Three-component synthesis of new unsymmetrical oxindoles via Friedel-Crafts type reaction.

The synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-diones as new unsymmetrical oxindoles via a Friedel-Crafts type three-component reaction of 1,3-indandion, N,N-dimethylaniline and isatins in ethanol in the presence of LiClO4 is reported.

Introduction

Multi-component reactions (MCRs) have offered many fascinating and challenging transformations in organic synthesis.1, (a), (b), (c), (d) The atom-economy, convergent character, operational simplicity, structural diversity, and complexity of the molecules are the major advantages associated with multi-component reactions. Besides this multi-component reactions are emerging as a powerful tool in the synthesis of biologically important compounds.2, (a), (b)

Friedel–Crafts reaction is one of the oldest carbon–carbon bond forming processes, and is still an attractive method to introduce substituents on aromatic rings. Initial works concerned Friedel–Crafts acylation from acyl chlorides or alkylation from alkyl halides. To perform acylations, Lewis acids are needed. More than stoichiometric amounts of AlCl3 or BF3 are required, whereas catalytic amounts of rare-earth triflates, more specially scandium triflate, perfluorinated rare-earth metals, gallium triflate or bismuth triflate,8, (a), (b) allow the formation of the expected products.

Isatin is a privileged lead molecule for designing potential bioactive agents, and its derivatives have been shown to possess a broad spectrum of bioactivity as many of which were assessed anti-HIV, antiviral, anti-tumor,(a), (b), 11 antifungal, anti-angiogenic, anticonvulsants, anti-Parkinson’s disease therapeutic, and effective SARS coronavirus 3CL protease inhibitor. These interesting properties prompted many efforts toward the synthesis and pharmacological screening of isatin derivatives. During these investigations, the indolin-2-one (oxindole) moiety has been recognized as a biologically active framework. Oxindole is an integral constituent of many natural products.18, (a), (b), (c) Thus, it is not surprising that access to several members of this class may be the goal of many research laboratories.

Recently, LiClO4 has emerged as a powerful promoter in many chemical processes and in different organic media.19, (a), (b), (c) The development of method, which allows the reaction under essentially mild and neutral conditions should heighten the synthetic potential of the reaction. The LiClO4 medium provides a convenient procedure to carry out reactions under simple and neutral conditions.

Although several isatin-based reactions have been reported by our(e), 20, (a), (b), (c), (d) or other research groups(b), (c), (d), (e), (f), (g), (h), 21, (a) for the synthesis of new oxindoles, the synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-indene-diones 4 has not been reported yet. In this paper, for the first time we report an efficient synthesis of new unsymmetrical oxindoles 4 based on a Friedel–Crafts type three-component reaction of 1,3-indandione 1, isatins 2 and N,N-dimethylaniline 3 in the presence of LiClO4 as an ‎inexpensive and available catalyst (Scheme 1 ).

Scheme 1

Synthesis of unsymmetrical oxindoles 4.

Results and discussion

Our initial experiments were focused on the three-component reaction of 1,3-indandione 1 (1 mmol), isatin 2a (1 mmol), and N,N-dimethylaniline 3 (1 mmol) as a simple model substrate using different catalysts in refluxing EtOH, and the results are listed in Table 1 .

Table 1

Screening of catalysts

Entry	Catalyst (mol %)	Time (h)	Yields 4a (%)	Yields 5a (%)
1	LiClO4 (5)	3	80	<10
2	LiClO4 (10)	3	95	Trace
3	LiClO4 (15)	3	96	Trace
4	p-TSA (10)	3	30	35
5	HOAc (10)	3	25	43
6	AlCl3 (10)	3	55	27
7	ZnCl2 (10)	3	37	46
8	CAN (10)	3	32	37
9	InCl3	3	35	49
10	None	7	Trace	Trace

Isolated yield based on precipitation.

