Condensed isoquinolines 32. Synthesis of 4H-thieno-[3′,2′:5,6]- and-[2′,3′: 5,6]pyrimido-[1,2-b]isoquinolines and 6,12-dihydro-5H-isoquino-[2,3-a]quinazoline-5,12-dione derivatives

Article abstract of DOI:10.1007/s10593-008-0119-0

Treatment of 2-(4-oxo-3,4-dihydrothieno[2,3-d]-and-[3,2-d]pyrimidin-2- ylmethyl)benzoic acids and 2-(4-oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic acid with acetic anhydride gave thieno[3′,2′:5,6]-and-[2′, 3′:5,6]pyrimido[1,2-b]isoquinoline-4,11-diones and isoquino[2,3-a] quinazoline-5,12-dione respectively. NMR spectroscopy showed that an intramolecular acylation of the above acids occurs at the atom N-1 of the pyrimidinone part of the bicycle.

Full text of DOI:10.1007/s10593-008-0119-0

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
CONDENSED ISOQUINOLINES
32*. SYNTHESIS OF 4H-THIENO-
[3',2':5,6]- AND -[2',3':5,6]PYRIMIDO-
[1,2-b]ISOQUINOLINES AND
6,12-DIHYDRO-5H-ISOQUINO-
[2,3-a]QUINAZOLINE-5,12-DIONE
DERIVATIVES
A. V. Zadorozhny, V. A. Kovtunenko, A. V. Turov, and T. T. Kucherenko
Treatment of 2-(4-oxo-3,4-dihydrothieno[2,3-d]- and -[3,2-d]pyrimidin-2-ylmethyl)benzoic acids and
2-(4-oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic acid with acetic anhydride gave thieno[3',2':5,6]-
and -[2',3':5,6]pyrimido[1,2-b]isoquinoline-4,11-diones and isoquino[2,3-a]quinazoline-5,12-dione
respectively. NMR spectroscopy showed that an intramolecular acylation of the above acids occurs at
the atom N-1 of the pyrimidinone part of the bicycle.
Keywords: isoquinoquinazoline-5,12-dione, 4-oxopyrimidinones, thienopyrimidinones, thieno-
pyrimidoisoquinoline-4,11-diones, quinazolines.
We have previously reported 2-(4-oxo-3,4-dihydrothieno[2,3-d]- and -[3,2-d]pyrimidin-2-ylmethyl)-
benzoic acids 1 and 2 [2] and 2-(4-oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic acid 3 [3]. This work
continues our investigation of thienopyrimidines and quinazolones.
The attempted esterification of acids 1-3 by a classical method [4] (heating an alcohol suspension in the
presence of concentrated sulfuric acid) gave yellow crystalline materials whose properties differed from the
starting materials although not being the esters. Hence like the starting acid they dissolve in a 2N solution of
base but, in contrast, are completely insoluble in 2N hydrochloric acid. According to TLC data their
chromatographic mobility is markedly greater than the starting acids and esters. The elemental analytical data
and chromato-mass spectra of the products obtained point to the loss of a molecule of water from the starting
acids, i.e. that an intramolecular acylation had occurred under these reaction conditions. It was found that the
sulfuric acid dehydrating agent originally used by us was not a totally suitable reagent since cyclization is
accompanied by a vigorous tarring of the reaction product and this significantly lowers the yields. A smoother
dehydration occurs upon refluxing a suspension of the acids 1-3 in acetic anhydride.
_______
* For Communication 31 see [1].
__________________________________________________________________________________________
Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: vkovtunenko@univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1053-1061, July, 2008. Original article
submitted July 27, 2007.
0009-3122/08/4407-0845©2008 Springer Science+Business Media, Inc.
845

