Synthesis of tetrahydropyrimidino[4,3-a]isoquinolines via regiospecific N-alkylation-annulation of 4-aryldihydropyrimidinones

Article abstract of DOI:10.1002/jhet.768

4-Aryldihydropyrimidinones were obtained in excellent yields via solid-phase Biginelli reaction of arylaldehydes, β-ketoester and urea, using bismuth nitrate, immobilized on Al₂O₃ as catalyst. Subsequently, the products were converte

Full text of DOI:10.1002/jhet.768

1398
Synthesis of Tetrahydropyrimidino[4,3-a]isoquinolines via
Regiospecific N-Alkylation-Annulation of
4-Aryldihydropyrimidinones
Vol 48
Jagjeet Singh, Nitu Mahajan, Rattan L. Sharma, and Tej K. Razdan*
Department of chemistry, University of Jammu, Ambedkar Road, Jammu 180006, India
*E-mail: tk_razdan@rediffmail.com
Received July 22, 2010
DOI 10.1002/jhet.768
Published online 4 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
4-Aryldihydropyrimidinones were obtained in excellent yields via solid-phase Biginelli reaction of
arylaldehydes, b-ketoester and urea, using bismuth nitrate, immobilized on Al2O3 as catalyst. Subse-
quently, the products were converted into corresponding tetrahydropyrimidino[4,3-a]isoquinolines (69–
73% yield) by one-pot regiospecific N-alkylation-annulation reaction using sodium hydride and
dimethylaminopyridine.
J. Heterocyclic Chem., 48, 1398 (2011).
INTRODUCTION
as catalyst and their one-pot base catalysed transforma-
tion to 4,6,7,11b-tetrahydropyrimido[4,3-a]isoquinolines,
using ethyl chloroacetate as N-alkylating agent.
The concept of privileged structural types [1], incorpo-
rating one or more moieties of proven bioactive com-
pounds, has immensely helped in offering lead com-
pounds for drug discovery [2]. Therefore, the interest in
the synthesis of new privileged chemo-types and devel-
opment of new methodologies for their synthesis [3] is
growing unabatedly. Pyrimidoisoquinolines also incorpo-
rate two structural moieties and exhibit a wide range of
pharmacological properties, such as antihypertensive [4],
bronchodilatory [5], inhibitors of platelet phosphodiester-
ase and platelet aggregation [6]. These structural scaf-
folds have been usually prepared by the ring closure of
tetrahydroisoquinolines [7] or N-phenylethylamides [8].
Despite their attractiveness, many of the known methods
have several limitations such as the involvement of mul-
tistage laborious processes, long reaction times and strin-
gent reaction conditions. Therefore, the development of a
simple and efficient methodology to synthesize pyrimi-
doisoquinolines, with the requisite structural features for
the calcium channel regulatory activity [9–11], would be
quiet useful because of their high therapeutic potential.
This article describes the synthesis of 4-aryl-3,4-dihy-
dropyrimidinones via solid-phase Biginelli reaction,
using bismuth nitrate, immobilized on neutral alumina,
RESULTS AND DISCUSSION
Our strategy for the synthesis of 4, 6, 7, 11b-tetrahy-
dropyrimido[4,3-a]isoquinolines 4a-4j involved regio-
specific N-alkylation of 4-aryl-dihydropyrimidinones 3a-
3j with readily available ethyl chloroacetate so that the
ester group in the products could provide a site for the
annulation with aromatic ring.
Several methodologies, each aiming at the improve-
ment of the percent yield, have been documented for the
preparation of 4-aryl-3,4-dihydropyrimidinones from
arylaldehydes, b-ketoester and urea via Biginelli reac-
tion [12]. These include the use of Lewis acids [13],
neat or in combination with protic solvents, solid-sup-
ports [14] and microwave irradiation [15]. Our interest
in exploring the efficiency of bismuth salts [16] in the
solid-phase synthesis of nitrogen heterocyclic com-
pounds, led us to assess the utility of immobilized bis-
muth nitrate in the preparation of 4-aryl-3, 4-dihydro-
pyrimidinones 3a-3j (Scheme 1), which were needed for
the preparation of the title compounds 4a-4j.
