 and 14 with primary amines was examined. It
was found to give the pyrazinoquinazolines 12a–d and
their thieno analogues 15a–d. It should be emphasized
that elimination of water from the intermediates 11 pro-
ceeded exclusively with formation of the endocyclic dou-
ble bond. By contrast, the closely related adducts that
arise after addition of organometallics to the 3-CO of de-
rivatives 1 (Figure 1) prefer exocyclic dehydration.12b The
Figure 2 X-ray molecular structure of compound 8 with the atom
numbering used in the crystallographic analysis
tion. The characteristic amidinium carbon (C3) signal ap-
peared in the 13C NMR spectra of derivatives 6 and 9 at
d = 153–158. The signals from the remaining hydrogen
O
O
O
Cl
R-NH2
N
N
OH
3
O
68%
N
N
N
R
11
Cl
10
– H2O
76–86%
O
N
N
N
R
12a–d
O
N
O
O
O
N
Cl
NH
R-NH2
N
N
S
49%
O
70–90%
N
S
N
S
R
Cl
13
14
Cl
15a–d
Scheme 2 a R = Et; b R = Pr; c R = cyclopropyl; d R = Bn
Synthesis 2007, No. 10, 1503–1508 © Thieme Stuttgart · New York

PAPER
Pyrazino[2,1-b]quinazolines
1505
triturated with H2O, filtered, and recrystallized (i-PrOH) to yield de-
rivatives 4 or 8.
different behavior can be, most probably, explained by the
influence of the substituent at position 4.
The structure of compounds 12 and 15 was initially de-
duced from 1H and 13C NMR spectra and then confirmed
unambiguously by an X-ray crystallographic study car-
ried out for derivative 15a (Figure 3). As regards the spec-
tral data the especially noticeable signals of the enamine
moiety, namely the H4 at d = 6.5–6.7 ppm and C4 at d =
95–97 ppm deserve to be mentioned. According to the
crystal data the thienopyrimidine moiety is planar (devia-
tions from the least-square plane do not exceed 0.008 Å).
The pyrazine ring adopts a half-boat conformation with
planar N5 atom coordination and slightly pyramidal N8
(sums of the bonds angles around these atoms are 360.0°
and 349.5°, respectively).
[2-(Chloromethyl)-4-oxo-3,4-dihydroquinazolin-3-yl]acetoni-
trile (4)
Yield: 4.20 g (60%); mp 154 °C (i-PrOH).
1H NMR: d = 4.96 (s, 2 H, CH2), 5.18 (s, 2 H, CH2), 7.60 (t, J = 8.2
Hz, 1 H, H6), 7.69 (d, J = 8.2 Hz, 1 H, H8), 7.80 (t, J = 8.2 Hz, 1 H,
H7), 8.16 (d, J = 8.2 Hz, 1 H, H5).
13C NMR: d = 33.6 (CH2), 44.8 (CH2Cl), 115.9 (CN), 120.3 (C4a),
126.8 (C5), 127.9 (C6), 128.9 (C8), 135.9 (C7), 146.5 (C8a), 151.7
(C2), 161.1 (4-CO).
Anal. Calcd for C11H8ClN3O: C, 56.55; H, 3.45; N, 17.98; Cl, 15.17.
Found: C, 56.35; H, 3.50; N, 17.94; Cl, 14.98.
[2-(Chloromethyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]benzo-
thieno[2,3-d]pyrimidin-3-yl]acetonitrile (8)
Yield: 6.26 g (71%); mp 194 °C (i-PrOH).
1H NMR: d = 1.86 (m, 4 H, 6,7-CH2), 2.82 (m, 2 H, 8-CH2), 3.01
(m, 2 H, 5-CH2), 4.70 (s, 2 H, CH2Cl), 5.21 (s, 2 H, NCH2).
13C NMR: d = 22.1 (CH2), 22.8 (CH2), 25.1 (CH2), 25.5 (CH2), 33.2
(NCH2), 44.6 (CH2Cl), 115.8 (CN), 121.1 (C4a), 131.6 (C8a), 135.9
(C4b), 151.5 (C9a), 157.3 (C2), 160.4 (4-CO).
To summarize, the present investigation has resulted in a
new approach to pyrazino[2,1-b]quinazolines. The key
step is the amination of 2-(chloromethyl)quinazolin-
4(3H)-one derivatives 4 and 10 bearing an electrophilic
functionality tethered to N3. Moreover, the method allows
pyrazino[1,2-a]thieno[2,3-d]pyrimidine derivatives 9 and
15, the bioisosteres of pyrazinoquinazolines 6 and 12, to
be obtained. Contrary to known procedures,8–10 no air- or
moisture-sensitive substances were used in the present
synthesis thus making it more convenient. The starting
materials and reagents are readily available. Finally, the
present approach provides substitution diversity at posi-
tions 2 and 3. Hence this method appears to be a good ad-
dition to the known set of synthetic tools in the field.