O
R1
S
O
O
3
NH
3
NH
3
NH
S
R
R
1
N
1
N
1
N
HOOC
HOOC
HOOC
3
2a–c
1a–d
R1
O
5
O
N
O
4
6
NH
5
NH
NH
3
2
S
R
R
S
1
6
N
7
6
N
1
1
7
O
8
9
O
7
O
10
8
11
8
10
9
10
9
4a–d
6
5a–c
R1
S
O
O
O
O
O
O
S
N
N
N
R
R
N
H
N
H
N
H
9
8
7
4 a R = R1 = Me; b R+R1 = (CH2)3; c R+R1 = (CH2)4; d R = H, R1 = Ph;
5 a R = H; b R = 4'-ClC6H4; c R = 4'-FC6H4
The series of 4-oxothieno[2,3-d]- and -[3,2-d]pyrimidine acids (1 and 2) and also the 4-oxoquinazoline
acid (3) have two nucleophilic centers of attack, viz. the N-1 and N-3 atoms. An intramolecular cyclization
involving these centers can lead to angular (4-6) or linear (7-9) tetracyclic systems. However, both our study of
the alkylation of the esters of the acids 1-3 [3, 4] and also from literature data for the alkylation [5] and acylation
[6] of 2-benzyl derivatives of the thienopyrimidine and quinazoline systems would infer that this reaction occurs
with the involvement of the N-3 atom exclusively. On this basis it would follow that the systems obtained have
the linear structures 7-9.
At the same time, quantum-chemical calculations of the energies of the isomeric angular and linear
systems 4 and 7, 5 and 8, and also the corresponding isoquinoquinazolinediones 6 and 9 using the computer
program [7] within the scope of the 3-21G** ab initio method (taking into account d-orbitals) and with full
optimization of the geometry showed these to be -792188.67 for the 4a molecule and -792170.65 kcal/mol for 7.
For the positional isomer 5a this is -743454.73 and its linear isomer 8 -743437.23 kcal/mol. For the molecule 6
this is -543176.13 and its linear isomer 9 -543165.97 kcal/mol. Hence, against literature data, the calculations
predict an intramolecular cyclization at the N-1 atom of the acid (1, 2, and 3) as the thermodynamically favored
process. The markedly lower difference in full energies of the linear and angular isomers in molecules 6/9 when
compared with the thiophene pairs 4/7 and 5/8 deserves mention.
Similar conclusions about the direction of cyclization at atom N-1 of the acids 1, 2, and 3 can be made
from the NMR data for compounds 4 (or 7), 5 (or 8) and also 6 (or 9). The linear or angular isomers formed
upon cyclization contain identical structural fragments and hence a direct determination of their structures based
1
on the spectra of their H or 13C nuclei was not possible. Hence we have carried out a 2D NMR spectroscopic
1
study using homonuclear (COSY, NOESY) and H–13C heteronuclear correlation through one (HMQC) and
through 2-3 bonds (HMBC).
846

In the first place an assignment of the signals in the 1H NMR spectra of the compounds was needed. The
spatial proximity of the NH proton to an aromatic proton and the long range correlations of the NH proton signal
with the carbon atoms of the molecular skeleton are the basis for the determination of the structure of compound
4 (or 7). We depict in Fig. 1 the results of the analysis for compound 4c only since all of the remaining
compounds of the 4 series are similar. Consideration of the formulae 4 and 7 shows that the only structurally
significant difference is the positioning of the NH proton relative to the carbonyl carbon atoms. Whereas there
are 2 chemical bonds between the NH proton and one of the carbonyl carbon atoms in the structure 4, in the
structure 7 they are separated by 4 bonds. Since the carbonyl group carbon atoms have quite a characteristic
positioning in the 13C NMR spectrum the presence of a spin-spin interaction between the NH proton signals and
carbon atom of one of the carbonyl groups unambiguously supports structure 4. Table 1 gives the correlations
for the signals of the protons in compound 4c. The correlations found (see Fig. 1) allowed us to assign the
signals securely and to choose between the alternative structures in favour of structure 4. The presence of a
correlation for the aromatic proton doublet with a chemical shift of 8.14 ppm with the signal of one of the
carbonyl carbon atoms found at 158.6 ppm makes possible its assignment as shown in the figure. The NH signal
correlates with that of the second carbonyl signal in the molecule which occurs at 156.8 ppm. The presence of
this correlation safely confirms the compound structure. The arrows in Fig. 1 show the HMBC correlations. The
signals for the carbon atoms bound to hydrogen atoms are assigned on the basis of the correlation in the HMQC
spectrum. The only carbon signal for which an HMBC correlation was not observed has a chemical shift of
141.5 ppm. We assign it to the carbon atom bridging between the heterocyclic nitrogen atoms and the sulfur. For
assignment of the signals of the cyclohexene fragment it was assumed that the methylene protons closest in
space to the carbonyl group absorb at somewhat lower field than the remaining aliphatic proton signals.
H
H
H
H
O
4
H
O
N
O
N
H
H
4
H
4
NOE
NOE
H
H
H
S
H
N
N
N
H
H
11
H
H
H
NOE
N
S
1
H
NOE
H
H
H
H
H
1
H
H
O
1
O
O
H
H
H
H
H
H
H
5a
6
4c
Fig. 1. Model of the HMQC and HMBC correlations for compounds 4c, 5a, and 6.
Conclusions regarding the structure of compounds of series 5 (or 8) are based on the occurrence of a
steric proximity of the NH proton to the aromatic protons on the one hand and of long range correlations of the
NH signal with the skeletal carbon atoms in the molecule. Correlations are only analyzed in this publication for
compound 5a because they are the same for all of the remaining compounds in the series (Table 2). Inspection of
the formulae of the isomers shows that a steric proximity of the NH proton to two aromatic protons would be
expected in the case of the linear isomer 8 but there would only be one in the example of the angular isomer 5a.
The experimental data shows that there is a cross peak in the NOESY spectrum between the NH proton signal
and that at 6.27 ppm. Other cross peaks were not seen for this signal and this supports the angular structure for
the compound, i.e. 5a. Further confirmation comes from the heteronuclear correlation data (see Fig. 1).
847

