aza-Annulation of Tetrahydroisoquinoline Derived Enamines: Efficient and Convergent Routes to Novel Functionalized Benzo[a]quinolizin-4-ones and Pyrimido[6,1-a]isoquinoline Derivatives

Abstract

The 1,2,3,4-tetrahydroisoquinoline derived push-pull enaminones and nitroenamine have been investigated in aza-annulation reactions with various 1,3-biselectrophiles leading to the synthesis of novel functionalized benzo[a]quinolizin-4-ones and pyrimido[6,1-a]isoquinoline derivatives.

aza-annulations - enamines - 1,3-biselectrophiles - benzo[a]quinolizin-4-ones - pyrimido[6,1-a]isoquinolines

References

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11 Barun O. Mohanta PK. Ila H. Junjappa H. Synlett  2000,  653 

12 Barun O. Chakrabarti S. Ila H. Junjappa H. J. Org. Chem.  2001,  66:  4457 

13 Review on aza-annulation of enamine related substrates: Stille JR. Barta NS. In Studies in Natural Products Chemistry: Stereoselective Synthesis   Vol. 18:  Atta-ur-Rahman; New York: 1996.  p.315 

14

All new compounds gave satisfactory spectral and analytical data.

15

Procedure for aza-Annulation of 1b with 3-Bromo-propionyl Chloride: To a well-stirred solution of enaminone 1b (0.5 g, 1.6 mmol) and Et₃N (0.6 mL, 4 mmol) in dry THF (15 mL) under N₂ atmosphere, 3-bromo-propionyl chloride (0.2 mL, 1.92 mmol) was added slowly through a syringe at 0 °C. The reaction mixture was allowed to stir at r.t. for 2 h and then refluxed gently under N₂ atmosphere for 4 h (monitored by TLC). The solvent was evaporated under reduced pressure and the residue was dissolved in CHCl₃ (20 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (anhyd Na₂SO₄) and concentrated to give the crude residue, which was purified by column chromatography over silica gel using hexane-EtOAc (7:3) as eluent to give pure 4b.
Data for Compound 4b: Yield 72% (0.42 g); red crystalline solid (CHCl₃-hexane); mp 153-154 °C; R_f = 0.2 (7:3 hexane-EtOAc). IR (KBr): 2897, 1666, 1637, 1367 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.67 (t, J = 6.9 Hz, 2 H, CH₂), 2.73-2.78 (m, 4 H, 2 × CH₂), 3.46 (s, 3 H, OCH₃), 3.71 (s, 3 H, OCH₃), 3.76 (t, J = 5.8 Hz, 2 H, NCH₂), 6.48 (s, 1 H, ArH), 6.49 (s, 1 H, ArH), 7.13 (m, 2 H, ArH), 7.25 (m, 1 H, ArH), 7.56 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.36, 28.74, 31.11, 39.37, 55.60, 55.89, 109.89, 113.35, 114.55, 122.19, 128.31, 128.98, 129.91, 132.63, 137.60, 140.16, 146.73, 149.94, 170.08, 197.73. MS (EI): m/z (%) = 364 (19.9) [M + 1⁺], 363 (57.2) [M⁺]. Anal. Calcd for C₂₂H₂₁NO₄ (363.41): C, 72.71; H, 5.82; N, 3.85%. Found: C, 72.89; H, 5.77; N, 3.81%.

16

Procedure for aza-Annulation of 1a with Itaconic Anhydride: A solution of enaminone 1a (0.3 g, 1.3 mmol) and itaconic anhydride (0.15 g, 1.3 mmol) in dry MeCN (15 mL) was refluxed under N₂ atmosphere with stirring for 7 h (monitored by TLC). The reaction mixture was brought to r.t. and the solvent was evaporated under reduced pressure to give a viscous residue which was dissolved in CHCl₃ (20 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (anhyd Na₂SO₄) and evaporated to afford the crude product, which was purified by column chromatography over neutral alumina using hexane-EtOAc (1:9) as eluent to give pure 5a.
Data for Compound 5a: Yield 81% (0.38 g); pale yellow solid; mp 178-179 °C; R_f = 0.5 (EtOAc). IR (KBr): 2938, 1701, 1669, 1639, 1511 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.99 (s, 3 H, CH₃), 2.37 (dd, J = 13.9 Hz, 16.1 Hz, 1 H, =CCHH), 2.57 (dd, J = 5.4 Hz, 16.1 Hz, 1 H, =CCHH), 2.86-3.12 (m, 5 H, CH₂CHCHHCO₂H and benzylic CH ₂), 3.32-3.37 (m, 1 H, NCHH), 3.84 (s, 3 H, OCH₃), 3.95 (s, 3 H, OCH₃), 4.17-4.22 (m, 1 H, NCHH), 6.78 (s, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 27.21, 28.32, 30.59, 34.59, 36.51, 39.68, 56.03, 56.11, 110.09, 113.59, 118.00, 122.0, 130.59, 142.17, 147.29, 151.10, 171.01, 176.40, 201.50. FAB-MS: m/z (%) = 360 (100) [M + 1⁺]. Anal. Calcd for C₁₉H₂₁NO₆ (359.38): C, 63.50; H, 5.89; N, 3.89%. Found: C, 63.62; H, 5.79; N, 3.81%.

