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Article

Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins

by
Zhen-Hua Wang
1,*,
Tong Zhang
1,
Li-Wen Shen
2,
Xiu Yang
1,
Yan-Ping Zhang
1,
Yong You
1,
Jian-Qiang Zhao
1 and
Wei-Cheng Yuan
1,*
1
Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
2
College of Chemistry and Chemical Engineering, Zunyi Normal University, Zunyi 563006, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(11), 4410; https://doi.org/10.3390/molecules28114410
Submission received: 16 May 2023 / Revised: 25 May 2023 / Accepted: 26 May 2023 / Published: 29 May 2023
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology.

Graphical Abstract

1. Introduction

Polyheterocyclic skeletons are frequently found as the common backbone in a variety of natural alkaloids and synthetic organic molecules with remarkable biological activities [1,2,3,4]. As shown in Figure 1, the oxo-evodiamine analogue (I), YM-201627 (II), and camptothecin (III) have been verified to be tumor inhibitors. Spirocyclic furan analog (IV) has been identified as a potent inhibitor of bacterial phenylalanyl-tRNA synthetase. Spirotryprostatin A (V) has been isolated as a novel cell cycle inhibitor in mammals. Therefore, the construction of highly functionalized polyheterocyclic compounds continues to be an important area of research in modern organic synthetic chemistry. A large number of efficient synthetic tactics have been developed for the synthesis of various functionalized polyheterocycles [5,6,7,8,9,10]. Among the various reported methods, [3 + 2] cycloaddition has become one of the most powerful and straightforward synthetic approaches that can be used to construct polycyclic compounds [11,12,13,14,15,16].
Nitrogen-ylides, in situ generated from imines or heteroarenium salts, have proven to be versatile and valuable three-atom 4π-component synthons for accessing diverse nitrogen-containing heterocyclic compounds (Scheme 1, top) [17,18,19,20,21,22]. Various types of [3 + 2] cycloadditions involving imines have been sufficiently reported [23,24,25,26,27,28,29,30,31,32]. In contrast, the study of the use of heteroarenium salts for [3 + 2] cycloadditions remains relatively underdeveloped, which may be due to the extra stability of the aromaticity of aromatic heterocyclic ring. Thus far, heteroarenium salts derived from quinoline, isoquinoline, pyridine, and benzothiazole have been successfully used in various annulation processes to access diverse nitrogen-containing polyheterocycles [33,34,35,36,37,38,39,40,41,42,43,44]. In particular, benzothiazolium salts serving as heteroaromatic N-ylide precursors are extremely valuable for the simple and efficient synthesis of N,S-polyheterocyclic derivatives which are frequently found in natural products and pharmaceuticals [45,46,47,48]. However, a literature search revealed that, although many types of electron-deficient olefins acting as 2π-component have been successfully applied in [3 + 2] cycloaddition with various three-atom 4π-component partners [11,12,13,14,15,16,49,50], the related [3 + 2] cycloaddition reaction concerning the heteroaromatic N-ylides, in situ generated from benzothiazolium salts, with diverse electron-deficient olefins is very limited [51,52,53,54,55,56]. In this context, given the importance of N,S-polyheterocyclic scaffolds in medicinal and natural product chemistry and the great potential of the benzothiazolium salts for cycloaddition, expanding the application of benzothiazolium salts in the reaction with different type of electron-deficient olefins for the [3 + 2] cycloaddition to access structurally diverse polyheterocyclic compounds is highly desired. Therefore, based on our unremitting efforts in developing new synthetic methods for the construction of structurally diverse heterocyclic compounds [57,58,59,60,61], the [3 + 2] cycloaddition reactions of benzothiazolium salts and diverse electron-deficient olefins including maleimides, 3-trifluoroethylidene oxindoles, and benzylidenemalononitriles have been realized, furnishing varieties of functionalized fused polyheterocyclic compounds (Scheme 1, bottom). Herein, we hope to report the results of our study.

2. Results and Discussion

Initially, optimization of the reaction conditions was conducted by choosing benzothiazolium salt 1a and N-phenylmaleimide 2a as the model substrates (Table 1). Several inorganic bases were first tested in DCM at room temperature, and the use of Na2CO3 gave product 3aa in a relatively high yield (entry 3 vs. entries 1, 2, and 4). Interestingly, triethylamine furnished trace product (entry 5). Upon further solvent examination (entries 6–9), the toluene was found to be an appropriate medium to yield the corresponding cycloaddition product with a 99% yield (entry 6). As a result, the best reaction condition consisted of a 1.5 equivalent of Na2CO3 and toluene as the solvent at room temperature.
To verify the scalability of the developed [3 + 2] cycloaddition, the optimal reaction conditions were applied to other benzothiazolium salts (Scheme 2). The electronic nature and size of the substituents on benzoyl group showed little influence on the reactivity of the reaction, and the desired products 3ba–3ha could be isolated in good to excellent yields (52–99%). Benzothiazolium salts 1i and 1j with two substituents on the benzene ring delivered good yields for 3ia (79%) and 3ja (73%). As for the introduction of naphthyl to benzothiazolium salt, the reaction also proceeded smoothly to provide the corresponding octahydropyrrolo[3,4-c]pyrrole 3ka with a 96% yield. A smooth conversion of the substrate 1l-bearing chlorine substituent on benzothiazole was observed in the reaction with 2a to give product 3la in a 92% yield.
Following this, the reaction scope with respect to maleimides 2 was investigated (Scheme 3). The electronic properties of the substituent on the para-position of the phenyl ring had almost no effect on the developed transformation, leading to products 3ab–3ad in excellent isolated yields (89–91%). Similarly, meta-substituted maleimides 2e–2g were well tolerated in [3 + 2] cycloaddition and smoothly switched into octahydropyrrolo[3,4-c]pyrroles 3ae–3ag with 88–94% yields. The reaction involving maleimide 2h also performed very well, and a good yield was produced. Moreover, N-alkyl substituted maleimides 2i and 2j were compatible with the current system, resulting in 93% and 99% yields, respectively.
The synthetic practicability of the developed [3 + 2] cycloaddition was demonstrated by the scale-up experiment of benzothiazolium salt 1a and N-phenylmaleimide 2a under the standard conditions, and the product octahydropyrrolo[3,4-c]pyrrole 3aa was isolated with a 85% yield (Scheme 4). In addition, the structure of 3aa was unambiguously determined using single crystal X-ray diffraction analysis (Scheme 4, CCDC 2193494 (3aa) contains the supplementary crystallographic data for this paper. For details, see the Supporting Information).
Owing to the unique properties of the trifluoromethyl unit in promoting the metabolic stability and bioavailability of many bioactive compounds [62,63], several CF3-containing heterocyclic compounds, in particular of trifluoromethyl-substituted pyrrolidines, have been synthesized with [3 + 2] cycloaddition reaction in the past few years [64,65,66,67,68]. To expand the application of benzothiazolium salts in constructing spiro-pyrrolidines, the [3 + 2] cycloaddition between benzothiazolium salts and 3-trifluoroethylidene oxindoles was conducted. After a careful screening of bases and solvents (For the detail of the procedure, see Supporting Information), the reaction of benzothiazolium salt 1a with 3-trifluoroethylidene oxindole 4a proceeded smoothly to produce the CF3-containing tetrahydrobenzo[d]pyrrolo[2,1-b]thiazole 5aa with a 95% isolated yield (Scheme 5). On this basis, other 3-trifluoroethylidene oxindoles 4b–4h were evaluated under the optimal reaction conditions, these substrates could be smoothly converted into the corresponding cycloadducts 5ab–5ah in good yields (70–90%). Moreover, 3-trifluoroethylidene benzofuranone was also compatible with the developed system to give product 5ai with a 85% yield.
Encouraged by the above success, we questioned whether the application of benzothiazolium salt can be further expanded. Subsequently, many benzylidenemalononitriles 6 were surveyed via reaction with 1a. The reaction optimization study demonstrated that triethylamine (TEA) was the best base for promoting the transformation (For the detail of the procedure, see Supporting Information). The reaction between 1a and 6a could furnish the desired product 7aa in 95% yield (Scheme 6). Further studies indicated that the substituents on the aryl ring (Ar) of benzylidenemalononitriles have a limited effect on the reactivity of the reaction. The benzylidenemalononitriles 6b–6f were compatible with the reaction condition to give the corresponding products 7ab–7af in 87–97% yields.

3. Materials and Methods

3.1. General Information

Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored with TLC. The NMR spectra were recorded with a Bruker Avance NEO 400 or 300. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.16 ppm, DMSO-d6 at 39.52 ppm). Melting points products were recorded on a Büchi Melting Point B-545. The HRMS was recorded with an Agilent 6545 LC/Q-TOF mass spectrometer.

