A Convenient One-Pot Synthesis of Spirocyclic Pyrido[1,2-a]indole Derivatives from 3-(2-Bromoethyl)indole

Abstract

A convenient one-pot approach for the synthesis of spirocyclic pyrido[1,2-a]indole derivatives is described. The method involves treatment of 1,3-diketones and 1,3-ketoesters with base to generate dianions, which react with 3-(2-bromoethyl)indole to construct a spirocyclopropyl ring and an N-heterocyclic ring sequentially in moderate to very good yields.

spirocyclic pyrido[1,2-a]indole derivatives - tandem reactions - heterocycles.

References and Notes

1a Joule JA. Science of Synthesis   Vol. 10:  Thomas EJ. Georg Thieme Verlag; Stuttgart: 2000.  p.361-652  

1b Bosch J. Bonjoch J. Amat M. Alkaloids  1996,  48:  75 

1c Sundberg RJ. Indoles   Academic Press; London: 1996. 

1d Chadwick DJ. Jones RA. Sundberg RJ. Comprehensive Heterocyclic Chemistry   Vol. 4:  Pergamon; Oxford: 1984.  p.155-376  

2a Saxton JE. The Chemistry of Heterocyclic Compounds   Vol. 25, Part IV:  Academic Press; New York: 1994. 

2b Clark RD. Miller AB. Berger J. Repke DB. Weinhardt KK. Kowalczyk BA. Eglen RM. Bonhaus DW. Lee CH. J. Med. Chem.  1993,  36:  2645 

3a Gross S. Reissig H.-U. Org. Lett.  2003,  5:  4305 

3b Hiroi K. Hiratsuka Y. Watanabe K. Abe I. Kato F. Hiror M. Tetrahedron: Asymmetry  2002,  13:  1351 

3c Teuber HJ. Worbs E. Cornelius D. Arch. Pharm.  1982,  315:  388 

3d Ozaki S. Mitoh S. Ohmori H. Chem. Pharm. Bull.  1996,  44:  2020 

4 Gribble GW. J. Chem. Soc., Perkin Trans. 1  2000,  1045 

5 Bytschkov I. Siebeneicher H. Doye S. Eur. J. Org. Chem.  2003,  2888 

6 Nicolaou KC. Roecker AJ. Hughes R. Summeren RV. Pfefferkorn JA. Winssinger N. Bioorg. Med. Chem.  2003,  11:  465 

7 Closson WD. Roman SA. Kwiatkowski GT. Corwin DA. Tetrahedron Lett.  1966,  21:  2271 

8 Johansen JE. Christie BD. Rapoport H. J. Org. Chem.  1981,  46:  4914 

9 Amombo MO. Hausherr A. Reissig H.-U. Synlett  1999,  1871 

10a Clive DLJ. Wang J. Yu M. Tetrahedron Lett.  2005,  46:  2853 

10b Rubiralta M. Diez A. Vila C. Troin Y. Feliz M. J. Org. Chem.  1991,  56:  6292 

11 Huckin SN. Weiler L. J. Am. Chem. Soc.  1974,  96:  1082 

12

General Procedure for Reaction Protocol: NaH (12 mmol, 0.29 g) was weighed out with a flask in a dry box and then THF (40 mL) was added. The flask was placed in an ice bath. The mixture was stirred and 1,3-diketones or 1,3-ketoesters 4 (6 mmol) in THF (5 mL) was added dropwise into the flask. The mixture was further stirred for 10 min at 0 °C and then n-BuLi (12 mmol, 7.6 mL of 1.6 M n-BuLi solution in hexane) was added dropwise. After 20 min, 3-(2-bromo­-ethyl) indole (5 mmol, 1.12 g) in THF (5 mL) was added dropwise with stirring. The reaction mixture was warmed to r.t. slowly and further stirred overnight. The reaction mixture was hydrolyzed with 1% HCl solution (30 mL) and extracted with Et₂O. The combined organic extracts were washed with H₂O and dried over MgSO₄. After filtration, the crude product was concentrated and purified with column chromatography. The obtained pure products 5 were characterized with 500 MHz NMR, GC-MS, and HRMS.