C
V
2011 HeteroCorporation

November 2011
Synthesis of Tetrahydropyrimidino[4,3-a]isoquinolines via Regiospecific
N-Alkylation-Annulation of 4-Aryldihydropyrimidinones
1399
Scheme 1
4-Aryl-5-carboethoxy-6-methyl-3,4-dihydropyrimidin-
2-ones 3a-3j (Scheme 1) were prepared by modified
Biginelli reaction of equimolar mixture of aryl alde-
hydes 1a-1j, ethylacetoacetate 2 and urea, using bismuth
nitrate, immobilized on neutral alumina, as catalyst, in
the absence of a solvent. The reactions were carried out
at 120–125ꢀC, in a hot air oven. On completion of reac-
tions (3–3.5 hrs) the products were extracted with hot
CHCl3, and purified to give products 3a-3j in high yield
(Table 1).The compounds were characterized by spectral
temperature led to the formation of multicomponent
mixture, with decomposition of the products to form a
black mass. At temperatures below 90ꢀC, the reaction
did not proceed satisfactorily, even on prolonged heat-
ing. Neat bismuth nitrate has been used as catalyst in
solution-phase Biginelli reaction [19,20], using acetoni-
trile as solvent. However, in the absence of the solvent
disappointing results were obtained when neat bismuth
nitrate or alumina was used as catalyst.
Earlier [16], our group observed that Bi(NO3)3-Al2O3
is an efficient catalyst for Michael addition. In analogy
with this it seems that the present reaction may be pro-
ceeding through the initial Perkin-type condensation fol-
lowed by Michael addition [16] and subsequent hetero-
annulation rather than through the formation of imine
intermediate [21].
1
methods (ms, IR, H-NMR and 13C-NMR). The spectral
data was in conformity with the refs. 17 and 18.
The reaction was optimized with respect to the con-
centration of the catalyst and temperature. The optimum
concentration of bismuth nitrate was found to be 0.5
mol % on neutral alumina which was taken in propor-
tion of 1.5 times the weight of aldehyde. No additives
were required for promoting the reaction. The optimum
temperature for the reaction was 120–125ꢀC; higher
Although, in 4-aryl-3,4-dihydropyrimidin-2-ones 3a-
3j, N-3 is more nucleophilic than N-1, the alkylation at
N-3 does not occur easily. Earlier [22], N-alkylation
with ethyl chloroacetate has been achieved with n-BuLi
at very low temperature (ꢁ78ꢀC). Our initial attempts to
carry out N-alkylation of dihydropyrimidinones with
ethyl chloroacetate, using Li2CO3, K2CO3 and Cs2CO3
in neat Me2CO, DMF, CH3CN and EtOH or mixture of
these solvents failed to give the desired results, even on
prolonged refluxing. Therefore, we resorted to organo-
molecular catalysis and observed that the addition of
DMAP to the reaction mixture in the presence of
K2CO3 and DMF, promoted the reaction, albeit in low
yield of product. Encouraged by this observation and af-
ter several trials we attempted N – alkylation of 3a with
ethyl chloroacetate in the presence of NaH (1.5 eq) and
DMAP, (20 mol %) using DMF-EtOH (4 : 1 v/v) as sol-
vent (Scheme 2). The reaction proceeded well at 100ꢀC.
Table 1
Percent yield of 3a–3j.
Reaction
time (h)
%
yield
Product
R1
R2
R3
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
Cl
Cl
H
H
H
3
90
92
96
88
83
86
84
82
91
87
OCH3
NO2
Cl
H
H
3.5
3.0
3.5
3.5
3.5
3.0
3.5
3.5
3.5
H
H
F
H
Cl
H
H
C4H9
H
Br
H
NO2
H
3j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1400
J. Singh, N. Mahajan, R. L. Sharma, and T. K. Razdan
Vol 48
Scheme 2
After usual work up, chromatographic purification and
spectral analysis, we observed that the reaction directly
afforded compound 4a via one-pot regiospecific N-alkyl-
ation-annulation. The optimization of the reaction condi-
tions revealed that the optimum concentration of NaH
and DMAP was 1.5-equivalent of 4-aryl-3,4-dihydropyr-
imidinones and 20 mol %, respectively. The optimum
proportion of the solvents in the solvent mixtures DMF
: EtOH was found to be 4 : 1 v/v.
resonance signals at d 4.22–4.38 (d, J ¼ 12.6 Hz, 1H;
Hax-6) and 4.38–4.62 (d, J ¼ 12.6 Hz, 1H; Heq- 6), at-
tributable to the geminal methylene protons at position
6, in addition to the expected characteristic signals due
to ester and vinylic methyl groups. The 13C-NMR and
DEPT 135ꢀ of the compounds confirmed the presence of
two methylenes carbons, dc 58.5–59.5 (C-6) and 59.5 –
59.9 (OCH2CH3). The mass spectra of the compounds
showed molecular ion peak as the base peak and ms
fragmentation agreed well with the assigned structure.
