Synthesis of 4-Aryl-4,6-dihydropyrimido[4,5-d]pyridazine-2,5(1H,3H)-diones from Biginelli Compounds

Article abstract of DOI:10.1002/hlca.201200109

Biginelli compounds 1 were first brominated at Me-C(6) with 2,4,4,6-tetrabromocyclohex-2,5-dien-1-one to give Br₂CH-C(6) derivatives 2. The hydrolysis of the 6-(dibromomethyl) group of 2c to give the 6-formyl derivative 3c in the presence of an

Full text of DOI:10.1002/hlca.201200109

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Synthesis of 4-Aryl-4,6-dihydropyrimido[4,5-d]pyridazine-2,5(1H,3H)-diones
from Biginelli Compounds
by Gopal Chandra Patra, Sankar Chandra Bhunia, Monoj Kumar Roy, and Sudhir Chandra Pal*
Chemistry Department, Midnapore College, Midnapore, W. B., India
(phone: þ 91-32-22275847; fax: þ 91-32-22275847; e-mail: sudhirpal08@gmail.com)
Biginelli compounds 1 were first brominated at MeꢀC(6) with 2,4,4,6-tetrabromocyclohex-2,5-dien-
1-one to give Br2CHꢀC(6) derivatives 2. The hydrolysis of the 6-(dibromomethyl) group of 2c to give the
6-formyl derivative 3c in the presence of an expensive Ag salt followed by reaction with N2H4 · H2O
yielded tetrahydropyrimido[4,5-d]pyridazine-2,5(1H,3H)-dione (4c; Scheme 1). However, treatment of
the 6-(dibromomethyl) derivatives 2 directly with N2H4 · H2O led to the fused heterocycles 4 in better
overall yield (Schemes 1 and 2; Table).
Introduction. – The Biginelli condensation [1][2] is an important multicomponent
reaction that yields compounds with a dihydropyrimidine core. These compounds are
reported to have useful pharmacological and other biological activities [3][4]. The
parent Biginelli products of type 1 have several functionalities that could be modified
easily, and numerous derivatives have been prepared for evaluation as drugs and
compounds with other biological functions [3]. Several products were synthesized via
6-(monobromomethyl) derivatives [5 – 9] and only one via a 6-(dibromomethyl)
derivative of type 2 [10]. We decided to prepare some useful derivatives via the
corresponding 6-formyl compound. But the direct oxidation of MeꢀC(6) of 1 to a CHO
group with SeO2 was not successful [11]. We expected that this could be done via the
CHBr2 derivative 2. Thus, syntheses of some fused N-heterocycles from these 6-
(dibromomethyl) derivatives 2 or the corresponding aldehydes were undertaken.
Results and Discussion. – Initially, we used Br2 in CHCl3 and in AcOH, respectively,
for the bromination of the Biginelli compounds 1 to give 2 [8][12][13]. The reactions
gave incomplete conversion and resulted in mixtures of monobromo and dibromo
products along with some unreacted starting material, even after a considerable period
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Helvetica Chimica Acta – Vol. 96 (2013)
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of time and in the presence of excess Br2. We obtained better yields of the 6-
(dibromomethyl) derivatives 2 from the Biginelli compounds 1 by means of 2,4,4,6-
tetrabromocyclohexa-2,5-dien-1-one (TBCO) as bromination reagent [14]. As an
example, the Biginelli product 1d furnished 65% of dibromo product 2d and 16% of
monobromo compound when treated with Br2 in CHCl3 or AcOH. But 1d afforded the
same two products in 86 and 8% yield, respectively, on treatment with 2.2 equiv. of
TBCO in CH2Cl2.
First, we tried to convert dibromo derivative 2c into formyl derivative 3c by alkaline
hydrolysis. However, the method was unsuccessful. However, we succeeded in
hydrolyzing 2c in the presence of AcOAg; the formyl derivative 3c was then treated
with N2H4 · H2O to obtain the targeted 4-(4-bromophenyl)-4,6-dihydro-pyrimido[4,5-
d]pyridazine-2,5-(1H,3H)-dione (4c) in an overall yield of 50.4% (Scheme 1). We then
treated 2c directly with N2H4 · H2O and isolated 3c in a much better yield (79%;
Scheme 1).
Scheme 1
We then tested successfully the generality of the method with a few more 6-
(dibromomethyl) derivatives 2 (see Table). The protocol failed only in the case of
compound 2f having a coumarin-6-yl (¼2-oxo-2H-1-benzopyran-6-yl) substituent at
C(4): a complex mixture resulted, possibly because of the involvement of the lactone
ring of the coumarin-6-yl group.
Table. Synthesis of Pyrimidopyridazinediones 4 from 2: Reaction Conditions (EtOH, AcOH, reflux) and
Yield
Substrate
Reflux time [h]
Product
Rf (solvent)of 4
Yield [%]
2a
2b
2c
2d
2e
8
7
7
9
10
4a
4b
4c
4d
4e
0.5 (2% MeOH/AcOEt)
74
75
79
82
57
0.4 (80% AcOEt/Petroleum ether)
0.45 (80% AcOEt/Petroleum ether)
0.5 (80% AcOEt/Petroleum ether)
0.5 (70% AcOEt/Petroleum ether)
In view of the report [15] on the reaction of N2H4 · H2O at the CO2Et group of
Biginelli compounds, we decided to test whether phenylhydrazine reacts with the 6-
(dibromomethyl) derivative 2a to yield 5 and then a cyclized product 6 (Scheme 2). But
none of these products was formed; instead the hydrazone derivative 7 was obtained.
From this result it may be concluded that N2H4 · H2O first reacts with the CHBr2 group,

