Open Access Published by De Gruyter June 12, 2017

Cyclodimerization of 3-phenacylideneoxindolines with amino esters for the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines]

Ren-Yin Yang, Jing Sun, Ju Xie and Chao-Guo Yan

Abstract

Triethylamine-promoted domino cyclodimerization reaction of 3-phenacylideneoxindolines with amino ester hydrochlorides in acetonitrile afforded substituted dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] in good yields. The relative configuration of the major diastereoisomers was determined by the X-ray diffraction analysis of three single crystal structures.

Introduction

The spirooxindole core is one of the most privileged heterocyclic rings, which not only exists in several naturally occurring substances, but is also featured in many medicinally relevant compounds with wide applications as antimicrobial and antitumor agents and inhibitors of the human neurokinin receptor [1], [2], [3], [4], [5]. These properties have prompted many efforts toward the multilateral investigations of various spirooxindoline derivatives [6], [7], [8], [9], [10], [11]. Consequently, many efficient synthetic procedures have been developed for the preparation of the diversely structural spirocyclic oxindoles [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. In recent years, carbocyclic dispirooxindole systems have attracted much attention due to their rich molecular diversity and particularly difficult synthetic methodology [24], [25], [26], [27], [28], [29], [30], [31], [32]. Recently, we found that the base-promoted domino reactions of two molecules of 3-phenacylideneoxindolines with nucleophiles such as alcohol, amine and thiols furnish versatile alkoxy- and amino-substituted and methylene- bridged dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] in satisfactory yields and with high diastereoselectivity [33], [34]. This finding provides a practical method for the construction of a complex polycyclic spirooxindoline system. Thennarasu has also reported a similar base-catalyzed reaction of 3-phenacylideneoxindolines with 2-aminopyridine or 4-aminopyrimidine to give the corresponding 2-pyridylamino- or 4-pyrimidylamino-substituted dispirocyclopentaneoxindolines [35]. To study the scope of this unique reaction and further demonstrate the synthetic value of this protocol, we wish to report the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indoline] with functionalized amino ester derivatives via a base-promoted cyclodimerization reaction of 3-phenacylideneoxindoles with amino ester hydrochlorides.

Results and discussion

According to our previously established reaction conditions [33], a mixture of 1-benzyl-5-chloro-3-(2-oxo-2-(p-tolyl)ethylidene)indolin-2-one (1.0 mmol) and ethyl glycinate hydrochloride (1.0 mmol) in acetonitrile in the presence of piperidine (1.2 mmol) was stirred at room temperature overnight (Table 1). After workup, the expected amino-ester-substituted dispiro[indoline-3,1′-cyclopentane-3′,3″-indoline] 1a was obtained in good yield. Unfortunately, the 1H NMR spectrum clearly showed that the obtained sample was contaminated with a piperidinyl-substituted dispirocyclopentaneoxindoline, which was obviously derived from the participation of piperidine acting as a competitive nucleophile in the reaction. To avoid this phenomenon, triethylamine was chosen as a scavenger of hydrogen chloride and as the base for the catalysis of the cyclodimerization reaction. The reaction proceeded smoothly to give the desired substituted dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] 1a–d in good yields (Table 1). Under similar conditions, other amino ester hydrochlorides were employed in the reaction. The desired amino-ester-substituted dispirocyclopentaneoxindolines 1e–l were obtained in satisfactory yields. The results are summarized in Table 1. Analysis of 1H nuclear magnetic resonance spectra revealed that the reaction usually results in the formation of a mixture of diastereoisomers, with molecular ratios in the range from 0.81:0.19 to 0.50:0.50, which cannot be easily separated by column or thin-layer chromatography. To determine the relative configuration of the products, single crystal structures of spiro compounds 1b (Figure 1), 1g (not shown) and 1k (Figure 2) were determined by X-ray diffraction. We were pleased to find that molecules in the three single crystals had the same configuration. As can be seen from Figure 1, the two oxindoline scaffolds at the 1,3-positions are in trans orientation in the newly formed cyclopentyl ring, while the 2-benzoyl group and the 5-aryl group are cis-oriented to each other. The 4-amino ester and 5-hydroxyl group are also in cis orientation. On the basis of 1H NMR spectra and single crystal structures, it can be concluded that all major products 1a–l have this relative configuration. It should be pointed out that this relative configuration of the major disatereoisomer is also the same as that of our previously reported alkoxy- and amino-substituted dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] [33]. This analysis indicates that the diastereoselectivity of the base-promoted cyclodimerization of 3-phenacylideneoxindole with various nucleophiles is controlled by molecular effects.

