Cascade cyclization of 1,2-diamino-4-phenylimidazole with aromatic aldehydes and Meldrum's acid

Article abstract of DOI:10.1016/j.mencom.2008.05.010

The three-component condensation of 1,2-diamino-4-phenylimidazole with aromatic aldehydes and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) led to 7-amino-4-aryl-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazin-2(1H)-ones.

Full text of DOI:10.1016/j.mencom.2008.05.010

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 141–143
Cascade cyclization of 1,2-diamino-4-phenylimidazole
with aromatic aldehydes and Meldrum’s acid
Victoria V. Lipson,*a Natalia V. Svetlichnaya,a Svetlana V. Shishkinab and Oleg V. Shishkinb
a V. Ya. Danilevsky Institute of Endocrine Pathology Problems, 61002 Kharkov, Ukraine. E-mail: lipson@ukr.net
b STC Institute for Single Crystals, National Academy of Sciences of Ukraine, 61001 Kharkov, Ukraine.
E-mail: sveta@xray.isc.kharkov.com
DOI: 10.1016/j.mencom.2008.05.010
The three-component condensation of 1,2-diamino-4-phenylimidazole with aromatic aldehydes and 2,2-dimethyl-1,3-dioxane-
4,6-dione (Meldrum’s acid) led to 7-amino-4-aryl-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazin-2(1H)-ones.
Four nonequivalent nucleophilic centres in 1,2-diamino-4-phenyl-
imidazole are responsible for various reactions with β-bielectro-
philic carbonyl reagents, their synthetic precursors or equivalents
and for the use of this compound in the synthesis of fused
heterocyclic systems. Originally, vicinal di- and triaminoazoles
containing the N-amino group in reaction with enones were
regarded only as 1,4-binucleophiles yielding azolotriazepine deriva-
tives.1,2 The reactions of 1,2-di- and 1,2,3-triaminoazoles with
α,β-unsaturated ketones, as well as with their bromo and dibromo
derivatives or β-aroylacrylic acids, give fused pyridazine3–5 and
pyrimidine6–9 systems rather than triazepine ones because the
amino groups of these azoles are less nucleophilic than their
endocyclic reactive sites. The goal of this work was to elucidate
the pathways of reactions of 1,2-diamino-4-phenylimidazole 1 with
aromatic aldehydes 2a–e and 2,2-dimethyl-1,3-dioxane-4,6-dione
(Meldrum’s acid) 3 under different reaction conditions.
We found that the three-component condensation of equi-
molar amounts of amine 1, para-substituted benzaldehydes 2a–e
and Meldrum’s acid 3 in methanol† or DMF‡ gives imidazo-
[5,1-b]pyridazin-2-one derivatives 9a–e (Scheme 1). Aryl-
methylene derivatives 4 and Michael adducts 5 are also possible
intermediates in these reactions. Compounds 4a,d and 5a,d
were also investigated in the reaction with aminoimidazole 1.§
In all cases, only imidazo[5,1-b]pyridazin-2-ones 9a,d were
obtained (Scheme 2). Isomeric compounds 6, 6' and 7, 7'
(Scheme 1) were not detected. For the elucidation of the causes
of modest imidazopyridazinones 9a–e yields on the example
Ph
R
+
O
N
O
O
MeOH/DMF
O
+
– CO2, – H2O,
– Me2CO
NH2
N
H
NH2
O
1
2a–e
3
a R = H
b R = OMe
c R = Me
d R = Cl
e R = NO2
Ph
Ph
N
R
N
N
N
N
N
+
R
NH
HN
O
O
†
A mixture of diamine 1 (0.001 mol, 0.17 g), benzaldehyde 2a (0.001 mol,
R
6
6'
0.1 g) and Meldrum’s acid 3 (0.001 mol, 0.14 g) in 2 ml of MeOH was
refluxed for 2 h. After cooling, the precipitate of imidazopyridazinone
9a was filtered off and crystallised from propan-2-ol. Compounds 9b–d
were synthesised by a similar method.
