New tricyclic ring systems of fused 1,4-diazepines

Article abstract of DOI:10.1055/s-0029-1218710

New heterocyclic systems of pyrimido[1,2-d][1,4]diazepine, [1,4]diazepino[7,1-b]quinazoline, and [1,4]diazepino[1,7-a][1,3]diazepine were obtained in specific reactions of DMAD with zwitterionic compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218710

1654
PAPER
New Tricyclic Ring Systems of Fused 1,4-Diazepines
T
ricyclicRingSy
a
stems of
F
r
used 1,4-
b
D
iazepine
s
ara Zaleska,*a Marcin Karelus,a Paweł Serdab
a
Department of Organic Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Kraków, Poland
Fax 48(12)6340515; E-mail: zaleska@chemia.uj.edu.pl
Regional Laboratory of Physicochemical Analysis and Structural Research, ul. R. Ingardena 3, 30-060 Kraków, Poland
b
Received 16 February 2010; revised 25 February 2010
ylenedicarboxylates are known to undergo cycloaddition
reactions easily, especially with ionic compounds; this
made the zwitterions 2–10 interesting reactants for pre-
paring polycyclic heterocycles. Reactions between
DMAD and the zwitterions 2–10 were performed in 1:1
molar ratio of the reagents in refluxing methanol.
Abstract: New heterocyclic systems of pyrimido[1,2-d][1,4]diaz-
epine, [1,4]diazepino[7,1-b]quinazoline, and [1,4]diazepino[1,7-
a][1,3]diazepine were obtained in specific reactions of DMAD with
zwitterionic compounds.
Key words: pyrimido[1,2-d][1,4]diazepine,
[1,4]diazepino[7,1-
b]quinazoline, [1,4]diazepino[1,7-a][1,3]diazepine, triazatricy-
clo[7.2.1.03,8]dodec-7-ene, DMAD
R
R
Biological activity of 1,4-diazepine derivatives1 have al-
ready been explored for many years. Undoubtedly
[1,4]benzodiazepines belong to the family of privileged
structures.2–5 When fused with pyrrole,3,4 or
benzimidazole5 rings, [1,4]diazepines play a crucial role
in a number of biologically active compounds. Pyrimi-
do[4,5]-1,4-benzodiazepine derivatives show appreciable
inhibitor activity against the KDR tyrosine kinase.6 The
diazepinoquinazoline system is present in naturally occur-
ring alkaloids such as asperlicin, which is a cholecystoki-
nin antagonist.7 A rare O-bridged azepine skeleton is
present in molecules of interesting zoanthamine alkaloids
such as zoanthamine,8 which have been isolated from the
polyps of marine zoanthis. Our recent work has focused
on synthetic applications of zwitterionic compounds 2–
109–12 (Figure 1), which we obtained as a result of an un-
usual rearrangement during reactions of 2-anilino-2-
methoxy-3-oxothiobutanoic acid anilide derivatives 1
with various aliphatic 1,3- and 1,4-diamines. Scheme 1
shows an example of the reaction. The process involved
cyclisation followed by a sigmatropic rearrangement of 3-
oxoacid derivatives to 2-hydroxy acid derivatives in their
zwitterionic forms 2–10. This mechanism and complexity
of the reactions is discussed more extensively in our pre-
vious work.9
HN
NH
OH
HN
NH
OH
HN
NH
OH
N
N
N
S
S
S
Ar
Ar
Ar
2–6
7, 8
9, 10
2 R = H, Ar = Ph
3 R = H, Ar = 4-ClC6H4
4 R = Me, Ar = Ph
7 Ar = Ph
8 Ar = 4-ClC6H4
5 R = Me, Ar = 4-ClC6H4
6 R = Me, Ar = 4-MeOC6H4
9 Ar = Ph
10 Ar = 4-ClC6H4
Figure 1 Zwitterionic compounds 2–10
(CH2)n
H2N(CH2)nNH2
MeO
O
NHPh
NH
HN
NH
MeOH, reflux
OH
Ar
65–95%
S
N
S
Ar
1
2, 3
n = 3, 4 Ar = Ph, 4-ClC6H4
Scheme 1
We have already found10–12 that the compounds 2–10 are
important synthetic precursors, capable of reacting both
with electrophiles and nucleophiles. The reactions led to
novel, highly functionalised, saturated, or partially satu-
rated heterocyclic systems. Those heterocycles also could
serve as ionic liquids,12 after transformation into salts of
various acids.