Anal. Calcd for C13H12ClN3OS: C, 53.15; H, 4.12; N, 14.30; Cl,
12.07; S, 10.91. Found: C, 53.06; H, 4.15; N, 14.15; Cl, 12.10; S,
10.90.
Pyrazino[2,1-b]quinazolines 6a–d and Pyrazino[1,2-
a]thieno[2,3-d]pyrimidines 9a–d; General Procedure
An appropriate amine (12 mmol) was added to a soln of 4 or 8 (3
mmol) in EtOH (10 mL) and resulting mixture was kept at 30–40 °C
for 2 h. The solvent was removed in vacuo and the residue was re-
crystallized (MeOH or i-PrOH) to give derivatives 6a–d or 9a–d.
3-Imino-1,2,3,4-tetrahydro-6H-pyrazino[2,1-b]quinazolin-6-
one Hydrochloride (6a)
Yield: 0.57 g (76%); mp >300 °C (MeOH).
1H NMR: d = 4.36 (s, 2 H, CH2), 4.62 (s, 2 H, CH2), 6.46 (br s, 1 H,
NH), 7.49 (t, J = 8.2 Hz, 1 H, H8), 7.62 (d, J = 8.2 Hz, 1 H, H10),
7.81 (t, J = 8.2 Hz, 1 H, H9), 7.93 (s, 1 H, NH), 8.12 (d, J = 8.2 Hz,
1 H, H7).
13C NMR: d = 40.5 (CH2), 51.7 (CH2), 120.0 (C6a), 126.5 (C7),
126.6 (C8), 127.1 (C10), 134.9 (C9), 147.9 (C10a), 153.9 (C11a),
158.6 (C3), 160.4 (6-CO).
Anal. Calcd for C11H10N4O·HCl: C, 52.70; H, 4.42; N, 22.35; Cl,
14.14. Found: C, 52.80; H, 4.54; N, 22.40; Cl, 14.20.
Figure 3 X-ray molecular structure of compound 15a with the atom
numbering used in the crystallographic analysis
2-Methyl-3-(methylimino)-1,2,3,4-tetrahydro-6H-pyrazino[2,1-
b]quinazolin-6-one Hydrochloride (6b)
Yield: 0.69 g (83%); mp 152 °C (MeOH).
Compounds 311b and 713a were prepared as reported. Other materials
and reagents were commercially available. All melting points were
determined in open capillary tubes in a Thiele apparatus and are un-
1H NMR: d = 2.87 (s, 3 H, CH3), 3.01 (s, 3 H, CH3), 4.39 (s, 2 H,
CH2), 4.82 (s, 2 H, CH2), 7.54 (t, J = 8.4 Hz, 1 H, H8), 7.65 (d,
J = 8.4 Hz, 1 H, H10), 7.84 (t, J = 8.4 Hz, 1 H, H9), 8.15 (d, J = 8.4
Hz, 1 H, H7).
13C NMR: d = 35.5 (CH3), 39.2 (CH3), 40.7 (CH2), 52.8 (CH2),
120.3 (C6a), 126.6 (C7), 127.1 (C8), 127.2 (C10), 135.0 (C9), 147.5
(C10a), 151.9 (C11a), 154.4 (C3), 160.3 (6-CO).
1
corrected. H and 13C NMR spectra were recorded on a Varian
1
UNITYplus 400 spectrometer (400 MHz for H and 100 MHz for
13C) in DMSO-d6 solns unless otherwise stated and with TMS as in-
ternal standard. The purity of all compounds obtained was checked
by 1H NMR and LC/MS on an Agilent 1100 instrument.
Chloronitriles 4 and 8; General Procedure
Anal. Calcd for C13H14N4O·HCl: C, 56.02; H, 5.42; N, 20.10; Cl,
12.72. Found: C, 56.24; H, 5.31; N, 20.10; Cl, 12.83.
Chloroacetonitrile (2.27 g, 0.03 mol) was added to a suspension of
3 or 7 (0.01 mol) and i-Pr2NEt (3.23 g, 0.025 mol) in DMF (10 mL)
and resulting mixture was stirred at 60–70 °C for 5–6 h. After cool-
ing, a small amount of insoluble material was removed by filtration
and the solvent was evaporated to dryness in vacuo. The residue was
2-Ethyl-3-(ethylimino)-1,2,3,4-tetrahydro-6H-pyrazino[2,1-
b]quinazolin-6-one Hydrochloride (6c)
Yield: 0.64 g (70%); mp 298 °C (i-PrOH).
Synthesis 2007, No. 10, 1503–1508 © Thieme Stuttgart · New York

1506
S. N. Kulik et al.
PAPER
1H NMR: d = 1.15 (m, 6 H, 2 CH3), 3.29 (q, J = 8.4 Hz, 2 H, NCH2),
3.98 (q, J = 8.4 Hz, 2 H, NCH2), 4.81 (s, 2 H, CH2), 5.12 (s, 2 H,
CH2), 7.57 (t, J = 9.6 Hz, 1 H, H8), 7.62 (d, J = 9.6 Hz, 1 H, H10),
7.92 (t, J = 9.6 Hz, 1 H, H9), 8.10 (d, J = 9.6 Hz, 1 H, H7).
