Cerium(III)-Catalyzed Cyclizations with 1-Cyanomethylene Tetrahydroisoquinoline: Substituent Controlled Formation of Fused Pyrroles or Pyridines

Abstract

1-Cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline reacts with α,β-unsaturated aldehydes and ketones in presence of cerium(III) chloride, to yield benzo[a]quinolizines. α-Alkyl substituted unsaturated aldehydes under the same conditions, however, afford pyrrolo[2,1-a]isoquinolines.

Key words

β-enaminonitrile - cyclization - cerium(III) chloride - pyrrolo[2,1-a]isoquinolines - benzo[a]quinolizines

References

• 1 Erian AW. Chem. Rev.  1993,  93:  1991 
• 2 O’Callaghan CN. Conlon DMA. Cardin CJ. J. Chem. Res., Synop.  1988,  288 
• 3 Yamaguchi Y. Katsumaya I. Funabiki K. Matsui M. Shibata K. J. Heterocycl. Chem.  1988,  35:  805 
• 4 Openshaw HT. Whittaker N. J. Chem. Soc.  1961,  4939 
• 5 Nemes P. Balázs B. Tóth G. Scheiber P. Synlett  1999,  222 
• 6 Nemes P. Vincze Z. Balázs B. Tóth G. Scheiber P. Synlett  2003,  250 
• 7 Kobayashi S. Synlett  1994,  689 
• 8 Kotsuki H. Arimura K. Tetrahedron Lett.  1997,  38:  7583 
• 9 Imamoto T. Lanthanides in Organic Synthesis   Academic Press; New York: 1994. 
• 10 Christoffers J. Eur. J. Org. Chem.  1998,  1259 
• 11 Boruah A. Baruah M. Prajapati D. Sandhu JS. Synth. Commun.  1998,  28:  653 
• 12 Bartoli G. Bosco M. Bellucci MC. Marcantoni E. Sambri L. Torregiani E. Eur. J. Org. Chem.  1999,  617 
• 14 Christoffers J. Werner T. Unger S. Frey W. Eur. J. Org. Chem.  2003,  425 

13

Preparation of Compounds 4a-e: Cerium(III) chloride heptahydrate (37 mg, 0.1 mmol) was added to stirred solution of 1 (230 mg, 1 mmol) and carbonyl compound (1 mmol) in MeCN (8 mL). The mixture was then stirred for 5-10 h at r.t. MeCN was evaporated under reduced pressure, and the residue was treated with CH₂Cl₂ (15 mL). The catalyst was then removed by filtration and rinsed with CH₂Cl₂. The combined solutions were concentrated under reduced pressure, and the crude product was purified by flash chromatography (hexane-EtOAc, 5:1).

15

Preparation of Compounds 5a-c, 6a,b: Compound 1 (230 mg, 1 mmol) of was dissolved in MeCN (8 mL). Carbonyl compound (1 mmol) and cerium(III) chloride heptahydrate (37 mg, 0.1 mmol) were added, and the mixture was then stirred for 6-10 h at r.t., under simultaneous, slow passing of oxygen (ca. 60 mL/h) through the mixture. MeCN was evaporated under reduced pressure. The residue was treated under stirring with CH₂Cl₂ (15 mL) and the catalyst was removed by filtration and rinsed with CH₂Cl₂. The filtered extracts were concentrated under reduced pressure, and then the crude product was purified by flash chromatography (hexane-EtOAc, 5:1).

16

NMR spectra were recorded at 300 K in CDCl₃ at 500/125 MHz on a Bruker-Avance DRX-500 instrument.
4a: ¹H NMR: δ = 7.84 (s, 1 H, H-11), 6.65 (s, 1 H, H-8), 4.47 (s, 1 H, H-3), 3.96 (s, 3 H, 10-MeO), 3.90 (s, 3 H, 9-MeO), 2,77 (t, 2 H, H₂-7), 3.49 (t, 2 H, H₂-6), 1.93 (s, 3 H, 4-Me), 1.26 (s, 6 H, 2-Me₂), ¹³C NMR: δ = 150.0 (C-9), 147.1 (C-10), 147.0 (C-11b), 132.6 (C-4), 129.9 (C-7a), 122.6 (1-CN), 121.6 (C-11a), 111.4 (C-11), 109.8 (C-8), 109.7 (C-3), 84.1 (C-1), 56.3 (10-MeO), 56.0 (9-MeO), 42.7 (C-6), 32.0 (C-2), 31.2 (2-Me₂), 29.6 (C-7), 19.4 (4-Me). 4b: ¹H NMR: δ = 7.83 (s, 1 H, H-11), 6.65 (s, 1 H, H-8), 4,28 (s, 1 H, H-3), 3.96 (s, 3 H, 10-MeO), 3.90 (s, 3 H, 9-MeO), 3.46 (t, 2 H, H₂-6), 2.76 (t, 2 H, H₂-7), 2.24 (q, 2 H, 4-CH ₂ -CH₃), 1.65 (q, 2 H, 2-CH ₂ -CH₃), 1.27 (s, 3 H, 2-Me), 0.94 (s, 3 H, 4-CH₂-CH ₃ ), 0.91 (s, 3 H, 2-CH₂-CH ₃ ). ¹³C NMR: δ = 150.1 (C-9), 148.3 (C-11b), 147.2 (C-10) 139.4 (C-4), 130.1 (C-7a), 122.8 (1-CN), 122.1 (C-11a), 111.7 (C-11), 109.9 (C-8), 106.4 (C-3), 82.5 (C-1), 56.5 (10-MeO), 56.2 (9-MeO), 42.4 (C-6), 36.3 (C-2), 35.8 (2-CH ₂ -CH₃), 31.0 (2-Me), 29.9 (C-7), 25.6 (4-CH ₂ -CH₃ ), 13.4 (4-CH₂-CH ₃ ), 9.9 (2-CH₂-CH ₃ ). 4c: ¹H NMR: δ = 7.87 (s, 1 H, H-11), 7.40 (d, 2 H, 2-Ph), 7.38 (t, 2 H, 2-Ph), 7.37 (d, 2 H, 4-p-Cl-C₆H₄), 7.29 (d, 2 H, 4-p-Cl-C₆H₄), 7.28 (t, 1 H, 2-Ph), 6.65 (s, 1 H, H-8), 4.94 (d, 1 H, H-3), 4.44 (d, 1 H, H-2), 3.93 (s, 3 H, 10-MeO), 3.89 (s, 3 H, 9-MeO), 3.48 (t, 2 H, H₂-6), 2.76 (t, 2 H, H₂-7). ¹³C NMR: δ = 150.3 (C-9), 147.3 (C-10), 147.2 (C-11b), 145.3 (C-4), 139.7 (2-Ph), 134.6 (4-p-ClC₆H₄), 134.6 (4-p-Cl-C₆H₄), 129.7 (4-p-Cl-C₆H₄), 128.7 (4-p-Cl-C₆H₄), 129.7 (C-7a), 128.8 (2-Ph), 127.4 (2-Ph), 127.1 (2-Ph), 123.0 (1-CN), 121.2 (C-11a), 110.9 (C-11), 110.0 (C-8), 106.4 (C-3), 79.2 (C-1), 56.0 (9-MeO), 56.3 (10-MeO), 45.5 (C-6), 42.2 (C-2), 29.7 (C-7). 4d: ¹H NMR: δ = 7.82 (s, 1 H, H-11), 7.36 (tm, 2 H, 2-Ph), 7.36 (dm, 2 H, 2-Ph), 7.26 (tm, 2 H, 2-Ph), 6.65 (s, 1 H, H-8), 6.08 (d, 1 H, H-4), 4.85 (dd, 1 H, H-3), 4.40 (d, 1 H, H-2), 3.89 (s, 3 H, 9-MeO), 3.89 (s, 3 H, 10-MeO), 3.51 (tm, 1 H, H_ax-6), 3.42 (dm, 1 H, H_eq-6), 2.92 (tm, 1 H, H_ax-7), 2.76 (dm, 1 H, H_eq-7). ¹³C NMR: δ = 150.3 (C-9), 147.3 (C-10), 146.0 (C-11b), 145.4 (2-Ph), 129.9 (C-7a), 129.7 (C-4), 128.7 (2-Ph), 127.6 (2-Ph), 127.0 (2-Ph), 123.6 (1-CN), 120.2 (C-11a), 111.1 (C-11), 110.2 (C-8), 103.6 (C-3), 76.7 (C-1), 56.2 (10-MeO), 55.9 (9-MeO), 48.7 (C-6), 42.6 (C-2), 29.5 (C-7). 4e: ¹H NMR: δ = 7.77 (s, 1 H, H-11), 6.64 (s, 1 H, H-8), 3.95 (s, 3 H, 10-MeO), 3.90 (s, 3 H, 9-MeO), 3.47 (m, 2 H, H₂-6), 3.21 (dd, 1 H, H-2), 2.76 (t, 2 H, H₂-7), 2.55 (dt, 1 H, H_eq-2d), 2.11 (dm, 1 H, H_eq-2a), 1.88 (s, 3 H, 4-Me), 1.87 (dm, 1 H, H_eq-2b), 1.80 (dm, 1 H, H_eq-2c), 1.72 (td, 1 H, H_ax-2d), 1.51 (tm, 1 H, H_ax-2b), 1.49 (tm, 1 H, H_ax-2a), 1.33 (tm, 1 H, H_ax-2c). ¹³C NMR: δ = 150.0 (C-9), 147.3 (C-11b), 147.0 (C-10), 129.7 (C-7a), 125.3 (C-4), 123.8 (1-CN), 121.9 (C-11a), 113.8 (C-3), 111.2 (C-11), 109.5 (C-8), 87.4 (C-1), 56.3 (10-MeO), 55.9 (9-MeO), 43.0 (C-6), 39.6 (C-2), 35.8 (C-2a), 30.6 (C-2d), 28.0 (C-2c), 29.7 (C-7), 26.6 (C-2b), 14.3 (4-Me). 5b: ¹H and ¹³C NMR data see Scheme [4] . 5a: ¹H NMR: δ = 7.71 (s, 1 H, H-10), 6.71 (s, 1 H, H-7), 3.96 (s, 3 H, 9-MeO), 3.91 (s, 3 H, 8-MeO), 3.91 (t, 2 H, H₂-5), 3.00 (t, 2 H, H₂-6), 2.57 (q, 2 H, H₂-2a), 2.17 (s, 3 H, 3-Me), 1.21 (t, 3 H, H₃-2b). ¹³C NMR: δ = 148.6 (C-8), 148.6 (C-9), 134.4 (C-6a), 125.6 (C-2), 124.7 (C-3), 123.8 (C-10b), 120.4 (C-10a), 118.6 (1-CN), 111.1 (C-7), 106.8 (C-10), 86.4 (C-1), 56.3 (9-MeO), 56.2 (8-MeO), 41.2 (C-5), 28.6 (C-6), 18.6 (C-2a), 15.8 (C-2b), 9.6 (3-Me). 5c: ¹H NMR: δ = 7.72 (s, 1 H, H-10), 6.73 (s, 1 H, H-7), 6.18 (s, 1 H, H-2), 3.96 (s, 3 H, 9-MeO), 3.93 (q, 2 H, H₂-3a), 3.91 (s, 3 H, 8-MeO), 3.01 (dd, 2 H, H₂-5), 2.57 (dd, 2 H, H₂-6), 1.26 (t, 3 H, H₃-3b). ¹³C NMR: δ = 148.9 (C-8), 148.7 (C-9), 135.6 (C-6a), 135.2 (C-3), 124.0 (C-10b), 120.4 (C-10a), 119.0 (1-CN), 111.1 (C-7), 108.8 (C-2), 106.9 (C-10), 85.8 (C-1), 56.2 (8-MeO), 56.1 (9-MeO), 41.1 (C-5), 28.7 (C-6), 19.5 (C-3a), 12.7 (C-3b). 6a: ¹H NMR: δ = 7.69 (s, 1 H, H-10), 6.71 (s, 1 H, H-7), 3.96 (s, 3 H, 9-MeO), 3.90 (s, 3 H, 8-MeO), 3.88 (t, 2 H, H₂-5), 2.98 (m, 2 H, H₂-6), 2.85, 2.74 (dd + m, 1 + 1 H, H₂-2a), 2.73, 1.43 (m + m, 1 + 1 H, H₂-2e), 2.34 (tt, 1 H, H-2b), 2.75 (m, 1 H, H-2d), 1.42 (s, 3 H, 2c-Me), 0.69 (s, 3 H, 2c-Me). ¹³C NMR: δ = 148.5 (C-9), 148.1 (C-8), 138.7 (C-3), 132.9 (C-6a), 123.2 (C-10b), 120.8 (C-10a), 118.4 (1-CN), 117.1 (C-2), 111.1 (C-7), 106.3 (C-10), 85.0 (C-1), 56.1 (9-MeO), 56.0 (8-MeO), 42.1 (C-2c), 41.7 (C-2b), 40.9 (C-5), 39.4 (C-2d), 33.2 (C-2e), 28.6 (C-6), 26.4 (2c-Me), 25.9 (C-2a), 21.5 (2c-Me). 6b: ¹H NMR δ = 7.68 (s, 1 H, H-10), 6.72 (s, 1 H, H-7), 3.95 (s, 3 H, 9-MeO), 3.90 (s, 3 H, 8-MeO), 3.86 (t, 2 H, H₂-5), 2.98 (t, 2 H, H₂-6), 2.59 (m, 2 H, H₂-2a), 2.51 (m, 2 H, H₂-2d), 1.85 (m, 2 H, H₂-2c), 1.78 (m, 2 H, H₂-2b). ¹³C NMR: δ = 148.7 (C-8), 148.7 (C-9), 134.4 (C-6a), 128.3 (C-3), 123.9 (C-10b), 121.6 (C-2), 120.5 (C-10a), 118.5 (1-CN), 111.3 (C-7), 106.9 (C-10), 85.4 (C-1), 56.3 (9-MeO), 56.2 (8-MeO), 40.8 (C-5), 28.6 (C-6), 23.2 (C-2b), 22.9 (C-2c), 21.8 (C-2a), 21.5 (C-2d).