HETEROCYCLES

Note | Special issue | Vol. 82, No. 1, 2010, pp. 825-832
Received, 28th February, 2010, Accepted, 15th April, 2010, Published online, 16th April, 2010.
DOI: 10.3987/COM-10-S(E)10

■ An Efficiently Sonochemical Synthesis of 2-(N-Arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines

Hui Xu,* Zhi-ping Che, and Qin Wang

Laboratory of Pharmaceutical Design & Synthesis, College of Life Sciences, Northwest A & F University, Yangling, Shaanxi, 712100, China

Abstract

An efficient and rapid synthesis of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines from N-arylsulfonyl-3-formylindole benzoyl hydrazones and anhydrides under ultrasonic irradiation in good yields is described.

The N-arylsulfonylindole subunits have gained widespread interest due to their key roles in medically important species, such as those displaying serotonin receptor affinity,1 potent antagonists against the peptidoleukotrienes,2 and anti-HIV-1 activity.3,4 On the other hand, the 1,3,4-oxadiazoline ones exhibit antibacterial activity,5 inhibiting activity against chitin synthesis,6 and antiviral activity.7 In continuation of our program aimed at the discovery and development of compounds with superior biological activities, therefore, we want to prepare some 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazoline analogs by combining the N-arylsulfonylindole units with the 1,3,4-oxadiazolines together.
Ultrasound has increasingly been used in organic synthesis in recent years. Compared with the traditional methods with stirring, many organic reactions could be carried out in higher yields, shorter reaction time and milder reaction conditions under ultrasonic irradiation.8 However, to the best of our knowledge, the ultrasound-assisted synthesis of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines from hydrazones and anhydrides has not yet been studied. Herein we report the synthesis of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines (3a-n) from N-arylsulfonyl-3- formylindole benzoyl hydrazones (1a-l) and anhydrides (2a-b) by ultrasonic irradiation (Scheme 1).

We firstly investigated the reaction of N-toluenesulfonyl-3-formylindole benzoyl hydrazone (1a) with acetic anhydride (2a) under different reaction conditions, and the results were summarized in Table 1. When the reaction mixture of 1a and 2a was stirred under the traditional conditions at 25 oC, 40 oC, or 60 oC for 48 h, the corresponding yields of 2-(N-toluenesulfonyl indol-3-yl)-3-N-acetyl-5-phenyl-1,3,4- oxadiazoline (3a) were < 2%, 22%, and 57%, respectively (Table1, entries 1, 3 and 5). Even if the reaction temperature was raised to 80 oC for 12 h, the yield of 3a was only 54% (Table1, entry 6), and when the reaction time was prolonged to 24 h, 3a was obtained in the 80% yield. On the contrary, once 1a reacted with 2a under ultrasonic irradiation, the yields were improved and the reaction time was shortened (Table1, entries 8-11). For example, when the mixture was reacted at 58 oC for 10 h under ultrasonic irradiation, the yield of 3a was 68% (Table1, entries 4 and 5 vs. 9). Consequently, the ultrasound could accelerate the synthesis of 3a. Especially, when the reaction temperature was raised from 68 oC to 78 oC, the yield of 3a was improved from 79% to 89%, while the reaction time was reduced from 10 h to 4 h (Table1, entries 10 and 11). Obviously, the ultrasonic irradiation and the reaction temperature were two very important factors to the above reaction. The optimized reaction condition for the synthesis of 3a was the reaction of 1a with 2a at 78 oC under ultrasonic irradiation.

Based upon the above findings, we further studied the reaction of different N-arylsulfonyl-3-formylindole benzoyl hydrazones (1a-l) with anhydrides (2a-b) at 78 oC under ultrasonic irradiation. As shown in Table 2, a wide range of 1 (R1 = H, Me, CN; and R2 = Me, Cl, NO2, OMe), including electron-withdrawing and electron-donating substituents, efficiently reacted with 2 (R3 = Me, Et) under the optimum reaction conditions. 2-(N-Arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines (3a-n) were obtained in 75-89% yields for 4-7 h. For example, when N-toluenesulfonyl-3- formyl-6-methylindole benzoyl hydrazone (1c) reacted with acetic anhydride (2a) at 78 oC for 5 h under ultrasonic irradiation, 2-(N-toluenesulfonyl-6-methylindol-3-yl)-3-N-acetyl-5-phenyl-1,3,4-oxadiazoline (3c) was obtained in a 76% yield (Table 2, entry 3); when N-toluenesulfonyl-3-formyl-5-cyanoindole benzoyl hydrazone (1k) reacted with acetic anhydride (2a) at 78 oC for 7 h under ultrasonic irradiation, the yield of 2-(N-toluenesulfonyl-5-cyanoindol-3-yl)- 3-N-acetyl-5-phenyl-1,3,4-oxadiazoline (3k) was 88% (Table 2, entry 11). On the other hand, when the propionic anhydride (2b) reacted with 1a or 1k at 78 oC under ultrasonic irradiation, the corresponding yields of 3m and 3n were 88% for 5.5 h, and 87% for 6.5 h, respectively (Table 2, entries 13 and 14).
Meanwhile, to obtain the precise three-dimensional structural information of 3a-n, the structure of 2-(N-4-chlorophenylsulfonyl-6-methylindol-3-yl)-3-N-acetyl-5-phenyl-1,3,4-oxadiazoline (3h) was confirmed by X-ray crystal analysis (Figure 1).9