13C NMR: d = 11.7 (CH3), 15.4 (CH3), 37.4 (NCH2), 38.5 (NCH2),
45.7 (CH2), 51.9 (CH2), 120.4 (C6a), 126.8 (C7), 127.4 (C8), 127.7
(C10), 135.5 (C9), 147.4 (C10a), 149.3 (C11a), 158.7 (C3), 159.7
(6-CO).
120.2 (C6a), 131.2 (C10a), 132.8 (C6b), 151.3 (C11a), 152.3
(C12a), 156.7 (C3), 161.5 (6-CO).
Anal. Calcd for C17H22N4OS·HCl: C, 55.65; H, 6.32; N, 15.27; Cl,
9.66; S, 8.74. Found: C, 55.64; H, 6.10; N, 15.25; Cl, 9.51; S, 8.93.
2-Benzyl-3-(benzylimino)-1,2,3,4,7,8,9,10-octahydro-6H-
[1]benzothieno[2,3-d]pyrazino[1,2-a]pyrimidin-6-one Hydro-
chloride (9d)
Yield: 1.01 g (69%); mp 127 °C (i-PrOH).
Anal. Calcd for C15H18N4O·HCl: C, 58.73; H, 6.24; N, 18.26; Cl,
11.56. Found: C, 58.67; H, 6.15; N, 18.46; Cl, 11.55.
1H NMR: d = 1.77 (m, 4 H, 8,9-CH2), 2.74 (m, 2 H, 10-CH2), 2.86
(m, 2 H, 7-CH2), 4.40 (s, 2 H, CH2), 4.54 (s, 2 H, CH2), 7.74 (s, 2 H,
CH2), 4.95 (s, 2 H, CH2), 7.17–7.31 (m, 10 H, 2 C6H5).
13C NMR: d = 22.2 (C9), 22.9 (C8), 25.0 (C10), 25.7 (C7), 38.5
(C1), 49.8 (NCH2), 50.3 (NCH2), 51.8 (C4), 120.2 (C6a), 126.6
(CR4), 127.5 (CR4¢), 127.6 (CR2,6), 128.4 (CR2¢,6¢), 128.6 (CR3,5),
128.8 (CR3¢,5¢), 131.2 (C10a), 132.9 (C6b), 138.2 (CR1), 142.2
(CR1¢), 151.9 (C11a), 152.8 (C12a), 156.7 (C3), 161.4 (6-CO).
2-Benzyl-3-(benzylimino)-1,2,3,4-tetrahydro-6H-pyrazino[2,1-
b]quinazolin-6-one Hydrochloride (6d)
Yield: 1.02 g (79%); mp 118 °C (i-PrOH).
1H NMR: d = 4.42 (s, 2 H, CH2), 4.55 (s, 2 H, CH2), 4.78 (s, 2 H,
CH2), 5.00 (s, 2 H, CH2), 7.17 (m, 1 H, HR), 7.24–7.37 (m, 9 H, HR),
7.52 (t, J = 8.8 Hz, 1 H, H8), 7.61 (d, J = 8.8 Hz, 1 H, H10), 7.32 (t,
J = 8.8 Hz, 1 H, H9), 8.15 (d, J = 8.8 Hz, 1 H, H7).
13C NMR: d = 39.0 (CH2), 49.9 (NCH2), 50.6 (NCH2), 51.8 (CH2),
120.4 (C6a), 126.6 (CR4¢), 126.7 (CR4), 127.2 (C7), 127.3 (C8),
127.5 (C10), 127.6 (CR2,6), 128.5 (CR2¢,6¢), 128.6 (CR3,5), 128.9
(CR3¢,5¢), 135.1 (C9), 138.3 (CR1), 142.3 (CR1¢), 147.5 (C10a),
152.0 (C11a), 152.9 (C3), 160.2 (6-CO).
Anal. Calcd for C27H26N4OS·HCl: C, 66.04; H, 5.54; N, 11.41; Cl,
7.22; S, 6.53. Found: C, 66.16; H, 5.57; N, 11.57; Cl, 7.30; S, 6.40.
Chloro Ketones 10 and 14; General Procedure
Chloroacetone (2.78 g, 0.03 mol) was added to a suspension of 3 or
13 (0.01 mol) and i-Pr2NEt (3.23 g, 0.025 mol) in DMF (10 mL) and
resulting mixture was stirred at 60–70 °C for 7–8 h. After cooling,
a small amount of insoluble material was removed by filtration and
the solvent was evaporated to dryness in vacuo. The residue was
triturated with H2O, filtered, and recrystallized (i-PrOH) affording
derivatives 10 or 14.
