Synthesis of N-(2-pyridyl)imidazolidin-2-ones and 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-ones with potential biological activities

Łukasz Balewski; Franciszek Sączewski; Maria Gdaniec; Patrick J. Bednarski; Izabela Jara

doi:10.1515/hc-2013-0125

Artikel Open Access

Synthesis of N-(2-pyridyl)imidazolidin-2-ones and 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-ones with potential biological activities

Łukasz Balewski , Franciszek Sączewski , Maria Gdaniec , Patrick J. Bednarski und Izabela Jara

Veröffentlicht/Copyright: 2. Oktober 2013

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Abstract

Small libraries of 1-(2-pyridyl)imidazolidin-2-one and 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one derivatives were prepared from substituted pyridine or quinoline N-oxides and 2-chloro-4,5-dihydroimidazole by means of the α-ureation and α-amination reactions. The α-ureation reaction of pyridine and quinoline N-oxides was studied theoretically by means of quantum chemical calculations at the density functional theory level. The newly obtained compounds were screened for their potential in vitro cytotoxic activity against human tumor cell lines LCLC-103H, 5637 and A-427.

Keywords: cytotoxic activity; 1-(2-pyridyl)imidazolidin-2-ones; 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-ones; synthesis; theoretical study; X-ray crystallography

Introduction

N-Aryl(heteroaryl)ureas constitute an important structural component of many interesting biologically active compounds including anticancer [1–7], antiparasitic [8–10], antiviral [11], and antibacterial [12] agents, central nervous system active compounds [13, 14], anti-inflammatory [15] and plant growth regulating agents [16]. In view of the fragment based drug discovery concept [17–19], these low molecular weight chemical fragments conform to the ‘rule of three’: molecular weight ≤300, Clog p-value ≤3, the number of hydrogen bond donors, hydrogen bond acceptors and rotatable bonds ≤3, polar surface area ≤60 [20] and, therefore, can be considered as valuable building blocks of more complex lead compounds. By contrast, various biologically active cyclic ureas have been designed as the bioisosters of aryl amides [21], ureas [22], guanidines and thiones [23].

With the above information in mind, it was decided to develop a small library of N-(2-pyridyl)imidazolidin-2-one fragments to identify compounds that possess cytotoxic activity against selected human tumor cell lines. As shown in Figure 1, there are at least four possible synthetic approaches to the synthesis of N-(2-pyridyl)imidazolidine-2-ones. According to method A, a 2-aminopyridine is subjected to the reaction with 2-chloroethyl isocyanate (formation of urea derivative) followed by the treatment with base which gives rise to the imidazolidin-2-one ring formation [24, 25]. A more straightforward Goldberg-Buchwald-Nandakumar method B utilizes a 2-bromo- or 2-iodopyridine which is used for N-heteroarylation of amides, ureas and imidazolidin-2-ones in the presence of Pd or Cu catalyst [26–32]. According to method C, a corresponding ethylenediamine derivative is subjected to the reaction with carbonylation reagent such as phosgene, dialkyl carbonate or carbonyldiimidazole [24]. However, various substituted 2-aminopyridines as well as 2-bromo- and 2-iodopyridines are difficult to prepare [33], which makes the methods discussed above of limited value for the generation of libraries of azine-containing fragments. Therefore, we decided to take advantage of a poorly explored α-ureation method D that comprises the reaction of an azine (pyridine or quinoline) N-oxide with 2-chloro-4,5-dihydroimidazole [34, 35].

Figure 1

Possible routes to 1-aryl(heteroaryl)imidazolidin-2-ones.

The only products of α-ureation of pyridine N-oxides described in the literature are N-(6-methyl-2-pyridyl)-imidazolidin-2-one and 1,3-bis-(4-methyl-2-pyridyl)-imidazolidin-2-one obtained from 2-picoline N-oxide and 4-picoline N-oxide, respectively [35]. Hence, in the present paper we describe the synthesis of a small library of various substituted N-(2-pyridyl)imidazolidin-2-ones and the results of the theoretical study of the α-ureation process carried out by means of quantum chemical calculations at the density functional theory level. Preliminary data regarding cytotoxic properties of the prepared fragments against selected human tumor cell lines are also presented.

Results and discussion

Chemistry

In contrast to the previously described heteroarylation of 2-aminopyridine N-oxide [36], the α-ureation of alkyl-, alkoxy- and halo-substituted pyridine N-oxides 1 with 2-chloro-4,5-dihydroimidazole (2), a formal 2-chloroamidine derivative, led to the complex mixtures of products. As shown in Scheme 1, pyridinium salts of type A were found to be the major products that upon workup in aqueous solution give back the substrates 1 and N-(imidazolin-2-yl)imidazolidin-2-one (B). However, using preparative thin layer chromatography (chromatotron™) or column chromatography we were able to isolate the desired α-ureation products, that is, 1-monosubstituted imidazolidin-2-ones 3 and 1,3-disubstituted imidazolidin-2-ones 4 in 4–11% of isolated yield. Occasionally, from a reaction mixture we also separated 1-(2-pyridyl)-2,3,7,8-tetrahydroimidazo[1,2-b][1,3,5]-triazepin-5(6H)-ones 5 resulting from α-amination reaction of pyridine N-oxides with 1. The products isolated from each reaction mixture are presented in Table 1. In this context, it should be pointed out that a complex mixture of products was also obtained by Abramovitch and co-workers from a mechanistically related α-acylamination reaction of pyridine N-oxides with imidoyl chlorides [37, 38].

Scheme 1

α-Ureation and α-amination of pyridine N-oxides 1 with 2-chloro-4,5-dihydroimidazole (2).

Table 1

Products of α-ureation and α-amination of substituted pyridine N-oxides.


1	R	3	4	5
a	3-Me	a	–	–
b	4-Me	b	b	–
c	4-Et	c	c	c
d	3,4-di-Me	d	–	d
e	4-Bu^t	e	–	–
f	4-Ph	f	f	–
g	4-(CH₂)₃Ph	g	–	g
h	2-OMe	h	–	–
i	4-OMe	i	i	i
j	2-OEt	j	–	–
k	4-OEt	k	k	k
l	4-OCH₂Ph	–	l	l
m	2-Me, 4-OMe	m	–	m
n	2-OPrⁿ	n	–	–
o	4-OPrⁿ	o	–	–
p	2-OPrⁱ	p	–	–
q	4-OPrⁱ	–	q	q
r	2-Me, 4-OEt	r	–	–
s	2-OBuⁿ	s	–	–
t	4-OBuⁿ	t	–	–
u	4-OCH₂CH(Me)₂	u	u	u
v	4-Cl	–	–	v
w	4-Br	–	–	w

Proposed mechanisms of α-ureation of azine N-oxides leading to N-heteroaryl-imidazolidin-2-ones of types 3 and 4 have been discussed previously [34], whereas a plausible route leading to the formation of α-amination products 5 is depicted in Scheme 2. We presume that the initially formed unstable pyridinium salt A undergoes α-amination reaction to give the dihydropyridine C which undergoes a spontaneous 1,5-proton shift accompanied by rearomatization of dihydropyridine moiety to generate the isocyanate derivative D. Then, the intramolecular addition of imidazolidine NH group to heterocumulene affords the final imidazo[1,2-b][1,3,5]-triazepin-5(6H)-one 5.

Scheme 2

α-Amination of pyridine N-oxides 1 with 2-chloro-4,5-dihydroimidazole (2).

