Regio- and stereoselective route to bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives via 1,3-dipolar cycloaddition under sonication

Haider Behbehani; Kamal M. Dawood; Hamada Mohamed Ibrahim; Noha S. Mostafa

doi:10.1016/j.arabjc.2017.05.016

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Original article

11 (

); 1053-1060

doi:

10.1016/j.arabjc.2017.05.016

Regio- and stereoselective route to bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives via 1,3-dipolar cycloaddition under sonication

Haider Behbehani^⁎, Kamal M. Dawood, Hamada Mohamed Ibrahim, Noha S. Mostafa

Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait

⁎Corresponding author. Fax: +965 248 164 82. drhaider.b@gmail.com (Haider Behbehani)

Received: 2017-3-22, Accepted: 2017-5-16, Published: 2017-11-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

Bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives are synthesized regio- and stereoselectively via 1,3-dipolar cycloaddition of the bis-hydrazonoyl chlorides with 4-arylidenepyrazol-5-one derivatives. The cycloaddition route is optimized under both ultrasonic irradiation and conventional heating modes. The regio- and stereoselectivity of the cycloadducts are confirmed by spectral and X-ray crystallographic analysis.

Keywords

Bis-hydrazonoyl chlorides

Spiro-pyrazolines

Ultrasonic irradiation

1,3-Dipolar cycloaddition

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1 Introduction

Recently, there has been an increasing interest in the chemistry of spiropyrazoline compounds because of their synthetic and biological significances (Farghaly et al., 2016; Dadiboyena et al., 2014; Santos, 2014; Dawood and Fuchigami, 2005 ). Spiropyrazoline moiety constitutes the core structure of several antiviral (Chan et al., 2014), antibacterial (Dawood, 2005a, 2005b), and anti-cancer agents (Monteiro et al., 2014) as well as acetyl-CoA carboxylase inhibitors (Kamata and Yamashita, 2009). Some commercially available drugs such as celecoxib and rimonabant encompass pyrazole moiety (Penning et al., 1997; Deng and Mani, 2008). The advantages of application of the environmentally sustainable ultrasonic technique in organic synthesis, in materials science, in medicinal chemistry and in life sciences are well established, where ultrasonic is superior over conventional heating due to high yields, high selectivity and shorter reaction time (Mason and Lorimer, 2002; Cravotto and Cintas, 2006; Bazgir et al., 2010; Ruano et al., 2011; Banerjee, 2017a,2017b; Puri et al., 2013 ). Recently, we conducted a series of research works on regioselective 1,3-dipolar cycloaddition reactions of bis-hydrazonoyl chlorides with various dipolarophiles and led to interesting heterocyclic systems (Behbehani et al., 2015; Dawood, 2005a, 2005b; Dawood and Elwan, 2004; Dawood et al., 2003; Shawali et al., 1994, 1993; Farag et al., 1994, 1993; Abdel-Wahab and Dawood, 2012 ). The aim of this work is to investigate a feasible regio- and stereoselective concerted access to bis-[spiro-pyrazoline-4,5′-pyrazoline] derivatives by examining the factors affecting the optimization of reaction conditions, such as types of substrates, heating modes (ultrasonic irradiation and conventional heating), solvents and types of bases. The twin 1,3-dipolar cycloaddition reaction, we report herein, is superior where it leads to products with two quaternary carbons (both spiro centers) in a one-pot reaction.

2 Material and methods

2.1

2.1 General

Melting points were recorded on a Griffin melting point apparatus and are reported uncorrected. IR spectra were recorded using KBr disks using a Perkin-Elmer System 2000 FT-IR spectrophotometer. ¹H NMR (400 MHz) or (600 MHz) and ¹³C NMR (100 MHz) or (150 MHz) spectra were recorded at 25 °C using CDCl₃ or DMSO-d₆ as solvent with TMS as internal standard on a Bruker DPX 400 or 600 super-conducting NMR spectrometer. Chemical shifts are reported in ppm. Low-resolution electron impact mass spectra [MS (EI)] and high-resolution electron impact mass spectra [HRMS (EI)] were performed on high resolution GC-MS (DFS) thermo spectrometers at 70.1 eV using magnetic sector mass analyzer. Follow up of the reactions and checking homogeneity of the prepared compounds were made by thin layer chromatography (TLC). The crystal structures were determined by a Rigaku R-AXIS RAPID diffractometer and Bruker X8 Prospector and the single crystal data collections were made by using Cu Kα radiation. The data were collected at room temperature. The structure was solved by direct methods and was expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. The structure was solved and refined using the Bruker SHELXTL Software Package (Structure solution program- SHELXS-97 and Refinement program- SHELXL-97) (Sheldrick, 2008). Data were corrected for the absorption effects using the multi-scan method (SADABS). Sonication was performed in MKC6, Guyson ultrasonic bath (Model-MKC6, operating frequency 38 kHz ± 10% and an output power of 110 W) with digital timer (6 s to 100 min.) and heater allows solution heating to be set from 20 °C to 80 °C in 1 °C increments. The inside tank dimensions are 150 × 300 × 150 mm (length x width x depth) with a fluid capacity of 6 liters. N,N′-Di-(aryl)ethane(bis-hydrazonoyl dichlorides) 1a-c (Dawood, 1992) and 4-arylidenepyrazol-3-one 3a-f derivatives were prepared following the literature procedures (Ma et al., 2010).

2.2

2.2 Synthesis of bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives 4a-l

2.2.1

2.2.1 General method A

To a mixture of the appropriate bis-hydrazonoyl chloride 1a–c (2 mmol) and the appropriate 4-arylidenepyrazol-3-one derivative 3a–f (4 mmol each) in the appropriate dry solvent (ethanol, benzene, toluene or chloroform) (25 mL), triethylamine (0.6 mL, 4 mmol) was added portion-wise. The mixture was heated at refluxing temperature and the reaction was followed up by TLC and continued for 36 h, then left to cool to room temperature. The solvent was removed, in each case, under reduced pressure and the residue was triturated with methanol to give yellow or pale-brown colored products. The solid products that formed were filtered off, washed with ethanol, dried and recrystallized from dioxane/ethanol (3:1) to afford the corresponding bis-[spiro-pyrazoline-4,5′-pyrazoline] derivatives 4a–l as pure products.

2.2.2

2.2.2 General method B

To a mixture of the appropriate bis-hydrazonoyl chloride 1a–c (2 mmol) and the appropriate 4-arylidenepyrazol-3-one derivative 3a–f (4 mmol each) in the appropriate dry solvent (ethanol, benzene, toluene or chloroform) (25 mL), triethylamine (0.6 mL, 4 mmol) was added portion-wise. The reaction mixture was irradiated in MKC6, Guyson ultrasonic cleaning bath (Model-MKC6, operating frequency 38 kHz ± 10% and an output power of 110 W) for 3 h at 70 °C. The reaction was controlled by TLC and continued until the starting substrates were completely consumed, then left to cool to room temperature. The solid products that formed were filtered off, washed with ethanol, dried and recrystallized from dioxane/ethanol (3:1) to afford the corresponding bis-[spiro-pyrazoline-4,5′-pyrazoline] derivatives 4a-l as pure products.

2.2.3

2.2.3 Bis-[1,1′,4′-triphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4a)

As yellow crystals, mp. 271–272 °C; IR (KBr): ν/cm⁻¹ 1725 (CO); ¹H NMR (CDCl₃): δ = 1.52 (s, 6H, H of CH₃), 5.54 (s, 2H, pyrazole-CH), 6.57 (d, J = 8.4 Hz, 4H, Ar-H), 6.85 (t, J = 7.2 Hz, 2H, Ar-H), 7.07 (t, J = 7.2 Hz, 4H, Ar-H), 7.28–7.33 (m, 6H, Ar-H), 7.37–7.39 (m, 10H, Ar-H) and 7.91 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (CDCl₃): δ = 15.60 (CH₃), 64.13 (pyrazole-CH), 80.07 (spiro-C), 114.20, 119.08, 122.09, 125.75, 128.61, 128.91, 128.99, 129.07, 129.39, 133.09, 137.68, 142.30, 142.97, 159.50 and 171.49 (Ar-C and CO); MS (EI): m/z (%) 760 (M⁺+2, 14.19), 759 (M⁺+1, 50.27), 758 (M⁺, 100.00); HRMS (EI): m/z calcd. for C₄₈H₃₈N₈O₂ (M⁺) 758.3112, found: 758.3113. Crystal Data, C₄₈H₃₈N₈O₂, M = 758.89, monoclinic, a = 10.6770(5) Å, b = 10.2775(5) Å, c = 18.5032(9) Å, V = 1958.21(16) Å³, α = γ = 90°, β = 105.325(3)°, space group: P121/c1, Z = 4, D_calc = 1.287 g cm⁻³, No. of reflection measured = 3355, θ_max = 66.35°, R1 = 0.0661 (The crystallographic data).

2.2.4

2.2.4 Bis-[4′-(4-chlorophenyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4b)

As yellow crystals, mp. >300 °C; IR (KBr): ν/cm⁻¹ 1723 (CO); ¹H NMR (DMSO-d₆): δ = 2.17 (s, 6H, H of CH₃), 5.83 (s, 2H, pyrazole-CH), 6.40 (d, J = 8.4 Hz, 4H, Ar-H), 6.85 (t, J = 7.2 Hz, 2H, Ar-H), 7.13 (t, J = 7.2 Hz, 4H, Ar-H), 7.21 (t, J = 8.0 Hz, 2H, Ar-H), 7.36–7.39 (m, 12H, Ar-H) and 7.44 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.54 (CH₃), 65.09 (pyrazole-CH), 79.12 (spiro-C), 114.49, 118.61, 122.30, 125.75, 127.98, 129.00, 129.03, 129.43, 129.61, 131.68, 133.29, 137.11, 142.17, 159.77 and 167.24 (Ar-C and CO); MS (EI): m/z (%) 828 (M⁺+2, 22.05), 827 (M⁺+1, 14.95), 826 (M⁺, 26.73); HRMS (EI): m/z calcd. for C₄₈H₃₆Cl₂N₈O₂ (M⁺) 826.2333, found: 826.2336.

2.2.5

2.2.5 Bis-[4′-(4-nitrophenyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4c)

As yellow crystals, mp. 280–281 °C; IR (KBr): ν/cm⁻¹ 1722 (CO); ¹H NMR (DMSO-d₆): δ = 2.20 (s, 6H, H of CH₃), 6.05 (s, 2H, pyrazole-CH), 6.42 (d, J = 8.4 Hz, 4H, Ar-H), 6.87 (t, J = 7.2 Hz, 2H, Ar-H), 7.15 (t, J = 7.8 Hz, 4H, Ar-H), 7.30–7.52 (m, 6H, Ar-H), 7.71–7.82 (m, 8H, Ar-H) and 8.35 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.47 (CH₃), 58.71 (pyrazole-CH), 79.34 (spiro-C), 114.08, 118.66, 122.66, 125.88, 129.12, 129.21, 129.73, 129.78, 130.53, 136.52, 137.00, 142.31, 142.70, 157.70 and 169.91(Ar-C and CO); MS (EI): m/z (%) 850 (M⁺+2, 17.65), 849 (M⁺+1, 55.02), 848 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₄₈H₃₆N₁₀O₆ (M⁺) 848.2814, found 848.2813.

2.2.6

2.2.6 Bis-[4′-(4-anisyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4d)

As yellow crystals, mp. >300 °C; IR (KBr): ν/cm⁻¹ 1726 (CO); ¹H NMR (DMSO-d₆): δ = 2.16 (s, 6H, H of CH₃), 3.74 (s, 6H, H of OCH₃) 5.71 (s, 2H, pyrazole-CH), 6.42 (d, J = 8.4 Hz, 4H, Ar-H), 6.84 (t, J = 7.2 Hz, 2H, Ar-H), 6.91 (d, J = 8.4 Hz, 4H, Ar-H), 7.12 (t, J = 7.8 Hz, 4H, Ar-H), 7.29–7.25 (m, 6H, Ar-H) and 7.36–7.41 (m, 8H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 13.34 (CH₃), 55.11 (OCH₃), 59.78 (pyrazole-CH), 79.29 (spiro-C), 113.22, 118.65, 121.59, 124.83, 125.55, 128.97, 129.20, 129.43, 130.82, 136.80, 142.61, 142.96, 158.95, 159.89 and 167.59 (Ar-C and CO); MS (EI): m/z (%) 820 (M⁺+2, 17.38), 819 (M⁺+1, 52.19), 818 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₅₀H₄₂N₈O₄ (M⁺): 818.3324, found: 818.3324.

2.2.7

2.2.7 Bis-[1,1′-diphenyl-4′-(4-tolyl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4e)

As yellow crystals, mp. >300 °C; IR (KBr): ν/cm⁻¹ 1722 (CO); ¹H NMR (DMSO-d₆): δ = 2.16 (s, 6H, H of CH₃), 2.29 (s, 6H, H of CH₃), 5.71 (s, 2H, pyrazole-CH), 6.40 (d, J = 8.4 Hz, 4H, Ar-H), 6.86 (t, J = 7.2 Hz, 2H, Ar-H), 7.11 (t, J = 8.4 Hz, 4H, Ar-H), 7.16 (d, J = 8.4 Hz, 4H, Ar-H), 7.20–7.22 (m, 6H, Ar-H) and 7.37–7.38 (m, 8H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.15 (CH₃), 19.96 (CH₃), 62.25 (pyrazole-CH), 79.63 (spiro-C), 114.39, 118.87, 125.69, 128.39, 128.65, 128.85, 129.07, 129.79, 131.39, 133.36, 137.07, 140.53, 142.85, 158.52 and 170.54 (Ar-C and CO); MS (EI): m/z (%) 788 (M⁺+2, 15.09), 787 (M⁺+1, 53.68), 786 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₅₀H₄₂N₈O₂ (M⁺): 786.3425, found: 786.3425.

2.2.8

2.2.8 Bis-[1,1′-diphenyl-4′-(thiophen-2-yl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4f)

As yellow crystals, mp. >300 °C; IR (KBr): ν/cm⁻¹ 1721 (CO); ¹H NMR (DMSO-d₆): δ = 2.17 (s, 6H, H of CH₃), 6.18 (s, 2H, pyrazole-CH), 6.50 (d, J = 7.8 Hz, 4H, Ar-H), 6.87 (t, J = 7.2 Hz, 2H, Ar-H), 7.04 (t, J = 4.8 Hz, 2H, thiophene H), 7.14–7.18 (m, 6H, Ar-H), 7.22 (t, J = 7.8 Hz, 2H, Ar-H), 7.41 (t, J = 7.8 Hz, 4H, Ar-H), 7.50 (d, J = 7.8 Hz, 4H, Ar-H) and 7.53 (d, J = 4.8 Hz, 2H, thiophene H); ¹³C NMR (DMSO-d₆): δ = 13.40 (CH₃), 55.02 (pyrazole-CH), 79.12 (spiro-C), 113.25, 118.64, 121.80, 125.62, 126.59, 126.84, 128.98, 129.04, 129.51, 134.23, 136.81, 141.87, 142.40, 159.60 and 167.18 (Ar-C and CO); MS (EI): m/z (%) 772 (M⁺+2, 12.18), 771 (M⁺+1, 25.99), 770 (M⁺, 51.78); HRMS (EI): m/z Calcd. for C₄₄H₃₄N₈O₂S₂ (M⁺): 770.2241, found: 770.2241.

2.2.9

2.2.9 Bis-[1,4′-diphenyl-1′-(4-tolyl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4g)

As yellow crystals, mp. 257–258 °C; IR (KBr): ν/cm⁻¹ 1723 (CO); ¹H NMR (DMSO-d₆): δ = 1.34 (s, 6H, H of CH₃), 2.12 (s, 6H, H of CH₃), 5.68 (s, 2H, pyrazole-CH), 6.43 (d, J = 8.4 Hz, 4H, Ar-H), 6.86 (d, J = 8.4 Hz, 4H, Ar-H), 7.27 (t, J = 7.8 Hz, 2H, Ar-H), 7.35–7.49 (m, 14H, Ar-H) and 7.78 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.20 (CH₃), 20.01 (CH₃), 62.28 (pyrazole-CH), 79.65 (spiro-C), 114.39, 118.86, 125.72, 128.42, 128.69, 128.88, 129.11, 129.84, 131.44, 133.38, 137.09, 140.46, 142.88, 158.55 and 170.55 (Ar-C and CO); MS (EI): m/z (%) 788 (M⁺+2, 17.89), 787 (M⁺+1, 56.97), 786 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₅₀H₄₂N₈O₂ (M⁺): 786.3425, found: 786.3423.

2.2.10

2.2.10 Bis-[4′-(4-chlorophenyl)-1′-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4h)

As yellow crystals, mp. 285–286 °C; IR (KBr): ν/cm⁻¹ 1726 (CO); ¹H NMR (DMSO-d₆): δ = 1.36 (s, 6H, H of CH₃), 2.15 (s, 6H, H of CH₃), 5.76 (s, 2H, pyrazole-CH), 6.55 (d, J = 8.4 Hz, 4H, Ar-H), 7.00 (d, J = 8.4 Hz, 4H, Ar-H), 7.29 (t, J = 7.8 Hz, 2H, Ar-H), 7.36–7.50 (m, 8H, Ar-H),7.61 (d, J = 8.4 Hz, 4H, Ar-H) and 7.80 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.53 (CH₃), 19.98 (CH₃), 60.09 (pyrazole-CH), 79.28 (spiro-C), 114.05, 118.89, 125.71, 129.05, 129.89, 129.99, 130.85, 131.43, 132.50, 133.47, 137.09, 140.43, 142.93, 158.16 and 170.21 (Ar-C and CO); MS (EI): m/z (%) 857 (M⁺+3, 38.68), 856 (M⁺+2, 55.91), 855 (M⁺+1, 79.37), 854 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₅₀H₄₀Cl₂N₈O₂ (M⁺): 854.2646, found: 854.2645.

2.2.11

2.2.11 Bis-[4′-(4-nitrophenyl)-1′-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4i)

As yellow crystals, mp. 262–263 °C; IR (KBr): ν/cm⁻¹ 1721 (CO); ¹H NMR (DMSO-d₆): δ = 1.41 (s, 6H, H of CH₃), 2.14 (s, 6H, H of CH₃), 6.00 (s, 2H, pyrazole-CH), 6.31 (d, J = 8.4 Hz, 4H, Ar-H), 6.92 (d, J = 8.4 Hz, 4H, Ar-H), 7.18 (t, J = 7.8 Hz, 2H, Ar-H), 7.37 (t, J = 7.8 Hz, 4H, Ar-H), 7.50 (t, J = 7.8 Hz, 4H, Ar-H), 7.78 (d, J = 8.4 Hz, 4H, Ar-H) and 8.25 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.40 (CH₃), 19.94 (CH₃), 60.77 (pyrazole-CH), 79.29 (spiro-C), 114.60, 118.44, 125.89, 129.11, 129.95, 130.48, 131.45, 136.55, 139.92, 140.74, 141.58, 142.16, 147.20, 159.63 and 167.18 (Ar-C and CO); MS (EI): m/z (%) 877 (M⁺+1, 5.12), 876 (M⁺, 17.85); HRMS (EI): m/z Calcd. for C₅₀H₄₀N₁₀O₆ (M⁺): 876.3127, found: 876.3129. Crystal Data, C₅₀H₄₀N₁₀O₆, M = 876.93, monoclinic, a = 21.616(3) Å, b = 12.810(1) Å, c = 16.191(2) Å, V = 4428.7(8) Å³, α = γ = 90°, β = 98.934(7)°, space group: C2/c, Z = 5, D_calc = 1.315 g cm⁻³, No. of reflection measured = 11,602, θ_max = 50.0°, R1 = 0.0701 (The crystallographic data).

2.2.12

2.2.12 Bis-[1′,4′-di-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4j)

As yellow crystals, mp. 286–287 °C; IR (KBr): ν/cm⁻¹ 1729 (CO); ¹H NMR (DMSO-d₆): δ = 1.35 (s, 6H, H of CH₃), 2.13 (s, 6H, H of CH₃), 2.34 (s, 6H, H of CH₃), 5.62 (s, 2H, pyrazole-CH), 6.45 (d, J = 7.8 Hz, 4H, Ar-H), 6.94 (d, J = 7.8 Hz, 4H, Ar-H), 7.17–7.38 (m, 10H, Ar-H),7.49 (d, J = 7.2 Hz, 4H, Ar-H) and 7.78 (d, J = 7.8 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.50 (CH₃), 20.19 (CH₃), 20.92 (CH₃), 62.25 (pyrazole-CH), 79.77 (spiro-C), 114.52, 119.01, 125.85, 128.93, 129.27, 129.40, 130.01, 130.60, 131.50, 137.32, 137.92, 140.78, 143.17, 158.87 and 170.84 (Ar-C and CO); MS (EI): m/z (%) 816 (M⁺+2, 17.98), 815 (M⁺+1, 59.22), 814 (M⁺, 100.00); HRMS (EI): m/z Calcd. for C₅₂H₄₆N₈O₂ (M⁺): 814.3738, found: 814.3734.

