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DOI: 10.1039/C5RA21995G (Paper) RSC Adv., 2015, 5, 103116-103122

Highly diastereoselective synthesis of imidazolidine-dispirooxindoles via three-component [3 + 2] cycloadditions of isatins, 2-(aminomethyl)pyridine and isatin-based imines†

Hong-Wu Zhao*, Xiao-Qin Chen, Zhao Yang, Ting Tian, Bo Li, Wei Meng, Xiu-Qing Song and Hai-Liang Pang
College of Life Science and Bio-engineering, Beijing University of Technology, No. 100 Pingleyuan, Chaoyang District, Beijing 100124, P. R. China. E-mail: hwzhao@bjut.edu.cn

Received 21st October 2015 , Accepted 24th November 2015

First published on 26th November 2015

Abstract

In the presence of Et3N, the [3 + 2] cycloaddition of isatins, 2-(aminomethyl)pyridine and isatin-based imines proceeded readily, and furnished novel imidazolidine-dispirooxindoles in up to 84% yield with up to >99[thin space (1/6-em)]:[thin space (1/6-em)]1 diastereoselectivity. The relative configuration of the imidazolidine-dispirooxindoles was firmly confirmed on the basis of X-ray single crystal structure analysis. The reaction mechanism was assumed to account for the diastereoselective formation of the imidazolidine-dispirooxindoles.

Introduction

Dispirooxindoles constitute a class of structurally and stereochemically diverse and complex chemical entities, and exhibit a wide range of important biological activities, for example, antidiabetic, anticancer, antitubercular, antibacterial as well as antimicrobial activities as summarized in Fig. 1.1 Since the biological and medicinal importance with dispirooxindoles, organic chemists and medicinal chemists have been involved in developing useful and powerful methodologies for the synthesis of dispirooxindoles with potential biological activities.2 Among the known synthetic methodologies, the [3 + 2] cycloaddition of azomethine ylides with various substituted dipolarophiles served as the main tools for the construction of dispirooxindoles.3 In particular, most of the present pyrrolidine-dispirooxindoles were easily and efficiently produced by means of the [3 + 2] cycloaddition of isatin-derived azomethine ylides with various olefin-based dipolarophiles.4 In spite of the progress made in the synthesis of an array of dispirooxindoles, it is still highly needed to develop more efficient and concise methodologies for the synthesis of dispirooxindoles bearing structural and stereochemical diversity.
image file: c5ra21995g-f1.tif
Fig. 1 Representative bioactive dispirooxindoles.

In the recent years, the diastereoselective construction of structurally unique dispirooxindoles consisting of two spirooxindole motifs has gained attentions from several research groups. For example, in 2012 Yuan and co-workers reported the diastereoselective synthesis of dispiro[imidazolidine-2-thione]bisoxindoles through [3 + 2] cycloaddition of 3-isothiocyanato oxindoles with isatinimines.5 In the same year, Taylor research group carried out the diastereoselective construction of spirocyclic bisoxindoles via a double C–H, Ar–H coupling process.6 In 2015, by following a similar self-cycloaddition strategy, Yang7 and Thennarsu8 research groups individually contributed to the first diastereoselective synthesis of imidazolidine-dispirooxindoles including two spirooxindoles at 2,5-positions of imidazolidine ring by treating azomethine ylides with isatin-based imines as shown in Scheme 1 (eqn (1) & (2)). In our work, we first designed the distereoselective three-component [3 + 2] cycloadditions of isatins, 2-(aminomethyl)pyridine and isatin-based imines for the construction of a series of novel imidazolidine-dispirooxindoles bearing two spirooxindoles at 4,5-positions of imidazolidine ring as outlined in Scheme 1 (eqn (3)). The [3 + 2] cycloadditions underwent smoothly, thus providing the designed unprecedented imidazolidine-dispirooxindoles in desirable chemical yields with high diastereoselectivities.


image file: c5ra21995g-s1.tif
Scheme 1 Diastereoselective synthesis of imidazolidine-dispirooxindoles.

Results and discussion

Initially, under the different reaction conditions, we examined the three-component [3 + 2] cycloaddition of 1a, 2 and 3a as shown in Table 1. Without any additives, we screened a series of solvents, and found that the use of CH2Cl2 gave 4aa in better chemical yield with comparable diastereoselectivity (Table 1, entries 1–5). Moreover, Lewis acids and protonic acids as additives could cause the different loss in chemical yield and diastereoselectivity (Table 1, entries 6–11). At last, we examined a variety of organic bases as additives as well as catalytic loading of Et3N, and discovered that 50 mol% of Et3N behaved most efficiently, and furnished 4aa in 70% yield with 92[thin space (1/6-em)]:[thin space (1/6-em)]8 dr (Table 1, entries 12–23). Considering the chemical yield and diastereoselectivity of 4aa comprehensively, we determined the optimal reaction conditions as below: 1a[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]3a = 1[thin space (1/6-em)]:[thin space (1/6-em)]1[thin space (1/6-em)]:[thin space (1/6-em)]1, 50 mol% Et3N, CH2Cl2, room temperature.
Table 1 Optimization of reaction conditionsa