The progress of the reactions was monitored by TLC,
though the formation of products could be easily observed
since they were generally yellow in contrast to the colour-
less substrates. In most cases products were formed within
seconds even at room temperature, but we found out that
heating to mild reflux for about 40 minutes gave the best
results. As a result of the reactions, pyrimido[1,2-
d][1,4]diazepine, [1,4]diazepino[7,1-b] quinazoline, and
[1,4]diazepino[1,7-a][1,3]diazepine derivatives were
formed. All the obtained compounds have O-bridges in
their 1,4-diazepine rings (Scheme 2).
Continuing our research we investigated the reactivity of
the zwitterionic compounds 2–10 towards DMAD. Acet-
SYNTHESIS 2010, No. 10, pp 1654–1658
Advanced online publication: 24.03.2010
DOI: 10.1055/s-0029-1218710; Art ID: Z03710SS
x
x.
x
x
.
2
0
1
0
Structures of the products were determined from their
spectra and confirmed by X-ray crystal structure of 11.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Tricyclic Ring Systems of Fused 1,4-Diazepines
1655
R
N
R
MeO2C
CO2Me
N
O
O
N
N
O
O
N
N
O
O
MeOH, reflux
2–10
CO2Me
CO2Me
CO2Me
60–70%
N
N
N
S
Ar
S
Ar
S
Ar
11 R = H, Ar = Ph
16 Ar = Ph
17 Ar = 4-ClC6H4
18 Ar = Ph
19 Ar = 4-ClC6H4
12 R = H, Ar = 4-ClC6H4
13 R = Me, Ar = Ph
14 R = Me, Ar = 4-ClC6H4
15 R = Me, Ar = 4-MeOC6H4
Scheme 2
There was a clear evidence for the formation of C=S bond
in the 13C NMR spectra: the thiocarbonyl carbon atom sig-
nals appeared at d = 196–198 ppm; they were not present
1
in the spectra of the substrates. Both H and 13C NMR
spectra indicated that, contrary to the substrates, all meth-
ylene groups of the pyrimidine and 1,3-diazepine rings in
the compounds 11–15, 18, and 19 were different. This
suggested that in each case, reactions took place on two
nitrogen atoms, one of the hetero ring and one of the
SCNAr moieties (Figure 1). Based on our previous work10
we expected the formation of C=N bond in the hetero
rings. We could not reveal if the OH groups of 2–10 par-
ticipated in the reactions, because corresponding signals
were not visible in the 1H NMR spectra of the substrates.
There were signals from two carbon atoms in 13C NMR
spectra of the products (at d = 95 ppm and d = 30–35 ppm,
respectively) that must have originated from the triple
bond of DMAD; as the atom absorption correspond to sp3
carbon atoms, the bond must have been fully reduced dur-
ing the reaction. The signals at d = 30–35 were attributed
to the CH2 group at C7 of the obtained system. The corre-
sponding signals of aliphatic hydrogen atoms appeared in
the range from d = 3.0 to 3.4 in the 1H NMR spectra. This
was confirmed with an HSQC experiment for the com-
pound 11.
Figure 2 X-ray crystal structure of 11
Table 1 Intramolecular Hydrogen Bonds in 11
D–H···A
D–A [Å] H···A [Å] D–H [Å] D–H···A [°]
C11–H111···N12 2.830(4) 2.75(3)
0.97(3)
0.95(3)
85(2)
97(2)
C16–H116···O6
C15–H215···O6
2.802(4) 2.52(4)
2.740(5) 2.52(4)
0.95(4) 106(3)
1.02(4) 87(3)
C20–H120···O18 2.650(7) 2.51(6)
The molecular structures of the products were finally con-
firmed by the X-ray analysis of 11.13 A perspective view
of the molecule of 11 with the crystallographic atom num-
bering scheme is shown in Figure 2. The unsaturated six-
membered pyrimidine hetero ring N7–C8–N12–C13–
C14–C15 adopted a boat conformation with the C14 atom
as the flap atom. There was one C=N bond (C8–N12,
1.261 Å) in the hetero ring. The C=S bond was rather
short (1.636 Å). The terminal phenyl ring C21–C22–C23–
C24–C25–C26 was disordered due to rotational freedom
around the N3–C21 single bond. No specific model of this
disorder could be found. As a result the atomic displace-
ment parameters of the atoms forming the ring were rather
high. The presence of the residual electron density peak of
0.61 e⋅Å–3 can also be attributed to this disorder. The con-
formation of the molecule was stabilised by a few in-
tramolecular close contacts (Table 1), of which the
strongest was C20–H120···O18. The crystal structure did
not show typical intermolecular hydrogen bonds.
