Solid-Supported Microwave-Accelerated Intramolecular Knoevenagel ­Hetero-Diels-Alder Reactions: A Protocol for the Synthesis of Indolo[2,1-a]pyrrolo[4′,3′:4,5]pyran Ring Systems

Rathna Durga R. S. Manian; Jayadevan Jayashankaran; Raghavachary Raghunathan

doi:10.1055/s-2007-970788

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Synlett 2007(6): 0874-0880
DOI: 10.1055/s-2007-970788

LETTER

Solid-Supported Microwave-Accelerated Intramolecular Knoevenagel Hetero-Diels-Alder Reactions: A Protocol for the Synthesis of Indolo[2,1-a]pyrrolo[4′,3′:4,5]pyran Ring Systems

Rathna Durga S. Manian, Jayadevan Jayashankaran, Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
Fax: +91(44)22352494; e-Mail: ragharaghunathan@yahoo.com;

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Publication History

Received 18 October 2006
Publication Date:
26 March 2007 (online)

Abstract
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Abstract

A novel and mild method was established to synthesize pyrroloindole derivatives. This method entails an ethylenediammonium diacetate (EDDA)-promoted Knoevenagel condensation of various diones with appropriately substituted aldehydes to yield the arylidene intermediate, which was smoothly converted to the final products by intramolecular Diels-Alder reaction in a tandem manner. This process describes a practical synthetic method to prepare pyrroloindole derivatives.

