A Greener Approach for the Regioselective Synthesis of Multifunctionalized Indolylpyrrole and Indolyltriazolylpyrrole Hybrids via Michael Addition of α-Azido Ketones

Abstract

A convergent synthesis of indolylpyrrole derivatives has been developed from domino coupling of α-azido ketones, aromatic aldehydes, and 3-cyanocetylindoles in the presence of piperidine in aqueous medium at 80 °C via cascade Knoevenagel condensation–Michael addition–annulation in excellent yields. Further, the synthesized ortho-azidoindolylpyrroles undergo [3+2] cycloaddition with phenyl acetylene to give indolyltriazolylpyrrole hybrids in good yields. This domino transformation, efficiently generates C–C and C–N bonds in a minimum of synthetic steps resulting in three important bioactive heterocyclic frameworks, indole–pyrrole–triazole hybrids.

Key words

domino reaction - greener approach - α-azido ketones - regioselective synthesis - indolylpyrroles - indolyltriazolylpyrroles

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• 15 General Procedure for the Synthesis of 5-Aroyl-2-(1H-indol-3-yl)-4-aryl-1H-pyrrole-3-carbonitrile Derivatives 4 To a stirred mixture of aromatic aldehydes 1 (1.0 mmol), 2-(1H-3-indolylcarbonyl)-3-aryl-2-propenenitriles 2 (1.0 mmol) and phenacylazide 3 (1.0 mmol) in H₂O (3 mL), piperidine (0.25 mmol) was added at 80 °C. The turbid solution slowly turned into a clear solution, followed by the formation of solid after the time specified in Table 2. After completion of the reaction as indicated by TLC, the solid was filtered and washed with PE–EtOAc mixture (1:1 ratio, v/v, 5 mL) to give pure compound 4, which was recrystallized from EtOH to yield yellow crystals. Yellow solid; yield 93%; mp 244–246 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.21 (s, 3 H, CH₃), 6.98 (d, J = 7.5 Hz, 2 H, ArH), 7.11 (d, J = 7.5 Hz, 2 H, ArH), 7.19 (q, J = 7.5 Hz, 3 H, ArH), 7.25 (t, J = 7.5 Hz, 1 H, ArH), 7.37 (t, J = 7.5 Hz, 1 H, ArH), 7.51–7.55 (m, 3 H, ArH), 7.87 (d, J = 7.5 Hz, 1 H, ArH), 7.93 (d, J = 2.0 Hz, 1 H, ArH), 11.82 (s, 1 H, D₂O exchangeable, NH), 12.74 (s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 21.2, 92.6, 104.6, 122.7, 117.3, 120.4, 120.5, 122.7, 125.1, 127.4, 127.9, 128.3, 129.0, 129.6, 129.7, 130.1, 132.3, 135.3, 136.7, 137.3, 138.0, 139.8, 139.8, 186.3.
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• 21 General Procedure for the Synthesis of Indolyltriazolylpyrroles 5 To a stirred suspension of (4-methylphenyl)acetylene (1.2 mmol) and CuI (20 mol%) in t-BuOH–H₂O (1:1, 10 mL), was added the azidopyrrole (1.0 mmol) and stirring continued for the specified time (Table 0). After reaction was complete, as indicated by TLC, the mixture was filtered through a bed of Celite to remove CuI, the filtrate was diluted with H₂O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were then dried (Na₂SO₄), filtered, and concentrated under vacuum to obtain the crude product which was washed with PE–EtOAc (4:1 ratio, v/v, 5 mL) to give pure 5, which was recrystallized from EtOH
• 22 5-Benzoyl-2-(1H-indol-3-yl)-4-[2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)phenyl]-1H-pyrrole-3-carbonitrile (5a) Yellow solid; yield 78%; mp 180–182 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.38 (s, 3 H, Me), 7.09–7.30 (m, 9 H, ArH), 7.35–7.42 (m, 3 H, ArH), 7.53–7.57 (m, 2 H, ArH), 7.69 (d, J = 7.2 Hz, 2 H, ArH), 7.77 (d, J = 7.6 Hz, 2 H, ArH), 7.98 (s, 1 H, ArH), 9.58 (s, 2 H, D₂O exchangeable, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 92.1, 104.3, 112.4, 116.1, 118.9, 121.4, 121.8, 123.2, 123.9, 124.9, 125.7, 125.9, 127.1, 127.6, 127.9, 128.3, 129.1, 129.2, 129.4, 129.7, 131.6, 131.8, 135.8, 136.1, 136.8, 138.4, 139.7, 147.3, 185.3. HRMS (EI): m/z calcd for C₃₅H₂₄N₆O [M]⁺: 544.2012; found: 544.1200.
• 23 Crystallographic data of compound 4a in this manuscript have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 893599. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].