The above results might be due to the “cavitation” from ultrasonic waves propagating in a liquid medium. During the rarefaction cycle of the wave, the molecules of the liquid are separated, generating bubbles that subsequently collapse in the compression cycle. These rapid and violent implosions generate short-lived regions with high temperatures and pressures, therefore, the highly reactive species are locally produced, and the energy of sound is transformed into a useful chemical form.10 Accordingly, sonication could probably provide more efficient influence on the reactions than the traditional conditions with stirring, and reduce the reaction time sharply.
In summary, we have described an efficient and rapid method for the synthesis of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines from N-arylsulfonyl-3-formylindole benzoyl hydrazones with acetic or propionic anhydride in good yields under ultrasonic irradiation. Compared to the traditional conditions using stirring, the main advantage of the present procedure is milder conditions and shorter reaction time.

EXPERIMENTAL
The materials were used as purchased. Analytical thin-layer chromatography (TLC) and preparative thin-layer chromatography (PTLC) were performed with silica gel plates using silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were uncorrected. 1H NMR spectra were recorded on a Bruker Avance DMX 300 or 400 MHz instrument using TMS as an internal standard and CDCl3 as a solvent. EI-MS and ESI-TRAP-MS were carried out with the HP 5988, and the Bruker ESI-TRAP Esquire 3000 plus mass spectrometry instruments, respectively. HRMS were carried out with APEX II Bruker 4.7T AS instrument. Ultrasonic irradiation was performed in Ningbo SB-5200DT ultrasonic cleaner with the size of the interior trough of 300 × 240 × 150 mm, the frequency of 40 kHz, and an output power of 200 W. The temperature of the water bath was controlled by addition or removal of water.
General procedure for the preparation of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4- oxadiazolines (3a-n) by ultrasonic irradiation
The 50 mL rockered flask which was filled with a mixture of 1 (0.5 mmol) and 2 (5 mL) was immersed into the zone of maximum cavitation of water bath of ultrasonic cleaner, and the surface of the reaction mixture was kept at a slightly lower level than the level of the water in the bath. Subsequently, the mixture was irradiated by ultrasound at 78 oC until complete consumption of the starting material checked by TLC, and the reaction time was indicated in Table 2. Then the reaction mixture was poured into ice water and stirred until the precipitate was produced, which was filtered, washed with water, and dissolved in CH2Cl2 (30 mL). Finally, the organic solution was washed with saturated aqueous NaHCO3 (30 mL × 2), brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by preparative TLC to give the pure 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines (3a-n). All compounds were characterized by 1H-NMR (300 or 400 MHz), EI-MS and mp. The yields of 3a-n were listed in Table 2.
Compound 3a: White solid, mp 54-55 oC; 1H-NMR (300 MHz, CDCl3) δ: 7.78-7.94 (m, 6H), 7.44-7.52 (m, 4H), 7.22-7.33 (m, 5H), 2.35 (s, 6H); EI-MS m/z: 459 (M+, 30); HRMS: Calcd. for C25H21N3O4NaS (M+Na+): 482.1145. Found: 482.1148.
Compound 3b: Yellow solid, mp 99-100 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 8.71 (s, 1H), 8.54 (d, J = 6.3 Hz, 2H), 8.42 (d, J = 6.3 Hz, 1H), 7.82-8.06 (m, 4H), 7.30-7.57 (m, 7H), 2.24 (s, 3H); EI-MS m/z: 490 (M+, 5); HRMS: Calcd. for C24H18N4O6NaS (M+Na+): 513.0839. Found: 513.0837.
Compound 3c: White solid, mp 145-146 °C; 1H-NMR (300 MHz, CDCl3) δ: 7.89 (d, J = 7.2 Hz, 2H), 7.73-7.79 (m, 4H), 7.24-7.50 (m, 7H), 7.03 (d, J = 7.8 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 6H); EI-MS m/z: 473 (M+, 10); HRMS: Calcd. for C26H23N3O4NaS (M+Na+): 496.1301. Found: 496.1308.