Theoretically, there were two possible regioisomers A and
B that could be formed in the case of the compounds 16
and 17 (Figure 3), but only one was isolated in each case.
The positions of the benzene rings in these products were
determined by HMBC spectra for compound 16. The
HMBC spectra showed a correlation between the carbon
atom of the amide carbonyl group (d = 162 ppm) and the
protons of the CH2 group (d = 5.08 and 4.90 ppm) in the
quinazoline ring, which would not have been possible in
the case of the B regioisomer. This clearly indicated that
the correct structures of 16 and 17 corresponded to A
shown in Figure 3.
The probable mechanism of the reactions leading to tricy-
clic systems 11–19 starts with an electrophilic attack of
the C2 carbon atom of a DMAD molecule on the nitrogen
atom of the iminothiolate fragment of 2–10 with simulta-
neous oxygenation of the 1,3-diazahetero ring in zwitter-
Synthesis 2010, No. 10, 1654–1658 © Thieme Stuttgart · New York

1656
B. Zaleska et al.
PAPER
pressure and the residue was dissolved in Et2O (5 mL) and cooled
to 10 °C until the product precipitated completely. The crude prod-
ucts were purified by crystallisation from EtOH or hexane–toluene
mixture.
N
N
O
O
N
N
O
O
9-Methyl-12-oxa-2-oxo-11-phenyl-10-thioxo-3,7,11-triazatricy-
clo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid Methyl Ester (11)
Yield: 0.41 g (68%); yellow crystals; mp 126–127 °C.
R
R
N
N
Ar
Ar
S
S
R = CH2CO2Me
IR (KBr): 1746 (C=O, ester), 1706 (C=O), 1657 (C=N), 1494
(C=S), 1289 (S=C–N), 1209 (C–O, ester), 1082 cm–1 (C–O–C).
A
B
1H NMR (DMSO-d6): d = 7.60–7.20 (m, 5 Harom), 3.70 (m, 2 H, py-
rimidine ring), 3.50 (t, J = 5.4 Hz, 2 H, pyrimidine ring), 3.59 (s, 3
H, OCH3), 3.27 (d, J = 16.8 Hz, 1 H, CH2C=O), 3.07 (d, J = 16.8
Hz, 1 H, CH2C=O), 1.91–1.70 (m, 2 H, pyrimidine ring), 1.77 (s, 3
H, CH3C–O).
13C NMR (DMSOd6): d = 199.3 (C=S), 166.9 (C=O, ester), 162.2
(C=O), 145.8 (N=CN), 135.3–127.6 (arom), 95.2 (OCC=O), 91.2
(CH3C–O), 51.8 (OCH3), 44.0 (CH2N=C), 38.6 (CH2N), 35.0
(CH2C=O), 19.8 (CCH2C, pyrimidine ring), 19.6 (CH3C–O).
Figure 3 Possible regioisomers A and B for compounds 16 and 17
ionic compounds 2–10. The second step is a 5-exo-trig
ring closure via addition of the same C2 carbon to the OH
group and formation of the oxazolidine ring. A following
intramolecular cyclocondensation process leads to the
formation of the 1,4-diazepine ring of the unusual systems
11–19 (Scheme 3).
MS (EI): m/z (%) = 373 (86.9, M+), 342 (22.4, M+ – 2 CH3 + H+),
273 (100, M+ – COCH2CO2CH3 + H+), 240 (50.2, M+ – PhNCS + 2
H+), 179 (68.4, M+ – PhNCS – CO2CH3), 77 (26.3, Ph).