The probable mechanism of the reaction is charted
out in Scheme 3. NaH is expected to react faster with
ethanol than with carbamide to form sodium ethoxide.
Therefore, it was presumed that sodium ethoxide may
be the actual base driving the reaction forward. For this
reason, we attempted the reaction of 3a-3c and ethyl
chloroacetate in the presence of Na in dry EtOH (10
mL). However, surprisingly, this reaction yielded the
compounds 4a-4c in low yield and most of the substrate
pyrimidinones 3a-3c were recovered unreacted by col-
umn chromatography. This also indicated that the pres-
ence of DMAP was necessary for the reaction Although
the exact mechanistic implications of the solvent mix-
ture are not clear, it seems that DMF, due to its basic
character, may be facilitating the reaction by facile re-
moval of proton from the N – 3 of pyrimidinone ring.
The nature of the substituents on the 4-aryl groups of
the 4-aryldihydropyrimidin-2-ones seems to have a sub-
stantial impact on the annulation process. As expected
the presence of deactivating groups, such as nitro group
at ortho and para position, does not favor facile annula-
tion reaction and products are obtained in low yield.
To study the scope and limitations of the reaction, the
reaction of 3b-3j and ethyl chloroacetate was carried out
under optimized reaction conditions when 4b-4j were
obtained in 46–73% yield (Table 2).
Compounds, 4a-4j were characterized by spectral
1
13
methods (IR, H-NMR, C-NMR, DEPT 135ꢀ, HMQC
and MS) and elemental analysis. The compounds 4a-4j
displayed IR bands characteristic for N-H (3215–3270
cmꢁ1), ester carbonyl (1710–1730 cmꢁ1), amide car-
bonyl (1610–1660 cmꢁ1) and aryl ACOACH2 (1660–
1680 cmꢁ1), in addition to the expected aromatic
absorption bands. The 1H-NMR spectra of 4a-4j
accounted for aromatic protons, one less than the parent
compound 3a-3j and did not contain the resonance sig-
nal due to NH proton neard 7.60. The spectra exhibited
a lone N-H resonance signal near d 7.90–8.20 (s, br,
1H). The resonance signal due to H-11b appeared as a
singlet near d 5.56. The spectra displayed two additional
Table 2
Percent yield of 4a–4j.
Product
R1
R2
R3
% Yield
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
Cl
Cl
H
H
H
62
68
66
73
71
69
73
71
46
67
OCH3
NO2
Cl
H
H
CONCLUSION
H
H
Bismuth nitrate, immobilized on neutral alumina, effi-
ciently catalyzes the solid-phase Biginelli reaction of
arylaldehyde, acetoacetic ester and urea, to afford ethyl-
4-aryl-6-methyl-3,4-dihydro-pyrimidin-2-one-5-carbox-
ylate in high yield. The nontoxic nature of the heteroca-
talyst mixture Bi(NO3)3-Al2O3 is an added advantage of
F
H
Cl
H
H
C4H9
H
Br
H
NO2
H
4j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis of Tetrahydropyrimidino[4,3-a]isoquinolines via Regiospecific
N-Alkylation-Annulation of 4-Aryldihydropyrimidinones
1401
Scheme 3
General procedure for the preparation of 4-aryl-5-car-
boethoxy-6-methyl-3,4-dihydropyrimidine-2(1H)-ones, 3a-
3j. A mixture of ethylacetoacetate 2 (20 mmol), aldehyde 1a-
1j (20 mmol), urea (20 mmol) and catalyst Bi(NO3)3-Al2O3
(in proportion by 1.5 times the weight of aldehyde) was
charged into conical flask. The reaction mixture was heated at
120–125ꢀC, in a thermostatically controlled hot air oven.
Simultaneously, separate experiments were run, to monitor the
reaction by TLC of the chloroform extracts of the aliquots
drawn out at 0.5 hr intervals of time. On completion of the
reaction (3–3.5 hr), the reaction mixture was cooled and prod-
ucts were extracted with hot CHCl3, in a soxhlet extractor.
The organic solution was washed with water, dried over anhy-
drous Na2SO4 and freed from the solvent. The residue was
crystallized twice from CHCl3-pet. ether (b.p. 40–60ꢀC). The
products, 3a-3j, were characterized by spectral methods and
comparison of the spectral data with ref. 20.
