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Synthesis 2022(24): 4121-4123  
DOI: 10.1055/s-2006-950373
SHORTPAPER
© Georg Thieme Verlag Stuttgart · New York

Bismuth(III) Triflate Catalyzed Condensation of Isatin with Indoles and Pyrroles­: A Facile Synthesis of 3,3-Diindolyl- and 3,3-Dipyrrolyl Oxindoles

Jhillu S. Yadav*, Basireddy V. SubbaReddy, Kamakolanu Uma Gayathri, Syeda Meraj, Attaluri R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax: 91(40)7160387; e-Mail: yadavpub@iict.res.in;

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Publication History

Received 10 March 2006
Publication Date:
21 November 2006 (online)

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Abstract

Indoles and pyrroles undergo a rapid condensation with isatin in the presence of 2 mol% of Bi(OTf)3, under mild reaction conditions, to afford the corresponding 3,3-di(3-indolyl)- and 3,3-di(2-pyrroryl)oxindoles in excellent yields and high regioselectivity. This method is ideal for the direct introduction of indoles and pyrroles onto an isatin moiety at the 3-position.

Keywords

bismuth - Bi(OTf)3 - oxindoles - 3,3-diindolyl oxindoles - 3,3-dipyrrolyl oxindoles

3,3-Diaryl oxindoles are known to exhibit a wide range of biological activities such as antibacterial, antiprotozoal and anti-inflammatory behavior. [1] Generally, 3,3-diaryl oxindoles are prepared by acid-catalyzed condensation of arenes with isatin, [2] [3] and recently, isatin-dibarbiturates have also been prepared from isatin and barbituric acid. [4] However, there are no precedents for the condensation of isatin with heteroaomatics, such as indoles and pyrroles, with which to prepare diindolyl or dipyrrolyl isatin analogues. Lanthanide triflates are unique Lewis acids that are currently of great research interest. [5] Their high catalytic activity, low toxicity, moisture and air tolerance and their recyclability, make lanthanide triflates attractive alternatives to conventional Lewis acids. [6] However, lanthanide triflates are rather expensive and thus their use in large-scale synthesis is limited. Therefore, cheaper and more efficient catalysts are obviously desirable. Recently, bismuth(III) triflate has attracted the interest of synthetic organic chemists because it is inexpensive and can be easily prepared in the laboratory, even on multigram scale, from commercially available bismuth(III) oxide and triflic acid. [7] Owing to its unique catalytic properties, bismuth(III) triflate has been extensively used for a plethora of organic transformations. [8] For example, recently, bismuth(III) triflate has been utilized as an efficient catalyst for the conjugate addition of indoles to unsaturated ketones and quinones. [9]

In this report, we wish to highlight the results of our studies on the Bi(OTf)3-catalyzed condensation of isatin with indoles and pyrroles to produce 3,3-diindolyl- and 3,3-dipyrrolyl oxindoles. For example, treatment of indole (1) with isatin (2) in the presence of 2 mol% of Bi(OTf)3 in acetonitrile resulted in the formation of 3,3-di(3-indolyl)oxindole (3a) in 92% yield (Scheme [1] ).

Scheme 1

The reaction proceeds smoothly at room temperature under very mild conditions. Encouraged by the results obtained with indole, we turned our attention towards a range of other indoles and isatin. Interestingly, substituted indoles such as 5-bromo, 5-methoxy, 7-ethyl, 2-methyl and ethyl 2-carboxyindole all gave the corresponding bis-indolyl oxindoles in high yields (entries b-f, Table [1] ). This method was also effective for the preparation of Boc-protected bis-indolyloxindole from the corresponding Boc-protected 2-methylindole without cleavage of the Boc group (entry g, Table [1] ). Furthermore, pyrrole and N-methylpyrrole also reacted efficiently with isatin, under similar conditions, to afford 3,3-di(2-pyrrolyl)oxindole derivatives (entries h and i, Table [1] and Scheme [2] ).