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and then the intramolecular condensation with CO2Et takes place resulting in the
formation of the condensed heterocycles 4 (Scheme 2).
Scheme 2
Conclusions. – An easy and efficient route to 4-aryl-4,6-dihydropyrimido[4,5-
d]pyridazine-2,5-(1H,3H)-diones was established starting with the Biginelli compounds
1 via TBCO-assisted bromination followed by reaction with N2H4 · H2O.
The authors are very grateful to the UGC for a minor research grant.
Experimental Part
General. Materials were used as received from the commercial suppliers. M.p.: determined in a metal
1
bath; uncorrected. IR Spectra: Spectrum-2 (Perkin-Elmer) spectrometer; ˜n in cmꢀ1. H- and 13C-NMR
Spectra: Bruker instruments; d in ppm rel. to Me4Si as internal standard, J in Hz. LC/MS: Micromass
(Water) apparatus; in m/z. HR-MS: 4a: Micromass-Q-TOF spectrometer (for 4a) and Micro-TOF-Q-II-
10320 spectrometer (for 2d); in m/z. Elemental analyses: Thermo-Finnigan-Flash-EA-1112 analyzer.
6-(Dibromomethyl) Derivatives 2: Typical Procedure [14]. To a soln. of 1d (2 mmol) in dry CH2Cl2
(ca. 10 ml), a soln. of TBCO (6.6 mmol) in dry CH2Cl2 (ca. 10 ml) was added slowly while stirring.
Stirring was continued for ca. 45 min during which almost complete conversion occurred. A little more
solvent was added, and the mixture was washed free from tribromophenol by repeated washings with aq.
K2CO3 soln. The org. layer was dried (Na2SO4) and slowly concentrated to give crystals. The solid was
recrystallized from CHCl3 to give pure 2d (86%). From the mother liquor, the monobromo compound
was obtained (8%).
Data of Ethyl 6-(Dibromomethyl)-1,2,3,4-tetrahydro-4-(4-methylphenyl)-2-oxopyrimidine-5-carbox-
1
ylate (2d): IR (KBr): 3413 (br.), 1722, 1661, 502. H-NMR (500 MHz, CDCl3): 8.02 (s, 1 H); 7.12 – 7.19
(AB, q, 4 H); 6.99 (s, 1 H); 5.34 (d, J ¼ 2.5, 1 H); 5.30 (s, 1 H); 4.13 (q, J ¼ 7, 2 H); 2.33, (s, 3 H); 1.19 (t,
J ¼ 7, 3 H ) . 13C-NMR (150 MHz, CDCl3): 163.88; 152.39; 144.12; 139.25; 138.30; 129.61; 126.55; 100.49;
61.25; 55.10; 31.95; 21.10; 13.89. LC/MS: 452.99 ([M þ 23]þ), 455, and 456.99 in the intensity ratio 1:2 :1.

