Enantioselective construction of novel chiral spirooxindoles incorporating a thiazole nucleus

Abstract

Asymmetric cascade Michael/cyclization reaction between 2-substituted thiazol-4-ones and 2-(2-oxoindolin-3-ylidene)malononitriles was investigated using a series of chiral bifunctional hydrogen-bonding organocatalysts. Good yields (up to 91%) and excellent enantioselectivities (up to 98% ee) were achieved by using a (1R,2R)-1,2-diphenylethane-1,2-diamine derived thiourea catalyst. This method provides an elegant synthetic route to access novel thiazole-fused spirooxindoles with potential bioactivity.

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Introduction

1,3-Thiazole, a five-membered heterocyclic ring with nitrogen and sulfur atoms, is one of the most important scaffolds in heterocyclic chemistry. The thiazole nucleus is recognized as a privileged pharmacophore in drug design and discovery.¹ In recent years, numerous thiazole derivatives have been reported to exhibit diverse biological activities including antibacterial,² antifungal,³ antitubercular,⁴ antiviral,⁵ anticancer,⁶ anticonvulsant,⁷ anti-inflammatory⁸ and antioxidant⁹ activity. Moreover, several thiazole-based enzyme inhibitors have proven to be useful for treatment of diabetes¹⁰ and Alzheimer's disease.¹¹ As a subtype of indole derivatives, spirooxindole is a very important structural motif that make ups the core of many naturally occurring¹² and synthetic products¹³ exhibiting a broad range of bioactivities. The considerable medicinal potential of both thiazole and spirooxindole has made them attractive synthetic targets. As such, a number of synthetic methods have been developed in pursuit of diversely functionalized chiral thiazole¹⁴ and spirooxindole derivatives.^15,16 Despite the elegant methods noted in the literature to synthesize spirooxindoles, the development of novel and efficient synthetic methods to access functionalized spirooxindoles with structural diversity is still desirable. In contrast to the importance of thiazole and spirooxindole units in pharmaceutical science and as promising candidates for drug discovery, the direct catalytic asymmetric approach to access optically active thiazole-fused spirooxindoles still remain unexplored. Intrigued by the diverse pharmacological activities of spirooxindole and thiazole derivatives, we wish to synthesize molecules which comprise both of these pharmacophores. The hybrid molecule, thiazole-fused spirooxindole, may inherit biological activities of both and thiazole skeletons. In this context, we report the organocatalyzed asymmetric Michael/cyclization cascade reaction between 2-substituted thiazol-4-ones and 2-(2-oxoindolin-3-ylidene)malononitriles, which provide a convenient approach to access enantiomerically enriched thiazole-fused spirooxindoles in good yields, and good to excellent enantioselectivities.

Results and discussion

The initial studies commenced with a cascade Michael/cyclization between 2-phenylthiazol-4(5H)-one (1a) and 2-(1-methyl-2-oxoindolin-3-ylidene)malononitrile (2a) catalyzed by bifunctional squaramide I (10 mol%) in 1 mL of dichloromethane at room temperature (20 °C) (Table 1, entry 1). As anticipated, the reaction proceeded smoothly to generate the desired product, (S)-5′-amino-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3aa) in an acceptable yield of 39%, but with a rather poor enantioselectivity of 7% ee (Table 1, entry 1). Subsequently, a variety of squaramide¹⁷- and thiourea-based¹⁸ bifunctional double hydrogen-bonding catalysts II–V (Fig. 1) were screened for the model reaction, and the results are summarized in Table 1. As shown, both the chiral diamine skeleton and the type of the hydrogen-bonding donor moiety played a crucial role on the enantioselectivity of the reaction. Thiourea Va containing a (1R,2R)-1,2-diphenylethane-1,2-diamine backbone gave the best results (62% yield, 89% ee) among these tested organocatalysts (Table 1, entry 6 vs. 1–5 and 7). By employing thiourea Va as the most promising catalyst, we then turned our attention to the solvent screening and found that chloroform was shown to be the ideal solvent as 3aa was generated with better yield and enantioselectivity (67% yield, 93% ee, Table 1, entry 8 vs. 6 and 7–14). Efforts to further improve the enantioselectivity by performing the reaction at lower reaction temperature did not bear any fruitful results (entries 15 and 16 vs. 9). Importantly, the cascade reaction proceeded smoothly with 5 mol% or even 2 mol% of catalyst Va with retained or slightly enhanced enantioselectivity (entries 17 and 18). Further lowering the amount of catalyst Va to 1 mol% resulted in an obviously decreased yield and enantioselectivity (entry 19).