Anal. Calcd for C25H22N4O·HCl: C, 69.68; H, 5.38; N, 13.00; Cl,
8.23. Found: C, 69.79; H, 5.30; N, 12.92; Cl, 8.23.
3-Imino-1,2,3,4,7,8,9,10-octahydro-6H-[1]benzothieno[2,3-
d]pyrazino[1,2-a]pyrimidin-6-one Hydrochloride (9a)
Yield: 0.69 g (74%); mp >300 °C (MeOH).
1H NMR (CF3CO2D): d = 1.89 (m, 4 H, 8,9-CH2), 2.85 (m, 2 H, 10-
CH2), 2.93 (m, 2 H, 7-CH2), 5.02 (s, 2 H, CH2), 5.15 (s, 2 H, CH2).
13C NMR (CF3CO2D): d = 20.7 (C9), 21.4 (C8), 24.2 (C10), 24.4
(C7), 40.6 (C1), 42.7 (C4), 121.3 (C6a), 132.3 (C10a), 139.6 (C6b),
148.9 (C11a), 152.6 (C12a), 154.8 (C3), 162.2 (6-CO).
2-(Chloromethyl)-3-(2-oxopropyl)quinazolin-4(3H)-one (10)
Yield: 1.70 g (68%); mp 171 °C (i-PrOH).
1H NMR: d = 2.79 (s, 3 H, CH3), 4.79 (s, 2 H, CH2), 5.10 (s, 2 H,
CH2), 7.60 (t, J = 9.0 Hz, 1 H, H6), 7.71 (d, J = 9.0 Hz, 1 H, H8),
7.88 (t, J = 9.0 Hz, 1 H, H7), 8.10 (d, J = 9.0 Hz, 1 H, H5).
13C NMR: d = 27.8 (CH3), 44.7 (CH2Cl), 53.7 (NCH2), 120.6 (C4a),
126.8 (C5), 127.8 (C6), 128.4 (C8), 135.4 (C7), 146.9 (C8a), 152.5
(C2), 161.2 (4-CO), 201.5 (CO).
Anal. Calcd for C13H14N4OS·HCl: C, 50.24; H, 4.86; N, 18.03; Cl,
11.41; S, 10.32. Found: C, 50.30; H, 4.74; N, 18.10; Cl, 11.40; S,
10.18.
Anal. Calcd for C12H11ClN2O2: C, 57.50; H, 4.42; N, 11.17; Cl,
14.14. Found: C, 57.60; H, 4.58; N, 11.20; Cl, 13.98.
2-Methyl-3-(methylimino)-1,2,3,4,7,8,9,10-octahydro-6H-
[1]benzothieno[2,3-d]pyrazino[1,2-a]pyrimidin-6-one Hydro-
chloride (9b)
2-(Chloromethyl)-5,6-dimethyl-3-(2-oxopropyl)thieno[2,3-
d]pyrimidin-4(3H)-one (14)
Yield: 1.40 g (49%); mp 177 °C (i-PrOH).
1H NMR: d = 2.27 (s, 3 H, CH3), 2.35 (s, 3 H, CH3), 2.37 (s, 3 H,
CH3), 4.77 (s, 2 H, CH2), 5.03 (s, 2 H, CH2).
13C NMR: d = 13.1 (CH3), 13.2 (CH3), 27.8 (CH3), 44.5 (CH2Cl),
53.2 (NCH2), 122.0 (C4a), 129.5 (C5), 132.2 (C6), 152.0 (C7a),
157.9 (C2), 159.9 (4-CO), 201.4 (CO).
Yield: 0.85 g (84%); mp 223 °C (MeOH).
1H NMR: d = 1.78 (m, 4 H, 8,9-CH2), 2.73 (s, 3 H, CH3), 2.84 (s, 3
H, CH3), 2.88 (m, 2 H, 10-CH2), 2.98 (m, 2 H, 7-CH2), 4.33 (s, 2 H,
CH2), 4.75 (s, 2 H, CH2).
13C NMR: d = 22.2 (C9), 22.9 (C8), 25.0 (C10), 25.7 (C7), 35.5
(CH3), 38.8 (CH3), 41.6 (C1), 52.5 (C4), 120.2 (C6a), 131.2 (C10a),
132.8 (C6b), 151.8 (C11a), 154.2 (C12a), 156.9 (C3), 161.4 (6-CO).
Anal. Calcd for C12H13ClN2O2S: C, 50.61; H, 4.60; N, 9.84; Cl,
12.45; S, 11.26. Found: C, 50.60; H, 4.76; N, 9.71; Cl, 12.58; S,
11.30.
Anal. Calcd for C15H18N4OS·HCl: C, 53.17; H, 5.65; N, 16.53; Cl,
10.46; S, 9.46. Found: C, 53.20; H, 5.69; N, 16.71; Cl, 10.52; S,
9.26.