image file: c5ra21995g-u1.tif
Entry Solvent Additive Time (h) Yieldb (%) drc
a Reaction was conducted with 5-Cl-isatin 1a (0.1 mmol), 2-(aminomethyl)pyridine 2 (0.1 mmol), isatin-based imine 3a (0.1 mmol) in the absence or presence of 10 mol% of additive in the indicated solvents (0.5 mL) at room temperature.b Isolated yield.c Determined by 1H NMR spectroscopy.
1 THF — 24 42 53[thin space (1/6-em)]:[thin space (1/6-em)]47
2 Toluene — 24 15 90[thin space (1/6-em)]:[thin space (1/6-em)]10
3 CH2Cl2 — 24 53 83[thin space (1/6-em)]:[thin space (1/6-em)]17
4 CH3CN — 24 33 84[thin space (1/6-em)]:[thin space (1/6-em)]16
5 EtOH — 24 19 72[thin space (1/6-em)]:[thin space (1/6-em)]28
6 CH2Cl2 CuI 40 Trace —
7 CH2Cl2 Yb(OTf)3 40 31 18[thin space (1/6-em)]:[thin space (1/6-em)]81
8 CH2Cl2 MgSO4 40 44 72[thin space (1/6-em)]:[thin space (1/6-em)]28
9 CH2Cl2 PhCO2H 40 55 70[thin space (1/6-em)]:[thin space (1/6-em)]30
10 CH2Cl2 2,2′-Biphenol 40 61 73[thin space (1/6-em)]:[thin space (1/6-em)]27
11 CH2Cl2 Stearic acid 40 58 74[thin space (1/6-em)]:[thin space (1/6-em)]26
12 CH2Cl2 Quinine 40 52 85[thin space (1/6-em)]:[thin space (1/6-em)]15
13 CH2Cl2 Pyridine 40 64 76[thin space (1/6-em)]:[thin space (1/6-em)]24
14 CH2Cl2 DIPEA 40 51 85[thin space (1/6-em)]:[thin space (1/6-em)]15
15 CH2Cl2 DMAP 40 48 85[thin space (1/6-em)]:[thin space (1/6-em)]15
16 CH2Cl2 DBN 40 47 86[thin space (1/6-em)]:[thin space (1/6-em)]14
17 CH2Cl2 DBU 40 35 88[thin space (1/6-em)]:[thin space (1/6-em)]12
18 CH2Cl2 TBD 40 58 81[thin space (1/6-em)]:[thin space (1/6-em)]19
19 CH2Cl2 Et3N (5 mol%) 72 58 88[thin space (1/6-em)]:[thin space (1/6-em)]12
20 CH2Cl2 Et3N (10 mol%) 72 65 88[thin space (1/6-em)]:[thin space (1/6-em)]12
21 CH2Cl2 Et3N (20 mol%) 72 58 89[thin space (1/6-em)]:[thin space (1/6-em)]11
22 CH2Cl2 Et3N (30 mol%) 72 61 89[thin space (1/6-em)]:[thin space (1/6-em)]11
23 CH2Cl2 Et3N (50 mol%) 72 70 92[thin space (1/6-em)]:[thin space (1/6-em)]8

Subsequently, we extended the reaction scope as outlined in Table 2 under the optimal reaction conditions by using variable substrates 1 and 3. In most cases, the [3 + 2] cycloadditions gave products 4 in the acceptable chemical yields with excellent diastereoselectivities (entries 1–2, 4, 7, 10–24). As for other cases, products 4 were formed in 63–80% chemical yields with 67[thin space (1/6-em)]:[thin space (1/6-em)]33–88[thin space (1/6-em)]:[thin space (1/6-em)]12 diastereoselectivities (entries 3, 5–6 and 8–9). Surprisingly, we found that the [3 + 2] cycloaddition of 1a, benzylamine and 3a did not take place at all (entry 25). Moreover, the use of single crystal X-ray analysis determined the relative configuration of 4de as presented in Fig. 2.9 Based on the relative configuration of 4de, the relative configurations of other imidazolidine-dispirooxindoles 4 were similarly assigned as shown in Table 2.

