Reactions of 6-aminopyrimidines with 2-dimethylaminomethylenetetralone. Regiospecific synthesis of 5,6-dihydrobenzo[h]pyrimido[4,5-b]quinolines

Article abstract of DOI:10.1002/jhet.5570380203

Benzo[h]pyrimido[4,5-b]quinolines (3) have been synthesized via a regiospecific cyclocondensation reaction between 6-aminopyrimidines (1) and 2-dimethylaminomethylentetralone hydrochloride (2). The linear structure of the final compounds were determined by nmr measurements, especially by ¹H, ¹H-, ¹H,¹³C COSY and DEPT experiments.

Full text of DOI:10.1002/jhet.5570380203

Mar-Apr 2001
Reactions of 6-Aminopyrimidines with
2-Dimethylaminomethylenetetralone. Regiospecific Synthesis of
5,6-Dihydrobenzo[h]pyrimido[4,5-b]quinolines.
339
Jairo Quiroga*, Braulio Insuasty, Henry Insuasty and Rodrigo Abonía
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle,
A.A. 25360, Cali, Colombia.
Antonio Ortíz, Adolfo Sánchez and Manuel Nogueras*
Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
Received June 22, 2000
Benzo[h]pyrimido[4,5-b]quinolines (3) have been synthesized via a regiospecific cyclocondensation
reaction between 6-aminopyrimidines (1) and 2-dimethylaminomethylentetralone hydrochloride (2). The
linear structure of the final compounds were determined by nmr measurements, especially by
1
1
1
13
H, H-, H, C COSY and DEPT experiments.
J. Heterocyclic Chem., 38, 339 (2001).
Introduction.
The pyrido[2,3-d]pyrimidine derivatives present inter-
esting biological properties. Thus, recent works showed
that these compounds have been used as dihydrofolate
reductase inhibitors as antitumor agents [1-3]; some of
them have shown a broad spectrum of antimicrobial -
activity [4-7], diuretic properties [8] and activity against
platelet aggregation [9].
As part of our continuing interest in the reaction of
aminopyrimidines with α,β-unsaturated compounds and
their precursors [10-16], in this work we studied the
cyclocondensation reaction between the 6-amino-
pyrimidines 1 and the hydrochloride of the Mannich base
2 (2-dimethylaminomethylentetralone hydrochloride).
Results and Discussion.
Thus, the reaction of equimolar amounts of amino-
pyrimidines 1a-h and 2-dimethylaminomethylentetralone
hydrochloride 2 in absolute ethanol at reflux yield the
linear dihydrobenzo[h]pyrimido[4,5-b]quinolines 3a-h in
good yields (60-70%) as unique products (Scheme 1).
The Mannich bases (2) are relatively unstable and
easily lose the amino group forming vinyl ketones
[17-20]. Addition of vinyl ketone, resulting from elimina-
tion of dimethylamine hydrochloride from 2, to the
nucleophilic 5 carbon atom of the pyrimidine ring and
subsequent cyclization with water elimination gives 3a-h.
On the other hand, the addition of the amino group of 1 to
the β-C atom of vinyl ketone followed by cyclization can
afford 4. The cyclocondensation of amines 1a-h with 2 gave
regiospecifically the linear isomer, dihydrobenzo[h]-
pyrimido[4,5-b]quinolines 3a-h. In each case, the reaction
gave a single product as determined on tlc. The support
The formation of 3a-h is assumed to proceed by a
Michael type addition of the most nucleophilic ring
carbon atom in the aminopyrimidine to the activated
double bond of vinyl ketone [11,15,16]. The inter-
mediate formed Michael adduct, cyclic and by water
elimination yield dihydrobenzo[h]pyrimido[4,5-b]-
quinolines 3a-h (Scheme 1).
1
for the linear structures for 3 was provided from H-nmr
spectra in particular with respect to the chemical shift of
the H-7 proton.