Helvetica Chimica Acta – Vol. 96 (2013)
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HR-MS: 430.9586, 432.9585, and 434.9567 ([M þ 1]þ, C15H17Br2N2O3þ ) in the intensity ratio of 1:2 :1;
calc. 430.9600, 432.9581, and 434.9560.
Fused Heterocycles 4: General Procedure. To a soln. of 2 (1 mmol) in EtOH (15 – 20 ml), N2H4 · H2O
(80%, ca. 1.5 mmol) was added followed by 5 – 8 drops of glacial AcOH. The mixture was heated under
reflux for 6 – 10 h (TLC monitoring). Then, the mixture was diluted with H2O (ca. 25 ml), neutralized
with NaHCO3, and then extracted with AcOEt (3 ꢁ 15 ml). The combined extract was dried (Na2SO4)
and concentrated and the residue subjected to column chromatography (silica gel, 230 – 400 mesh). The
products 4 were eluted with petroleum ether/AcOEt 2 :3 to 1:4. For Rf values and yields, see Table.
4,6-Dihydro-4-phenylpyrimido[4,5-d]pyridazine-2,5-(1H,3H)-dione (4a): M.p. 3358 (MeOH). IR
1
(KBr): 3412, 3172, 1678, 1643. H-NMR (400 MHz, CDCl3): 12.56 (s, 1 H); 9.70 (s, 1 H); 7.91 (s, 1 H);
7.59 – 7.63 (m, 2 H); 7.33 – 7.36 (m, 2 H); 7.15 – 7.25 (m, 2 H); 5.42 (d, J ¼ 3.0, 1 H). 13C-NMR (125 MHz,
CDCl3): 159.01; 151.95; 142.90; 138.77; 129.02; 128.45; 127.67; 126.28; 110.76; 52.07. HR-MS: 243.0877
([M þ 1]þ, C12H11N4Oþ2 ; calc. 243.0822).
4-(4-Chlorophenyl)-4,6-dihydropyrimido[4,5-d]pyridazine-2,5-(1H,3H)-dione (4b): M.p. 343 – 448
(MeOH). IR (KBr): 3249 (br.), 1702, 1647, 1621, 1259, 540. 1H-NMR (600 MHz, CDCl3): 12.76 (s, 1 H);
9.81 (s, 1 H); 7.87 (s, 1 H); 7.61 (s, 1 H); 7.32 – 7.60 (AB, q, 4 H); 5.35 (d, J ¼ 3.0, 1 H). 13C-NMR
(125 MHz, CDCl3): 158.96; 151.74; 141.81; 138.82; 132.24; 129.03; 128.44; 128.24; 110.22; 51.60. Anal.
calc. for C12H9ClN4O2 (276.68): C 52.09, H 3.28, N 20.25; found: C 52.31, H 3.26, N 20.33.
4-(4-Bromophenyl)-4,6-dihydropyrimido[4,5-d]pyridazine-2,5-(1H,3H)-dione (4c): M.p. 3618
1
(MeOH). IR (KBr): 3323 (br.), 1692, 1642, 1252. H-NMR (500 MHz, CDCl3): 12.76 (s, 1 H); 9.81 (s,
1 H); 7.88 (s, 1 H); 7.62 (s, 1 H); 7.55 (d, J ¼ 8.3, 2 H); 7.29 (d, J ¼ 8.3, 2 H); 5.35 (d, J ¼ 2.5, 1 H).
13C-NMR (125 MHz, CDCl3): 159.00; 151.78; 142.25; 138.87; 131.43; 129.09; 128.65; 120.85; 110.23; 51.71.
LC/MS: 323 and 325 ([M þ 1]þ) in the ratio 1:2. Anal. calc. for C12H9BrN4O2 (321.13): C 44.88, H 2.82, N
17.45; found: C 45.02, H 2.91, N 17.38.
4,6-Dihydro-4-(4-methylphenyl)pyrimido[4,5-d]pyridazine-2,5-(1H,3H)-dione (4d). M.p. 3528
1
(MeOH). IR (KBr): 3341 (br.), 1678, 1651. H-NMR (500 MHz, CDCl3): 12.70 (s, 1 H); 9.73 (s, 1 H);