2.2.13

2.2.13 Bis-[1′-(4-chlorophenyl)-3-methyl-4′-(4-nitrophenyl)-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4k)

As yellow crystals, mp. >300 °C; IR (KBr): ν/cm⁻¹ 1731 (CO); ¹H NMR (DMSO-d₆): δ = 2.23 (s, 6H, H of CH₃), 6.12 (s, 2H, pyrazole-CH), 6.39 (d, J = 8.4 Hz, 4H, Ar-H), 7.18–7.26 (m, 8H, Ar-H),7.36 (d, J = 8.4 Hz, 8H, Ar-H), 7.65 (t, J = 7.2 Hz, 2H, Ar-H) and 8.26 (d, J = 8.4 Hz, 4H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 13.32 (CH₃), 58.87 (pyrazole-CH), 79.17 (spiro-C), 114.79, 118.75, 125.27, 125.96, 128.16, 128.85, 129.04, 129.58, 136.35, 137.31, 140.26, 140.81, 142.12, 147.28, 159.41 and 166.79 (Ar-C and CO); MS (EI): m/z (%) 919 (M⁺+3, 21.95), 918 (M⁺+2, 31.45), 917 (M⁺+1, 44.12), 916 (M⁺, 54.17); HRMS (EI): m/z Calcd. for C₄₈H₃₄Cl₂N₁₀O₆(M⁺): 916.2034, found: 916.2032. Crystal Data, moiety formula: C₄₈H₃₄Cl₂N₁₀O₆, M = 917.78, monoclinic, a = 22.3975(10) Å, b = 15.6733(7) Å, c = 18.9319(9) Å, V = 6122.6(5) Å³, α = γ = 90°, β = 112.889(3)°, space group: C 1 2/c 1, Z = 4, D_calc = 1.291 g cm⁻³, No. of reflection measured = 28,968, θ_max = 66.54°, R1 = 0.0628 (The crystallographic data).

2.2.14

2.2.14 Bis-[1,4′-di-(4-chlorophenyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4l)

As yellow crystals, mp. 255–256 °C; IR (KBr): ν/cm⁻¹ 1728 (CO); ¹H NMR (DMSO-d₆): δ = 1.33 (s, 6H, H of CH₃), 5.89 (s, 2H, pyrazole-CH), 6.67 (d, J = 7.8 Hz, 4H, Ar-H) and 7.22–7.80 (m, 22H, Ar-H); ¹³C NMR (DMSO-d₆): δ = 15.48 (CH₃), 59.77 (pyrazole-CH), 78.90 (spiro-C), 115.33, 119.02, 125.81, 126.07, 129.02, 129.19, 129.58, 130.78, 132.33, 133.67, 137.02, 141.48, 143.96, 157.91 and 169.69 (Ar-C and CO); MS (EI): m/z (%) 897 (M⁺+3, 5.4700), 896 (M⁺+2, 9.34), 895 (M⁺+1, 3.74), 894 (M⁺, 6.84); HRMS (EI): m/z Calcd. for C₄₈H₃₄Cl₄N₈O₂(M⁺): 894.1553, found: 894.1554.

3 Results and discussion

Our initial attempts were to synthesize the bis-hydrazonoyl chlorides 1a-c (Dawood, 1992), and 4-arylidene-pyrazolin-5-ones 3a–f (Ma et al., 2010) using reported protocols in literature. Then, optimization conditions for 1,3-dipolar cycloaddition reaction of the bis-nitrilimine 2a, [generated in situ from the bis-hydrazonoyl chloride 1a with base] with double equivalent of 4-benzylidene-3-methyl-1-phenylpyrazolin-5-one (3a), as a model example of dipolar cycloaddition, was examined in details under various reaction conditions (different solvents, bases and heating modes) and the results are depicted in Table 1. Effect of solvents (ethanol, benzene, toluene and chloroform), bases (TEA, DBU, DABCO, CsF) and modes of heating (ultrasonic irradiation and conventional heating) were the factors to be evaluated. Using ethanol as reaction solvent and triethylamine (TEA) as a base, the 1,3-dipolar cycloaddition reaction of the bis-nitrilimine 2a with 3a was completed after 3 hours under ultrasonic irradiation at 70 °C (110 W) with 79% isolated yield. However, carrying out the reaction under conventional heating resulted in only 28% isolated yield (entry 1, Table 1). Using benzene or toluene in the presence of TEA the reaction did not complete and led to the formation of the product 4a in 15 and 22% yields, respectively, under ultrasonic irradiation, and 7 and 14% yields, respectively, under conventional heating mode (entries 2–4, Table 1). Using ethanol as solvent in the presence of DABCO or DBU were not appropriate conditions for the cycloaddition reaction, where the product 4a was obtained in 45 and 51%, respectively, under ultrasonic and 18 and 20%, respectively, under conventional heating (entries 5–6, Table 1). The use of EtOH/CsF or chloroform/TEA resulted in no reaction at all under both conventional heating and ultrasonic irradiation and the starting substrate 3a was, in all cases, completely recovered (entries 4, 7, Table 1). Therefore, ethanol proved itself as the proper solvent for conducting this 1,3-dipolar cycloaddition reaction under ultrasonic condition and the efficiency of ultrasonic irradiation (using EtOH/TEA) was much higher than conventional heating mode, where higher yields in shorter time. Two possible regioisomeric cycloadducts 4a and 5a can be assigned for the reaction product, however spectral data (¹H and ¹³C NMR) exhibited a characteristic singlet signal at δ 5.54 (in ¹H NMR) and δ 64.13 (in ¹³C NMR) due to the pyrazole-4-CH but not pyrazole-5-CH [16,17]. The regio- and stereoselectivity of the reaction product bis-[3-methyl-1,1′,4′-triphenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4a) was unambiguously confirmed by X-ray single crystal structural analysis (The crystallographic data) (Fig. 1). The synthetic route to 4a is depicted in Scheme 1.