Table 1 Screening of catalysts and optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Time (h)	Yield^b %	Ee^c (%)
a Unless noted, the reactions were carried out with 1a (0.2 mmol), 2a (0.2 mmol), and catalyst (10 mol%) in 1.0 mL of dichloromethane at 20 °C.b Isolated yield.c Determined by HPLC analysis with a chiral stationary phase.d The reaction was performed at 0 °C.e The reaction was carried out at −20 °C.f The loading of Va is 5 mol%.g The amount of Va is 2 mol%.h In the presence of 1 mol% of Va.
1	I	CH2Cl2	0.4	39	7
2	II	CH2Cl2	0.15	91	–6
3	III	CH2Cl2	0.1	20	–18
4	IVa	CH2Cl2	0.25	38	69
5	IVb	CH2Cl2	0.15	50	82
6	Va	CH2Cl2	0.5	62	89
7	Vb	CH2Cl2	0.15	75	81
8	Va	ClCH2CH2Cl	0.4	66	89
9	Va	CHCl3	0.3	67	93
10	Va	PhCH3	0.25	96	85
11	Va	CH3CN	0.15	76	68
12	Va	Et2O	0.3	72	85
13	Va	EA	0.5	92	85
14	Va	THF	4	92	71
15^d	Va	CHCl3	0.5	83	92
16^e	Va	CHCl3	2	78	92
17^f	Va	CHCl3	0.4	87	91
18^g	Va	CHCl3	0.8	74	94
19^h	Va	CHCl3	1	69	84

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Fig. 1 Screened bidentate hydrogen bond donor catalysts.

Having established the optimal reaction conditions (Table 1, entry 18), we then explored the substrate scope and the generality of the reaction. The results are summarized in Table 2. At first, a broad range of 3-ylideneoxindoles 2b–h with different substitution groups either on the nitrogen atom or the aromatic ring were explored in the reactions with thiazolone 1a (entries 2–8). All the reactions progressed smoothly to give the corresponding products 3 in moderate to good yields. N-substitution has an obvious influence on the stereoselectivity of the reaction. The replacement of methyl with benzyl group led to a sharply decreased enantioselectivity (entry 2 vs. 1). The electronic nature of the substituent on the aromatic ring has a minor impact on the stereochemical outcomes of the reaction. Generally, 3-ylideneoxindoles bearing neutral or electron-withdrawing groups (2a–f) provided higher ee values than those bearing electron-donating groups (2g–h). On the other hand, a number of thiazolones 1b–j with either electron-withdrawing (entries 9–14) or electron-donating groups (entries 15–17) on the aryl ring also were well tolerated in the reactions with 3-ylideneoxindole 2a. The position of the substituent on substrate 1 had a significant effect on the stereocontrol of the reaction. For instance, compared with the results obtained from 4-chloro and 3-bromo substituted thiazolones 1c and 1f, much better enantioselectivities were observed for 4-bromo and 2-chloro substituted thiazolones 1d and 1e (entry 11 vs. 10, entry 12 vs. 13). Since all the obtained products are solids with high melting point, in some cases, the optical purity of the products could be markedly improved via a single recrystallization (entries 2, 13 and 14). To demonstrate the potential of this method for preparative purposes, the reaction is also carried out in gram scale giving the isolated product with comparable ee value and chemical yield (entry 2 vs. 1).