Rather low yields of α-ureation of pyridine N-oxides with 1 contrast with our finding that an analogous reaction of quinoline N-oxides 6 provides the corresponding 1-(2-quinolyl)imidazolidin-2-ones 7 in fairly good yields (Scheme 3).

Scheme 3

α-Ureation of quinoline N-oxides.

Therefore, to rationalize the observed difference in reactivity of pyridine N-oxides and quinoline N-oxides, we calculated the α-ureation reaction energies yielding 1-(2-pyridyl)imidazolidin-2-one and 1-(2-quinolyl)imidazolidin-2-one, respectively. Quantum chemical calculations carried out at the B3LYP level clearly show that both reactions are highly exothermic (-76.4 kcal/mol and -78.8 kcal/mol, respectively), whereas the activation energy for α-ureation of quinoline N-oxide is 19.1 kcal/mol, which is lower than the barrier for α-ureation of pyridine N-oxide (25.9 kcal/mol). This may explain why the yields of pyridine α-ureation (Figure 2) products are reduced. It is worth noting that the previously investigated α-bromination of quinoline and pyridine N-oxides gave similar results, that is, 2-bromoquinolines were obtained in high yields, whereas regioselective bromination of pyridine N-oxides failed [33].

Figure 2

Thermodynamic reaction profile of α-ureation of pyridine N-oxide 1 (top) and quinoline N-oxide 6 (bottom) with 2-chloro-4,5-dihydroimidazole (2) in dichloromethane solution. Relative electronic energies E_e and free Gibbs energies (G⁰, 298.15 K) calculated for intermediates (azinium salts and dihydroazines), transition states and products at B3LYP/6-31+G* in kcal/mol.

Structures of all compounds 3–5 and 7 were confirmed by elemental analyses and IR, ¹H NMR and ¹³C NMR spectroscopy. Moreover, the structures of 3a, 3g, 3r, 4l, 5m and 7a were analyzed by X-ray crystallography diffraction (Figure 3). It is interesting to note that 1-(azin-2-yl)imidazolidin-2-one molecules in the studied crystals adopt E configuration and are slightly non-planar due to steric interactions between the azine C3-H atoms and the imidazolidin-2-one O atom.

Figure 3

Views of the molecular structures of compounds 3a (top left), 3g (top center), 3r (top right), 4l (bottom left), 5m (bottom center) and 7a (bottom right) with displacement ellipsoids drawn at the 50% probability level.

Antitumor studies

Preliminary in vitro studies of new compounds for cytotoxic activity were performed on three human tumor cell lines: two non-small-cell lung cancer lines LCLC-103H and A-427, and the bladder cancer cell line 5637. Data presented in Table 2 indicate that most of the tested compounds are not active enough to inhibit the cell growth by 50% at concentration of 20 mm, which is the concentration that can typically be attained in the human body. The only active compounds are 1-monosubstituted imidazolidin-2-ones 3j and 3s, 1,3-disubstituted imidazolidin-2-one 4i and imidazo[2,1-b][1,3,5]triazepin-5(6H)-one 5w. The most sensitive to these compounds are the 5637 and A-427 cell lines, whereas the LCLC-103H cell line proved to be much less sensitive.

Table 2

The relative % of cell growth (%) compared to untreated control at a concentration of 20 μm (average of three determinations).

Cell line Comp.	LCLC-103H	5637	A-427
3a	137.04±27.2	129.44±25.08	133.21±24.14
3c	101.2±7.2	95.9±32.2	74.2±7.3
3g	52.87±5.35	87.6±14.53	106.04±1.6
3h	101.2±6.4	126.8±10.8	101.3±6.7
3j	96.7±20.3	23.9±13.2	18.4±7.7
3r	100.5±8.8	130.3±11.3	93.5±27.7
3s	93.4±9.3	124.3±46.7	38.54±9.8
4i	74.1±13.8	25.9±2.0	79.7±13.3
4l	58.97±16.98	82.9±10.97	115.75±13.72
5i	99.3±14.1	86.5±12.7	87.1±20.1
5q	96.8±4.2	57.6±12.8	86.2±22.1
5w	91.3±5.2	38.4±4.7	38.4±11.1

Conclusion

A small library of various substituted N-(2-pyridyl)-imidazolidin-2-ones was synthesized by α-ureation of corresponding pyridine N-oxides 1 with 2-chloro-4,5-dihydroimidazole (2). Most of these compounds and 1-(2-pyridyl)-2,3,7,8-tetrahydroimidazo[2,1-b][1,3,5]-triazepin-5(6H)-one derivatives resulting from α-amination of pyridine N-oxides with 2 were obtained for the first time. Quantum chemical calculations of the α-ureation process revealed that lower reactivity of pyridine N-oxides in comparison with quinoline N-oxides is due to thermodynamic factors. The investigated compounds exhibit a general lack of cytotoxic activity on the human cancer cell lines tested. The cell lines 5637 and A-427 are the ones moderately sensitive to imidazolidin-2-ones 3j, 3s and 4i and imidazo[2,1-b][1,3,5]triazepin-5(6H)-one 5w.

Experimental

General

All melting points were determined on a Boetius apparatus and are uncorrected. FT-IR spectra were measured by the Nicolet-380 model. Unless stated otherwise, the ¹H NMR and ¹³C NMR spectra were recorded on a Varian Gemini instrument operating at 200 MHz and 50 MHz, respectively.

Chromatographic separations were performed on silica gel 60 PF₂₅₄ containing gypsum (Merck) by use of chromatotron™ or flash column chromatography (silica gel 0.040–0.063 mm, Alfa Aesar). Analytical thin layer chromatography was performed with Merck silica gel plates and spots were visualized with UV light at 254 nm.

N-oxides 1a, 1b, 1f, 1g, 1i, 1l and 6 were acquired from commercial suppliers (Sigma-Aldrich) and used as provided; other N-oxides were prepared according to literature procedures [39–42].

The diffraction data for single crystals of compounds 3a, 3g, 3r and 7 were collected with an Oxford Diffraction Xcalibur diffractometer using Mo Kα radiation, whereas an Oxford Diffraction SuperNova diffractometer using Cu Kα radiation was used for compounds 4l and 5m. The intensity data were collected and processed using Oxford Diffraction CrysAlis Software [43]. The structures were solved by direct methods with the program SHELXS-97 [44] and refined by full-matrix least-squares method on F² with SHELXL-97 [44]. Crystallographic data for compounds have been deposited with the Cambridge Crystallographic Data Centre, with the deposition Nos. CCDC 778723–778725, 780760, 808498 and 953311. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.

All cell culture reagents were purchased from Sigma (Deisenhofen, Germany). Cancer cell lines were obtained from the German Collection of Microorganisms and Cell Cultures (DSMZ, Brauschweig, Germany). These included: human large cell lung carcinoma LCLC-103H, human urinary bladder carcinoma 5637 and human lung carcinoma A-427. The culture medium for all cancer cell lines was RPMI-1640 medium containing 2 g/L HCO₃^-, and 10% fetal calf serum. Cells were grown in 75 cm² plastic culture flasks (Sarstedt, Nümbrecht, Germany) in a humid atmosphere of 5% CO₂ at 37°C and passaged shortly before becoming confluent. Cytotoxicity determinations were based on cellular staining with crystal violet and were performed as previously described [45]. Cells were automatically counted by using a Coulter Counter Z2 (Beckman-Coulter) instrument.

