Sage Journals: Discover world-class research

Abstract

A facile one-pot synthesis of highly functionalized dialkyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate derivatives via the reaction between acetylenic esters, triphenylphosphine, and ethyl 2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino]-2-oxoacetate is developed. The structure of the products is confirmed by spectroscopic methods.

Keywords

acetylenic esters intramolecular Wittig reaction pyrrolidinone ethyl 2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino]-2-oxoacetate triphenylphosphine

One-pot synthesis of 4-ethyl 2,3-dimethyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3,4-tricarboxylate derivatives via intramolecular Wittig reaction.

Introduction

Exhibiting interesting biological behavior, heterocyclic compounds have found a special place in the pharmaceutical industry.^1,2 Many substances containing five-membered heterocycles demonstrate a variety of interesting biological activities. In this category, 1,3,4-thiadiazoles and 2-pyrrolidinones have been used as structural motifs in the construction of substances having multi-target active, such as anti-inflammatory,^3,4 antimicrobial,⁵ anticonvulsant,^6,7 and antihypertensive.^8,9 1,3,4-Thiadiazoles have also been frequently used as important building blocks for the synthesis of biologically active heterocyclic molecules. Heterocycles, bearing a 1,3,4-thiadiazole moiety, are reported to demonstrate a broad spectrum of biological activity such as antimicrobial, tranquilizer, antiepilepsy, antiinflamatory, antiviral, anti-coagulant, and antitumor (Figure 1, structures A and B).^10,11 As for other examples, and compound C displays both antibacterial along with antifungal activity, while compound D is an effective antitumor agent (Figure 1).¹²

Figure 1.

Biologically active thiadiazole and lactam molecules.

Moreover, 2-pyrrolidinones, as a class of five-membered lactams with a four-carbon heterocyclic ring structure, are of interest to biologists.^13,14 2-Pyrrolidinone play a significant role in natural products and pharmaceuticals. Some known biologically important natural products comprising a 2-pyrrolidinone unit are cotinine, a tobacco alkaloid,¹⁵ doxapram, a respiratory stimulatant,¹⁶ and ethosuximide, a succinimide containing anticonvulsant.¹⁷ Moreover, substituted 2-pyrrolidinone derivatives have various therapeutic properties, for example, anti-cancer,¹⁸ antitumor,¹⁹ HIV-1 integrase inhibition,^20,21 antimicrobial,²² antibacterial,²³ and anti-inflammatory.²⁴ In addition, the 2-pyrrolidinone moiety is used in the drug PI-091, consisting of anti-coagulant properties, as well as in Jatropham, which is an antitumor alkaloid (Figure 1, structures E and F).^25,26 Due to their importance, a variety of synthetic protocols have been reported for the preparation of substituted pyrrolidinones.^27–36

The Wittig reaction of phosphonium ylides with carbonyl compounds has been adopted widely for the construction of C=C double bonds in an inter- or intramolecular approach under mild reaction conditions.^37,38 The intramolecular Wittig reaction is one of the most common methods for the synthesis of different five-membered heterocycles through intramolecular cyclization of phosphorus ylides with various carbonyl groups, such as aldehyde, ketone, ester, amide, and imide.^39–43 To date, a number of synthetic approaches to pyrrolidinones structures have been developed.^44–49 In 2007, Anary-Abbasinejad et al.⁵⁰ reported the synthesis of novel highly functionalized pyrrolidinones via intramolecular Wittig reactions. Inspired by the biological profiles of 1,3,4-thiadiazoles and pyrrolidinones and as part of our interest in the synthesis of heterocyclic compounds via intramolecular Wittig reactions,^51,52 we sought to synthesize the title compounds. For this purpose, first ethyl chlorooxoacetate was reacted with 2-amino-1,3,4-thiadiazoles for the synthesis of ethyl 2-oxo-2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino]acetate derivatives (Scheme 1). Subsequent reaction with triphenylphosphine and acetylenic esters gave the desired products (Scheme 2).

Scheme 1.

Synthesis of ethyl 2-oxo-2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino] acetates.

Scheme 2.

Synthesis of the final products.