Table 1 Optimization of the reaction conditions for synthesis of 4a.

Entry	Solvent	Base	Yield% of 4a^a
Entry	Solvent	Base	))) [3 h]	Δ [36 h]
1	Ethanol	TEA	79	28^b
2	Benzene	TEA	15^b	7^b
3	Toluene	TEA	22^b	14^b
4	Chloroform	TEA	Trace^c	Trace^c
5	Ethanol	DABCO	45	18^b
6	Ethanol	DBU	51^b	20^b
7	Ethanol	CsF	Trace^c	Trace^c

a Reaction conditions: bis-hydrazonoyl chlorides 1a (2 mmoles), 4-benzylidenepyrazol-3-one 3a (4 mmoles), Et₃N (4 mmoles) and solvent (25 mL) under sonication (at 70 °C for 3 h) or conventional heating (at reflux for 36 h).

b 4-Benzylidenepyrazol-3-one 3a was detected.

c 4-Benzylidenepyrazol-3-one 3a was completely recovered.

ORTEP plot of the X-ray crystallographic data determined for 4a.

Regio- and stereoselective synthesis of bis-[spiro-pyrazoline-4,5′-pyrazoline] 4a.

Once the reaction condition was standardized, we extended the 1,3-dipolar cycloaddition reaction of the bis-nitrilimine 2a with various 4-arylidene-pyrazolin-5-ones 3b–f. Thus, treatment of bis-nitrilimine 2a with 4-arylidene-pyrazolin-5-ones 3b–f in 1:2 molar ratio, in the presence of EtOH/Et₃N under both ultrasonic irradiation and conventional heating afforded the corresponding bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives 4b–f as outlined in Scheme 2. Ultrasonic irradiation was found to be superior again where the yields of the cycloadducts 4b–f varied between 73 and 88% (after 3 h of irradiation), however the yields decreased dramatically under conventional heating ranging between 19 and 35% yields (after 36 h heating) as shown in Table 2, entries 1–6. Structures of the cycloadducts 4b-f were elucidated based on their detailed spectral analyses (IR, MS, HRMS, ¹H and ¹³C NMR).

Regioselective synthesis of the bis-[spiro-pyrazoline-4,5′-pyrazolines] 4a–l.

Table 2 1,3-Dipolar cycloaddition of 1a-c with 4-arylidenepyrazol-3-ones 3a–f.

Entry	Reactants	Products	Ar¹	Ar²	Yield% 4a-l^a
Entry	Reactants	Products	Ar¹	Ar²	))) [3 h]^b	Δ [36 h]^c
1	1a + 3a	4a	C₆H₅	C₆H₅	79	28
2	1a + 3b	4b	C₆H₅	4-ClC₆H₄	81	26
3	1a + 3c	4c	C₆H₅	4-NO₂C₆H₄	88	35
4	1a + 3d	4d	C₆H₅	4-MeOC₆H₄	80	34
5	1a + 3e	4e	C₆H₅	4-MeC₆H₄	83	25
6	1a + 3f	4f	C₆H₅	C₄H₃S	73	19
7	1b + 3a	4g	4-MeC₆H₄	C₆H₅	78	23
8	1b + 3b	4h	4-MeC₆H₄	4-ClC₆H₄	82	30
9	1b + 3c	4i	4-MeC₆H₄	4-NO₂C₆H₄	85	27
10	1b + 3e	4j	4-MeC₆H₄	4-MeC₆H₄	72	21
11	1c + 3b	4k	4-ClC₆H₄	4-NO₂C₆H₄	77	24
12	1c + 3c	4l	4-ClC₆H₄	4-ClC₆H₄	90	33

a Reaction conditions: bis-hydrazonoyl chlorides 1a–c (2 mmoles), 4-arylidenepyrazol-3-one 3a–f (4 mmoles), Et₃N (4 mmoles) and EtOH (25 mL) under sonication (at 70 °C for 3 h) or conventional heating (at reflux for 36 h).

b 4-Arylidenepyrazol-3-ones 3a–f were completely consumed.

c 4-Arylidenepyrazol-3-one 3a–f were detected by TLC.

Next, we applied the same cycloaddition protocol in the reaction of the bis-nitrilimine 2b with 4-arylidene-pyrazolin-5-ones 3a,b,c,e as shown in Table 2 and Scheme 2. In all cases, the corresponding bis-[spiro-pyrazoline-4,5′-pyrazoline] 4g–j were obtained in good yields (72–81%) after 3 h of ultrasonic irradiation, however the yields reduced sharply under conventional heating to become 21–30% after 36 h (entries 7–10, Table 2). The cycloadducts 4g–j were well characterized by IR, MS, HRMS, ¹H NMR, and ¹³C NMR and by measuring the single crystal X-ray analysis of compound 4i as depicted in Fig. 2.

ORTEP plot of the X-ray crystallographic data determined for 4i.

The reaction conditions developed for the regio- and stereoselective 1,3-dipolar cycloaddition of 1a,b with 2a–f also employed in the cycloaddition of the bis-nitrilimine 2c with 4-arylidene-pyrazolin-5-ones 3b,c and the results are outlined in Table 2 (entries 11 and 12) and Scheme 2. Thus, conducted the reaction of 2c with 3b,c in ethanol/Et₃N system led to the formation of the bis-[spiro-pyrazoline-4,5′-pyrazoline] derivatives 4k,l in 77 and 90% yields, respectively, (under ultrasonic irradiation) and in 24 and 33% yields, respectively, (under conventional heating) as shown in Table 2, entries 11–12. Spectral data of the reaction products 4k,l and the single crystal X-ray analysis of compound 4l (Fig. 3) (The crystallographic data) provided exclusive evidence for the regio- and stereoselective manner of the cycloaddition process.