7.79 (s, 1 H); 7.61 (s, 1 H); 7.13 – 7.21 (AB, q, 4 H); 5.30 (d, J ¼ 3.0, 1 H); 2.27 (s, 3 H). 13C-NMR
(125 MHz, CDCl3): 159.00; 151.98; 140.01; 138.65; 136.88; 129.00; 128.94; 126.16; 110.94; 51.75; 20.60.
LC/MS: 257 ([M þ 1]þ). Anal. calc. for C13H12N4O2 (256.26): C 60.93, H 4.72, N 21.86; found: C 60.50, H
4.76, N 22.03.
4,6-Dihydro-4-(4-methoxyphenyl)pyrimido[4,5-d]pyridazine-2,5-(1H,3H)-dione (4e). M.p. 3368
1
(MeOH). IR (KBr): 3231 (br.), 1673, 1661. H-NMR (500 MHz, CDCl3): 12.70 (s, 1 H); 9.73 (s, 1 H);
7.79 (s, 1 H); 7.61 (s, 1 H); 7.23 (d, J ¼ 8.7, 2 H); 6.90 (d, J ¼ 8.7, 2 H); 5.29 (d, J ¼ 2.8, 1 H); 3.73 (s, 3 H).
13C-NMR (125 MHz, CDCl3): 158.96; 151.74; 138.69; 136.60; 130.72; 129.06; 126.81; 112.70; 110.32;
56.26; 51.08. LC/MS: 273 ([M þ 1]þ). Anal. calc. for C13H12N4O3 (272.26): C 57.35, H 4.44, N 20.58; found:
C 57.55, H 4.48, N 20.43.
Ethyl 4-(4-Bromophenyl)-6-formyl-1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylate (3c). To a soln.
of 2c (0.5 mmol) in MeOH, a cold aq. MeOH soln. of AcOAg (0.5 mmol) was added and the mixture
stirred for 20 min. Then, the MeOH was evaporated; the mixture diluted with H2O (20 ml) and then
extracted with AcOEt, the extract concentrated, and the residue recrystallized from CHCl3/MeOH: 3c
(63%). Colorless solid. M.p 1488. IR (KBr): 3411, 1717, 1696, 1644. 1H-NMR (300 MHz, CDCl3): 10.48 (s,
1 H); 7.50 (d, J ¼ 8.1, 2 H); 7.43 (s, 1 H); 7.23 (d, J ¼ 8.1, 2 H); 5.94 (s, 1 H); 5.53 (d, J ¼ 2.7, 1 H); 4.21 (q,
J ¼ 7.0, 2 H); 1.25 (t, J ¼ 7.2, 3 H). 13C-NMR (125 MHz, (D6)DMSO): 191.78; 163.00; 151.78; 142.26;
138.87; 131.43; 129.09; 128.85; 108.20; 62.26; 51.72; 14.26. Anal. calc. for C14H13BrN2O4 (353.17): C 47.61,
H 3.71, N 7.93; found: C 47.50, H 3.74, N 8.01.
Ethyl 1,2,3,4-Tetrahydro-2-oxo-4-phenyl-6-[(2-phenylhydrazinylidene)methyl]pyrimidine-5-carbox-
ylate (7). As described above for 4 (General Procedure), with 2a and phenylhdrazine in place of
N2H4 · H2O: 7 (73%) M.p. 328 – 3308. IR (KBr): 3406 (br.), 3236, 1694, 1629, 1254. 1H-NMR (300 MHz,
CDCl3): 8.56 (s, 1 H); 8.19 (s, 1 H); 7.71 (s, 1 H); 7.01 – 7.30 (m, 10 H); 5.41 (d, J ¼ 2.7, 1 H); 5.28 (s, 1 H);
4.52 (d, J ¼ 7.2, 2 H); 1.12 (t, J ¼ 7.2, 3 H). 13C-NMR (150 MHz, CDCl3): 165.07; 151.85; 143.30; 142.66;
140.95; 129.48; 128.83; 128.19; 127.71; 126.70; 121.99; 113.40; 102.69; 60.52; 56.13; 14.11. Anal. calc. for
C20H20N4O3 (364.40): C 65.92, H 5.53, N 15.38; found: C 66.05, H 5.49, N 15.44.

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Received February 20, 2012