Keywords

hetero-Diels-Alder - Knoevenagel condensation - domino process - indole

References and Notes

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14

General Procedure for the Intramolecular Domino Knoevenagel Hetero-Diels-Alder Reaction:Method A: To a refluxing solution of activated ketones or 1,3-diones (1 mmol) in anhyd toluene (10 mL), the aldehydes 1a or 1b (1 mmol) was added and the reaction mixture was refluxed until the disappearance of the starting material as evidenced by TLC. After completion of the reaction, the solvent was evaporated in a rotary evaporator and the residue was subjected to flash column chromatography using hexane-EtOAc mixture.
Method B: A solution of activated ketones or 1,3-diones (1 mmol) and the corresponding aldehyde (1 mmol) in anhyd toluene was irradiated with microwave (600 W power) until the TLC showed the disappearance of the starting material. After removal of the solvent, the crude reaction mixture was subjected to flash column chromatography (silica gel) to yield the product.
Method C: A mixture of activated ketones or 1,3-dione (1 mmol), the corresponding aldehyde (1 mmol) and K-10 montmorillonite clay (1.0 g) was thoroughly ground in a mortar. The reaction mixture was irradiated with microwave until the disappearance of the starting material as evidenced by TLC. After completion of the reaction, the montmorillonite clay was separated by filtration after extracting the product with CH₂Cl₂ (2 × 15 mL). Removal of the solvent and purification of the crude reaction mixture by flash column chromatography gave the pure product.
3a,10b- cis -3,11,11-Trimethyl-1-phenyl-3a,10,10b,11-tetrahydroindolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[2,3- c ]pyrazole ( 3a): pale pink solid; mp 150-152 °C. IR (KBr): 1654 cm^-1. ¹H NMR (CDCl₃): δ = 1.51 (s, 3 H), 1.56 (s, 3 H), 2.36 (s, 3 H), 3.16-3.20 (m, 1 H, H_b), 3.99 (dd, J = 7.2, 9.7 Hz, 1 H), 4.23 (dd, J = 8.0, 9.7 Hz, 1 H), 4.38 (d, J = 6.8 Hz, 1 H, H_a), 6.38 (s, 1 H), 7.04-7.70 (m, 9 H). ¹³C NMR: δ = 13.65, 25.47, 26.27, 31.64, 43.51, 51.60, 80.65, 94.11, 95.00, 109.34, 119.45, 120.56, 120.79, 120.99, 125.53, 128.97, 132.12, 132.51, 138.74, 143.71, 147.26, 158.19. MS: m/z = 369 [M⁺]. Anal. Calcd for C₂₄H₂₃N₃O: C, 78.02; H, 6.27; N, 11.37. Found: C, 78.23; H, 6.41; N, 11.21.
3a,10b- trans -3,11,11-Trimethyl-1-phenyl-3a,10,10b,11-tetrahydroindolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[2,3- c ]pyrazole ( 4a): pink solid; mp 163-164 °C. IR (KBr): 1650 cm^-1. ¹H NMR (CDCl₃): δ = 1.56 (s, 3 H), 1.61 (s, 3 H), 2.32 (s, 3 H), 3.21-3.25 (m, 1 H, H_b), 4.10 (dd, J = 7.0, 9.8 Hz, 1 H), 4.32 (dd, J = 8.0, 9.8 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H, H_a), 6.26 (s, 1 H), 7.15-7.85 (m, 9 H). ¹³C NMR: δ = 14.27, 24.15, 27.32, 32.65, 40.26, 53.15, 82.75, 96.23, 98.15, 110.56, 120.12, 121.55, 122.78, 124.56, 126.78, 128.16, 135.26, 137.25, 145.10, 148.21, 159.10. MS: m/z = 369 [M⁺].
4,5-Dihydro-5-(3-methylbut-2-enyl)-3-methyl-1-phenylindolo[3,2- b ]pyrano[2,3- c ]pyrazole ( 5a): pale pink solid; mp 178-180 °C. IR (KBr): 1660 cm^-1. ¹H NMR (CDCl₃): δ = 1.62 (s, 2 H), 1.73 (s, 3 H), 1.89 (s, 3 H), 2.28 (s, 3 H), 4.87 (d, J = 6.3 Hz, 2 H), 5.19 (t, J = 6.3 Hz, 1 H), 7.11-8.01 (m, 9 H). ¹³C NMR: δ = 13.24, 18.39, 25.66, 41.67, 110.10, 117.57, 119.16, 120.63, 121.16, 123.55, 123.86, 124.75, 127.05, 127.93, 128.86, 130.49, 132.36, 135.25, 138.72, 140.21, 150.06, 162.16. MS: m/z = 369 [M⁺]. Anal. Calcd for C₂₄H₂₃N₃O: C, 78.02; H, 6.27; N, 11.37. Found: C, 78.19; H, 6.34; N, 11.45.