Vol. 38
J. Quiroga, B. Insuasty, H. Insuasty, R. Abonía, A. Ortíz, A. Sánchez, and M. Nogueras
340
1
The determination of linear structures was based on the
The H nmr spectra of compounds 3a-h (see Table 1)
contain one singlet at 8.18-8.61 ppm for the H-7 proton
and signals at 2.94-3.06 ppm for methylene protons of the
C(5)H2-C(6)H2 fragment.
1
13
signals assignment in the H- and C-nmr spectra of
1
1
3a-h, which is supported by H, H COSY technique and
1
13
1
H, C shift correlation, as well as by comparison with H
13
nmr and C nmr data which has been previously estab-
lished by us [14-16] and others [25-28] for similar
systems. HMBC experiments indicate a two-bond correla-
tion between H-7 and C-7a and three-bond correlations
between the H-7 proton and C-8 and between the H-7
proton and C-6. These experiments rule out the formation
of the angular structure 4 (Scheme 1).
Table 1
1
H-NMR Data of 3a-h δ Values, Tetramethylsilane as the Internal Standard, in
Dimethyl Sulfoxide-d , 300 MHz
6
EXPERIMENTAL
Compound 5-CH 6-CH 7-CH
Aromatic protons
9-R 10-X
2
2
H-1 H-2 H-3 H-4
Melting points were determined on a Buchi Melting Point
1
13
3a
3b
3c
2.95
2.95
2.99
3.00
3,00
2.94
2.99
2.95
3.00
3.03
3.05
3.06
3,10
2.99
2.99
2.99
8.22
8.25
8.25
8.32
8,61
8.18
8.23
8.42
7.45 7.38 8.30 7.35 12.47 4.02
7.46 7.38 8.30 7.35 12.57 2.63
7.42 7.33 8.42 7.29 3.50 4.19
7.40 7.37 8.53 7.38 3.64 2.79
8,24 7,50 7,60 7,46 [b]
7.45 7.41 8.23 7.35
Apparatus and are uncorrected. The H- and C nmr spectra
were recorded on a Bruker DPX 300 spectrometer operating
at 300 MHz and 75 MHz respectively, using dimethyl sulf-
oxide-d6 as solvent and tetramethylsilane as internal standard.
The mass spectra were scanned on a Hewlett Packard 5989-B
mass spectrometer (EI, 70 eV). Samples were introduced via
a DIP. The elemental analysis were obtained using a LECO
CHNS-900.
3d
3e[a]
3f[c]
3g[d]
3h[e]
[b]
7.41 7.38 8.34 7.22 3.81
7.43 7.37 8.25 7.34
[a] Trifluor acetic acid and dimethyl sulfoxide-d (50%) as solvent. [b] Appears
6
General procedure for the Preparation of the 5,6-Dihydro-
benzo[h] pyrimido[4,5-b]quinolines 3.
+
together H O signal. [c] 9-H and 11-H at 12,54 and 13,08 ppm respectively. [d] 9-
3
CH and 11-CH at 3,81 and 3,49 ppm respectively. [e] 8-NH and 10-NH at 8,31
3
3
2
2
and 7,20 ppm respectively.
A solution of 6-aminopyrimidines 1a-h (2.0 mmoles) and an
equimolar amount of the 2-dimethylaminomethylentetralone
(2-[(dimethylamino)methyl]-3,4-dihydro-1-(2H)-napthalenone)
hydrochloride 2 (2.0 mmoles) in ethanol (10 ml) with a catalytic
amount of triethylamine (5 drops) was refluxed for 1-12 hours
(tlc monitoring), and allowed to cool overnight. The resulting
white precipitate was filtered, washed with ethanol and recrys-
tallized from ethanol (the products 3e-h were recrystallized from
a mixture water/dimethylformamide) to afford 60-72 % of the
desired products 3a-h.
13
In the C-nmr spectra of compounds 3, the number of
signals belonging to quaternary, tertiary, secondary and
primary carbon atoms were determined (DEPT experiments,
Table 2). It is worth mentioning that these compounds 3a-h
13
showed in their C-nmr spectra the signals for C-11a at
higher δ value 156-161 ppm and, in contrast, carbon atoms
C-7a appeared at unusually low δ values (103-113 ppm).
10-Methoxy-5,6-dihydro-9H-benzo[h]pyrimido[4,5-b]quinolin-
8-one (3a).
Table 2
13
C-NMR Data of 3a-h δ Values, Tetramethylsilane as the Internal
Standard, in Dimethyl Sulfoxide-d , 75 MHz
6
This compound was obtained according to the general proce-
dure as yellow crystals, mp 238 °C, yield 60%. The mass spec-
trum shows the following peaks: ms:(70 eV) m/z (%) = 280
(34), 279 (M+, 100), 278 (22), 264 (11), 221 (10), 193 (10).
Anal. Calcd. for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05.
Found: C, 68.65; H, 4.83; N, 11.93.
3a
3b
3c
3d
3e[a]
3f
3g
3h
C-1 130.4 130.5 130.1 130.7 127,6 130.9 130.9 130.5
C-2 127.0 127.0 126.5 127.3 129,3 127.0 127.3 127.0
C-3 125.7 125.8 126.0 127.1 135,3 125.7 126.2 125.4
C-4 128.1 128.1 127.5 127.9 130,4 128.2 128.2 128.1
C-4a 139.4 139.4 139.0 139.5 143,1 139.6 139.5 139.5
10-Methylthio-5,6-dihydro-9H-benzo[h]pyrimido[4,5-b]quin-
olin-8-one (3b).
C-5
C-6
27.2
26.7
27.0
26.7
27.3
26.9
28.0
27.9
28,1
27,6
26.9
26.3
27.9
27.0
27.3
26.9
C-6a 128.5 129.8 128.5 130.4 132,4 128.7 127.2 126.4
C-7 134.5 134.3 134.7 135.1 141,9 135.1 136.3 132.5
C-7a 112.7 113.7 111.4 112.7 112,2 110.5 108.9 103.7
C-8 162.6 161.1 161.7 161.9 161,3 150.3 149.7 154.5
C-10 156.2 155.3 155.1 161.4 155,0 175.4 151.7 162.9
C-11a 157.6 159.6 157.3 156.0 152,0 159.6 161.5 159.4
C-12a 156.9 156.9 155.5 158.6 156,4 156.3 156.7 156.5
C-12b 133.3 133.1 132.9 133.5 129,2 132.4 133.2 133.0
This compound was obtained according to the general proce-
dure as yellow crystals, mp 283 °C, yield 65%. The mass spec-
trum shows the following peaks: ms:(70 eV) m/z (%) = 296
(26), 295 (M+, 100), 294 (12), 221 (21), 193 (10).
Anal. Calcd. for C16H13N3OS: C, 65.06; H, 4.44; N, 14.23.
Found: C, 65.15; H, 4.13; N, 14.09.
10-Methoxy-9-methyl-5,6-dihydro-9H-benzo[h]pyrimido-
[4,5-b]quinolin-8-one (3c).
[a] Trifluor acetic acid and dimethyl sulfoxide-d (50%) as solvent.
6
This compound was obtained according to general procedure
as white crystals, mp 215 °C, yield 70%. The mass spectrum
shows the following peaks: ms:(70 eV) m/z (%) = 294 (21), 293
CH S for 3b and 3d 12.9 and 15.3 ppm, respectively; CH O for 3a and
3
3
3c 54.8 and 55.6 ppm, 9-CH for 3c and 3d 27.8 and 30.4 ppm, respec-
3
tively; 9-CH and 11-CH for 3g 29.4 and 28.4 ppm, respectively.
3
3