Results and discussion

Initially, a model reaction was conducted using triphenylphosphine (1 mmol), ethyl (5-benzyl-1,3,4-thiadiazol-2-ylcarbamoyl)formate (3a) (1 mmol), and dimethyl acetylenedicarboxylate (DMAD) (4a) (1 mmol) in CH₂Cl₂ at room temperature. This model reaction was examined under different conditions, as shown in Table 1. Upon changing the solvent, temperature, and amount of triphenylphosphine, it was found that using CH₂Cl₂ and 1.5 equiv. of Ph₃P the desired product can be afforded in 70% yield in 24 h (Table 1, entry 8).

Table 1.

Optimization of the reaction conditions.


Entry	Solvent	Time (h)	Temperature	Yield (%)
1	EtOAc	24	r.t.	50
2	MeCN	24	r.t.	65
3	MeCN	24	Reflux	65
4	EtOH	24	r.t.	43
5	THF	24	r.t.	27
6	DMF	24	r.t.	10
7	Et₂O	24	r.t.	60
8	CH₂Cl₂	24	r.t.	70
9	CH₂Cl₂	12	r.t.	50

Ultimately, CH₂Cl₂, room temperature, and 1.5 mmol triphenylphosphine were selected as the optimized conditions. With optimized conditions established, we next tested the scope of various reactants. Ethyl 2-oxo-2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino]acetates 3 were examined in reactions with dialkyl acetylenedicarboxylates 4 in the presence of Ph₃P via a one-pot procedure leading to the corresponding products 5a–n in 48%–85% yields (Table 2). Ethyl 2-oxo-2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino] acetates containing electron-donating groups at positions 5, such as benzyl-, phenyl-, 4-methylphenyl-, and 3-methyphenyl-thiadiazole, exhibited good reactivities (5, 51%–71% yield). Ethyl 2-oxo-2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino] containing electron-withdrawing groups such as 4-bromophenyl group were also well tolerated (5i, 85% and 5n, 48%).

Table 2.

Synthesis of compounds 5a–n.


Product	R¹	R²	Yield (%)
5a	C₆H₅–CH₂–	Me	70
5b	4-Me–C₆H₄–	Me	55
5c	3-Me–C₆H₄–	Me	79
5d	C₆H₅–	Me	57
5e	C₆H₅–CH₂–	Et	51
5f	4-Me–C₆H₄–	Et	54
5g	3-Me–C₆H₄–	Et	71
5h	C₆H₅–	Et	69
5i	4-Br–C₆H₄–	Et	85
5j	C₆H₅–CH₂–	i-Pr	71
5k	4-Me–C₆H₄–	i-Pr	67
5l	3-Me–C₆H₄–	i-Pr	61
5m	C₆H₅–	i-Pr	72
5n	4-Br–C₆H₄–	i-Pr	48

The structure elucidation of compounds 5a–n was carried out on the basis of ¹H NMR, ¹³C NMR, Fourier-transform infrared spectroscopy (FTIR), mass spectrometry, and elemental analysis (Supplemental material). For example, the ¹H NMR spectrum of 5a contained a triplet for CH₃ (1.42 ppm, ${}^{3}{J_{HH}} = 6.0 Hz$ ), two singlets for CH₃O (3.84 and 3.85 ppm), a singlet for PhCH₂ (4.36 ppm), a quartet for OCH₂ (4.75 ppm, ${}^{3}{J_{HH}} = 6.0 Hz$ ), a singlet for CH (5.58 ppm), and a multiplet for ArH (7.28–7.34 ppm). The ¹H-decoupled ¹³C NMR spectrum of 5a is in agreement with the suggested structure. The mass spectrum of 5a, for example, demonstrated the molecular ion peak at m/z = 418. Also, the IR spectrum of compound 5a showed absorption bands at 1750, 1641, and 1702 cm⁻¹ due to the nonconjugated, conjugated, and Y-lactam carbonyl groups.

The reaction mechanism is presented in Scheme 3. The initial step is formation of zwitterion intermediate A from the reaction of Ph₃P and dicarboxylate 4. Next, the intermediate A is protonated by the NH amide of 3 to produce triphenylphosphonium salt B. The resulting phosphonium salt B is attacked by the conjugate base of the NH acid to give ylide C, which undergoes intramolecular cyclization to produce triphenylphosphine oxide and product 5 (Scheme 3).