7a,14b- cis -7,7-Dimethyl-7a,8,14,14b-tetrahydro-indolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[1,2- b ]indan-1-one ( 11a): purple solid; mp 166-168 °C. IR (KBr): 1715 cm^-1. ¹H NMR (CDCl₃): δ = 1.32 (s, 3 H), 1.35 (s, 3 H), 3.24-3.27 (m, 1 H, H_b), 3.69 (dd, J = 6.7, 9.8 Hz, 1 H), 3.90 (dd, J = 8.1, 9.8 Hz, 1 H), 4.21 (d, J = 6.8 Hz, 1 H, H_a), 6.13 (s, 1 H), 6.91-7.37 (m, 8 H). ¹³C NMR: δ = 23.37, 23.53, 35.91, 40.79, 47.28, 56.37, 109.07, 110.00, 117.72, 120.51, 121.93, 122.21, 122.30, 123.19, 123.83, 124.03, 125.81, 127.92, 130.10, 135.77, 193.51. MS: m/z = 341 [M⁺]. Anal. Calcd for C₂₃H₁₉NO₂: C, 80.92; H, 5.61; N, 4.10. Found: C, 81.11; H, 5.76; N, 4.22.
7a,14b- trans -7,7-Dimethyl-7a,8,14,14b-tetrahydroindolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[1,2- b ]indan-1-one ( 12a): purple solid; mp 170-172 °C. IR (KBr): 1721 cm^-1. ¹H NMR (CDCl₃): δ = 1.40 (s, 3 H), 1.43 (s, 3 H), 3.46-3.50 (m, 1 H, H_b), 3.84 (dd, J = 7.0, 10.0 Hz, 1 H), 4.20 (dd, J = 8.2, 10.0 Hz, 1 H), 4.53 (d, J = 12.2 Hz, 1 H, H_a), 6.10 (s, 1 H), 6.33-7.21 (m, 8 H). ¹³C NMR: δ = 22.92, 23.26, 37.20, 44.82, 49.17, 59.70, 110.94, 112.14, 119.26, 121.52, 122.50, 122.99, 123.08, 124.72, 125.92, 127.70, 128.81, 129.09, 130.23, 134.66, 136.16, 140.38, 200.17. MS: m/z = 341 [M⁺].
11,12-Dihydro-11-(3-methylbut-2-enyl) indolo[3,2- b ]pyrano[2,1- c ]indan-1-one ( 13a): purple solid; mp 183-185 °C. IR (KBr): 1725 cm^-1. ¹H NMR (CDCl₃): δ = 1.59 (s, 3 H), 1.63 (s, 3 H), 1.69 (s, 2 H), 4.37 (d, J = 5.7 Hz, 2 H), 5.32 (t, J = 5.7 Hz, 1 H), 6.74-7.03 (m, 8 H). ¹³C NMR: δ = 20.52, 23.93, 24.02, 43.41, 107.75, 110.66, 111.23, 119.82, 120.79, 120.97, 121.49, 121.87, 122.77, 124.22, 126.99, 127.71, 128.88, 132.92, 133.16, 134.98, 135.26, 139.18, 198.10. MS: m/z = 341 [M⁺]. Anal. Calcd for C₂₃H₁₉NO₂: C, 80.92; H, 5.61; N, 4.10. Found: C, 81.07; H, 5.72; N, 4.23.
6a,13b- cis -3,3-Dimethyl-6-phenyl-6a,7,13,13b-tetrahydroindolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[1,2- b ]cyclohexan-1-one ( 19b): yellow solid; mp 162-163 °C. IR (KBr): 1734 cm^-1. ¹H NMR (CDCl₃): δ = 1.15 (s, 3 H), 1.19 (s, 3 H), 1.93 (s, 2 H), 2.55 (s, 2 H), 3.49-3.52 (m, 1 H, H_b), 3.79 (dd, J = 7.3, 10.1 Hz, 1 H), 3.85 (dd, J = 8.2, 10.1 Hz, 1 H), 4.37 (d, J = 6.8 Hz, 1 H, H_a), 5.22 (d, J = 9.8 Hz, 1 H), 5.91 (s, 1 H), 6.37-7.19 (m, 9 H). ¹³C NMR: δ = 27.35, 27.90, 30.45, 37.00, 44.52, 48.73, 50.22, 53.77, 70.82, 113.14, 114.77, 115.24, 120.78, 122.37, 124.67, 125.05, 125.31, 127.92, 128.18, 129.42, 130.02, 130.83, 132.56, 133.82, 137.28, 193.72. MS: m/z = 383 [M⁺]. Anal. Calcd for C₂₆H₂₅NO₂: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.61; H, 6.43; N, 3.52.
6a,13b- trans -3,3-Dimethyl-6-phenyl-6a,7,13,13b-tetrahydroindolo[2,1- a ]pyrrolo[4′,3′:4,5]pyrano[1,2- b ]cyclohexan-1-one ( 20b): yellow solid; mp 155-157 °C. IR (KBr): 1735 cm^-1. ¹H NMR (CDCl₃): δ = 1.20 (s, 3 H), 1.22 (s, 3 H), 1.84 (s, 2 H), 2.37 (s, 2 H), 3.42-3.44 (m, 1 H, H_b), 3.81 (dd, J = 7.0, 10.0 Hz, 1 H), 3.92 (dd, J = 8.3, 10.0 Hz, 1 H), 4.45 (d, J = 11.5 Hz, 1 H, H_a), 5.30 (d, J = 9.8 Hz, 1 H), 6.12 (s, 1 H), 6.45-7.01 (m, 9 H). ¹³C NMR: δ = 25.34, 26.07, 32.00, 35.58, 41.87, 48.23, 50.58, 56.81, 71.52, 119.19, 121.00, 121.82, 122.77, 123.45, 124.16, 125.41, 126.45, 127.78, 130.09, 131.70, 134.99, 135.68, 140.25, 143.39, 147.55, 192.85. MS: m/z = 383 [M⁺].
10-Cinnamyl-3,3-dimethyl-3,4,10,11-tetrahydro-indolo[3,2- b ]chromen-1 (2 H )-one ( 21b): yellow solid; mp 160-162 °C. IR (KBr): 1727 cm^-1. ¹H NMR (CDCl₃): δ = 1.21 (s, 3 H), 1.23 (s, 3 H), 1.69 (s, 2 H), 1.73 (s, 2 H), 2.41 (s, 2 H), 4.25 (d, J = 6.0 Hz, 2 H), 4.78 (dt, J = 6.0, 6.3 Hz, 1 H), 5.65 (d, J = 6.3 Hz, 1 H), 6.70-7.13 (m, 9 H). ¹³C NMR: δ = 22.57, 28.50, 28.91, 32.05, 43.00, 44.53, 52.69, 116.13, 120.65, 121.15, 121.58, 124.54, 124.90, 127.39, 127.65, 128.19, 129.09, 129.81, 131.95, 134.62, 136.61, 138.22, 139.05, 142.12, 192.37. MS: m/z = 383 [M⁺]. Anal. Calcd for C₂₆H₂₅NO₂: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.58; H, 6.64; N, 3.53.