17

Data for Compound 7c: Yield 61% (0.28 g); yellow solid; mp 100-101 °C; R_f = 0.25 (8:2 hexane-EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 2.34 (s, 3 H, SCH₃), 2.62 (t, J = 8.0 Hz, 2 H, =CCH₂), 2.79 (dd, J = 5.4 Hz, 8.3 Hz, 2 H, O=CCH₂), 2.87 (t, J = 6.6 Hz, 2 H, CH₂), 3.84 (s, 3 H, OCH₃), 3.87 (s, 3 H, OCH₃), 4.22 (t, J = 6.6 Hz, 2 H, NCH₂), 6.72-6.79 (m, 3 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 18.32, 22.22, 31.28, 34.52, 46.88, 55.84, 55.85, 111.10, 111.91, 120.92, 129.74, 138.52, 147.84, 148.23, 148.82, 169.69. FAB-MS: m/z (%) = 353 (100) [M + 1⁺]. Anal. Calcd for C₁₆H₂₀N₂O₅S (352.41): C, 54.53; H, 5.72; N, 7.95%. Found: C, 54.66; H, 5.81; N, 7.89%.

18

Procedure for TFA Induced Cyclization of 7c to 4c: To a solution of 3,4-dihydropyridin-2-one 7c (0.2 g, 0.6 mmol) in dry CH₂Cl₂ (15 mL), TFA (0.14 mL, 1.8 mmol) was added at r.t. and the reaction mixture was refluxed for 12 h (monitored by TLC). The reaction mixture was poured into ice-cold H₂O (15 mL) and extracted with CH₂Cl₂ (2 × 15 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (anhyd Na₂SO₄) and concentrated to give the crude product, which was purified by column chromatography over silica gel using hexane-EtOAc (8:2) as eluent to give pure 4c.
Data for Compound 4c: Yield 95% (0.17 g); yellow crystals (CHCl₃-hexane); mp 192-193 °C; R_f = 0.23 (8:2 hexane-EtOAc). IR (KBr): 2995, 1686, 1512 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.79 (t, J = 8.3 Hz, 2 H, =CCH₂), 2.84 (t, J = 5.9 Hz, 2 H, CH₂), 3.14 (t, J = 8.3 Hz, 2 H, O=CCH₂), 3.76 (t, J = 5.9 Hz, 2 H, NCH₂), 3.81 (s, 3 H, OCH₃), 3.94 (s, 3 H, OCH₃), 6.71 (s, 1 H, ArH), 6.89 (s, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 22.34, 28.18, 30.27, 39.15, 55.91, 56.06, 109.49, 112.12, 118.89, 128.93, 131.73, 141.45, 147.25, 151.70, 168.71. FAB-MS: m/z (%) = 305 (100) [M + 1⁺]. Anal. Calcd for C₁₅H₁₆N₂O₅ (304.30): C, 59.21; H, 5.30; N, 9.21%. Found: C, 59.29; H, 5.22; N, 9.32%.

19

Procedure for aza-Annulation of 1b with Malonyl Chloride: To a stirred solution of the enaminone 1b (0.5 g, 1.6 mmol) and Et₃N (1.2 mL, 8 mmol) in dry THF (15 mL) under N₂ atmosphere, malonyl chloride (0.3 mL, 3.52 mmol) was added slowly through a syringe at 0 °C. The reaction mixture was allowed to stir at r.t. for 5 h (monitored by TLC). The solvent was evaporated under reduced pressure and the residue was dissolved in CHCl₃ (20 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (anhyd Na₂SO₄) and the solvent evaporated under reduced pressure to give the crude residue, which was purified by column chromatography over silica gel using hexane-EtOAc (7:3) as eluent to give pure 10b.
Data for Compound 10b: Yield 60% (0.43 g); yellow crystalline solid (CHCl₃-hexane); mp 241-242 °C; R_f = 0.26 (7:3 hexane-EtOAc). IR (KBr): 2938, 1726, 1671, 1563, 1536, 1511 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.98 (t, J = 6.0 Hz, 2 H, CH₂), 3.33 (s, 3 H, OCH₃), 3.88 (s, 3 H, OCH₃), 4.29 (m, 2 H, NCH₂), 5.49 (s, 1 H, =CH), 6.74 (s, 1 H, ArH), 6.90 (s, 1 H, ArH), 7.43-7.47 (m, 2 H, ArH), 7.57-7.61 (m, 1 H, ArH), 7.91-7.93 (m, 2 H, ArH), 12.79 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 27.56, 39.91, 55.36, 56.07, 89.73, 99.23, 110.07, 110.39, 112.06, 118.83, 129.17, 129.53, 131.55, 134.57, 136.72, 144.62, 147.99, 152.18, 160.62, 160.80, 162.15, 168.04, 191.54. MS (EI): m/z (%) = 446 (94) [M + 1⁺], 445 (100) [M⁺]. Anal. Calcd for C₂₅H₁₉NO₇ (445.43): C, 67.41; H, 4.30; N, 3.14%. Found: C, 67.22; H, 4.43; N, 3.06%.

