A Facile Entry into Benzo-/Naphtho-pyrano-indolizino-indole through Sequential Intramolecular 1,3-Dipolar Cycloaddition and Pictet-Spengler Cyclisation

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

doi:10.1055/s-2005-865216

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Synlett 2005(7): 1167-1169
DOI: 10.1055/s-2005-865216

LETTER

A Facile Entry into Benzo-/Naphtho-pyrano-indolizino-indole through Sequential Intramolecular 1,3-Dipolar Cycloaddition and Pictet-Spengler Cyclisation

G. Subramaniyan, Jayadevan Jayashankaran, Rathna Durga R. S. Manian, Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai - 600 025, India
Fax: +91(44)22352494; e-Mail: ragharaghunathan@yahoo.com;

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Publication History

Received 10 October 2004
Publication Date:
14 April 2005 (online)

Abstract
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Abstract

An assembly of polycyclic N-heterocycles, with the formation of four bonds and three rings, was obtained in good yield by the sequential intramolecular 1,3-dipolar cycloaddition via the N-metallation Ag(I)-catalysed imine route and subsequent Pictet-Spengler cyclisation.

Key words

N-metallation - azomethine ylide - intramolecular - 1,3-dipolar cycloaddition - Pictet-Spengler reaction

References

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Representative Experimental Procedure of Compound 3a. A mixture of imine (1 mmol), silver(I) acetate (1.2 mmol) and Et₃N (1.2 mmol) in dry MeCN (6 mL) was stirred at r.t. for 3 h and quenched with aq NH₄Cl. The mixture was extracted with Et₂O (3 × 10 mL), washed with brine and dried over Na₂SO₄. After the removal of solvent under reduced pressure the residue was subjected to column chromatography on silica gel eluting with petroleum ether-EtOAc (4:1) to afford cycloadduct.

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2-Methoxycarbonyl-2-indolo-3-ethoxycarbonyl-4 H -2,3,3a,9b-tetrahydropyrro[2,3- d ]benzo[ b ]pyran ( 3a). Colourless crystals; yield 75%; mp 171-172 °C. IR (KBr): 3293, 1726 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.27 (t, J = 7.3 Hz, 3 H), 1.87 (br s, 1 H), 2.83 (d, J = 11.7 Hz, 1 H), 2.91 (d, J = 14.8 Hz, 1 H), 3.04 (q, J = 7.3 Hz, 2 H), 3.12-3.17 (m, H_b), 3.49 (s, 3 H), 3.82 (d, J = 9.0 Hz, 1 H_a), 3.87 (d, J = 14.8 Hz, 1 H), 3.90 (dd, J = 12.0, 6.0 Hz, 1 H), 4.55 (dd, J = 12.0, 8.8 Hz, 1 H), 6.67-7.53 (m, 9 H), 8.21 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.19, 33.85, 45.85, 52.69, 55.25, 58.47, 61.19, 69.03, 74.95, 110.39, 111.09, 115.86, 119.15, 119.48, 120.15, 121.88, 124.39, 124.57, 124.71, 128.35, 128.43, 135.76, 152.96, 171.38, 173.39. MS: m/z = 434 [M⁺].
2,3-Dimethoxycarbonyl-2-indolo-4 H -2,3,3a,9b-tetrahydropyrro[2,3- d ]benzo[ b ]pyran ( 3b). Colourless crystals; yield 79%; mp 175-176 °C. IR (KBr): 3303, 1735 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.94 (br s, 1 H), 2.47 (d, J = 11.5 Hz, 1 H), 2.86 (d, J = 15.0 Hz, 1 H), 2.93-2.96 (m, H_b), 3.59 (s, 3 H), 3.77 (s, 3 H), 3.79 (d, J = 9.0 Hz, 1 H_a), 3.78 (d, J = 15.0 Hz, 1 H), 3.82 (dd, J = 12.2, 6.0 Hz, 1 H), 4.50 (dd, J = 12.2, 8.8 Hz, 1 H), 6.74-7.79 (m, 9 H), 8.21 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 33.39, 46.02, 52.26, 52.80, 55.31, 58.51, 68.94, 75.21, 110.42, 111.09, 115.90, 119.21, 119.51, 120.18, 121.36, 121.91, 124.42, 124.60, 128.32, 128.45, 135.77, 152.97, 171.91, 173.35. MS: m/z = 420 [M⁺].
2-Methoxycarbonyl-2-indolo-3-ethoxycarbonyl-4 H -2,3,3a,11c-tetrahydropyrro[2,3- d ]naphtho[ b ]pyran ( 7a). Colourless crystals; yield 80%; mp 182-183 °C. IR (KBr): 3285, 1735 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (t, J = 7.3 Hz, 3 H), 1.84 (br s, 1 H), 2.89 (d, J = 12.5 Hz, 1 H), 3.07 (d, J = 15.5 Hz, 1 H), 3.22 (q, J = 7.0, 2 H), 3.24-3.27 (m, H_b), 3.51 (s, 3 H), 3.58 (d, J = 9.0 Hz, 1 H_a), 3.82 (d, J = 15.5 Hz, 1 H), 3.85 (dd, J = 12.0, 6.2 Hz, 1 H), 4.52 (dd, J = 12.0, 8.7 Hz, 1 H), 7.03-7.72 (m, 11 H), 8.12 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.36, 29.76, 41.78, 52.56, 54.81, 61.25, 65.02, 71.75, 110.82, 111.02, 115.28, 118.61, 118.94, 119.18, 121.73, 123.71, 126.73, 128.15, 128.26, 129.35, 129.43, 133.30, 135.04, 152.44, 171.69, 174.85. MS: m/z = 484 [M⁺].
2,3-Dimethoxycarbonyl-2-indolo-4 H -2,3,3a,11c-tetrahydropyrro[2,3- d ]naphtho[ b ]pyran ( 7b). Colourless crystals; yield 85%; mp 185-187 °C. IR (KBr): 3255, 1725 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.82 (br s, 1 H), 2.32 (d, J = 11.2 Hz, 1 H), 2.94 (d, J = 14.7 Hz, 1 H), 2.94-2.99 (m, H_b), 3.52 (s, 3 H), 3.60 (s, 3 H), 3.86 (d, J = 8.6 Hz, 1 H_a), 3.83 (d, J = 14.7 Hz, 1 H), 3.85 (dd, J = 12.0, 6.3 Hz, 1 H), 4.69 (dd, J = 12.0, 9.0 Hz, 1 H), 6.80-7.95 (m, 11 H), 8.39 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 34.05, 46.08, 52.31, 52.87, 55.39, 58.56, 68.99, 75.24, 110.55, 111.08, 115.94, 119.29, 119.58, 120.22, 121.98, 124.42, 124.62, 128.37, 128.49, 135.80, 153.02, 171.93, 173.37. MS m/z = 470 [M⁺].