General procedure for the reaction of azine N-oxides 1 and 6 with 2-chloro-4,5- dihydroimidazole (2); synthesis of 3–5, 7

To a stirred solution of 2-chloro-4,5-dihydro-1H-imidazole (2, 0.025 mol) [46] in dichloromethane (30 mL) was added appropriate pyridine N-oxide 1a–w (0.0125 mol). When the exothermic reaction had subsided, the reaction mixture was stirred at room temperature for 12 h. Then the solvent was evaporated under reduced pressure, and the oily residue was basified with 20% aqueous potassium carbonate. The product was extracted with chloroform, and the extract was dried with anhydrous MgSO₄ and concentrated. The residue was separated on a chromatotron™ or flash column chromatography. In the case of the reactions of pyridine N-oxides 1v, 1w and quinoline N-oxides 6a, 6b, the only products 5v, 5w, 7a and 7b, respectively, were separated by suction after basification of the reaction mixture with K₂CO₃ and purified by crystallization.

1-(5-Methyl-2-pyridyl)imidazolidin-2-one (3a)

Compound 3a was purified by use of chromatotron (eluent: chloroform/ethyl acetate, 2:1, v/v). The resulting oil was mixed with anhydrous methanol and cooled to give white solid; yield 5%; mp 202–204°C ([24]; mp 200–202°C); IR: ν 3234 (NH), 1697 (CO), 1608, 1500, 1487, 1415, 1261 cm^-1; ¹H NMR (DMSO-d₆): δ 2.21 (s, 3H, CH₃), 3.38 (t, 2H, CH₂), 3.95 (t, 2H, CH₂), 7.10 (br s, 1H, NH), 7.51 (dd, J₁ = 2 Hz, J₂ = 8.5 Hz, 1H, Ar-H), 8.06 (m, 2H, Ar-H); ¹³C NMR (DMSO-d₆): δ 17.4, 36.7, 43.8, 111.6, 126.1, 138.1, 147.2, 150.8, 158.7. Anal. Calcd for C₉H₁₁N₃O: C, 61.00; H, 6.26; N, 23.71. Found: C, 60.94; H, 6.22; N, 23.43.

Crystal data for 3a: C₉H₁₁N₃O, triclinic, space group P-1, a = 6.8020(8), b = 7.1679(7), c = 10.1343(9) Å, α = 99.816(8), β = 102.607(9), γ = 114.186(11)°, V = 420.70(9) Å³, Z = 2, T = 100 K, d_x = 1.399 g cm^-3, μ(Mo Kα) = 0.096 mm^-1, 4585 data were collected up to θ_max = 28.96° for a crystal with dimensions 0.3×0.3×0.2 mm³ (R_int = 0.0199, R_σ = 0.0325). Final R indices for 1479 reflections with I>2σ(I) and 123 refined parameters are: R₁ = 0.0377, wR₂ = 0.0977 (R₁ = 0.0513, wR₂ = 0.1016 for all 1953 data). CCDC 778723.

1-(4-Methyl-2-pyridyl)imidazolidin-2-one (3b)

Compound 3b was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone, 6:3:1, v/v/v); yield 11%; mp 141–143°C ([15]; mp 145–146°C); IR: ν 3234 (NH), 1703 (CO), 1602, 1559, 1481, 1413, 1261 cm^-1; ¹H NMR (DMSO-d₆): δ 2.29 (s, 3H, CH₃); 3.39 (t, 2H, CH₂); 3.97 (t, 2H, CH₂); 6.82 (d, J = 5 Hz, 1H, Ar-H); 7.17 (s, 1H, NH); 8.02 (s, 1H, Ar-H); 8.13 (d, J = 5 Hz, 1H, Ar-H); ¹³C NMR: (DMSO-d₆): δ 21.2, 36.7, 43.8, 112.3, 118.7, 147.3, 147.9, 153.0, 158.6. Anal. Calcd for C₉H₁₁N₃O: C, 61.00; H, 6.26; N, 23.71. Found: C, 60.88; H, 6.19; N, 23.77.

1-(4-Ethyl-2-pyridyl)imidazolidin-2-one (3c)

Compound 3c was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 4%; mp 111–113°C; IR: ν 3236 (NH), 1705 (CO), 1604, 1558, 1431, 1263 cm^-1; ¹H NMR (DMSO-d₆): δ 1.16 (t, 3H, CH₃), 2.55 (q, 2H, CH₂), 3.38 (t, 2H, CH₂), 3.97 (t, 2H, CH₂), 6.84 (d, J = 5 Hz, 1H, Ar-H), 7.16 (s, 1H, NH), 8.05 (s, 1H, Ar-H), 8.15 (d, J = 5 Hz, 1H, Ar-H); ¹³C NMR (CDCl₃): δ 15.0, 29.1, 37.9, 44.7, 112.6, 118.4, 147.3, 153.1, 155.2, 159.8. Anal. Calcd for C₁₀H₁₃N₃O: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.74; H, 6.81; N, 21.73.

1-(4,5-Dimethyl-2-pyridyl)imidazolidin-2-one (3d)

Compound 3d was purified by use of chromatotron (chloroform/acetone, 5:1, v/v); yield 4%; mp 170–173°C; IR: ν 3236 (NH), 1698 (CO), 1611, 1488, 1414; ¹H NMR (CDCl₃): δ 2.16 (s, 3H, CH₃); 2.26 (s, 3H, CH₃); 3.55 (t, 2H, CH₂); 4.14 (t, 2H, CH₂); 5.67 (br s, 1H, NH); 7.98 (s, 1H, Ar-H); 8.03 (s, 1H, Ar-H); ¹³C NMR (CDCl₃): δ 16.32, 20.16, 37.92, 44.56, 113.77, 126.89, 147.23, 147.79, 151.36, 159.95. Anal. Calcd for C₁₀H₁₃N₃O: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.48; H, 6.70; N, 21.63.

1-(4-tert-Butyl-2-pyridyl)imidazolidin-2-one (3e)

Compound 3e was purified by use of chromatotron (eluent: chloroform/ethyl acetate, 2:1, v/v); yield 6%; mp 135–137°C; IR: ν 3261 (NH), 1715, 1701 (CO), 1599, 1548, 1252 cm^-1; ¹H NMR (CDCl₃): δ 1.31 (s, 9H, 3×CH₃), 3.56 (t, 2H, CH₂), 4.18 (t, 2H, CH₂), 5.36 (br s, 1H, NH), 6.94 (dd, J₁ = 1.5 Hz, J₂ = 5.5 Hz, 1H, Ar-H), 8.19 (d, J= 5.5 Hz, 1H, Ar-H), 8.31 (d, J = 1.5 Hz, 1H, Ar-H); ¹³C NMR (CDCl₃): δ 31.05 (three overlapping signals), 35.5, 37.9, 44.8, 110.3, 115.9, 147.1, 153.1, 159.7, 162.3. Anal. Calcd for C₁₂H₁₇N₃O: C, 65.73; H, 7.81; N, 19.16. Found: C, 65.61; H, 7.68; N, 18.85.