Mar-Apr 2001
Reactions of 6-Aminopyrimidines with 2-Dimethylaminomethylenetetralone
341
REFERENCES AND NOTES
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Anal. Calcd. for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.55; H, 5.26; N, 14.48.
10-Methythio-9-methyl-5,6-dihydro-9H-benzo[h]pyrimido-
[4,5-b]quinolin-8-one (3d).
This compound was obtained according to the general proce-
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spectrum shows the following peaks: ms:(70 eV) m/z (%) = 310
(24), 309 (M+, 100), 308 (10), 295 (14), 265 (17), 264 (71), 263
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10-Amino-5,6-dihydro-9H-benzo[h]pyrimido[4,5-b]quinolin-8-
one (3e).
This compound was obtained according to the general proce-
dure as pale yellow crystals, mp > 360 °C, yield 63%. The mass
spectrum shows the following peaks: ms:(70 eV) m/z (%) = 265
(19), 264 (M+, 100), 263 (27), 84 (17), 66 (18).
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10-Thioxo-5,6,10,11-tetrahydro-9H-benzo[h]pyrimido-
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9,11-Dimethyl-5,6-dihydro-11H-benzo[h]pyrimido[4,5-b]quin-
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This compound was obtained according to general procedure
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(23), 293 (M+, 100), 292 (19), 265 (17), 264 (16), 181 (16).
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(3h).
This compound was obtained according to the general proce-
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spectrum shows the following peaks: ms:(70 eV) m/z (%) = 264
(22), 263 (M+, 100), 262 (24), 220 (10).
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Acknowledgement.
The authors thank The Colombian Institute for Science and
Research (COLCIENCIAS) and UNIVERSIDAD DEL VALLE
for the financial support of this work.