CO2Me
Anal. Calcd for C18H19N3O4S: C, 57.90; H, 5.13; N, 11.25. Found:
C, 57.93; H, 5.16; N, 11.45.
CO2Me
HN
NH
OH
N
NH
OH
CO2Me
CO2Me
11-(4¢-Chlorophenyl)-9-methyl-12-oxa-2-oxo-10-thioxo-3,7,11-
triazatricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid Methyl Es-
ter (12)
N
N
S
S
Ph
Ph
Yield: 0.46 g (70%); yellow crystals; mp 147–148 °C.
7
IR (KBr): 1752 (C=O, ester), 1698 (C=O), 1657 (C=N), 1494
(C=S), 1293 (S=C–N), 1201 (C–O, ester), 1092 cm–1 (C–O–C).
1H NMR (DMSO-d6): d = 7.62 (d, J = 9.0 Hz, 2 Harom), 7.28 (d,
J = 9.0 Hz, 2 Harom), 3.84–3.54 (m, 2 H, pyrimidine ring), 3.60 (s, 3
H, OCH3), 3.49 (t, J = 5.7 Hz, 2 H, pyrimidine ring), 3.29 (d,
J = 17.0 Hz, 1 H, CH2C=O), 3.12 (d, J = 17.0 Hz, 1 H, CH2C=O),
1.93–1.69 (m, 2 H, pyrimidine ring), 1.76 (s, 3 H, CH3C–O).
13C NMR (DMSO-d6): d = 199.6 (C=S), 166.9 (C=O, ester), 162.2
(C=O), 145.7 (N=CN), 134.3–129.7 (arom), 95.4 (OCC=O), 91.3
(CH3C–O), 51.9 (OCH3), 44.1 (CH2N=C), 35.0 (CH2N), 30.6
(CH2CO), 19.8 (CCH2C, pyrimidine ring), 19.7 (CH3C–O).
N
NH
O
N
N
O
– MeOH
O
CO2Me
CO2Me
CO2Me
N
N
S
Ph
S
Ph
16
MS (EI): m/z (%) = 408 (88.2, M+), 374 (27.6, M+ – SH), 308 (100,
Scheme 3
M+ – OCCH2CO2CH3 – H), 181 (55.4, M+ – ClC6H4NH –
OCCH2CO2CH3
OCCH2CO2CH3 – H), 110 (30.5, pyrimidine ring + C=O).
– – ClC6H4NHCS –
H), 137 (48.2, M+
In conclusion, we have used zwitterionic compounds 2–
10 in the tandem addition–cyclocondensation reactions
with dimethyl acetylenedicarboxylate. This clean and fast
reactions, proceeding under moderately mild conditions,
led to the hitherto unknown unusual triazatricyc-
Anal. Calcd for C18H18ClN3O4S: C, 53.01; H, 4.42; N, 10.31.
Found: C, 52.99; H, 4.41; N, 10.15.
5,5,9-Trimethyl-12-oxa-2-oxo-11-phenyl-10-thioxo-3,7,11-tri-
azatricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid Methyl Ester
(13)
lo[7.2.1.03,8]dodec-7-ene
lo[8.2.1.03,9]dodec-8-ene tricyclic systems.
and
triazatricyc-
Yield: 0.39 g (61%); yellow crystals; mp 164–166 °C.
IR (KBr): 1750 (C=O, ester), 1717 (C=O), 1663 (C=N), 1496
(S=C), 1168 (C–O, ester), 1076 cm–1 (C–O–C).
Melting points were determined on an Electrothermal IA9000 digi-
tal melting point apparatus and are uncorrected. The IR spectra were
obtained on a Bruker IFS 48 spectrometer at r.t.. 1H and 13C NMR
spectra were recorded on a Bruker AMX 500 NMR spectrometer
using TMS as an internal standard. Chemical shifts are reported in
ppm downfield from TMS. Yields are given for pure products.