1-(4-Phenyl-2-pyridyl)imidazolidin-2-one (3f)

Compound 3f was purified by use of chromatotron (eluent: chloroform/ethyl acetate, 2:1, v/v); yield 10%; mp 221–213°C; IR: ν 3227 (NH), 1716 (CO), 1592, 1475, 1268 cm^-1; ¹H NMR (DMSO-d₆): δ 3.42 (t, 2H, CH₂), 4.03 (t, 2H, CH₂), 7.26–7.29 (m, 2H, Ar-H), 7.43–7.56 (m, 3H, Ar-H+NH), 7.69 (m, 2H, Ar-H), 8.33 (d, J = 5 Hz, 1H, Ar-H), 8.49 (s, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 36.7, 43.9, 109.3, 115.5, 127.0 (two overlapping signals), 129.4, 129.5 (two overlapping signals), 138.2, 148.0, 148.6, 153.6, 158.7. Anal. Calcd for C₁₄H₁₃N₃O: C, 70.28; H, 5.48; N, 17.56. Found: C, 70.19; H, 5.38; N, 17.74.

1-[4-(3-Phenylpropyl)-2-pyridyl]imidazolidin-2-one (3g)

Compound 3g was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/methanol, 13:6:1, v/v/v); yield 7%; mp 157–158°C; IR: ν 3220 (NH), 1698 (CO), 1599, 1476, 1264 cm^-1; ¹H NMR (DMSO-d₆): δ 1.88 (m, 2H, CH₂); 2.59 (m, 4H, 2×CH₂); 3.39 (t, 2H, CH₂); 3.97 (t, 2H, CH₂); 6.85 (d, J = 5 Hz, 1H, Ar-H); 7.25 (m, 6H, Ar-H+NH); 8.05 (s, 1H, Ar-H); 8.16 (d, J = 5 Hz, 1H, Ar-H). Anal. Calcd for C₁₇H₁₉N₃O: C, 72.57; H, 6.81; N, 14.94. Found: C, 72.41; H, 6.68; N, 14.56.

Crystal data for 3g: C₁₇H₁₉N₃O, monoclinic, space group P2₁/c, a = 9.6609(2), b = 5.8864(1), c = 25.8096(6) Å, β = 98.026(2)°, V = 1453.36(5) Å³, Z = 4, T = 100 K, d_x = 1.286 g cm^-3, μ(Mo Kα) = 0.082 mm^-1, 12 518 data were collected up to θ_max = 26.37° for a crystal with dimensions 0.3×0.3×0.1 mm³ (R_int = 0.0246, R_σ = 0.0253). Final R indices for 2368 reflections with I>2σ(I) and 195 refined parameters are: R₁ = 0.0319, wR₂ = 0.0761 (R₁ = 0.0435, wR₂ = 0.0783 for all 2964 data). CCDC 953311.

1-(6-Methoxy-2-pyridyl)imidazolidin-2-one (3h)

Compound 3h was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 8%; mp 185–186°C; IR: ν 3259 (NH), 1706 (CO), 1677, 1590, 1352, 1265 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 3.40 (t, 2H, CH₂), 3.83 (s, 3H, OCH₃), 4.02 (t, 2H, CH₂), 6.37 (d, J = 7.5 Hz, 1H, Ar-H), 7.18 (s, 1H, NH), 7.60 (t, 1H, Ar-H), 7.70 (d, J = 7.5 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 36.7, 43.5, 53.0, 102.0, 103.7, 140.3, 151.1, 158.4, 162.4. Anal. Calcd for C₉H₁₁N₃O₂: C, 55.95; H, 5.74; N, 21.75. Found: C, 55.78; H, 5.56; N, 21.66.

1-(4-Methoxy-2-pyridyl)imidazolidin-2-one (3i)

Compound 3i was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 10%; mp 133–135°C; IR: ν 3219 (NH), 1724, 1707 (CO), 1594, 1560, 1420, 1229 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 3.37 (t, 2H, CH₂), 3.78 (s, 3H, OCH₃), 3.96 (t, 2H, CH₂), 6.59 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H), 7.20 (br s, 1H, NH), 7.79 (d, J = 2 Hz, 1H, Ar-H), 8.08 (d, J = 6 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 36.6, 44.0, 55.3, 96.5, 105.45, 148.6, 154.4, 158.6, 166.2. Anal. Calcd for C₉H₁₁N₃O₂: C, 55.95; H, 5.74; N, 21.75. Found: C, 55.85; H, 5.72; N, 21.50.

1-(6-Ethoxy-2-pyridyl)imidazolidin-2-one (3j)

Compound 3j was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 4%; mp 171–172°C; IR: ν 3261 (NH), 1697 (CO), 1675, 1589, 1457, 1267 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 1.31 (t, 3H, CH₃), 3.34 (t, 2H, CH₂), 3.99 (t, 2H, CH₂), 4.27 (q, 2H, OCH₂), 6.34 (d, J = 7.5 Hz, 1H, Ar-H), 7.16 (s, 1H, NH), 7.58 (t, 1H, Ar-H), 7.68 (d, J=7.5 Hz, 1H, Ar-H), ¹³C NMR (CDCl₃): δ 15.2, 37.8, 44.4, 62.0, 103.4, 104.8, 140.5, 150.9, 159.8, 162.8. Anal. Calcd for C₁₀H₁₃N₃O₂: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.79; H, 6.19; N, 20.18.

1-(4-Ethoxy-2-pyridyl)imidazolidin-2-one (3k)

Compound 3k was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone, 6:3:1, v/v/v); yield 4%; mp 165–167°C; IR: ν 3235 (NH), 1702 (CO), 1596, 1439, 1257, 1220 cm^-1; ¹H NMR (DMSO-d₆): δ 1.33 (t, 3H, CH₃), 3.37 (t, 2H, CH₂), 4.01 (m, 4H, 2×CH₂), 6.57 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H), 7.19 (s, 1H, NH), 7.77 (d, J = 2 Hz, 1H, Ar-H), 8.06 (d, J = 6 Hz, 1H, Ar-H); ¹³C NMR [(CD₃)₂SO]: δ 14.6, 36.6, 43.9, 63.5, 96.9, 105.7, 148.6, 154.4, 158.6, 165.5. Anal. Calcd for C₁₀H₁₃N₃O₂: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.72; H, 6.19; N, 20.19.

1-(4-Methoxy-6-methyl-2-pyridyl)imidazolidin-2-one (3m)

Compound 3m was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone/methanol, 14:2:2:1, v/v/v/v); yield 8%; mp 187–190°C; IR: ν 3234 (NH), 1696 (CO), 1597, 1577, 1262 cm^-1; ¹H NMR (DMSO-d₆): δ 2.32 (s, 3H, CH₃); 3.34 (t, 2H, CH₂); 3.38 (s, 3H, OCH₃); 3.95 (t, 2H, CH₂); 6.47 (d, J = 2 Hz, 1H, Ar-H); 7.14 (s, 1H, NH); 7.61 (d, J = 2 Hz, 1H, Ar-H). Anal. Calcd for C₁₀H₁₃N₃O₂: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.88; H, 6.16; N, 20.12.

1-(6-Propoxy-2-pyridyl)imidazolidin-2-one (3n)

Compound 3n was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 9%; mp 154–156°C; IR: ν 3264 (NH), 1699 (CO), 1581, 1442, 1264 cm^-1; ¹H NMR (DMSO-d₆): δ 0.95 (t, 3H, CH₃); 1.73 (m, 2H, CH₂); 3.38 (t, 2H, CH₂); 3.98 (t, 2H, CH₂); 4.17 (t, 2H, OCH₂); 6.33 (d, J= 7.5 Hz, 1H, Ar-H); 7.15 (s, 1H, NH); 7.60 (m, 2H, Ar-H); ¹³C NMR (CDCl₃): δ 11.1, 22.9, 37.8, 44.4, 67.9, 103.4, 104.7, 140.5, 150.9, 159.7, 162.9. Anal. Calcd for C₁₁H₁₅N₃O₂: C, 59.71; H, 6.83; N, 18.99. Found: C, 59.65; H, 6.71; N, 18.66.