13

The NMR spectra were recorded with 500 MHz NMR spectrometer. GC-MS method: initial temperature: 50 °C (hold for 3 min), rate: 15 °C/min, final temperature: 280 °C (hold for 7 min). Compound 5a: The general procedure was followed with the use of substrate 4a (0.6 g) and product 5a (0.95g, 85%) was obtained as a brown solid after purification. ¹H NMR (500 MHz, CDCl₃): δ = 7.21 (d, J = 8.2 Hz, 1 H), 7.12 (t, J = 7.3 Hz, 1 H), 6.94 (t, J = 7.4 Hz, 1 H), 6.72 (d, J = 7.2 Hz, 1 H), 5.19 (s, 1 H), 4.41 (dd, J = 4.1, 16.5 Hz, 1 H), 2.47 (s, 3 H), 2.42 (t, J = 16.2 Hz, 1 H), 2.14 (dd, J = 4.0, 15.8 Hz, 1 H), 1.22-1.29 (m, 2 H), 0.90-0.95 (m, 1 H), 0.71-0.76 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 191.5, 156.7, 143.1, 137.8, 127.2, 122.9, 119.5, 112.3, 104.4, 64.3, 38.4, 26.6, 22.5, 15.4, 12.1. GC-MS (t _R = 19.96 min): m/z = 225 (56) [M⁺], 197 (100), 154 (48), 115 (13). HRMS (FAB): m/z [M + H⁺] calcd for C₁₅H₁₆ON: 226.1232; found: 226.1216.
5b: The general procedure was followed with the use of substrate 4b (0.68 g) and product 5b (0.97 g, 81%) was obtained as a orange-brown solid after purification. ¹H NMR (500 MHz, CDCl₃): δ = 7.18 (d, J = 8.2 Hz, 1 H), 7.10 (t, J = 7.5 Hz, 1 H), 6.88 (t, J = 7.4 Hz, 1 H), 6.69 (d, J = 7.4 Hz, 1 H), 4.30 (dd, J = 4.0, 16.4 Hz, 1 H), 2.50 (s, 3 H), 2.47 (t, J = 16.1 Hz, 1 H), 2.18 (dd, J = 3.9, 15.9 Hz, 1 H), 1.86 (s, 3 H), 1.21-1.27 (m, 2 H), 0.90-0.93 (m, 1 H), 0.73-0.76 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 191.7, 153.8, 143.8, 137.8, 127.1, 121.8, 119.3, 111.9, 111.1, 64.0, 39.2, 29.9, 18.7, 14.9, 13.4, 10.6. GC-MS (t _R = 20.02 min): m/z = 239 (100) [M⁺], 211 (90), 196 (20), 182 (35), 168 (88), 129 (18), 115 (29). HRMS (FAB): m/z [M + H⁺] calcd for C₁₆H₁₈ON: 240.1388; found: 240.1388.
5c: The general procedure was followed with the use of substrate 4c (0.97 g) and product 5c (1.09 g, 76%) was obtained as a brown-black solid after purification. ¹H NMR (500 MHz, CDCl₃): δ = 7.50-7.52 (m, 5 H), 6.79 (td, J = 1.0, 7.4 Hz, 1 H), 6.73 (td, J = 1.4, 7.5 Hz, 1 H), 6.65 (dd, J = 1.0, 7.3 Hz, 1 H), 5.71 (d, J = 8.2 Hz, 1 H), 5.38 (s, 1 H), 4.65 (dd, J = 4.0, 15.9 Hz, 1 H), 2.75 (t, J = 16.1 Hz, 1 H), 2.24 (dd, J = 4.0, 16.3 Hz, 1 H), 1.19-1.22 (m, 2 H), 1.08-1.12 (m, 1 H), 0.88-0.91 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 192.4, 157.8, 145.1, 139.5, 135.7, 131.1, 128.0, 127.1, 122.6, 118.5, 116.2, 114.9, 108.8, 66.3, 39.9, 27.0, 16.0, 13.8. GC-MS (t _R = 24.35 min): m/z = 287 (81) [M⁺], 258 (100), 230 (85), 154 (26), 129 (45). HRMS (FAB): m/z [M + H⁺] calcd for C₂₀H₁₈ON: 288.1388; found: 288.1390.
5d: The general procedure was followed with the use of substrate 4d (0.70 g) and product 5d (0.75 g, 66%) was obtained as a yellow solid after purification. ¹H NMR (500 MHz, CDCl₃; enol-keto mixture): δ = 8.15 (d, J = 8.0 Hz, 0.4 H), 7.20 (t, J = 7.5 Hz, 0.6 H), 7.06 (t, J = 7.4 Hz, 0.5 H), 6.97 (td, J = 1.0, 7.6 Hz, 0.9 H), 6.69 (d, J = 7.6 Hz, 0.6 H), 6.65 (t, J = 7.3 Hz, 0.8 H), 6.56 (t, J = 7.0 Hz, 1.6 H), 5.28 (s, 0.1 H), 4.67 (m, 0.5 H), 4.11 (m, 1 H), 3.73 (s, 3.5 H), 2.73 (m, 1 H), 2.51-2.59 (m, 2 H), 1.22-1.39 (m, 3 H), 0.79-1.03 (m, 6.5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 202.5, 167.3, 150.0, 133.3, 127.5, 127.0, 125.0, 118.8, 118.5, 116.0, 108.9, 59.8, 58.8, 52.5, 49.9, 49.5, 46.7, 42.3, 30.2, 28.0, 15.9, 15.5, 14.6, 12.2. GC-MS (t _R = 19.26 min): m/z = 227 (35) [M⁺], 199 (82), 130 (100), 115 (48). HRMS (FAB): m/z [M + H⁺] calcd for C₁₄H₁₄O₂N: 228.1025; found: 228.1013.

14a Revuelta J. Cicchi S. Brandi A. J. Org. Chem.  2005,  70:  5636 

14b Cicchi S. Revuelta J. Zanobini A. Betti M. Brandi A. Synlett  2003,  2305