1H NMR (DMSO-d6): d = 7.55 (d, J = 9.0 Hz, 2 Harom), 7.18 (d,
J = 9.0 Hz, 2 Harom), 3.59 (s, 3 H, OCH3), 3.59 (d, J = 12.5 Hz, 1 H,
pyrimidine ring), 3.31 (d, J = 17 Hz, 1 H, CH2C=O), 3.25 (s, 2 H,
pyrimidine ring), 3.23 (d, J = 12.5 Hz, 1 H, pyrimidine ring), 3.08
(d, J = 17 Hz, 1 H, CH2C=O), 1.82 (s, 3 H, CH3C–O), 0.97 (s, 3 H,
CH3), 0.84 (s, 3 H, CH3).
Reaction of DMAD with Zwitterionic Compounds 2–18; Gener-
al Procedure
A mixture of the corresponding zwitterionic compound 2–10 (1.6
mmol) and DMAD (1.6 mmol, 0.21 mL) was stirred for 40 min in
refluxing MeOH (30 mL). The solvent was removed under reduced
13C NMR (DMSO-d6): d = 199.4 (C=S), 166.8 (C=O, ester), 162.7
(C=O), 144.7 (N=CN), 135.2–127.5 (arom), 95.3 (OCC=O), 91.1
Synthesis 2010, No. 10, 1654–1658 © Thieme Stuttgart · New York

PAPER
Tricyclic Ring Systems of Fused 1,4-Diazepines
1657
(CH3C–O), 55.8 (CH2N=C), 51.8 (OCH3), 48.7 (CH2N), 35.1
(CH2CO), 27.1 [C(CH3)2], 23.9 (CH3), 23.0 (CH3).
1H NMR (DMSO-d6): d = 7.27–7.55 (m, 9 Harom), 5.08 (d, J = 16.8
Hz, 1 H, CH2N), 4.90 (d, J = 16.8 Hz, 1 H, CH2N), 3.61 (s, 3 H,
OCH3), 3.35 (d, J = 16.8 Hz, 2 H, CH2C=O,), 3.13 (d, CH2C=O,
J = 16.8 Hz, 1 H), 1.93 (s, 3 H, CH3C–O).
13C NMR (DMSO-d6): d = 198.1 (C=S), 167.0 (C=O, ester), 162.0
(C=O), 145.8 (N=CN), 122–138 (arom), 95.5 (OCC=O), 91.0
(CH3C–O), 52.0 (OCH3), 41.8 (CH2N), 35.2 (CH2CO), 19.6
(CH3C–O).
MS (EI): m/z (%) = 401 (92.6, M+), 301 (100.0, M+
–
COCH2CO2CH3 + H), 268 (45.0, M+ – COCH2CO2CH3 – S), 209
(37.5, M+ – PhNCOCH2CO2CH3), 193 (22.5, M+ – PhNCS –
CH2CO2CH3).
Anal. Calcd for C20H23N3O4S: C, 59.83; H, 5.77; N, 10.47. Found:
C, 60.10; H, 5.78; N, 10.56.
MS (EI): m/z (%) = 335 (46.8, M+ – CCH2CO2CH3 – H), 284 (37.0,
M+ – PhNHCS – H), 256 (79.4, M+ – CH2CO2CH3 – NHPh), 169
(99.6, quinazoline + CC=O – H), 129 (100.0. quinazoline ring – H).
11-(4¢-Chlorophenyl)-5,5,9-trimethyl-12-oxa-2-oxo-10-thioxo-
3,7,11-triazatricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid
Methyl Ester (14)
Anal. Calcd for C22H19N3O4S: C, 62.69; H, 4.54; N, 9.97. Found: C,
62.51; H, 4.56; N, 10.00.
Yield: 0.45 g (65%); yellow crystals; mp 175–176 °C.
IR (KBr): 1750 (C=O, ester), 1696 (C=O), 1660 (C=N), 1450
(C=S), 1295 (S=C–N), 1205 (C–O, ester), 1094 cm–1 (C–O–C).