3.2. General Experimental Procedures for the Synthesis of Compounds 3 (Scheme 2 and Scheme 3)

In an ordinary vial charged with a magnetic stirring bar, N-phenacylbenzothiazolium bromides 1 (0.15 mmol, 1.5 equiv), maleimides 2 (0.1 mmol, 1.0 equiv), Na2CO3 (0.15 mmol, 1.5 equiv), and toluene (1.0 mL) were successively added. Then, the mixture was stirred at room temperature for the indicated time. Products 3 were isolated using flash chromatography on silica gel.
  • 10-Benzoyl-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3aa): Eluent: petroleum ether/EtOAc = 4:1, white solid (42.2 mg, 99% yield); Rf = 0.50 (petroleum ether/EtOAc = 3:1); m.p. 190.2–192.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 7.4 Hz, 2H, Ar-H), 7.71 (dd, J = 7.2 Hz, 1H, Ar-H), 7.64–7.54 (m, 2H, Ar-H), 7.36–7.28 (m, 4H, Ar-H), 7.21 (d, J = 7.6 Hz, 1H, Ar-H), 7.08 (dd, J = 7.7 Hz, 1H, Ar-H), 6.87 (dd, J = 7.5 Hz, 1H, Ar-H), 6.46 (dd, J = 6.7, 3.0 Hz, 2H, Ar-H), 6.31 (s, 1H, N-CH), 5.47 (d, J = 8.3 Hz, 1H, S-CH-N), 4.13 (d, J = 7.8 Hz, 1H, CH), 3.66 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.2 (C=O), 176.3 (C=O), 173.4 (C=O), 146.5, 133.9, 133.8, 132.0, 129.1, 128.8, 128.7, 128.5, 126.7, 126.2, 125.2, 122.6, 121.8, 110.4, 71.3 (N-C), 68.3 (S-C-N), 50.3 (CH), 47.9 (CH); IR (neat) ν 3068, 2968, 1773, 1696, 1683, 1595, 1577, 1499, 1461, 1448, 1389, 1320, 1292, 1222, 1204, 1176, 1163, 991, 747, 688 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H19N2O3S 427.1111; found 427.1119.
  • 10-(4-Methylbenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ba): Eluent: petroleum ether/EtOAc = 4:1, white solid (43.6 mg, 99% yield); Rf = 0.54 (petroleum ether/EtOAc = 3:1); m.p. 195.4–197.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.1 Hz, 2H, Ar-H), 7.40 (d, J = 8.0 Hz, 2H, Ar-H), 7.34–7.30 (m, 3H, Ar-H), 7.29 (d, J = 8.2 Hz, 1H, Ar-H), 7.20 (d, J = 7.6 Hz, 1H, Ar-H), 7.07 (dd, J = 7.7 Hz, 1H, Ar-H), 6.87 (dd, J = 7.5 Hz, 1H, Ar-H), 6.45 (dd, J = 6.4, 3.1 Hz, 2H, Ar-H), 6.25 (s, 1H, N-CH), 5.46 (d, J = 8.3 Hz, 1H, S-CH-N), 4.09 (d, J = 7.8 Hz, 1H, CH), 3.64 (t, J = 8.1 Hz, 1H, CH), 2.40 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) δ 194.7 (C=O), 176.4 (C=O), 173.4 (C=O), 146.6, 144.6, 132.1, 131.4, 129.4, 129.3, 128.8, 128.5, 126.7, 126.2, 125.2, 122.6, 121.8, 110.4, 71.4 (N-C), 68.2 (S-C-N), 50.3 (CH), 48.0 (CH), 21.3 (CH3); IR (neat) ν 3063, 3025, 2940, 1776, 1708, 1677, 1603, 1578, 1495, 1468, 1453, 1387, 1256, 1224, 1207, 1176, 1165, 1024, 990, 803, 751, 687 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O3S 441.1267; found 441.1275.
  • 10-(4-Methoxybenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ca): Eluent: petroleum ether/EtOAc = 4:1, white solid (43.4 mg, 95% yield); Rf = 0.35 (petroleum ether/EtOAc = 3:1); m.p. 189.0–189.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.7 Hz, 2H, Ar-H), 7.37–7.27 (m, 4H, Ar-H), 7.21 (d, J = 7.6 Hz, 1H, Ar-H), 7.12 (d, J = 8.7 Hz, 2H, Ar-H), 7.07 (dd, J = 7.6 Hz, 1H, Ar-H), 6.87 (dd, J = 7.5 Hz, 1H, Ar-H), 6.47–6.43 (m, 2H, Ar-H), 6.24 (s, 1H, N-CH), 5.46 (d, J = 8.3 Hz, 1H, S-CH-N), 4.10 (d, J = 7.8 Hz, 1H, CH), 3.86 (s, 3H, OCH3), 3.64 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 193.4 (C=O), 176.4 (C=O), 173.4 (C=O), 163.7, 146.6, 132.1, 131.6, 128.7, 128.5, 126.7, 126.5, 126.1, 125.2, 122.6, 121.8, 114.1, 110.4, 71.4 (N-C), 68.0 (S-C), 55.7 (OCH3), 50.3 (CH), 48.0 (CH); IR (neat) ν 3060, 2917, 2847, 1777, 1707, 1675, 1596, 1574, 1495, 1469, 1388, 1320, 1254, 1226, 1207, 1173, 1164, 1022, 819, 752, 688 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O4S 457.1217; found 457.1227.
  • 10-(4-Bromobenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3da): Eluent: petroleum ether/EtOAc = 4:1, white solid (50.0 mg, 99% yield); Rf = 0.57 (petroleum ether/EtOAc = 3:1); m.p. 177.5–179.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.4 Hz, 2H, Ar-H), 7.82 (d, J = 8.3 Hz, 2H, Ar-H), 7.37–7.26 (m, 4H, Ar-H), 7.21 (d, J = 7.6 Hz, 1H, Ar-H), 7.08 (dd, J = 7.7 Hz, 1H, Ar-H), 6.87 (dd, J = 7.5 Hz, 1H, Ar-H), 6.44 (dd, J = 6.5, 3.1 Hz, 2H, Ar-H), 6.28 (s, 1H, N-CH), 5.43 (d, J = 8.4 Hz, 1H, S-CH-N), 4.13 (d, J = 7.8 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 194.6 (C=O), 176.3 (C=O), 173.3 (C=O), 146.4, 133.1, 132.0, 131.8, 131.0, 128.7, 128.5, 128.0, 126.7, 126.2, 125.2, 122.6, 121.9, 110.4, 71.3 (N-C), 68.4 (S-C-N), 50.3 (CH), 47.7 (CH); IR (neat) ν 3064, 2925, 2849, 1777, 1707, 1680, 1581, 1498, 1467, 1452, 1391, 1256, 1220, 1210, 1180, 1168, 1068, 1026, 1006, 859, 806, 755, 687 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18BrN2O3S 505.0216, 507.0198; found 505.0218, 507.0203.
  • 4-(1,3-Dioxo-2-phenyl-2,3,3a,3b,10,10a-hexahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-10-carbonyl)benzonitrile (3ea): Eluent: petroleum ether/EtOAc = 4:1, white solid (40.2 mg, 89% yield); Rf = 0.24 (petroleum ether/EtOAc = 3:1); m.p. 182.1–184.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.2 Hz, 2H, Ar-H), 8.08 (d, J = 8.2 Hz, 2H, Ar-H), 7.38–7.27 (m, 4H, Ar-H), 7.22 (d, J = 7.5 Hz, 1H, Ar-H), 7.09 (dd, J = 7.6 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.50–6.41 (m, 2H, Ar-H), 6.35 (s, 1H, N-CH), 5.42 (d, J = 8.4 Hz, 1H, S-CH-N), 4.17 (d, J = 7.8 Hz, 1H, CH), 3.64 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.0 (C=O), 176.2 (C=O), 173.3 (C=O), 146.4, 137.7, 132.7, 132.0, 129.6, 128.7, 128.5, 126.7, 126.2, 125.2, 122.7, 122.0, 118.1, 115.5, 110.5, 71.2 (N-C), 68.7 (S-C-N), 50.3 (CH), 47.5 (CH); IR (neat) ν 3060, 2964, 2920, 2850, 2229, 1777, 1703, 1678, 1579, 1499, 1466, 1448, 1387, 1195, 1177, 1171, 1009, 752, 742, 686 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H18N3O3S 452.1063; found 452.1070.
  • Methyl 4-(1,3-dioxo-2-phenyl-2,3,3a,3b,10,10a-hexahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-10-carbonyl) benzoate (3fa): Eluent: petroleum ether/EtOAc = 4:1, white solid (25.2 mg, 52% yield); Rf = 0.31 (petroleum ether/EtOAc = 3:1); m.p. 183.9–186.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.5 Hz, 2H, Ar-H), 8.13 (d, J = 8.4 Hz, 2H, Ar-H), 7.36–7.26 (m, 4H, Ar-H), 7.21 (d, J = 8.2 Hz, 1H, Ar-H), 7.08 (dd, J = 7.3 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.50–6.40 (m, 2H, Ar-H), 6.32 (s, 1H, N-CH), 5.44 (d, J = 8.4 Hz, 1H, S-CH-N), 4.14 (d, J = 7.9 Hz, 1H, CH), 3.89 (s, 3H, CH3), 3.65 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.1 (C=O), 176.2 (C=O), 173.3 (C=O), 165.5 (C=O), 146.4, 137.7, 133.6, 132.0, 129.4, 129.3, 128.7, 128.5, 126.7, 126.2, 125.2, 122.6, 122.0, 110.5, 71.2 (N-C), 68.6 (S-C-N), 52.6 (CH3), 50.3 (CH), 47.7 (CH); IR (neat) ν 3058, 2953, 2920, 2850, 1777, 1726, 1706, 1685, 1575, 1496, 1467, 1388, 1283, 1258, 1223, 1179, 1169, 1106, 1014, 868, 755, 707, 687 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C27H21N2O5S 485.1166; found 485.1171.
  • 10-(3-Bromobenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ga): Eluent: petroleum ether/EtOAc = 4:1, white solid (42.4 mg, 84% yield); Rf = 0.48 (petroleum ether/EtOAc = 3:1); m.p. 177.5–179.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H, Ar-H), 8.15 (d, J = 7.9 Hz, 1H, Ar-H), 7.90 (d, J = 9.0 Hz, 1H, Ar-H), 7.56 (dd, J = 7.9 Hz, 1H, Ar-H), 7.37–7.28 (m, 4H, Ar-H), 7.21 (d, J = 8.2 Hz, 1H, Ar-H), 7.09 (dd, J = 8.1 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.51–6.39 (m, 2H, Ar-H), 6.31 (s, 1H, N-CH), 5.46 (d, J = 8.4 Hz, 1H, S-CH-N), 4.13 (d, J = 7.9 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 194.3 (C=O), 176.2 (C=O), 173.3 (C=O), 146.5, 136.3, 136.1, 132.0, 131.7, 131.0, 128.7, 128.5, 128.0, 126.7, 126.2, 125.1, 122.6, 122.0, 121.9, 110.4, 71.3 (N-C), 68.6 (S-C-N), 50.2 (CH), 47.8 (CH); IR (neat) ν 3061, 2963, 2923, 2850, 1779, 1709, 1698, 1681, 1566, 1499, 1464, 1450, 1390, 1369, 1220, 1210, 1182, 1164, 1135, 1030, 843, 767, 744, 694 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18BrN2O3S 505.0216, 507.0198; found 505.0218, 507.0206.