Table 1 Bi(OTf)3-Catalyzed Synthesis of 3,3-Diindolyl or 3,3-Dipyrrolyl Oxindoles
Entry Indole/pyrrole 1 Oxindole 2 Producta 3 Yield (%)b Time (h)

a R = H; R′ = H; X = H 3a 92 3.0
b R = H; R′ = 2-Me; X = H 3b 95 2.5
c R = 5-Br; R′ = H; X = H 3c 89 3.5
d R = 5-MeO; R′ = H; X = H 3d 93 3.0
e R = 7-Et; R′ = H; X = H 3e 91 2.5
f R = H; R′= 2-CO2Et; X = H 3f 85 3.0
g R = H: R′= Me; X = Boc 3g 82 4.0

h X = H 4h 87 3.0
i X = Me 4i 80 4.0
a All products were characterized by 1H NMR and mass spectroscopy.
b Unoptimized, isolated yields.

Scheme 2

In all cases, the reactions proceeded rapidly at ambient temperature with high regioselectivity. When a range of metal triflates such as Bi(OTf)3, Yb(OTf)3, In(OTf)3 and Ce(OTf)4 were studied for this transformation, bismuth(III) triflate was found to be the most effective catalyst in terms of both conversion and reaction rates. Similar yields and selectivity were also obtained when 5 mol% of scandium(III) triflate was used. To establish the catalytic role of bismuth triflate, indole was treated with isatin in the absence of catalyst. In this case, the reaction did not proceed even under reflux conditions over prolonged reaction times (8-12 h). Although the coupling of isatin with indoles was successful in the presence of catalytic amounts of triflic acid (2 mol%), pyrrole and N-methylpyrrole underwent rapid polymerization, resulting in low yields (20-35%). Furthermore, N-Boc cleavage was observed in N-Boc-protected 2-methylindole under triflic acid conditions. An investigation into the effect of solvent on the efficiency of the reaction revealed that acetonitrile gave optimal results both in terms of yield and rate. The probable pathway seems to be an addition of the indole to the carbonyl group of isatin, followed by the condensation of a second indole moiety on the same carbon, resulting in the formation of 3,3-di(3-indolyl)oxindole (Scheme [3] ).

Scheme 3

The scope and generality of this process is illustrated with respect to various indoles and pyrroles in Table [1] . [9]

In summary, we describe a novel and efficient protocol for the preparation of 3,3-di(3-indolyl)- and 3,3-di(2-pyrrol­yl)oxindoles through bismuth(III) triflate catalyzed, one-pot 1:2 coupling of isatin with indoles or pyrroles. This method offers several advantages including mild reaction conditions, high conversions, cleaner reactions, no production of by-products from dimerization of indoles, ready availability of starting materials, small quantity of catalyst, high regioselectivity, and operational simplicity. All these attributes make this approach a useful and attractive strategy for the synthesis of bis(3-indolyl)- and bis(2-pyrrolyl)oxindoles.

Melting points were recorded on a Büchi R-535 apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectrometer using KBr optics. 1H NMR spectra were recorded on Gemini-200 and Bruker Avance (300 MHz) spectrometers in CDCl3 using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV. Columm chromatography was perfomed using mesh silica gel (Merck, 60-120). All solvents were distilled, dried over CaH2 and stored under nitrogen prior to use. Starting materials and reagents used in the reactions were obtained commercially from Aldrich, Lancaster, Fluka and were used without purification, unless otherwise indicated.

Synthesis of 3,3-Di(3-indolyl)-2-indolinone (3a); Typical Procedure

A mixture of isatin (147 mg, 1 mmol), indole (234 mg, 2 mmol) and Bi(OTf)3 (0.05 mmol) in MeCN (10 mL) was stirred at r.t. for 3 h. Upon completion of the reaction (indicated by TLC), the reaction mixture was quenched with H2O (15 mL) and extracted with CH2Cl2 (2 × 10 mL). Evaporation of the solvent, followed by purification on silica gel (Merck, 100-200 mesh, EtOAc-hexane, 3:7) afforded pure 3,3-di(3-indolyl)-2-indolinone derivative 3a in 92% (334 mg) yield.