11-(4¢-Chlorophenyl)-9-methyl-12-oxa-2-oxo-10-thioxo-3,7,11-
triazabenzo[e]tricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid
Methyl Ester (17)
1H NMR (DMSO-d6): d = 7.64 (d, J = 9.0 Hz, 2 Harom), 7.22 (d,
J = 9.0 Hz, 2 Harom), 3.60 (s, 3 H, OCH3), 3.56 (d, J = 12.5 Hz, 1 H,
pyrimidine ring), 3.33 (d, J = 17 Hz, 1 H, CH2C=O), 3.24 (s, 2 H,
pyrimidine ring), 3.23 (d, J = 12.5 Hz, 1 H pyrimidine ring), 3.13 (d,
J = 17 Hz, 1 H, CH2C=O), 1.79 (s, 3 H, CH3C–O), 0.96 (s, 3 H,
CH3), 0.83 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 199.6 (C=S), 166.8 (C=O, ester), 162.7
(C=O), 144.6 (N=CN), 134.3– 129.4 (arom), 95.3 (OCC=O), 91.1
(CH3C–O), 55.8 (CH2N=C), 51.8 (OCH3), 48.7 (CH2N), 34.9
(CH2CO), 27.1 [C(CH3)2], 23.8 (CH3), 23.1 (CH3).
Yield: 0.45 g (62%); pale yellow crystals; mp 231–232 °C.
IR (KBr): 1752 (C=O, ester), 1707 (C=O), 1641 (C=N), 1492
(C=S), 1292 (S=C–N), 1175 (C–O, ester), 1073 cm–1 (C–O–C).
1H NMR (DMSO-d6): d = 7.57–7.24 (m, 8 Harom), 5.10 (d, J = 16.8
Hz, 1 H, CH2N), 4.92 (d, J = 16.8 Hz, 1 H, CH2N), 3.61 (s, 3 H,
OCH3), 3.37 (d, J = 16.8 Hz, 2 H, CH2C=O), 3.12 (d, J = 16.8 Hz,
1 H, CH2C=O), 1.93 (s, 3 H, CH3C–O).
13C NMR (DMSO-d6): d = 198.0 (C=S), 166.8 (C=O, ester), 161.9
(C=O), 145.7 (N=CN), 137.3–122.3 (arom), 95.4 (OCC=O), 90.9
(CH3C–O), 51.9 (OCH3), 41.7 (CH2N), 35.0 (CH2CO), 19.5
(CH3C–O).
MS (EI): m/z (%) = 436 (89.2, M+), 336 (100.0, M+
COCH2CO2CH3 + H), 303 (37.8, M+ – COCH2CO2CH3 – S), 209
(39.2, M+ C6H4ClNCOCH2CO2CH3), 194 (25.3, M+
C6H4ClNCS – CH2CO2CH3).
–
–
–
MS (EI): m/z (%) = 370 (50.5, M+ – CCH2CO2CH3 – H), 284 (40.6,
Anal. Calcd for C20H22ClN3O4S: C, 55.10; H, 5.09; N, 9.64. Found:
C, 55.41; H, 4.95; N, 9.70.
M+ – C6H4ClNHCS – H), 256 (82.3, M+ – CH2CO2CH3
–
NHC6H4Cl), 169 (84.4, quinazoline + CC=O – H), 129 (100.0,
quinazoline ring – H).
11-(4¢-Methoxyphenyl)-5,5,9-trimethyl-12-oxa-2-oxo-10-
thioxo-3,7,11-triazatricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic
Acid Methyl Ester (15)
Anal. Calcd for C22H18ClN3O4S: C, 57.96; H, 3.98; N, 9.22. Found:
C, 58.07; H, 4.12; N, 9.03.
Yield: 0.41 g (60%); yellow crystals; mp 168–169 °C.
10-Methyl-13-oxa-2-oxo-12-phenyl-11-thioxo-3,8,12-triazatri-
cyclo[8.2.1.03,9]tridec-8-en-1-ylacetic Acid Methyl Ester (18)
Yield: 0.44 g (65%); yellow crystals; mp 151–152 °C.
IR (KBr): 1751 (C=O, ester), 1705 (C=O), 1664 (C=N), 1511
(S=C), 1163 (C–O, ester), 1073 cm–1 (C–O–C).
