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Synlett 2004(6): 1023-1026  
DOI: 10.1055/s-2004-822904
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Zoltán Vinczea, Péter Nemes*a, Barbara Balázsb, Gábor Tóthb,c, Pál Scheibera
a Department of Chemistry, Faculty of Veterinary Science, Szent István University, 1400 Budapest, P. O. Box 2, Hungary
b Research Group for Technical Analytical Chemistry of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry, Budapest University of Technology and Economics, 1111 Budapest, Hungary
c IVAX Drug Research Institute Ltd., 1325 Budapest, Hungary
Fax: +36(1)4784268; e-Mail: pnemes@univet.hu;
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Publication History

Received 5 December 2003
Publication Date:
01 April 2004 (online)

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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

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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, Hax-6), 3.42 (dm, 1 H, Heq-6), 2.92 (tm, 1 H, Hax-7), 2.76 (dm, 1 H, Heq-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, Heq-2d), 2.11 (dm, 1 H, Heq-2a), 1.88 (s, 3 H, 4-Me), 1.87 (dm, 1 H, Heq-2b), 1.80 (dm, 1 H, Heq-2c), 1.72 (td, 1 H, Hax-2d), 1.51 (tm, 1 H, Hax-2b), 1.49 (tm, 1 H, Hax-2a), 1.33 (tm, 1 H, Hax-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).