March 2016
The Pseudo-Michael Reaction of 2-Hydrazinylidene-1-Arylimidazolidines with
Diethyl Ethoxymethylenemalonate
577
7.04–7.6 (m, 5H), 4.3 (s, 4H), 4.22 (q, J = 7.2 Hz, 2H), 1.3 (t,
J = 7.2 Hz, 3H). EIMS, m/z: 300 (M+, 34%), 224 (100%). Anal.
Calcd for C15H16N4O3: C 59.99; H 5.37; N 18.66. Found: C
60.11; H 5.29; N 18.71.
259 (100%). Anal. Calcd for C15H15ClN4O3: C 53.82; H 4.52;
N 16.74; Cl 10.59. Found: C 53.93; H 4.55; N 16.70; Cl 10.61.
4d and 5d: Rf = 0.51/0.48; 1H NMR (200 MHz, CDCl3) d:
10.54 (bs, 0.7H, enol OH), 7.5 (s, 1H), 7.15–7.65 (m, 4H), 4.28
(s, 4H), 4.26 (q, J = 7.2 Hz, 2H), 3.8 (s, 0.3H, NH), 1.7 (s, 3H),
1.24 (t, J = 7.2 Hz, 3H). EIMS, m/z: 314 (M+, 43%), 238
(100%). Anal. Calcd for C16H18N4O3: C 61.13; H 5.77; N
17.82. Found: C 61.03; H 5.75; N 17.77.
Ethyl 1-(2-chlorophenyl)-5(1H)hydroxy-2,3-dihydroimidazo
[2,1-c][1,2,4]triazepine-6-carboxylate (5b).
mp 199–201°C;
yield 95%; Rf =0.49; 1H NMR (600 MHz, CDCl3), 10.35 (bs, 1H),
7.67 (s, 1H), 7.06–7.64 (m, 4H), 4.42 (s, 4H), 4.16 (q, J=7.2Hz,
2H), 1.27 (t, J=7.2Hz, 3H); 13C NMR (151 MHz, CDCl3) 166.66,
164.02, 152.06, 150.05, 138.93, 129.12, 128.10, 125.82, 89.54,
58.68, 53.05, 42.08, 14.62. EIMS, m/z: 335 (M+, 39%), 259
(100%). Anal. Calcd for C15H15ClN4O3: C 53.82; H 4.52; N
16.74; Cl 10.59. Found: C 53.66; H 4.54; N 16.81; Cl 10.63.
Ethyl 1-(4-chlorophenyl)-5(1H)hydroxy-2,3-dihydroimidazo
1
4e and 5e: Rf = 0.56/0.5; H NMR (200 MHz, CDCl3) d: 10.6
(bs, 0.6H, enol OH), 7.61 (s, 1H), 7.18, 7.46 (2 × d, J = 9 Hz,
4H), 4.24 (s, 4H), 4.22 (q, J = 7.3 Hz, 2H), 3.66 (s, 0.4H, NH),
1.8 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H). EIMS (15 eV), m/z: 314
(M+, 39%), 238 (100%). Anal. Calcd for C16H18N4O3: C 61.13;
H 5.77; N 17.82. Found: C 61.23; H 5.69; N 17.66.
Molecular modeling.
The molecular structures of 2a–e,
[2,1-c][1,2,4]triazepine-6-carboxylate (5c).
mp 224–226°C;
1
DEEM, 3a–e, and 4a–4e in the ground state were optimized
with the B3LYP DFT (the variant of the DFT method using
Becke’s three-parameter hybrid functional (B3) [13] with
correlation functional such as the one proposed by Lee, Yang,
and Parr (LYP) [14]) using 6-311G(d,p) as included in
Gaussian09 [15]. The calculations were performed using the
Polarizable Continuum Model [16]. This method creates a
solute cavity through a set of overlapping spheres. Furthermore,
frontal molecular orbital analysis was performed with
Gaussian09 on the 6-311G(d,p)/B3LYP level of theory.
yield 90%; Rf = 0.51; H NMR (600 MHz, CDCl3) 10.5 (bs, 1H),
7.65 (s, 1H), 7.14, 7.38 (2× d, J = 9.2 Hz, 4H), 4.2 (s, 4H), 4.16
(q, J = 7.3 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H). EIMS, m/z: 335 (M+,
31%), 259 (100%). Anal. Calcd for C15H15ClN4O3: C 53.82; H
4.52; N 16.74; Cl 10.59. Found: C 53.94; H 4.53; N 16.72; Cl
10.67.
mp 212–214°C; yield 64%; Rf = 0.48; 1H NMR (600 MHz,
CDCl3) 10.5 (bs, 1H), 7.51 (s, 1H), 7.1–7.64 (m, 4H), 4.28 (s,
4H), 4.21 (q, J = 7.2 Hz, 2H), 1.78 (s, 3H), 1.26 (t, J = 7.2 Hz,
3H). EIMS, m/z: 314 (M+, 43%), 238 (100%). Anal. Calcd for
C16H18N4O3: C 61.13; H 5.77; N 17.82. Found: C 60.98; H
5.79; N 17.81.