General method for the preparation of tetrahydropyri-
mido[6,1a]isoquinolines, 4a-4j. The pyrimidone 3a-3j (1 ꢂ
10ꢁ3 moles) was dissolved in DMF (8 mL) and EtOH (2 mL).
The solution was cooled in an ice-bath and NaH (1.5 eq), in
DMF (5 mL), was added slowly to the reaction flask. The
reaction mixture was stirred for 0.5 h in ice-bath, using CaCl2
guard tube. Subsequently ethyl chloroacetate (1 ꢂ 10ꢁ3 mol)
and DMAP (20 mol %) was introduced into the reaction flask
and stirring was continued for another 1.0–1.5 h. The reaction
was monitored by t.l.c, using CH2Cl2-EtOAc (19 : 1 v/v) sol-
vent system. On consumption of the substrates, the ice-bath
was removed and the reaction mixture was brought to room-
temperature. Subsequently, the reaction mixture was heated
with stirring on a water bath, under anhydrous conditions. Af-
ter completion of the reaction (2.5–3 hr), the mixture was
diluted with EtOH (15 mL) and H2O (2 ꢂ 15 mL). The prod-
uct was extracted with CHCl3 (3 ꢂ 20 mL). The CHCl3 layer
the reaction. We have developed a simple and efficient
methodology for the one-pot regiospecific N-alkylation-
annulation of 4-aryl-pyrimidin-2-ones to afford corre-
sponding novel tetrahydropyrimido[4,3-a]isoquinolines
in moderate to high yield, under mild reaction condi-
tions. Moreover, this methodology is eco-friendly does
not need any specialized reaction conditions.
EXPERIMENTAL
General. Melting points were determined on Perfit melting
point apparatus and are uncorrected. IR in KBr discs were
recorded on Brucker 4800 IR spectrometer. 1H-NMR (300
MHz) and 13C-NMR (50.3 MHz) were obtained on Varian
Gemini-300 MHz instrument, using TMS as an internal stand-
ard. hrms were recorded at 70 eV, using JEOL D-300 mass
spectrometer. CHN analysis was performed on Leco 932, using
Helium gas. TLC was done on 0.5 mm thick plates, using
BDH silica gel-G adsorbent. Column chromatography was per-
formed on silica gel (Sisco Research Lab., Mumbai), using
graded solvent systems of pet.ether (b.p. 40–60ꢀC, pet.ether-
CH2Cl2, pet.ether-CHCl3 and CHCl3-EtOAc. The calculated
mass values are based on the values obtained by Chem.4D
Draw (Chem innovations) software.
Preparation of Bi (NO3)3-Al2O3 catalyst. A solution of
bismuth nitrate (2.5 g) in methanol (30 mL) and neutral alu-
mina (47.5 g) was stirred, at room temperature, for 12 hrs. The
mixture was air dried and then heated at 110ꢀC 6 5ꢀC, in a
thermostatic hot air oven, for 6 hrs. The activated bismuth ni-
trate-alumina mixture was cooled and preserved in a dessica-
tor. The catalyst was reactivated at 110ꢀC 6 5ꢀC for 0.5 hrs
every time, before use.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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J. Singh, N. Mahajan, R. L. Sharma, and T. K. Razdan
Vol 48
was washed with brine (10%), H2O (2 ꢂ 20 mL), dried over
anhydrous Na2SO4, filtered, concentrated. The crude mixture
was purified by column chromatography using graded solvent
systems of petroleum-CHCl3 and petroleum-EtOAc. The prod-
ucts were crystallized from MeOH- pet.ether (b.p. 40–60ꢀC).
(Mþ) (calcd. for C16H15ClN2O4, 334.0720), 306 (28), 292
(42), 179 (61), 151 (55), 141 (38), 129 (37), 125 (70).110
(14), 70 (75). Anal. Calcd. for C16H15ClN2O4: C, 57.41; H,
4.52; N, 8.37. Found: C, 57.49; H, 4.51; N, 8.36.