Pyrazino[2,1-b]quinazolines 12a–d and Pyrazino[1,2-
a]thieno[2,3-d]pyrimidines 15a–d; General Procedure
An appropriate amine (9 mmol) was added to a soln of 10 or 14 (3
mmol) in EtOH (10 mL) and resulting mixture was kept at 30–40 °C
for 2 h. The solvent was removed in vacuo and the residue was re-
crystallized (MeOH or i-PrOH) to give derivatives 12a–d or 15a–d.
2-Ethyl-3-(ethylimino)-1,2,3,4,7,8,9,10-octahydro-6H-[1]ben-
zothieno[2,3-d]pyrazino[1,2-a]pyrimidin-6-one Hydrochloride
(9c)
Yield: 0.92 g (84%); mp 176 °C (i-PrOH).
1H NMR: d = 1.05 (t, J = 9.8 Hz, 3 H, CH3), 1.11 (t, J = 9.8 Hz, 3
H, CH3), 1.76 (m, 4 H, 8,9-CH2), 2.74 (m, 2 H, 10-CH2), 2.86 (m, 2
H, 7-CH2), 3.26 (q, J = 9.8 Hz, 2 H, NCH2), 3.45 (q, J = 9.8 Hz, 2
H, NCH2), 4.37 (s, 2 H, CH2), 4.30 (s, 2 H, CH2).
13C NMR: d = 11.6 (CH3), 17.9 (CH3), 22.2 (C9), 22.9 (C8), 25.0
(C10), 25.6 (C7), 37.8 (C1), 41.5 (NCH2), 42.7 (NCH2), 50.1 (C4),
2-Ethyl-3-methyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazolin-6-
one (12a)
Yield: 0.56 g (77%); mp 116 °C (MeOH).
Synthesis 2007, No. 10, 1503–1508 © Thieme Stuttgart · New York

PAPER
Pyrazino[2,1-b]quinazolines
1507
1H NMR: d = 1.09 (t, J = 11.6 Hz, 3 H, CH3), 1.96 (s, 3 H, CH3),
3.20 (q, J = 11.6 Hz, 2 H, NCH2), 4.20 (s, 2 H, 1-CH2), 6.52 (s, 1 H,
H4), 7.47 (t, J = 7.8 Hz, 1 H, H8), 7.59 (d, J = 7.8 Hz, 1 H, H10),
7.75 (t, J = 7.8 Hz, 1 H, H9), 8.12 (d, J = 7.8 Hz, 1 H, H7).
13C NMR: d = 13.0 (CH3), 16.2 (CH3), 43.7 (NCH2), 51.0 (C1), 95.6
(C4), 120.5 (C6a), 126.8 (C8), 127.0 (C10), 127.4 (C7), 134.2 (C9),
136.1 (C3), 146.9 (C10a), 147.6 (C11a), 156.1 (6-CO).
Anal. Calcd for C14H17N3OS: C, 61.06; H, 6.22; N, 15.26; S, 11.64.
Found: C, 61.28; H, 6.28; N, 15.34; S, 11.82.
2,3,7-Trimethyl-8-propyl-8,9-dihydro-4H-pyrazino[1,2-
a]thieno[2,3-d]pyrimidin-4-one (15b)
Yield: 0.76 g (87%); mp 115 °C (i-PrOH).
1H NMR: d = 0.93 (t, J = 6.9 Hz, 3 H, CH3), 1.57 (m, 2 H, CH2),
1.97 (s, 3 H, 7-CH3), 2.36 (s, 3 H, 2-CH3), 2.41 (s, 3 H, 3-CH3), 3.10
(t, J = 7.4 Hz, 2 H, NCH2), 4.10 (s, 2 H, 9-CH2), 6.51 (s, 1 H, H6).
13C NMR: d = 11.4 (CH3), 13.1 (2-CH3), 13.3 (3-CH3), 16.4 (7-
CH3), 21.2 (CH2), 50.8 (NCH2), 51.4 (C9), 95.2 (C6), 120.9 (C3a),
129.2 (C3), 129.3 (C2), 136.4 (C7), 144.9 (C10a), 153.6 (C9a),
160.2 (4-CO).
Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C,
69.74; H, 6.09; N, 17.18.
3-Methyl-2-propyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazolin-
6-one (12b)
Yield: 0.60 g (78%); mp 97 °C (i-PrOH).
1H NMR: d = 0.96 (t, J = 8.1 Hz, 3 H, CH3), 1.62 (m, 2 H, CH2),
1.99 (s, 3 H, CH3), 3.13 (t, J = 7.5 Hz, 2 H, NCH2), 4.17 (s, 2 H, 1-
CH2), 6.54 (s, 1 H, H4), 7.40 (t, J = 7.2 Hz, 1 H, H8), 7.53 (d, J = 7.2
Hz, 1 H, H10), 7.65 (t, J = 7.2 Hz, 1 H, H9), 8.14 (d, J = 7.2 Hz, 1
H, H7).