Scheme 3.

The mechanism of reaction.

Conclusion

In summary, we have established that the one-pot reaction between Ph₃P, acetylenic esters 4 and 2-[(5-aryl-1,3,4-thiadiazol-2-yl)amino]-2-oxoacetates 3 represents a simple method for the preparation of dialkyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylates 5 of potential synthetic and pharmacological interest. The ready availability of the starting materials, the simplicity of the reaction, and mild conditions are among the distinguishing features of this method. The present method is applied under neutral conditions with no prior activation required.

Experimental

Melting points were determined on an Electrothermal 9100 apparatus. Infrared (IR) spectra were recorded using a Nicolet Avatar 370 FTIR Therma spectrometer as KBr pellets and are reported in cm⁻¹. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX-300 Avance instrument at 300 and 75.47 MHz, respectively. CDCl₃ were used as the solvent and shifts are given in ppm. Elemental analyses were performed using a Thermo Finnegan Flash EA 1112 series instrument. Mass spectra were recorded with a Varian Meth ch-7 at 70 eV. Column chromatography was performed on silica gel (160–200 mesh, E. Merck). Thiadiazole derivatives 3, were prepared according to the literature source.⁵³

Dimethyl 1-(5-benzyl-1,3,4-thiadiazol-2-yl)-4-ethoxy-2,5-dihydro-5-oxo-1H-pyrrole-2,3-dicarboxylate (5a); typical procedure

To a stirred solution of ethyl (5-benzyl-1,3,4-thiadiazol-2-ylcarbamoyl)formate (5a; 0.291 g, 1 mmol) and Ph₃P (0.393 g, 1.5 mmol) in CH₂Cl₂ (10 mL) at room temperature was added dropwise a solution of DMAD (0.142 g, 1.0 mmol) in CH₂Cl₂ (2 mL) over 10 min. The reaction mixture was stirred for 24 h. The solvent was removed under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (hexane/EtOAc) to obtain the dimethyl 1-(5-benzyl-1,3,4-thiadiazol-2-yl)-4-ethoxy-2,5-dihydro-5-oxo-1H-pyrrole-2,3-dicarboxylate (5a) (0.292 g, 70%) as a pale yellow powder.

Pale yellow powder (0.292 g, 70%), m.p. 118 °C–119 °C; IR (KBr) (υ_max/cm⁻¹): 1750, 1702, 1641 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.42 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz,$ CH₂ CH₃), 3.84 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.36 (2H, s, CH₂), 4.75 (2H, q, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂), 5.58 (1H, s, CH), 7.28–7.34 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.63, 36.42, 52.36, 53.63, 59.88, 69.09, 114.46, 127.55, 128.88, 129.06, 136.66, 152.44, 156.38, 161.58, 162.48, 166.04, 167.53; MS m/z (%) = 418 (M⁺+1, 37), 416 (100), 401 (38), 355 (10), 312 (85), 294 (43), 266 (50), 200 (17), 148 (45), 90 (47), 59 (10), 29 (22). Anal. calcd for C₁₉H₁₉N₃O₆S (417.44): C, 54.67; H, 4.59; N, 10.07%. Found: C, 54.94; H, 4.59; N, 10.35%.

Dimethyl 4-ethoxy-5-oxo-1-[5-(p-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5b): White powder: (0.300 g, 55%), m.p. 178 °C; IR (KBr) (υ_max/cm⁻¹): 1747, 1725, 1698 (3 C=O), ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.49 (3H, t, ${}^{3}{J_{HH}} = 9.0 Hz,$ CH₂ CH₃), 2.44 (3H, s, OCH₃), 3.89 (3H, s, OCH₃), 3.90 (3H, s, CH₃), 4.83 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.68 (1H, s, CH), 7.31 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar), 7.85 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 10.91, 16.76, 47.65, 48.95, 55.25, 64.28, 109.71, 122.50, 122.62, 125.14, 136.73, 147.77, 150.45, 156.87, 157.78, 159.94, 162.78; MS m/z (%) = 417 (M⁺, 55), 416 (100), 355 (17), 312 (100), 294 (65), 266 (85), 200 (30), 173 (27), 134 (30), 116 (22), 59 (25), 28 (17). Anal. calcd for C₁₉H₁₉N₃O₆S (417.44): C, 54.67; H, 4.59; N, 10.07%. Found: C, 54.91; H, 4.39; N, 9.77%.