Ethyl
9-fluoro-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinolin e-1-carboxylate, (4e). Colorless
needles mp 178–179ꢀC; IR: umax cm-1 3291, 3020, 1723,
1682, 1660, 1595, 1495, 1460, 1410, 1346, 1265, 1050, 980,
Ethyl
2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-3H-pyri-
mido[4,3-a]isoquinoline-1-carbo xylate, (4a). Colorless cubes,
mp 197–198ꢀC; IR: umax cm-1 3287, 3020, 1730, 1682, 1660,
1410, 1250, 1145, 1050, 990, 940. 1H-NMR (300 MHz,
CDCl3): d 1.30 (t, J ¼ 7.1 Hz, 3H), 2.13 (s, 3H), 4.12 (q, J ¼
7.2 Hz, 2H), 4.24 (d, J ¼ 12.3 Hz, 1H), 4.36 (d, J ¼ 12.3
Hz,1H), 5.40 (s, 1H), 7.18–7.36 (m, 3H), 7.68 (m, 1H), 8.28
(s, br, exch. D2O, 1H); 13C-NMR (CDCl3): dc 13.4, 17.5, 45.1,
58.5, 59.9, 115.4, 126.7, 128.0, 128.4, 132.7, 136.5, 137.3,
137.5, 157.8, 167.5, 196.5; hrms: m/z (rel. int.): 300.1116
(100) (Mþ) (calc. for C16H16N2O4, 300.1110), 272 (22), 258
(40), 145 (61), 141 (32), 129 (35), 117 (4), 101 (41), 91 (73),
76 (11), 70 (73). Anal. Calcd. for C16H16N2O4: C, 63.99; H,
5.37; N, 9.33. Found: C, 63.95; H, 5.38; N, 9.33.
1
860, 720; H-NMR (200 MHz, CDCl3): d 1.30 (t, J ¼ 7.2 Hz,
3H), 2.21 (s, 3H), 4.10 (q, J ¼ 7.2 Hz, 2H), 4.26 (d, J ¼ 12.6
Hz, 1H), 4.38 (d, J ¼ 12.6 Hz,1H), 5.54 (s, 1H), 7.00 (d, J ¼
8.1 Hz, 1H), 7.13 (dd, J ¼ 8.1, 1.9 Hz, 1H), 7.56 (d, J ¼ 1.9
Hz, 1H), 7.89 (s, br, 1H); 13C-NMR (CDCl3): dc 13.7, 20.9,
49.6, 58.5, 60.0, 106.4, 127.9, 129.1, 133.4, 134.3, 135.9,
136.7, 139.3, 158.1, 165.5, 198.2; hrms: m/z (rel. int.):
318.1023 (100) (Mþ) (calcd. for C16H15FN2O4, 318.1016), 290
(24), 276 (42), 163 (62), 141 (36), 135 (53), 129 (35), 109
(71), 101 (41), 94 (14), 70 (74). Anal. Calcd. for
C16H15FN2O4: C, 60.37; H, 4.75; N,8.80. Found: C, 60.38; H,
4.72; N, 8.81.
Ethyl 9-methoxy-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquino line-1-carboxylate, (4b). Colorless
needles, mp 210–211ꢀC; IR: umax cm-1 3295, 3030, 1720,
1680, 1665, 1525, 1510, 1480, 1415, 1240, 1135, 1042, 1050,
Ethyl 11-chloro-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinolin e-1-carboxylate, (4f). Colorless
needles, mp 165ꢀC; IR: umax cm-1 3295, 3058, 1730, 1684,
1
1
980, 920; H-NMR (300 MHz, CDCl3): d 1.30 (t, J ¼ 7.2 Hz,
1663, 1545, 1510, 1460, 1420, 1230, 1050, 980, 780; H-NMR
3H), 2.23 (s, 3H), 3.82 (s, 3H), 4.10 (q, J ¼ 7.2 Hz, 2H), 4.28
(d, J ¼12.3 Hz, 1H,), 4.38 (d, J ¼12.3 Hz, 1H), 5.42 (s, 1H),
6.84 (d, J ¼ 8.2 Hz, 1H), 7.06 (d, J ¼ 8.2 Hz, 1H), 7.32 (s,
1H), 8.01 (s, br, 1H); 13C-NMR (CDCl3): dc 13.7, 17.2, 45.1,
56.0, 58.5, 59.5, 106.2, 115.2, 118.3, 128.7, 130.9, 138.9,
139.3, 157.8, 159.3, 165.3, 198.6; hrms: m/z (rel. int.):
330.1220 (calc. for C17H18N2O5, 330.1216) (100) (Mþ), 302
(26), 229 (44), 176 (67), 147 (50), 142 (35), 130 (40), 110
(75), 106 (12), 102 (40), 70 (77). Anal. Calcd. for
C17H18N2O5: C, 61.81; H, 5.49; N, 8.48. Found: C, 61.83; H,
5.45; N, 8.43.