Anal. Calcd for C15H19N3OS: C, 62.25; H, 6.62; N, 14.52; S, 11.08.
Found: C, 62.26; H, 6.51; N, 14.60; S, 11.04.
8-Isopropyl-2,3,7-trimethyl-8,9-dihydro-4H-pyrazino[1,2-
a]thieno[2,3-d]pyrimidin-4-one (15c)
Yield: 0.78 g (90%); 133 °C (i-PrOH).
13C NMR: d = 11.4 (CH3), 16.4 (CH3), 21.2 (CH2), 50.8 (NCH2),
51.6 (C1), 95.5 (C4), 120.5 (C6a), 126.7 (C8), 126.8 (C10), 127.3
(C7), 134.1 (C9), 136.1 (C3), 146.6 (C10a), 147.6 (C11a), 156.2 (6-
CO).
1H NMR: d = 1.10 (d, J = 7.8 Hz, 6 H, 2 CH3), 1.95 (s, 3 H, 7-CH3),
2.31 (s, 3 H, 2-CH3), 2.36 (s, 3 H, 3-CH3), 3.84 (m, 1 H, NCH<),
4.07 (s, 2 H, 9-CH2), 6.53 (s, 1 H, H6).
Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.68; H, 6.70; N, 16.69.
13C NMR: d = 13.1 (2-CH3), 13.4 (3-CH3), 16.5 (7-CH3), 20.0 (2
CH3), 45.1 (NCH<), 47.5 (C9), 96.1 (C6), 120.8 (C3a), 129.2 (C3),
129.3 (C2), 136.5 (C7), 145.2 (C10a), 153.5 (C9a), 160.2 (4-CO).
2-Isopropyl-3-methyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazo-
lin-6-one (12c)
Yield: 0.58 g (76%); mp 76 °C (i-PrOH).
Anal. Calcd for C15H19N3OS: C, 62.25; H, 6.62; N, 14.52; S, 11.08.
Found: C, 62.25; H, 6.62; N, 14.72; S, 11.25.
1H NMR: d = 1.11 (d, J = 7.9 Hz, 6 H, 2 CH3), 1.96 (s, 3 H, CH3),
3.83 (m, 1 H, NCH<), 4.09 (s, 2 H, CH2), 6.53 (s, 1 H, H4), 7.44 (t,
J = 8.2 Hz, 1 H, H8), 7.62 (d, J = 8.2 Hz, 1 H, H10), 7.76 (t, J = 8.2
Hz, 1 H, H9), 8.12 (d, J = 8.2 Hz, 1 H, H7).
13C NMR: d = 16.4 (CH3), 20.0 (2 CH3), 45.4 (NCH<), 47.6 (C1),
96.5 (C4), 120.5 (C6a), 126.7 (C8), 126.8 (C10), 127.3 (C7), 134.1
(C9), 136.1 (C3), 147.0 (C10a), 147.7 (C11a), 156.2 (6-CO).
8-Benzyl-2,3,7-trimethyl-8,9-dihydro-4H-pyrazino[1,2-
a]thieno[2,3-d]pyrimidin-4-one (15d)
Yield: 0.71 g (70%); mp 164 °C (i-PrOH).
1H NMR: d = 2.03 (s, 3 H, 7-CH3), 2.31 (s, 3 H, 2-CH3), 2.39 (s, 3
H, 3-CH3), 4.13 (s, 2 H, 9-CH2), 4.37 (s, 2 H, NCH2), 6.58 (s, 1 H,
H6), 7.26–7.35 (m, 5 H, C6H5).
13C NMR: d = 13.1 (2-CH3), 13.3 (3-CH3), 16.7 (7-CH3), 51.7 (C9),
52.8 (NCH2), 95.9 (C6), 121.0 (C3a), 127.8 (C4R), 128.0 (CR3,5),
129.1 (CR2,6), 129.3 (C3), 129.5 (C2), 136.1 (C7), 138.1 (CR1),
145.0 (C10a), 153.6 (C9a), 160.1 (4-CO).
Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.60; H, 6.82; N, 16.48.
2-Benzyl-3-methyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazolin-
6-one (12d)
Yield: 0.78 g (86%); mp 153 °C (i-PrOH).
Anal. Calcd for C19H19N3OS: C, 67.63; H, 5.68; N, 12.45; S, 9.50.
Found: C, 67.69; H, 5.65; N, 12.45; S, 9.29.
X-ray Crystal Structure Determination
1H NMR: d = 2.03 (s, 3 H, CH3), 4.14 (s, 2 H, CH2), 4.38 (s, 2 H,
CH2), 6.58 (s, 1 H, H4), 7.32 (m, 5 H, C6H5), 7.48 (t, J = 8.3 Hz, 1
H, H8), 7.55 (d, J = 8.3 Hz, 1 H, H10), 7.74 (t, J = 8.3 Hz, 1 H, H9),
8.10 (d, J = 8.3 Hz, 1 H, H7).