1-(4-Propoxy-2-pyridyl)imidazolidin-2-one (3o)

Compound 3o was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 4%; mp 141–143°C; IR: ν 3232 (NH), 1701 (CO), 1593, 1468, 1433, 1270 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 0.98 (t, 3H, CH₃), 1.75 (m, 2H, CH₂), 3.38 (t, 2H, CH₂), 3.97 (m, 4H, OCH₂+CH₂), 6.60 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H), 7.20 (s, 1H, NH), 7.78 (d, J = 2 Hz, 1H, Ar-H), 8.07 (d, J = 6 Hz, 1H, Ar-H). Anal. Calcd for C₁₁H₁₅N₃O₂: C, 59.71; H, 6.83; N, 18.99. Found: C, 59.57; H, 6.69; N, 18.63.

1-(6-Isopropoxy-2-pyridyl)imidazolidin-2-one (3p)

Compound 3p was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 4%; mp 160–162°C; IR: ν 3281 (NH), 1716 (CO), 1680, 1580, 1448, 1264 cm^-1; ¹H NMR (DMSO-d₆): δ 1.28 (d, J = 6 Hz, 6H, 2×CH₃), 3.38 (t, 2H, CH₂), 3.98 (t, 2H, CH₂), 5.13 (m, 1H, OCH), 6.28 (d, J = 7.5 Hz, 1H, Ar-H), 7.14 (s, 1H, NH), 7.59 (m, 2H, Ar-H). Anal. Calcd for C₁₁H₁₅N₃O₂: C, 59.71; H, 6.83; N, 18.99. Found: C, 59.57; H, 6.74; N, 18.65.

1-(4-Ethoxy-6-methyl-2-pyridyl)imidazolidin-2-one (3r)

Compound 3r was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone, 7:2:1, v/v/v); yield 9%; mp 193–195°C; IR: ν 3240 (NH), 1698 (CO), 1595, 1263 cm^-1; ¹H NMR (DMSO-d₆): δ 1.31 (t, 3H, CH₃), 2.30 (s, 3H, CH₃), 3.35 (t, 2H, CH₂), 4.00 (m, 4H, CH₂+OCH₂), 6.45 (d, J = 1.5 Hz, 1H, Ar-H), 7.13 (s, 1H, NH), 7.59 (d, J = 1.5 Hz, 1H, Ar-H). Anal. Calcd for C₁₁H₁₅N₃O₂: C, 59.71; H, 6.83; N, 18.99. Found: C, 59.47; H, 6.71; N, 18.74.

Crystal data for 3r: C₁₁H₁₅N₃O₂, monoclinic, space group P2₁/c, a = 8.6347(3), b = 13.5280(5), c = 9.5159(3) Å, β = 102.420(3)°, V = 1085.54(6) Å³, Z = 4, T = 100 K, d_x = 1.354 g cm^-3, μ(Mo Kα) = 0.096 mm^-1, 9745 data were collected up to θ_max = 29.03° for a crystal with dimensions 0.3×0.3×0.3 mm³ (R_int = 0.0215, R_σ = 0.0274). Final R indices for 1982 reflections with I>2σ(I) and 151 refined parameters are: R₁ = 0.0368, wR₂ = 0.0985 (R₁ = 0.0509, wR₂ = 0.1014 for all 2958 data). CCDC 778724.

1-(6-Butoxy-2-pyridyl)imidazolidin-2-one (3s)

Compound 3s was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 9%; mp 146–148°C; IR: ν 3246 (NH), 1732, 1695 (CO), 1592, 1456, 1270 cm^-1; ¹H NMR (DMSO-d₆): δ 0.92 (t, 3H, CH₃), 1.34–1.45 (m, 2H, CH₂), 1.61–1.75 (m, 2H, CH₂), 3.38 (t, 2H, CH₂), 3.98 (t, 2H, CH₂), 4.21 (t, 2H, OCH₂), 6.32 (d, J= 7.7 Hz, 1H, Ar-H), 7.15 (s, 1H, NH), 7.52–7.69 (m, 2H, Ar-H); ¹³C NMR (CDCl₃): δ 14.4, 19.8, 31.6, 37.9, 44.4, 66.1, 103.4, 104.7, 140.6, 150.9, 159.7, 162.9. Anal. Calcd for C₁₂H₁₇N₃O₂: C, 61.26; H, 7.28; N, 17.86. Found: C, 61.02; H, 7.09; N, 17.89.

1-(4-Butoxy-2-pyridyl)imidazolidin-2-one (3t)

Compound 3t was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 3:2, v/v); yield 6%; mp 101–103°C; IR: ν 3237 (NH), 1698 (CO), 1602, 1590, 1560, 1264 cm^-1; ¹H NMR (DMSO-d₆): δ 0.94 (t, 3H, CH₃); 1.44 (m, 2H, CH₂); 1.73 (m, 2H, CH₂); 3.32 (t, 2H, CH₂); 4.06 (m, 4H, CH₂+OCH₂); 6.71 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H); 7.82 (d, J = 2 Hz, 1H, Ar-H); 8.16 (d, J = 6 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 13.9, 18.9, 30.7, 36.6, 44.0, 67.4, 97.0, 105.7, 148.6, 154.4, 158.6, 165.6. Anal. Calcd for C₁₂H₁₇N₃O₂: C, 61.26; H, 7.28; N, 17.86. Found: C, 60.97; H, 7.11; N, 17.76.

1-(4-Isobutoxy-2-pyridyl)imidazolidin-2-one (3u)

Compound 3u was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone, 2:1:1, v/v/v); yield 5%; mp 170–171°C; IR: ν 3226 (NH), 1701 (CO), 1605, 1590, 1440, 1259; ¹H NMR (500 MHz, CDCl₃): δ 1.04 (d, J = 7 Hz, 6H, 2×CH₃), 2.12 (q, 1H, CH), 3.59 (t, 2H, CH₂), 3.82 (d, J = 6 Hz, 2H, OCH₂), 4.21 (t, 2H, CH₂), 5.16 (br s, 1H, NH), 6.54 (dd, J₁ = 2 Hz, J₂ = 5.5 Hz, 1H, Ar-H), 7.87 (d, J = 2 Hz, 1H, Ar-H), 8.10 (d, J = 5.5 Hz, 1H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): δ 19.4 (two overlapping signals), 28.3, 37.5, 44.6, 74.5, 97.7, 107.3, 147.7, 154.1, 159.3, 166.8. Anal. Calcd for C₁₂H₁₇N₃O₂: C, 61.26; H, 7.28; N, 17.86. Found: C, 61.12; H, 7.21; N, 18.01.

1,3-Bis(4-methyl-2-pyridyl)imidazolidin-2-one (4b)

Compound 4b was purified by crystallization from methanol; yield 11%; mp 188–190°C ([35], mp 189–191°C); IR and NMR data are virtually identical to those described in [35].