(200 MHz,CDCl3): d 1.30 (t, J ¼ 7.1 Hz, 3H), 1.71 (s, 3H),
4.10 (q, J ¼ 7.1 Hz, 2H), 4.39 (d, J ¼ 12.5 Hz, 1H), 4.56 (d,
J ¼ 12.5 Hz, 1H), 5.50 (s, 1H), 7.12 (m, 1H), 7.34 (m, 1H),
7.62 (m, 1H), 8.02 (s, br, 1H); 13C-NMR (CDCl3): dc 13.7,
17.2, 38.3, 58.5, 59.9, 106.4, 126.5, 128.1, 131.3, 137.1, 138.4,
139.3, 139.8, 157.8, 165.0, 196.5; hrms: m/z (rel. int.):
336.0699, 334.0689 (100) (Mþ) (calcd. for C16H15ClN2O4,
334.0720), 306 (23), 292 (43), 179 (162), 151 (56), 141 (34),
129 (38), 125 (71), 110 (14), 70 (74). Anal. Calcd. for
C16H15ClN2O4: C, 57.41; H, 4.52; N, 8.37. Found: C, 57.44;
H, 4.59; N, 8.32.
Ethyl 2-methyl-9-nitro-4,7-dioxo-4,6,7,11b-tetrahydro-3H-
pyrimido[4,3-a]isoquinoline-1-carboxylate,
Ethyl 9,11-dichloro-2-methyl-4,7-dioxo-4,6,7,11b-tetrahy-
dro-3H-pyrimido[4,3-a]isoquin oline-1-carboxylate, (4g).
Colorless crystals, mp 235–236ꢀC; IR: cm-1 3286, 3010, 1730,
(4c). Colorless
plates, mp185ꢀC; IR: umax cm-1 3290, 3030, 2956, 1710, 1685,
1662, 1590, 1480, 1370, 1245, 1150, 1045, 980, 820; H-NMR
1
1
1685, 1660, 1410, 1395, 1380, 1255, 1190, 980, 720; H-NMR
(300MHz, CDCl3): 1.13 (t, J ¼ 7.1 Hz, 3H), 2.20 (s, 3H), 4.10
(q, J ¼ 7.1 Hz, 2H), 4.34 (d, J ¼ 12.4 Hz, 1H), 4.52 (d, J ¼
12.4 hz, 1H), 5.69 (s, 1H), 7.50 (d, J ¼ 8.2 Hz, 1H), 8.20 (s,
br, 1H), 8.23 (dd, J ¼ 8.2, 1.9 Hz, 1H), 8.54 (s, 1H); 13C-
NMR (CDCl3): dc 14.1, 17.8, 50.3, 58.8, 58.9, 109.5, 129.1,
134.3, 138.6, 144.6, 146.7, 147.0, 149.3, 157.2, 165.3, 199.4;
hrms: m/z (rel. int.): 345.0968 (100) (Mþ) (calcd. for
C16H15N3O6, 345.0961), 317 (28), 303 (41), 189 (62), 141
(38), 162 (52), 136 (73), 129 (33), 121 (10), 101 (44), 70 (78).
Anal. Calcd. for C16H15N3O6: C, 55.65; H, 4.38; N, 12.17.
Found: C, 55.67; H, 4.33; N, 12.18.
(200 MHz, CDCl3): d 1.17 (t, J ¼ 7.1 Hz, 3H), 2.34 (s, 3H),
4.05 (q, J ¼ 7.1 Hz, 2H), 4.58 (d, J ¼ 12.6, 1H), 4.58 (d, J ¼
12.6,1H), 5.36 (s, 1H), 7.35 (s, 1H), 7.63 (s, 1H), 7.93 (s, br,
1H); 13C-NMR (CDCl3): dc 14.1, 18.6, 40.1, 59.1, 59.6, 101.6,
127.6, 133.9, 134.7, 134.9, 135.2, 139.3, 139.8, 159.2, 167.2,
198.2; hrms: m/z (rel. int.): 372.0284 (37), 368.0276 (100)
(Mþ) (calcd. for C16H14Cl2N2O4, 368.0331), 369 (100), 341
(23), 327 (46), 214 (70), 186 (48), 160 (76), 145 (13), 141
(37), 129 (34), 101 (41), 70 (72). Anal. Calcd. for
C16H14Cl2N2O4: C, 52.05; H, 3.82; N,7.59. Found: C, 52.09;
H, 3.80; N, 7.63.