13C NMR: d = 16.7 (CH3), 51.8 (C1), 52.9 (NCH2), 96.1 (C4), 120.6
(C6a), 126.8 (C8), 126.9 (C10), 127.3 (C7), 127.8 (CR4), 128.1
(CR3,5), 129.1 (CR2,6), 134.2 (C9), 135.8 (C3), 138.2 (CR1), 146.6
(C10a), 147.5 (C11a), 156.2 (6-CO).
Compound 8: Intensities of 2512 reflections (2355 independent,
Rint = 0.079) were measured on an automatic four circles Siemens
P3/PC diffractometer (graphite monochromated Mo Ka radiation,
q/2q scanning, 2qmax = 50°). Crystal data: C13H12ClN3OS,
Mr = 293.77,
monoclinic,
a = 12.106(2),
b = 12.600(3),
c = 9.456(2) Å, b = 110.64(3)°, V = 1349.8(5) Å3, T = 293 K, space
group P21/c, Z = 4, m(Mo Ka) = 0.432 mm–1. The structure was
solved by direct method with the SHELXTL program package.16
Positions of hydrogen atoms were located from electron density dif-
ference maps and refined isotropically. Full-matrix least-squares re-
finement against F2 in anisotropic approximation using 2349
reflections was converged to R1 = 0.044 [for 1810 reflections with
F > 4s(F)], wR2 = 0.112, S = 1.041. Full crystallographic parame-
ters have been deposited at Cambridge Crystallographic Data Cen-
tre (CCDC); reference number CCDC 616747.
Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found: C,
75.36; H, 5.78; N, 13.83.
8-Ethyl-2,3,7-trimethyl-8,9-dihydro-4H-pyrazino[1,2-
a]thieno[2,3-d]pyrimidin-4-one (15a)
Yield: 0.65 g (79%); mp 137 °C (MeOH).
1H NMR: d = 1.15 (t, J = 8.4 Hz, 3 H, CH3), 1.97 (s, 3 H, 7-CH3),
2.37 (s, 3 H, 2-CH3), 2.49 (s, 3 H, 3-CH3), 3.17 (q, J = 8.4 Hz, 2 H,
NCH2), 4.16 (s, 2 H, 9-CH2), 6.67 (s, 1 H, H6).
13C NMR: d = 12.9 (CH3), 13.0 (2-CH3), 13.3 (3-CH3), 16.2 (7-
CH3), 43.6 (NCH2), 50.9 (C9), 95.5 (C6), 120.9 (C3a), 129.2 (C3),
129.3 (C2), 136.1 (C7), 145.1 (C10a), 153.5 (C9a), 160.1 (4-CO).
Compound 15a: Crystallographic measurements were performed at
120 K on a Bruker Smart 6 CCD diffractometer. The intensities of
10735 reflections (2178 unique, Rint = 0.063) were collected within
the range 1.2 < q < 30.3° (–6 < h < 6, –11 < k < 10, –47 < l < 44)
using graphite monochromated Mo Ka radiation (l = 0.71073 Å).
The data were corrected for Lorentz and polarization effects and ab-
sorption correction using the SADABS17 procedure was applied.
Synthesis 2007, No. 10, 1503–1508 © Thieme Stuttgart · New York

1508
S. N. Kulik et al.
PAPER
(9) (a) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57,
Crystal data: C14H17N3OS, Mr = 275.38, orthorhombic,
a = 5.0003(3), b = 7.8752(4), c = 33.681(2) Å, V = 1326.3(1) Å3,
Z = 4, T = 120 K, space group P212121, m(Mo Ka) = 0.240 mm–1.
The structure was solved by direct methods and refined by full-ma-
trix least-squares technique in the anisotropic approximation using
the CRYSTALS program package.18 In the refinement 883 reflec-
tions with I > 3s(I) were used. All hydrogen atoms were located in
the difference Fourier maps and included in the refinement with the
fixed positional and thermal parameters. Convergence was obtained
at R1 = 0.047 and wR2 = 0.048, GOF = 1.181. Chebushev weight-
ing scheme19 with parameters 2.63, –2.90, 2.11, and –0.76 was ap-
plied. Full crystallographic parameters have been deposited at
Cambridge Crystallographic Data Centre (CCDC); reference num-
ber CCDC 614542.
3301. (b) He, F.; Snider, B. B. Synlett 1997, 483.
(c) Hernandez, F.; Lumetzberger, A.; Avendano, C.;
Söllhuber, M. Synlett 2001, 1387. (d) Cledera, P.;
Avendano, C.; Menendez, J. C. J. Org. Chem. 2000, 65,
1743.
(10) (a) Cledera, P.; Sanchez, J. D.; Caballero, E.; Avendano, C.;
Ramos, M. T.; Menendez, J. C. Synlett 2004, 803.
(b) Sanchez, J. D.; Ramos, M. T.; Avendano, C. J. Org.