TABLE 1. Results of the Heteronuclear Correlation Experiments (HMBC
and HMQC) for Compound 4c
Atom position
δ, ppm
HMQC
HMBC
5
11.71
8.14
7.63
7.51
7.31
6.26
2.82
2.65
1.73
—
128.1
134.0
125.6
124.7
86.5
156.8; 137.6; 118.2; 86.5
158.6; 137.3; 134.0
10
8
137.3; 128.1
7
137.3; 124.7; 118.8; 86.5
125.6; 118.8
9
6
137.6; 141.5; 125.6; 118.8
132.9; 130.6; 23.0; 22.5
132.9; 130.6; 23.0; 22.5
132.9; 130.6; 25.4; 24.0; 23.0; 22.5
3(4')
2(1')
2', 3'
25.4
24.0
23.0; 22.5
TABLE 2. Results of the Homonuclear (NOESY Spectrum) and
Heteronuclear (HMBC and HMQC) Correlation Experiments for
Compound 5a
Atom position
δ, ppm
HMQC
HMBC
NOESY
6.27
5
12.03
8.68
8.21
8.17
7.65
7.53
7.33
6.27
—
123.9
128.3
133.8
133.9
125.3
124.7
87.2
138.8; 120.6; 155.6; 82.7
141.7; 133.8; 120.6
137.1; 133.8; 159.9
141.7; 123.9; 120.6; 155.6
137.1; 128.3
1
8.17
10
2
—
8.68
8
7.54; 7.33
7.65
7
124.7; 120.6; 87.2
125.2; 120.6
141.7; 138.8; 125.3; 120.6
9
6
7.65; 8.21
12.03; 7.54
TABLE 3. Results of the Heteronuclear Correlation Experiments (HMBC
and HMQC) for Compound 6
Atom position
δ, ppm.
HMQC
HMBC
119.9; 137.8; 158.4
6
11.86
9.22
8.17
8.09
7.75
7.61
7.46
7.45
7.30
6.18
—
121.6
128.7
127.5
134.2
134.1
126.8
125.1
125.0
87.7
1
158.4; 138.7; 126.8; 119.9
162.7; 136.9; 134.1
158.4; 138.7; 134.2
138.7; 127.5; 121.6
136.9; 128.7
11
4
2
9
3
121.6; 119.9
8
136.9; 125.0; 122.2; 87.7
125.1; 122.2; 136.9; 134.1; 128.7
137.8; 125.1; 122.2
10
7
Assignments of the chemical shifts of the carbon atoms bound to the hydrogen atoms are made based on HMQC
correlations and those of the quaternary carbon atoms on those showing in the HMBC. From the viewpoint of
establishing the structure of the compound the absence of a correlation between the NH proton signal and the
carbon atom signal with a shift of 123.9 ppm corresponding to the C-4 atom of the thiophene ring is most
important. In the alternative linear structure this correlation would have to be rather strong.
For determining the structure of compound 6 (or 9) difficulties arise because the spin systems for the
two benzene rings occurring in the composition of the molecules are identical. The assignment can be made
848