Ethyl 9-chloro-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinoline-1-carboxylate, (4d). Colorless
needles, mp 230–231ꢀC. IR: umax cm-1 3260, 3035, 1730,
1685, 1660, 1585, 1490, 1470, 1405, 1260, 1180, 1040, 990,
Ethyl 9-n-butyl-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinolin e-1-carboxylate, (4h). Colorless
crystals, mp 163ꢀC; IR: umax cm-1 3230, 2998, 1725, 1675,
1
1662, 1580, 1490, 1370, 1245, 1055, 1040, 985, 780; H-NMR
1
820; H-NMR (200 MHz,CDCl3): d 1.32 (t, J ¼ 7.2 Hz, 3H),
(CDCl3): d 0.96 (t, J ¼ 6.9 Hz, 3H), 1.20 (t, J ¼ 7.1 Hz, 3H),
1.33–1.62 (m, 4H) 2.26 (s, 3H), 2.55 (m, 2H), 4.01 (q, J ¼ 7.1
Hz, 2H), 4.12 (d, J ¼ 12.1 Hz, 1H), 4.46 (d, J ¼ 12.1 Hz,
1H), 5.43 (s, 1H), 6.98 (d, J ¼ 8.2 Hz, 1H), 7.19 (d, J ¼ 8.2
Hz, 1H), 7.79 (s, br, 1H), 8.09 (d, J ¼ 2.0 Hz, 1H); 13C-NMR
(CDCl3): dc 13.7, 14.0, 17.5, 22.7, 34.6, 35.5, 58.3, 59.8, 59.9,
103.5, 128.2, 132.5, 132.9, 134.5, 136.8, 139.5, 137.1, 158.0,
2.23 (s, 3H), 4.01 (q, J ¼ 7.2 Hz, 2H), 4.38 (d, J ¼ 12.6 Hz,
1H), 4.49 (d, J ¼ 12.6 Hz, 1H), 5.56 (s, 1H), 7.11 (d, J ¼ 8.1
Hz, 1H), 7.36 (d, J ¼ 8.1 Hz, 1H), 7.75 (s, 1H), 8.10 (s, br,
1H); 13C-NMR (CDCl3): dc 13.7, 17.3, 47.4, 58.5, 59.5, 106.4,
129.1, 129.4, 132.1, 133.4, 135.6, 138.4, 139.6, 157.8, 165.3,
198.2; hrms: m/z (rel. int.): 336.0704 (70), 334.0699 (100)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis of Tetrahydropyrimidino[4,3-a]isoquinolines via Regiospecific
N-Alkylation-Annulation of 4-Aryldihydropyrimidinones
1403
165.3, 197.8; hrms: m/z (rel. int.): 356.1740 (100) (Mþ) (calcd.
for C20H24N2O4, 356.1736), 314 (23), 328 (43), 201 (59), 173
(46), 147 (74), 141 (34), 132 (13), 129 (37), 101 (43), 70 (70).
Anal. Calcd. for C20H24N2O4: C, 67.40; H, 6.79; N,7.86.
Found: C, 67.48; H, 6.76; N, 7.81.
[4] Lal, B.; Dohadwalla, A. N.; Dadkar, N. K.; D’Sa, A.; de
Sousa, N. J. J Med Chem 1984, 27, 1470.
[5] Boswell-Smith, V.; Spina, D.; Oxford, A.W.; Comer, M.
B.; Seeds, E. A.; Page, C. P. J Pharmacol Exp Therap 2006, 318, 840.
[6] Ruppert, D.; Weithmann, K. U. Life Sci 1982, 31, 2037.
[7] (a) Chakrabarti, S.; Srivastava, M. C.; Ila, H.; Jungappa, H.
Synlett 2003, 2369; (b) Fulop, P.; Semega, E.; Bernath, G.; Sohar, P.
J Heterocycl Chem 1990, 27, 957; (c) Kobor, J.; Fulop, F.; El-Gharib,
M. S.; Bernath, G. H. J. J Heterocycl Chem 1984, 21, 149; (d) Kiss,
P.; Holly, S. Chem Ber 1981, 114, 61; (e) Angelov, P. A.; Ivanov, I.
I.; Venkov, A. P. Molecules 2004, 9, 694.