1H NMR (DMSO-d6): d = 7.60 (d, J = 9.0 Hz, 2 Harom), 7.23 (d,
J = 9.0 Hz, 2 Harom), 3.60 (d, J = 12.5 Hz, 1 H, pyrimidine ring),
3.27 (s, 2 H, pyrimidine ring), 3.25 (d, J = 12.5 Hz, 1 H, pyrimidine
ring), 3.62 (s, 3 H, OCH3), 3.50 (s, 3 H, CH3–O), 3.32 (d, J = 17 Hz,
1 H, CH2C=O), 3.11 (d, J = 17 Hz, 1 H, CH2C=O), 1.90 (s, 3 H,
CH3C–O), 1.02 (s, 3 H, CH3), 0.88 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 199.6 (C=S), 167.0 (C=O, ester), 162.9
(C=O), 145.1 (N=CN), 127.0– 135.5 (arom), 95.7 (OCC=O), 91.5
(CH3C–O), 55.9 (CH2N=C), 52.0 (OCH3), 50.2 (OCH3), 48.8
(CH2N), 35.2 (CH2CO), 27.4 [C(CH3)2], 23.8 (CH3), 23.1 (CH3).
IR (KBr): 1743 (C=O, ester), 1710 (C=O), 1658 (C=N), 1498
(C=S), 1290 (S=C–N), 1209 (C–O, ester), 1085 cm–1 (C–O–C).
1H NMR (DMSO-d6): d = 7.55–7.18 (m, 5 Harom), 3.76 (m, 2 H, di-
azepine ring), 3.52 (m, 2 H, diazepine ring), 3.60 (s, 3 H, OCH3),
3.25 (d, J = 16.8 Hz, 1 H, CH2C=O), 3.05 (d, J = 16.8 Hz, 1 H,
CH2C=O), 1.96–1.80 (m, 4 H, diazepine ring), 1.76 (s, 3 H, CH3C–
O).
13C NMR (DMSO-d6): d = 199.4 (C=S), 167.0 (C=O, ester), 162.4
(C=O), 145.6 (N=CN), 135.3–127.6 (arom), 95.1 (OCC=O), 91.0
(CH3C–O), 51.7 (OCH3), 44.2 (CH2N=C), 38.5 (CH2N), 35.0
(CH2CO), 20.0 (CH2, diazepine ring), 19.8 (CH2, diazepine ring),
19.6 (CH3C–O).
MS (EI): m/z (%) = 432 (90.1, M+), 332 (100.0, M+
–
COCH2CO2CH3 + H), 299 (40.0, M+ – COCH2CO2CH3 – S), 210
[32.7, M+ – C6H4(OCH3)NCOCH2CO2CH3], 194 [28.7, M+
C6H4(OCH3)NCS, – CH2CO2CH3].
–
MS (EI): m/z (%) = 387 (78.2, M+), 286 (100, M+ – COCH2CO2CH3
+ H+), 254 (45.6, M+ – PhNCS + 2 H+) 193 (52.8, M+ – PhNCS –
CO2CH3), 77 (20.1, Ph).
Anal. Calcd for C21H25N3O5S: C, 58.45; H, 5.84; N, 9.74. Found: C,
58.70; H, 5.89; N, 9.61.
Anal. Calcd for C19H21N3O4S: C, 58.90; H, 5.46; N, 10.85. Found:
C, 59.06; H, 5.55; N, 10.74.
9-Methyl-12-oxa-2-oxo-11-phenyl-10-thioxo-3,7,11-triazaben-
zo[e]tricyclo[7.2.1.03,8]dodec-7-en-1-ylacetic Acid Methyl Ester
(16)
12-(4¢-Chlorophenyl)-13-oxa-2-oxo-10-methyl-11-thioxo-
3,8,12-triazatricyclo[8.2.1.03,9]tridec-8-en-1-ylacetic Acid
Methyl Ester (19)
Yield: 0.38 g (57%); yellow crystals; mp 212–214 °C.
IR (KBr): 1751 (C=O, ester), 1707 (C=O), 1640 (C=N), 1492
(C=S), 1291 (S=C–N), 1175 (C–O, ester), 1073 cm–1 (C–O–C).
Yield: 0.46 g (68%); yellow crystals; mp 174–175 °C.
IR (KBr): 1751 (C=O, ester), 1700 (C=O), 1658 (C=N), 1490
(C=S), 1294 (S=C–N), 1200 (C–O, ester), 1090 cm–1 (C–O–C).
Synthesis 2010, No. 10, 1654–1658 © Thieme Stuttgart · New York

1658
B. Zaleska et al.
PAPER
(5) Ruano, J. L. G.; Fajardo, C.; Fraile, A.; Martin, M. R.;
Soriano, J. F. ARKIVOC 2010, (iii), 303.