O
N
Ph
Ph
N
‡
A mixture of diamine 1 (0.001 mol, 0.17 g), benzaldehyde 2a (0.001 mol,
+
N
0.1 g), dioxanedione 3 (0.001 mol, 0.14 g) in 0.5 ml of DMF was refluxed
for 20 min. After cooling, 2 ml of propan-2-ol was added, then 0.13 g,
yield 43%, of compound 9a was filtered off and crystallised from
propan-2-ol. After the separation of a precipitate of 9a from the filtrate,
the solvent was evaporated. The residual dark oil was crystallised from
N
N
N
O
H2N
R
H2N
7
7'
ethanol and 0.04 g (16%) of azomethine 10 [mp 213 °C (decomp.)11–13
]
Ph
R
N
and 0.02 g (10%) of acetyl derivative 11 [mp 243 °C (decomp.)] were
separated.10
NH2
NH3
§
N
O
A mixture of diamine 1 (0.001 mol, 0.17 g) and benzylidene derivative
4a (0.001 mol, 0.23 g) in 2 ml of MeOH was refluxed for 2 h. After
cooling, 0.17 g (55%) of precipitate 9a was filtered off and crystallised
from propan-2-ol. The presence of azomethine 10 and acetyl derivative
11 in the reaction mixture was checked by TCL on Silufol UV-254 plates
with CHCl3–MeOH (9:1) as an eluent. Compound 9d was synthesised
from 1 and 4d in a similar way in 58% yield.
A mixture of diamine 1 (0.001 mol, 0.17 g) and Michael adduct 5a
(0.001 mol, 0.38 g) in 2 ml of MeOH was refluxed for 2 h. After cooling,
0.16 g (53%) of the precipitate of imidazopyridazinone 9a was filtered
off and crystallised from propan-2-ol. The presence of azomethine 10 and
acetyl derivative 11 in the reaction mixture was checked. Compound 9d
was synthesised from 1 and 5d in a similar way in 51% yield.
O
Ph
8
R
N
NH2
N
– H2O
NH
O
9a–e
Scheme 1
– 141 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 141–143
aromatic nuclei with d 7.64–7.05 ppm, there are broad singlets
R
of the NH (12.3–12.1 ppm) and NH2 (5.75–5.63 ppm) groups,
which disappeared after exchange for deuterium with CD3OD, and
also signals of the CH2–CH moiety as a typical ABX system
(two doublets and doublet of doublets: JAB 15.2–16.0 Hz,
JAX 0 Hz, JBX 6.2–6.0 Hz). According to these experimental
data, the structures of triazepinones 6, 6' and imidazo-
pyrimidinones 7, 7' were rejected. Product 12 was obtained by
refluxing compound 9a with benzaldehyde 2a (Scheme 4).††
R
O
O
O
O
O
O
O
O
O
O
O
O
5a,d
4a,d
Ph
N
MeOH
1
Ph
N
Ph
N
9a,d
2a + 9a
NH
Scheme 2
O
of the interaction of amine 1 with benzaldehyde 2a and
Meldrum’s acid 3 in DMF, it was shown that 2-amino-4-phenyl-
1-benzylideneaminoimidazole 10 and 2-amino-1-acetylamino-4-
phenylimidazole 11 were present in the reaction mixture with the
target product (Scheme 3). These substances occurred in the
reaction with amine 1 and compound 4a or 5a in methanol, as
confirmed by TLC. Probably, acetylaminoimidazole 11 and
corresponding azomethines are formed in the condensations
as by-products and reduced the yields of target imidazopyri-
dazinones 9.
12
Scheme 4
In its IR spectrum, absorption bands of C=O at 1680 cm–1 and
associated NH groups at 3060 cm–1 were presented. Bands due
to the amino group at 3340 and 3440 cm–1 were not observed.