IR (KBr): 3410, 1705, 1107, 1065, 727 cm-1.

1H NMR (200 MHz, CDCl3): δ = 6.80 (d, J = 8.1 Hz, 2 H), 6.85 (d, J = 1.9 Hz, 2 H), 6.95 (t, J = 7.9 Hz, 4 H), 7.20 (t, J = 7.9 Hz, 2 H), 7.25 (d, J = 8.1 Hz, 4 H), 10.0 (br s, 2 H, NH), 10.1 (br s, 1 H, NH).

13C NMR (50 MHz, CDCl3): δ = 52.5, 111.5, 114.2, 118.1, 120.7, 120.8, 121.4, 124.2, 124.8, 125.6, 127.8, 134.5, 136.8, 141.3, 178.7.

MS (FAB): m/z = 363 [M+], 327, 281, 267, 251, 221, 207, 191, 147, 133, 109, 83, 73, 55.

tert -Butyl 3-3-[1-( tert -Butyloxycarbonyl)-2-methyl-3-indolyl]-2-oxo-2,3-dihydro-3-indolyl-2-methyl-1-indolecarboxylate (3g)

IR (KBr): 3479, 1720, 1455, 1315, 1257, 1120, 1025, 1078, 768 cm-1.

1H NMR (200 MHz, CDCl3): δ = 1.65 (s, 18 H), 2.25 (s, 3 H), 2.30 (s, 3 H), 6.40 (d, J = 8.5 Hz, 1 H), 6.80-6.99 (m, 4 H), 7.0-7.30 (m, 5 H), 8.0-8.10 (m, 2 H), 10.5 (br s, 1 H, NH).

13C NMR (50 MHz, CDCl3): δ = 20.1, 25.0, 26.4, 27.3, 29.8, 46.8, 56.3, 68.7, 73.5, 78.0, 103.1, 110.2, 129.4, 155.0, 160.2.

MS (FAB): m/z = 591 [M+], 479, 434, 376, 361, 348, 305, 261, 221, 191, 147, 57.

Synthesis of 3,3-Di(3-pyrrolyl)-2-indolinone (4h); Typical Procedure

A mixture of isatin (147 mg, 1 mmol), pyrrole (201 mg, 3 mmol) and Bi(OTf)3 (0.05 mmol) in MeCN (10 mL) was stirred at r.t. for 3 h. After completion of the reaction (indicated by TLC), the reaction mixture was quenched with H2O (15 mL) and extracted with CH2Cl2 (2 × 10 mL). Evaporation of the solvent, followed by purification on silica gel (Merck, 100-200 mesh, EtOAc-hexane, 3:7) afforded pure 3,3-di(3-pyrrolyl)-2-indolinone derivative 4h in 87% (287 mg) yield.

IR (KBr): 3458, 2935, 1705, 1050, 772 cm-1.

1H NMR (200 MHz, CDCl3): δ = 5.80 (d, J = 3.4 Hz, 2 H), 6.05 (dd, J = 2.4, 3.4 Hz, 2 H), 6.60 (d, J = 2.4 Hz, 2 H), 6.90 (d, J = 8.1 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 9.70 (br s, 2 H, NH), 10.2 (br s, 1 H, NH).

13C NMR (50 MHz, CDCl3): δ = 27.6, 84.2, 110.1, 114.5, 119.5, 122.1, 123.3, 125.4, 127.3, 129.0, 132.8, 133.7, 135.2, 141.2, 149.7, 177.7.

MS (FAB): m/z = 263 [M+], 199, 176, 154, 136, 105, 92, 77, 63, 46.

Acknowledgment

K.U.G. and S.M. thank CSIR, New Delhi, for the award of fellowships.

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Scheme 1

Scheme 2

Scheme 3