Table 2 Extension of substrate scopea

image file: c5ra21995g-u2.tif
Entry 1 (R1, R2) 3 (R3, R4) Yieldb (%) drc
a Reactions were conducted with isatins 1 (0.1 mmol), 2-(aminomethyl)pyridine 2 (0.1 mmol), isatin-based imines 3 (0.1 mmol), Et3N (0.05 mmol) in CH2Cl2 (0.5 mL) at room temperature for 72 h.b Isolated yield.c Determined by 1H NMR spectroscopy.d Benzylamine was used.e No reaction.
1 1a (5-Cl, H) 3a (H, H) 70 (4aa) 92[thin space (1/6-em)]:[thin space (1/6-em)]8
2 1b (H, H) 3a (H, H) 76 (4ba) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
3 1b (H, H) 3b (5-MeO, H) 63 (4bb) 85[thin space (1/6-em)]:[thin space (1/6-em)]15
4 1a (5-Cl, H) 3c (5-Cl, H) 77 (4ac) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
5 1a (5-Cl, H) 3b (5-MeO, H) 70 (4ab) 88[thin space (1/6-em)]:[thin space (1/6-em)]12
6 1c (5-MeO, H) 3c (5-Cl, H) 83 (4cc) 67[thin space (1/6-em)]:[thin space (1/6-em)]33
7 1c (5-MeO, H) 3b (5-MeO, H) 61 (4cb) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
8 1d (H, Bn) 3a (H, H) 80 (4da) 75[thin space (1/6-em)]:[thin space (1/6-em)]25
9 1e (H, Me) 3a (H, H) 71 (4ea) 76[thin space (1/6-em)]:[thin space (1/6-em)]24
10 1d (H, Bn) 3d (H, Me) 78 (4dd) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
11 1b (H, H) 3d (H, Me) 63 (4bd) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
12 1d (H, Bn) 3e (H, Bn) 81 (4de) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
13 1f (5-F, H) 3e (H, Bn) 61 (4fe) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
14 1a (5-Cl, H) 3e (H, Bn) 83 (4ae) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
15 1g (6-Cl, H) 3e (H, Bn) 63 (4ge) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
16 1h (5-Br, H) 3e (H, Bn) 78 (4he) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
17 1i (6-Br, H) 3e (H, Bn) 61 (4ie) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
18 1b (H, H) 3e (H, Bn) 84 (4be) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
19 1j (5-Me, H) 3e (H, Bn) 78 (4je) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
20 1c (5-MeO, H) 3e (H, Bn) 64 (4ce) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
21 1b (H, H) 3f (5-Cl, Bn) 84 (4bf) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
22 1b (H, H) 3g (5-Br, Bn) 81 (4bg) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
23 1b (H, H) 3h (5-Me, Bn) 77 (4bh) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
24 1b (H, H) 3i (5-MeO, Bn) 75 (4bi) >99[thin space (1/6-em)]:[thin space (1/6-em)]1
25d 1a (5-Cl, H) 3a (H, H) NRe —


image file: c5ra21995g-f2.tif
Fig. 2 X-ray single crystal structure of dispirooxindole 4de.

To shed light on the formation and diastereoselectivity of 4de, we proposed the mechanism for the [3 + 2] cycloaddition as illustrated in Scheme 2. Initially, under catalysis of Et3N, isatin 1d condenses easily with 2-(aminomethyl)pyridine 2 to afford imine 5. Subsequently, the deprotonation of imine 5 with Et3N give rise to enolate 6. Finally, the cyclization of the resulted enolate 6 with imine 3e formed diastereoisomer 4de via the transition state TS1. In our case, the formation of diastereoisomer 7de was not observed through the transition state TS2. With the aid of molecular model, it was found that two 2-indolinone rings have a face-to-face overlap in the transition state TS2, and the stronger electronstatic repulsion exists between the two π systems; in comparison, this type of electronstatic repulsion decrease remarkably in the transition state TS1 owing to the parallel-displaced orientation between the two 2-indolinone rings.10 Therefore, the transition state TS1 is more stable than the transition state TS2. Noticeably, the [3 + 2] cycloaddition prefer to adopt the transition state TS1 to lead to formation of thermodynamically more stable diastereoisomer 4de instead of diastereoisomer 7de bearing the severe steric hindrance between the two 2-indolinone moieties. Overall, it was deduced that the preference for the transition state TS1 over the transition state TS2 account for the excellent diastereoselectivity in the [3 + 2] cycloaddition.


image file: c5ra21995g-s2.tif
Scheme 2 Proposed mechanism for [3 + 2] cycloaddition.

Conclusions

In conclusion, by means of Et3N-catalyzed [3 + 2] cycloaddition of isatin-derived azomethine ylides with isatin-based imines, we first accomplished the synthesis of imidazolidine-dispirooxindoles featuring two spirooxindoles at 4,5-positions of the imidazolidine ring. Significantly, our methodology not only enriched the synthetic chemistry of imidazolidine-dispirooxindoles, but also benefited to the discovery of novel dispirooxindoles with potential biological activities. At present, the design and stereoselective synthesis of new type of dispirooxindoles is undergoing in our lab, and will be reported in due course.

Experimental section

General methods

Unless noted otherwise, all reagents were commercially available and used without further purification. All solvents were distilled from the appropriate drying agents immediately before use. Reactions were monitored by TLC carried out on 0.25 mm SDS silica gel coated glass plates (60F254) and compounds were detected with UV light. The compound melting point was determined by a melting point instrument. NMR spectra were recorded on 400 MHz instrument and calibrated using tetramethylsilane (TMS) as internal reference. High resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI) conditions.