The 1H NMR spectrum of compound 12 differs from the
spectrum of its synthetic precursor 9a by the presence of a
singlet due to the CH proton of the azomethine fragment at
d 9.25 ppm and by the absence of NH2 group signals. At the
same time, the nature of the splitting of the signals for protons of
the CH2–CH moiety as a ABX system (two doublets and doublet
of doublets: JAB 15.2 Hz, JAX 0 Hz, JBX 6.2 Hz) preserves. The
structure of the compounds as imidazo[5,1-b]pyridazin-2-ones
was unambiguously proved by X-ray diffraction analysis of
azomethine 12.‡‡ The dihydropyridazine cycle in compound 12
adopts a half-chair conformation. Deviations of the C(2) and
C(3) atoms from the mean plane of remaining atoms of the
ring are –0.38 and 0.30 Å, respectively. The benzylidenamino
fragment and phenyl substituent at the C(5) atom are slightly
non-coplanar relatively to the plane of the imidazole cycle
[the C(7)–N(4)–C(6)–N(3) and C(4)–C(5)–C(20)–C(21) torsion
angles are –16.3(2)° and 18.1(2)°, respectively] in spite of the
H(7)···N(3) 2.60 Å and H(25)···N(3) 2.59 Å attractive interac-
tions (the sum of van der Waals radii14 is 2.67 Å). The phenyl
subsituent at the C(3) atom has a pseudoaxial orientation [the
C(1)–C(2)–C(3)–C(14) torsion angle is –75.1(2)°] and it is
turned almost orthogonally relatively to the C(2)–C(3) bond
Ph
Ph
N
N
DMF
NH2
NH2
N
N
N
1 + 2a
+
3
9a +
+
NHCOMe
11
Ph
10
Scheme 3
The structures of compounds 9a–e were proved by IR and
1H NMR spectroscopy,¶ and the structures of azomethine 10
and acetyl derivative 11, by a comparison of physico-chemical
and spectral characteristics with published data.10–13 In the
IR spectrum of compounds 9a–e, the absorption band of the
carbonyl group at 1672–1676 cm–1 and broad bands of the
associated NH and NH2 groups at 3424–2800 cm–1 are charac-
teristic. In the 1H NMR spectrum, beside multiplets of two
¶
9a: yield 52%, mp 292–295 °C. 1H NMR (200 MHz, [2H6]DMSO) d:
12.20 (s, 1H), 7.40–7.05 (m, 10H), 5.63 (s, 2H), 4.72 (d, 1H), 3.07–3.04
(dd, 1H), 2.66–2.58 (d, 1H). IR (KBr, n/cm–1): 3424–2800, 1676. Found
(%): C, 70.94; H, 5.24; N, 18.38. Calc. for C18H16N4O (%): C, 71.05;
H, 5.26; N, 18.42.
9b: yield 50%, mp 290–292 °C. 1H NMR (200 MHz, [2H6]DMSO) d:
12.20 (s, 1H), 7.41–7.11 (m, 9H), 5.57 (s, 2H), 4.63 (d, 1H), 3.71 (s, 3H),
3.01–2.89 (dd, 1H), 2.71–2.64 (d, 1H). IR (KBr, n/cm–1): 3432–2800,
1676. Found (%): C, 68.20; H, 5.34; N, 16.73. Calc. for C19H18N4O2
(%): C, 68.26; H, 5.39; N, 16.77.
C(24)
C(23)
C(25)
C(22)
C(20)
C(21)
N(3)
C(9)
C(5)
C(4)
C(10)
C(7)
C(8)
C(6)
N(1)
N(2)
C(11)
C(12)
C(3)
C(14)
N(4)
C(13)
9c: yield 51%, mp > 300 °C. 1H NMR (200 MHz, [2H6]DMSO) d:
12.20 (s, 1H), 7.27–7.39 (dd, 4H), 7.20–7.12 (m, 5H), 5.65 (s, 2H),
4.65 (d, 1H), 3.03–2.92 (dd, 1H), 2.63–2.55 (d, 1H). IR (KBr, n/cm–1):
3464–2800, 1672. Found (%): C, 71.67; H, 5.70; N, 17.65. Calc. for
C19H18N4O (%): C, 71.70; H, 5.66; N, 17.61.
9d: yield 55%, mp > 300 °C. 1H NMR (200 MHz, [2H6]DMSO) d:
12.10 (s, 1H), 7.41–7.05 (m, 9H), 5.55 (s, 2H), 4.74 (d, 1H), 3.06–2.95
(dd, 1H), 2.67–2.58 (d, 1H). IR (KBr, n/cm–1): 3464–2800, 1672. Found
(%): C, 63.79; H, 4.42; N, 16.50; Cl, 10.47. Calc. for C18H15N4ClO (%):
C, 63.81; H, 4.43; N, 16.54; Cl, 10.49.
9e: yield 60%, mp 204–207 °C. 1H NMR (200 MHz, [2H6]DMSO) d:
12.10 (s, 1H), 8.20–7.49 (dd, 4H), 7.37–7.10 (m, 5H), 5.75 (s, 2H),
4.93 (d, 1H), 3.15–3.04 (dd, 1H), 2.71–2.61 (d, 1H). IR (KBr, n/cm–1):
3304–2800, 1676, 1352. Found (%): C, 61.85; H, 4.34; N, 20.10. Calc.
for C18H15N5O3 (%): C, 61.89; H, 4.30; N, 20.06.
C(2)
C(1)
O(1)
C(19)
C(18)
C(15)
C(16)
C(17)
Figure 1 Molecular structure of 12. Selected bond lengths (Å): O(1)–C(1)
1.227(2), N(1)–C(6) 1.369(2), N(1)–N(2) 1.379(2).
