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

  • Ren-Yin Yang , Jing Sun EMAIL logo , Ju Xie and Chao-Guo Yan EMAIL logo
Published/Copyright: June 12, 2017
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 23 Issue 4

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.

Keywords: amino acid; cyclization; domino reaction; isatin; spirocyclopentaneoxindoline; spirooxindoline

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

CompdR1R2ArR3R4Yield (%)b
1aClBnp-CH3C6H4HC2H564
1bCln-Bup-CH3OC6H4HC2H555
1cClBnp-ClC6H4HC2H553
1dFBnp-CH3C6H4HC2H562
1eClBnp-CH3C6H4HOCH2C2H565
1fFBnp-CH3C6H4CH3C2H572 (0.81:0.19)
1gClBnp-CH3C6H4CH3C2H570 (0.52:0.48)
1hClBnp-CH3C6H4iso-PrC2H563 (0.61:0.39).
1iClBnp-CH3C6H4sec-BuC2H561 (0.65:0.35)
1jClBnp-CH3C6H4p-HOC6H4CH2C2H567 (0.5:0.5)
1kClBnp-CH3C6H4C6H5CH2CH2C2H562 (0.6:0.4)
1lClBnp-CH3C6H43-indolyl-CH2CH370 (0.61:0.39)

  1. 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.

  2. 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.

Corresponding authors: Jing Sun and Chao-Guo Yan, College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China

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

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Chemical and pharmacological research on the plants from genus Ajuga
  4. Research Articles
  5. One-pot synthesis of annulated 1,8-naphthyridines
  6. Visible-light mediated regioselective (phenylsulfonyl)difluoromethylation of fused imidazoles with iododifluoromethyl phenyl sulfone
  7. Synthesis of thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
  8. Regioselective 1,4-conjugate aza-Michael addition of dienones with benzotriazole
  9. A simple one-pot synthesis of 2,4-diaryl- 9H-pyrido[2,3-b]indoles under solvent-free conditions
  10. Cyclodimerization of 3-phenacylideneoxindolines with amino esters for the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines]
  11. An efficient approach to the synthesis of coumarin-fused dihydropyridinones
  12. Halogenoheterocyclization of terminally substituted 2-allylthio(seleno)quinolin- 3-carbaldehydes
  13. A new synthetic route to benzophenone derivatives
  14. Design, synthesis, docking and in vitro antifungal study of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines
  15. Synthesis, antimicrobial activity and anti-biofilm activity of novel tetrazole derivatives
https://doi.org/10.1515/hc-2017-0002
Keywords for this article
amino acid; cyclization; domino reaction; isatin; spirocyclopentaneoxindoline; spirooxindoline
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Chemical and pharmacological research on the plants from genus Ajuga
  4. Research Articles
  5. One-pot synthesis of annulated 1,8-naphthyridines
  6. Visible-light mediated regioselective (phenylsulfonyl)difluoromethylation of fused imidazoles with iododifluoromethyl phenyl sulfone
  7. Synthesis of thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
  8. Regioselective 1,4-conjugate aza-Michael addition of dienones with benzotriazole
  9. A simple one-pot synthesis of 2,4-diaryl- 9H-pyrido[2,3-b]indoles under solvent-free conditions
  10. Cyclodimerization of 3-phenacylideneoxindolines with amino esters for the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines]
  11. An efficient approach to the synthesis of coumarin-fused dihydropyridinones
  12. Halogenoheterocyclization of terminally substituted 2-allylthio(seleno)quinolin- 3-carbaldehydes
  13. A new synthetic route to benzophenone derivatives
  14. Design, synthesis, docking and in vitro antifungal study of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines
  15. Synthesis, antimicrobial activity and anti-biofilm activity of novel tetrazole derivatives
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