ORTEP plot of the X-ray crystallographic data determined for 4k.

4 Conclusions

We showed a one-pot regio- and stereoselective route to several bis-[spiro-pyrazoline-4,5′-pyrazoline] derivatives 4a-l employing the versatile bis-hydrazonoyl chlorides 1a-c, will find a wide spread application for the synthesis spiro systems. We also showed that solvent polarity and heating modes played a role in the reaction efficiency. Ultrasonic irradiation proved to be an economic and efficient tool for such 1,3-dipolar cycloaddition reactions. X-ray crystallographic data of the obtained cycloadducts unambiguously determined their regio- and stereoselectivity.

Acknowledgements

The financial support for this research work was provided by the University of Kuwait through a research grant (SC06/15). The facilities of ANALAB and SAF supported by research grants GS01/01, GS01/05, GS01/03, and GS03/08 are gratefully acknowledged.

References

Abdel-Wahab B.F., Dawood K.M., . ARKIVOC. 2012;i:491.
Bazgir A., Ahadi S., Ghahremanzadeh R., Khavasi H.R., Mirzaei P., . Ultrason. Sonochem.. 2010;17:447.
Banerjee B., . Ultrason. Sonochem.. 2017;35:1.
Banerjee B., . Ultrason. Sonochem.. 2017;35:15.
Behbehani H., Ibrahim H.M., Dawood K.M., . RSC Adv.. 2015;5:25642.
Chan W.L., Ding M., Zou B., . PCT Int. Appl. WO. 2014;2014167528(A1):20141016.
Cravotto G., Cintas P., . Chem. Soc. Rev.. 2006;35:180.
Dadiboyena S., Valente E.J., Hamme A.T. II, . Tetrahedron Lett.. 2014;55:2208.
Dawood K.M., Fuchigami T., . J. Org. Chem.. 2005;70:7537.
Dawood K.M., . J. Heterocycl. Chem.. 2005;42:221.
Deng X., Mani N.S., . Org. Lett.. 2008;10:1307.
Dawood K.M., . Tetrahedron. 2005;61:5229.
Dawood K.M., Elwan N.M., . J. Chem. Res.. 2004;264
Dawood K.M., Raslan M.A., Farag A.M., . Synth. Commun.. 2003;33:4075.
Dawood K.M., . Synthesis and Reactivity of some Nitrogen and Phosphorus Dipoles. Cairo University; 1992. M.Sc. Thesis
Farghaly T.A., Gomha S.M., Dawood K.M., Shaaban M.R., . RSC Adv.. 2016;6:17955.
Farag A.M., Kandeel Z.E., Algharib M.S., Dawood K.M., . Phosph. Sulfur Silicon. 1994;91:129.
Farag A.M., Shawali A.S., Abed N.M., Dawood K.M., . Gazz. Chim. Ital.. 1993;123:467.
Kamata, M., Yamashita, T., 2009, Jpn. Kokai Tokkyo Koho, JP 2009196966 A 20090903.
Monteiro Â., Gonçalves L.M., Santos M.M.M., . Eur. J. Med. Chem.. 2014;79:266.
Mason T.J., Lorimer J.P., . Applied Sonochemistry: Uses of Power Ultrasound in Chemistry and Processing. Weinheim: Wiley-VCH; 2002.
Ma R., Zhu J., Liu J., Chen L., Shen X., Jiang H., Li J., . Molecules. 2010;15:3593.
Penning T.D., Talley J.J., Bertenshaw S.R., Carter J.S., Collins P.W., Docter S., Graneto M.J., Lee L.F., Malecha J.W., Miyashiro J.M., Rogers R.S., Rogier D.J., Yu S.S., Anderson G.D., Burton E.G., Cogburn J.N., Gregory S.A., Koboldt C.M., Perkins W.E., Seibert K., Veenhuizen A.W., Zhang Y.Y., Isakson P.C., . J. Med. Chem.. 1997;40:1347.
Puri S., Kaur B., Parmar A., Kumar H., . Curr. Org. Chem.. 2013;17:1790.
Ruano J.L.G., Parra A., Marzo L., Yuste F., Mastranzo V.M., . Tetrahedron. 2011;67:2905.
Santos M.M.M., . Tetrahedron. 2014;70:9735.
Shawali A.S., Farag A.M., Algharib M.S., Dawood K.M., . Tetrahedron. 1994;50:5091.
Shawali A.S., Farag A.M., Albar H.A., Dawood K.M., . Tetrahedron. 1993;49:2761.
Sheldrick G.M., . Acta Cryst.. 2008;A64:112.
The crystallographic data for 4a (ref. CCDC 1537567), 4i (ref. CCDC 1537568), 4l (ref. CCDC 1537569) can be obtained on request from the director, Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EW, UK.

Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2017.05.016.

Appendix A

Supplementary material

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[1] Abdel-Wahab B.F., Dawood K.M., . ARKIVOC. 2012;i:491.

[2] Bazgir A., Ahadi S., Ghahremanzadeh R., Khavasi H.R., Mirzaei P., . Ultrason. Sonochem.. 2010;17:447.

[3] Banerjee B., . Ultrason. Sonochem.. 2017;35:1.

[4] Banerjee B., . Ultrason. Sonochem.. 2017;35:15.

[5] Behbehani H., Ibrahim H.M., Dawood K.M., . RSC Adv.. 2015;5:25642.

[6] Chan W.L., Ding M., Zou B., . PCT Int. Appl. WO. 2014;2014167528(A1):20141016.

[7] Cravotto G., Cintas P., . Chem. Soc. Rev.. 2006;35:180.

[8] Dadiboyena S., Valente E.J., Hamme A.T. II, . Tetrahedron Lett.. 2014;55:2208.

[9] Dawood K.M., Fuchigami T., . J. Org. Chem.. 2005;70:7537.

[10] Dawood K.M., . J. Heterocycl. Chem.. 2005;42:221.

[11] Deng X., Mani N.S., . Org. Lett.. 2008;10:1307.

[12] Dawood K.M., . Tetrahedron. 2005;61:5229.

[13] Dawood K.M., Elwan N.M., . J. Chem. Res.. 2004;264

[14] Dawood K.M., Raslan M.A., Farag A.M., . Synth. Commun.. 2003;33:4075.

[15] Dawood K.M., . Synthesis and Reactivity of some Nitrogen and Phosphorus Dipoles. Cairo University; 1992. M.Sc. Thesis

[16] Farghaly T.A., Gomha S.M., Dawood K.M., Shaaban M.R., . RSC Adv.. 2016;6:17955.

[17] Farag A.M., Kandeel Z.E., Algharib M.S., Dawood K.M., . Phosph. Sulfur Silicon. 1994;91:129.

[18] Farag A.M., Shawali A.S., Abed N.M., Dawood K.M., . Gazz. Chim. Ital.. 1993;123:467.

[19] Kamata, M., Yamashita, T., 2009, Jpn. Kokai Tokkyo Koho, JP 2009196966 A 20090903.

[20] Monteiro Â., Gonçalves L.M., Santos M.M.M., . Eur. J. Med. Chem.. 2014;79:266.

[21] Mason T.J., Lorimer J.P., . Applied Sonochemistry: Uses of Power Ultrasound in Chemistry and Processing. Weinheim: Wiley-VCH; 2002.

[22] Ma R., Zhu J., Liu J., Chen L., Shen X., Jiang H., Li J., . Molecules. 2010;15:3593.

[23] Penning T.D., Talley J.J., Bertenshaw S.R., Carter J.S., Collins P.W., Docter S., Graneto M.J., Lee L.F., Malecha J.W., Miyashiro J.M., Rogers R.S., Rogier D.J., Yu S.S., Anderson G.D., Burton E.G., Cogburn J.N., Gregory S.A., Koboldt C.M., Perkins W.E., Seibert K., Veenhuizen A.W., Zhang Y.Y., Isakson P.C., . J. Med. Chem.. 1997;40:1347.

[24] Puri S., Kaur B., Parmar A., Kumar H., . Curr. Org. Chem.. 2013;17:1790.

[25] Ruano J.L.G., Parra A., Marzo L., Yuste F., Mastranzo V.M., . Tetrahedron. 2011;67:2905.

[26] Santos M.M.M., . Tetrahedron. 2014;70:9735.

[27] Shawali A.S., Farag A.M., Algharib M.S., Dawood K.M., . Tetrahedron. 1994;50:5091.

[28] Shawali A.S., Farag A.M., Albar H.A., Dawood K.M., . Tetrahedron. 1993;49:2761.

[29] Sheldrick G.M., . Acta Cryst.. 2008;A64:112.

[30] The crystallographic data for 4a (ref. CCDC 1537567), 4i (ref. CCDC 1537568), 4l (ref. CCDC 1537569) can be obtained on request from the director, Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EW, UK.

Regio- and stereoselective route to bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives via 1,3-dipolar cycloaddition under sonication

Abstract

Abstract

Keywords

Bis-hydrazonoyl chlorides

Spiro-pyrazolines

Ultrasonic irradiation

1,3-Dipolar cycloaddition

1 Introduction

2 Material and methods

2.1 General

2.2 Synthesis of bis-[3-methyl-1,1′,4′-triaryl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] derivatives 4a-l

2.2.1 General method A

2.2.2 General method B

2.2.3 Bis-[1,1′,4′-triphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4a)

2.2.4 Bis-[4′-(4-chlorophenyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4b)

2.2.5 Bis-[4′-(4-nitrophenyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4c)

2.2.6 Bis-[4′-(4-anisyl)-1,1′-diphenyl-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4d)

2.2.7 Bis-[1,1′-diphenyl-4′-(4-tolyl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4e)

2.2.8 Bis-[1,1′-diphenyl-4′-(thiophen-2-yl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4f)

2.2.9 Bis-[1,4′-diphenyl-1′-(4-tolyl)-3-methyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4g)

2.2.10 Bis-[4′-(4-chlorophenyl)-1′-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4h)

2.2.11 Bis-[4′-(4-nitrophenyl)-1′-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4i)

2.2.12 Bis-[1′,4′-di-(4-tolyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4j)

2.2.13 Bis-[1′-(4-chlorophenyl)-3-methyl-4′-(4-nitrophenyl)-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4k)

2.2.14 Bis-[1,4′-di-(4-chlorophenyl)-3-methyl-1-phenyl-5-oxo-spiro-pyrazoline-4,5′-pyrazoline] (4l)

3 Results and discussion

4 Conclusions

Acknowledgements

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 2

Supplementary data 3

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