Pd-Catalyzed Cyclization of 1-Allyl-2-indolecarboxamides by Intramolecular Amidation of Unactivated Ethylenic Bond

Abstract

The intramolecular Pd(II)-mediated cyclization of 1-allyl-2-indolecarboxamides leads to pyrazino[1,2-a]indoles through the conversion of the olefinic C-H bond into a C-N bond by ­reaction with an amide group. When operating on the allylamide, a domino process was observed with a double C-H functionalization.

cyclizations - fused-ring systems - indoles - palladium - domino reactions

References and Notes

For reviews, see:

1a Wolfe JP. Wagaw S. Marcoux J.-F. Buchwald SL. Acc. Chem. Res.  1998,  31:  805 

1b Hartwig JF. Angew. Chem. Int. Ed.  1998,  37:  2046 

2a Sigman MS. Schultz MJ. Org. Biomol. Chem.  2004,  2:  2551 

2b Bar GLJ. Lloyd-Jones GC. Booker-Milburn KI. J. Am. Chem. Soc.  2005,  127:  7308 

2c Brice JL. Harang JE. Timokhin VI. Anastasi NR. Stahl SS. J. Am. Chem. Soc.  2005,  127:  2868 

2d Timokhin VI. Anastasi NR. Stahl SS. J. Am. Chem. Soc.  2003,  125:  12996 

2e Gowan M. Caillé AS. Lau CK. Synlett  1997,  1312 

2f Andersson PG. Bäckvall J.-E. J. Am. Chem. Soc.  1992,  114:  8696 

2g Bäckvall J.-E. Andersson PG. J. Am. Chem. Soc.  1990,  112:  3683 

2h Pugin B. Venanzi LM. J. Am. Chem. Soc.  1983,  105:  6877 

2i Hegedus LS. Allen GF. Bozell JJ. Waterman EL. J. Am. Chem. Soc.  1978,  100:  5800 

3 Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry, A Guide for the Synthetic Chemist   Pergamon; New York: 2000. 

For recent contributions, see:

4a Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 

4b Capito E. Brown JM. Ricci A. Chem. Commun.  2005,  1854 

4c Grimster NP. Gauntlett C. Godfrey CRA. Gaunt MJ. Angew. Chem. Int. Ed.  2005,  44:  3125 

4d Cacchi S. Fabrizi G. Parisi LM. Synthesis  2004,  1889 

4e Siebeneicher H. Bytschkov I. Doye S. Angew. Chem. Int. Ed.  2003,  42:  3042 

4f Willis MC. Brace GN. Holmes IP. Angew. Chem. Int. Ed.  2005,  44:  403 

4g Watanabe T. Arai S. Nishida A. Synlett  2004,  907 

5a Sundberg RJ. Indoles   Academic Press; London: 1996. 

5b Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 

5c Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  1999,  2848 

5d Gribble GW. J. Chem. Soc., Perkin Trans. 1  2000,  1045 

5e Bräse S. Gil C. Knepper K. Bioorg. Med. Chem.  2002,  10:  2415 

6a Beccalli EM. Broggini G. Marchesini A. Rossi E. Tetrahedron  2002,  58:  6673 

6b Beccalli EM. Broggini G. Tetrahedron Lett.  2003,  44:  1919 

6c Abbiati G. Beccalli EM. Broggini G. Zoni C. J. Org. Chem.  2003,  68:  7625 

6d

Abbiati, G.; Beccalli, E. M.; Broggini, G.; Paladino, G.; Rossi, E. Synthesis, in press.

7a Tiwari RK. Singh J. Singh D. Verma AK. Chandra R. Tetrahedron  2005,  61:  9513 

7b Abbiati G. Arcadi A. Bellinazzi A. Beccalli EM. Rossi E. Zanzola S. J. Org. Chem.  2005,  70:  4088 

8a Ruppelt M, Bartel S, Guarnieri W, Raddatz S, Rosentreter U, Wild H, Endermann R, and Kroll HP. inventors; Ger. Offen. DE  19802235.  ; Chem. Abstr. 1999, 131, 129985

9a Davis PD, Hill CH, and Lawton G. inventors; Eur. Pat.  384349.  ; Chem. Abstr. 1991, 114, 81582p

9b Bit RA. Davis PD. Elliott LH. Harris W. Hill CH. Keech E. Kumar H. Lawton G. Maw A. Nixon JS. Vesey DR. Wadsworth J. Wilkinson SE. J. Med. Chem.  1993,  36:  21 

10 Wyss PC. Gerber P. Hartman PG. Hubschwerlen C. Locher H. Marty H.-P. Stahl M. J. Med. Chem.  2003,  46:  2304 

11 McCort G, Hoornaert C, Duclos O, Guilpain E, Cadilhac C, and Dellac G. inventors; Fr. Patent FR 2 761  073.  ; Chem. Abstr. 1999, 130, 384000

12 Tapia RA. Prieto Y. Pautet F. Domard M. Sarciron M.-E. Walchshofer N. Fillion H. Eur. J. Org. Chem.  2002,  4005 

13 Vigushin DM. Brooke G. Willows D. Coombes RC. Moody CJ. Bioorg. Med. Chem. Lett.  2003,  13:  3661 

14 Chang-Fong J. Addo J. Dukat M. Smith C. Mitchell NA. Herrick-Davis K. Teitler M. Glennon RA. Bioorg. Med. Chem. Lett.  2002,  12:  155 

15 Padwa A. Hertzog DL. Nadler WR. Osterhout MH. Price AT. J. Org. Chem.  1994,  59:  1418 

16

Experimental Procedure.
A suspension of 2a (276 mg, 1.0 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), Na₂CO₃ (318 mg, 3.0 mmol), Bu₄NCl (278 mg, 1.0 mmol) and p-benzoquinone (108 mg, 1 mmol) in DMF (10 mL) was stirred for 24 h at 100 °C. The solution was washed with brine (25 mL) and extracted with Et₂O (2 × 25 mL). The organic layer was dried over Na₂SO₄ and taken to dryness under reduced pressure. The residue was chromatographed on a silica gel column with light PE-EtOAc 12:1 as eluent to give 3a.
Data for 3-Methyl-2-phenyl-2 H -pyrazino[1,2- a ]indol-1-one (3a).
Mp 249-250 °C (diisopropyl ether). IR (nujol): 1682 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.95 (3 H, s), 7.24 (1 H, s), 7.29-7.34 (3 H, m), 7.39-7.45 (2 H, m), 7.48-7.56 (3 H, m), 7.68 (1 H, d, J = 8.2 Hz), 7.85 (1 H, d, J = 8.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7 (q), 103.5 (d), 104.1 (d), 110.8 (d), 122.6 (d), 123.0 (s), 123.1 (d), 124.3 (d), 127.4 (s), 128.0 (s), 129.1 (d), 129.4 (d), 129.9 (d), 132.3 (s), 137.9 (s), 158.4 (s). MS: m/z = 274 [M⁺]. Anal. Calcd for C₁₈H₁₄N₂O: C, 78.81; H, 5.14; N, 10.21. Found: C, 78.97; H, 4.99; N, 10.32.

17 Jeffery T. Tetrahedron  1996,  30:  10113 

18

3-Methyl-2-(pyridin-2-yl)-3,4-dihydro-2 H -pyrazino[1,2- a ]indol-1-one (8).
Mp 198-199 °C (diisopropyl ether). IR (nujol): 1678 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.46 (3 H, d, J = 6.7 Hz), 4.32 (1 H, d, J = 12.0 Hz), 4.44 (1 H, dd, J = 4.0, 12.0 Hz), 5.43-5.51 (1 H, m), 7.13 (1 H, dd, J = 5.0, 7.0 Hz), 7.18-7.24 (1 H, m), 7.34-7.44 (2 H, m), 7.45 (1 H, s), 7.71-7.80 (2 H, m), 8.17 (1 H, d, J = 8.4 Hz), 8.47 (1 H, d, J = 4.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 19.3 (q), 46.4 (t), 51.5 (d), 107.9 (d), 110.1 (d), 120.1 (d), 120.7 (d), 121.2 (d), 123.2 (d), 125.3 (d), 128.0 (s), 129.2 (s), 137.3 (s), 137.7 (d), 148.1 (d), 152.9 (s), 159.7 (s). MS: m/z = 277 [M⁺]. Anal. Calcd for C₁₇H₁₅N₃O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.51; H, 5.27; N, 15.01.

19 Chacun-Lefèvre L. Bénéteau V. Joseph B. Mérour J.-Y. Tetrahedron  2002,  58:  10181 

20

2-Methyl-12,12a-dihydro-1 H -pyrrolo[1′,2′:4,5]pyr-azino[1,2- a ]indol-5-one (10).
Oil. IR (nujol): 1657 cm^-1. ¹H NMR (400 MHz, DMSO): δ = 1.83 (3 H, s), 2.59-2.69 (1 H, m), 2.78 (1 H, dd, J = 9.2, 15.9 Hz), 3.97 (1 H, dd, J = 12.1, 12.2 Hz), 4.52-4.65 (1 H, m), 4.92 (1 H, dd, J = 4.4, 12.1 Hz), 6.80 (1 H, s), 7.08 (1 H, s), 7.12 (1 H, dd, J = 7.7, 8.3 Hz), 7.31 (1 H, dd, J = 7.7, 8.0 Hz), 7.57 (1 H, d, J = 8.3 Hz), 7.67 (1 H, d, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO): δ = 14.4 (q), 38.8 (t), 45.9 (t), 57.5 (d), 106.6 (d), 109.9 (d), 116.6 (d), 121.1 (d), 122.6 (s), 123.2 (d), 125.0 (d), 128.0 (s), 129.6 (s), 136.8 (s), 169.7 (s). MS: m/z 238 [M⁺]. Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.79; H, 6.01; N, 11.92.

21a Kasahara A. Izumi T. Murakami S. Miyamoto K. Hino T. J. Heterocycl. Chem.  1989,  26:  1405 

21b Izumi T. Nishimoto Y. Kohei K. Kasahara A. J. Heterocycl. Chem.  1990,  27:  1419 

22a Alexanian EJ. Lee C. Sorensen EJ. J. Am. Chem. Soc.  2005,  127:  7690 

22b Beccalli EM. Broggini G. Paladino G. Penoni A. Zoni C. J. Org. Chem.  2004,  69:  5627 

22c Fix SR. Brice JL. Stahl SS. Angew. Chem. Int. Ed.  2002,  41:  164 

22d Larock RC. Hightower TR. Hasvold LA. Peterson KP. J. Org. Chem.  1996,  61:  3584 

22e Rönn M. Bäckvall J.-E. Andersson PG. Tetrahedron Lett.  1995,  36:  7749 

22f Hegedus LS. McKearin JM. J. Am. Chem. Soc.  1982,  104:  2444