  • 10-(3-Chlorobenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ha): Eluent: petroleum ether/EtOAc = 4:1, white solid (45.6 mg, 99% yield); Rf = 0.51 (petroleum ether/EtOAc = 3:1); m.p. 185.7–186.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H, Ar-H), 8.11 (d, J = 7.9 Hz, 1H, Ar-H), 7.77 (d, J = 9.2 Hz, 1H, Ar-H), 7.63 (dd, J = 7.9 Hz, 1H, Ar-H), 7.39–7.26 (m, 4H, Ar-H), 7.21 (d, J = 7.5 Hz, 1H, Ar-H), 7.09 (dd, J = 7.7 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.53–6.37 (m, 2H, Ar-H), 6.31 (s, 1H, N-CH), 5.46 (d, J = 8.4 Hz, 1H, S-CH-N), 4.13 (d, J = 7.9 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 194.4 (C=O), 176.2 (C=O), 173.3 (C=O), 146.5, 135.9, 133.6, 133.5, 132.0, 130.8, 128.8, 128.7, 128.5, 127.7, 126.7, 126.2, 125.1, 122.6, 121.9, 110.4, 71.3 (N-C), 68.6 (S-C-N), 50.2 (CH), 47.8 (CH); IR (neat) ν 3064, 2977, 2920, 2850, 1780, 1708, 1678, 1579, 1498, 1466, 1450, 1387, 1253, 1222, 1196, 1180, 1162, 1028, 841, 753, 742, 685 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18ClN2O3S 461.0721, 463.0700; found 461.0728, 463.0706.
  • 10-(3,4-Dichlorobenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ia): Eluent: petroleum ether/EtOAc = 4:1, white solid (39.1 mg, 79% yield); Rf = 0.51 (petroleum ether/EtOAc = 3:1); m.p. 212.4–213.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 2.0 Hz, 1H, Ar-H), 8.08 (dd, J = 8.4, 2.0 Hz, 1H, Ar-H), 7.88 (d, J = 8.4 Hz, 1H, Ar-H), 7.40–7.28 (m, 4H, Ar-H), 7.22 (d, J = 7.5 Hz, 1H, Ar-H), 7.09 (dd, J = 7.3 Hz, 1H, Ar-H), 6.88 (dd, J = 7.4 Hz, 1H, Ar-H), 6.53–6.39 (m, 2H, Ar-H), 6.31 (s, 1H, N-CH), 5.45 (d, J = 8.4 Hz, 1H, S-CH-N), 4.14 (d, J = 7.9 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 193.7 (C=O), 176.2 (C=O), 173.3 (C=O), 146.4, 136.6, 134.3, 132.0, 131.7, 131.1, 131.0, 129.1, 128.8, 128.6, 126.7, 126.2, 125.2, 122.7, 122.0, 110.4, 71.3 (N-C), 68.6 (S-C-N), 50.2 (CH), 47.7 (CH); IR (neat) ν 3098, 3063, 2973, 2963, 1778, 1708, 1685, 1578, 1498, 1469, 1450, 1387, 1344, 1264, 1220, 1169, 1027, 969, 807, 801, 756, 714, 686, 671 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H17Cl2N2O3S 495.0331, 497.0307, 499.0288; found 495.0336, 497.0312, 499.0295.
  • 10-(2,5-Dimethoxybenzoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ja): Eluent: petroleum ether/EtOAc = 4:1, white solid (35.5 mg, 73% yield); Rf = 0.29 (petroleum ether/EtOAc = 3:1); m.p. 197.5–199.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.35–7.29 (m, 3H, Ar-H), 7.23 (d, J = 2.8 Hz, 1H, Ar-H), 7.20–7.12 (m, 3H, Ar-H), 7.05 (dd, J = 7.3 Hz, 1H, Ar-H), 6.89 (d, J = 7.9 Hz, 1H, Ar-H), 6.83 (dd, J = 7.5 Hz, 1H, Ar-H), 6.54–6.39 (m, 2H, Ar-H), 6.04 (s, 1H, N-CH), 5.49 (d, J = 8.4 Hz, 1H, S-CH-N), 4.10 (d, J = 7.8 Hz, 1H, CH), 3.91 (s, 3H, CH3), 3.76 (s, 3H, CH3), 3.63 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 198.1 (C=O), 176.2 (C=O), 173.4 (C=O), 153.0, 152.3, 146.7, 132.1, 128.7, 128.5, 126.7, 126.1, 125.7, 125.1, 122.4, 121.6, 119.9, 114.5, 113.5, 110.3, 71.6 (N-C), 71.3 (S-C-N), 56.3 (OCH3), 55.6 (OCH3), 50.4 (CH), 47.7 (CH); IR (neat) ν 3060, 3011, 2948, 2923, 2830, 1779, 1711, 1675, 1577, 1494, 1458, 1416, 1378, 1222, 1188, 1173, 1013, 836, 811, 743, 731, 690, 622 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C27H23N2O5S 487.1322; found 487.1330.
  • 10-(2-Naphthoyl)-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ka): Eluent: petroleum ether/EtOAc = 4:1, white solid (45.8 mg, 96% yield); Rf = 0.51 (petroleum ether/EtOAc = 3:1); m.p. 201.3–203.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H, Ar-H), 8.15 (dd, J = 8.6, 1.4 Hz, 1H, Ar-H), 8.10 (dd, J = 9.4 Hz, 2H, Ar-H), 8.03 (d, J = 8.1 Hz, 1H, Ar-H), 7.71 (dd, J = 7.0 Hz, 1H, Ar-H), 7.65 (dd, J = 7.0 Hz, 1H, Ar-H), 7.43 (d, J = 8.0 Hz, 1H, Ar-H), 7.37–7.30 (m, 3H, Ar-H), 7.22 (d, J = 7.1 Hz, 1H, Ar-H), 7.11 (dd, J = 7.7 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.51–6.46 (m, 2H, Ar-H), 6.45 (s, 1H, N-CH), 5.53 (d, J = 8.3 Hz, 1H, S-CH-N), 4.17 (d, J = 7.9 Hz, 1H, CH), 3.69 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.1 (C=O), 176.4 (C=O), 173.4 (C=O), 146.6, 135.3, 132.1, 131.9, 131.3, 131.1, 129.7, 129.1, 128.7, 128.5, 128.4, 127.8, 127.2, 126.7, 126.2, 125.2, 124.4, 122.6, 121.8, 110.5, 71.4 (N-C), 68.3 (S-C-N), 50.4 (CH), 48.1 (CH); IR (neat) ν 3059, 2919, 2849, 1781, 1708, 1680, 1497, 1462, 1381, 1274, 1179, 1154, 1124, 1024, 1002, 815, 746, 690 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C29H21N2O3S 477.1267; found 477.1276.
  • 10-Benzoyl-7-chloro-2-phenyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3la): Eluent: petroleum ether/EtOAc = 4:1, white solid (42.4 mg, 92% yield); Rf = 0.15 (petroleum ether/EtOAc = 3:1); m.p. 175.1–177.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.4 Hz, 2H, Ar-H), 7.71 (dd, J = 7.4 Hz, 1H, Ar-H), 7.61 (dd, J = 7.6 Hz, 2H, Ar-H), 7.48 (d, J = 1.9 Hz, 1H, Ar-H), 7.37 (dd, J = 5.5, 1.9 Hz, 3H, Ar-H), 7.21 (d, J = 8.2 Hz, 1H, Ar-H), 6.87 (dd, J = 8.2, 1.9 Hz, 1H, Ar-H), 6.64–6.52 (m, 2H, Ar-H), 6.37 (s, 1H, N-CH), 5.59 (d, J = 8.3 Hz, 1H, S-CH-N), 4.10 (d, J = 7.8 Hz, 1H, CH), 3.67 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.0 (C=O), 176.1 (C=O), 173.2 (C=O), 148.3, 133.9, 133.6, 132.0, 130.7, 129.2, 128.9, 128.8, 128.6, 126.4, 124.4, 123.4, 121.2, 110.3, 72.1 (N-C), 68.5 (S-C-N), 50.2 (CH), 48.3 (CH); IR (neat) ν 3078, 3058, 2963, 2817, 1788, 1722, 1706, 1682, 1595, 1578, 1498, 1458, 1448, 1381, 1251, 1227, 1196, 1166, 1153, 1020, 989, 867, 806, 752, 698, 691, 682 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18ClN2O3S 461.0721, 463.0700; found 461.0722, 463.0701.
  • 10-Benzoyl-2-(p-tolyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ab): Eluent: petroleum ether/EtOAc = 4:1, white solid (40.1 mg, 91% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 185.7–187.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.5 Hz, 2H, Ar-H), 7.70 (dd, J = 7.3 Hz, 1H, Ar-H), 7.59 (dd, J = 7.6 Hz, 2H, Ar-H), 7.30 (d, J = 8.0 Hz, 1H, Ar-H), 7.20 (d, J = 7.5 Hz, 1H, Ar-H), 7.12 (d, J = 8.1 Hz, 2H, Ar-H), 7.07 (dd, J = 7.6 Hz, 1H, Ar-H), 6.86 (dd, J = 7.5 Hz, 1H, Ar-H), 6.33 (d, J = 8.1 Hz, 2H, Ar-H), 6.29 (s, 1H, N-CH), 5.46 (d, J = 8.3 Hz, 1H, S-CH-N), 4.10 (d, J = 7.8 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH), 2.26 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) δ 195.2 (C=O), 176.4 (C=O), 173.4 (C=O), 146.5, 138.1, 133.9, 133.8, 129.4, 129.2, 129.1, 128.8, 126.4, 126.1, 125.2, 122.6, 121.8, 110.4, 71.3 (N-C), 68.3 (S-C-N), 50.2 (CH), 47.8 (CH), 20.7 (CH3); IR (neat) ν 2999, 2954, 2920, 2849, 1777, 1698, 1686, 1675, 1514, 1459, 1449, 1395, 1309, 1253, 1238, 1224, 1170, 1157, 847, 784, 703, 682, 640, 609 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O3S 441.1267; found 441.1273.
  • 10-Benzoyl-2-(4-bromophenyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ac): Eluent: petroleum ether/EtOAc = 4:1, white solid (45.0 mg, 89% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 180.4–183.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.7 Hz, 2H, Ar-H), 7.70 (dd, J = 7.3 Hz, 1H, Ar-H), 7.59 (dd, J = 7.6 Hz, 2H, Ar-H), 7.55 (d, J = 8.4 Hz, 2H, Ar-H), 7.31 (d, J = 8.0 Hz, 1H, Ar-H), 7.20 (d, J = 7.6 Hz, 1H, Ar-H), 7.07 (dd, J = 7.7 Hz, 1H, Ar-H), 6.86 (dd, J = 7.5 Hz, 1H, Ar-H), 6.43 (d, J = 8.5 Hz, 2H, Ar-H), 6.31 (s, 1H, N-CH), 5.45 (d, J = 8.4 Hz, 1H, S-CH-N), 4.12 (d, J = 7.8 Hz, 1H, CH), 3.66 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.1 (C=O), 176.1 (C=O), 173.1 (C=O), 146.5, 134.8, 133.9, 131.8, 131.2, 129.1, 128.8, 128.6, 126.2, 125.1, 122.6, 121.9, 121.6, 110.5, 71.4 (N-C), 68.3 (S-C-N), 50.4 (CH), 47.9 (CH); IR (neat) ν 3094, 3059, 2917, 2849, 1786, 1708, 1690, 1579, 1488, 1463, 1450, 1389, 1257, 1226, 1165, 1063, 1010, 845, 799, 738, 726, 705, 695, 634, 604 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18BrN2O3S 505.0216, 507.0198; found 505.0217, 507.0203.