20 Harsanyi K. Kiss P. Korbonits D. J. Heterocycl. Chem.  1973,  10:  435 

21a Fülöp F. Wamhoff H. Sohár P. Synthesis  1995,  863 

21b Hermecz I. In Advances in Heterocyclic Chemistry   Vol. 70:  Katritzky AR. Academic Press; New York: 1998.  p.1 

22

Procedure for Cyclocondensation of 1b with Formaldehyde/Aniline: A mixture of formaldehyde (37-40% w/w aq solution, 0.2 mL, 3.2 mmol), aniline (0.15 mL, 1.6 mmol) and enaminone 1b (0.5 g, 1.6 mmol) in MeOH was stirred at r.t. for 4 h (monitored by TLC). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in CHCl₃ (20 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (anhyd Na₂SO₄) and the solvent was evaporated under reduced pressure to give crude oily product which was purified by column chromatography over silica gel using hexane-EtOAc (8:2) as eluent to give pure 11bb.
Data for Compound 11bb: Yield 58% (0.39 g); yellow oil; R_f = 0.25 (8:2 hexane-EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 2.81 (t, J = 6.0 Hz, 2 H, CH₂), 3.39 (t, J = 6.0 Hz, 2 H, NCH₂), 3.55 (s, 3 H, OCH₃), 3.76 (s, 3 H, OCH₃), 4.57 (s, 2 H, NCH₂), 4.88 (s, 2 H, NCH₂N), 6.46 (s, 1 H, ArH), 6.57 (s, 1 H, ArH), 6.85-6.89 (m, 1 H, ArH), 6.99-7.12 (m, 5 H, ArH), 7.23-7.27 (m, 2 H, ArH), 7.38-7.40 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 29.13, 46.13, 51.97, 55.49, 55.75, 67.94, 102.72, 109.59, 115.49, 117.26, 120.42, 121.83, 127.33, 128.94, 129.20, 129.65, 129.93, 141.43, 146.01, 148.50, 150.12, 154.20, 192.54. MS (EI): m/z (%) = 426 (17) [M⁺], 310 (42.1). Anal. Calcd for C₂₇H₂₆N₂O₃ (426.51): C, 76.03; H, 6.14; N, 6.57%. Found: C, 76.18; H, 6.26; N, 6.49%.

23

Procedure for aza-Annulation of 1a with Benzoyl Isothiocyanate: To a well-stirred solution of enaminone 1a (0.5 g, 2 mmol) in dry THF under N₂ atmosphere, benzoyl isothiocyanate (0.27 mL, 2 mmol) was added and the reaction mixture was refluxed for 24 h (monitored by TLC). The solvent was evaporated under reduced pressure and the crude residue was dissolved in CHCl₃ (20 mL). The organic layer was washed with H₂O (2 × 10 mL), dried (anhyd Na₂SO₄) and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography over silica gel using hexane-EtOAc (8:2) as eluent to give pure 12a.
Data for Compound 12a: Yield 63% (0.49 g); yellow solid; mp 240 °C; R_f = 0.35 (8:2 hexane-EtOAc). IR (KBr): 2929, 1703, 1584, 1555 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.49 (s, 3 H, CH₃), 3.04 (t, J = 5.9 Hz, 2 H, CH₂), 3.77 (s, 3 H, OCH₃), 3.92 (s, 3 H, OCH₃), 4.27 (t, J = 5.9 Hz, 2 H, NCH₂), 7.01 (s, 1 H, ArH), 7.22 (s, 1 H, ArH), 7.60 (t, J = 7.7 Hz, 2 H, ArH), 7.69 (t, J = 7.6 Hz, 1 H, ArH), 7.99 (d, J = 7.8 Hz, 2 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 26.30, 31.03, 49.81, 55.76, 56.15, 111.12, 111.36, 116.19, 128.48, 129.92, 130.48, 131.39, 132.17, 133.79, 145.56, 147.87, 153.34, 157.07, 180.96, 201.37. FAB-MS: m/z (%) = 393 (100) [M + 1⁺]. Anal. Calcd for C₂₂H₂₀N₂O₃S (392.47): C, 67.33; H, 5.14; N, 7.14%. Found: C, 67.45; H, 5.08; N, 7.22%.