Typical procedure for the diastereoselective synthesis of imidazolidine-dispirooxindoles 4

Triethylamine (0.05 mmol, 6.9 μL, 5.0 mg) was added to a mixture of isatins 1 (0.1 mmol), 2-(aminomethyl)pyridine 2 (0.1 mmol, 9.8 μL, 10.8 mg) and isatin-based imines 3 (0.1 mmol) in anhydrous CH2Cl2 (0.5 mL). The reaction was stirred at room temperature for 72 hours. After completion of the reaction, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1[thin space (1/6-em)]:[thin space (1/6-em)]2) to afford the pure products 4 as white powder (61–84% yield; 67[thin space (1/6-em)]:[thin space (1/6-em)]33 ≥ 99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).
4aa. Reaction time: 72 h; yield: 70% (0.07 mmol, 34.5 mg); white powder, mp > 320 °C; dr = 92[thin space (1/6-em)]:[thin space (1/6-em)]8; 1H NMR (400 MHz, DMSO): δ 10.90 (s, 1H), 10.51 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 7.31–7.25 (m, 2H), 14 (s, 1H), 6.89–6.63 (m, 7H), 6.44 (d, J = 6.0 Hz, 1H), 6.06 (s, 2H), 4.50 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 178.5, 175.9, 160.6, 148.6, 142.7, 142.6, 142.5, 137.6, 130.6, 130.2, 128.6, 127.3, 126.5, 126.0, 125.6, 124.0, 123.6, 122.9, 122.1, 118.0, 115.9, 111.3, 110.6, 79.5, 74.7, 73.5; HRMS (ESI) calculated for C28H21ClN5O2 (M + H+): 494.13783, found 494.13620.
4ba. Reaction time: 72 h; yield: 76% (0.076 mmol, 34.9 mg); white powder, mp > 320 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.47 (s, 2H), 8.58 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 5.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.97–6.88 (m, 2H), 6.82–6.61 (m, 6H), 6.43 (t, J = 7.2 Hz, 1H), 6.04 (d, J = 6.0 Hz, 2H), 4.14 (d, J = 5.2 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 178.7, 175.8, 160.6, 148.8, 144.7, 142.7, 142.6, 137.7, 130.7, 128.5, 127.3, 125.9, 124.0, 123.4, 123.3, 123.2, 122.1, 122.0, 117.9, 115.9, 110.5, 109.9, 79.5, 74.9, 73.3; HRMS (ESI) calculated for C28H22N5O2 (M + H+): 460.17680, found 460.17548.
4bb. Reaction time: 72 h; yield: 63% (0.063 mmol, 30.8 mg); white powder, mp > 320 °C; dr = 85[thin space (1/6-em)]:[thin space (1/6-em)]15; 1H NMR (400 MHz, DMSO): δ 10.63 (s, 1H), 10.48 (s, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 5.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 2H), 6.72–6.62 (m, 4H), 6.54 (s, 1H), 6.45 (t, J = 7.2 Hz, 2H), 6.06 (d, J = 6.8 Hz, 2H), 4.11 (d, J = 9.2 Hz, 1H), 3.52 (s, 3H); 13C NMR (100 MHz, DMSO): δ 178.5, 175.7, 160.6, 154.8, 148.8, 143.5, 142.7, 137.7, 136.0, 130.7, 128.6, 125.9, 124.6, 124.0, 123.4, 123.3, 122.1, 117.9, 115.9, 114.8, 113.9, 110.7, 109.9, 79.6, 75.0, 73.4, 55.7; HRMS (ESI) calculated for C29H24N5O3 (M + H+): 490.18737, found 490.18607.
4ac. Reaction time: 72 h; yield: 77% (0.077 mmol, 40.6 mg); white powder, mp > 320 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 11.04 (s, 1H), 10.69 (s, 1H), 8.56 (d, J = 4.4 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.33–7.20 (m, 3H), 6.87–6.94 (m, 3H), 6.76 (d, J = 8.4 Hz, 1H), 6.68–6.63 (m, 2H), 6.49 (t, J = 7.2 Hz, 1H), 6.06 (d, J = 6.8 Hz, 2H), 4.61 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 178.1, 175.9, 160.3, 148.6, 142.3, 141.7, 137.6, 130.8, 130.1, 128.8, 126.9, 126.5, 126.2, 126.1, 125.2, 125.1, 124.1, 126.6, 118.5, 115.9, 112.1, 111.4, 79.5, 75.0, 73.4; HRMS (ESI) calculated for C28H20Cl2N5O2 (M + H+): 528.09886, found 528.09767.
4ab. Reaction time: 72 h; yield: 70% (0.07 mmol, 36.6 mg); white powder, mp > 320 °C; dr = 88[thin space (1/6-em)]:[thin space (1/6-em)]12; 1H NMR (400 MHz, DMSO): δ 10.75 (s, 1H), 10.58 (s, 1H), 8.56 (d, J = 4.4 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.33–7.25 (m, 2H), 6.82 (t, J = 7.6 Hz, 2H), 6.74–6.71 (m, 1H), 6.66–6.63 (m, 3H), 6.50 (d, J = 2.4 Hz, 1H), 6.45 (t, J = 7.2 Hz, 1H), 6.06 (d, J = 7.2 Hz, 2H), 4.48 (d, J = 8.8 Hz, 1H), 3.52 (s, 3H); 13C NMR (100 MHz, DMSO): δ 178.2, 175.9, 160.5, 154.8, 148.6, 142.6, 142.4, 137.6, 135.8, 130.6, 128.6, 126.5, 126.0, 125.5, 124.4, 124.0, 123.6, 118.0, 115.9, 114.8, 114.1, 111.3, 110.8, 79.5, 74.8, 73.5, 55.7; HRMS (ESI) calculated for C29H23ClN5O3 (M + H+): 524.14839, found 524.14740.
4cc. Reaction time: 72 h; yield: 83% (0.083 mmol, 43.5 mg); white powder, mp > 320 °C; dr = 67[thin space (1/6-em)]:[thin space (1/6-em)]33; 1H NMR (400 MHz, DMSO): δ 10.96 (s, 1H), 10.41 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.41 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.34–7.28 (m, 1H), 7.23–7.16 (m, 2H), 6.87–6.73 (m, 5H), 6.68–6.63 (m, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.48 (t, J = 7.6 Hz, 1H), 6.06 (s 2H), 4.30 (d, J = 9.2 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, DMSO): δ 178.3, 175.8, 160.3, 155.1, 148.8, 142.5, 141.8, 137.7, 136.4, 129.9, 128.8, 127.0, 126.0, 125.4, 125.2, 124.2, 124.1, 123.4, 118.3, 115.9, 115.4, 113.3, 112.0, 110.3, 79.7, 75.4, 73.4, 55.9; HRMS (ESI) calculated for C29H23ClN5O3 (M + H+): 524.14839, found 524.14746.
4cb. Reaction time: 72 h; yield: 61% (0.061 mmol, 31.7 mg); white powder, mp > 320 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.66 (s, 1H), 10.30 (s, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7.18 (s, 1H), 6.84–6.63 (m, 6H), 6.54 (s, 2H), 6.44 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.2 Hz, 2H), 4.14 (d, J = 9.2 Hz, 1H), 3.69 (s, 3H), 3.51 (s, 3H); 13C NMR (100 MHz, DMSO): δ 178.5, 175.7, 160.5, 155.0, 154.8, 148.8, 142.7, 137.7, 136.5, 135.9, 128.6, 124.6, 124.5, 124.0, 123.3, 117.9, 115.9, 115.2, 114.9, 113.9, 113.3, 110.7, 110.2, 79.7, 75.3, 73.5, 55.9, 55.7; HRMS (ESI) calculated for C30H26N5O4 (M + H+): 520.19793, found 520.19666.
4da. Reaction time: 72 h; yield: 80% (0.08 mmol, 44 mg); white powder, mp 251–253 °C; dr = 75[thin space (1/6-em)]:[thin space (1/6-em)]25; 1H NMR (400 MHz, DMSO): δ 10.77 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 4.8 Hz, 1H), 7.20–7.16 (m, 4H), 7.02 (t, J = 7.6 Hz, 1H), 6.85–6.71 (m, 9H), 6.53 (d, J = 8.0 Hz, 1H), 6.45 (t, J = 7.2 Hz, 1H), 6.07 (d, J = 7.2 Hz, 2H), 4.88 (d, J = 16.0 Hz, 1H), 4.52 (d, J = 16.0 Hz, 1H), 4.35 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 178.7, 174.2, 160.6, 148.7, 143.9, 142.9, 142.6, 137.3, 135.7, 130.8, 130.0, 128.9, 127.6, 127.5, 127.3, 125.9, 124.1, 123.4, 123.1, 123.0, 122.9, 122.2, 118.1, 116.0, 110.7, 109.7, 79.5, 74.7, 73.6, 42.7; HRMS (ESI) calculated for C35H28N5O2 (M + H+): 550.22375, found 550.22229.
4ea. Reaction time: 72 h; yield: 71% (0.071 mmol, 33.6 mg); white powder, mp 266–269 °C; dr = 76[thin space (1/6-em)]:[thin space (1/6-em)]24; 1H NMR (400 MHz, DMSO): δ 10.76 (s, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33–7.28 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.82–6.67 (m, 7H), 6.43 (t, J = 7.2 Hz, 1H), 6.06 (d, J = 7.2 Hz, 2H), 4.27 (d, J = 9.2 Hz, 1H), 2.85 (s, 3H); 13C NMR (100 MHz, DMSO): δ 178.4, 174.2, 160.6, 148.8, 144.7, 142.7, 142.6, 137.7, 130.9, 130.1, 128.6, 126.8, 125.5, 124.1, 123.4, 122.9, 122.7, 122.6, 121.7, 118.0, 115.9, 110.5, 108.9, 79.7, 74.9, 73.5, 25.8; HRMS (ESI) calculated for C29H24N5O2 (M + H+): 474.19245, found 474.19119.
4dd. Reaction time: 72 h; yield: 78% (0.078 mmol, 44 mg); white powder, mp 114–116 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 8.59 (d, J = 4.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.35–7.26 (m, 2H), 7.19–7.16 (m, 4H), 7.02–6.95 (m, 2H), 6.88–6.76 (m, 7H), 6.53 (d, J = 7.6 Hz, 1H), 6.45 (t, J = 7.6 Hz, 1H), 6.04 (d, J = 6.8 Hz, 2H), 4.86 (d, J = 15.6 Hz, 1H), 4.52 (d, J = 15.6 Hz, 1H), 4.47 (d, J = 8.8 Hz, 1H), 3.08 (s, 3H); 13C NMR (100 MHz, DMSO): δ 176.9, 174.1, 160.5, 148.7, 144.1, 143.9, 142.5, 137.7, 135.7, 130.9, 130.1, 128.9, 128.6, 127.6, 127.3, 126.9, 125.5, 124.1, 123.5, 122.8, 122.7, 122.6, 122.4, 118.2, 116.2, 109.7, 109.6, 79.6, 74.9, 73.5, 42.7, 26.5; HRMS (ESI) calculated for C36H30N5O2 (M + H+): 564.23940, found 564.23779.
4bd. Reaction time: 72 h; yield: 63% (0.063 mmol, 29.8 mg); white powder, mp 253–255 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 5.6 Hz, 1H), 7.24–7.16 (m, 2H), 6.92 (d, J = 7.2 Hz, 3H), 6.87–6.77 (m, 3H), 6.72 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.43 (t, J = 8.0 Hz, 1H), 6.00 (d, J = 7.2 Hz, 2H), 4.24 (d, J = 9.2 Hz, 1H), 3.07 (s, 3H); 13C NMR (100 MHz, DMSO): δ 176.9, 175.7, 160.6, 148.8, 144.0, 143.4, 142.6, 137.7, 130.8, 130.1, 128.6, 126.8, 125.4, 124.1, 123.4, 123.1, 122.6, 122.5, 121.8, 118.0, 117.7, 116.0, 110.0, 109.4, 79.6, 75.1, 73.3, 26.4; HRMS (ESI) calculated for C29H24N5O2 (M + H+): 474.19245, found 474.19101.
4de. Reaction time: 72 h; yield: 81% (0.081 mmol, 51.8 mg); white powder, mp 108–110 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 8.60 (d, J = 4.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.35–7.32 (m, 1H), 7.25–7.10 (m, 10H), 6.94–6.91 (m, 2H), 6.84–6.72 (m, 7H), 6.57 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 8.8 Hz, 1H), 6.05 (d, J = 7.2 Hz, 2H), 4.90 (s, 2H), 4.86 (d, J = 16.0 Hz, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 177.1, 174.5, 160.6, 148.7, 144.0, 143.6, 142.4, 137.8, 136.2, 135.7, 130.8, 130.1, 129.0, 128.5, 127.9, 127.8, 127.6, 127.3, 126.0, 124.1, 123.5, 123.0, 122.9, 122.8, 122.7, 118.3, 116.2, 110.4, 109.8, 79.6, 74.9, 73.5, 43.6, 42.7; HRMS (ESI) calculated for C42H34N5O2 (M + H+): 640.27070, found 640.26917.
4fe. Reaction time: 72 h; yield: 61% (0.061 mmol, 34.6 mg); white powder, mp 277–279 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.34–7.25 (m, 5H), 7.14–7.04 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.77–6.72 (m, 4H), 6.66 (m, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.02 (d, J = 7.2 Hz, 2H), 5.05 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.62 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.9, 176.4, 160.6, 157.0, 148.6, 143.6, 142.4, 139.7, 137.7, 136.1, 130.2, 129.0, 128.5, 127.9, 127.4, 127.2, 124.1, 123.6, 122.9, 122.6, 118.3, 116.3, 110.3, 79.3, 75.2, 73.4, 43.6; HRMS (ESI) calculated for C35H27FN5O2 (M + H+): 568.21433, found 568.21271.
4ae. Reaction time: 72 h; yield: 83% (0.083 mmol, 48.4 mg); white powder, mp 285–287 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.54 (s, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.34–7.26 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 7.04 (s, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.77–6.66 (m, 5H), 6.43 (t, J = 7.2 Hz, 1H), 6.02 (d, J = 6.0 Hz, 2H), 5.08 (d, J = 15.6 Hz, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.9, 176.3, 160.6, 148.6, 143.6, 142.6, 142.4, 137.6, 136.1, 130.7, 130.2, 129.1, 128.5, 127.9, 127.4, 127.2, 126.8, 126.4, 125.6, 124.0, 123.7, 122.9, 122.6, 118.3, 116.2, 111.4, 110.3, 79.7, 74.9, 73.5, 43.6; HRMS (ESI) calculated for C35H27ClN5O2 (M + H+): 584.18478, found 584.18353.
4ge. Reaction time: 72 h; yield: 63% (0.063 mmol, 36.8 mg); white powder, mp 172–174 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.34–7.27 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 2H), 6.94 (d, J = 7.2 Hz, 1H), 6.86–6.71 (m, 6H), 6.67 (s, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.02 (d, J = 7.2 Hz, 2H), 4.98 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.9, 176.4, 160.7, 148.6, 145.0, 143.5, 142.4, 137.7, 136.2, 135.2, 130.2, 128.9, 128.5, 127.9, 127.8, 127.7, 127.1, 124.1, 123.6, 122.8, 122.6, 122.4, 122.0, 118.3, 116.1, 110.3, 110.0, 79.5, 74.6, 73.3, 43.6; HRMS (ESI) calculated for C35H27ClN5O2 (M + H+): 584.18478, found 584.18384.
4he. Reaction time: 72 h; yield: 78% (0.078 mmol, 49 mg); white powder, mp 289–291 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.51 (s, 1H), 8.57 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34–7.27 (m, 4H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (s, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.84–6.70 (m, 5H), 6.62 (d, J = 8.0 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.01 (d, J = 6.0 Hz, 2H), 5.07 (d, J = 15.6 Hz, 1H), 4.97 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.9, 176.2, 160.6, 148.6, 143.5, 143.0, 142.4, 137.6, 136.1, 133.5, 130.2, 129.5, 129.1, 128.5, 127.9, 127.4, 127.2, 126.0, 124.0, 123.7, 122.9, 122.6, 118.3, 116.1, 114.1, 112.0, 110.3, 79.6, 74.9, 73.5, 43.6; HRMS (ESI) calculated for C35H27BrN5O2 (M + H+): 628.13426, found 628.13330.
4ie. Reaction time: 72 h; yield: 61% (0.061 mmol, 38.3 mg); white powder, mp 175–177 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.53 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.79–7.15 (m, 5H), 7.06 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 3.6 Hz, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.95–6.70 (m, 6H), 6.43 (t, J = 7.2 Hz, 1H), 6.01 (d, J = 6.8 Hz, 2H), 5.10 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.9, 176.3, 160.7, 148.6, 145.1, 143.5, 142.4, 137.7, 136.2, 130.2, 128.9, 128.5, 128.1, 127.9, 127.8, 127.7, 127.1, 124.9, 124.1, 123.7, 123.5, 122.9, 122.8, 122.6, 118.3, 116.1, 112.8, 110.3, 79.5, 74.7, 73.2, 43.6; HRMS (ESI) calculated for C35H27BrN5O2 (M + H+): 628.13426, found 628.13385.
4be. Reaction time: 72 h; yield: 84% (0.084 mmol, 46.2 mg); white powder, mp 248–250 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.45 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.33 (t, J = 5.6 Hz, 1H), 7.25–7.21 (m, 4H), 7.14–7.07 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.88–6.71 (m, 6H), 6.65 (d, J = 7.6 Hz, 1H), 6.43 (t, J = 6.8 Hz, 1H), 6.10 (d, J = 6.8 Hz, 2H), 4.93 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.35 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 177.1, 176.1, 160.6, 148.8, 143.5, 142.5, 137.8, 136.2, 130.8, 130.0, 129.0, 128.5, 127.9, 127.7, 127.2, 126.0, 124.1, 123.4, 122.8, 122.2, 118.2, 116.1, 110.2, 110.0, 79.7, 75.1, 73.3, 43.6; HRMS (ESI) calculated for C35H28N5O2 (M + H+): 550.22375, found 550.22229.
4je. Reaction time: 72 h; yield: 78% (0.078 mmol, 44 mg); white powder, mp 233–235 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.26 (s, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.34–7.21 (m, 5H), 7.12 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 3H), 6.82 (t, J = 7.2 Hz, 1H), 6.77–6.72 (m, 3H), 6.67 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.02 (d, J = 7.2 Hz, 2H), 5.04 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.27 (d, J = 9.2 Hz, 1H), 2.08 (s, 3H); 13C NMR (100 MHz, DMSO): δ 177.2, 176.1, 160.7, 148.8, 143.7, 142.6, 141.0, 137.7, 136.2, 131.2, 131.0, 129.0, 128.5, 127.8, 127.3, 127.2, 126.8, 124.1, 123.5, 123.4, 122.8, 122.7, 118.1, 116.1, 110.2, 109.8, 79.7, 75.1, 73.4, 43.5, 21.1; HRMS (ESI) calculated for C36H30N5O2 (M + H+): 564.23940, found 564.23816.
4ce. Reaction time: 72 h; yield: 64% (0.064 mmol, 37.1 mg); white powder, mp 221–224 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.23 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 5.6 Hz, 1H), 7.24 (s, 3H), 7.14–7.10 (m, 2H), 7.00 (d, J = 7.2 Hz, 3H), 6.83–6.68 (m, 6H), 6.58 (d, J = 8.8 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.01 (d, J = 6.4 Hz, 2H), 5.06 (d, J = 16.0 Hz, 1H), 4.83 (d, J = 16.0 Hz, 1H), 4.38 (d, J = 8.8 Hz, 1H), 3.55 (s, 3H); 13C NMR (100 MHz, DMSO): δ 177.1, 176.1, 160.6, 155.2, 148.7, 143.6, 142.6, 137.8, 136.5, 136.1, 130.1, 129.0, 128.5, 127.8, 127.4, 127.3, 124.4, 124.1, 123.4, 122.8, 118.2, 116.1, 116.0, 112.9, 110.5, 110.2, 79.8, 75.4, 73.4, 55.7, 43.5; HRMS (ESI) calculated for C36H30N5O3 (M + H+): 580.23432, found 580.23254.
