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

Jayabal Kamalraja; Ramachandran Sowndarya; Paramasivan Thirumalai Perumal

doi:10.1055/s-0034-1378523

Synlett, Table of Contents

Synlett 2014; 25(15): 2208-2212
DOI: 10.1055/s-0034-1378523

letter

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

Jayabal Kamalraja

Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India Fax: +91(44)24911589 Email: ptperumal@gmail.com

,

Ramachandran Sowndarya

Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India Fax: +91(44)24911589 Email: ptperumal@gmail.com

,

Paramasivan Thirumalai Perumal*

Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India Fax: +91(44)24911589 Email: ptperumal@gmail.com

› Author Affiliations

Abstract

All articles of this category

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

Full Text

References

References and Notes

1a Schreiber SL. Science 2000; 287: 1964
1b Thompson LA. Curr. Opin. Chem. Biol. 2000; 4: 324
1c Trost BM. Angew. Chem., Int. Ed. Engl. 1995; 34: 259
1d Tietze LF. Chem. Rev. 1996; 96: 115

2a For the first discussion of the ‘on-water reaction’ concept, see: Narayan S, Muldoon J, Finn MG, Fokin VV, Kolb HC, Sharpless KB. Angew. Chem. Int. Ed. 2005; 44: 3275

For reviews of the synthetic applications of ‘on-water’ chemistry, see:

2b Chanda A, Fokin VV. Chem. Rev. 2009; 109: 725
2c Butler RN, Coyne AG. Chem. Rev. 2010; 110: 6302
2d Lindström UM. Chem. Rev. 2002; 102: 2751

3a Jones RA. Pyrroles. Wiley; New York: 1992. Part II
3b Trofimov BA, Sobenina LN, Demenev AP, Mikhaleva AI. Chem. Rev. 2004; 104: 2481
3c Bellina F, Rossi R. Tetrahedron 2006; 62: 7213

4a Thompson RB. FASEB J. 2001; 15: 1671
4b Laderoute KR, Calaoagan JM, Madrid PB, Klon AE, Ehrlich PJ. Cancer Biol. Ther. 2010; 10: 68

5a Brenelli EC. S, Fernandes JL. N. Tetrahedron: Asymmetry 2003; 14: 1255
5b Wallner SR, Lavandera I, Mayer SF, Ohrlein R, Hafner A, Edegger K, Faber K, Kroutil W. J. Mol. Catal. B: Enzym. 2008; 55: 126

6 Benaissa T, Hamman S, Beguin CG. J. Fluorine Chem. 1988; 38: 163
7 Nakajima M, Loeschorn CA, Cimbrelo WE, Anselme JP. Org. Prep. Proced. Int. 1980; 12: 265
8 Marco JL, Martinez-Grau A, Martin N, Seoane C. Tetrahedron Lett. 1995; 36: 5393

9a Langer P, Freifeld I, Shojaei H. Chem. Commun. 2003; 3044
9b Freifeld I, Shojaei H, Langer P. J. Org. Chem. 2006; 71: 4965
9c Freifeld I, Shojaei H, Dede R, Langer P. J. Org. Chem. 2006; 71: 6165

10a Hantzsch A. Ber. Dtsch. Chem. Ges. 1890; 23: 1474
10b Knorr L. Ber. Dtsch. Chem. Ges. 1884; 17: 1635
10c Paal C. Ber. Dtsch. Chem. Ges. 1885; 18: 367

11 Dieter RK, Yu H. Org. Lett. 2000; 2: 2283

12a Ln X, Mao Z, Dai X, Lu P, Wang Y. Chem. Commun. 2011; 47: 6620
12b Yan RL, Luo J, Wang CX, Ma CW, Huang GS, Liang YM. J. Org. Chem. 2010; 75: 5395
12c Khalili B, Jajarmi P, Eftekhari-Sis B, Hashemi MM. J. Org. Chem. 2008; 73: 2090
12d Liu X, Hao L, Lin M, Chen L, Zhan Z. Org. Biomol. Chem. 2010; 8: 3064
12e Bharadwaj AR, Scheidt KA. Org. Lett. 2004; 6: 2465
12f Cyr DJ. S, Martin N, Arndtsen BA. Org. Lett. 2007; 9: 449
12g Fontaine P, Masson G, Zhu J. Org. Lett. 2009; 11: 1555
12h Freifeld I, Shojaei H, Langer P. J. Org. Chem. 2006; 71: 4965

13 Babu TH, Kamalraja J, Muralidharan D, Perumal PT. Tetrahedron Lett. 2011; 52: 4093
14 Kamalraja J, Babu TH, Muralidharan D, Perumal PT. Synlett 2012; 23: 1950
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.
16 Boyer JH, Canter FC. Chem. Rev. 1954; 54: 1
17 Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004
18 For a review on copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis, see: Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
19 1,3-Dipolar Cycloaddition Chemistry . Vol. 1. Huisgen R, Padwa AI. Wiley; New York: 1984: 1

20a Tornøe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057
20b Rostovtsev VV, Green LG, Fokin VV, Sharpless B. Angew. Chem. Int. Ed. 2002; 41: 2596

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: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].

Supplementary Material

Supporting Information