  • 10-Benzoyl-2-(4-chlorophenyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ad): Eluent: petroleum ether/EtOAc = 4:1, white solid (41.0 mg, 89% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 182.3–185.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.1 Hz, 2H, Ar-H), 7.69 (dd, J = 7.3 Hz, 1H, Ar-H), 7.58 (dd, J = 7.6 Hz, 2H, Ar-H), 7.36 (d, J = 8.5 Hz, 2H, Ar-H), 7.27 (d, J = 7.8 Hz, 1H, Ar-H), 7.17 (d, J = 7.6 Hz, 1H, Ar-H), 7.06 (dd, J = 7.7 Hz, 1H, Ar-H), 6.86 (dd, J = 7.5 Hz, 1H, Ar-H), 6.50 (d, J = 8.8 Hz, 2H, Ar-H), 6.28 (s, 1H, N-CH), 5.47 (d, J = 8.2 Hz, 1H, S-CH-N), 4.13 (d, J = 7.9 Hz, 1H, CH), 3.68 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 194.7 (C=O), 176.0 (C=O), 173.0 (C=O), 146.3, 133.8, 133.7, 133.2, 130.6, 129.0, 128.7, 128.6, 128.1, 126.0, 125.2, 122.5, 121.8, 110.3, 71.4 (N-C), 68.2 (S-C-N), 50.3 (CH), 47.9 (CH); IR (neat) ν 3060, 2984, 2919, 2850, 1787, 1709, 1690, 1579, 1491, 1465, 1450, 1390, 1260, 1227, 1168, 1083, 1016, 735, 700, 636, 605 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18ClN2O3S 461.0721, 463.0700; found 461.0730, 463.0711.
  • 10-Benzoyl-2-(m-tolyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ae): Eluent: petroleum ether/EtOAc = 4:1, white solid (41.4 mg, 94% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 187.9–190.1 °C: 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.3 Hz, 2H, Ar-H), 7.71 (dd, J = 7.4 Hz, 1H, Ar-H), 7.60 (dd, J = 7.6 Hz, 2H, Ar-H), 7.31 (d, J = 7.9 Hz, 1H, Ar-H), 7.21 (dd, J = 7.7 Hz, 2H, Ar-H), 7.13 (d, J = 7.6 Hz, 1H, Ar-H), 7.09 (dd, J = 8.2 Hz, 1H, Ar-H), 6.89 (dd, J = 7.3 Hz, 1H, Ar-H), 6.38 (d, J = 7.8 Hz, 1H, Ar-H), 6.30 (s, 1H, Ar-H), 6.01 (s, 1H, N-CH), 5.46 (d, J = 8.3 Hz, 1H, S-CH-N), 4.11 (d, J = 7.8 Hz, 1H, CH), 3.63 (t, J = 8.1 Hz, 1H, CH), 2.21 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) δ 195.1 (C=O), 176.4 (C=O), 173.4 (C=O), 146.6, 138.3, 133.9, 133.8, 132.0, 129.1, 128.8, 128.5, 127.1, 126.2, 125.2, 123.8, 122.6, 121.8, 110.4, 71.3 (N-C), 68.3 (S-C-N), 50.3 (CH), 47.8 (CH), 20.8 (CH3); IR (neat) ν 3059, 2963, 2919, 2850, 1785, 1708, 1685, 1596, 1579, 1490, 1460, 1446, 1383, 1256, 1231, 1224, 1186, 1168, 1130, 1028, 1016, 986, 884, 844, 768, 742, 704, 690, 630, 605, 735, 700, 636, 607 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O3S 441.1267; found 441.1275.
  • 10-Benzoyl-2-(3-chlorophenyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3af): Eluent: petroleum ether/EtOAc = 4:1, white solid (40.6 mg, 88% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 213.4–214.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.3 Hz, 2H, Ar-H), 7.70 (dd, J = 7.4 Hz, 1H, Ar-H), 7.59 (dd, J = 7.6 Hz, 2H, Ar-H), 7.45–7.36 (m, 2H, Ar-H), 7.34 (d, J = 8.0 Hz, 1H, Ar-H), 7.23 (d, J = 6.9 Hz, 1H, Ar-H), 7.10 (dd, J = 7.7 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.57 (dt, J = 7.4, 1.7 Hz, 1H, Ar-H), 6.33 (s, 1H, N-CH), 6.32–6.31 (m, 1H, Ar-H), 5.45 (d, J = 8.3 Hz, 1H, S-CH-N), 4.13 (d, J = 7.8 Hz, 1H, CH), 3.67 (t, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.0 (C=O), 176.1 (C=O), 173.0 (C=O), 146.5, 133.9, 133.2, 132.9, 130.4, 129.1, 128.8, 128.6, 126.5, 126.2, 125.5, 125.2, 122.6, 122.0, 110.5, 71.4 (N-C), 68.3 (S-C-N), 50.4 (CH), 47.9 (CH); IR (neat) ν 3064, 2952, 2921, 2850, 1779, 1710, 1676, 1593, 1577, 1477, 1460, 1448, 1382, 1255, 1240, 1222, 1174, 1153, 979, 848, 783, 748, 740, 684, 678, 630 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18ClN2O3S 461.0721, 463.0700; found 461.0729, 463.0705.
  • 10-Benzoyl-2-(3-fluorophenyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ag): Eluent: petroleum ether/EtOAc = 4:1, white solid (40.0 mg, 90% yield); Rf = 0.15 (petroleum ether/EtOAc = 6:1); m.p. 190.7–192.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 7.2 Hz, 2H, Ar-H), 7.70 (dd, J = 7.4 Hz, 1H, Ar-H), 7.60 (dd, J = 7.6 Hz, 2H, Ar-H), 7.44–7.36 (m, 1H, Ar-H), 7.36–7.32 (m, 1H, Ar-H), 7.25–7.18 (m, 2H, Ar-H), 7.10 (dd, J = 7.2 Hz, 1H, Ar-H), 6.88 (dd, J = 7.5 Hz, 1H, Ar-H), 6.41 (d, J = 8.7 Hz, 1H, Ar-H), 6.33 (s, 1H, N-CH), 6.26–6.09 (m, 1H, Ar-H), 5.46 (d, J = 8.3 Hz, 1H, S-CH-N), 4.14 (d, J = 7.9 Hz, 1H, CH), 3.68 (dd, J = 8.1 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.0 (C=O), 176.1 (C=O), 173.0 (C=O), 161.6 (d, J = 244.8 Hz, 1C), 146.5, 133.9, 133.4 (d, J = 10.2 Hz, 1C), 130.5 (d, J = 8.8 Hz, 1C), 129.1, 128.8, 126.2, 125.2, 122.9 (d, J = 3.0 Hz, 1C), 122.6, 121.9, 115.6 (d, J = 20.8 Hz, 1C), 113.8 (d, J = 23.6 Hz, 1C), 110.5, 71.4 (N-C), 68.3 (S-C-N), 50.4 (CH), 47.9 (CH); IR (neat) ν 3055, 2969, 2918, 1780, 1702, 1681, 1594, 1579, 1490, 1461, 1450, 1386, 1320, 1291, 1255, 1224, 1180, 1162, 1136, 995, 899, 787, 744, 721, 681, 606 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18FN2O3S 445.1017; found 445.1024.
  • 10-Benzoyl-2-(2,6-dimethylphenyl)-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ah): Eluent: petroleum ether/EtOAc = 4:1, white solid (37.7 mg, 83% yield); Rf = 0.23 (petroleum ether/EtOAc = 6:1); m.p. 201.3–203.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.3 Hz, 2H, Ar-H), 7.71 (dd, J = 7.4 Hz, 1H, Ar-H), 7.64–7.56 (m, 2H, Ar-H), 7.22 (d, J = 8.0 Hz, 1H, Ar-H), 7.17 (d, J = 7.6 Hz, 1H, Ar-H), 7.11 (dd, J = 7.6 Hz, 2H, Ar-H), 7.06–6.95 (m, 2H, Ar-H), 6.78 (dd, J = 7.8 Hz, 1H, Ar-H), 6.21 (s, 1H, N-CH), 5.69 (d, J = 8.7 Hz, 1H, S-CH-N), 4.36 (d, J = 9.5 Hz, 1H, CH), 3.90 (t, J = 8.6 Hz, 1H, CH), 1.98 (s, 3H, CH3), 1.07 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) δ 195.3 (C=O), 176.1 (C=O), 172.8 (C=O), 145.8, 136.0, 135.6, 134.9, 133.9, 133.8, 130.4, 129.0, 128.8, 128.1, 126.0, 125.4, 122.4, 121.4, 109.9, 70.5 (N-C), 67.6 (S-C-N), 50.3 (CH), 47.7 (CH), 17.4 (CH3), 15.6 (CH3); IR (neat) ν 3060, 2965, 2920, 1780, 1706, 1684, 1596, 1577, 1466, 1446, 1368, 1232, 1192, 1173, 1028, 772, 740, 687 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C27H23N2O3S 455.1424; found 455.1427.
  • 2-Benzhydryl-10-benzoyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3ai): Eluent: petroleum ether/EtOAc = 4:1, white solid (48.0 mg, 93% yield); Rf = 0.33 (petroleum ether/EtOAc = 6:1); m.p. 204.3–205.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.2 Hz, 2H, Ar-H), 7.69 (dd, J = 7.4 Hz, 1H, Ar-H), 7.63–7.53 (m, 2H, Ar-H), 7.26 (dd, J = 5.0, 1.8 Hz, 3H, Ar-H), 7.18 (d, J = 7.3 Hz, 1H, Ar-H), 7.14–7.07 (m, 4H, Ar-H), 7.07–7.02 (m, 1H, Ar-H), 6.95 (dd, J = 6.8, 2.9 Hz, 2H, Ar-H), 6.86 (dd, J = 7.8 Hz, 1H, Ar-H), 6.58 (d, J = 7.6 Hz, 2H, Ar-H), 6.16 (s, 1H, N-CH), 6.07 (s, 1H, N-CHPh2), 5.64 (d, J = 8.6 Hz, 1H, S-CH-N), 4.04 (d, J = 9.1 Hz, 1H, CH), 3.69 (t, J = 8.5 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.2 (C=O), 176.6 (C=O), 173.7 (C=O), 145.7, 137.3, 137.2, 133.8, 133.7, 129.0, 128.8, 128.3, 128.2, 128.2, 127.7, 127.5, 127.0, 126.0, 124.8, 122.2, 121.4, 109.9, 70.7 (N-C), 67.9 (S-C-N), 58.0 (N-CHPh2), 50.0 (CH), 47.8 (CH); IR (neat) ν 3059, 2970, 2919, 1781, 1703, 1596, 1579, 1494, 1465, 1448, 1383, 1354, 1230, 1164, 1076, 1027, 743, 695, 605 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C32H25N2O3S 517.1580; found 517.1586.
  • 10-Benzoyl-2-benzyl-3a,3b,10,10a-tetrahydro-1H-benzo[d]pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole-1,3(2H)-dione (3aj): Eluent: petroleum ether/EtOAc = 4:1, white solid (43.6 mg, 99% yield); Rf = 0.18 (petroleum ether/EtOAc = 6:1); m.p. 179.3–182.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.3 Hz, 2H, Ar-H), 7.70 (t, J = 7.4 Hz, 1H, Ar-H), 7.59 (t, J = 7.6 Hz, 2H, Ar-H), 7.18–7.05 (m, 4H, Ar-H), 7.04 (d, J = 7.6 Hz, 1H, Ar-H), 6.99 (t, J = 7.2 Hz, 1H, Ar-H), 6.80 (t, J = 7.2 Hz, 1H, Ar-H), 6.65 (d, J = 7.0 Hz, 2H, Ar-H), 6.11 (s, 1H, N-CH), 5.54 (d, J = 8.5 Hz, 1H, S-CH-N), 4.38–4.16 (m, 2H, CH2), 4.02 (d, J = 8.2 Hz, 1H, CH), 3.65 (t, J = 8.3 Hz, 1H, CH); 13C NMR (101 MHz, DMSO-d6) δ 195.3 (C=O), 177.2 (C=O), 174.0 (C=O), 145.8, 135.2, 133.9, 133.8, 129.0, 128.8, 128.5, 126.9, 126.5, 125.9, 124.9, 122.2, 121.5, 109.8, 70.7 (N-C), 67.7 (S-C-N), 50.3 (CH), 47.8 (CH), 42.0 (CH2); IR (neat) ν 3061, 2970, 2922, 1781, 1700, 1595, 1579, 1465, 1448, 1428, 1395, 1340, 1227, 1164, 1154, 1026, 1001, 872, 741, 730, 694, 605 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H21N2O3S 441.1267; found 441.1275.

3.3. Experimental Procedures for the Scale-Up Experiment (Scheme 4)

To a solution of benzothiazolium salt 1a (4.5 mmol, 1.5 equiv) and N-phenylmaleimide 2a (3.0 mmol, 1.0 equiv) in toluene (30 mL) was added Na2CO3 (4.5 mmol, 1.5 equiv) successively. Then, the mixture was stirred at room temperature for 20 h. The product 3aa (1.09 g, 85% yield) was isolated using flash chromatography on silica gel.

3.4. General Experimental Procedures for Synthesis of Compounds 5 (Scheme 5)

In an ordinary vial charged with a magnetic stirring bar, N-phenacylbenzothiazolium bromide 1a (0.15 mmol, 1.5 equiv), 4 (0.1 mmol, 1.0 equiv), Na2CO3 (0.15 mmol, 1.5 equiv), and DCM (1.0 mL) were successively added. The mixture was stirred at room temperature for 20 h. Products 5 were isolated using flash chromatography on silica gel.
  • Tert-butyl 1-benzoyl-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5aa): Eluent: petroleum ether/EtOAc = 40:1, white solid (53.8 mg, 95% yield); Rf = 0.33 (petroleum ether/EtOAc = 20:1); m.p. 160.7–162.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.0 Hz, 2H, Ar-H), 7.95 (d, J = 8.2 Hz, 1H, Ar-H), 7.71 (dd, J = 7.4 Hz, 1H, Ar-H), 7.65–7.54 (m, 2H, Ar-H), 7.31 (dd, J = 7.4 Hz, 1H, Ar-H), 7.02–6.91 (m, 1H, Ar-H), 6.88–6.81 (m, 1H, Ar-H), 6.80–6.72 (m, 2H, Ar-H), 6.47 (dd, J = 8.0 Hz, 2H, Ar-H), 6.05 (s, 1H, N-CH-S), 5.49 (d, J = 9.7 Hz, 1H, N-CH), 4.45–4.26 (m, 1H, CF3-CH), 1.66 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 197.0 (C=O), 171.9 (C=O), 148.6, 147.1, 140.3, 135.4, 134.5, 129.7, 129.4, 128.7, 126.9, 126.1, 125.8, 124.5 (q, J = 278.9 Hz, 1C, CF3), 123.8, 122.7, 121.9, 121.8, 115.3, 108.9, 85.4 (CBoc), 81.0 (N-C-S), 66.2 (N-C), 62.2 (C-CONBoc), 54.7 (q, J = 28.5 Hz, 1C, CF3-C), 28.1 ((CH3)3); IR (neat) ν 3059, 2982, 2971, 2934, 1756, 1731, 1692, 1578, 1473, 1467, 1448, 1396, 1369, 1299, 1273, 1253, 1210, 1173, 1146, 1117, 1081, 972, 840, 759, 745, 699, 654 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C30H26F3N2O4S 567.1560; found 567.1565.
  • Tert-butyl 1-benzoyl-6′-fluoro-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5ab): Eluent: petroleum ether/EtOAc = 40:1, white solid (40.9 mg, 70% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 173.2–174.8 °C; 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 7.3 Hz, 2H, Ar-H), 7.79–7.67 (m, 2H, Ar-H), 7.66–7.52 (m, 2H, Ar-H), 7.06–6.89 (m, 1H, Ar-H), 6.87–6.70 (m, 2H, Ar-H), 6.58–6.50 (m, 1H, Ar-H), 6.48 (d, J = 7.9 Hz, 1H, Ar-H), 6.41–6.26 (m, 1H, Ar-H), 5.98 (s, 1H, N-CH-S), 5.46 (d, J = 9.5 Hz, 1H, N-CH), 4.47–4.22 (m, 1H, CF3-CH), 1.66 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 196.7 (C=O), 171.9 (C=O), 163.3 (d, J = 247.1 Hz, 1C), 148.4, 147.1, 141.7 (d, J = 12.5 Hz, 1C), 135.5, 134.5, 129.4, 128.8, 127.0 (d, J = 9.8 Hz, 1C), 126.8, 126.3, 124.6 (q, J = 278.9 Hz, 1C, CF3), 122.1, 122.0, 118.2 (d, J = 3.4 Hz, 1C), 110.7 (d, J = 22.7 Hz, 1C), 109.0, 104.2 (d, J = 29.8 Hz, 1C), 85.9 (CBoc), 81.0 (N-C-S), 66.1 (N-C), 62.0 (C-CONBoc), 54.5 (q, J = 28.5 Hz, 1C, CF3-C), 28.2 ((CH3)3); IR (neat) ν 3058, 2987, 2971, 2935, 1762, 1731, 1692, 1606, 1597, 1579, 1497, 1473, 1447, 1396, 1368, 1359, 1326, 1299, 1270, 1257, 1237, 1209, 1179, 1145, 1128, 1112, 1083, 1031, 889, 861, 848, 813, 755, 746 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C30H25F4N2O4S 585.1466; found 585.1474.
  • Tert-butyl 1-benzoyl-6′-chloro-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5ac): Eluent: petroleum ether/EtOAc = 40:1, white solid (45.1 mg, 75% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 165.4–167.0 °C; 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 7.2 Hz, 2H, Ar-H), 8.02 (d, J = 2.0 Hz, 1H, Ar-H), 7.72 (dd, J = 7.4 Hz, 1H, Ar-H), 7.65–7.53 (m, 2H, Ar-H), 7.06–6.90 (m, 1H, Ar-H), 6.87–6.69 (m, 3H, Ar-H), 6.48 (d, J = 8.0 Hz, 1H, Ar-H), 6.31 (d, J = 8.2 Hz, 1H, Ar-H), 5.98 (s, 1H, N-CH-S), 5.46 (d, J = 9.5 Hz, 1H, N-CH), 4.48–4.21 (m, 1H, CF3-CH), 1.66 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 196.7 (C=O), 171.6 (C=O), 148.4, 147.0, 141.4, 135.7, 135.5, 134.5, 129.4, 128.8, 126.7, 126.6, 126.3, 124.6 (d, J = 279.0 Hz, 1C, CF3), 123.9, 122.1, 122.0, 121.2, 116.2, 109.0, 85.9 (CBoc), 81.0 (N-C-S), 66.1 (N-C), 62.2 (C-CONBoc), 54.6 (q, J = 28.6 Hz, 1C, CF3-C), 28.2 ((CH3)3); IR (neat) ν 2981, 2936, 1764, 1735, 1687, 1604, 1596, 1581, 1483, 1469, 1448, 1426, 1396, 1367, 1354, 1321, 1275, 1238, 1210, 1182, 1165, 1142, 1125, 1086, 1081, 1011, 971, 747, 740 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C30H25ClF3N2O4S 601.1170, 603.1153; found 601.1178, 603.1164.
  • Tert-butyl 1-benzoyl-6′-bromo-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5ad): Eluent: petroleum ether/EtOAc = 40:1, white solid (51.6 mg, 80% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 179.7–181.6 °C; 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 1.8 Hz, 1H, Ar-H), 8.14 (d, J = 7.1 Hz, 2H, Ar-H), 7.71 (dd, J = 7.3 Hz, 1H, Ar-H), 7.65–7.54 (m, 2H, Ar-H), 7.06–6.91 (m, 2H, Ar-H), 6.87–6.70 (m, 2H, Ar-H), 6.48 (d, J = 7.9 Hz, 1H, Ar-H), 6.25 (d, J = 8.2 Hz, 1H, Ar-H), 5.98 (s, 1H, N-CH-S), 5.46 (d, J = 9.4 Hz, 1H, N-CH), 4.49–4.20 (m, 1H, CF3-CH), 1.66 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 196.6 (C=O), 171.5 (C=O), 148.4, 147.0, 141.5, 135.5, 134.5, 129.4, 128.7, 126.9, 126.8, 126.7, 126.3, 124.6 (q, J = 279.2 Hz, 1C, CF3), 123.6, 122.1, 122.0, 121.7, 118.9, 108.9, 85.9 (CBoc), 80.9 (N-C-S), 66.0 (N-C), 62.2 (C-CONBoc), 54.5 (q, J = 28.6 Hz, 1C, CF3-C), 28.1 ((CH3)3); IR (neat) ν 2981, 2935, 1764, 1733, 1686, 1598, 1580, 1468, 1448, 1396, 1367, 1353, 1319, 1274, 1237, 1209, 1181, 1165, 1142, 1126, 1089, 1029, 1010, 972, 871, 833, 798, 765, 748, 740, 653 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C30H25BrF3N2O4S 645.0665, 647.0649; found 645.0672, 647.0655.
  • Tert-butyl 1-benzoyl-5′-fluoro-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5ae): Eluent: petroleum ether/EtOAc = 40:1, white solid (42.7 mg, 73% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 150.7–152.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz, 2H, Ar-H), 7.94 (dd, J = 9.1, 4.7 Hz, 1H, Ar-H), 7.72 (dd, J = 7.4 Hz, 1H, Ar-H), 7.67–7.53 (m, 2H, Ar-H), 7.07–6.94 (m, 2H, Ar-H), 6.87–6.73 (m, 2H, Ar-H), 6.51 (d, J = 7.8 Hz, 1H, Ar-H), 6.11 (d, J = 6.9 Hz, 1H, Ar-H), 5.99 (s, 1H, N-CH-S), 5.49 (d, J = 9.4 Hz, 1H, N-CH), 4.53–4.15 (m, 1H, CF3-CH), 1.65 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 196.6 (C=O), 171.5 (C=O), 159.1 (d, J = 243.6 Hz, 1C), 148.6, 146.9, 136.5 (d, J = 2.5 Hz, 1C), 135.5, 134.5, 129.4, 128.8, 126.5 (d, J = 16.4 Hz, 1C), 126.4, 124.6 (q, J = 278.9 Hz, 1C, CF3), 124.5 (d, J = 8.7 Hz, 1C), 122.2, 122.0, 116.6, 116.4 (d, J = 13.6 Hz, 1C), 113.5 (d, J = 26.1 Hz, 1C), 109.0, 85.6 (CBoc), 80.9 (N-C-S), 65.8 (N-C), 62.6 (C-CONBoc), 54.5 (q, J = 28.6 Hz, 1C, CF3-C), 28.2 ((CH3)3); IR (neat) ν 3058, 2983, 2936, 1798, 1761, 1741, 1735, 1690, 1607, 1594, 1579, 1481, 1471, 1450, 1396, 1371, 1343, 1324, 1295, 1272, 1242, 1212, 1172, 1145, 1125, 1084, 999, 819, 747, 732, 641 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C30H25F4N2O4S 585.1466; found 585.1470.
  • Tert-butyl 1-benzoyl-7′-methyl-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5af): Eluent: petroleum ether/EtOAc = 40:1, white solid (40.6 mg, 70% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 167.8–170.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 2H, Ar-H), 7.71 (dd, J = 7.3 Hz, 1H, Ar-H), 7.65–7.56 (m, 2H, Ar-H), 7.12 (d, J = 7.7 Hz, 1H, Ar-H), 6.95 (dd, J = 7.5 Hz, 1H, Ar-H), 6.83–6.69 (m, 3H, Ar-H), 6.44 (d, J = 7.8 Hz, 1H, Ar-H), 6.31 (d, J = 7.6 Hz, 1H, Ar-H), 6.06 (s, 1H, N-CH-S), 5.46 (d, J = 9.8 Hz, 1H, N-CH), 4.41–4.22 (m, 1H, CF3-CH), 2.26 (s, 3H, CH3), 1.64 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 197.2 (C=O), 172.9 (C=O), 148.5, 147.1, 138.9, 135.5, 134.5, 132.7, 129.4, 128.8, 127.2, 126.0, 124.5 (q, J = 279.3 Hz, 1C, CF3), 124.0, 123.8, 123.5, 121.9, 121.8, 109.0, 85.7 (CBoc), 80.5 (N-C-S), 66.3 (N-C), 62.2 (C-CONBoc), 55.1 (q, J = 28.6 Hz, 1C, CF3-C), 27.9 ((CH3)3), 19.8 (CH3); IR (neat) ν 3056, 3011, 2984, 2965, 2923, 1735, 1697, 1596, 1577, 1473, 1448, 1396, 1368, 1353, 1296, 1272, 1248, 1203, 1177, 1144, 1116, 1033, 999, 971, 843, 781, 756, 744, 696 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C31H28F3N2O4S 581.1716; found 581.1721.
  • Tert-butyl 1-benzoyl-5′,7′-dimethyl-2′-oxo-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indoline]-1′-carboxylate (5ag): Eluent: petroleum ether/EtOAc = 40:1, white solid (46.4 mg, 78% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 168.7–170.7 °C; 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 2H, Ar-H), 7.71 (dd, J = 7.4 Hz, 1H, Ar-H), 7.65–7.54 (m, 2H, Ar-H), 7.03–6.94 (m, 1H, Ar-H), 6.91 (s, 1H, Ar-H), 6.84–6.69 (m, 2H, Ar-H), 6.49 (d, J = 7.8 Hz, 1H, Ar-H), 6.00 (s, 2H, Ar-H, N-CH-S), 5.46 (d, J = 9.6 Hz, 1H, N-CH), 4.42–4.18 (m, 1H, CF3-CH), 2.21 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.63 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 197.1 (C=O), 173.1 (C=O), 148.6, 147.5, 136.6, 135.6, 134.4, 133.3, 133.2, 129.4, 128.8, 127.3, 126.0, 124.6 (q, J = 279.1 Hz, 1C, CF3), 124.6, 124.0, 123.6, 121.8, 121.7, 108.9, 85.4 (CBoc), 80.6 (N-C-S), 66.5 (N-C), 62.5 (C-CONBoc), 54.6 (q, J = 28.4 Hz, 1C, CF3-C), 27.99 ((CH3)3), 20.8 (CH3), 19.7 (CH3); IR (neat) ν 3072, 2983, 2930, 1754, 1727, 1696, 1596, 1578, 1466, 1446, 1401, 1371, 1324, 1272, 1262, 1251, 1219, 1179, 1146, 1124, 1000, 971, 838, 827, 747, 696, 642 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C32H30F3N2O4S 595.1873; found 595.1876.
  • 1-Benzoyl-2-(trifluoromethyl)-1,2-dihydro-3aH-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,3′-indolin]-2′-one (5ah): Eluent: petroleum ether/EtOAc = 4:1, white solid (42.0 mg, 90% yield); Rf = 0.20 (petroleum ether/EtOAc = 6:1); m.p. 158.7–161.7 °C, 1H NMR (300 MHz, CDCl3) δ 9.41 (s, 1H, NH), 8.20 (d, J = 7.4 Hz, 2H, Ar-H), 7.72 (dd, J = 7.3 Hz, 1H, Ar-H), 7.66–7.53 (m, 2H, Ar-H), 7.24 (dd, J = 7.7 Hz, 1H, Ar-H), 7.10–6.90 (m, 2H, Ar-H), 6.87–6.65 (m, 3H, Ar-H), 6.51 (d, J = 7.8 Hz, 1H, Ar-H), 6.41 (d, J = 7.6 Hz, 1H, Ar-H), 6.02 (s, 1H, N-CH-S), 5.56 (d, J = 9.4 Hz, 1H, N-CH), 4.49–4.21 (m, 1H, CF3-CH); 13C NMR (75 MHz, CDCl3) δ 197.3 (C=O), 175.3 (C=O), 147.3, 141.4, 135.6, 134.4, 129.5, 129.4, 128.8, 127.0, 126.4, 126.0, 124.8 (q, J = 279.0 Hz, 1C, CF3), 124.2, 122.0, 121.9, 121.8, 110.7, 109.0, 80.1 (N-C-S), 66.1 (N-C), 62.2 (C-CONH), 53.7 (q, J = 28.6 Hz, 1C, CF3-C); IR (neat) ν 3205, 3098, 3063, 2959, 2929, 1716, 1680, 1618, 1580, 1467, 1395, 1272, 1237, 1213, 1204, 1170, 1125, 1110, 1072, 1027, 1013, 964, 743, 738, 734, 698, 683 cm−1;HRMS (ESI) m/z: [M + H]+ calcd for C25H18F3N2O2S 467.1036; found 467.1038.
  • 1′-Benzoyl-2′-(trifluoromethyl)-1′,2′-dihydro-2H,3a’H-spiro[benzofuran-3,3′-benzo[d]pyrrolo[2,1-b]thiazol]-2-one (5ai): Eluent: petroleum ether/EtOAc = 40:1, white solid (39.7 mg, 85% yield); Rf = 0.37 (petroleum ether/EtOAc = 20:1); m.p. 171.9–173.8 °C; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 7.4 Hz, 2H, Ar-H), 7.73 (dd, J = 7.4 Hz, 1H, Ar-H), 7.67–7.54 (m, 2H, Ar-H), 7.32 (dd, J = 7.9 Hz, 1H, Ar-H), 7.16 (d, J = 8.1 Hz, 1H, Ar-H), 7.08–6.94 (m, 1H, Ar-H), 6.90–6.74 (m, 3H, Ar-H), 6.54 (d, J = 7.8 Hz, 1H, Ar-H), 6.34 (d, J = 7.7 Hz, 1H, Ar-H), 5.99 (s, 1H, N-CH-S), 5.54 (d, J = 9.1 Hz, 1H, N-CH), 4.51–4.26 (m, 1H, CF3-CH); 13C NMR (75 MHz, CDCl3) δ 196.3 (C=O), 173.6 (C=O), 153.8, 146.8, 135.5, 134.6, 130.6, 129.5, 128.8, 126.4, 126.3, 124.5 (q, J = 278.9 Hz, 1C), 123.8, 122.3, 122.1, 122.0, 111.3, 109.1, 80.7 (N-C-S), 65.6 (N-C), 60.8 (C-CO2), 54.4 (q, J = 28.6 Hz, 1C, CF3-C); IR (neat) ν 3080, 3056, 2960, 2938, 1796, 1685, 1620, 1592, 1469, 1446, 1397, 1356, 1346, 1275, 1255, 1228, 1207, 1166, 1155, 1139, 1126, 1093, 977, 811, 752, 740, 693, 688, 652 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H17F3NO3S 468.0876; found 468.0891.

3.5. General Experimental Procedures for Synthesis of Compounds 7 (Scheme 6)

In an ordinary vial charged with a magnetic stirring bar, N-phenacylbenzothiazolium bromide 1a (0.15 mmol, 1.5 equiv), 2-benzylidenemalononitrile 6a–h (0.1 mmol, 1.0 equiv), TEA (0.15 mmol, 1.5 equiv), and DEM (1.0 mL) were added. The mixture was then stirred at room temperature for 3 h. Products 7 were isolated with flash chromatography on silica gel.
  • 1-Benzoyl-2-phenyl-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3,3(3aH)-dicarbonitrile (7aa): Eluent: petroleum ether/DCM = 1:2, white solid (38.7 mg, 95% yield); Rf = 0.17 (petroleum ether/EtOAc = 6:1); m.p. 80.5–82.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.94–7.87 (m, 2H, Ar-H), 7.65–7.58 (m, 1H, Ar-H), 7.55–7.49 (m, 2H, Ar-H), 7.48–7.43 (m, 2H, Ar-H), 7.43–7.39 (m, 3H, Ar-H), 7.24–7.16 (m, 1H, Ar-H), 7.10–6.99 (m, 1H, Ar-H), 6.97–6.86 (m, 1H, Ar-H), 6.48 (d, J = 7.7 Hz, 1H, Ar-H), 6.07 (s, 1H, N-CH-S), 5.59 (d, J = 9.3 Hz, 1H, N-CH), 4.36 (d, J = 9.3 Hz, 1H, CH); 13C NMR (101 MHz, CDCl3) δ 196.9 (C=O), 146.3, 135.1, 134.7, 130.4, 130.1, 129.7, 129.3, 128.9, 128.8, 126.7, 124.8, 122.9, 122.6, 112.3, 111.0, 109.8, 79.5 (N-C-S), 69.2 (N-C), 58.0 (C), 51.0 (CH); IR (neat) ν 3066, 2935, 2839, 2221, 1730, 1696, 1671, 1663, 1603, 1577, 1511, 1469, 1447, 1308, 1254, 1223, 1177, 1021, 832, 750, 688, 612 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C25H18N3OS 408.1165; found 408.1170.
  • 1-Benzoyl-2-(p-tolyl)-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3,3(3aH)-dicarbonitrile (7ab): Eluent: petroleum ether/DCM = 1:2, white solid (36.7 mg, 87% yield); Rf = 0.23 (petroleum ether/EtOAc = 6:1); m.p. 82.7–84.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 2H, Ar-H), 7.65–7.59 (m, 1H, Ar-H), 7.49–7.43 (m, 2H, Ar-H), 7.42–7.38 (m, 2H, Ar-H), 7.23–7.17 (m, 3H, Ar-H), 7.02 (dd, J = 7.6 Hz, 1H, Ar-H), 6.91 (dd, J = 7.4 Hz, 1H, Ar-H), 6.46 (d, J = 7.7 Hz, 1H, Ar-H), 6.06 (s, 1H, N-CH-S), 5.56 (d, J = 9.4 Hz, 1H, N-CH), 4.33 (d, J = 9.3 Hz, 1H, CH), 2.34 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 197.1 (C=O), 146.3, 140.5, 135.2, 134.7, 130.3, 129.3, 128.8, 128.7, 126.9, 126.7, 124.8, 122.8, 122.6, 112.4, 111.1, 109.8, 79.4 (N-C-S), 69.1 (N-C), 57.9 (C), 51.2 (CH), 21.3 (CH3); IR (neat) ν 3066, 2926, 2224, 2210, 1733, 1669, 1581, 1469, 1448, 1341, 1301, 1222, 1178, 1093, 1014, 828, 748, 686cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H20N3OS 422.1322; found 422.1326.
  • 1-Benzoyl-2-(4-methoxyphenyl)-1,2-dihydrobenzo[d]pyrrolo[2,1-b] thiazole-3,3(3aH)-dicarbonitrile (7ac): Eluent: petroleum ether/DCM = 1:2, white solid (41.1 mg, 94% yield); Rf = 0.23 (petroleum ether/EtOAc = 6:1); m.p. 86.3–87.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 2H, Ar-H), 7.64–7.59 (m, 1H, Ar-H), 7.49–7.41 (m, 4H, Ar-H), 7.19 (d, J = 7.6 Hz, 1H, Ar-H), 7.05–6.98 (m, 1H, Ar-H), 6.94–6.88 (m, 3H, Ar-H), 6.44 (d, J = 7.9 Hz, 1H, Ar-H), 6.05 (s, 1H, N-CH-S), 5.52 (d, J = 9.2 Hz, 1H, N-CH), 4.30 (d, J = 9.5 Hz, 1H, CH), 3.79 (s, 3H, OCH3); 13C NMR (101 MHz, CDCl3) δ 197.2 (C=O), 161.1, 146.4, 135.2, 134.7, 130.2, 129.3, 128.8, 126.7, 124.9, 122.8, 122.6, 121.6, 115.0, 112.4, 111.2, 109.8, 79.3 (N-C-S), 69.3 (N-C), 57.8 (C), 55.5 (OCH3), 51.2 (CH); IR (neat) ν 3065, 2926, 2227, 2207, 1734, 1669, 1593, 1581, 1513, 1489, 1469, 1448, 1344, 1302, 1254, 1222, 1178, 1073, 1010, 822, 747, 687, 660 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H20N3O2S 438.1271; found 438.1274.
  • 1-Benzoyl-2-(m-tolyl)-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3,3(3aH)-dicarbonitrile (7ad): Eluent: petroleum ether/DCM = 1:2, white solid (37.5 mg, 89% yield); Rf = 0.32 (petroleum ether/EtOAc = 6:1); m.p. 101.3–102.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.92–7.88 (m, 2H, Ar-H), 7.64–7.58 (m, 1H, Ar-H), 7.49–7.43 (m, 2H, Ar-H), 7.36–7.32 (m, 1H, Ar-H), 7.32–7.26 (m, 2H, Ar-H), 7.22–7.18 (m, 2H, Ar-H), 7.03 (td, J = 7.7, 1.3 Hz, 1H, Ar-H), 6.92 (td, J = 7.6, 1.1 Hz, 1H, Ar-H), 6.46 (d, J = 7.8 Hz, 1H, Ar-H), 6.06 (s, 1H, N-CH-S), 5.56 (d, J = 9.4 Hz, 1H, N-CH), 4.31 (d, J = 9.4 Hz, 1H, CH), 2.33 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 197.1 (C=O), 146.3, 139.6, 135.2, 134.7, 131.2, 130.0, 129.9, 129.5, 129.3, 128.8, 126.7, 125.6, 124.9, 122.9, 122.6, 112.4, 111.1, 109.8, 79.5 (N-C-S), 69.2 (N-C), 58.0 (C), 51.0 (CH), 21.5 (CH3); IR (neat) ν 3064, 2955, 2920, 2850, 2228, 2214, 1682, 1579, 1465, 1448, 1296, 1245, 1224, 1210, 1180, 1027, 1001, 964, 737, 705, 686, 660 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H20N3OS 422.1322; found 422.1325.
  • 1-Benzoyl-2-(3,4-dimethylphenyl)-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3,3(3aH)-dicarbonitrile (7ae): Eluent: petroleum ether/DCM = 1:2, white solid (42.2 mg, 97% yield); Rf = 0.26 (petroleum ether/EtOAc = 6:1); m.p. 88.5–90.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.94–7.90 (m, 2H, Ar-H), 7.64–7.59 (m, 1H, Ar-H), 7.49–7.44 (m, 2H, Ar-H), 7.29–7.26 (m, 1H, Ar-H), 7.21–7.17 (m, 2H, Ar-H), 7.17–7.14 (m, 1H, Ar-H), 7.02 (td, J = 7.7, 1.3 Hz, 1H, Ar-H), 6.91 (td, J = 7.6, 1.1 Hz, 1H, Ar-H), 6.46 (d, J = 7.7 Hz, 1H, Ar-H), 6.05 (s, 1H, N-CH-S), 5.55 (d, J = 9.5 Hz, 1H, N-CH), 4.30 (d, J = 9.5 Hz, 1H, CH), 2.23 (s, 6H, (CH3)2); 13C NMR (101 MHz, CDCl3) δ 197.2 (C=O), 146.4, 139.2, 138.1, 135.3, 134.6, 130.8, 130.3, 129.2, 128.8, 127.2, 126.7, 125.8, 124.9, 122.8, 122.6, 112.5, 111.1, 109.8, 79.4 (N-C-S), 69.1 (N-C), 57.9 (C), 51.2 (CH), 19.9 (CH3), 19.7 (CH3); IR (neat) ν 3066, 3037, 2934, 2231, 2205, 1738, 1671, 1593, 1582, 1469, 1448, 1303, 1219, 1179, 1135, 1031, 824, 747, 686 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C27H22N3OS 436.1478; found 436.1472.
  • 1-Benzoyl-2-(naphthalen-2-yl)-1,2-dihydrobenzo[d]pyrrolo[2,1-b]thiazole-3,3(3aH)-dicarbonitrile (7af): Eluent: petroleum ether/DCM = 1:2, white solid (41.6 mg, 91% yield); Rf = 0.36 (petroleum ether/EtOAc = 6:1); m.p. 125.1–126.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.79–7.76 (m, 2H, Ar-H), 7.72–7.68 (m, 1H, Ar-H), 7.55–7.51 (m, 1H, Ar-H), 7.39–7.35 (m, 2H, Ar-H), 7.35–7.30 (m, 3H, Ar-H), 7.30–7.22 (m, 2H, Ar-H), 7.21–7.13 (m, 2H, Ar-H), 7.00 (td, J = 7.7, 1.2 Hz, 1H, Ar-H), 6.88 (td, J = 7.6, 1.1 Hz, 1H, Ar-H), 6.46 (d, J = 7.9 Hz, 1H, Ar-H), 6.01 (s, 1H, N-CH-S), 5.42 (d, J = 9.0 Hz, 1H, N-CH), 5.20 (d, J = 8.9 Hz, 1H, CH); 13C NMR (101 MHz, CDCl3) δ 196.2 (C=O), 145.9, 136.1, 135.0, 134.6, 131.2, 130.8, 129.2, 129.1, 128.8, 128.7, 127.9, 126.8, 124.9, 123.1, 122.9, 112.0, 111.2, 109.7, 79.9 (N-C-S), 70.5 (N-C), 51.8 (C), 49.8 (CH); IR (neat) ν 3072, 2919, 2850, 2207, 1732, 1675, 1589, 1579, 1466, 1444, 1293, 1250, 1216, 1201, 1181, 1032, 855, 746, 703, 687 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C29H20N3OS 458.1322; found 458.1330.