(6) Smish, L.; Wong, W. C.; Kiselyov, A.; Burdzvic-Wizeman,
S.; Mao, Y.; Xu, Y.; Duncton, M. A. J.; Kim, K.; Piatnitski,
E. L.; Doody, J. F.; Wang, Y.; Rosler, R. L.; Milligan, D.;
Columbus, J.; Balagtas, C.; Lee, S. P.; Konovalov, A.;
Hadari, Y. R. Bioorg. Med. Chem. Lett. 2006, 16, 5102.
(7) Al-Said, N. H.; Al-Qaisi, L. S. Tetrahedron Lett. 2006, 47,
693.
1H NMR (DMSO-d6): d = 7.60 (d, J = 9.0 Hz, 2 Harom), 7.27 (d,
J = 9.0 Hz, 2 Harom), 3.76 (m, 2 H, diazepine ring), 3.52 (m, 2 H, di-
azepine ring), 3.60 (s, 3 H, OCH3), 3.24 (d, J = 16.8 Hz, 1 H,
CH2C=O), 3.03 (d, J = 16.8 Hz, 1 H, CH2C=O), 1.96–1.80 (m, 4 H,
diazepine ring), 1.75 (s, 3 H, CH3C–O).
13C NMR (DMSO-d6): d = 199.6 (C=S), 166.9 (C=O, ester), 162.3
(C=O), 145.5 (N=CN), 135.8–129.2 (arom), 95.1 (OCC=O), 91.0
(CH3C–O), 51.7 (OCH3), 44.1 (CH2N=C), 38.5 (CH2N), 35.0
(CH2CO), 20.0 (CH2, diazepine ring), 19.8 (CH2, diazepine ring),
19.6 (CH3C–O).
(8) Hill, R. A. Annu. Rep. Prog. Chem., Chem. Sect. B 2009,
105, 150.
MS (EI): m/z (%) = 421 (80.1, M+), 319 (100, M+ – OCCH2CO2CH3
– H), 192 (43.8, M+ – ClC6H4NH – OCCH2CO2CH3 – H), 148 (47.8,
M+ – ClC6H4NHCS – OCCH2CO2CH3 – H).
(9) Zaleska, B.; Bazanek, T.; Socha, R.; Karelus, M.;
Grochowski, J.; Serda, P. J. Org. Chem. 2002, 67, 4526.
(10) Zaleska, B.; Karelus, M. Synlett 2002, 1831.
(11) Zaleska, B.; Karelus, M.; Zadora, E.; Kruszewska, H.
Synthesis 2005, 2946.
(12) Zaleska, B.; Karelus, M.; Flasinski, M.; Serda, P. ARKIVOC
2007, (vi), 64.
Anal. Calcd for C19H20ClN3O4S: C, 54.09; H, 4.78; N, 9.96. Found:
C, 54.21; H, 4.65; N, 10.04.
References
(13) Compound 11 with formula C18H19N3O4S crystallises in the
triclinic system, space group P1, with unit cell parameters
a = 8.8020 (2), b = 10.1138 (2), c = 11.1187 (2) Å,
a = 74.932 (1), b = 75.122 (1), g = 74.018 (1)°, V = 900.36
(3) Å3, Z = 2. A total of 4115 independent reflections
[R(int) = 0.0278] were collected on a sample (size
0.3 × 0.2 × 0.15 mm) using KappaCCD diffractometer and
MoKa radiation. The structure was solved by direct methods
with SHELXS9714 and refined by the full-matrix least-
squares method on F2 using SHELXL9715 program. Final
discrepancy indices for I > 2s(I) were equal R1 = 0.0573,
wR2 = 0.1048 and R1 = 0.091, wR2 = 0.1642 for all data.
The final difference Fourier map of electron density had the
largest peak and hole of 0.61 and –0.305 e·Å–3, respectively.
All calculations and molecular graphics were done using the
WinGX package.16 The structural data were deposited at the
Cambridge Crystallographic Data Centre. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html, or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk, under reference number CCDC
720638
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Synthesis 2010, No. 10, 1654–1658 © Thieme Stuttgart · New York