Pymol v. 0.99 [17], Yasara Structure [18], and ArgusLab [19]
were also used for the visualization of the results.
Ethyl 1-(4-methylphenyl)-5(1H)hydroxy-2,3-dihydroimidazo
[2,1-c][1,2,4]triazepine-6-carboxylate (5e).
mp 229–231°C;
1
Acknowledgments. The paper was developed using the equipment
purchased within the project “The Equipment of Innovative
Laboratories Doing Research on New Medicines Used in the
Therapy Of Civilization and Neoplastic Diseases” within the
Operational Program Development of Eastern Poland 2007–2013,
Priority Axis I Modern Economy, Operations I.3 Innovation
Promotion. The research was partially performed during the
postdoctoral fellowship of Agnieszka A. Kaczor at the University
of Eastern Finland in Kuopio, Finland under the Marie Curie
fellowship. The calculations were carried out under the framework
of a computational grant from the Interdisciplinary Center of
Mathematical and Computational Modeling (ICM, Warsaw,
Poland) and under the resources of CSC, Finland.
yield 95%; Rf = 0.5; H NMR (600 MHz, CDCl3) 10.65 (bs, 1H),
7.62 (s, 1H), 7.2, 7.5 (2 × d, J = 9 Hz, 4H), 4.28 (s, 4H), 4.2 (q,
J = 7.3 Hz, 2H), 1.84 (s, 3H), 1.28 (t, J = 7.3 Hz, 3H). EIMS, m/z:
314 (M+, 40%), 238 (100%). Anal. Calcd for C16H18N4O3: C
61.13; H 5.77; N 17.82. Found: C 61.24; H 5.73; N 17.90.
Method B (xylene/n-butanol). Respective ester (0.01 mol)
of (1-arylimidazolidine-2-ylidene)hydrazinomethylenemalonate
3a–e was refluxed in 50 mL of xylene for 2 h and left in
ambient temperature overnight. Yielded precipitate was
collected, solved in 50 mL of n-butanol, and refluxed for 24 h.
Solvent was removed under reduced pressure. Crude solid was
washed with 2-propanol and crystallized from ethanol. Physical
and spectral properties were identical with compounds obtained
by Method A. Solids separated from xylene were mixtures of
4a–e and 5a–e identified by their spectra.
4a and 5a: Rf = 0.54/0.48; 1H NMR (200 MHz, CDCl3) d: 10.7
(bs, 0.65H, enol OH), 7.85 (s, 1H), 7.05–7.57 (m, 5H), 4.24 (q,
J = 7.2 Hz, 2H), 4.2 (s, 4H), 3.74 (s, 0.35H, NH), 1.28 (t,
J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) 166.64, 164.14,
152.81, 151.09, 139.80, 130.29, 130.17, 128.88, 123.36,
119.59, 89.70, 58.86, 51.49, 42.38, 14.62. EIMS, m/z: 300 (M+,
34%), 224 (100%). Anal. Calcd for C15H16N4O3: C 59.99; H
5.37; N 18.66. Found C 59.70, H 5.33, N 18.44.
REFERENCES AND NOTES
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[4] Matosiuk, D.; Tkaczyński, T. Polish patent, 1996, 182916.
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[6] Priimienko, B. A. Izv Vyssh Uchebn Zaved, Khim Khim
Tekhnol 1982, 25, 149.
4b and 5b: Rf = 0.56/0.49; 1H NMR (200 MHz, CDCl3) d:
10.45 (bs, 0.66 H, enol OH), 7.67 (s, 1H), 7.02–7.6 (m, 4H), 4.2
(s, 4H), 4.1 (q, J = 7.1 Hz, 2H), 3.8 (s, 0.33H, NH), 1.25 (t,
J = 7.1 Hz, 3H). EIMS, m/z: 335 (M+, 36%), 259 (100%). Anal.
Calcd for C15H15ClN4O3: C 53.82; H 4.52; N 16.74; Cl 10.59.
Found: C 53.69; H 4.51; N 16.80; Cl 10.61.
[7] Savelli, F.; Boido, A.; Satta, M.; Peana, A. Farmaco 1996, 51, 141.
[8] Sztanke, K.; Tkaczyński, T. Acta Pol Pharm 1997, 54, 147.
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4c and 5c: Rf = 0.55/0.51; 1H NMR (200 MHz, CDCl3) d: 10.4
(bs, 0.64 H, enol OH), 7.6 (s, 1H), 7.15, 7.44 (2 × d, J = 9.1 Hz,
4H), 4.2 (s, 4H), 4.2 (q, J = 7.1 Hz, 2H), 3.72 (s, 0.36H, NH),
1.24 (t, J = 7.1 Hz, 3H). EIMS (15 eV), m/z: 335 (M+, 24%),
[10] Sztanke, K.; Fidecka, S.; Kedzierska, E.; Karczmarzyk, Z.;
Pihlaja, K.; Matosiuk, D. Eur J Med Chem 2005, 40, 127.
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Kandefer-Szerszeń, M. Eur J Med Chem 2008, 43, 404.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet