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. 2021 Sep 9;78:105748. doi: 10.1016/j.ultsonch.2021.105748

Ultrasound-assisted one-pot three-component synthesis of new isoxazolines bearing sulfonamides and their evaluation against hematological malignancies

Aicha Talha a, Cécile Favreau b, Maxence Bourgoin b, Guillaume Robert b, Patrick Auberger b, Lahcen EL Ammari c, Mohamed Saadi c, Rachid Benhida d,e, Anthony R Martin e,⁎,1, Khalid Bougrin a,d,⁎
PMCID: PMC8436160  PMID: 34520963

Highlights

  • •

    Ultrasound-assisted, one-pot green synthesis of new isoxazolines bearing sulfonamides.

  • •

    Selective synthesis of isoxazolines using trichloroisocyanuric acid (TCCA) in EtOH-water as solvent.

  • •

    Good to excellent yields and shorter reaction times under sonication.

  • •

    Compound 3 h displayed promising cytotoxic activities against K562 and HL-60 cells.

Keywords: Sulfonamides-Isoxazolines, One-pot synthesis, Radical processes, Ultrasound, Hematological Malignancies

Abstract

In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60).

1. Introduction

Nitrogen-based heterocyclic chemistry is an important and unique class of organic molecules with immense utility in medicinal chemistry [1], [2]. A major goal of current medicinal research is to identify new, safer and more effective treatments for a wider range of neoplastic conditions, with the hope of reducing morbidity and mortality. This led to the development of targeted therapies for cancer [3], including differentiation therapies [4]. Nevertheless, the quest for new anti-cancer drugs to combat leukemic cells is still an ongoing field of research [5], [6]. In line with this consideration, and in continuation of our recent research in identifying new and original routes to bioactive anticancer agents [7], we synthesized a series of new isoxazoline-linked sulfonamide structures and evaluated their biological activity against CML and APL.

Isoxazoline derivatives are a very important class of N,O-containing heterocycles that received significant attention in modern organic chemistry. They are widely present in different biologically active molecules such as anticancer [8], antimicrobial [9], antibacterial [10], anti-inflammatory and analgesics [11]. Additionally, sulfonamides are recurrent motifs in therapeutic agents exhibiting a broad spectrum of biological activities, such as antibacterial [12], antitumor [13], diuretic [14] and hypoglycemic [15] (Fig. 1).

Fig. 1.

Fig. 1

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Selected examples of therapeutic agents containing an isoxazoline or sulfonamide function [16], [17], [18], [19].

Isoxazolines are frequently synthesized by 1,3-dipolar cycloadditions between an alkene and a nitrile oxide, in the presence of oxidants such as CrO2 [20], MnO2 [21], Mg (OAc)2 [22], CeIII/NaI/I2 [23], N-chlorosuccinimide [24] and hypervalent iodine reagents [25]. However, all these methods involve the use of either powerful oxidants, toxic solvents or drastic reaction conditions. Thus, we developed a new synthetic method for isooxazoline preparation using an inexpensive, ecological and water-soluble oxidant, namely the trichloroisocyanuric acid (TCCA) [26]. It is coupled with ultrasounds as an efficient activation method as recently disclosed for the synthesis of this type of heterocycle [27]. TCCA was first used as a disinfectant and industrial deodorant, also used in swimming pools. In organic chemistry, TCCA proved efficient in chlorination reactions under mild conditions, as well as oxidation of ethers, thioethers, aldehydes, acetals and alcohols [28]. TCCA was recently used in the heterocyclic synthesis of 2-substituted oxazolines, imidazolines, thiazolines and coumarin, at room temperature [29].

More recently Zhang et al. [30] and Bhatt et al. [31] reported a novel method for the synthesis of isoxazoles/isoxazolines based on an intramolecular oxidative cyclization using a large excess of TCCA in MeCN or EtOH and long reaction time (ca. 10 h). In addition, Aghapour et al. [32] successfully used TCCA as a catalyst, in combination with hydroxylamine hydrochloride, for the preparation of oximes starting from tetrahydropyran (THP) ethers under solvent-free conditions at 110 °C.

To our knowledge, there are no reports in the literature on the preparation of isoxazolines in the presence of TCCA under ultrasonic irradiation in water. Inspired by the methods described above for the synthesis of isoxazolines and isoxazoles, we disclose herein the one-pot two-step synthesis of novel isoxazoline substituted sulfonamides (3a-r) promoted by TCCA at room temperature. It directly starts from aldehydes (1a-f) and operates in aqueous medium under ultrasonic irradiation (Scheme 1). The important features of this new method are its ease, straightforwardness and environmentally friendly protocol.

Scheme 1.

Scheme 1

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One-pot synthesis of sulfonamides 4-substituted-isoxazolines catalyzed by TCCA in ethanol/water under sonication.

2. Experimental

2.1. Material and methods

All organic solvents were purchased from commercial sources and used as received or dried using standard procedures; all chemicals were purchased from Aldrich, Merck and used without further purification. Analytical thin layer-chromatographies (TLC) have been performed on pre-coated silica gel plates (Kieselgel 60 F254, E. Merck, Germany), and chromatograms were visualized by UV- light irradiation (254 and 360 nm), then by staining with ninhydrin or H2SO4/EtOH. Purifications by column chromatography have been performed using silica gel, 100–200 mesh (Merck, Germany). NMR spectroscopies were recorded in dry deuterated solvent (DMSO or chloroform) a Bruker AC 200, or on a Bruker AC 400 spectrometer at 200 MHz or 400 MHz for 1H NMR and 50 MHz or 101 MHz for 13C NMR; δ is expressed in ppm related to TMS (0 ppm) as internal standard. Splitting patterns are designated as follow: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad). Coupling constants (J values) are listed in Hertz (Hz). Mass spectra (ESI-MS) were recorded on a Bruker Daltonics Esquire 3000+, and the samples were diluted in methanol. Melting points were measured on a Wagner and Munz Köfler Bench System. The purity of compounds was further verified by HPLC analysis was performed on a Jasco LC-Net II /ADC apparatus using phenomenex columns (conditions: unless otherwise stated: 1.0 mL/min, gradient 75% A/25% B (1 min.) then increasing to 0% A/100% B in 6 min. and a plateau of 3 min. before returning to 75% A/25% B in 1 min. A is water and B is CH3CN, both containing 1‰ HCOOH). Purity of all compounds was found to be ≥ 95% as determined by HPLC using UV detection at 254 nm. The ultrasound-assisted reactions were carried out in an “'Elmasonic S 30/S 30H UltraSonic Bath Cleaner”, with an effective ultrasound power of 80 W at a frequency of 47 kHz. This ultrasonic cleaner has internal dimensions W/D/H (mm) of 240/137/100 with a liquid retention capacity of 2.75 l. The reactions were carried out in a flask with a capacity of 25 mL in suspension in the center of the cleaning bath, 5 cm below the surface of the liquid. The reaction temperatures were controlled by adding or removing water from the ultrasonic bath.

2.2. Synthesis

2.2.1. General procedure for the synthesis of allyl-sulfonamides (2a-l)

The primary amine (1 equiv) and K2CO3 (2 equiv) were dissolved in EtOH/H2O (v/v, 1:1) (20 mL) and alkyl/phenyl sulfonyl chloride (1.1 equiv) was added dropwise. After completion of the reaction (as monitored via TLC), allyl bromide (1.1 equiv) was added dropwise with constant stirring or sonication until complete consumption of the starting material (6–10 h under stirring or 15–20 min under sonication). The salts were then removed by filtration, and filtrate was concentrated under reduced pressure. The crude material was purified on silica gel column chromatography (cyclohexane/ethyl acetate: 9/1 to 6/4), to afford the desired pure products 2a-l.

2.2.1.1. N-Allyl-N-(4-bromo-phenyl)-benzenesulfonamide (2a)

Brown solid; MP 63–65 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.67; 1H NMR (300 MHz, DMSO‑d6) δ 7.73–7.64 (m, 1H), 7.58 (d, J = 4.3 Hz, 4H), 7.50 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.76–5.50 (m, 1H), 5.17–4.99 (m, 2H), 4.19 (dd, J = 6.0, 1.2 Hz, 2H). 13C NMR (75 MHz, DMSO‑d6) δ 133.8, 133.1, 132.3 (2C), 130.8 (2C), 129.8 (2C), 127.7 (2C), 119.6, 52.9; MS (EI): m/z = 351.99 [M + H] +.

2.2.1.2. N-Allyl-N-phenyl-methanesulfonamide (2b)

Orange solid; MP 67–69 °C. TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.58; 1H NMR (400 MHz, Chloroform-d) δ 7.45–7.31 (m, 5H), 5.96–5.72 (m, 1H), 5.24–5.12 (m, 2H), 4.34–4.27 (m, 2H), 2.94 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 139.3, 132.8, 129.4 (2C), 128.5 (2C), 128.1, 119.1, 53.7, 38.1; MS (EI): m/z = 212.07 [M + H] +.

2.2.1.3. N-Allyl-N-phenyl-benzenesulfonamide (2c)

Beige solid, MP 80–82 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.65; 1H NMR (400 MHz, Chloroform-d) δ 7.65–7.55 (m, 3H), 7.47 (t, J = 7.7 Hz, 2H), 7.33–7.27 (m, 3H), 7.08–7.02 (m, 2H), 5.84–5.63 (m, 1H), 5.14–5.01 (m, 2H), 4.21 (d, J = 6.3 Hz, 2H).13C NMR (101 MHz, Chloroform-d) δ 138.9, 138.3, 132.7, 132.7, 128.9 (2C), 128.8 (4C), 127.9, 127.6 (2C), 118.9, 53.6; MS (EI): m/z = 274.08 [M + H] +.

2.2.1.4. N-Allyl-N-(4-methoxy-phenyl)-methanesulfonamide (2d)

Black solid, MP 68–70 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.56; 1H NMR (400 MHz, Chloroform-d) δ 7.26 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 5.94–5.73 (m, 1H), 5.24–5.06 (m, 2H), 4.33–4.16 (m, 2H), 3.82 (s, 3H), 2.92 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 159.2, 133.1, 131.7, 130.1(2C), 119.1, 114.5 (2C), 55.4, 53.9, 37.9; MS (EI): m/z = 242.08 [M + H] +.

2.2.1.5. N-Allyl-N-(4-methoxy-phenyl)-ethanesulfonamide (2e)

Black solid, MP 70–72 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.40; 1H NMR (400 MHz, Chloroform-d) δ 7.26 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 5.90–5.72 (m, 1H), 5.23–5.01 (m, 2H), 4.31–4.18 (m, 2H), 3.80 (s, 3H), 3.04 (q, J = 7.4 Hz, 2H), 1.39 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 159.1, 133.5, 131.6, 130.3 (2C), 118.7, 114.5 (2C), 55.4, 54.4, 45.4, 8.1; MS (EI): m/z = 256.09 [M + H] +.

2.2.1.6. N-Allyl-N-propyl-benzenesulfonamide (2f)

Brown oil, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.40; 1H NMR (400 MHz, Chloroform-d) δ 7.83–7.79 (m, 2H), 7.57–7.54 (m, 1H), 7.53–7.49 (m, 2H), 5.67–5.56 (m, 1H), 5.21–5.07 (m, 2H), 3.81 (d, J = 6.4 Hz, 2H), 3.09 (dd, J = 8.4, 6.8 Hz, 2H), 1.53 (dd, J = 15.0, 7.5 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 140.1, 133.1, 132.4, 129.1 (2C), 127.1 (2C), 118.6, 50.5, 49.1, 21.4, 11.1; MS (EI): m/z = 240.1 [M + H] +.

2.2.1.7. N-allyl-N-(4-methoxyphenyl) benzenesulfonamide (2 g)

Gray Solid, MP 91–94 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.54; 1H NMR (200 MHz, Chloroform-d) δ 7.66–7.40 (m, 5H), 6.92 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 2H), 5.87–5.56 (m, 1H), 5.15–4.95 (m, 2H), 4.14 (d, J = 6.3 Hz, 2H), 3.78 (s, 3H).13C NMR (50 MHz, Chloroform-d) δ 158.9, 138.5, 132.8, 132.5, 131.4, 130.2 (2C), 128.7 (2C), 127.6 (2C), 118.7, 114. (2C), 55.4, 53.9; MS (EI): m/z = 304,09 [M + H] +.

2.2.1.8. N-Allyl-N-(4-chloro-phenyl)-benzenesulfonamide (2 h)

Green Solid, MP 65–67 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.6; 1H NMR (400 MHz, Chloroform-d) δ 7.65–7.57 (m, 3H), 7.53–7.46 (m, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.80–5.64 (m, 1H), 5.13–5.03 (m, 2H), 4.18 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 137.9, 137.4, 133.7, 132.9, 132.3, 130.1 (2C), 129.1 (2C), 128.9 (2C), 127.6 (2C), 119.3, 53.5; MS (EI): m/z = 308.04 [M + H] +.

2.2.1.9. N-Allyl-N-p-tolyl-methanesulfonamide (2i)

Beige Crystals, MP 67–68 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.47; 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 5.95–5.78 (m, 1H), 5.21–5.09 (m, 2H), 4.30 (d, J = 6.3 Hz, 2H), 2.41 (s, 3H), 2.37 (s, 3H).13C NMR (101 MHz, Chloroform-d) δ 140.7, 133.4, 130.8 (2C), 130.2 (2C), 128.6, 21.2, 8.1, 7.8; MS (EI): m/z = 226.08 [M + H] +.

2.2.1.10. N-Allyl-N-(4-chloro-phenyl)-ethanesulfonamide (2j)

Green-Yellow Solid, MP 65–67 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.61. MS (EI): m/z = 259.04 M 1H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 5.88–5.73 (m, 1H), 5.18–5.09 (m, 2H), 4.29 (d, J = 6.4 Hz, 2H), 3.05 (q, J = 7.4 Hz, 2H), 1.38 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 137.8, 133.5, 132.9, 129.9 (2C), 129.4 (2C), 119.2, 54.1, 45.8, 8.1; MS (EI): m/z = 260.04 [M + H] +.

2.2.1.11. N-Allyl-N-p-tolyl-ethanesulfonamide (2 k)

Beige Solid, MP 66–69 °C, TLC (cyclohexane/AcOEt, 6/4, v/v) Rf = 0.52; 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.92–5.76 (m, 1H), 5.20–5.08 (m, 2H), 4.30 (d, J = 6.3 Hz, 2H), 3.06 (q, J = 7.4 Hz, 2H), 2.37 (s, 3H), 1.40 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 137.8, 136.6, 133.5, 130.8 (2C), 130.2 (2C), 118.6, 49.9, 45.6, 21.2, 7; MS (EI): m/z = 240.10 [M + H] +.

2.2.1.12. N-Allyl-N-(4-chloro-phenyl)-methanesulfonamide (2 l)

Green Solid, MP 97–99 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.38; 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.96–5.72 (m, 1H), 5.21–5.07 (m, 2H), 4.30 (d, J = 6.3 Hz, 2H), 2.37 (s, 3H).13C NMR (101 MHz, Chloroform-d) δ 140.7, 133.48, 131.1, 130.8 (2C), 130.2 (2C), 118.6, 49.9, 45.6; MS (EI): m/z = 246,03 [M + H] + .

2.2.2. General procedure for the one-pot synthesis of compounds (3a-r)

To a solution of aldehyde (1 equiv) and hydroxylamine hydrochloride (1.5 equiv) in EtOH/H2O (v/v, 1:1) (20 mL) TCCA (0.5 equiv) and allyl-sulfonamides 2a-l (1 equiv) were added successively and the mixture was sonicated according to the time reported in Table 3. Reactions were then extracted with CH2Cl2 (20 mL × 2). The organic phase was washed with water (20 mL) and saturated brine solution (20 mL), dried over MgSO4 and concentrated in vacuum to give the crude product, which was purified by flash silica gel chromatography (cyclohexane/ EtOAc: 9/1 to 7/3) to afford the pure adducts 3a-r.

Table 3.

Generalization of the one-pot two-steps procedure under sonication.

Inline graphic
Entry a Isoxazoline R1 R2 Ar Time (min) Yield (%)b
1 3a Ph 4-Cl C6H4 4-Cl C6H4 17 86
2 3b Me 4-MeO C6H4 3,4-di Cl C6H3 18 77
3 3c Ph 4-MeO C6H4 3-NO2 C6H4 20 81
4 3d Ph 4-Br C6H4 3-NO2 C6H4 22 63
5 3e Ph 4-MeO C6H4 C6H5 16 68
6 3f Ph 4-Cl C6H4 3-NO2 C6H4 21 81
7 3g Ph 4-Cl C6H4 C6H5 16 59
8 3h Ph C6H5 3,4-di Cl C6H3 16 75
9 3i Ph C6H5 4-Me C6H4 14 85
10 3j Ph C6H5 3,4,5-tri MeO C6H2 12 67
11 3k Ph C3H7 3,4-di Cl C6H3 16 65
12 3l Me C6H5 3,4-di Cl C6H3 14 84
13 3m Ph 4-MeO C6H4 3,4-di Cl C6H3 16 70
14 3n Et 4-MeO C6H4 3-NO2 C6H4 18 86
15 3o Et 4-Cl C6H4 C6H5 19 58
16 3p Me 4-Cl C6H4 C6H5 18 53
17 3q Me 4-Me C6H4 3-NO2 C6H4 19 52
18 3r Ph C3H7 3-NO2 C6H4 17 60
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a

Reactions carried out with (1 mmol) of aldehyde, (1.5 mmol) NH2OH.HCl, (0.5 mmol) TCCA and (1 mmol) alkene, in EtOH/H2O (10 mL, 1 :1) at 25 °C under sonication (ultrasonic bath, 47 kHz).

b

Yield of products after purification.

2.2.2.1. N-(4-Chloro-phenyl)-N-[3-(4-chloro-phenyl)-isoxazolin-5-ylmethyl] benzenesulfonamide (3a)

White Solid, Mp 195–197 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.14; 1H NMR (400 MHz, Chloroform-d) δ 7.62 (t, J = 7.4 Hz, 3H), 7.60–7.55 (m, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.33–7.27 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.88–4.73 (m, 1H), 3.82 (dd, J = 13.9, 7.0 Hz, 1H), 3.72 (dd, J = 13.9, 4.9 Hz, 1H), 3.52 (dd, J = 16.9, 6.6 Hz, 1H), 3.40 (dd, J = 16.9, 10.5 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 155.6, 137.8, 137.3, 136.3, 134.3, 133.2, 129.9 (2C), 129.4 (2C), 129.1 (4C), 128.1 (2C), 127.6 (2C), 127.6, 78.9, 53.2, 37.8; MS (EI): m/z = 460.40 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 4.55 min).

2.2.2.2. N-[3-(3,4-Dichloro-phenyl)-isoxazolin-5-ylmethyl]-N-(4-methoxy-phenyl)-methane sulfonamide (3b)

White Solid, MP 170–172 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.52 ;1H NMR (200 MHz, Chloroform-d) δ 7.70–7.64 (m, 1H), 7.42 (d, J = 1.4 Hz, 2H), 7.27–7.17 (m, 3H), 6.86 (d, J = 9.0 Hz, 2H), 4.87–4.69 (m, 1H), 3.84 (dd, J = 14.1, 6.0 Hz, 1H), 3.75 (s, 3H), 3.72 (dd, J = 7.3, 2.1 Hz, 1H), 3.64 (dd, J = 9.5, 4.6 Hz, 1H), 3.26 ((dd, J = 14.1, 6.0 Hz, 1H), 2.89 (s, 3H). 13C NMR (50 MHz, Chloroform-d) δ 159.6, 154.8, 134.4, 133.2, 131.5, 130.8, 130.1 (2C), 129.2, 128.5, 125.8, 114.9 (2C), 79.1, 55.5, 53.6, 37.7, 37.5; MS (EI): m/z = 429.04 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 4.15 min)

2.2.2.3. N-(4-Methoxy-phenyl)-N-[3-(3-nitro-phenyl)-isoxazolin-5-ylmethyl]-benzene sulfonamide (3c)

White Solid, MP 145–147 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.5;1H NMR (300 MHz, DMSO‑d6) δ 8.37–8.26 (m, 2H), 8.09–8.02 (m, 1H), 7.78–7.64 (m, 2H), 7.56 (d, J = 4.4 Hz, 4H), 6.96–6.84 (m, 4H), 4.81–4.62 (m, 1H), 3.84 (dd, J = 14.2, 6.8 Hz, 1H), 3.67 (dd, J = 15.9, 11.0 Hz, 1H), 3.54 (dd, J = 20.5, 9.8 Hz, 1H), 3.37 (dd, J = 12.8, 5.6 Hz, 1H). 13C NMR (75 MHz, DMSO‑d6) δ 159.2, 156.1, 148.5, 138.2, 133.6, 133.2, 131.8, 131.3, 131.1, 130.7(2C), 129.7 (2C), 127.8 (2C), 125.1, 121.3, 114.6 (2C), 79.8, 55.7, 54.1, 37.5; MS (EI): m/z = 467.12 [M + H] +; IR (KBr, cm−1): 1134 (S = O),1162 (S = O), 732–646 (5HAr-Adjacent), 1506 (N = O), 1420 (Ph-O-C), 3312–2700 (C = CAr); HPLC analysis (luna column, λ = 254 nm, purity 95 %, t R = 4.11 min).

2.2.2.4. N-(4-Bromo-phenyl)-N-[3-(3-nitro-phenyl)-isoxazolin-5-ylmethyl]-benzene sulfonamide (3d)

White Solid, MP 167–169 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.57;1H NMR (300 MHz, DMSO‑d6) δ 8.36–8.26 (m, 2H), 8.06 (d, J = 7.9 Hz, 1H), 7.79–7.67 (m, 2H), 7.58 (d, J = 1.5 Hz, 2H), 7.56 (s, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.86–4.68 (m, 1H), 3.88 (dd, J = 14.5, 6.7 Hz, 1H), 3.76 (dd, J = 14.5, 4.5 Hz, 1H), 3.58 (dd, J = 17.3, 10.8 Hz, 1H), 3.34 (dd, J = 13.6, 10.5 Hz, 1H). 13C NMR (75 MHz, DMSO‑d6) δ 156.1, 148.5, 138.9, 137.6, 133.9, 133.2, 132.4 (2C), 131.3, 131.2 (2C), 131.1, 129.8 (2C), 127.7 (2C), 125.1, 121.6, 121.3, 80.1, 53.5, 37.4; MS (ESI + ): m/z = 516.01 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 95 %, t R = 4.33 min).

2.2.2.5. N-(4-Methoxy-phenyl)-N-(3-phenyl-isoxazolin-5-ylmethyl)-benzenesulfonamide (3e)

White Solid, MP 127–129 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.52;1H NMR (300 MHz, DMSO‑d6) δ 7.68 (m, 1H), 7.57 (d, J = 4.4 Hz, 4H), 6.91 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 5.66 (ddt, J = 17.2, 10.2, 6.0 Hz, 1H), 5.14–4.94 (m, 2H), 4.14 (d, J = 6.1 Hz, 2H), 3.71 (s, 3H). 13C NMR (75 MHz, DMSO‑d6) δ 158.9, 138.3, 133.5, 133.5, 131.5, 130.2 (2C),129.7 (2C), 127.7 (2C), 119.1, 114.4 (2C), 55.7, 53.5; MS (EI): m/z = 422.13 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 96 %, t R = 4.34 min).

2.2.2.6. N-(4-Chloro-phenyl)-N-[3-(3-nitro-phenyl)-isoxazolin-5-ylmethyl]-benzene sulfonamide (3f)

White Solid, Mp 152–154 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.29;1H NMR (400 MHz, Chloroform-d) δ 8.49 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.67–7.56 (m, 4H), 7.51 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 4.98–4.84 (m, 1H), 3.85 (dd, J = 13.9, 6.8 Hz, 1H), 3.76 (dd, J = 13.9, 4.9 Hz, 1H), 3.59 (dd, J = 16.9, 6.7 Hz, 1H), 3.48 (dd, J = 16.9, 10.6 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 154.9, 148.5, 137.8, 137.3, 134.4, 133.3, 132.3, 130.9, 129.9 (2C), 129.9, 129.5 (2C), 129.1 (2C), 127.6 (2C), 124.7, 121.6, 79.5, 53.2, 37.5; MS (EI): m/z = 471.91 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 4.30 min).

2.2.2.7. N-(4-Chloro-phenyl)-N-(3-phenyl-isoxazolin-5-ylmethyl)-benzenesulfonamide (3 g)

White Solid, Mp 148–150 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.34; 1H NMR (400 MHz, Chloroform-d) δ 7.70 (dd, J = 6.5, 3.1 Hz, 2H), 7.64––7.58 (m, 3H), 7.51–7.41 (m, 5H), 6.97 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.84–4.73 (m, 1H), 3.76 (dd, J = 20.5, 7.4 Hz, 1H), 3.69 (dd, J = 13.5, 4.9 Hz, 1H), 3.55 (dd, J = 16.9, 6.5 Hz, 1H), 3.42 (dd, J = 16.9, 10.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.3, 156.5, 137.8, 132.9, 131.6, 130.2, 129.9 (2C), 129.2, 128.9 (2C), 128.7 (2C), 127.7 (2C), 126.8 (2C), 114.4 (2C), 78.5, 55.4, 53.5, 38.2; MS (EI): m/z = 426.92 [M + H] +; IR (KBr, cm−1): 1114 (S = O), 1335 (S = O), 750–690 (5HAr-Adjacent), 685 (C-Cl), 3415–2830 (C = CAr); HPLC analysis (luna column, λ = 254 nm, purity 99 %, t R = 4.15 min).

2.2.2.8. N-[3-(3,4-Dichloro-phenyl)-isoxazolin-5-ylmethyl]-N-phenyl-benzenesulfonamide (3 h)

White Solid, Mp 148–150 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.34;1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 1.7 Hz, 1H), 7.66–7.56 (m, 3H), 7.53–7.46 (m, 4H), 7.37–7.33 (m, 3H), 7.08–7.04 (m, 2H), 4.89–4.75 (m, 1H), 3.84 (dd, J = 13.7, 7.8 Hz, 1H), 3.74 (dd, J = 13.7, 4.8 Hz, 1H), 3.54 (dd, J = 16.9, 6.5 Hz, 1H), 3.38 (dd, J = 16.9, 10.6 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 154.8, 139.1, 137.6, 134.3, 133.1, 133.1, 130.8, 129.3 (2C), 129.2, 128.9 (2C), 128.6 (2C), 128.5 (2C), 127.7 (2C), 125.8, 79.1, 53.1, 37.7; MS (EI): m/z = 461.36 [M + H] +; IR (KBr, cm−1): 1171 (S = O), 1309 (S = O), 895–826 (2HAr-Adjacent), 757 (C-Cl), 688 (C-Cl), 3415–2830 (C = CAr) and (C-HAr) elongation; HPLC analysis (luna column, λ = 254 nm, purity 96 %, t R = 4.55 min).

2.2.2.9. N-Phenyl-N-(3-p-tolyl-isoxazolin-5-ylmethyl)-benzenesulfonamide (3i)

White Solid, Mp 148–150 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.34; 1H NMR (400 MHz, Chloroform-d) δ 7.63–7.55 (m, 5H), 7.48 (t, J = 7.7 Hz, 2H), 7.37–7.32 (m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.10–7.05 (m, 2H), 4.83–4.71 (m, 1H), 3.83 (dd, J = 13.5, 7.9 Hz, 1H), 3.73 (dd, J = 13.6, 4.8 Hz, 1H), 3.53 (dd, J = 16.9, 6.4 Hz, 1H), 3.40 (dd, J = 16.8, 10.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 156.5, 140.5, 139.2, 137.7, 133.0, 129.4 (2C), 129.2 (2C), 128.9 (2C), 128.7 (2C), 128.4, 127.7 (2C), 126.8 (2C), 126.3, 78.3, 53.2, 38.3, 21.5; MS (EI): m/z = 406.50 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 4.28 min).

2.2.2.10. N-Phenyl-N-[3-(3,4,5-trimethoxy-phenyl)-isoxazolin-5-ylmethyl]-benzene sulfonamide (3j)

White Solid, Mp 175–177 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.55; 1H NMR (400 MHz, Chloroform-d) δ 7.64–7.55 (m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.35–7.32 (m, 3H), 7.09–7.05 (m, 2H), 4.83–4.72 (m, 1H), 3.91 (s, J = 3.1 Hz, 6H), 3.90 (s, 3H), 3.85 (dd, J = 13.6, 8.0 Hz, 1H), 3.70 (dd, J = 13.6, 4.8 Hz, 1H), 3.56 (dd, J = 16.8, 6.3 Hz, 1H), 3.40 (dd, J = 16.8, 10.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 156.5, 153.3, 139.9, 139.1, 137.6, 133.1, 129.2 (2C), 128.95 (2C), 128.9 (2C), 128.4, 127.6 (2C), 124.6, 104.1 (2C), 78.5, 60.9, 56.3(2CH3), 53.1, 38.2; MS (EI): m/z = 482.15 [M + H] +; IR (KBr, cm−1): 1320 (S = O), 1186 (S = O), 784–650 (5HAr-Adjacent), 1454 (Ph-O-C), 1387 (Ph-O-C), 1119 (Ph-O-C), 3362–2794 (C = CAr) and (C-HAr) elongation ; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 4.02 min).

2.2.2.11. N-[3-(3,4-Dichloro-phenyl)-isoxazolin-5-ylmethyl]-N-propyl-benzenesulfonamide (3 k)

Monocrystal, Mp 115–116 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.34; 1H NMR (400 MHz, Chloroform-d) δ 7.85–7.80 (m, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.65–7.59 (m, 1H), 7.58–7.49 (m, 4H), 5.12–4.78 (m, 1H), 3.54 (dd, J = 14.8, 5.8 Hz, 1H), 3.46 (dd, J = 17.0, 7.7 Hz, 1H), 3.39 (dd, J = 17.0, 10.4 Hz, 1H), 3.29 (t, J = 6.2 Hz, 1H), 3.27–3.23 (m, 1H), 3.11 (dd, J = 14.8, 6.9 Hz, 1H), 1.65–1.55 (m, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 155.3, 139.2, 134.3, 133.1, 132.8, 130.8, 129.2 (2C), 129.2, 128.5, 127.1 (2C), 125.8, 80.7, 51.9, 50.9, 37.7, 21.8, 11.1; MS (EI): m/z = 427.34 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100%, t R = 4.53 min).

2.2.2.12. N-[3-(3,4-Dichloro-phenyl)-soxazolin-5-ylmethyl]-N-phenyl-methanesulfonamide (3 l)

White Solid, Mp 135–137 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.14; 1H NMR (400 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.53–7.47 (m, 2H), 7.47–7.43 (m, 2H), 7.42–7.39 (m, 3H), 4.92–4.80 (m, 1H), 3.97 (dd, J = 14.2, 6.0 Hz, 1H), 3.86 (dd, J = 14.2, 6.3 Hz, 1H), 3.37 (dd, J = 13.2, 5.6 Hz, 1H), 3.34–3.25 (m, 1H), 2.99 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 154.9, 139.1, 134.3, 133.1, 130.8, 129.8 (2C), 129.1, 128.7, 128.7 (2C), 128.5, 125.8, 79.1, 53.4, 37.8, 37.5. MS (EI): m/z = 399.30 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 95 %, t R = 4.13 min).

2.2.2.13. N-(4-Methoxy-phenyl)-N-[3-(3,4-dichloro-phenyl)-isoxazolin-5-ylmethyl]-benzene sulfonamide (3 m)

White Solid, MP 109–111 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.59; 1H NMR (300 MHz, DMSO‑d6) δ 7.81 (d, J = 1.8 Hz, 1H), 7.72–7.64 (m, 2H), 7.61 (dd, J = 8.4, 1.9 Hz, 1H), 7.56 (d, J = 4.3 Hz, 4H), 6.93 (d, J = 9.1 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 4.75–4.61 (m, 1H), 3.81 (dd, J = 14.1, 6.8 Hz, 1H), 3.72 (s, 3H), 3.66 (dd, J = 14.2, 4.9 Hz, 1H), 3.48 (dd, J = 17.3, 10.8 Hz, 1H), 3.24 (dd, J = 17.3, 6.9 Hz, 1H). 13C NMR (75 MHz, DMSO‑d6) δ 159.2, 155.6, 138.2, 133.6, 133.1, 132.2, 131.8, 131.5, 130.4 (2C), 130.3, 129.7 (2C), 128.7, 127.8 (2C), 127.1, 114.6 (2C), 79.7, 55.7, 54.1, 37.5; MS (EI): m/z = 491.05 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 98 %, t R = 4.55 min)

2.2.2.14. N-(4-Methoxy-phenyl)-N-[3-(3-nitro-phenyl)-isoxazolin-5-ylmethyl]-ethane sulfonamide (3n)

White Solid, Mp 136–138 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.28; 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.7 Hz, 2H), 7.44–7.41 (m, 2H), 7.35 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 4.88–4.73 (m, 1H), 3.92 (dd, J = 14.6, 6.6 Hz, 1H), 3.86 (dd, 1H), 3.84 (s, 3H), 3.41 (dd, J = 14.7, 7.7 Hz, 1H), 3.35 (dd, J = 14.7, 5.4 Hz, 1H), 3.12 (qd, J = 7.2, 1.9 Hz, 2H), 1.42 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 159.4, 156.6, 131.6, 130.3 (2C), 130.2, 129.2, 128.8 (2C), 126.8 (2C), 114.8 (2C), 78.5, 55.5, 54.2, 45.3, 38.1, 8.1; MS (EI): m/z = 419.45 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 95 %, t R = 3.86 min).

2.2.2.15. N-(4-Chloro-phenyl)-N-(3-phenyl-isoxazolin-5-yl)methyl)-ethanesulfonamide (3o)

White Solid, Mp 98–100 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.29; 1H NMR (400 MHz, Chloroform-d) δ 7.69–7.64 (m, 2H), 7.46–7.41 (m, 3H), 7.37 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 11.1 Hz, 2H), 4.89–4.78 (m, 1H), 3.41 (dd, J = 16.8, 10.3 Hz, 1H), 3.33 (dd, J = 16.9, 7.0 Hz, 1H), 3.13 (dd, J = 7.4, 1.9 Hz, 1H), 3.10 (dd, J = 7.4, 1.8 Hz, 1H), 1.42 (t, J = 7.4 Hz, 3H), 1.33 (q, J = 30.9, 10.6 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 156.6, 137.9, 134.3, 130.3, 130.1 (2C), 129.8 (2C), 129.1, 128.7 (2C), 126.7 (2C), 78.6, 54.2, 45.7, 37.9, 8.1; MS (EI): m/z = 378.45 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity100 %, t R = 4.03 min).

2.2.2.16. N-(4-chlorophenyl)-N-((3-phenyl-isoxazolin-5-yl)methyl)-methanesulfonamide (3p)

White Solid, Mp 160–162 °C, TLC (cyclohexane/AcOEt, 80/20, v/v) Rf = 0.27; 1H NMR (400 MHz, Chloroform-d) δ 7.67 (dd, J = 7.4, 2.2 Hz, 2H), 7.45–7.41 (m, 3H), 7.41 (s, 2H), 7.37 (d, J = 8.9 Hz, 2H), 4.93–4.80 (m, 1H), 3.94 (dd, J = 14.4, 6.5 Hz, 1H), 3.85 (dd, J = 14.4, 5.4 Hz, 1H), 3.42 (dd, J = 16.9, 10.4 Hz, 1H), 3.31 (dd, J = 16.9, 6.8 Hz, 1H), 3.01 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 156.6, 137.8, 134.5, 130.4, 130.1 (2C), 129.9 (2C), 128.9 (2C), 128.8, 126.79(2C), 78.3, 78.1, 53.8, 38.2, 37.9. MS (EI): m/z = 365.06 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 100 %, t R = 3.95 min).

2.2.2.17. N-[3-(3-Nitro-phenyl)-isoxazolin-5-ylmethyl]-N-p-tolyl-methanesulfonamide (3q)

White Solid, Mp 177–179 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.27; 1H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 4.98–4.85 (m, 1H), 3.98 (dd, J = 14.2, 5.9 Hz, 1H), 3.86 (dd, J = 14.2, 6.4 Hz, 1H), 3.43 (d, J = 8.7 Hz, 2H), 2.98 (s, 3H), 2.39 (s, J = 10.5 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 155.1, 148.4, 138.9, 136.4, 132.3, 131.1, 130.4 (2C), 129.8, 128.4 (2C), 124.7, 121.5, 79.3, 53.4, 37.7, 37.5, 21.2; MS (EI): m/z = 389.10 [M + H] +; HPLC analysis (luna column, λ = 254 nm, purity 98 % , t R = 3.87 min).

2.2.2.18. N-((3-(3-Nitro-phenyl)-isoxazolin-5-yl)methyl)-N-propyl-benzenesulfonamide (3r)

White Solid, Mp 102–104 °C, TLC (cyclohexane/AcOEt, 8/2, v/v) Rf = 0.25; 1H NMR (400 MHz, Chloroform-d) δ 8.51 (t, J = 1.8 Hz, 1H), 8.33–8.26 (m, 1H), 8.08–8.04 (m, 1H), 7.85–7.80 (m, 2H), 7.66–7.59 (m, 2H), 7.58–7.52 (m, 2H), 5.10–5.01 (m, 1H), 3.57 (dd, J = 14.9, 5.7 Hz, 1H), 3.53–3.42 (m, 2H), 3.31 (dd, J = 10.5, 4.3 Hz, 1H), 3.27 (dd, J = 10.8, 4.8 Hz, 1H), 3.13 (dd, J = 14.8, 7.1 Hz, 1H), 1.61 (q, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 155.4, 148.5, 139.2, 132.8, 132.3, 131.1, 129.8, 129.2 (2C), 127.1 (2C), 124.6, 121.6, 80.9, 51.9, 50.9, 37.6, 21.8, 11.1; MS (EI): m/z = 403.12 [M + H] +; IR (KBr, cm−1): 1336 (S = O), 1188 (S = O), 1046 (Propyl),1500 (N = O), 3312–2700 (C = CAr) and (C-HAr) elongation 818–670 (3HAr-Adjacent); HPLC analysis (luna column, λ = 254 nm, purity 99 %, t R = 4.12 min).

2.2.3. General procedure for the radical trapping experiment

To a solution of p-chlorobenzaldehyde 1a (1.0 equiv, 70 mg) and hydroxylamine hydrochloride (1.5 equiv, 52. 1 mg) in EtOH/H2O (v/v, 1:1) (10 mL) TCCA (0.5 equiv, 58.1 mg), TEMPO (0.5 equiv, 78.1 mg) and alkene 2 h (1 equiv, 153.5 mg) were added successively and the mixture was sonicated for 20 min using ultrasonic bath (47 kHz) at 25 °C (the temperature of the reaction has been maintained by the addition of crushed ice). After completion of the reaction (TLC), the reaction mixture was concentrated under pressure to remove ethanol and then extracted with CH2Cl2 (20 mL). The organic phase was washed with water (20 mL) and saturated brine solution (20 mL), dried over MgSO4 and concentrated in vacuum. The resulting residue was then purified by silica gel column chromatography (cyclohexane/ EtOAc: 9/1 to 7/3) to afford the pure 3a (≈ 125 mg), with inseparable mixture of trapped-TEMPO products.

2.3. Crystallography

One crystal suitable for X-ray diffraction analysis was coated with dry perfluoropolyether, mounted on glass fiber, and fixed in a cold nitrogen stream to the goniometer head. Data collection was performed on a Bruker D8 VENTURE Super DUO diffractometer, using graphite monochromatized Mo radiation (Mo Kα radiation, l = 0.71073 Å). The data were reduced (SAINT) and corrected for absorption effects by the multiscan method (SADABS). The corresponding crystallographic data were deposited with the Cambridge Crystallographic Data Centre as supplementary publications. CCDC 2,040,890 3 k. The data can be obtained free of charge via: https://www.ccdc.cam.ac.uk/structures/.

3. Results and discussion

3.1. Effect of sonication on one-pot, tandem synthesis of allyl sulfonamides

Firstly, we synthesize different allyl-sulfonamides 2a-l directly from phenyl/alkyl sulfonyl chloride and a primary amine in presence of potassium carbonate, and subsequently allyl bromide is added; this process was performed in a one-pot under ultrasound activation. The results presented in Table 1 clearly show the effect of ultrasound on the acceleration of the reaction rate (15–27 min) compared with conventional agitation (6–13 h). Of note, both methods afforded the expected allyl-sulfonamides (2 a-l) in comparable yields.

Table 1.

One-pot synthesis of allyl-sulfonamides under sonication. 2a-l.

Inline graphic
Entry a Allyl R1 R2 Conventional stirring
 Sonication
Time (h) Yield (%)b Time (min) Yield (%)b
1 2a Ph 4-Br C6H4 11 70 27 75
2 2b Me C6H5 9 60 18 66
3 2c Ph C6H5 12 75 25 79
4 2d Me 4-MeO C6H4 8 56 16 65
5 2e Et 4-MeO C6H4 10 78 17 81
6 2f Ph C3H7 6 66 19 69
7 2 g Ph 4-MeO C6H4 10.5 75 21 83
8 2h Ph 4-Cl C6H4 14 55 26 69
9 2i Me 4-Me C6H4 9.5 60 15 69
10 2j Et 4-Cl C6H4 8.5 64 21 68
11 2k Et 4-Me C6H4 9 72 18 76
12 2l Me 4-Cl C6H4 13 77 22 86
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a

Phenyl/alkyl sulfonyl chloride (1.1 mmol), primary amine (1.0 mmol), K2CO3 (2.0 mmol) in EtOH/H2O (20 mL, 1:1) at 25 °C, then allyl bromide (1.1 mmol). b Isolated yield after purification.

3.2. Effect of sonication and different oxidant on one-pot synthesis of sulfonamides 4-substituted-isoxazolines

Next, we examined the reactivity of p-chlorobenzaldehyde 1a (1.0 equiv1) with hydroxylamine hydrochloride (1.5 equiv), and alkene 2 h (1.0 equiv) as the benchmark reaction for the 1,3-dipolar cycloaddition under oxidative condition leading to sulfonamides 4-substituted-isoxazolines (Table 2). For this purpose, different oxidizing agents were screened, with or without base, under conventional stirring or sonication, at room temperature (25 °C).

Table 2.

Optimization of the reaction conditions for the ‘one-pot’ synthesis of sulfonamide-isoxazolines under sonication.

Inline graphic
Entry a
 Oxidant
 Base
 Conventional stirring
 Sonication
(1 equiv) (1.2 equiv) Time (h) Yield (%) b Time (min) Yield (%) b
1 None – 12 nr 30 nr
2 NCS – 6 <10 20 15
3 NCS Et3N 5 50 16 65
4 p-Chloranil – 4 <5 15 10
5 p-Chloranil K2CO3 4 45 12 52
6 Chloramine-T – 6 20 17 36
7 Chloramine-T K2CO3 5 49 22 61
8 CAN K2CO3 6 56 20 75
9 TCCA – 4 72 12 87
10 TCCA K2CO3 4 70 12 86
11c TCCA – 4 71 12 89
12 d TCCA – 4 53 20 62
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a

aryl aldehyde/ HONH2.HCl (1/1.5 mmol), in EtOH/H2O (v/v, 1:1) at 25 °C.

b

Pure isolated yield under stirring and sonication (ultrasonic bath, 47 kHz).

c

Reaction conditions with 0.5 equiv of TCCA.

d

Reaction performed with 0.3 equiv of TCCA.

First, we proceeded to the optimization of the one-pot two steps conversion of the aldehyde 1a to the corresponding nitrile oxide, using different oxidants (1,0 equiv.) with or without base, and its cycloaddition with the model N-allyl compound 2 h (Table 2, entries 2–7). We first confirmed that the presence of an oxidant is mandatory (entry 1). Therefore, we subsequently assessed different oxidants (N-chlorosuccinimide, chloranil and chloramine-T), in the presence/absence of a base. It appeared that the reaction performs poorly when the base is omitted. Low yields of isolated product 3a were obtained under such conditions (10–36%, Table 2, entries 2, 4, 6). However, once the base is added the reactions proceed more smoothly and the isolated yields were improved. For instance, a 40% yield increase was observed with p-Chloranil in the presence of K2CO3 (Table 2, entries 4 and 5). Similarly, a 50% yield increase was observed for N-chlorosuccinimide in the presence of Et3N (Table 2, entries 2 and 3). Of note, the combination of ceric ammonium nitrate (CAN) as the oxidant, and K2CO3 [33] afforded the expected product 3a in good yield (75%, entry 8).

We then pursued our investigation using TCCA as the oxidant. While the other oxidants required presence of a base, TCCA could be used alone, without affecting the isolated yields. In fact, the desired product 3a was obtained in excellent yield, up to 87%, and short reaction time (Table 2, entries 9 and 10). It is noteworthy that the ultrasound assistance speeded up the reaction by 20-fold (12 min vs 4 h) compared with conventional stirring.

Afterwards, we focused on reducing the quantity of TCCA, decreasing from 1.0 equiv to 0.5 equiv promoted the reaction similarly in terms of yield and reaction time (Table 2, entry 11; 89 %). Although, a further decrease in the amount of TCCA (from 0.5 to 0.3 equiv.) induced a reduction in yield (Table 2, entry 12; 65%).

3.3. High efficiency synthesis of sulfonamides 4-substituted-isoxazolines 3a-r under sonication

After optimizing the experimental conditions, we explored the scope of this new one-pot reaction to synthesize a series of isoxazolines (Table 3).

All experiments were performed in short overall reaction time (12–22 min) and isolated yields ranged between 52 and 86% (Table 3). A variety of aldehyde substituents were explored first, by using either electron-donating groups such as methoxy and methyl or electron-withdrawing groups such as chlorine, bromine and nitro. All these substitutions were well tolerated. The corresponding cycloadducts were obtained in good yields (Table 3, entries 1–4, 11–14 and 17–18). In addition, the substrates with an electron donor or acceptor group all reacted well to generate the desired isoxazolines (3a-r) with good to high yields.

The isoxazolines (3a-r), were fully characterized by IR, 1H, 13C NMR, 2D NMR, MS and their HPLC traces were acquired. For example, the 1H NMR spectrum of N-[3-(3,4-Dichloro-phenyl)-isoxazolin-5-ylmethyl]-N-propyl-benzenesulfonamide 3 k showed a multiplet with a chemical shift δ = 5.06–4.92 ppm for the H-isoxazolinic proton, two doublets appear at δ = 3.10 and 3.39 ppm characteristic of the two CH2-isoxazolinic protons, two other signals in the form of doublets at δ = 3.54 and 3.46 ppm correspond to the two protons of methylene, thus the presence of the signals between 4.92 and 7.85 ppm attributable to the different aromatic protons. The 13C NMR spectrum showed characteristic signals at 11.13 ppm (CH2-CH2-CH3), 21.85 ppm (CH2-CH2-CH3), 37.70 ppm (CH2isoxazoline), 51.96 ppm (CH2-CH2-CH3), 50.99 ppm (N-CH2-CH), 80.69 ppm (CHisoxazoline) and 125.87–132.81, 127.13, 128.55, 129.24, 133.16 ppm attributable for aromatic carbons (Fig. 2).

Fig. 2.

Fig. 2

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Characteristic 1H, 13C NMR of 3 k.

The regioselectivity of the cycloaddition was further ascertained by X-ray diffraction of single crystal of 3 k. The single crystals were obtained by slow evaporation from a saturated ethanolic solution (Fig. 3). The crystallographic data (see ESI) relative to the structure of 3 k has been deposited with the Cambridge Crystallographic Data Centre [34].

Fig. 3.

Fig. 3

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The ORTEP diagram of novel single crystal of product (3 k).

3.4. The study of acceleration mechanism under sonication

In this work, the remarkable acceleration and yield improvement observed under US can be explained by the simultaneous coexistence of chemical and mechanical effects of ultrasound [35]; the chemical effects generating free radicals with a high propensity to react due to the implosion of microbubbles and the mechanical effects that enhance heterogeneous solid–liquid or liquid–liquid reactions due to microjets formed during cavitation [36]. In fact, cavitation accelerates much more easily mass transport between the two phases such as alkene and aldehyde that are poorly soluble at the beginning of the reaction. The 1,3-dipolar cycloaddition reaction can take place in both concerted or radical mechanism [37]. Depending on the reaction conditions used, TCCA can release either an electrophilic chlorine atom (Cl+) or a chlorine radical (Cl.) selectively promoting two plausible concerted and /or radical mechanistic approaches [38].

The use of direct-ultrasonic irradiation, the radical or radical-ion intermediates are generated more possibly in water [39]. For the present hypothesis, a series of control experiments were carried out (Scheme 2). The reaction yields have dramatically changed under different conditions. When a radical scavenger, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy), was added under sonication, a significant decrease in yield of 3a (≈ 55 %) was observed along with the formation of other non-identified products trapped by TEMPO (Scheme 2, a), which suggests that the reaction under ultrasonication evolves the two mechanisms i.e., radical and ionic. This observation was supported with other experiments under O2 or air as the radical initiator, without TEMPO under suitable conditions. The reaction gave the isoxazoline product 3a with excellent yields, 90% and 89% respectively (Scheme 2, b and c).

Scheme 2.

Scheme 2

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Radical scavenging and control experiments.

Based on the above-mentioned experimental observations, a plausible mechanism has been propozed as shown in scheme 3. Firstly, the chlorine radical atom (Cl.) and dichloroisocyanuric acid radical were generated by the homolytic cleavage of N–Cl bond in TCCA assisted by ultrasound [40]. The amidyl radical N-centered will then react as a proton acceptor during the first step of reaction with hydroxylamine hydrochloride to provide the aldoxime (not isolated) [32], which is then converted to hydroximoyl chloride with TCCA [41], [42]. The latter was subsequently oxidized to unstable bi-radical nitrile oxide (II) [43], promoted by the chemical effect of ultrasound, followed by a rapid 1,3-cycloaddition reaction with allyl-sulfonamide 2, to deliver the corresponding isoxazoline product (Path A, Scheme 3).

Scheme 3.

Scheme 3

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Plausible mechanism of the isoxazoline formation under heterogeneous ultrasound conditions.

Following similar approach, an electrophilic chlorine atom (Cl+) and cyanurate anion were generated from TCCA the mechanical effect of ultrasound that promotes an ionic process through the generation of nitrile oxide (III) which reacts with the alkene to give the corresponding isoxazoline by 1,3-cycloaddition reaction (Path B, scheme 3).

Taking into account all these considerations, we suggested that the mechanistic outcome of this heterogeneous reaction might be explained by a switch from a radical mechanism (Path A, scheme 3) to a concerted mechanism (Path B, scheme 3) upon sonication [44]. In both pathways the reaction affords only one regiosiomer 4-substituted isoxazoline. This high regioselectivity can be explained by considering the steric interactions that prevents the formation of C5-substituted isoxazolines in favor of the exclusive formation of C4-substituted isoxazolines [45]. In fact, the acceleration observed in this reaction is maybe due to the cooperative effects of ultrasound activation and the TCCA catalytic capacity.

4. Biology

All these newly synthesized isooxazoline 3a-r, were evaluated for their anti-cancer activity against K562 cell line (CML) at 1 µM 10 µM and 50 µM (48 h) using XTT and DAPI assays. This first screening against K562 cells revealed a couple of compounds (3 h and 3 l) decreases the cell viability between 10 and 50 µM. Thus, we decided to investigate further the biological effect of 3 h. It is interesting to note that these two compounds share the same structure except for the sulfonamide part (R1 = Ph for 3 h and R1 = CH3 for 3 l).

Next, we evaluated the dose–response effect of 3 h (12.5–100 µM) on HL-60 cell line (APL, Fig. 4-A). This was performed in a DAPI assay by flow cytometry. The percentage of HL-60 DAPI positive cells (dead cells) increased from 18% in the untreated control population (and at the dose of 12.5 µM) to 31, 44 and 67% in cultures treated by 3 h for 48 h with respectively 25, 50 and 100 µM doses. The determined value of EC50 (i.e. the concentration leading to a cell viability rate of 50%) of the compound 3 h on HL-60 cell was found at 62 ± 2 µM. In addition, to get insights into the mode of action of this new compound (3 h), we had a look at cell death mechanism induced by 3 h. HL-60 cells were treated for 48 h with 94 μM of 3 h and PARP (poly ADP-ribose polymerase, marker of apoptosis) and caspase 3 (apoptosis-related cysteine peptidase) cleavage were analyzed by Western blot (Fig. 4-B, 3-C). Compound 3 h display a strong induction of apoptosis when HL60 cells were treated at the EC50 concentration as suggested by cleavage of PARP and more evidently caspase 3.

Fig. 4.

Fig. 4

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Upper-left panel (A) HL-60 cells were treated with increasing doses (12.5–100 µM) of 3 h and cell viability was evaluated after 48 h with DAPI staining and flow cytometry analysis. Upper-right panel (B) HL-60 cells were treated with 94 μM of 3 h (48 h), and expression of cleaved forms of PARP and caspase 3 were analyzed by Western blot. HSP60 was used as loading control. Lower panel (C) Quantification of the cleaved form of PARP and caspase 3, normalized against loading control HSP60.

To confirm that 3 h induced a caspase dependent apoptotic cell death, we performed an AV/DAPI labeling in the presence of a pan-caspsae inhibitor (QvD) on HL60 cell line at 24 and 48 h (Fig. 5). While 3 h alone induced a significant drop in the cell viability, the co-treatment with QvD completely restored it. In fact, the co-treatment induced a cell viability comparable with control experiment (untreated cells). This experiment shows us in a formal way that the death induced by compound 3 h is a caspases-dependent process at 24 and 48 h, thus confirming the first results obtained by western blot (Fig. 4).

Fig. 5.

Fig. 5

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HL-60 cells were treated during 24 h or 48 h with 94 μM of 3 h in presence or absence of QvD (Av = Annexin V).

5. Conclusion

In summary, we reported the synthesis, chemical characterization and anticancer activity of a novel functionalized 3,5-disubstituted sulfonamide-isoxazoline series. These molecules were synthesized using a new, versatile and efficient “two-step one-pot” methodology through a 1,3-dipolar cycloaddition reaction. This environmentally friendly process was carried out efficiently in an aqueous medium. It is based on the use of inexpensive and environmentally friendly TCCA as an oxidant to generate nitrile oxides in-situ. In addition, the use of a cooperative effect of ultrasound activation and TCCA catalytic capacity allows significant reaction rate acceleration. Among this series of isoxazoline analogues one compound, 3 h, impairs the cell viability of leukemia K562 and HL-60 cells. In addition, 3 h behaved as an apoptotic cell death inducer. Altogether, these results clearly demonstrated the potential of this class of molecules for the optimization of apoptosis inducer owing to their ease of synthesis the herein report two-step one-pot strategy.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financially supported by Erasmus + program, key action 1 “Mobility of persons for education and training” (2018-2019), CNRST-Morocco, UM5-Rabat, Université Côte d’Azur-Nice (UCA) and UM6P-Benguérir, and are gratefully acknowledged.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ultsonch.2021.105748.

Contributor Information

Anthony R. Martin, Email: anthony.martin@umontpellier.fr.

Khalid Bougrin, Email: k.bougrin@um5r.ac.ma.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1
mmc1.docx (2.8MB, docx)

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