13

Representative Procedure for Pictet-Spengler Cyclisation. A mixture of cycloadduct (1 mmol), the aromatic aldehyde (1 mmol) and p-toluene sulfonic acid (0.1 mmol) in dry toluene was boiled under reflux using Dean-Stark apparatus. After 24 h the solvent was removed under vacuum and the crude product was purified by flash column chromatography with petroleum ether-EtOAc (9:1) as eluent to give the Pictet-Spengler cyclised product.

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Ethyl-15a-carbomethoxy-9-phenyl-1,1a,2,9,15,15a-hexahydrobenzo[ b ]4 H -pyrano[4,3- a ]indolizino[9,10- b ]indole-1-carboxylate ( 4a). Colourless crystals; yield 55%; mp 101-102 °C. IR (KBr): 3359, 1735 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (t, J = 7.3 Hz, 3 H), 1.73 (br s, 1 H), 2.5 (d, J = 11.7 Hz, 1 H), 2.85 (d, J = 15.2 Hz, 1 H), 2.90 (q, J = 7.0 Hz, 2 H), 3.06-3.10 (m, H_b), 3.58 (s, 3 H), 3.65 (d, J = 8.7 Hz, 1 H_a), 3.80 (d, J = 15.2 Hz, 1 H), 3.92 (dd, J = 11.8, 5.7 Hz, 1 H), 4.63 (dd, J = 11.8, 9.0 Hz, 1 H), 5.55 (s, 1 H_c), 6.87-7.68 (m, 14 H), 8.46 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.08, 26.47, 40.24, 52.05, 53.55, 60.56, 61.05, 65.04, 71.01, 73.25, 110.94, 111.45, 115.74, 118.13, 119.22, 119.52, 120.03, 120.15, 121.81, 122.42, 124.38, 124.77, 127.50, 127.98, 128.15, 135.74, 136.59, 152.96, 171.42, 173.52. MS: m/z = 522 [M⁺].
Methyl-9-phenyl-1,1a,2,9,15,15a-hexahydro-benzo[ b ]4 H -pyrano[4,3- a ]indolizino[9,10- b ]indole-1,15a-dicarboxylate ( 4b). Colourless crystals; yield 60%; mp 145-147 °C. IR (KBr): 3399, 1725 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.55 (br s, 1 H), 2.64 (d, J = 11.3 Hz, 1 H), 3.07 (d, J = 15.1 Hz, 1 H), 3.12-3.15 (m, H_b), 3.58 (s, 3 H), 3.62 (d, J = 9.0 Hz, 1 H_a), 3.73 (d, J = 15.1 Hz, 1 H), 3.79 (dd, J = 11.5, 5.8 Hz, 1 H), 4.37 (dd, J = 11.5, 9.0 Hz, 1 H), 5.35 (s, 1 H_c), 6.59-7.79 (m, 14 H), 8.46 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.64, 31.84, 47.47, 50.80, 52.24, 52.50, 55.13, 70.76, 85.45, 106.17, 110.27, 113.90. 114.00, 117.28, 117.36, 118.76, 119.41, 121.08, 121.23, 126.19, 129.70, 129.85, 130.55, 133.36, 135.18, 137.34, 158.03, 169.05, 171.46, 172.09. MS: m/z = 508 [M⁺].
Methyl-11b-phenyl-1,1a,2,11,17,17a-hexahydro-naphtho[ b ]4 H -pyrano[4,3- a ]indolizino[11,12- b ]indole-1,17a-dicarboxylate ( 8b). Colourless crystals; yield 50%; mp 230-231 °C. IR (KBr): 3362, 1745 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.82 (br s, 1 H), 2.29 (d, J = 11.0 Hz, 1 H), 3.05 (d, J = 15.2 Hz, 1 H), 3.11-3.16 (m, H_b), 3.56 (s, 3 H), 3.65 (s, 3 H), 3.78 (d, J = 9.0 Hz, 1 H_a), 3.8 (d, J = 15.2 Hz, 1 H), 3.84 (dd, J = 11.4, 6.0 Hz, 1 H), 4.62 (dd, J = 11.4, 8.8 Hz, 1 H), 5.62 (s, 1 H_c), 7.07-7.83 (m, 16 H), 8.40 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.66, 38.49, 51.60, 52.27, 53.27, 54.50, 55.28, 65.39, 69.62, 109.21, 11.91, 116.46, 118.71, 119.45, 119.53, 121.35,122.20, 123.48, 126.68, 126.77, 127.18, 127.42, 28.29, 128.65, 128.91, 129.29, 129.39, 129.70, 133.79, 136.65, 140.20, 156.60, 171.70, 172.12. MS: m/z = 558 [M⁺].