Compound 3d: Yellow solid, mp 54-55 °C; 1H-NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H), 7.88-7.95 (m, 4H), 7.80 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.30-7.52 (m, 7H), 2.33 (s, 3H); EI-MS m/z: 524 (M+, 3); HRMS: Calcd. for C24H17N4O6NaSCl (M+Na+): 547.0450. Found: 547.0457.
Compound 3e: Yellow solid, mp 81-82 °C; 1H-NMR (300 MHz, CDCl3) δ: 8.77 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 9.9 Hz, 2H), 7.66-7.71 (m, 1H), 7.37-7.54 (m, 4H), 7.29 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H); EI-MS m/z: 504 (M+, 28); HRMS: Calcd. for C25H20N4O6NaS (M+Na+): 527.0996. Found: 527.0994.
Compound 3f: Yellow solid, mp 84-85 °C; 1H-NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H), 7.87-7.90 (m, 3H), 7.73 (s, 2H), 7.62-7.65 (m, 1H), 7.27-7.52 (m, 5H), 7.09 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.32 (s, 3H); EI-MS m/z: 538 (M+, 85); HRMS: Calcd. for C25H19N4O6NaSCl (M+Na+): 561.0606. Found: 561.0613.
Compound 3g: White solid, mp 148-149 °C; 1H-NMR (300 MHz, CDCl3) δ: 7.81-7.93 (m, 6H), 7.19-7.52 (m, 9H), 2.35 (s, 3H); EI-MS m/z: 479 (M+, 70); HRMS: Calcd. for C24H18N3O4NaSCl (M+Na+): 502.0599. Found: 502.0592.
Compound 3h: White solid, mp 221-222 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (s, 1H), 8.10 (d, J = 5.7 Hz, 2H), 7.78-7.82 (m, 3H), 7.73 (d, J = 6.9 Hz, 2H), 7.52-7.59 (m, 3H), 7.43 (s, 1H), 7.09-7.23 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H); MS (ESI-TRAP) m/z: 494 ((M+H)+, 100); HRMS: Calcd. for C25H20N3O4NaSCl (M+Na+): 516.0755. Found: 516.0759.
Compound 3i: White solid, mp 63-64 °C; 1H-NMR (400 MHz, CDCl3) δ: 7.83-7.93 (m, 6H), 7.49-7.52 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.28-7.33 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H), 3.82 (s, 3H), 2.35 (s, 3H); EI-MS m/z: 475 (M+, 24); HRMS: Calcd. for C25H21N3O5NaS (M+Na+): 498.1094. Found: 498.1089.
Compound 3j: White solid, mp 78-79 °C; 1H-NMR (400 MHz, CDCl3) δ: 7.83-7.88 (m, 4H), 7.76 (s, 1H), 7.73 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H); EI-MS m/z: 489 (M+, 56); HRMS: Calcd. for C26H23N3O5NaS (M+Na+): 512.1251. Found: 512.1260.
Compound 3k: White solid, mp 231-232 °C; 1H-NMR (400 MHz, CDCl3) δ: 8.04 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.87-7.89 (m, 3H), 7.81 (d, J = 8.0 Hz, 2H), 7.52-7.58 (m, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.31 (d, J = 9.6 Hz, 3H), 2.37 (s, 6H); MS (ESI-TRAP) m/z: 485 ((M+H)+, 65); HRMS: Calcd. for C26H20N4O4NaS (M+Na+): 507.1097. Found: 507.1094.
Compound 3l: Yellow solid, mp 227-228 °C; 1H-NMR (300 MHz, CDCl3) δ: 8.78 (s, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.86-7.94 (m, 4H), 7.79 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.44-7.54 (m, 3H), 7.30 (s, 1H), 2.36 (s, 3H); MS (ESI-TRAP) m/z: 516 ((M+H)+, 100); HRMS: Calcd. for C25H17N5O6NaS (M+Na+): 538.0792. Found: 538.0797.
Compound 3m: White solid, mp 119-120 °C; 1H-NMR (300 MHz, CDCl3) δ: 7.78-7.94 (m, 6H), 7.18-7.51 (m, 9H), 2.69-2.79 (m, 2H), 2.34 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H); EI-MS m/z: 473 (M+, 8); HRMS: Calcd. for C26H23N3O4NaS (M+Na+): 496.1301. Found: 496.1306.
Compound 3n: White solid, mp 174-175 °C; 1H-NMR (300 MHz, CDCl3) δ: 7.79-8.04 (m, 7H), 7.45-7.58 (m, 4H), 7.28-7.36 (m, 3H), 2.71-2.78 (m, 2H), 2.37 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H); EI-MS m/z: 498 (M+, 7); HRMS: Calcd. for C27H22N4O4NaS (M+Na+): 521.1254. Found: 521.1255.

ACKNOWLEDGEMENTS
This work has been supported by the program for New Century Excellent University Talents, State Education Ministry of China (NCET-06-0868), and the Key Project of Chinese Ministry of Education (No.107105).

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