Table 2 Substrate scope of the thiourea catalyzed cascade Michael/cyclization reactions^a

Entry	3 (R, R^1, R^2)	Time (h)	Yield^b (%)	Ee^c (%)
a Unless noted, all reactions were carried out with 1 (0.20 mmol), 2 (0.20 mmol) in the presence of 2 mol% of catalyst Va in chloroform (1 mL) at 20 °C.b Isolated yield.c Determined by HPLC analysis using a chiral stationary phase.d The reaction was carried out using a 4 mmol-scale.e Data in parentheses were obtained after a single recrystallization.f The reaction was performed at −20 °C.
1	3aa (Me, H, Ph)	0.7	74	94
2^d	3aa (Me, H, Ph)	0.7	70	92
3	3ab (Bn, H, Ph)	0.3	77 (63)^e	78 (90)^e
3^f	3ac (Me, 5-F, Ph)	1	75	90
4	3ad (Me, 5-Cl, Ph)	0.3	90	98
5^f	3ae (Me, 4-Cl, Ph)	0.7	93	89
6	3af (Me, 5-Br, Ph)	0.4	54	98
7	3ag (Me, 5-Me, Ph)	0.8	92	87
8^f	3ah (Me, 5-MeO, Ph)	3	84	83
9	3ba (Me, H, 2,6-F2C6H3)	0.3	51	89
10	3ca (Me, H, 4-ClC6H4)	1.5	80	82
11	3da (Me, H, 2-ClC6H4)	4.5	80	93
12	3ea (Me, H, 4-BrC6H4)	0.3	64	97
13	3fa (Me, H, 3-BrC6H4)	4.5	89 (60)^e	75 (90)^e
14	3ga (Me, H, 4-CF3C6H4)	3	94 (63)^e	69 (93)^e
15	3ha (Me, H, 4-MeC6H4)	10	64	88
16	3ia (Me, H, 4-MeOC6H4)	0.3	61	95
17	3ja (Me, H, 3,5-(MeO)2C6H3)	0.4	56	91

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The absolute configuration of compound 3ad was determined unambiguously as (R) based on the X-ray structure of 3ad (Fig. 2) and the stereochemistry of other title compounds were assigned by analogy.¹⁹

Fig. 2 X-ray crystal structure of (S)-3ad. Most of the hydrogen atoms have been omitted for clarity.

To account for the observed stereochemistry of this cascade transformation, a plausible mechanism is shown in Scheme 1. In light of the above results and the recent studies,²⁰ thiourea Va is believed to act in a bifunctional fashion. An enolate is formed via the deprotonation of 1a by the tertiary amine group. Simultaneously, the isatylidenemalononitrile 2a is fixed and activated by the neighboring thiourea moiety through weak hydrogen bonding interaction. The enolate then predominantly attacks the si-face of the electron-deficient isatylidenemalononitrile 2a to generate the Michael addition intermediate A. Finally, subsequent intramolecular Thorpe–Ziegler-type cyclization of the intermediate A with the aid of the bifunctional thiourea catalyst Va via a similar dual activation fashion gave rise to the desired thiazole-fused spirooxindole 3aa.

Scheme 1 Proposed mechanistic model.

Experimental

General methods

All reagents and solvents were commercial grade and purified prior to use when necessary. NMR spectra were acquired on Varian 400 MHz instrumental. Chemical shifts are measured relative to residual solvent peaks as an internal standard set to δ 7.26 and δ 77.0 (CDCl₃), δ 2.50 and δ 39.5 (DMSO-d₆). Specific rotations were measured on a Perkin-Elmer 341MC polarimeter. Enantiomeric excesses were determined on a Shimadzu LC-20A instrument (chiral column; mobile phase: hexane/i-PrOH). HRMS was performed on a Varian QFT-ESI instrumental. Melting points were determined on a Taike X-4 melting point apparatus. All temperatures were uncorrected.

General procedure for Va catalyzed cascade Michael/cyclization reaction between thiazolones 1 and 2-(2-oxoindolin-3-ylidene)malononitriles 2

A solution of thiourea catalyst Va (2 mol %), thiazolones (1, 0.20 mmol) and 2-(2-oxoindolin-3-ylidene)malononitriles (2, 0.20 mmol) in chloroform (1 mL) was stirred at 20 °C. Upon completion of the reaction (monitored by TLC), the product was directly purified by column chromatography on silica gel (200–300 mesh, PE/EtOAc = 12/1) to afford the desired thiazole-fused spirooxindoles 3. The title compounds were fully characterized by ¹H NMR, ¹³C NMR, HRMS and specific rotation data. The enantiomeric excess of the pure products was determined by HPLC analysis using a chiral stationary phase.

(S)-5′-Amino-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3aa). White solid, m.p. 169 °C (dec.), 61% yield, [α]²⁰_D + 53.6 (c 0.25, CHCl₃), 94% ee. ¹H NMR (400 MHz, CDCl₃): δ 3.31 (s, 3H), 5.06 (s, 2H), 6.95 5(d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 6.4 Hz, 1H), 7.38–7.45 (m, 4H), 7.78 (d, J = 8.0 Hz, 2H). ¹³C NMR (100.6 MHz, CDCl₃): δ 27.0, 49.4, 59.0, 106.6, 109.0, 116.9, 124.0, 124.9, 125.9, 129.0, 130.3, 131.1, 131.7, 132.3, 142.6, 154.5, 161.5, 166.2, 175.6. IR (KBr): ν 3252, 3186, 2197, 1715, 1643, 1610, 1556, 1469, 1417, 1355, 1260, 1089 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₅N₄O₂S [M + H]⁺: 387.0910, found 387.0912. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 14.30 (major) and 17.12 min (minor).

(S)-5′-Amino-1-benzyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ab). White solid, m.p. 225 °C (dec.), 77% yield, [α]²⁰_D + 39.0 (c 0.80, CHCl₃), 78% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 5.00 (d, J = 5.6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.27–7.40 (m, 7H), 7.46–7.53 (m, 3H), 7.67 (s, 2H), 7.85 (d, J = 6.4 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 43.2, 49.3, 54.3, 106.4, 110.0, 117.9, 123.8, 125.0, 125.7, 127.1, 127.6, 128.7, 129.4, 130.0, 131.4, 131.8, 132.1, 135.7, 141.4, 154.5, 162.0, 164.9, 176.0. IR (KBr): ν 3309, 3186, 2195, 1712, 1641, 1609, 1555, 1466, 1355, 755 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₇H₁₉N₄O₂S [M + H]⁺: 463.1223, found 463.1222. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 24.17 (major) and 29.06 min (minor).

(S)-5′-Amino-5-fluoro-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ac). White solid, m.p. 237 °C (dec.), 75% yield, [α]²⁰_D + 48.4 (c 0.50, CHCl₃), 90% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 7.20 (dd, J = 7.6, 3.2 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 3H), 7.65 (s, 2H), 7.85 (d, J = 6.8 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.9, 49.6, 54.0, 105.7, 110.6 (d, J = 8.1 Hz), 112.9 (d, J = 25.4 Hz), 116.5 (d, J = 23.4 Hz), 117.7, 125.6, 129.4, 131.4, 131.8, 133.7 (d, J = 7.7 Hz), 138.7, 154.6, 159.2 (d, J = 239.5 Hz), 161.9, 164.9, 175.6. IR (KBr): ν 3359, 3303, 3170, 2196, 1714, 1652, 1610, 1556, 1495, 1463, 1359, 1271, 1125 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄FN₄O₂S [M + H]⁺: 405.0816, found 405.0815. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 9.48 (major) and 11.85 min (minor).

(S)-5′-Amino-5-chloro-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ad). White solid, m.p. 242 °C (dec.), 90% yield, [α]²⁰_D + 93.6 (c 0.90, CHCl₃), 98% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 7.22 (d, J = 8.4 Hz, 1H), 7.47–7.50 (m, 4H), 7.55 (s, 1H), 7.66 (s, 2H), 7.85 (d, J = 6.8 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.9, 49.4, 53.9, 105.4, 111.0, 117.7, 125.1, 125.6, 127.7, 129.4, 130.0, 131.4, 131.8, 134.0, 141.4, 154.7, 161.9, 164.9, 175.4. IR (KBr): ν 3313, 3182, 2925, 2198, 1717, 1644, 1607, 1486, 1357, 1261, 1097, 1023, 808 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄ClN₄O₂S [M + H]⁺: 421.0521, found 421.0517. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 10.40 (major) and 13.42 min (minor).

(S)-5′-Amino-4-chloro-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ae). White solid, m.p. 249 °C (dec.), 93% yield, [α]²⁰_D + 63.0 (c 0.20, CHCl₃), 89% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.25 (s, 3H), 7.15 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.45–7.53 (m, 4H), 7.69 (s, 2H), 7.86 (d, J = 7.2 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 27.0, 49.7, 52.3, 103.8, 108.6, 117.4, 124.0, 125.7, 127.1, 129.4, 130.6, 131.5, 131.7, 131.8, 144.3, 155.1, 162.3, 164.9, 174.8. IR (KBr): ν 3317, 3184, 2195, 1722, 1643, 1607, 1558, 1460, 1417, 1357, 1114, 765 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄ClN₄O₂S [M + H]⁺: 421.0521, found 421.0518. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 12.46 (major) and 22.80 min (minor).

(S)-5′-Amino-5-bromo-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3af). White solid, m.p. 171 °C (dec.), 54% yield, [α]²⁰_D + 152.2 (c 0.46, CHCl₃), 98% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.21 (s, 3H), 7.16 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.2 Hz, 3H), 7.62 (d, J = 8.4 Hz, 2H), 7.66 (s, 2H), 7.86 (d, J = 6.4 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.8, 49.3, 53.9, 105.4, 111.5, 115.4, 117.7, 125.6, 127.7, 129.4, 131.4, 131.8, 132.8, 134.3, 141.8, 154.7, 161.9, 164.9, 175.3. IR (KBr): ν 3311, 3182, 2196, 1717, 1645, 1607, 1555, 1484, 1461, 1420, 1357, 1073 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄BrN₄O₂S [M + H]⁺: 465.0015, found 465.0011. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 75 : 25, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 12.88 (major) and 17.44 min (minor).

(S)-5′-Amino-1,5-dimethyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ag). White solid, m.p. 251 °C (dec.), 92% yield, [α]²⁰_D + 89.0 (c 0.20, CHCl₃), 87% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 2.27 (s, 3H), 3.20 (s, 3H), 7.06 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.46–7.51 (m, 3H), 7.58 (s, 2H), 7.85 (d, J = 7.2 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 20.6, 26.7, 49.2, 54.5, 106.6, 109.1, 117.8, 125.1, 125.6, 129.4, 130.2, 131.3, 131.8, 132.2, 132.9, 140.0, 154.5, 161.9, 164.7, 175.5. IR (KBr): ν 3362, 3300, 3160, 2197, 1715, 1652, 1604, 1551, 1500, 1285, 1092 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₂H₁₇N₄O₂S [M + H]⁺: 401.1067, found 401.1071. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 12.54 (major) and 15.64 min (minor).

(S)-5′-Amino-5-methoxy-1-methyl-2-oxo-2′-phenylspiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ah). White solid, m.p. 156–158 °C, 94% yield, [α]²⁰_D + 104.7 (c 0.60, CHCl₃), 83% ee. ¹H NMR (400 MHz, CDCl₃): δ 3.28 (s, 3H), 3.77 (s, 3H), 5.20 (s, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 7.36–7.42 (m, 3H), 7.76 (dd, J = 8.0, 1.2 Hz, 2H). ¹³C NMR (100.6 MHz, CDCl₃): δ 27.0, 49.8, 55.8, 58.8, 106.6, 109.5, 111.5, 115.1, 117.0, 125.9, 129.0, 131.0, 132.3, 132.9, 135.8, 154.4, 157.0, 161.5, 166.2, 175.4. IR (KBr): ν 3314, 3181, 2948, 2197, 1709, 1643, 1604, 1556, 1492, 1462, 1356, 1286, 1135, 1025, 775, 689 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₂H₁₇N₄O₃S [M + H]⁺: 417.1016, found 417.1013. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 15.01 (major) and 18.40 min (minor).

(S)-5′-Amino-2′-(2,6-difluorophenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ba). White solid, m.p. 204 °C (dec.), 51% yield, [α]²⁰_D + 40.0 (c 0.11, CHCl₃), 89% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.23 (s, 3H), 7.14 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 9.2 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.56–7.62 (m, 1H), 7.65 (s, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.0, 54.4, 108.6 (t, J = 4.3 Hz), 109.5, 109.8 (t, J = 14.8 Hz), 112.8 (dd, J = 22.8, 2.1 Hz), 117.6, 123.7, 124.7, 130.1, 132.0, 132.9 (t, J = 9.6 Hz), 142.5, 152.3 (dd, J = 6.3, 2.8 Hz), 154.3, 159.3 (dd, J = 254.7 Hz), 161.9, 175.5. IR (KBr): ν 3314, 3194, 2205, 1717, 1647, 1610, 1555, 1470, 1362, 1008, 792 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₃F₂N₄O₂S [M + H]⁺: 423.0722, found 423.0726. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 10.99 (major) and 15.28 min (minor).

(S)-5′-Amino-2′-(4-chlorophenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ca). White solid, m.p. 235 °C (dec.), 80% yield, [α]²⁰_D − 27.3 (c 0.26, CHCl₃), 82% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.44 (dt, J = 8.0, 0.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.61 (s, 2H), 7.86 (d, J = 8.8 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.2, 54.3, 107.0, 109.4, 117.7, 123.7, 124.7, 127.4, 129.4, 130.1, 130.6, 132.0, 135.9, 142.4, 154.6, 161.9, 163.4, 175.6. IR (KBr): ν 3315, 3185, 2197, 1714, 1646, 1609, 1554, 1496, 1454, 1418, 1354, 1089, 755 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄ClN₄O₂S [M + H]⁺: 421.0521, found 421.0520. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 17.50 (major) and 21.28 min (minor).

(S)-5′-Amino-2′-(2-chlorophenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3da). White solid, m.p. 226 °C (dec.), 80% yield, [α]²⁰_D + 43.6 (c 0.72, CHCl₃), 93% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.23 (s, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.43 (dt, J = 7.6, 0.8 Hz, 1H), 7.48–7.54 (m, 2H), 7.61–7.62 (m, 1H), 7.63 (s, 2H), 8.18–8.21 (m, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.1, 54.5, 108.3, 109.5, 117.6, 123.7, 124.7, 128.0, 129.6, 130.0, 130.1, 130.7, 131.0, 132.0 (2C), 142.5, 154.1, 159.8, 161.9, 175.6. IR (KBr): ν 3448, 3310, 3195, 2207, 1720, 1649, 1609, 1555, 1471, 1364, 1088, 764 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄ClN₄O₂S [M + H]⁺: 421.0521, found 421.0519. HPLC analysis (Chiralpak AS-H column, hexane : 2-propanol = 80 : 20, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 32.93 (minor) and 38.94 min (major).

(S)-5′-Amino-2′-(4-bromophenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ea). White solid, m.p. 220 °C (dec.), 64% yield, [α]²⁰_D − 147.0 (c 0.80, CHCl₃), 97% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 7.13 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.42 (dt, J = 7.6, 0.8 Hz, 1H), 7.63 (s, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.2, 54.4, 107.0, 109.4, 117.7, 123.6, 124.7, 127.5, 130.1, 130.9, 132.0, 132.3, 142.4, 154.6, 161.9, 163.5, 175.6. IR (KBr): ν 3317, 3185, 2197, 1713, 1643, 1610, 1554, 1493, 1417, 1364, 1353, 1087, 1071, 754 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄BrN₄O₂S [M + H]⁺: 465.0015, found 465.0012. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 80 : 20, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 35.66 (minor) and 40.74 min (major).

(S)-5′-Amino-2′-(3-bromophenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3fa). White solid, m.p. 203 °C (dec.), 89% yield, [α]²⁰_D + 22.7 (c 0.15, CHCl₃), 75% ee (60% yield and 90% ee after a single recrystallization). ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.65 (s, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.2, 54.3, 107.5, 109.4, 117.7, 122.5, 123.7, 124.7, 127.8, 130.1, 131.4, 132.0, 133.8, 142.4, 154.6, 161.9, 162.8, 175.6. IR (KBr): ν 3315, 3183, 2197, 1713, 1643, 1610, 1555, 1491, 1470, 1419, 1355, 1237, 1086, 754 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₁H₁₄BrN₄O₂S [M + H]⁺: 465.0015, found 465.0009. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 11.48 (major) and 14.36 min (minor).

(S)-5′-Amino-1-methyl-2-oxo-2′-(4-trifluoromethylphenyl)spiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ga). White solid, m.p. 172 °C (dec.), 94% yield, [α]²⁰_D + 46.8 (c 0.50, CHCl₃), 69% ee (63% yield and 93% ee after a single recrystallization). ¹H NMR (400 MHz, DMSO-d₆): δ 3.23 (s, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.66 (s, 2H), 7.81 (d, J = 7.6 Hz, 2H), 8.04 (d, J = 7.6 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.2, 54.4, 108.2, 109.4, 117.6, 123.7, 123.8 (q, J = 272.2 Hz), 124.7, 126.3, 126.4, 130.1, 130.8 (q, J = 32.1), 132.0, 135.3, 142.5, 154.9, 161.9, 162.7, 175.5. IR (KBr): ν 3319, 3184, 2198, 1711, 1646, 1611, 1555, 1471, 1416, 1362, 1326, 1128, 1089, 845, 755 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₂H₁₄F₃N₄O₂S [M + H]⁺: 455.0784, found 455.0781. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 85 : 15, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 50.50 (major) and 58.51 min (minor).

(S)-5′-Amino-1-methyl-2-oxo-2′-(p-tolyl)spiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ha). White solid, m.p. 256 °C (dec.), 64% yield, [α]²⁰_D − 64.39 (c 0.41, CHCl₃), 88% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 2.33 (s, 3H), 3.22 (s, 3H), 7.13 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.59 (s, 2H), 7.73 (d, J = 8.0 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 21.0, 26.7, 49.1, 54.4, 105.8, 109.4, 117.7, 123.6, 124.7, 125.6, 129.2, 129.9, 130.0, 132.1, 141.4, 142.4, 154.4, 161.9, 164.9, 175.7. IR (KBr): ν 3321, 3185, 2196, 1715, 1643, 1610, 1556, 1469, 1353, 1088 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₂H₁₇N₄O₂S [M + H]⁺: 401.1067, found 401.1067. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 15.85 (major) and 19.65 min (minor).

(S)-5′-Amino-2′-(4-methoxyphenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ia). White solid, m.p. 157–159 °C, 61% yield, [α]²⁰_D + 48.8 (c 0.25, CHCl₃), 95% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 3.80 (s, 3H), 7.01 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.57 (s, 2H), 7.78 (d, J = 8.4 Hz, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.6, 49.2, 54.4, 55.5, 105.0, 109.3, 114.7, 117.8, 123.6, 124.6, 124.7, 127.4, 130.0, 132.1, 142.4, 154.3, 161.7, 161.9, 164.7, 175.7. IR (KBr): ν 3318, 3183, 2195, 1712, 1644, 1608, 1558, 1519, 1467, 1352, 1256, 1173, 1086 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₂H₁₇N₄O₃S [M + H]⁺: 417.1016, found 417.1018. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 80 : 20, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 49.94 (major) and 63.40 min (minor).

(S)-5′-Amino-2′-(3,5-dimethoxyphenyl)-1-methyl-2-oxospiro[indoline-3,7′-pyrano[2,3-d]thiazole]-6′-carbonitrile (3ja). White solid, m.p. 197 °C (dec.), 56% yield, [α]²⁰_D + 34.1 (c 0.51, CHCl₃), 91% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 3.22 (s, 3H), 3.77 (s, 6H), 6.62 (s, 1H), 6.95 (s, 2H), 7.14 (t, J = 6.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.60 (s, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 26.7, 49.2, 54.4, 55.5, 103.3, 103.4, 106.7, 109.4, 117.7, 123.7, 124.7, 130.0, 132.1, 133.6, 142.4, 154.3, 160.9, 161.9, 164.4, 175.6. IR (KBr): ν 3320, 3215, 2196, 1711, 1644, 1608, 1553, 1469, 1419, 1355, 1314, 1152 cm⁻¹. HRMS (ESI) m/z calc'd for C₂₃H₁₉N₄O₄S [M + H]⁺: 447.1122, found 447.1124. HPLC analysis (Chiralpak AS-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 254 nm): R_t = 19.12 (minor) and 23.66 min (major).

Conclusions

In conclusion, we have demonstrated herein an efficient organocatalytic cascade Michael/cyclization reaction of 2-substituted thiazol-4-ones and 2-(2-oxoindolin-3-ylidene)-malononitriles. The present process enabled the formation of a variety of structurally diverse thiazole-fused spirooxindole derivatives in moderate to good yields and with high levels of enantioselectivity in a one-pot manner.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 21421062), the Key laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and Engineering for generous financial support for our programs.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1481047. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra14178a

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