849

using a comparison of the correlations existing in the COSY and NOESY spectra. The key in the assignment of
signals is the presence of an NOE between the H-7 proton singlet absorbing at 6.18 ppm and the doublet at
7.45 ppm. Since the assignment of the singlet is not in doubt the NOE can only be observed for the H-8 proton
signal near to it. All of the remaining signals for this spin system can be assigned on the basis of their COSY
correlation. The signals of the protons of the second benzene ring can be assigned if one assumes that the proton
near to the carbonyl carbon atom has the chemical shift of 9.22 ppm. The assignments of the remaining signals
of the spin system then follow from their COSY correlation. This data supports the existence of the studied
molecule as having the structure 6. This follows from the occurrence of the H-1 proton signal at anomalously
low field due to steric proximity to the unshared electron pair of the carbonyl oxygen atom (in the alternative
structure 9 such a situation does not arise). In addition the NH proton signal only has a COSY correlation with
one aromatic proton signal. For structure 9 there would be two such correlations. Additional confirmation of
structure 6 was obtained from the heteronuclear correlations. The HMQC and HMBC correlations found for the
proton signals in the heterocycle synthesized are given in Table 3. Most important in establishing the structure
as 6 for this product is the correlation of the NH proton signal absorbing at 11.86 ppm with one of the carbonyl
group carbons (found at 158.4 ppm). Such a correlation would not have been possible in the case of the
alterative structure 9 since the carbonyl carbon atoms in it are separated from the NH by more than 3 chemical
bonds. Figure 1 shows the carbon signal assignments indicated by the arrows for the important HMBC
correlations which served as a basis for the structure. The assignment of the bridging carbon atoms was based on
the presence of correlations with the proton signals found in a meta position relative to it. The signal of the
bridging carbon atom placed between the heterocyclic nitrogen atoms was assigned on the basis of the
correlation with the singlet at 6.18 ppm and with the NH protons signal. The signals of the carbon atoms bonded
to hydrogen atoms are assigned from the presence of their correlation with the bonded protons in the HMQC
spectrum.
Table 4 shows the 1H NMR spectroscopic data for all of the synthesized compounds 4-6.
EXPERIMENTAL
The 1H and 13C NMR spectra of compounds 4-6, the NOE and 2D COSY 1H NMR experiments, and the
HMQC and HMBC heteronuclear correlation spectra were recorded on a Varian Mercury-400 spectrometer (400
and 100 MHz respectively). All of the 2D experiments were carried out with gradient selection of useful signals.
1
2-3
The mixing times in the pulse sequences were respectively JCH = 140 and
J
CH
= 8 Hz. The numbers of
increments in the COSY and HMQC spectra were 128 and in the HMBC spectra 400. In all cases the solvent
was DMSO-d6 and the internal standard TMS.
Mass spectra were measured on an Agilent 1100 series mass spectrometer with an Agilent LC/MSD SL
detector, the sample was introduced in a trifluoroacetic matrix, EI ionization was used and the m/z values
(Irel, %) are given. [M++1] was the molecular ion peak. Melting points for the synthesized materials were
measured in a Pyrex capillary using a Thiele apparatus and are not corrected. TLC was performed on Merck 60
F254 plates with benzene–methanol (9:1) as eluent. The products 4-6 have Rf 0.90-0.92. The esters have Rf
0.65-0.68 and the starting acids 1-3 have Rf 0.25-0.28.
2,3-Dimethyl-4H-thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione (4a). Acetic anhydride
(10 ml, 106 mmol) was added to 2-(5,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)benzoic acid
(1a) (0.31 g, 10 mmol) and refluxed with stirring for 4 h using a reflux condenser. The precipitate was filtered
off and washed with ether. Yield 90%; mp 325ºC (DMF). Mass spectrum, m/z: 297 [M++1]. Found, %: C 64.80;
H 4.00; N 9.39; S 10.78. C16H12N2O2S. Calculated, %: C 64.85; H 4.08; N 9.45; S 10.82.
2,3-Dihydro-1H,4H-cyclopenta[4',5']thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione (4b)
was obtained similarly from 2-(4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl)-
850