1,3-Bis(4-ethyl-2-pyridyl)imidazolidin-2-one (4c)

Compound 4c was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 4%; mp 155–157°C; IR: ν 1720 (CO), 1603, 1557, 1478, 1416 cm^-1; ¹H NMR (CDCl₃): δ 1.28 (t, 6H, 2×CH₃), 2.68 (q, 4H, 2×CH₂), 4.19 (s, 4H, 2×CH₂), 6.87 (d, J = 5.5 Hz, 2H, 2×Ar-H), 8.23 (m, 4H, 2×Ar-H). Anal. Calcd for C₁₇H₂₀N₄O: C, 68.89; H, 6.80; N, 18.90. Found: C, 68.76; H, 6.74; N, 18.76.

1,3-Bis(4-phenyl-2-pyridyl)imidazolidin-2-one (4f)

Compound 4f was purified by use of chromatotron (eluent: chloroform/ethyl acetate, 2:1, v/v); yield 4%; mp 224–225°C; IR: ν 1724 (CO), 1593, 1546, 1387, 1245; ¹H NMR (CDCl₃): δ 4.27 (s, 4H, CH₂), 7.25 (dd, J₁ = 1.5 Hz, J₂ = 5 Hz, 2H, 2×Ar-H), 7.48 (m, 6H, 2×Ar-H), 7.73 (m, 4H, 2×Ar-H), 8.40 (d, J = 5 Hz, 2H, 2×Ar-H), 8.64 (s, 2H, 2×Ar-H). Anal. Calcd for C₂₅H₂₀N₄O: C, 76.51; H, 5.14; N, 14.28. Found: C, 76.42; H, 5.01; N, 14.40.

1,3-Bis(4-methoxy-2-pyridyl)imidazolidin-2-one (4i)

Compound 4i was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 5%; mp 198–199°C; IR: ν 1717 (CO), 1595, 1567, 1483, 1393, 1240 cm^-1; ¹H NMR (DMSO-d₆): δ 3.84 (s, 6H, 2×OCH₃), 4.05 (s, 4H, 2×CH₂), 6.72 (dd, J₁ = 2.0 Hz, J₂ = 6 Hz, 2H, 2×Ar-H), 7.83 (d, J= 2 Hz, 2H, 2×Ar-H), 8.17 (d, J = 6 Hz, 2H, 2×Ar-H). Anal. Calcd for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N, 18.66. Found: C, 59.78; H, 5.34; N, 18.55.

1,3-Bis(4-ethoxy-2-pyridyl)imidazolidin-2-one (4k)

Compound 4k was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/triethylamine, 12:7:1, v/v/v); yield 4%; mp 141–143°C; IR: ν 1708 (CO), 1600, 1570, 1426, 1243 cm^-1; ¹H NMR (DMSO-d₆): δ 1.35 (t, 6H, 2×CH₃), 4.04 (s, 4H, 2×CH₂), 4.11 (q, 4H, 2×OCH₂), 6.69 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 2H, 2×Ar-H), 7.82 (d, J = 2 Hz, 2H, 2×Ar-H), 8.16 (d, J = 6 Hz, 2H, 2×Ar-H). Anal. Calcd for C₁₇H₂₀N₄O₃: C, 62.18; H, 6.14; N, 17.06. Found: C, 61.98; H, 6.06; N, 16.88.

1,3-Bis(4-benzyloxy-2-pyridyl)imidazolidin-2-one (4l)

Compound 4l was purified by use of flash column chromatography (eluent: chloroform/ethyl acetate, 5:4, v/v); yield 5%; mp 219–221°C; IR: ν 1719 (CO), 1590, 1476, 1394, 1237; ¹H NMR (CDCl₃): δ 4.23 (s, 4H, 2×CH₂), 5.19 (s, 4H, 2×OCH₂), 6.68 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 2H, 2×Ar-H), 7.44 (m, 10H, 2×Ar-H), 8.09 (d, J = 2 Hz, 2H, 2×Ar-H), 8.18 (d, J = 6 Hz, 2H, 2×Ar-H). Anal. Calcd for C₂₇H₂₄N₄O₃: C, 71.67; H, 5.35; N, 12.38. Found: C, 71.59; H, 5.19; N, 12.53.

Crystal data for 4l: C₂₇H₂₄N₄O₃, monoclinic, space group P2₁/c, a = 23.1330(3), b = 5.4593(1), c = 17.9505(2) Å, β = 100.195(1)°, V = 2231.18(6) Å³, Z = 4, T = 293 K, d_x = 1.347 g cm^-3, μ(Cu Kα) = 0.726 mm^-1, 23 091 data were collected up to θ_max = 76.62° for a crystal with dimensions 0.50×0.05×0.05 mm³ (R_int = 0.0255, R_σ = 0.0149). Final R indices for 3688 reflections with I>2σ(I) and 308 refined parameters are: R₁ = 0.0351, wR₂ = 0.1032 (R₁ = 0.0445, wR₂ = 0.1075 for all 4646 data). CCDC 808498.

1,3-Bis(4-isopropoxy-2-pyridyl)imidazolidin-2-one (4q)

Compound 4q was purified by use of chromatotron (eluent: chloroform/ethyl acetate/acetone, 2:1:1, v/v/v); yield 4%; mp 171–173°C; IR: ν 1720 (CO), 1598, 1477, 1395, 1238 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 1.32 (d, J = 6 Hz, 12H, 4×CH₃), 4.05 (s, 4H, 2×CH₂), 4.70–4.75 (m, 2H, 2×CH), 6.52 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 2H, 2×Ar-H), 7.80 (s, 2H, 2×Ar-H), 8.16 (d, J = 6 Hz, 2H, 2×Ar-H). Anal. Calcd for C₁₉H₂₄N₄O₃: C, 64.03; H, 6.79; N, 15.72. Found: C, 63.89; H, 6.65; N, 15.52.

1,3-Bis(4-isobutoxy-2-pyridyl)imidazolidin-2-one (4u)

Compound 4u was purified by use of chromatotron (eluent: chloroform/ethyl acetate/acetone, 2:1:1, v/v/v); yield 4%; mp 201–203°C; IR: ν 1718 (CO), 1595, 1567, 1396, 1238 cm^-1; ¹H NMR (500 MHz, CDCl₃): δ 1.06 (d, J = 6.5 Hz, 12H, 4×CH₃), 2.13 (q, 2H, 2×CH), 3.85 (d, J = 6.5 Hz, 4H, 2×OCH₂), 4.20 (s, 4H, 2×CH₂), 6.59 (d, J = 6 Hz, 2H, 2×Ar-H), 7.92 (s, 2H, 2×Ar-H), 8.14 (d, J = 6 Hz, 2H, 2×Ar-H); ¹³C NMR (125 MHz, CDCl₃): δ 19.4 (four overlapping signals), 28.4 (two overlapping signals), 41.3 (two overlapping signals), 74.6 (two overlapping signals), 98.5 (two overlapping signals), 107.6 (two overlapping signals), 148.1 (two overlapping signals), 153.7 (two overlapping signals), 154.6, 166.9 (two overlapping signals). Anal. Calcd for C₂₁H₂₈N₄O₃: C, 65.60; H, 7.34; N, 14.57. Found: C, 65.52; H, 7.26; N, 14.49.