4. Conclusions

In summary, we developed an efficient strategy for the [3 + 2] cycloaddition reactions of heteroaromatic N-ylides with different electron-deficient olefins for the diverse synthesis of fused polyheterocyclic compounds under mild reaction conditions. With the N-phenacylbenzothiazolium bromides as the heteroaromatic N-ylides precursors, the heteroaromatic N-ylides can smoothly react with maleimides to give fused polycyclic octahydropyrrolo[3,4-c]pyrroles in moderate to excellent isolated yields (52–99%). Moreover, this [3 + 2] cycloaddition concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins, affording a series of structurally diverse functionalized polyheterocyclic compounds in good to excellent yields (70–97%). Further studies about exploring benzothiazolium salts to synthesize other new structurally unique N,S-polyheterocycle compounds are currently underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114410/s1, X-ray data for products 3aa; copies of 1H, 13C NMR spectra. References [69,70,71] are cited in the supplementary materials.

Author Contributions

Conceptualization, Z.-H.W. and W.-C.Y.; methodology, Z.-H.W., T.Z. and L.-W.S.; investigation, X.Y., Y.-P.Z., Y.Y. and J.-Q.Z.; writing—original draft preparation, Z.-H.W. and W.-C.Y.; writing—review and editing, W.-C.Y.; supervision, Z.-H.W. and W.-C.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Natural Science Foundation of China (nos. 22171029, 21901024, 21871252, and 22271027) and the Sichuan Science and Technology Program (nos. 2023NSFSC1080 and 2021YFS0315).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All the required data are reported in the manuscript and Supplementary Materials.

Acknowledgments

This work was performed using the equipment of Chengdu University.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 28 04410 g001 550
Figure 1. Representative biologically active molecules containing fused polyheterocyclic skeleton.
Figure 1. Representative biologically active molecules containing fused polyheterocyclic skeleton.
Molecules 28 04410 g001
Molecules 28 04410 sch001 550
Scheme 1. Profile of [3 + 2] cycloaddition of nitrogen-ylides in situ generated from imines or heteroarenium salts and the strategy for the diverse synthesis of structurally diverse fused polyheterocyclic compounds in this study.
Scheme 1. Profile of [3 + 2] cycloaddition of nitrogen-ylides in situ generated from imines or heteroarenium salts and the strategy for the diverse synthesis of structurally diverse fused polyheterocyclic compounds in this study.
Molecules 28 04410 sch001
Molecules 28 04410 sch002 550
Scheme 2. The substrate scope of benzothiazolium salts 1. Reaction conditions: The reaction was carried out with 1a–1l (0.15 mmol), 2a (0.10 mmol), and Na2CO3 (0.15 mmol) in toluene (1.0 mL) at room temperature for 3 h. The yields refer to the isolated yield of product.
Scheme 2. The substrate scope of benzothiazolium salts 1. Reaction conditions: The reaction was carried out with 1a–1l (0.15 mmol), 2a (0.10 mmol), and Na2CO3 (0.15 mmol) in toluene (1.0 mL) at room temperature for 3 h. The yields refer to the isolated yield of product.
Molecules 28 04410 sch002
Molecules 28 04410 sch003 550
Scheme 3. The substrate scope for maleimides 2. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 2b–2j (0.10 mmol), and Na2CO3 (0.15 mmol) in toluene (1.0 mL) at room temperature for 3 h.
Scheme 3. The substrate scope for maleimides 2. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 2b–2j (0.10 mmol), and Na2CO3 (0.15 mmol) in toluene (1.0 mL) at room temperature for 3 h.
Molecules 28 04410 sch003
Molecules 28 04410 sch004 550
Scheme 4. Scale-up experiment.
Scheme 4. Scale-up experiment.
Molecules 28 04410 sch004
Molecules 28 04410 sch005 550
Scheme 5. The [3 + 2] cycloaddition reaction of benzothiazolium salt with 3-trifluoroethylidene oxindoles. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 4a–4i (0.10 mmol), and Cs2CO3 (0.15 mmol) in DCM (1.0 mL) at room temperature for 18 h.
Scheme 5. The [3 + 2] cycloaddition reaction of benzothiazolium salt with 3-trifluoroethylidene oxindoles. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 4a–4i (0.10 mmol), and Cs2CO3 (0.15 mmol) in DCM (1.0 mL) at room temperature for 18 h.
Molecules 28 04410 sch005
Molecules 28 04410 sch006 550
Scheme 6. The [3 + 2] cycloaddition reaction of benzothiazolium salt with various benzylidenemalononitriles. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 6a–6f (0.10 mmol), and TEA (0.15 mmol) in 1,2-dimethoxyethane (DME, 1.0 mL) at room temperature for 3 h.
Scheme 6. The [3 + 2] cycloaddition reaction of benzothiazolium salt with various benzylidenemalononitriles. Reaction conditions: The reaction was carried out with 1a (0.15 mmol), 6a–6f (0.10 mmol), and TEA (0.15 mmol) in 1,2-dimethoxyethane (DME, 1.0 mL) at room temperature for 3 h.
Molecules 28 04410 sch006
Table
Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
Molecules 28 04410 i001
EntryBaseSolventYield (%) [b]
1Cs2CO3DCM63
2K3PO4DCM88
3Na2CO3DCM95
4K2HPO4DCM75
5TEADCMn.d.
6Na2CO3toluene99
7Na2CO3DCE75
8Na2CO3MeCN33
9Na2CO3THFn.d.
[a] The reaction was carried out with 1a (0.15 mmol), 2a (0.10 mmol), and base (0.15 mmol) in solvent (1.0 mL) at room temperature for the specified reaction time. [b] Isolated yield. n.d.—not detected.
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Wang, Z.-H.; Zhang, T.; Shen, L.-W.; Yang, X.; Zhang, Y.-P.; You, Y.; Zhao, J.-Q.; Yuan, W.-C. Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins. Molecules 2023, 28, 4410. https://doi.org/10.3390/molecules28114410

AMA Style

Wang Z-H, Zhang T, Shen L-W, Yang X, Zhang Y-P, You Y, Zhao J-Q, Yuan W-C. Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins. Molecules. 2023; 28(11):4410. https://doi.org/10.3390/molecules28114410

Chicago/Turabian Style

Wang, Zhen-Hua, Tong Zhang, Li-Wen Shen, Xiu Yang, Yan-Ping Zhang, Yong You, Jian-Qiang Zhao, and Wei-Cheng Yuan. 2023. "Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins" Molecules 28, no. 11: 4410. https://doi.org/10.3390/molecules28114410

APA Style

Wang, Z. -H., Zhang, T., Shen, L. -W., Yang, X., Zhang, Y. -P., You, Y., Zhao, J. -Q., & Yuan, W. -C. (2023). Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins. Molecules, 28(11), 4410. https://doi.org/10.3390/molecules28114410

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