It was observed that when HOAc, p-TSA, ZnCl2, CAN, and InCl3 were used, it led to the formation of 5 as major product and desired product 4a as a minor product in a low yield (Table 1). AlCl3 showed better selectivity for 4a in comparison to 5. LiClO4 was found to be the best catalyst for the synthesis of unsymmetrical oxindole 4a. As can be seen from Table 1, when the amount of the LiClO4 increased from 5 to 10, and 15 mol %, the yields increased from 80 to 95 and 96%, respectively. It was found that 10 mol % LiClO4 in EtOH is sufficient to push this reaction forward (Table 1, entry 2). More amounts of the LiClO4 (15 mol %) did not improve the yields and decreasing the amount of LiClO4 (5 mol %) resulted in a decrease in the yield of 4a and increase in the yield of 5. When this reaction was carried out without LiClO4 the yield of the product was Trace even after 7 h (entry 10).

Then, we examined the solvent effect on the LiClO4-catalyzed model reaction. The results of Table 2 demonstrate that solvent affected the efficiency of the reaction and EtOH was the best choice of solvent (Table 2). In other solvents, such as CH3CN, CH2Cl2, THF, H2O, and CHCl3, low yield of 4a was obtained with significant formation of 5. Therefore, the use of the commercially available, inexpensive, and easily handled LiClO4 in EtOH provides a convenient procedure for the synthesis of unsymmetrical oxindole 4a under neutral and simple conditions.

Table 2

Solvent effect on the reactiona

Entry	Solvent (Reflux)	Yield 4a (%)	Yield 5b (%)
1	CH3CN	33	52
2	CH2Cl2	Trace	37
3	THF	<20	63
4	H2O	Trace	52
5	EtOH	95	Trace
6	CHCl3	<20	49

Reaction time=3 h, LiClO4 (10 mol %).

Isolated yield.

To study the generality of this protocol, a library of nine substituted 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-diones 4a–i were built using 1,3-indandione 1, isatins 2a–i, and N,N-dimethylaniline 3 (Table 3 ). All compounds are stable solids whose structures were established by IR, 1H and 13C NMR spectroscopy, and elemental analysis.

Table 3

Synthesis of unsymmetrical oxindoles 4

Product 4	R	X	Yields (%)	Timea (h)
a	H	H	95	3
b	Me	H	90	4.5
c	Et	H	87	6
d	H	Br	90	4
e	H	NO2	91	3.5
f	H	Me	94	4
g	H	F	98	4
h	Me	Br	90	6
i	Et	NO2	85	7

Isolated yields.

The plausible mechanism of this Friedel–Crafts type reaction is given in Scheme 2 . Aromatic amine 3 reacts with isatin 2 to generate an intermediate 6, followed by a nucleophilic addition with 1,3-indandione 1 to afford unsymmetrical oxindole 4. Compound 5 was also formed by the attack of another molecule of 3 on intermediate 6.

Scheme 2

Proposed mechanism of the reaction.

To further explore the potential of the reaction, we investigated the reaction of acenaphthylene-1,2-dione 7 and ninhydrin 8 instead of isatin 2 and obtained 2-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydroacenaphthylen-1-yl)-1H-indene-1,3(2H)-dione 9 and 2-(4-(dimethylamino)phenyl)-1H,1′H-2,2′-biindene-1,1′,3,3′(2H,2′H)-tetraone 10 in 73% and 60% yield, respectively (Scheme 3 ).

Scheme 3

Examining acenaphthylene-1,2-dione and ninhydrin instead of isatin.

It is notable, when we carried out the reaction with another cyclic 1,3-dicarbonyl compounds 11, the TLC and 1H NMR spectra of the reaction mixture showed a combination of starting materials and numerous products; low yields of desired products 12 were obtained and compound 5 was produced as a major product (Scheme 4 ).

Scheme 4

Examining different CH-acids instead of 1,3-indandione.

Conclusion

In conclusion, we have developed an efficient three-component reaction of 1,3-indandione, isatins, and N,N-dimethylaniline using LiClO4 as a catalyst. The reaction is operationally simple and offers high yields of the new unsymmetrical oxindole derivatives. Prominent among the advantages of this new method are novelty, operational simplicity and easy work-up procedures employed.

Experimental

General

Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz, respectively. 1H and 13C NMR spectra were obtained on solutions in DMSO­d 6. IR spectra were recorded using an FTIR apparatus. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer.

The chemicals used in this work were obtained from Fluka and Merck and were used without purification.

2-(3-(4-(Dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4a)

A mixture of 1,3-indandione (1 mmol), isatin (1 mmol), N,N-dimethylaniline (1 mmol), and LiClO4 (10 mol %) in refluxing ethanol (5 mL) was stirred for 3 h (the progress of the reaction was monitored by TLC). After completion, the reaction mixture was filtered and the precipitate washed with diethyl ether (10 ml) to afford the pure product 4a as greenish powder (0.396 g, 95%); mp 240 °C dec; IR (KBr) (ν max, cm−1): 3357, 3080, 1737, 1706. 1H NMR (300 MHz, DMSO­d 6): δ H=2.86 (6H, s, 2CH3), 4.71 (1H, s, CH), 6.64–7.89 (12H, m, H–Ar), 10.47 (1H, s, NH). 13C NMR (75 MHz, DMSO­d 6): δ C=40.6, 55.5, 57.2, 110.3, 112.5, 121.6, 123.0, 124.8, 128.1, 129.1, 129.5, 136.5, 143.3, 144.2, 149.2, 178.0, 179.4, 197.7, 198.0. MS (EI, 70 eV) m/z: 396 (M+). Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N, 7.07. Found: C, 75.65; H, 5.03; N, 7.01%.

2-(3-(4-(Dimethylamino)phenyl)-1-methyl-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4b)

Yellow powder (0.41 g, 90%); mp 230 °C dec; IR (KBr) (ν max, cm−1): 3425, 3043, 1742, 1706. 1H NMR (300 MHz, DMSO­d 6): δ H=3.00 (6H, s, CH3), 3.13 (3H, s, CH3), 4.78 (1H, s, CH), 6.62–7.90 (12H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=26.8, 40.5, 54.8, 57.5, 109.4, 112.4, 122.3, 123.1, 124.5, 128.2, 128.6, 129.3, 136.4, 136.6, 141.7, 142.4, 143.0, 144.8, 176.5, 197.5, 197.6, 197.8. MS (EI, 70 eV) m/z: 410 (M+). Anal. Calcd for C26H22N2O3: C, 76.08; H, 5.40; N, 6.82. Found: C, 75.97; H, 5.47; N, 6.74%.

2-(3-(4-(Dimethylamino)phenyl)-1-ethyl-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4c)

Yellow powder (0.42 g, 87%); mp 243 °C dec; IR (KBr) (ν max, cm−1): 3415, 3045, 1718, 1605. 1H NMR (300 MHz, DMSO­d 6): δ H=1.17 (3H, t, J=5.7 Hz, CH3), 2.86 (6H, s, CH3), 3.58–3.76 (2H, m, CH2), 4.80 (1H, s, CH), 6.46–7.91 (12H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=12.4, 34.7, 40.5, 54.8, 57.5, 109.4, 112.4, 122.1, 123.0, 123.1, 124.7, 125.0, 128.1, 129.0, 129.3, 136.4, 136.6, 141.7, 143.0, 143.8, 149.9, 176.1, 197.5, 197.8. MS (EI, 70 eV) m/z: 424 (M+). Anal. Calcd for C27H24N2O3. C, 76.39; H, 5.70; N, 6.60. Found: C, 76.45; H, 5.66; N, 6.69%.

2-(5-Bromo-3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4d)

Cream powder (0.474 g, 90%); mp 250 °C dec; IR (KBr) (ν max, cm−1): 3190, 3111, 1711, 1617. 1H NMR (300 MHz, DMSO­d 6): δ H=2.87 (6H, s, 2CH3), 4.83 (1H, s, CH), 6.66–7.92 (11H, m, H–Ar), 10.66 (1H, s, NH). 13C NMR (75 MHz, DMSO­d 6): δ C=40.4, 55.9, 57.0, 112.3, 112.5, 113.1, 123.0, 124.8, 127.4, 127.9, 131.8, 136.6, 141.9, 142.5, 142.7, 149.9, 177.6, 197.2, 197.9. MS (EI, 70 eV) m/z: 476 (M+), 474 (M+). Anal. Calcd for C25H19BrN2O3: C, 63.17; H, 4.03; N, 5.89. Found: C, 63.10; H, 4.11; N, 5.98%.

2-(3-(4-(Dimethylamino)phenyl)-5-nitro-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4e)

Cream powder (0.44 g, 91%); mp 215 °C dec; IR (KBr) (ν max, cm−1): 3451, 3184, 1742, 1706, 1612. 1H NMR (300 MHz, DMSO­d 6): δ H=2.88 (6H, s, 2CH3), 5.00 (1H, s, CH), 6.66–8.15 (11H, m, H–Ar), 11.29 (1H, s, NH). 13C NMR (75 MHz, DMSO­d 6): δ C=40.5, 56.4, 57.3, 110.5, 112.6, 120.3, 123.2, 124.3, 126.6, 127.9, 131.3, 136.8, 141.7, 142.1, 142.7, 149.7, 150.0, 178.4, 197.1, 197.6. MS (EI, 70 eV) m/z: 441 (M+). Anal. Calcd for C25H19N3O5: C, 68.02; H, 4.34; N, 9.52. Found: C, 67.91; H, 4.28; N, 9.43%.

2-(3-(4-(Dimethylamino)phenyl)-5-methyl-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4f)

Cream powder (0.41 g, 94%); mp 239 °C dec; IR (KBr) (ν max, cm−1): 3362, 3190, 1742, 1721, 1690. 1H NMR (300 MHz, DMSO­d 6): δ H=1.96 (3H, s, CH3), 2.87 (6H, s, 2CH3), 4.69 (1H, s, CH), 6.47–7.90 (11H, m, H–Ar), 10.36 (1H, s, NH). 13C NMR (75 MHz, DMSO­d 6): δ C=21.0, 40.5, 55.6, 57.2, 110.0, 112.4, 122.9, 125.5, 128.1, 129.3, 129.7, 130.2, 136.3, 136.4, 140.8, 141.9, 149.8, 178.0, 198.0. MS (EI, 70 eV) m/z: 410 (M+). Anal. Calcd for C26H22N2O3: C, 76.08, H, 5.40; N, 6.82. Found: C, 75.99; H, 5.46; N, 6.77%.

2-(3-(4-(Dimethylamino)phenyl)-5-fluoro-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4g)

Cream powder (0.41 g, 98%); mp 252 °C dec; IR (KBr) (ν max, cm−1): 3398, 1737, 1711, 1705. 1H NMR (300 MHz, DMSO­d 6): δ H=2.87 (6H, s, 2CH3), 4.78 (1H, s, CH), 6.53–7.91 (11H, m, H–Ar), 10.54 (1H, s, NH). 13C NMR (75 MHz, DMSO­d 6): δ C=40.5, 56.2, 56.9, 111.1, 112.1, 112.5, 115.3, 123.1, 124.8, 128.0, 136.6, 139.4, 141.9, 142.8, 149.9, 177.9, 197.3, 197.8. MS (EI, 70 eV) m/z: 414 (M+). Anal. Calcd for C25H19FN2O3: C, 72.45, H, 4.62; N, 6.76. Found: C, 72.55; H, 4.68; N, 6.69%.

2-(5-Bromo-3-(4-(dimethylamino)phenyl)-1-methyl-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4h)

Cream powder (0.49 g, 90%); mp 220 °C dec; IR (KBr) (ν max, cm−1): 3420, 1742, 1715, 1701. 1H NMR (300 MHz, DMSO­d 6): δ H=2.50 (6H, s, 2CH3), 3.12 (3H, s, CH3), 4.91 (1H, s, CH), 6.65–8.31 (11H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=26.9, 40.4, 55.1, 57.5, 111.4, 112.5, 113.9, 123.1, 123.2, 127.1, 128.0, 131.7, 132.0, 136.7, 141.7, 142.7, 150.6, 176.0, 197.2, 197.7. MS (EI, 70 eV) m/z: 490 (M+), 488 (M+). Anal. Calcd for C26H21BrN2O3: C, 63.81, H, 4.33; N, 5.72. Found: C, 63.70; H, 4.25; N, 5.61%.

2-(3-(4-(Dimethylamino)phenyl)-1-ethyl-5-nitro-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-dione (4i)

Yellow powder (0.47 g, 85%); mp 220 °C dec; IR (KBr) (ν max, cm−1): 3085, 1748, 1732, 1711. 1H NMR (300 MHz, DMSO­d 6): δ H=1.19 (3H, t, J=6.8 Hz, CH3), 2.87 (6H, s, 2CH3), 3.77–3.81 (2H, m, CH2), 5.09 (1H, s, CH), 6.65–8.23 (11H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=12.3, 35.4, 40.4, 54.6, 57.7, 109.7, 112.6, 120.0, 123.3, 123.6, 126.6, 127.9, 130.6, 136.8, 136.8, 141.6, 142.4, 142.7, 149.8, 150.1, 176.6, 197.0, 197.4. MS (EI, 70 eV) m/z: 469 (M+). Anal. Calcd for C27H23N3O5: C, 69.07, H, 4.94; N, 8.95. Found: C, 69.13; H, 4.99; N, 8.87.

2-(1-(4-(Dimethylamino)phenyl)-2-oxo-1,2-dihydroacenaphthylen-1-yl)-1H-indene-1,3(2H)-dione (9)

Yellow powder (0.43 g, 73%); mp 284 °C dec; IR (KBr) (ν max, cm−1): 3278, 3075, 1717, 1654. 1H NMR (300 MHz, DMSO­d 6): δ H=2.81 (6H, s, 2CH3), 5.19 (1H, s, CH), 6.58–8.21 (14H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=40.4, 58.3, 60.0, 112.4, 121.9, 122.9, 123.1, 125.3, 125.5, 128.3, 128.9, 129.4, 130.6, 131.9, 132.2, 136.4, 136.7, 138.9, 141.2, 141.6, 143.2, 149.8, 198.2, 201.0. MS (EI, 70 eV) m/z: 431 (M+). Anal. Calcd for C29H21NO3: C, 80.72, H, 4.91; N, 3.25. Found: C, 80.65; H, 4.99; N, 3.32%.

2-(4-(Dimethylamino)phenyl)-1H,1′H-2,2′-biindene-1,1′,3,3′(2H,2′H)-tetraone (10)

Yellow powder (0.41 g, 60%); mp 291 °C dec; IR (KBr) (ν max, cm−1): 3243, 3078, 1716, 1702. 1H NMR (300 MHz, DMSO­d 6): δ H=2.86 (6H, s, 2CH3), 4.76 (1H, s, CH), 6.64–7.99 (12H, m, H–Ar). 13C NMR (75 MHz, DMSO­d 6): δ C=40.4, 57.7, 109.7, 112.6, 120.0, 123.3, 123.8, 126.6, 127.9, 130.6, 135.8, 136.8, 141.6, 142.4, 142.7, 149.8, 150.1, 197.0, 197.4, 198.3, 199.9. MS (EI, 70 eV) m/z: 409 (M+). Anal. Calcd for C26H19NO4: C, 76.27, H, 4.68; N, 3.42. Found: C, 76.16; H, 4.60; N, 3.51%.