benzoic acid (1b) (0.33 g, 10 mmol). Yield 92%; mp 305ºC (DMF). Mass spectrum, m/z: 309 [M++1]. Found,
%: C 66.12; H 3.86; N 8.96; S 10.35. C17H12N2O2S. Calculated, %: C 66.22; H 3.92; N 9.08; S 10.40.
8,9,10,11-Tetrahydro-7H-benzo[1]thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-4,14(6H)-dione (4c)
was prepared similarly from 2-(4-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl)-
benzoic acid (1c) (0.34 g, 10 mmol). Yield 93%; mp 325ºC (DMF). Mass spectrum, m/z: 323 [M++1]. Found, %:
C 66.95; H 4.31; N 8.57; S 9.86. C18H14N2O2S. Calculated, %: C 67.06; H 4.38; N 8.69; S 9.95.
3-Phenyl-4H-thieno[3',2':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione (4d) was prepared
similarly from 2-(4-oxo-5-phenyl-3,4-dihydrothioeno[2,3-d]pyrimidin-2-ylmethyl)benzoic acid (1d) (0.36 g,
10 mmol). Yield 90%; mp 300ºC (DMF). Mass spectrum, m/z: 345 [M++1]. Found, %: C 69.72; H 3.46; N 8.05;
S 9.52. C20H12N2O2S. Calculated, %: C 69.75; H 3.51; N 8.13; S 9.31.
4H-Thieno[2',3':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione (5a) was prepared similarly from
2-(4-oxo-3,4-dihydrothieno[3,2-b]pyrimidin-2-ylmethyl)benzoic acid (2a) (0.29 g, 10 mmol) in acetic anhydride
(10 ml, 106 mmol). Yield 92%; mp 290ºC (HOAc). Mass spectrum, m/z: 269 [M++1]. Found, %: C 62.72;
H 3.09; N 10.52; S 11.84. C14H8N2O2S. Calculated, %: C 62.68; H 3.01; N 10.44; S 11.95.
2-(4-Chlorophenyl)-4H-thieno[2',3':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione
(5b)
was
prepared similarly from 2-[6-(4-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-ylmethyl]benzoic
acid (2b) (0.40 g, 10 mmol). Yield 90%; mp 320ºC (DMF). Found, %: C 63.32; H 2.90; N 7.43; S 8.38.
C20H11ClN2O2S. Calculated, %: C 63.41; H 2.93; N 7.39; S 8.46.
2-(4-Fluorophenyl)-4H-thieno[2',3':5,6]pyrimido[1,2-b]isoquinoline-4,11(5H)-dione
(5c)
was
prepared similarly from 2-[6-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-ylmethyl]benzoic
acid (2c) (0.38 g, 10 mmol). Yield 93%; mp 300ºC (DMF). Mass spectrum, m/z: 363 [M++1]. Found, %:
C 66.11; H 3.11; N 7.65; S 8.93. C20H11FN2O2S. Calculated, %: C 66.29; H 3.06; N 7.73; S 8.85.
5H-Isoquino[2,3-a]quinazoline-5,12(6H)-dione (6) was prepared similarly from 2-[(4-oxo-
3,4-dihydro-2-quinazolinyl)methyl]benzoic acid (3) (0.28 g, 10 mmol) in acetic anhydride (10 ml, 106 mmol).
Yield 90%; mp 305ºC (HOAc). Mass spectrum, m/z: 263 [M++1]. Found, %: C 73.16; H 3.76; N 10.60.
C16H10N2O2. Calculated, %: C 73.27; H 3.84; N 10.68.
The authors thank the Enamine company (Kiev) for supporting this project.
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