Dimethyl 4-ethoxy-5-oxo-1-[5-(m-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5c): White powder: (0.330 g, 79%), m.p. 160 °C–162 °C; IR (KBr) (υ_max/cm⁻¹): 1748, 1719, 1702 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.45 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 2.40 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 3.85 (3H, s, CH₃), 4.78 (2H, q, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂), 5.64 (1H, s, CH), 7.26–7.76 (4H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.60, 36.42, 52.33, 53.61, 59.84, 69.06, 77.20, 84.84, 114.39, 127.53, 128.85, 129.03, 136.60, 152.42, 156.35, 161.56, 162.29, 166.04, 167.50; MS m/z (%) = 418 (M⁺+1, 40), 415 (100), 400 (22), 356 (35), 312 (95), 267 (95), 200 (78), 173 (83), 134 (70), 117 (95), 91 (48), 59 (95), 29 (67). Anal. calcd for C₁₉H₁₉N₃O₆S (417.44): C, 54.67; H, 4.59; N, 10.07%. Found: C, 54.35; H, 4.34; N, 9.81%.

Dimethyl 4-ethoxy-5-oxo-1-[5-phenyl-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5d): pale yellow powder: (0.228 g, 57%), m.p. 153 °C–154 °C; IR (KBr) (υ_max/cm⁻¹): 1750, 1720, 1699 (3 C=O), ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.45 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 3.85 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.79 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.65 (1H, s, CH), 7.70 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.60, 52.37, 53.66, 59.95, 69.20, 114.44, 127.39, 129.16, 129.92, 130.97, 152.41, 155.44, 161.55, 162.52, 164.49, 167.46; MS m/z (%) = 403 (M⁺, 10), 400 (100), 298 (47), 280 (25), 253 (33), 202 (10), 160 (20), 103 (13), 59 (8), 29 (30). Anal. calcd for C₁₈H₁₇N₃O₆S (403.41): C, 53.59; H, 4.25; N, 10.42%. Found: C, 53.37; H, 3.96; N, 10.22%.

Diethyl 1-[5-benzyl-1,3,4-thiadiazol-2-yl]-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5e): pale yellow liquid; (0.226 g, 51%); IR (KBr) (υ_max/cm⁻¹): 1740, 1722, 1638 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.29 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂CH₃), 1.33 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂CH₃), 1.39 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂CH₃), 4.24–4.32 (4H, m, OCH₂), 4.34 (2H, s, CH₂), 4.71 (2H, q, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂) 5.58 (1H, s, CH), 7.24–7.35 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 14.04, 15.52, 36.38, 60.09, 61.43, 62.73, 69.07, 84.84, 114.67, 127.49, 128.81, 129.00, 136.64, 152.28, 156.41, 160.99, 162.56, 165.97, 166.87; MS m/z (%) = 445 (M+, 65), 398 (32), 369 (95), 340 (95), 294 (94), 266 (100), 241 (37), 200 (87), 173 (92), 148 (47), 116 (26), 91 (95), 53 (10), 30 (92). Anal. calcd for C₂₁H₂₃N₃O₆S (445.49): C, 56.62; H, 5.20; N, 9.43%. Found: C, 56.35; H, 4.96; N, 9.32%.

Diethyl 4-ethoxy-5-oxo-1-[5-(p-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5f): White powder (0.240 g, 54%), m.p. 124 °C–125 °C; IR (KBr) (υ_max/cm⁻¹): 1742, 1724, 1710 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm)= 1.31 (3H, t, ${}^{3}{J_{HH}} = 9.0 Hz$ , CH₂ CH₃), 1.34 (3H, t, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂ CH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 2.39 (3H, s, CH₃), 4.24–4.33 (4H, m, OCH₂), 4.76 (2H, q, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂), 5.63 (1H, s, CH), 7.26 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar), 7.81 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 13.97, 14.05, 15.53, 21.44, 60.20, 61.45, 62.77, 69.17, 114.72, 127.23, 127.31, 129.81, 141.34, 152.29, 155.20, 161.02, 162.60, 164.54, 166.83; MS m/z (%) = 445 (M⁺, 100), 369 (42), 340 (92), 312 (98), 294 (93), 266 (100), 200 (50), 174 (47), 134 (38), 116 (65), 29 (100). Anal. calcd for C₂₁H₂₃N₃O₆S (445.49): C, 56.62; H, 5.20; N, 9.43%. Found: C, 56.76; H, 5.10; N, 9.62%.

Diethyl 4-ethoxy-5-oxo-1-[5-(m-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5g): White powder (0.318 g, 71%), m.p. 97 °C–98 °C; IR (KBr) (υ_max/cm⁻¹): 1754, 1726, 1699 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.31 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 1.35 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 2.41 (3H, s, CH₃), 4.25–4.34 (4H, m, OCH₂), 4.76 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.65 (1H, s, CH), 7.29–7.37 (4H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 14.06, 15.54, 21.29, 60.26, 61.48, 62.79, 69.20, 84.84, 114.70, 124.63, 127.94, 129.02, 129.84, 131.72, 138.99, 152.29, 155.40, 161.02, 162.63, 164.63, 166.84; MS m/z (%) = 445 (M⁺, 100), 397 (5), 369 (58), 340 (90), 313 (100), 294 (90), 266 (100), 200 (50), 174 (55), 134 (33), 116 (60), 90 (18), 30 (85). Anal. calcd for C₂₁H₂₃N₃O₆S (445.49): C, 56.62; H, 5.20; N, 9.43%. Found: C, 56.90; H, 4.96; N, 9.14%.

Diethyl 4-ethoxy-5-oxo-1-[5-phenyl-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5h): White powder (0.308 g, 69%), m.p. 99 °C–101 °C; IR (KBr) (υ_max/cm⁻¹): 1736, 1719, 1701 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.31 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 1.35 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 4.25–4.34 (4H, m, OCH₂), 4.76 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.64 (1H, s, CH), 7.45–7.94 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 13.98, 14.06, 15.54, 60.21, 61.49, 62.81, 69.21, 114.75, 127.41, 129.14, 129.97, 130.91, 152.25, 155.51, 161.01, 162.65, 164.42, 166.82; MS m/z (%) = 431 (M⁺, 100), 416 (13), 364 (45), 355 (85), 327 (87), 299 (87), 253 (93), 166 (79), 160 (79), 102 (79), 76 (68), 52 (32), 29 (95). Anal. calcd for C₂₀H₂₁N₃O₆S (431.46): C, 55.68; H, 4.91; N, 9.74%. Found: C, 55.58; H, 4.83; N, 9.60%.

Diethyl 1-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5i): White powder (0.432 g, 85%), m.p. 128 °C–129 °C; IR (KBr) (υ_max/cm⁻¹): 1736, 1726, 1703 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm)= 1.31 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 1.35 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂ CH₃), 4.25–4.34 (4H, m, OCH₂), 4.75 (2H, q, ${}^{3}{J_{HH}} = 9.0 Hz$ , OCH₂), 5.64 (1H, s, CH), 7.60 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar), 7.80 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 13.98, 14.06, 15.52, 60.23, 61.53, 62.85, 69.26, 84.84, 114.84, 125.31, 128.73, 132.38, 152.15, 155.63, 160.97, 162.69, 163.26, 166.75; MS m/z (%) = 510 (M⁺, 78), 464 (5), 437 (78), 407 (79), 358 (78), 330 (80), 264 (48), 236 (45), 197 (43), 181 (75), 125 (55), 98 (50), 53 (45), 30 (100). Anal. calcd for C₂₀H₂₀BrN₃O₆S (510.36): C, 47.07; H, 3.95; N, 8.23%. Found: C, 47.38; H, 3.94; N, 8.05%.

Diisopropyl 1-[5-benzyl-1,3,4-thiadiazol-2-yl]-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5j): Colorless liquid (0.336 g, 71%); IR (KBr) (υ_max/cm⁻¹): 1739, 1719, 1638 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.24 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.32 (9H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , 3 CHCH₃), 1.40 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 4.35 (2H, s, CH₂), 4.69 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.07 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.14 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.54 (1H, s, CH), 7.24–7.35 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.47, 21.51, 21.55, 21.73, 21.77, 36.38, 60.40, 68.95, 69.45, 70.84, 84.84, 115.30, 127.47, 128.79, 128.99, 136.70, 151.92, 156.47, 160.59, 165.92, 166.18; MS m/z (%) = 473 (M⁺, 25), 428 (65), 384 (87), 368 (65), 341 (73), 284 (85), 266 (100), 241 (80), 200 (78), 173 (68), 148 (65), 116 (58), 83 (92), 66 (90), 43 (83), 29 (70). Anal. calcd for C₂₃H₂₇N₃O₆S (473.54): C, 58.34; H, 5.75; N, 8.87%. Found: C, 58.52; H, 5.79; N, 8.61%.

Diisopropyl 4-ethoxy-5-oxo-1-[5-(p-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5k): pale yellow powder (0.316 g, 67%), m.p. 146 °C–148 °C; IR (KBr) (υ_max/cm⁻¹): 1751, 1725, 1701 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.28 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz,$ CHCH₃), 1.36 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.37 (6H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , 2 CHCH₃), 1.47 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 2.43 (3H, s, CH₃), 4.78 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.12 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.19 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.66 (1H, s, CH), 7.30 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar), 7.85 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.54, 21.51, 21.58, 21.64, 21.79, 21.84, 60.56, 69.12, 69.57, 70.96, 115.37, 127.36, 127.41, 129.85, 141.34, 151.93, 155.32, 160.70, 162.83, 164.54, 166.16; MS m/z (%) = 473 (M⁺, 95), 411 (40), 383 (90), 341 (77), 326 (85), 294 (82), 266 (100), 241 (78), 200 (75), 173 (73), 134 (50), 116 (73), 43 (90). Anal. calcd for C₂₃H₂₇N₃O₆S (473.54): C, 58.34; H, 5.75; N, 8.87%. Found: C, 58.62; H, 5.70; N, 8.63%.

Diisopropyl 4-ethoxy-5-oxo-1-[5-(m-tolyl)-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5l): pale yellow powder (0.292 g, 61%), m.p. 107 °C–108 °C; IR (KBr) (υ_max/cm⁻¹): 1732, 1700, 1637 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.24 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.33 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.34 (6H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , 2 CHCH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 2.41 (3H, s, CH₃), 4.74 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.08 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.16 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.62 (1H, s, CH), 7.26–7.77 (4H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.48, 21.28, 21.52, 21.58, 21.73, 21.78, 60.50, 69.07, 69.52, 70.90, 115.33, 124.66, 127.95, 129.00, 129.91, 131.66, 138.96, 151.86, 155.45, 160.63, 162.79, 164.55, 166.09; MS m/z (%) = 473 (M⁺, 100), 412 (5), 385 (100), 341 (60), 326 (85), 294 (67), 267 (100), 241 (45), 173 (15), 116 (18), 43 (100), 29 (82). Anal. calcd for C₂₃H₂₇N₃O₆S (473.54): C, 58.34; H, 5.75; N, 8.87%. Found: C, 58.26; H, 5.71; N, 8.71%.

Diisopropyl 4-ethoxy-5-oxo-1-[5-phenyl-1,3,4-thiadiazol-2-yl]-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5m): White powder (0.340 g, 72%), m.p. 148 °C–149 °C; IR (KBr) (υ_max/cm⁻¹): 1747, 1720, 1702 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.24 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.33 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.34 (6H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , 2 CHCH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 4.74 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.08 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.16 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.63 (1H, s, CH), 7.44–7.95 (5H, m, ArH); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm)= 15.48, 21.52, 21.57, 21.73, 21.78, 60.52, 69.08, 69.53, 70.92, 84.84, 115.37, 127.43, 129.11, 130.05, 130.85, 151.82, 155.55, 160.61, 162.82, 166.07; MS m/z (%) = 459 (M⁺, 78), 398 (12), 370 (80), 327 (75), 280 (75), 253 (85), 228 (75), 186 (70), 160 (75), 120 (73), 77 (53), 43 (100), 29 (78); Anal. calcd for C₂₂H₂₅N₃O₆S (459.52): C, 57.50; H, 5.48; N, 9.14%. Found: C, 57.74; H, 5.42; N, 8.87%.

Diisopropyl 1-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (5n): pale yellow powder (0.262 g, 48%), m.p. 163 °C–164 °C; IR (KBr) (υ_max/cm⁻¹): 1752, 1723, 1704 (3 C=O); ¹H NMR (300.13 MHz, CDCl₃): δ (ppm) = 1.24 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.33 (3H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , CHCH₃), 1.34 (6H, d, ${}^{3}{J_{HH}} = 6.0 Hz$ , 2 CHCH₃), 1.44 (3H, t, ${}^{3}{J_{HH}} = 6.0 Hz$ , CH₂ CH₃), 4.73 (2H, q, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH₂), 5.08 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.16 (H, sep, ${}^{3}{J_{HH}} = 6.0 Hz$ , OCH), 5.62 (1H, s, CH), 7.59 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar), 7.79 (2H, d, ${}^{3}{J_{HH}} = 9.0 Hz$ , 2 CH_Ar); ¹³C NMR (75.46 MHz, CDCl₃): δ (ppm) = 15.47, 21.52, 21.57, 21.73, 21.78, 60.53, 69.13, 69.58, 70.99, 84.84, 115.45, 125.25, 128.75, 128.99, 132.35, 151.72, 155.67, 160.58, 163.18, 166.02; MS m/z (%) = 538 (M⁺, 33), 450 (58), 407 (30), 357 (25), 331 (63), 305 (20), 181 (18), 125 (18), 97 (23), 41 (68), 43 (100), 28 (88). Anal. calcd for C₂₂H₂₄BrN₃O₆S (538.41): C, 49.08; H, 4.49; N, 7.80%. Found: C, 49.32; H, 4.42; N, 7.58%.

Supplemental Material

Supplementary_material – Supplemental material for One-pot synthesis of 4-ethyl 2,3-dimethyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3,4-tricarboxylate derivatives via intramolecular Wittig reaction

Supplemental material, Supplementary_material for One-pot synthesis of 4-ethyl 2,3-dimethyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3,4-tricarboxylate derivatives via intramolecular Wittig reaction by Samin Iravani and Abbas Ali Esmaeili in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Research Council of Ferdowsi University of Mashhad is acknowledged for financial support (Grant No. 3/50159).

ORCID iD

Abbas Ali Esmaeili

Supplemental material

Supplemental material for this article is available online.

References

Matin

Gavande

Kim

, et al. J Med Chem 2009; 52: 6835.

Galal

El-All

ASA

Abdallah

, et al. Bioorg Med Chem Lett 2009; 19: 2420.

Mullican

Wilson

Connor

, et al. J Med Chem 1993; 36: 1090.

Boschelli

Connor

Bornemeier

, et al. J Med Chem 1993; 36: 1802.

El-Emam

Al-Deeb

Al-Omar

, et al. Bioorg Med Chem 2004; 12: 5107.

Chapleo

Myers

, et al. J Med Chem 1986; 29: 2273.

Chapleo

Myers

Smith

, et al. J Med Chem 1988; 31: 7.

Turner

Myers

Gadie

, et al. J Med Chem 1988; 31: 902.

Turner

Myers

Gadie

, et al. J Med Chem 1988; 31: 907.

10.

Supuran

Scozzafava

Curr Med Chem Immunol Endocrinol Agents 2001; 1: 61.

11.

Jaina

Sharmaa

Vaidyaa

, et al. Chem Biol Drug Des 2013; 81: 557.

12.

Matysiak

Opolski

Bioorg Med Chem 2006; 14: 4483.

13.

Priebbenow

Bolm

RSC Adv 2013; 3: 10318.

14.

Liu

Zhang

Lin

, et al. RSC Adv 2014; 3: 27582.

15.

Dwoskin

Teng

Buxton

, et al. J Pharmacol Exp Ther 1999; 288: 905.

16.

Singh

Dimitriou

Mahajan

, et al. Br J Anaesth 1993; 71: 685.

17.

Patsalos

PN.

Epilepsia 2005; 46: 140.

18.

Michael

Andreas

, et al. WO2008055945 A1, 2008.

19.

Geng

Wang

Yang

, et al. PLoS ONE 2015; 10: 1.

20.

Wang

, et al. Bioorg Med Chem Lett 2011; 21: 6724.

21.