Chem. 2001, 66, 5731. (c) Sanchez, J. D.; Ramos, M. T.;
Avendano, C. Tetrahedron Lett. 2000, 41, 2745.
(d) Buenadicha, F. L.; Avendano, C.; Söllhuber, M.
Tetrahedron: Asymmetry 1998, 9, 4275. (e) Sanchez, J. D.;
Ramos, M. T.; Avendano, C. Tetrahedron 1998, 54, 969.
(f) Rajappa, S.; Advani, B. G. J. Chem. Soc., Perkin Trans.
1 1974, 2122.
(11) (a) Vojkovsky, T.; Weichsel, A.; Patek, M. J. Org. Chem.
1998, 63, 3162. (b) Reddy, P. S. N.; Nagaraju, C. Synth.
Commun. 1991, 21, 173.
(12) (a) Bhandari, K.; Virmani, V.; Aruna Murti, V.; Jain, C.;
Anand, N. Indian J. Chem. 1979, 17, 107. (b) Heredia, M.
L.; de la Cuesta, E.; Avendano, C. Tetrahedron 2001, 57,
1987.
(13) (a) Sauter, F.; Stanetty, P.; Schrom, E.; Sengstschmid, G.
Monatsh. Chem. 1978, 109, 53. (b) Sauter, F.; Stanetty, P.;
Schrom, E. Arch. Pharm. (Weinheim, Ger.) 1977, 310, 337.
(14) (a) Orfi, L.; Waczek, F.; Pato, J.; Varga, I.; Hegimegi-
Barakonyi, B.; Houghten, R. A.; Keri, G. Curr. Med. Chem.
2004, 11, 2549. (b) Reddy, P. S.; Reddy, P. P.; Vasantha, T.
Heterocycles 2003, 60, 183. (c) Witt, A.; Bergman, J. Curr.
Org. Chem. 2003, 7, 659.
(15) (a) Chen, G. S.; Kalchar, S.; Kuo, C.-W.; Chang, S.-C.;
Usifoh, C. O.; Chern, J.-W. J. Org. Chem. 2003, 68, 2502.
(b) Wippich, P.; Gutschow, M.; Leistner, S. Synthesis 2000,
714. (c) Jain, K. K.; Rout, S. P.; Pujari, H. K. Indian J.
Chem. 1990, 29, 379. (d) Volovenko, Yu. M.;
Resnyanskaya, E. V. Mendeleev Commun. 2002, 119.
(e) Gakhar, H. K.; Kiran, S.; Gupta, S. J. Indian Chem. Soc.
1982, 59, 666.
(16) Sheldrick, G. M. SHELXTL PLUS. PC Version. A system
of computer programs for the determination of crystal
structure from X-ray diffraction data, Rev. 5.1, 1998.
(17) Sheldrick, G. M. SADABS: Program for scaling and
correction of area detector data, University of Göttingen,
Germany, 1996.
(18) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P.
W. CRYSTALS, Issue 10, Oxford: Chemical Crystallography
Laboratory, University of Oxford, 1996.
References
(1) Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N. J.
Chem. Soc., Perkin Trans. 1 1992, 1495.
(2) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto,
T.; Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi,
H.; Shingu, T. Tetrahedron Lett. 1992, 33, 1621.
(b) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.;
Shingu, T.; Kumeda, Y.; Numata, A. J. Chem. Soc., Perkin
Trans. 1 1995, 2345. (c) Belofsky, G. N.; Anguera, M.;
Jensen, P. P.; Fenical, W.; Kock, M. Chem. Eur. J. 2000, 6,
1355.
(3) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.;
Gillum, A. M.; Cooper, R. J. Antibiot. 1993, 46, 545.
(b) Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.;
Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843.
(4) Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.;
Christophersen, C. J. Nat. Prod. 1998, 61, 1154.
(5) Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471.
(6) (a) Mendez-Vidal, C.; Rodrigues de Quesada, A. Cancer
Lett. 1998, 132, 45. (b) Wang, H.; Ganesan, A. J. Org.
Chem. 2000, 65, 1022. (c) Martin-Santamaria, S.;
Buenadicha, F. L.; Espada, M.; Söllhuber, M.; Avendano, C.
J. Org. Chem. 1997, 62, 6424. (d) Martin-Santamaria, S.;
Espada, M.; Avendano, C. Tetrahedron 1997, 53, 16795.
(7) Griot, R. G. US 3280117, 1966; Chem. Abstr., 1967, 66,
2584.
(8) (a) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
(b) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
(c) Hart, D. J.; Magomedov, N. Tetrahedron Lett. 1999, 40,
5429. (d) Hernandez, F.; Buenadicha, F. L.; Avendano, C.;
Söllhuber, M. Tetrahedron: Asymmetry 2001, 12, 3387.
(19) Carruthers, J. R.; Watkin, D. J. Acta Crystallogr. Sect. A
1979, 35, 698.
Synthesis 2007, No. 10, 1503–1508 © Thieme Stuttgart · New York