4bf. Reaction time: 72 h; yield: 84% (0.084 mmol, 49 mg); white powder, mp 274–276 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.60 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.36–7.33 (m, 1H), 7.27–7.22 (m, 5H), 7.04–7.01 (m, 2H), 6.93 (s, 1H), 6.89 (t, J = 10.4 Hz, 1H), 6.86–6.74 (m, 3H), 6.69 (t, J = 9.6 Hz, 2H), 6.48 (t, J = 7.6 Hz, 1H), 6.02 (d, J = 7.2 Hz, 2H), 4.93 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.7, 176.2, 160.3, 148.7, 143.4, 142.5, 142.3, 137.8, 135.8, 131.0, 130.0, 129.1, 128.7, 128.0, 127.7, 126.9, 126.8, 126.2, 125.1, 124.1, 123.4, 123.1, 122.4, 118.6, 116.2, 111.7, 110.2, 79.7, 75.4, 73.2, 43.7; HRMS (ESI) calculated for C35H28ClN5O2 (M + H+): 584.18478, found 584.18414.
4bg. Reaction time: 72 h; yield: 81% (0.081 mmol, 50.8 mg); white powder, mp 280–282 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.58 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.36–7.32 (m, 2H), 7.25 (s, 4H), 7.05–7.02 (m, 3H), 6.87 (t, J = 7.6 Hz, 1H), 6.80 (t, J = 7.6 Hz, 2H), 6.71–6.67 (m, 3H), 6.48 (t, J = 6.8 Hz, 1H), 6.01 (d, J = 5.6 Hz, 2H), 4.92 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 176.6, 176.2, 160.3, 148.7, 143.4, 142.9, 142.2, 137.8, 135.8, 132.8, 131.0, 130.2, 129.5, 129.2, 129.1, 128.7, 128.0, 127.8, 127.7, 126.2, 125.4, 124.1, 123.4, 123.1, 122.4, 118.6, 117.6, 116.1, 114.7, 112.2, 110.2, 79.7, 75.4, 73.1, 43.6; HRMS (ESI) calculated for C35H28BrN5O2 (M + H+): 628.13426, found 628.13348.
4bh. Reaction time: 72 h; yield: 77% (0.077 mmol, 43.4 mg); white powder, mp 225–228 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.51 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 5.6 Hz, 1H), 7.25–7.20 (m, 4H), 7.07 (d, J = 2.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.88–6.84 (m, 2H), 6.77–6.71 (m, 3H), 6.66–6.61 (m, 2H), 6.43 (t, J = 7.2 Hz, 1H), 6.00 (d, J = 7.2 Hz, 2H), 4.87 (s, 2H), 4.30 (d, J = 9.2 Hz, 1H), 2.03 (s, 3H); 13C NMR (100 MHz, DMSO): δ 177.0, 176.2, 160.7, 148.7, 143.5, 142.5, 141.2, 137.8, 136.3, 131.4, 130.8, 130.4, 129.0, 128.5, 127.9, 127.8, 127.6, 126.0, 124.1, 123.4, 122.2, 118.0, 115.9, 110.0, 79.8, 75.1, 73.2, 43.6, 21.2; HRMS (ESI) calculated for C36H30N5O2 (M + H+): 564.23940, found 564.23840.
4bi. Reaction time: 72 h; yield: 75% (0.075 mmol, 43.4 mg); white powder, mp 219–221 °C; dr > 99[thin space (1/6-em)]:[thin space (1/6-em)]1; 1H NMR (400 MHz, DMSO): δ 10.50 (s, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.34–7.21 (m, 5H), 7.07 (d, J = 2.8 Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.78–6.60 (m, 7H), 6.45 (t, J = 7.2 Hz, 1H), 6.03 (d, J = 7.2 Hz, 2H), 4.89 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.31 (d, J = 9.2 Hz, 1H), 3.51 (s, 3H); 13C NMR (100 MHz, DMSO): δ 176.7, 176.1, 160.6, 155.3, 148.8, 143.5, 142.5, 137.8, 136.7, 136.3, 130.8, 129.0, 128.6, 127.9, 127.8, 126.1, 124.3, 124.1, 123.4, 123.3, 122.2, 118.2, 116.1, 115.0, 113.6, 110.5, 110.0, 79.7, 75.3, 73.3, 55.7, 43.6; HRMS (ESI) calculated for C36H30N5O3 (M + H+): 580.23432, found 580.23279.

Acknowledgements

We thank Beijing Municipal Commission of Education (No. JC015001200902), Beijing Municipal Natural Science Foundation (No. 7102010, No. 2122008), Basic Research Foundation of Beijing University of Technology (X4015001201101), Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR201008025), Doctoral Scientific Research Start-up Foundation of Beijing University of Technology (No. 52015001200701) for financial supports.

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  11. ESI†.

Footnote

† Electronic supplementary information (ESI) available: Copies of NMR for imidazolidine-dispirooxindoles 4; X-ray single crystal structure analysis data for 4de.11 CCDC 1054674. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra21995g
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