Pendri

Troyer

Sofia

, et al. J Comb Chem 2010; 12: 84.

22.

Gein

Armisheva

Rassudikhina

, et al. Pharm Chem J 2011; 45: 162.

23.

Gein

Mihalev

Kasimova

, et al. Pharm Chem J 2007; 41: 208.

24.

Gein

Yushkov

Kasimova

, et al. Pharm Chem J 2005; 39: 484.

25.

Kawashima

Yoshimura

Sakai

, et al. Jpn Pat Appl 1990 (JP 02062859 A 19900302).

26.

Thomas

Sah

Sharma

PB.

Curr Pharm Biotechnol 2008; 9: 315.

27.

Franco

MSF

Casagrande

Raminelli

, et al. Synth Commun 2015; 45: 692.

28.

Anada

Hashimoto

SI.

Tetrahedron Lett 1998; 39: 79.

29.

Choi

Lee

Chung

, et al. Arch Pharm Res 2005; 28: 151.

30.

Burgess

Meyers

AI.

J Org Chem 1992; 57: 1656.

31.

Overman

Remarchuk

TP.

J Am Chem Soc 2002; 124: 12.

32.

Singh

Saxena

Batra

J Org Chem 2005; 70: 353.

33.

Sarkar

Mukhopadhyay

Ch.

Tetrahedron Lett 2013; 54: 3706.

34.

Sun

Xia

, et al. Eur J Org Chem 2011; 2981.

35.

Zhu

Jiang

, et al. J Comb Chem 2009; 11: 685.

36.

Ramazani

Ahankar

Ślepokura

, et al. J Struct Chem 2018; 60: 662.

37.

Zeng

Cao

Wang

, et al. J Am Chem Soc 2016; 138: 416.

38.

Srimani

Leitus

Ben-David

, et al. Angew Chem Int Ed 2014; 53: 11092.

39.

Yavari

Adib

Sayahi

MH.

J Chem Soc Perkin Trans 1 2002; 1517.

40.

Yavari

Adib

Sayahi

MH.

Tetrahedron Lett 2002; 43: 2927.

41.

Yavari

Adib

Jahani-Moghaddam

Monatsh Chem 2002; 133:1431.

42.

Yavari

Moradi

Nasiri

, et al. Monatsh Chem 2005; 136: 1757.

43.

Ganjeie

Ramazani

Kazemizadeh

AR.

Phosphorus Sulfur Silicon Relat Elem 2007; 182: 1703.

44.

Duris

Daich

Berkes

Synlett 2011; 1631.

45.

Beck

Picard

Herdtweck

, et al. Org Lett 2004; 6: 39.

46.

Yang

Jurkauskas

Mackintosh

, et al. Can J Chem 2000; 78: 800.

47.

Bhat

Tilve

SG.

Tetrahedron Lett 2013; 54: 245.

48.

Błaszczyk

Krawczyk

Janecki

Synlett 2004; 2685.

49.

Hirota

Sakai

Kitamura

, et al. Tetrahedron 2010; 66: 653.

50.

Anary-Abbasinejad

Anaraki-Ardakania

Dehghana

, et al. J Chem Res 2007; 574.

51.

Rad-Moghadam

Esmaeili

Ghalandarabad

, et al. J Heterocycl Chem 2014; 51: 1791.

52.

Esmaeili

Kheybari

J Chem Res 2002; 9: 465.

53.

Guan

Sun

Hou

, et al. Bioorg Med Chem 2012; 20: 3865.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

6.59 MB

One-pot synthesis of 4-ethyl 2,3-dimethyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-5-oxo-2,5-dihydro-1 H -pyrrole-2,3,4-tricarboxylate derivatives via intramolecular Wittig reaction

Abstract

Keywords

Introduction

Results and discussion

Conclusion

Experimental

Dimethyl 1-(5-benzyl-1,3,4-thiadiazol-2-yl)-4-ethoxy-2,5-dihydro-5-oxo-1H-pyrrole-2,3-dicarboxylate (5a); typical procedure

Supplemental Material

Supplementary_material – Supplemental material for One-pot synthesis of 4-ethyl 2,3-dimethyl 1-(5-aryl-1,3,4-thiadiazol-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3,4-tricarboxylate derivatives via intramolecular Wittig reaction

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material