1-(4-Ethyl-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]- triazepin-5(6H)-one (5c)

Compound 5c was purified by use of chromatotron (eluent: ethyl acetate/dichloromethane/triethylamine, 5:4:1, v/v/v); yield 6%; mp 205–207°C; IR: ν 3374, 3339, 3309, 3218 (NH), 1705 (CO), 1662, 1600, 1554, 1417, 1238 cm^-1; ¹H NMR (CDCl₃): δ 1.25 (t, 3H, CH₃), 2.65 (q, 2H, CH₂), 3.41 (m, 2H, CH₂), 3.74 (m, 2H, CH₂), 4.00 (m, 4H, 2×CH₂), 6.38 (br s, 1H, NH), 6.77 (d, J = 5 Hz, 1H, Ar-H), 8.18 (d, J = 5 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H); ¹³C NMR (CDCl₃): δ 15.0, 29.1, 43.0, 43.2, 43.6, 49.1, 114.2, 118.1, 147.5 (two overlapping signals), 153.7, 154.5, 157.0. Anal. Calcd for C₁₃H₁₇N₅O: C, 60.21; H, 6.61; N, 27.01. Found: C, 60.01; H, 6.48; N, 27.14.

1-(4,5-Dimethyl-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5d)

Compound 5d was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/methanol/triethylamine, 12:6:1:1, v/v/v/v); yield 5%; mp 239–241°C; IR: ν 3308, 3215 (NH), 1698 (CO), 1664, 1461, 1214 cm^-1; ¹H NMR (DMSO-d₆): δ 2.13 (s, 3H, CH₃), 2.20 (s, 3H, CH₃), 3.18 (m, 2H, CH₂), 3.53 (m, 2H, CH₂), 3.74 (m, 2H, CH₂), 3.86 (m, 2H, CH₂), 7.68 (t, 1H, NH), 8.00 (s, 1H, Ar-H), 8.20 (s, 1H, Ar-H). Anal. Calcd for C₁₃H₁₇N₅O: C, 60.21; H, 6.61; N, 27.01. Found: C, 59.99; H, 6.55; N, 26.86.

1-[4-(3-Phenylpropyl)-2-pyridyl]-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-one (5g)

Compound 5g was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/methanol, 13:6:1, v/v/v); yield 4%; mp 166–168°C; IR: ν 3307, 3217 (NH), 1700 (CO), 1661, 1557, 1470, 1239 cm^-1; ¹H NMR (DMSO-d₆): δ 1.86 (m, 2H, CH₂); 2.59 (m, 4H, 2×CH₂); 3.20 (m, 2H, CH₂); 3.54 (m, 2H, CH₂); 3.76 (m, 2H, CH₂); 3.89 (m, 2H, CH₂); 6.83 (d, J = 5 Hz, 1H, Ar-H); 7.25 (m, 5H, Ar-H); 7.68 (t, 1H, NH); 8.17 (d, J = 5 Hz, 1H, Ar-H); 8.35 (s, 1H, Ar-H). Anal. Calcd for C₂₀H₂₃N₅O: C, 68.74; H, 6.63; N, 20.04. Found: C, 68.61; H, 6.59; N, 19.81.

1-(4-Methoxy-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5i)

Compound 5i was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/triethylamine, 12:7:1, v/v/v); yield 5%; mp 239–241°C; IR: ν 3305, 3213 (NH), 1707 (CO), 1604, 1447, 1384, 1221 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 3.19 (m, 2H, CH₂), 3.53 (m, 2H, CH₂), 3.74 (t, 2H, CH₂), 3.77 (s, 3H, OCH₃), 3.90 (t, 2H, CH₂), 6.60 (dd, J₁ = 1.9 Hz, J₂ = 5.9 Hz, 1H, Ar-H), 7.70 (br s, 1H, NH), 8.10 (d, J = 5.9 Hz, 1H, Ar-H), 8.18 (s, 1H, Ar-H); ¹³C NMR (50 MHz, DMSO-d₆): δ 41.7, 42.3, 42.7, 49.0, 55.3, 99.0, 104.7, 142.3, 148.4, 154.7, 155.7, 166.0. Anal. Calcd for C₁₂H₁₅N₅O₂: C, 55.16; H, 5.79; N, 26.80. Found: C, 55.02; H, 5.68; N, 26.48.

1-(4-Ethoxy-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5k)

Compound 5k was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/triethylamine, 12:7:1, v/v/v); yield 12%; mp 221–223°C; IR: ν 3302, 3220 (NH), 1707 (CO), 1661, 1597, 1569, 1470, 1223 cm^-1; ¹H NMR (DMSO-d₆): δ 1.33 (t, 3H, CH₃); 3.19 (m, 2H, CH₂); 3.54 (m, 2H, CH₂); 3.74–3.00 (m, 2H, CH₂); 3.88 (m, 2H, CH₂); 4.05 (q, 2H, OCH₂); 6.57 (dd, J₁ = 2.5 Hz, J₂ = 5.5 Hz, 1H, Ar-H); 7.07 (t, 1H, NH); 8.08 (d, J = 5.5 Hz, 1H, Ar-H); 8.15 (d, J = 2.5 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 14.6, 41.7, 42.3, 42.7, 49.0, 63.4, 99.5, 105.0, 142.3, 148.4, 154.7, 155.7, 165.2. Anal. Calcd for C₁₃H₁₇N₅O₂: C, 56.71; H, 6.22; N, 25.44. Found: C, 56.56; H, 6.15; N, 25.63.

1-(4-Benzyloxy-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5l)

Compound 5l was purified by use of the flash column chromatography (chloroform/ethyl acetate, 5:4, v/v); yield 10%; mp 211–212°C; IR: ν 3307, 3218 (NH), 1701 (CO), 1660, 1560, 1463, 1353 cm^-1; ¹H NMR (DMSO-d₆): δ 3.23 (m, 2H, CH₂), 3.54 (m, 2H, CH₂), 3.73 (t, 2H, CH₂), 3.89 (t, 2H, CH₂), 5.14 (s, 2H, CH₂), 6.67 (dd, J₁ = 1.5 Hz, J₂ = 5.5 Hz, 1H, Ar-H), 7.38 (m, 5H, Ar-H), 7.69 (t, 1H, NH), 8.09 (d, J = 5.5 Hz, 1H, Ar-H), 8.27 (d, J = 1.5 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ 41.7, 42.3, 42.6, 49.0, 69.4, 99.7, 105.4, 128.2 (two overlapping signals), 128.3, 128.7 (two overlapping signals), 136.6, 142.2, 148.4, 154.7, 155.7, 165.0. Anal. Calcd for C₁₈H₁₉N₅O₂: C, 64.08; H, 5.68; N, 20.76. Found: C, 63.92; H, 5.56; N, 20.56.

1-(4-Methoxy-6-methyl-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-one (5m)

Compound 5m was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone/methanol/triethylamine, 14:2:2:1:1, v/v/v/v/v); yield 6%; mp 219–222°C; IR: ν 3306 (NH), 1685 (CO), 1664, 1592, 1234 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 2.34 (s, 3H, CH₃), 3.18 (m, 2H, CH₂), 3.34 (s, 3H, OCH₃), 3.55 (m, 2H, CH₂), 3.74 (m, 2H, CH₂), 3.90 (m, 2H, CH₂), 6.48 (d, J = 2 Hz, 1H, Ar-H), 7.69 (t, 1H, NH), 8.01 (d, J = 2 Hz, 1H, Ar-H). Anal. Calcd for C₁₃H₁₇N₅O₂: C, 56.71; H, 6.22; N, 25.44. Found: C, 56.59; H, 5.98; N, 25.74.