Table 1

Synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] 1a–j.a

Compd R1 R2 Ar R3 R4 Yield (%)b
1a Cl Bn p-CH3C6H4 H C2H5 64
1b Cl n-Bu p-CH3OC6H4 H C2H5 55
1c Cl Bn p-ClC6H4 H C2H5 53
1d F Bn p-CH3C6H4 H C2H5 62
1e Cl Bn p-CH3C6H4 HOCH2 C2H5 65
1f F Bn p-CH3C6H4 CH3 C2H5 72 (0.81:0.19)
1g Cl Bn p-CH3C6H4 CH3 C2H5 70 (0.52:0.48)
1h Cl Bn p-CH3C6H4 iso-Pr C2H5 63 (0.61:0.39).
1i Cl Bn p-CH3C6H4 sec-Bu C2H5 61 (0.65:0.35)
1j Cl Bn p-CH3C6H4 p-HOC6H4CH2 C2H5 67 (0.5:0.5)
1k Cl Bn p-CH3C6H4 C6H5CH2CH2 C2H5 62 (0.6:0.4)
1l Cl Bn p-CH3C6H4 3-indolyl-CH2 CH3 70 (0.61:0.39)

    aReaction conditions: 3-phenacylideneoxindoline (1.0 mmol), amino ester hydrochloride (0.6 mmol) and Et3N (1.2 mmol) in CH3CN (10 mL), rt, 12 h.

    bIsolated yields, the ratio of diastereomers was detemined by 1H NMR spectra.

Figure 1 ORTEP drawing of the crystal structure of compound 1b (major).

Figure 1

ORTEP drawing of the crystal structure of compound 1b (major).

Figure 2 ORTEP drawing of the crystal structure of compound 1k (major).

Figure 2

ORTEP drawing of the crystal structure of compound 1k (major).

A plausible reaction mechanism for products 1 is presented in Scheme 1. In the presence of triethylamine, the amino ester hydrochloride is converted into the free amino ester. Then, the Michael addition of the free amino ester to 3-phenacylideneoxindole generates an adduct A, which, in turn, undergoes addition to the second molecule of 3-phenacylideneoxindole to give a double adduct B. Then, the carbanionic center of B undergoes an intramolecular nucleophilic addition to the carbonyl group to afford a cyclic intermediate product C, which is the final precursor to product 1. In the cyclization step, the most stable diastereoisomer would be preferentially formed as the major isomer, as observed.

Scheme 1 Proposed mechanism for formation of products 1.

Scheme 1

Proposed mechanism for formation of products 1.

Conclusions

An efficient synthetic protocol for the synthesis of compounds 1 by a base-mediated reaction of two molecules of 3-phenacylideneoxindole with amino ester hydrochloride is described. The reaction uses readily available starting materials, proceeds under mild conditions and the products are obtained in good yields and with high diastereoselectivity.

Experimental

The 1H NMR and 13C NMR spectra were obtained in DMSO-d6 at 600 MHz and 150 MHz, respectively. The IR spectra were obtained using KBr pellets.

General procedure for the preparation of dispirocyclopentanebisoxindolines 1a–l

A solution of 3-phenacylideneoxindoline (1.0 mmol), amino ester hydrochlorides (0.6 mmol) and triethylamine (1.2 mmol) in acetonitrile (10 mL) was stirred at room temperature for 12 h. The resulting precipitate was collected by filtration and washed with cold ethanol to give analytically pure products 1a–l.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)glycinate (1a)

White solid; yield 64%; mp 244–246°C; 1H NMR: δ 8.11 (d, J=2.4 Hz, 1H, ArH), 8.00 (d, J=1.8 Hz, 1H, ArH), 7.45–7.44 (m, 2H, ArH), 7.32–7.29 (m, 3H, ArH), 7.21–7.18 (m, 2H, ArH), 7.13–7.11 (m, 2H, ArH), 7.09–7.06 (m, 4H, ArH), 7.05 (brs, 1H, ArH), 6.95 (d, J=8.4 Hz, 2H, ArH), 6.91 (d, J=8.4 Hz, 2H, ArH), 6.61 (d, J=7.2 Hz, 2H, ArH), 6.58 (s, 1H, OH), 6.53 (d, J=8.4 Hz, 1H, ArH), 6.41 (d, J=8.4 Hz, 1H, ArH), 5.55 (d, J=9.0 Hz, 1H, CH), 5.36 (s, 1H, CH), 5.16 (d, J=15.6 Hz, 1H, CH), 4.98 (d, J=16.2 Hz, 1H, CH), 4.50 (d, J=16.2 Hz, 1H, CH), 4.37 (d, J=15.6 Hz, 1H, CH), 3.85 (q, J=7.2 Hz, 2H, CH2), 2.97–2.94 (m, 1H, CH), 2.87–2.84 (m, 1H, CH), 2.36–2.32 (m, 1H, NH), 2.28 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.00 (t, J=7.2 Hz, 3H, CH3); 13C NMR: δ 196.0, 179.3, 176.2, 170.4, 143.2, 142.2, 141.0, 136.8, 135.4, 135.1, 134.1, 133.7, 132.6, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6, 127.3, 127.0, 126.8, 126.7, 126.5, 126.3, 125.6, 125.5, 123.5, 110.0, 109.6, 84.7, 69.9, 64.6, 62.3, 60.0, 59.2, 48.8, 43.9, 43.0, 21.1, 20.8, 13.8; IR: υ 3331, 3067, 2922, 1712, 1686, 1608, 1486, 1431, 1375, 1346, 1269, 1179, 1083, 1033, 936, 809, 735, 694 cm−1. HRMS (ESI). Calcd. for C52H45Cl2N3NaO6 ([M+Na]+): m/z 900.2578. Found: m/z 900.2571.

Ethyl 1,1″-dibutyl-5,5″-dichloro-4′-hydroxy-2′-(4-methoxybenzoyl)- 4′-(4-methoxyphenyl)-2,2″-dioxodispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)glycinate (1b)

White solid; yield 55%; mp 176–178°C; 1H NMR: δ 8.05 (brs, 1H, ArH), 7.85 (brs, 1H, ArH), 7.31 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H, ArH), 7.15–7.13 (m, 3H, ArH), 6.95 (d, J=8.4 Hz, 2H, ArH), 6.82 (d, J=8.4 Hz, 1H, ArH), 6.73–6.70 (m, 3H, ArH), 6.63 (d, J=8.4 Hz, 2H, ArH), 6.41 (s, 1H, OH), 5.49 (d, J=8.4 Hz, 1H, ArH), 5.16 (s, 1H, CH), 3.88–3.82 (m, 3H, 3CH), 3.72 (s, 3H, OCH3), 3.64 (brs, 4H, CH, OCH3), 3.37–3.35 (m, 1H, CH), 3.22–3.20 (m, 1H, CH), 3.03–2.93 (m, 2H, CH), 2.23–2.20 (m, 1H, NH), 1.57–1.51 (m, 1H, CH), 1.47–1.41 (m, 1H, CH), 1.37–1.30 (m, 2H, CH), 1.02 (t, J=6.6 Hz, 3H, CH3), 0.98–0.95 (m, 1H, CH), 0.92–0.84 (m, 5H, 5CH), 0.80–0.78 (m, 1H, CH), 0.75–0.72 (m, 3H, 3CH); 13C NMR: δ 195.8, 179.5, 176.3, 170.4, 158.8 (d, J=240.0 Hz), 157.8 (d, J=234.8 Hz), 143.2, 139.6, 138.3, 136.7, 135.6, 135.2, 134.1, 133.6, 132.5 (d, J=9.3 Hz), 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6, 127.0, 126.8, 126.7, 126.5, 114.6 (d, J=19.4 Hz), 114.5 (d, J=19.8 Hz), 114.1 (d, J=25.1 Hz), 113.4 (d, J=26.3 Hz), 109.5, 108.9, 108.8, 84.8, 69.9, 64.7, 62.2, 60.0, 59.4, 48.8, 43.9, 43.1, 21.1, 20.8, 13.8; IR: υ 3370, 3261, 3069, 2958, 1744, 1684, 1604, 1484, 1431, 1351, 1257, 1180, 1115, 1030, 977, 811, 735, 675 cm−1. HRMS (ESI). Calcd. for C46H49Cl2N3NaO8 ([M+Na]+): m/z 864.2789. Found: m/z 864.2795.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-2′-(4-chlorobenzoyl)-4′-(4-chlorophenyl)-4′-hydroxy-2,2″-dioxodispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)glycinate (1c)

White solid; yield 53%; mp 224–226°C; 1H NMR: δ 8.37 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.40 (d, J=8.4 Hz, 1H, ArH), 7.24–7.23 (m, 7H, ArH), 7.20–7.16 (m, 6H, ArH), 7.06–7.05 (m, 4H, ArH), 6.78 (d, J=7.8 Hz, 1H, ArH), 6.73 (s, 1H, OH), 6.61–6.60 (m, 2H, ArH), 6.41 (d, J=8.4 Hz, 1H, ArH), 5.54 (d, J=12.6 Hz, 1H, CH), 5.31 (s, 1H, CH), 4.86 (d, J=16.2 Hz, 1H, CH), 4.41 (d, J=16.2 Hz, 1H, CH), 4.33 (d, J=15.6 Hz, 1H, CH), 3.98 (d, J=15.6 Hz, 1H, CH), 3.86 (m, 2H, CH), 3.09–3.05 (m, 1H, CH), 2.74 (d, J=15.0 Hz, 1H, CH), 1.86 (brs, 1H, NH), 1.03 (t, J=6.6 Hz, 3H, CH3); 13C NMR: δ 196.4, 177.2, 174.5, 170.6, 143.0, 142.9, 138.1, 138.0, 136.4, 135.8, 135.6, 133.0, 132.1, 130.3, 130.0, 129.2, 129.0, 128.9, 128.7, 128.6, 128.5, 128.1, 127.9, 127.8, 127.5, 127.3, 127.2, 126.9, 125.6, 110.1, 109.2, 84.6, 70.6, 65.1, 62.7, 60.4, 59.0, 48.4, 43.5, 43.3, 14.3; IR: υ 3407, 3072, 2982, 2899, 1733, 1700, 1602, 1486, 1433, 1341, 1268, 1205, 1165, 1092, 1018, 974, 812, 738, 699 cm−1. HRMS (ESI). Calcd. for C50H39Cl4N3NaO6 ([M+Na]+): m/z 940.1485. Found: m/z 940.1476.

Ethyl (1,1″-dibenzyl-5,5″-difluoro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)glycinate (1d)

White solid; yield 62%; mp 248–250°C; 1H NMR: δ 7.95 (dd, J1=9.6 Hz, J2=2.4 Hz, 1H, ArH), 7.82 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H, ArH), 7.44–7.43 (m, 2H, ArH), 7.30–7.29 (m, 3H, ArH), 7.20–7.17 (m, 1H, ArH), 7.14–7.09 (m, 4H, ArH), 7.06–7.05 (m, 2H, ArH), 6.99–6.96 (m, 1H, ArH), 6.95–6.92 (m, 4H, ArH), 6.86 (m, 1H, ArH), 6.64 (d, J=7.8 Hz, 2H, ArH), 6.60 (s, 1H, OH), 6.52–6.50 (m, 1H, ArH), 6.40–6.37 (m, 1H, ArH), 5.57 (d, J=8.4 Hz, 1H, CH), 5.33 (s, 1H, CH), 5.18 (d, J=15.6 Hz, 1H, CH), 4.97 (d, J=16.2 Hz, 1H, CH), 4.49 (d, J=16.2 Hz, 1H, CH), 4.34 (d, J=15.6 Hz, 1H, CH), 3.87–3.84 (m, 2H, CH), 2.98–2.95 (m, 1H, CH), 2.86–2.83 (m, 1H, CH), 2.34–2.31 (m, 1H, NH), 2.28 (s, 3H, CH3), 2.24 (s, 3H, CH3), 0.99 (t, J=7.2 Hz, 3H, CH3); 13C NMR: δ 195.8, 179.5, 176.3, 170.4, 159.6, 158.0, 157.0, 143.2, 139.6, 138.3, 136.7, 135.6, 135.2, 134.1, 133.6, 132.5, 132.4, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6, 127.0, 126.8, 126.7, 126.5, 114.7, 114.5, 114.4, 114.2, 114.0, 113.5, 113.3, 109.5, 108.9, 108.8, 84.8, 69.9, 64.7, 62.2, 60.0, 59.4, 48.8, 43.9, 43.1, 21.1, 20.8, 13.8; IR: υ 3264, 3063, 2919, 1742, 1692, 1610, 1489, 1452, 1379, 1344, 1266, 1219, 1178, 1029, 984, 940, 898, 810, 743, 693 cm−1. HRMS (ESI). Calcd. for C52H45F2N3NaO6 ([M+Na]+): m/z 868.3169. Found: m/z 868.3167.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)serinate (1e)

White solid; yield 65%; mp 239–241°C; 1H NMR: δ 8.17 (s, 1H, ArH), 7.68 (s, 1H, ArH), 7.58 (d, J=7.2 Hz, 2H, ArH), 7.39–7.37 (m, 4H, ArH), 7.33–7.31 (m, 1H, ArH), 7.23–7.21 (m, 1H, ArH), 7.16–7.11 (m, 4H, ArH), 7.03 (dd, J1=7.2 Hz, J2=1.8 Hz, 1H, ArH), 6.96 (d, J=8.4 Hz, 4H, ArH), 6.93 (d, J=8.4 Hz, 1H, ArH), 6.87 (d, J=8.4 Hz, 2H, ArH), 6.61 (d, J=7.2 Hz, 2H, ArH, OH), 6.25 (d, J=7.8 Hz, 1H, ArH), 5.25 (d, J=16.2 Hz, 1H, CH), 5.13 (d, J=16.2 Hz, 1H, CH), 5.06–5.05 (m, 2H, CH, OH), 4.67 (d, J=15.6 Hz, 1H, CH), 3.88 (q, J=7.2 Hz, 2H, CH), 3.83 (d, J=16.2 Hz, 1H, CH), 3.55–3.52 (m, 1H, CH), 3.05–3.03 (m, 2H, CH), 2.77–2.74 (m, 1H, CH), 2.32 (t, J=6.0 Hz, 1H, NH), 2.27 (s, 3H, CH3), 2.16 (s, 3H, CH3), 1.09 (t, J=6.6 Hz, 3H, CH3); 13C NMR: δ 195.5, 180.1, 177.7, 143.2, 141.9, 141.3, 136.7, 135.5, 135.4, 134.8, 133.6, 133.1, 128.8, 128.6, 128.5, 128.2, 128.0, 127.8, 127.7, 127.5, 127.3, 127.2, 127.1, 127.0, 126.6, 125.7, 122.6, 111.1, 109.5, 87.0, 68.0, 65.6, 63.4, 63.0, 60.6, 60.4, 60.1, 43.9, 43.5, 20.9, 20.7, 13.8; IR: υ 3439, 3072, 2989, 1713, 1678, 1606, 1557, 1486, 1432, 1375, 1347, 1244, 1184, 1025, 977, 806, 735, 692 cm−1. HRMS (ESI). Calcd. for C53H48Cl2N3O7 ([M+H]+): m/z 908.2864. Found: m/z 908.2872.

Ethyl (1,1″-dibenzyl-5,5″-difluoro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)alaninate (1f)

White solid; yield 72%; mp 224–226°C; 1H NMR: δ (major isomer) 8.25 (s, 1H, ArH), 7.59–7.58 (m, 3H, ArH), 7.35–7.33 (m, 2H, ArH), 7.30–7.28 (m, 1H, ArH), 7.26–7.23 (m, 1H, ArH), 7.22–7.20 (m, 1H, ArH), 7.15–7.09 (m, 5H, ArH), 7.00–6.96 (m, 4H, ArH), 6.94–6.92 (m, 1H, ArH), 6.91–6.88 (m, 2H, ArH), 6.83–6.80 (m, 1H, ArH), 6.59–6.55 (m, 2H, ArH, OH), 6.23–6.19 (m, 1H, ArH), 5.35 (d, J=15.6 Hz, 1H, CH), 5.08 (brs, 1H, CH), 5.03 (d, J=16.2 Hz, 1H, CH), 4.89 (d, J=6.0 Hz, 1H, CH), 4.70–4.66 (m, 1H, CH), 3.87 (q, J=7.2 Hz, 2H, CH2), 3.81–3.78 (m, 1H, CH), 2.95–2.91 (m, 1H, CH), 2.35–2.33 (m, 1H, NH), 2.27 (s, 3H, CH3), 2.17 (s, 3H, CH3), 1.05 (t, J=7.2 Hz, 3H, CH3), 0.63 (t, J=6.6 Hz, 3H, CH3); δ (minor isomer) 8.22 (s, 1H, ArH), 7.66–7.65 (m, 1H, ArH), 5.19 (d, J=16.2 Hz, 1H, CH), 5.12–5.10 (m, 1H, CH), 4.94–4.92 (m, 1H, CH), 3.81–3.78 (m, 1H, CH), 3.75–3.72 (m, 1H, CH), 3.05–3.03 (m, 1H, CH), 2.28 (s, 3H, CH3), 2.00–1.98 (m, 1H, NH), 1.01 (t, J=7.2 Hz, 3H, CH3), 0.86 (t, J=6.6 Hz, 3H, CH3); ratio of isomers=0.81:0.19; 13C NMR: δ 195.4, 190.4, 180.5, 177.8, 173.4, 166.8, 159.7, 158.1, 156.8, 145.0, 143.2, 141.1, 139.2, 138.7, 136.7, 135.8, 135.6, 135.5, 135.0, 134.4, 133.6, 129.7, 128.8, 128.7, 128.5, 128.4, 128.1, 127.7, 127.6, 127.5, 127.3, 127.2, 127.1, 127.0, 126.9, 126.6, 123.4, 120.4, 118.9, 118.7, 115.6, 115.4, 115.1, 115.0, 114.5, 114.4, 113.6, 113.4, 110.6, 110.5, 110.4, 108.9, 108.8, 86.9, 69.2, 65.8, 62.7, 61.1, 60.2, 59.9, 54.4, 49.4, 43.7, 43.6, 43.0, 21.3, 20.9, 20.7, 19.8, 13.7; IR: υ 3438, 3175, 2977, 2926, 1704, 1678, 1614, 1492, 1451, 1375, 1350, 1265, 1180, 1032, 983, 814, 741, 695 cm−1. HRMS (ESI). Calcd. for C53H48F2N3NaO6 ([M+Na]+): m/z 860.3506. Found: m/z 860.3537.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)alaninate (1g)

White solid; yield 70%; mp 236–238°C; 1H NMR: δ (major isomer) 8.06 (s, 1H, ArH), 7.47 (brs, 2H, ArH), 7.31 (brs, 3H, ArH), 7.18–7.05 (m, 10H, ArH), 6.97–6.92 (m, 5H, ArH), 6.65–6.61 (m, 3H, ArH, OH), 6.39 (t, J=9.0, 1H, ArH), 5.58–5.54 (m, 1H, CH), 5.34 (s, 1H, CH), 5.06 (d, J=15.6 Hz, 1H, CH), 4.98 (d, J=16.2 Hz, 1H, CH), 4.55–4.49 (m, 1H, CH), 4.45 (d, J=16.2 Hz, 1H, CH), 3.85–3.78 (m, 2H, CH), 3.61–3.56 (m, 1H, CH), 2.32–2.31 (m, 1H, NH), 2.27 (s, 3H, CH3), 2.24 (s, 2H, CH), 2.20 (s, 1H, CH3), 1.02–1.00 (m, 1H, CH), 0.93–0.91 (m, 2H, CH), 0.85 (d, J=5.4 Hz, 2H, CH), 0.56 (d, J=6.0 Hz, 1H, CH); δ (minor isomer) 8.14 (s, 1H, ArH), 8.01–7.99 (m, 2H, ArH), 6.85–6.84 (m, 2H, ArH), 6.65–6.61 (m, 1H, ArH), 6.50–6.49 (m, 1H, ArH), 5.14 (d, J=15.0 Hz, 1H, CH), 4.40 (d, J=15.6 Hz, 1H, CH), 3.70–3.67 (m, 1H, CH), 3.04–3.03 (m, 1H, CH), 2.80–2.78 (m, 1H, NH), 2.37–2.35 (m, 1H, CH), 2.20 (s, 1H, CH), 1.02–1.00 (m, 1H, CH), 0.56 (d, J=6.0 Hz, 1H, CH); ratio of isomers=0.52:0.48; 13C NMR: δ 196.0, 195.9, 179.3, 179.0, 176.4, 176.1, 173.1, 173.0, 143.2, 143.1, 142.1, 142.0, 141.4, 141.0, 136.9, 136.8, 135.3, 135.2, 135.0, 134.2, 133.7, 133.6, 133.5, 132.4, 132.3, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.4, 127.3, 127.0, 126.9, 126.8, 126.6, 126.5, 126.4, 126.3, 126.2, 125.6, 125.5, 125.4, 110.1, 109.8, 109.6, 85.0, 84.7, 69.1, 68.3, 64.6, 64.5, 62.4, 61.9, 60.2, 60.0, 59.5, 59.1, 54.4, 53.5, 44.0, 43.7, 43.0, 21.1, 21.0, 20.8, 20.7, 18.9, 17.9, 13.7, 13.6; IR: υ 3278, 3069, 2979, 1711, 1698, 1608, 1484, 1435, 1358, 1237, 1180, 1088, 1030, 988, 944, 807, 732, cm−1. HRMS (ESI). Calcd. for C53H47Cl2N3NaO6 ([M+Na]+): m/z 914.2734. Found: m/z 914.2740.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)- 2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)valinate (1h)

White solid; yield 63%; mp 254–256°C 1H NMR: δ (major isomer) 8.09 (brs, 1H, ArH), 8.02–8.00 (m, 1H, ArH), 7.53–7.49 (m, 2H, ArH), 7.39–7.35 (m, 3H, ArH), 7.21–7.13 (m, 4H, ArH), 7.07–7.03 (m, 5H, ArH), 6.96 (d, J=7.8 Hz, 2H, ArH), 6.75–6.69 (m, 4H, ArH), 6.67–6.66 (m, 1H, ArH), 6.61–6.60 (m, 1H, OH), 6.38 (d, J=8.4 Hz, 1H, ArH), 5.53 (d, J=10.2 Hz, 1H, CH), 5.32–5.30 (m, 1H, CH), 4.98–4.91 (m, 2H, CH), 4.63–4.52 (m, 2H, CH), 3.70–3.52 (m, 2H, CH), 2.78–2.76 (m, 1H, CH), 2.27–2.23 (m, 4H, NH, CH3), 2.16 (s, 3H, CH3), 1.60–1.54 (m, 1H, CH), 0.97–0.87 (m, 3H, 3CH), 0.50 (d, J=6.6 Hz, 3H, CH3), 0.41 (d, J=7.2 Hz, 3H, CH3); δ (minor isomer) 7.21–7.13 (m, 2H, ArH), 7.10–7.09 (m, 2H, ArH), 6.91 (d, J=7.8 Hz, 2H, ArH), 5.49 (d, J=9.0 Hz, 1H, CH), 2.66–2.64 (m, 1H, CH), 2.17 (s, 3H, CH3), 1.34–1.29 (m, 1H, CH), 0.36 (d, J=6.6 Hz, 3H, CH3), 0.29 (d, J=7.2 Hz, 3H, CH3); ratio of isomers=3:2; 13C NMR: δ 196.4, 180.2, 177.0, 173.2, 172.9, 143.5, 142.6, 142.1, 137.2, 135.9, 135.5, 134.2, 134.1, 132.8, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 127.8, 127.5, 127.4, 127.3, 127.1, 127.0, 126.8, 126.1, 125.7, 110.7, 110.1, 85.5, 85.3, 70.2, 65.7, 65.5, 65.4, 65.2, 62.3, 60.4, 60.3, 59.9, 59.8, 44.8, 43.6, 32.2, 30.7, 21.5, 21.2, 18.8, 18.4, 18.2, 18.1, 14.3, 14.2; IR: υ 3273, 2965, 1711, 1684, 1609, 1485, 1432, 1354, 1260, 1180, 1081, 1029, 979, 810, 735, 696 cm−1. HRMS (ESI). Calcd. for C55H51Cl2N3NaO6 ([M+Na]+): m/z 942.3047. Found: m/z 942.3054.

Ethyl 2-((1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)-2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)amino)-3-methylpentanoate (1i)

White solid, 61%; mp 246–248°C; 1H NMR: δ (major isomer) 8.10–8.09 (m, 1H, ArH), 8.03–8.02 (m, 1H, ArH), 7.48 (brs, 2H, ArH), 7.39–7.35 (m, 3H, ArH), 7.21–7.16 (m, 2H, ArH), 7.14–7.09 (m, 3H, ArH), 7.04–7.02 (m, 4H, ArH), 6.96–6.95 (m, 2H, ArH), 6.74–6.71 (m, 3H, ArH), 6.68–6.66 (m, 2H, ArH), 6.62 (d, J=8.4 Hz, 1H, ArH), 6.39–6.37 (m, 1H, OH), 5.55 (d, J=10.2 Hz, 1H, CH), 5.33 (s, 1H, CH), 4.99–4.92 (m, 2H, CH), 4.62–4.52 (m, 2H, CH), 3.73–3.69 (m, 1H, CH), 3.68–3.62 (m, 1H, CH), 2.86–2.85 (m, 1H, CH), 2.32–2.29 (m, 1H, NH), 2.27 (s, 3H, CH3), 2.17 (s, 3H, CH3), 1.42–1.38 (m, 1H, CH), 0.94 (t, J=7.2 Hz, 3H, CH3), 0.84 (t, J=7.2 Hz, 2H, CH), 0.49–0.46 (m, 3H, CH3), 0.41 (t, J=7.2 Hz, 3H, CH3); δ (minor isomer) 8.06–8.05 (m, 1H, ArH), 8.00 (brs, 1H, ArH), 7.55–7.54 (m, 2H, ArH), 6.93–6.91 (m, 2H, ArH), 6.76 (d, J=8.4 Hz, 1H, ArH), 6.68–6.66 (m, 2H, ArH), 5.45–5.43 (m, 1H, CH), 5.30 (s, 1H, CH), 3.59–3.54 (m, 1H, CH), 2.74–2.72 (m, 1H, CH), 2.26 (s, 3H, CH3), 2.16 (s, 3H, CH3), 0.94 (t, J=7.2 Hz, 2H, CH), 0.63–0.58 (m, 1H, CH), 0.28 (d, J=6.6 Hz, 3H, CH3); ratio of isomers=0.65:0.35; 13C NMR: δ 195.9, 195.8, 179.6, 176.4, 176.3, 172.3, 172.2, 143.0, 142.1, 141.5, 136.8, 135.4, 135.0, 133.8, 133.7, 133.6, 133.4, 132.4, 128.9, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 126.9, 126.8, 126.7, 126.6, 126.5, 126.3, 125.7, 125.6, 125.3, 110.2, 110.1, 109.6, 84.9, 71.2, 68.9, 64.9, 64.6, 64.3, 62.3, 62.0, 61.8, 59.9, 59.8, 59.5, 59.3, 44.3, 43.1, 36.4, 25.1, 24.6, 21.0, 20.7, 14.5, 14.2, 13.8, 13.7, 11.3, 10.5; IR: υ 3436, 3072, 2968, 1710, 1685, 1610, 1486, 1432, 1371, 1236, 1180, 1080, 1029, 980, 811, 735, 693 cm−1. HRMS (ESI). Calcd. for C56H54Cl2N3O6 ([M+H]+): m/z 934.3384. Found: m/z 934.3396.

Ethyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)-2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)tyrosinate (1j)

White solid; yield 67%, mp 259–261°C; 1H NMR: δ (major isomer) 9.23–9.11 (m, 1H, OH), 8.02–7.97 (m, 2H, ArH), 7.56 (brs, 1H, ArH), 7.52 (brs, 1H, ArH), 7.38–7.35 (m, 3H, ArH), 7.19–7.11 (m, 5H, ArH), 7.04 (brs, 3H, ArH), 6.99 (m, 2H, ArH), 6.92 (brs, 1H, ArH), 6.78 (brs, 1H, ArH), 6.71–6.67 (m, 3H, ArH), 6.62 (brs, 2H, ArH), 6.44 (brs, 2H, ArH), 6.38–6.35 (m, 3H, ArH, OH), 5.57–5.54 (m, 1H, CH), 5.33–5.29 (m, 1H, CH), 5.01–4.93 (m, 2H, CH), 4.57–4.49 (m, 2H, CH), 3.64–3.55 (m, 1H, CH), 3.25 (brs, 1H, CH), 3.04–2.98 (m, 1H, CH), 2.80 (brs, 1H, CH), 2.43–2.37 (m, 1H, NH), 2.30–2.27 (m, 3H, 3CH), 2.17 (brs, 3H, 3CH), 1.14 (brs, 1H, CH), 0.83–0.78 (m, 3H, 3CH); δ (minor isomer) 8.10 (brs, 1H, ArH), 6.52 (brs, 1H, ArH), 2.75–2.74 (m, 1H, CH); ratio of isomers=1:1. 13C NMR: δ 195.9, 195.8, 179.6, 179.5, 176.4, 176.2, 172.4, 172.3, 162.3, 155.7, 143.0, 142.2, 142.0, 141.6, 141.2, 136.9, 136.8, 135.4, 135.3, 134.9, 133.8, 133.6, 133.5, 132.4, 132.2, 129.6, 129.4, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.5, 127.4, 127.2, 127.0, 126.9, 126.8, 126.6, 126.5, 126.3, 126.2, 126.1, 125.6, 125.3, 114.9, 114.7, 110.2, 110.0, 109.6, 85.0, 84.8, 70.0, 69.5, 64.8, 64.7, 62.1, 61.6, 61.4, 61.1, 59.9, 59.8, 59.6, 59.1, 45.5, 44.4, 43.8, 43.0, 37.4, 35.7, 21.0, 13.6, 13.5; IR: υ 3433, 3208, 2933, 1708, 1682, 1608, 1513, 1485, 1434, 1363, 1333, 1244, 1181, 1108, 1032, 978, 885, 811, 737, 692 cm−1. HRMS (ESI). Calcd. for C59H52Cl2N3O7 ([M+H]+): m/z 984.3177. Found: m/z 984.3184.

Ethyl 2-((1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)-2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)amino)-4-phenylbutanoate (1k)

White solid; yield 62%; mp 216–218°C; 1H NMR: δ (major isomer) 8.10 (brs, 1H, ArH), 8.00 (brs, 1H, ArH), 7.51–7.47 (m, 2H, ArH), 7.32–7.26 (m, 3H, ArH), 7.21–7.16 (m, 3H, ArH), 7.14–7.09 (m, 5H, ArH), 7.07–7.05 (m, 4H, ArH), 6.93–6.90 (m, 2H, ArH), 6.87–6.85 (m, 2H, ArH), 6.79–6.78 (m, 2H, ArH), 6.69–6.64 (m, 3H, ArH), 6.53 (d, J=8.4 Hz, 1H, ArH), 6.38–6.37 (m, 1H, OH), 5.56 (d, J=10.2 Hz, 1H, CH), 5.34 (s, 1H, CH), 5.01–4.94 (m, 2H, CH), 4.55–4.51 (m, 2H, CH), 3.69–3.63 (m, 1H, CH), 3.60–3.54 (m, 1H, CH), 3.06 (brs, 1H, CH), 2.42–2.40 (m, 1H, NH), 2.27 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.16–2.12 (m, 1H, CH), 2.08–2.04 (m, 1H, CH), 1.60–1.54 (m, 1H, CH), 1.45–1.38 (m, 1H, CH), 0.92 (t, J=7.2 Hz, 3H, CH3); δ (minor isomer) 8.17 (brs, 1H, ArH), 7.03–7.02 (m, 2H, ArH), 6.62–6.61 (m, 2H, ArH), 6.57 (d, J=8.4 Hz, 1H, ArH), 5.49 (d, J=9.6 Hz, 1H, CH), 5.07–5.05 (m, 1H, CH), 4.44–4.42 (m, 1H, CH), 3.83–3.78 (m, 1H, CH), 2.92–2.89 (m, 1H, CH), 2.59–2.57 (m, 1H, NH), 2.24 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.90–1.87 (m, 2H, CH), 1.31–1.28 (m, 1H, CH), 0.99 (t, J=7.2 Hz, 3H, CH3); ratio of isomers=0.6:0.4; 13C NMR: δ 196.5, 180.1, 179.8, 176.9, 173.3, 173.2, 143.7, 143.6, 142.6, 142.1, 141.9, 141.3, 137.3, 137.2, 135.9, 135.5, 134.5, 134.2, 134.1, 132.9, 132.8, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 127.0, 126.8, 126.2, 126.1, 125.9, 110.4, 110.1, 85.4, 85.1, 70.3, 70.1, 65.6, 65.2, 62.3, 62.2, 60.8, 60.6, 60.1, 60.0, 59.8, 58.7, 44.5, 43.5, 35.3, 34.5, 31.3, 30.6, 21.5, 21.3, 21.2, 14.6, 14.2; IR: υ 3423, 3278, 3066, 2920, 2852, 1711, 1683, 1609, 1486, 1432, 1353, 1235, 1180, 1080, 1033, 980, 942, 811, 732, 694 cm−1. HRMS (ESI). Calcd. for C60H54Cl2N3O6 ([M+H]+): m/z 982.3384. Found: m/z 982.3379.

Methyl (1,1″-dibenzyl-5,5″-dichloro-4′-hydroxy-2′-(4-methylbenzoyl)-2,2″-dioxo-4′-(p-tolyl)dispiro[indoline-3,1′-cyclopentane-3′,3″-indolin]-5′-yl)tryptophanate (1l)

White solid; yield 70%; mp 254–256°C; 1H NMR: δ (major isomer) 10.65 (brs, 1H, NH), 8.11 (s, 1H, ArH), 8.03–7.97 (m, 1H, ArH), 7.53–7.46 (m, 2H, ArH), 7.39–7.31 (m, 3H, ArH), 7.21–7.14 (m, 7H, ArH), 7.06 (brs, 3H, ArH), 6.98–6.89 (m, 4H, ArH), 6.79 (brs, 3H, ArH), 6.71–6.68 (m, 3H, ArH), 6.51–6.47 (m, 2H, ArH, CH), 6.38 (s, 1H, OH), 5.58 (brs, 1H, CH), 5.35–5.31 (m, 1H, CH), 5.03–4.94 (m, 2H, CH), 4.61–4.44 (m, 2H, CH), 3.46 (s, 1H, CH), 3.17 (s, 1H, CH), 2.98 (s, 2H, CH), 2.66 (brs, 1H, CH), 2.46 (brs, 1H, CH), 2.37 (brs, 1H, CH), 2.30 (s, 3H, CH3), 2.18 (s, 3H, CH3); δ minor isomer 8.03–7.97 (m, 1H, ArH), 6.98–6.89 (m, 1H, ArH), 6.71–6.68 (m, 1H, ArH), 6.63 (brs, 2H, ArH, CH), 4.61–4.44 (m, 1H, CH), 2.66 (brs, 1H, CH), 2.26 (s, 3H, CH3), 2.14 (s, 3H, CH3); ratio of isomers=0.60:0.40; 13C NMR: δ 196.0, 179.6, 176.5, 173.0, 143.0, 142.0, 141.6, 136.9, 135.9, 135.4, 135.0, 133.7, 133.6, 132.3, 128.8, 128.6, 128.4, 128.1, 127.8, 126.8, 126.6, 123.1, 122.8, 120.8, 118.2, 118.1, 117.7, 111.2, 110.0, 109.6, 108.9, 108.5, 85.1, 84.9, 70.3, 64.8, 64.6, 61.6, 60.9, 60.8, 59.7, 59.3, 51.1, 51.0, 43.8, 43.0, 30.1, 28.5, 21.0, 20.8, 20.7; IR: υ 3443, 3271, 2921, 2852, 1706, 1684, 1608, 1485, 1432, 1351, 1180, 1082, 1025, 977, 938, 816, 741, 691 cm−1. HRMS (ESI). Calcd. for C60H50Cl2N4NaO6 ([M+Na]+): m/z 1015.3000. Found: m/z 1015.2990.

Supporting information

Crystallographic data for 1b (CCDC 1480217), 1g (CCDC 1480218) and 1k (CCDC1480219) have been deposited at the Cambridge Crystallographic Database Centre.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Grant 21272200) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We thank the Analysis and Test Center of Yangzhou University for providing analytical instruments.

References

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Received: 2017-1-21
Accepted: 2017-3-10
Published Online: 2017-6-12
Published in Print: 2017-8-28

©2017 Walter de Gruyter GmbH, Berlin/Boston

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