Ethyl 2-methyl-10-nitro-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinolin e-1-carboxylate, (4i). Colorless
cubes, m.p. 189ꢀC; IR: umax cm-1 3315, 3020, 1730,1680,
1675, 1595, 1580, 1510, 1465, 1450, 1380, 1290, 1170, 1040,
1
980, 710; H-NMR (CDCl3): d 1.36 (t, J ¼ 7.1 Hz, 3H), 2.13
(s, 3H), 4.10 (q, J ¼ 7.1 Hz, 2H), 4.21 (d, J ¼ 12.6 Hz, 1H),
4.43 (d, J ¼ 12.6 Hz, 1H), 5.47 (s, 1H), 7.70 (d, J ¼ 7.9 Hz,
1H), 7.93 (d, J ¼ 7.9 Hz, 1H), 8.08 (s br, 1H), 8.18 (s, 1H);
13C-NMR (CDCl3): dc 14.1, 17.3, 46.4, 59.5, 59.9, 103.5,
122.5, 123.7, 125.2, 131.2, 134.2, 139.2, 152.6, 155.3, 165.2,
198.6; hrms: m/z (rel. int.): 345.0969 (100) (Mþ), (calcd. for
C16H15N3O6, 345.0961), 317 (26), 303 (41), 189 (62), 162
(50), 141 (38), 136 (74), 129 (34), 121 (10), 101 (43), 70 (71).
Anal. Calcd. for C16H15N3O6: C, 55.65; H, 4.38; N, 12.17.
Found: C, 55.67; H, 4.33; N, 12.15.
[8] (a) Yamazaki, T.; Yakugaku Zasshi 1959, 79, 1008; (a)
Yamazaki, T.; Chem Abstr 1961, 54, 5679; (b) Kametani, T.; Iida, H.;
Kano, S. Chem Abstr 1961, 55, 19933.
[9] Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv Drug Res
1987, 16, 309.
[10] Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu,
M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka,
T.; Kawai, M.; Yakeda, M.; Ishihara, T.; Funahashi, K.; Satah, F.;
Morita, M.; Noguchi, T. J Med Chem 1989, 32, 2399.
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Schwartz, J. J Org Chem 1989, 54, 5898; (b) Atwal, K.; Rovnyak,
G. C., Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutus, J. Z.;
Malley, M. F.; Floyd, D. M. J Med Chem 1990, 33, 1510; (c)
Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.; Normadinum, C.
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26, 289; (d) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A.
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Ethyl 9-bromo-2-methyl-4,7-dioxo-4,6,7,11b-tetrahydro-
3H-pyrimido[4,3-a]isoquinolin e-1-carboxylate, (4j). Colorless
cubes, mp 201–202ꢀC; IR: umax cm-1 3265, 3015, 1730, 1685,
1
1662, 1490, 1410, 1395, 1386, 1240, 1060, 980, 720; H-NMR
(200 MHz, CDCl3): d 1.17 (t, J ¼ 7.2 Hz, 3H), 2.30 (s, 3H),
4.10 (q, J ¼ 7.2 Hz, 2H), 4.46 (d, J ¼ 12.5 Hz, 1H), 4.67 (d,
J ¼ 12.5 Hz, 1H), 5.36 (s, 1H), 7.34 (dd, J ¼ 8.1, 2.3 Hz,
1H), 7.46 (d, J ¼ 8.1 Hz, 1H), 8.01 (s, br, 1H), 8.22 (d, J ¼
2.3 Hz, 1H); 13C-NMR (CDCl3): dc 13.9, 17.9, 45.8, 59.1,
60.01, 103.2, 122.3, 130.2, 132.3, 136.5, 136.8, 139.1, 146.2,
158.2, 165.3, 197.9; hrms: m/z (rel. int.): 380.0201 (40)
378.0810 (100) (Mþ) (calcd. for C16H15BrN2O4, 380.0215,
378.0215), 351 (29), 337 (43), 224 (64), 196 (50), 170 (74),
155 (14), 141 (30), 129 (31), 101 (44), 70 (76). Anal. Calcd.
for C16H15BrN2O4: C, 50.68; H, 3.99; N, 7.39. Found: C,
50.64; H, 3.92; N, 7.41.
[12] Biginelli, P. Gazz Chim Ital 1893, 23, 330.
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Tetrahedron Lett 1995, 36, 7819; (d) Xia, M. Y. Synthesis 2003, 2,
262.
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1799; (b) Stadler, A.; Kappe, C. O. J Combin Chem 2001, 3, 624.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet