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Synthesis 2024; 56(20): 3199-3205
DOI: 10.1055/s-0043-1775386
paper

Regio- and Chemoselective Synthesis of 4,6-Dithia-1,2,9-triazaspiro[4.4]non-2-en-8-ones through an Ultrasound-Promoted One-Pot Sequential Pseudo-Five-Component Reaction

Abdolali Alizadeh∗
,
Ebrahim Amir Chelebari
,
Reza Rezaiyehraad

We are grateful to the Research Council of Tarbiat Modares University for supporting this work.
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Abstract

Spiro-heterocycles have attracted significant interest due to their unique biological properties with fewer side effects compared to traditional drugs. Herein, a novel method is reported for the synthesis of a series of spiro-heterocycles possessing a quinoline motif. The strategy utilizes rhodanine derivatives, hydrazonoyl chlorides, and 2-chloroquinoline-3-carbaldehyde, and proceeds via a one-pot sequential pseudo-five-component reaction. The reactions are found to proceed in a regioselective and chemoselective manner.


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Key words

rhodanine - hydrazonoyl chlorides - 2-chloroquinoline-3-carbaldehyde - 4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-ones - five-component reaction - regioselective - chemoselective - ultrasound

1,3-Dipolar cycloaddition reactions play a prominent role in the preparation of pharmacologically important five-membered heterocycles and natural products. Furthermore, they are also important for the production of cycloadducts that can be used in subsequent transformations and for the installation of several stereocenters in a one-pot synthetic method. In addition, the straightforward access to diverse 1,3-dipolar species that can react with a wide range of dipolarophiles has made 1,3-dipolar reactions an efficient and trusted synthetic tool. Consequently, 1,3-dipolar reactions have found a privileged position in the toolbox of synthetic chemists.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

The major motivation for the synthesis of spiro-heterocyclic compounds is their diverse biological activities.[6] [11] [12] For example, 4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one A exhibits good antimicrobial features (Figure [1]).[13] In addition, antitumor, antifungal, anti-inflammatory, antibacterial, anticonvulsant, antiparasitic, and anti-anxiety activities are among the biological properties of spiro-heterocycles.[11] [12] The presence of a spiro carbon in spiro-heterocycles affects their biological properties.[14] Consequently, many studies have been directed toward synthesizing these compounds through various approaches. In this regard, the one-pot multicomponent 1,3-dipolar cycloaddition reaction is one of the most efficient.[6] [15] [16]

Zoom Image
Figure 1 Examples of bioactive thiazolidine derivatives

The establishment of chemical libraries of complex compounds with highly diverse biologically important heterocyclic skeletons represents a prominent and challenging goal of modern synthetic organic chemistry.[15] Regarding their pharmacological importance, quinoline derivatives have been used directly or as precursors to design and develop novel pharmaceutical agents.[17] [18] [19] These compounds can play a key role in the development of anticancer drugs.[20,21] Antibacterial, antimalarial, antitubercular, anti-inflammatory, antifungal, and anticancer activities are among the most important medicinal activities of quinoline derivatives.[17,22] Two examples of quinoline derivatives with biological activity are depicted in Figure [1].[22] Similarly, thiadiazole[23] [24] [25] and thiazolidine[15] , [26] [27] [28] derivatives have also found privileged positions in medicinal chemistry. Thiadiazole derivatives possess significant biological properties such as antimicrobial, anticonvulsant, anti-inflammatory, antioxidant, antidepressant, and anticancer.[24] [25] [29] [30] Similarly, thiazolidine derivatives also exhibit antiviral, anti-inflammatory, antifungal, antimicrobial, antibacterial, and anticancer activities.[31] [32] [33] The biological importance of the above heterocyclic compounds has encouraged research on the synthesis of quinoline derivatives[34] [35] [36] [37] and spiro-heterocycles[38] [39] [40] [41] through dipolar cycloaddition reactions[34] [37] [42] in order to generate spiro-heterocycles possessing thiadiazole, thiazolidine, and 2-chloroquinoline motifs.

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Scheme 1 Synthesis of spiro-heterocycle 7a via a pseudo-five-component reaction

Initially, the rhodanine 3a was synthesized by reacting benzylamine (1a), carbon disulfide, and ethyl bromoacetate (2) in acetonitrile under sonication conditions (20 KHz). Next, quinoline 4 was synthesized from an acetanilide precursor through the Vilsmeier–Haack reaction. Subsequently, a mixture of rhodanine 3a and quinoline 4 was ultrasonicated (20 KHz) in MeCN in the presence of Et3N for 50 minutes and then hydrazonoyl chloride 6a was added to the reaction medium, followed by 20 minutes of ultrasonication (20 KHz). The progress of the reactions was monitored by TLC. Finally, the desired product, 6,4-dithia-9,2,1-triazaspiro[4.4]non-2-en-8-one 7a, was obtained by filtering the resulting precipitate and washing with MeCN (Scheme [1]).

After confirming the product structure by spectral methods, the reaction was successfully performed through a one-pot method (Scheme [2]).

The reaction in Scheme [2] was considered as a model system for optimizing the conditions, and the reaction progress was evaluated in the presence of different solvents and bases. According to Table [1], the best yield was achieved in the presence of Et3N (as the base) in MeCN under sonication (Table [1], entry 7). In the case of other solvents, the reaction efficiency was low or the product did not precipitate. In addition to the efficient formation and easy purification of the product, the solvent also affected the reaction time.

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Scheme 2 Synthesis of spiro-heterocycle 7a via a one-pot pseudo-five-component reaction

Using the optimized reaction conditions, five additional spiro-heterocyclic derivatives 7b–f were synthesized to investigate the efficiency and diversity of this method and its ability to tolerate various substituents. The structures and yields of 7a and the derivatives 7b–f are listed in Table [2].

Table 1 Optimization of the Reaction Conditions

Entry

Solvent

Base

Method

Time (h)

Yield (%)a

1

MeCN

Et3N

r.t.

16

65

2

EtOH

Et3N

r.t.

16

45

3

EtOH

KOH

r.t.

10

20

4

EtOH

K2CO3

r.t.

12

25

5

DMF

Et3N

r.t.

16

40

6

CH2Cl2

Et3N

r.t.

16

50

7

MeCN

Et3N

ultrasound

1.5

80

8

EtOH

Et3N

ultrasound

2.5

55

9

DMF

Et3N

ultrasound

2.5

45

a Isolated yields.

The structures of compounds 7a–f were assessed by IR, 1H NMR and 13C NMR spectroscopy, mass spectrometry and elemental analysis. Furthermore, the structure of compound 7a was verified by X-ray crystallographic analysis (Figure [2]). In the mass spectrum of compound 7a, a mass ion was observed at m/z 554, and the IR spectrum of compound 7a clearly showed stretching vibrations due to C=O (1698 cm–1), C=N and C=C (1595, 1580, 1559 and 1489 cm–1) bonds.

Zoom Image
Figure 2 The ORTEP diagram of 7a

The characteristic peaks in the 1H NMR spectrum of 7a include signals related to the diastereotopic hydrogens of the methylene group with an ABq pattern at 4.80 and 4.93 ppm, and singlet peaks at 7.84 and 8.28 ppm corresponding to the olefinic hydrogen and CH4 of the quinoline ring, respectively. Other protons of the quinoline ring with expected multiplicities at 7.65 (triplet), 7.82 (triplet), 7.93 (doublet), and 8.12 (doublet) ppm were also observed. The signals related to the phenyl moieties were also consistent with the established structure of 7a. The 13C NMR of 7a includes 27 distinct peaks that fully match the proposed structure. The peaks at 47.04 (methylene group), 106.39 (spiro carbon), 146.38 and 149.89 (C8a′ and C2′ of the quinoline ring), and 163.71 (carbonyl group) are among the characteristic signals.

According to the spectral data and the ORTEP diagram of 7a, the reaction proceeded in a chemo- and regioselective manner. This outcome is related to the nature of the 1,3-dipolar cycloaddition reactions of nitrilimines derived from hydrazonoyl halides with double bonds. Previous reports have shown that this reaction is influenced by the interaction of the HOMO of the nitrilimine and the LUMO of the dipolarophile (double bond) as well as the relative magnitude of the orbital coefficients in these frontier orbitals leading to the regioselectivity of the reaction.[43] [44] Moreover, nitrilimines tend to react with the most polar double bonds of a compound. In intermediate 5a (Scheme [3]), the polarity of the double bonds increases in the following order: C=C, C=O, and C=S.[15] , [43] [44] [45]

Table 2 Synthesis of 4,6-Dithia-1,2,9-triazaspiro[4.4]non-2-en-8-ones 7a–f a

a Isolated yields are given.

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Scheme 3 The proposed mechanism for the formation of 7a

Accordingly, Scheme [3] shows the proposed mechanism for the formation of 7a. Initially, the reaction between benzylamine (1a), CS2, and ethyl bromoacetate (2) results in the formation of intermediate II. Subsequently, rhodanine 3a is obtained through an intramolecular 5-exo-trig cyclization of intermediate II. Subsequently, 5a is formed via the condensation reaction of rhodanine 3a and quinoline 4 in the presence of Et3N. Finally, the product 7a is obtained by the cycloaddition reaction of 5a with a nitrilimine, which is formed in situ from hydrazonoyl chloride 6a.

In conclusion, this study has reported an efficient one-pot pseudo-five-component reaction to prepare 4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-ones bearing a 2-chloroquinoline motif under ultrasound irradiation using benzylamine derivatives, CS2, ethyl bromoacetate, 2-chloroquinoline-3-carbaldehyde, and hydrazonoyl chloride derivatives. All the synthesized compounds are potentially valuable due to their thiadiazole, thiazolidine, and quinoline motifs, which are of pharmaceutical importance. This synthetic process proceeds in a regio- and chemoselective manner. The easy product purification and high tolerance to different functional groups are significant advantages of this method.

The starting materials were supplied by Merck or Aldrich. Melting points were determined by using an Electrothermal 9100 apparatus. IR spectra were recorded on a NICOLET FT-IR 100 spectrophotometer. 1H NMR (500.13 MHz) and 13C NMR (125.77 MHz) spectra were obtained on a Bruker DRX-500 AVANCE instrument in DMSO-d 6 as the solvent. Mass spectra were recorded with an Agilent Technologies 5975C VL MSD mass spectrometer at 70 eV. Elemental analysis was performed using a Heraeus CHN–O–Rapid analyzer.


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(5R,7Z)-9-Benzyl-7-[(2-chloroquinolin-3-yl)methylene]-1,3-diphenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7a); Typical Procedure

A mixture of benzylamine (1a) (1 mmol, 0.107 g), CS2 (1.2 mmol, 0.076 g), and ethyl bromoacetate (2) (1.2 mmol, 0.167 g) in acetonitrile (8 mL) was sonicated at a frequency of 20 KHz for 20 minutes. Next, 2-chloroquinoline-3-carbaldehyde (4) (1 mmol, 0.192 g) was added to the reaction mixture along with Et3N (1 mmol, 0.101 g), and the mixture was ultrasonicated for another 50 minutes. The hydrazonoyl chloride 6a (1 mmol, 0.231 g) was subsequently added and the resulting mixture was subjected to ultrasound irradiation for another 20 minutes. The progress of each step was monitored by TLC. The obtained yellow precipitate was filtered using a sintered glass funnel, washed several times with acetonitrile and dried to give product 7a. Derivatives 7b–f were synthesized in a similar fashion.

Yield: 0.47 g (80%); yellow powder; mp 180–182 °C.

IR (KBr): 1698 (C=O), 1595 and 1580 (C=N), 1559 and 1489 (Ar), 747 (C–Cl), 590 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 4.80 (d, 2 J HH = 15.8 Hz, 1 H, CH2), 4.93 (d, 2 J HH = 15.8 Hz, 1 H, CH2), 7.10 (t, 3 J HH = 7.4 Hz, 1 H, CH para of Ph), 7.19 (d, 3 J HH = 8.0 Hz, 2 H, CH ortho of Ph), 7.22 (d, 3 J HH = 7.2 Hz, 2 H, CH ortho of Bn), 7.23 (t, 3 J HH = 7.2 Hz, 1 H, CH para of Bn), 7.27 (t, 3 J HH = 7.5 Hz, 2 H, CH meta of Ph), 7.30 (t, 3 J HH = 7.5 Hz, 2 H, CH meta of Bn), 7.49–7.50 (m, 3 H, 2 CH meta and CH para of Ph), 7.61 (d, 3 J HH = 6.8 Hz, 2 H, CH ortho of Ph), 7.65 (t, 3 J HH = 7.6 Hz, 1 H, CH7 of quinoline), 7.82 (t, 3 J HH = 8.0 Hz, 1 H, CH6 of quinoline), 7.84 (s, 1 H, CH), 7.93 (d, 3 J HH = 8.4 Hz, 1 H, CH5 of quinoline), 8.12 (d, 3 J HH = 8.2 Hz, 1 H, CH8 of quinoline), 8.28 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 47.04 (CH2), 106.39 (C5 spiro ), 120.55 (CH para of Ph), 120.73 (CH ortho of Ph), 125.44 (CH), 126.57 (CH meta of Ph), 126.71 (CH6′ of quinoline), 127.01 (CH5 ′of quinoline), 128.02 (C3′ of quinoline), 128.08 (CH para of Bn), 128.50 (CH8′ of quinoline), 128.54 (CH meta of Ph), 128.75 (CH ortho of Bn), 128.85 (C4a′ of quinoline), 129.14 (CH7′ of quinoline), 129.49 (CH meta of Bn), 129.65 (CH ortho of Ph), 130.14 (C ipso of Ph), 131.05 (CH para of Ph), 132.40 (CH4 ′of quinoline), 135.69 (C ipso of Bn), 137.93 (C ipso of Ph), 140.62 (C7), 143.25 (C3), 146.38 (C8a′ of quinoline), 149.89 (C2′ of quinoline), 163.71 (C8=O).

MS (EI, 70 eV): m/z (%) = 554 (M+ – Cl), 463 (7), 420 (21), 360 (13), 227 (22), 194 (86), 165 (24), 91 (100), 64 (36).

Anal. Calcd for C33H23ClN4OS2 (590.10): C, 67.05; H, 3.92; N, 9.48. Found: C, 67.01; H, 3.94; N, 9.50.

Crystal data for 7a (CCDC 2231969): C33H23ClN4OS2, formula weight = 591.12, triclinic, space group = P-1, a = 10.616(2) Å, b = 12.030(2) Å, c = 13.452(3) Å, α = 66.95(2), β = 67.94(3), γ = 69.09(3), V = 1420.0(7) Å3, Z = 2, density (calcd) = 1.382 mg/m3, F(000) = 612, crystal dimensions = 0.2 × 0.15 × 0.1 mm, radiation, MoKα (λ = 0.71073 Å), 1.711 ≤ 2θ ≤ 26.361, intensity data were collected at 290 K with a Bruker APEX area-detector diffractometer, employing the ω/2θ scanning technique, in the range of –11 ≤ h ≤ 13, –15 ≤ k ≤ 14, –16 ≤ l ≤ 15; the structure was solved by a direct method, all non-hydrogen atoms were positioned and anisotropic thermal parameters refined from 5373 observed reflections with R(int) = 0.0638 by a full-matrix least-squares technique converged to R1 = 0.0601, and wR2 = 0.1670 [I > 2σ(I)].


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(5R,7Z)-9-Benzyl-3-(4-chlorophenyl)-7-[(2-chloroquinolin-3-yl)methylene]-1-phenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7b)

Yield: 0.50 g (80%); yellow powder; mp 202–204 °C.

IR (KBr): 1685 (C=O), 1596 and 1577 (C=N), 1560 and 1492 (Ar), 828 and 744 (C–Cl), 699 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 4.78 (d, 2 J HH = 16.1 Hz, 1 H, CH2), 4.92 (d, 2 J HH = 16.1 Hz, 1 H, CH2), 7.10 (t, 3 J HH = 7.3 Hz, 1 H, CH para of Ph), 7.18 (d, 3 J HH = 8.0 Hz, 2 H, CH ortho of Ph), 7.22 (t, 3 J HH = 6.4 Hz, 2 H, CH meta of Ph), 7.22 (t, 3 J HH = 6.4 Hz, 1 H, CH para of Bn), 7.26 (d, 3 J HH = 8.5 Hz, 2 H, CH ortho of Bn), 7.29 (t, 3 J HH = 7.6 Hz, 2 H, CH meta of Bn), 7.54 (d, 3 J HH = 8.5 Hz, 2 H, CH meta of Ar), 7.60 (d, 3 J HH = 8.5 Hz, 2 H, CH ortho of Ar), 7.64 (t, 3 J HH = 7.5 Hz, 1 H, CH7 of quinoline), 7.82 (t, 3 J HH = 7.9 Hz, 1 H, CH6 of quinoline), 7.84 (s, 1 H, CH), 7.93 (d, 3 J HH = 8.4 Hz, 1 H, CH5 of quinoline), 8.11 (d, 3 J HH = 8.2 Hz, 1 H, CH8 of quinoline), 8.27 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 47.02 (CH2), 106.59 (C5 spiro ), 120.65 (CH para of Ph), 120.69 (CH ortho of Ph), 125.50 (CH), 126.67 (CH6′ of quinoline), 126.99 (CH5′ of quinoline), 128.04 (CH para of Bn), 128.08 (C3 ′of quinoline), 128.19 (CH meta of Ar), 128.49 (CH8′ of quinoline), 128.56 (CH meta of Ph), 128.74 (CH ortho of Bn), 129.02 (C4a′ of quinoline), 129.12 (CH7′ of quinoline), 129.49 (CH meta of Bn), 129.69 (CH ortho of Ar), 132.40 (CH4′ of quinoline), 135.45 (C ipso -Cl), 135.63 (C ipso of Bn), 137.92 (C ipso of Ph), 140.46 (C7), 142.04 (C3), 146.38 (C8a′ of quinoline), 149.86 (C2′ of quinoline), 163.68 (C8=O).

MS (EI, 70 eV): m/z (%) = 588 (M+ – Cl), 454 (3), 360 (10), 255 (5), 228 (68), 165 (7), 137 (6), 91 (100), 51 (25).

Anal. Calcd for C33H22Cl2N4OS2 (624.06): C, 63.36; H, 3.54; N, 8.96. Found: C, 63.40; H, 3.52; N, 8.94.


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(5R,7Z)-9-Benzyl-7-[(2-chloroquinolin-3-yl)methylene]-3-(4-me­thylphenyl)-1-phenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7c)

Yield: 0.45 g (75%); yellow powder; mp 170–172 °C (dec.).

IR (KBr): 1704 (C=O), 1593 and 1488 (C=N), 1562 and 1370 (Ar), 816 (C–Cl), 691 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 2.57 (s, 3 H, CH3), 4.81 (d, 2 J HH = 15.7 Hz, 1 H, CH2), 4.94 (d, 2 J HH = 15.7 Hz, 1 H, CH2), 7.11 (t, 3 J HH = 7.4 Hz, 1 H, CH para of Ph), 7.19 (d, 3 J HH = 8.5 Hz, 2 H, CH ortho of Ph), 7.22 (t, 3 J HH = 6.7 Hz, 2 H, CH meta of Bn), 7.23 (t, 3 J HH = 6.7 Hz, 1 H, CH para of Bn), 7.24 (d, 3 J HH = 6.7 Hz, 2 H, CH ortho of Bn), 7.28 (t, 3 J HH = 7.8 Hz, 2 H, CH meta of Ph), 7.32 (d, 3 J HH = 8.1 Hz, 2 H, CH of Ar), 7.52 (d, 3 J HH = 7.9 Hz, 2 H, CH of Ar), 7.68 (t, 3 J HH = 7.6 Hz, 1 H, CH7 of quinoline), 7.85 (t, 3 J HH = 7.8 Hz, 1 H, CH6 of quinoline), 7.85 (s, 1 H, CH), 7.97 (d, 3 J HH = 8.5 Hz, 1 H, CH5 of quinoline), 8.18 (d, 3 J HH = 8.5 Hz, 1 H, CH8 of quinoline), 8.34 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 21.55 (CH3), 47.07 (CH2), 105.40 (C5 spiro ), 119.39 (CH ortho of Ph), 121.50 (CH para of Ph), 124.34 (CH), 126.28 (CH of Ar), 126.77 (CH6′ of quinoline), 127.32 (CH5 ′of quinoline), 127.50 (C ipso of Ar), 127.66 (C4a′ of quinoline), 127.85 (CH para of Bn), 127.90 (C3′ of quinoline), 128.35 (CH meta of Ph), 128.40 (CH8 ′of quinoline), 128.48 (CH7′ of quinoline), 128.96 (CH ortho of Bn), 128.99 (CH meta of Bn), 129.57 (CH of Ar), 131.35 (CH4′ of quinoline), 135.20 (C ipso of Bn), 137.32 (C ipso of Ph), 140.69 (C7), 140.71 (Cipso -Me), 143.17 (C3), 146.61 (C8a′ of quinoline), 150.64 (C2′ of quinoline), 163.76 (C8=O).

MS (EI, 70 eV): m/z (%) = 554 (M+ – Cl, 2), 396 (3), 357 (8), 244 (8), 208 (88), 183 (7), 140 (7), 91 (100), 65 (13).

Anal. Calcd for C34H25ClN4OS2 (604.12): C, 67.48; H, 4.16; N, 9.26. Found: C, 67.50; H, 4.18; N, 9.22.


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(5R,7Z)-9-Benzyl-7-[(2-chloroquinolin-3-yl)methylene]-3-(4-methoxyphenyl)-1-phenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7d)

Yield: 0.48 g (77%); yellow powder; mp 145–147 °C (dec.).

IR (KBr): 1689 (C=O), 1602 and 1579 (C=N), 1561 and 1489 (Ar), 751 (C–Cl), 698 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 3.82 (s, 3 H, OCH3), 4.81 (d, 2 J HH = 15.7 Hz, 1 H, CH2), 4.95 (d, 2 J HH = 15.8 Hz, 1 H, CH2), 7.05 (d, 3 J HH = 8.5 Hz, 2 H, CH of Ar), 7.10 (t, 3 J HH = 7.5 Hz, 1 H, CH para of Ph), 7.19 (d, 3 J HH = 8.2 Hz, 2 H, CH ortho of Ph), 7.20–7.31 (m, 7 H, 5 CH of Bn and 2 CH meta of Ph ), 7.56 (d, 3 J HH = 8.7 Hz, 2 H, CH of Ar), 7.67 (t, 3 J HH = 7.4 Hz, 1 H, CH7 of quinoline), 7.84 (s, 1 H, CH), 7.85 (t, 3 J HH = 7.4 Hz, 1 H, CH6 of quinoline), 7.96 (d, 3 J HH = 8.4 Hz, 1 H, CH5 of quinoline), 8.16 (d, 3 J HH = 8.5 Hz, 1 H, CH8 of quinoline), 8.32 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 47.05 (CH2), 55.94 (OCH3), 106.44 (C5 spiro ), 115.08 (CH of Ar), 120.44 (CH para of Ph), 120.73 (CH ortho of Ph), 122.58 (C ipso of Ar), 125.30 (CH), 126.74 (CH6′ of quinoline), 127.05 (CH5′ of quinoline), 128.01 (CH para of Bn), 128.08 (C3′ of quinoline), 128.24 (CH of Ar), 128.47 (CH meta of Ph), 128.53 (CH8′ of quinoline), 128.77 (CH ortho of Bn), 128.96 (C4a′ of quinoline), 129.18 (CH7′ of quinoline), 129.46 (CH meta of Bn), 132.43 (CH4′ of quinoline), 135.76 (C ipso of Bn), 137.97 (C ipso of Ph), 140.80 (C7), 143.80 (C3), 146.39 (C8a′ of quinoline), 149.88 (C2′ of quinoline), 161.52 (Cipso -OMe), 163.79 (C8=O).

MS (EI, 70 eV): m/z (%) = 584 (M+ – Cl, 5), 396 (5), 360 (22), 224 (93), 183 (12), 133 (14), 91 (100), 65 (13).

Anal. Calcd for C34H25ClN4O2S2 (620.11): C, 65.74; H, 4.06; N, 9.02. Found: C, 65.75; H, 4.04; N, 9.03.


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(5R,7Z)-9-Benzyl-7-[(2-chloroquinolin-3-yl)methylene]-3-(2,4-dichlorophenyl)-1-phenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7e)

Yield: 0.48 g (73%); yellow powder; mp 178–180 °C.

IR (KBr): 1686 (C=O), 1596 and 1539 (C=N), 1566 and 1494 (Ar), 776, 758 and 735 (C–Cl), 696 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 4.79 (d, 2 J HH = 15.5 Hz, 1 H, CH2), 4.90 (d, 2 J HH = 15.7 Hz, 1 H, CH2), 7.10 (t, 3 J HH = 8.1 Hz, 1 H, CH para of Ph), 7.17 (d, 3 J HH = 8.5 Hz, 2 H, CH ortho of Ph), 7.20 (t, 3 J HH = 8.0 Hz, 2 H, CH meta of Ph), 7.26 (t, 3 J HH = 7.5 Hz, 2 H, CH meta of Bn), 7.31 (d, 3 J HH = 7.8 Hz, 2 H, CH ortho of Bn), 7.48 (d, 3 J HH = 7.5 Hz, 1 H, CH of Ar), 7.53 (t, 3 J HH = 7.3 Hz, 1 H, CH para of Bn), 7.60 (d, 3 J HH = 7.7 Hz, 1 H, CH of Ar), 7.66 (t, 3 J HH = 6.9 Hz, 1 H, CH7 of quinoline), 7.84 (s, 1 H, CH of Ar), 7.84 (t, 3 J HH = 7.2 Hz, 1 H, CH6 of quinoline), 7.88 (s, 1 H, CH), 7.95 (d, 3 J HH = 8.6 Hz, 1 H, CH5 of quinoline), 8.15 (d, 3 J HH = 8.3 Hz, 1 H, CH8 of quinoline), 8.32 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 46.95 (CH2), 105.79 (C5 spiro ), 120.32 (CH ortho of Ph), 120.72 (CH para of Ph), 125.33 (CH), 126.72 (CH6′ of quinoline), 127.04 (CH5′ of quinoline), 128.02 (CH para of Bn), 128.08 (C3′ of quinoline), 128.32 (CH of Ar), 128.51 (C ipso of Ar), 128.65 (CH8′ of quinoline), 128.67 (CH ortho of Bn and CH meta of Ph), 128.93 (C4a′ of quinoline), 129.17 (CH7′ of quinoline), 129.49 (CH meta of Bn), 130.90 (CH of Ar), 131.23 (CH of Ar), 131.48 (C ipso -2-Cl), 132.27 (C ipso -4-Cl), 132.42 (CH4′ of quinoline), 135.63 (C ipso of Bn), 137.94 (C ipso of Ph), 140.03 (C3), 140.44 (C7), 146.41 (C8a′ of quinoline), 149.88 (C2′ of quinoline), 163.45 (C8=O).

MS (EI, 70 eV): m/z (%) = 588 (M+ – 2Cl, trace), 396 (15), 360 (67), 299 (9), 255 (21), 228 (52), 183 (26), 137 (21), 91 (100), 65 (20).

Anal. Calcd for C33H21Cl3N4OS2 (660.02): C, 60.05; H, 3.21; N, 8.49. Found: C, 60.03; H, 3.22; N, 8.50.


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(5R,7Z)-7-[(2-Chloroquinolin-3-yl)methylene]-9-(4-methylbenzyl)-3-(4-methylphenyl)-1-phenyl-4,6-dithia-1,2,9-triazaspiro[4.4]non-2-en-8-one (7f)

Yield: 0.51 g (83%); yellow powder; mp 150–152 °C (dec.).

IR (KBr): 1682 (C=O), 1639 and 1595 (C=N), 1575 and 1492 (Ar), 744 (C–Cl), 590 (C–S) cm–1.

1H NMR (500.13 MHz, DMSO-d 6): δ = 2.23 (s, 3 H, Me of Bn), 2.37 (s, 3 H, Me of Ar), 4.74 (d, 2 J HH = 15.6 Hz, 1 H, CH2), 4.89 (d, 2 J HH = 15.6 Hz, 1 H, CH2), 7.03 (d, 3 J HH = 7.8 Hz, 2 H, CH ortho of Ph), 7.10 (t, 3 J HH = 7.4 Hz, 1 H, CH para of Ph), 7.17 (d, 3 J HH = 7.7 Hz, 2 H, CH meta of Bn), 7.18 (d, 3 J HH = 7.7 Hz, 2 H, CH ortho of Bn), 7.28 (t, 3 J HH = 7.2 Hz, 2 H, CH meta of Ph), 7.31 (d, 3 J HH = 8.5 Hz, 2 H, CH of Ar), 7.50 (d, 3 J HH = 8.3 Hz, 2 H, CH of Ar), 7.67 (t, 3 J HH = 7.0 Hz, 1 H, CH7 of quinoline), 7.83 (s, 1 H, CH), 7.85 (t, 3 J HH = 7.0 Hz, 1 H, CH6 of quinoline), 7.96 (d, 3 J HH = 8.3 Hz, 1 H, CH5 of quinoline), 8.16 (d, 3 J HH = 6.7 Hz, 1 H, CH8 of quinoline), 8.31 (s, 1 H, CH4 of quinoline).

13C NMR (125.77 MHz, DMSO-d 6): δ = 21.15 (Me of Bn), 21.48 (Me of Ar), 46.85 (CH2), 106.38 (C5 spiro ), 120.45 (CH para of Ph), 120.75 (CH ortho of Ph), 125.35 (CH), 126.76 (CH6′ of quinoline), 127.05 (CH5′ of quinoline), 127.44 (C ipso of Ar), 128.08 (C3′ of quinoline), 128.50 (CH ortho of Bn), 128.52 (CH8′ of quinoline), 128.95 (C4a′ of quinoline), 129.18 (CH7′ of quinoline), 129.30 (CH meta of Ph), 129.45 (CH meta of Bn), 130.18 (CH of Ar), 132.42 (CH4′ of quinoline), 137.18 (Cipso -Me of Bn), 137.97 (C ipso of Ph), 140.69 (C7), 141.05 (Cipso -Me of Ar), 143.39 (C3), 146.40 (C8a′ of quinoline), 149.87 (C2′ of quinoline), 163.74 (C8).

MS (EI, 70 eV): m/z (%) = 582 (M+ – Cl, trace), 410 (5), 371 (15), 332 (6), 244 (20), 208 (77), 183 (7), 135 (18), 91 (100), 65 (18).

Anal. Calcd for C35H27ClN4OS2 (618.13): C, 67.89; H, 4.40; N, 9.05. Found: C, 67.85; H, 4.43; N, 9.06.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0043-1775386.
  • Supporting Information

Corresponding Author

Abdolali Alizadeh
Department of Chemistry, Tarbiat Modares University
P.O. Box 14115-175, Tehran
Iran   

Publication History

Received: 21 January 2024

Accepted after revision: 03 July 2024

Article published online:
22 July 2024

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Zoom Image
Figure 1 Examples of bioactive thiazolidine derivatives
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Scheme 1 Synthesis of spiro-heterocycle 7a via a pseudo-five-component reaction
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Scheme 2 Synthesis of spiro-heterocycle 7a via a one-pot pseudo-five-component reaction
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Figure 2 The ORTEP diagram of 7a
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Scheme 3 The proposed mechanism for the formation of 7a