†† A mixture of imidazopyridazinone 9a (0.001 mol, 0.3 g) and benzal-
dehyde 2a (0.001 mol, 0.1 g) in 2 ml of MeOH was refluxed for 3 h.
After cooling, 0.3 g of the precipitate of azomethine 12 was filtered off
and crystallised from propan-2-ol. Yield 77%, mp 281–283 °C. 1H NMR
(200 MHz, [2H6]DMSO) d: 12.30 (s, 1H), 9.25 (s, 1H), 7.57–7.24 (m,
15H), 4.90 (d, 1H), 3.21–3.18 (dd, 1H), 2.76–2.68 (d, 1H). IR (KBr,
n/cm–1): 3060, 1680. Found (%): C, 76.57; H, 5.14; N, 14.34. Calc. for
C25H20N4O (%): C, 76.53; H, 5.10; N, 14.29.
– 142 –

Mendeleev Commun., 2008, 18, 141–143
3
4
N. N. Kolos, V. D. Orlov, B. V. Paponov and O. V. Shishkin, Khim.
Geterotsikl. Soedin., 1999, 1388 [Chem. Heterocycl. Compd. (Engl.
Transl.), 1999, 35, 1207].
N. N. Kolos, V. D. Orlov, B. V. Paponov and V. N. Baumer, Khim.
Geterotsikl. Soedin., 1998, 1397 [Chem. Heterocycl. Compd. (Engl.
Transl.), 1998, 34, 1189].
[the C(2)–C(3)–C(14)–C(15) torsion angle is 98.7(2)°]. In the
crystal phase, the molecules of 10 form centrosymmetric dimers
due to the intermolecular hydrogen bond N(2)–H(2N)···O(1)'
(–x, 1 – y, –z) H···O 1.94 Å, N–H···O 167°.
Thus, the cascade cyclocondensation of diamino-4-phenyl-
imidazole 1 with aromatic aldehydes 2 and Meldrum’s acid 3
is a regioselective process, which exclusively leads to imidazo-
[5,1-b]pyridazin-2-ones 9. The direction of the formation of
partially hydrogenated pyridazine ring corresponds to the inter-
action of β-carbon atom in intermediate arylmethylene deriva-
tive 4 or Michael adduct 5 with a carbon nucleophilic centre
and the carbonyl group with the N-amino group in the diamino-
imidazole molecule.
5
6
N. N. Kolos, T. V. Beryozkina and V. D. Orlov, Mendeleev Commun.,
2002, 91.
S. M. Desenko, N. N. Kolos, M. Tueni and V. D. Orlov, Khim. Geterotsikl.
Soedin. 1990, 838 [Chem. Heterocycl. Compd. (Engl. Transl.), 1990,
26, 782].
N. N. Kolos, V. D. Orlov, B. V. Paponov, V. N. Baumer, O. V. Shishkin
and N. A. Kvashnitskaya, Khim. Geterotsikl. Soedin., 1999, 796 [Chem.
Heterocycl. Compd. (Engl. Transl.), 1999, 35, 708].
N. N. Kolos, V. D. Orlov, B. V. Paponov and O. V. Shishkin, Khim.
Geterotsikl. Soedin., 2001, 368 [Chem. Heterocycl. Compd. (Engl.
Transl.), 2001, 37, 338].
7
8
9
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‡‡ X-ray diffraction study. Crystals of 12 are orthorhombic. At 293 K,
a = 9.835(2), b = 20.780(2) and c = 20.987(8) Å, V = 4289(2) Å3, Mr =
= 392.45, Z = 8, space group Pbca, dcalc = 1.215 g cm–3, m(MoKα) =
= 0.077 mm–1, F(000) = 1648. Intensities of 31103 reflections (6245
independent, Rint = 0.060) were measured on an Xcalibur-3 diffractometer
(MoKα radiation, graphite monochromator, CCD detector, w-scans,
2qmax = 60°). The structure was solved by a direct method using the
SHELXTL package.15 Positions of hydrogen atoms were located from
electron density difference maps and refined by the ‘riding’ model with
Uiso = 1.2Ueq of carrier non-hydrogen atom. Full-matrix least-squares
refinement against F2 in anisotropic approximation using 6171 reflec-
tions was converged to wR2 = 0.095 [R1 = 0.039 for 1618 reflections
with F > 4s(F), S = 0.611].
CCDC 662071 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
Received: 25th October 2007; Com. 07/3034
– 143 –