Crystal data for 5m: C₁₃H₁₇N₅O₂, triclinic, space group P-1, a = 8.1785(5), b = 8.8308(5), c = 9.7563(5) Å, α = 81.049(5), β = 74.533(5), γ = 73.360(5)°, V = 648.27(6) Å³, Z = 2, T = 293 K, d_x = 1.410 g cm^-3, μ(Cu Kα) = 0.818 mm^-1, 6677 data were collected up to θ_max = 75.45° for a crystal with dimensions 0.3×0.3×0.2 mm³ (R_int = 0.0132, R_σ = 0.0124). Final R indices for 2342 reflections with I>2σ(I) and 199 refined parameters are: R₁ = 0.0366, wR₂ = 0.0981 (R₁ = 0.0389, wR₂ = 0.0998 for all 2542 data). The iminoethylene fragment of the seven-membered ring shows a minor disorder. CCDC 778725.

1-(4-Isopropoxy-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5q)

Compound 5q was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone/methanol/triethylamine, 14:2:2:1:1, v/v/v/v/v); yield 4%; mp 218–220°C; IR: ν 3302, 3214 (NH), 1708 (CO), 1664, 1596, 1385, 1224 cm^-1; ¹H NMR (500 MHz, DMSO-d₆): δ 1.28 (d, J = 6.0 Hz, 6H, 2×CH₃); 3.19–3.30 (m, 2H, CH₂), 3.53–3.56 (m, 2H, CH₂), 3.74 (m, 2H, CH₂), 3.89 (m, 2H, CH₂), 4.63 (m, 1H, OCH), 6.56 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H), 7.67 (t, 1H, NH), 8.07 (d, J = 6 Hz, 1H, Ar-H), 8.12 (d, J = 2 Hz, 1H, Ar-H). Anal. Calcd for C₁₄H₁₉N₅O₂: C, 58.12; H, 6.62; N, 24.21. Found: C, 57.94; H, 6.51; N, 23.99.

1-(4-Isobutoxy-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5u)

Compound 5u was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate/acetone/methanol/triethylamine, 14:2:2:1:1, v/v/v/v/v); yield 9%; mp 195–196°C; IR: ν 3311, 3232 (NH), 1707 (CO), 1591, 1416, 1385, 1222 cm^-1; ¹H NMR (500 MHz, CDCl₃): δ 0.98 (d, J = 6.8 Hz, 6H, 2×CH₃); 2.04 (m, 1H, CH); 3.19 (m, 2H, CH₂); 3.56 (m, 2H, CH₂); 3.77 (m, 4H, CH₂+OCH₂); 3.91 (t, 2H, CH₂); 6.59 (dd, J₁ = 2 Hz, J₂ = 6 Hz, 1H, Ar-H); 7.69 (t, 1H, NH); 8.09 (d, J = 6 Hz, 1H, Ar-H); 8.17 (s, 1H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): δ 19.7 (two overlapping signals), 28.5, 43.0, 43.3, 43.5, 49.2, 74.6, 100.1, 106.2, 143.0, 148.5, 155.1, 157.0, 166.5. Anal. Calcd for C₁₅H₂₁N₅O₂: C, 59.39; H, 6.98; N, 23.09. Found: C, 59.23; H, 6.92; N, 22.91.

1-(4-Chloro-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5v)

Compound 5v was purified by crystallization from isopropanol; yield 4%; mp 265–269°C; IR: ν 3305, 3211 (NH), 1697 (CO), 1664, 1578, 1245 cm^-1; ¹H NMR (DMSO-d₆): δ 3.20 (m, 2H, CH₂), 3.57 (m, 2H, CH₂), 3.76 (m, 2H, CH₂), 3.93 (m, 2H, CH₂), 7.07 (dd, J₁ = 2 Hz, J₂ = 5.5 Hz, 1H, Ar-H), 7.75 (t, 1H, NH), 8.27 (d, J = 5.5 Hz, 1H, Ar-H), 8.67 (d, J = 2 Hz, 1H, Ar-H). Anal. Calcd for C₁₁H₁₂ClN₅O: C, 49.72; H, 4.55; N, 26.36. Found: C, 49.54; H, 4.36; N, 25.99.

1-(4-Bromo-2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-one (5w)

Compound 5w was purified by crystallization from ethanol; yield 11%; mp 263–266°C; IR: ν 3307, 3209 (NH), 1698 (CO), 1664, 1572, 1385, 1243 cm^-1; ¹H NMR (DMSO-d₆): δ 3.20 (m, 2H, CH₂), 3.57 (m, 2H, CH₂), 3.76 (m, 2H, CH₂), 3.90 (m, 2H, CH₂), 7.20 (dd, J₁ = 2 Hz, J₂ = 5.5 Hz, 1H, Ar-H); 7.73 (t, 1H, NH), 8.19 (d, J = 5.5 Hz, 1H, Ar-H); 8.82 (d, J = 2 Hz, 1H, Ar-H). Anal. Calcd for C₁₁H₁₂BrN₅O: C, 42.60; H, 3.90; N, 22.58. Found: C, 42.48; H, 3.78; N, 22.36.

1-(2-Quinolyl)imidazolidin-2-one (7a)

Compound 7a was prepared by reacting quinoline N-oxide (6a) with 2-chloro-4,5-dihydroimidazole (2), as described previously [34], and purified by crystallization from ethanol; yield 36%, mp 245–247°C ([34], mp 244–246°C).

Crystal data for 7a: C₁₂H₁₁N₃O, monoclinic, space group P2₁/c, a = 19.7129(19), b = 6.6524(7), c = 7.7984(8) Å, β = 98.710(9)°, V = 1010.87(18) Å³, Z = 4, T = 293 K, d_x = 1.401 g cm^-3, μ(Mo Kα) = 0.093 mm^-1, 6373 data were collected up to θ_max = 25.02° for a crystal with dimensions 0.5×0.5×0.3 mm³ (R_int = 0.0231, R_σ = 0.0219). Final R indices for 1234 reflections with I>2σ(I) and 150 refined parameters are: R₁ = 0.0387, wR₂ = 0.0997 (R₁ = 0.0657, wR₂ = 0.1233 for all 1775 data). CCDC 780760.

1-(6-Methoxy-2-quinolyl)imidazolidin-2-one (7b)

Compound 7b was purified by crystallization from N,N-dimethylformamide/methanol (1:1, v/v); yield 65%; mp 254–257°C; IR: ν 3252 (NH), 1694 (CO), 1605, 1500, 1421, 1365, 1268, 1228 cm^-1; ¹H NMR (DMSO-d₆): δ 3.44 (t, 2H, CH₂), 3.86 (s, 3H, OCH₃), 4.11 (t, 2H, CH₂), 7.30 (m, 3H, Ar-H+NH), 7.68 (m, 1H, Ar-H), 8.13 (d, J = 9 Hz, 1H, Ar-H), 8.42 (d, J = 9 Hz, 1H, Ar-H). Anal. Calcd for C₁₃H₁₃N₃O₂: C, 64.19; H, 5.39; N, 17.27. Found: C, 64.02; H, 5.18; N, 17.60.

Corresponding author: Franciszek Sączewski, Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk, Poland, e-mail: saczew@gumed.edu.pl

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Received: 2013-8-7

Accepted: 2013-8-26

Published Online: 2013-10-02

Published in Print: 2013-10-01

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Artikel in diesem Heft

https://doi.org/10.1515/hc-2013-0125

Schlagwörter für diesen Artikel

cytotoxic activity; 1-(2-pyridyl)imidazolidin-2-ones; 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b]- [1,3,5]triazepin-5(6H)-ones; synthesis; theoretical study; X-ray crystallography

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