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Synlett 2010(8): 1209-1214  
DOI: 10.1055/s-0029-1219792
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Convenient Stereoselective Synthesis of trans-4a,5,8,8a-Tetrahydro-2H-isoquinolin-1-ones via trans 3-Allylation of 4-Allyl-3,4-dihydropyridine-2-thiones and RCM as Key Steps

Jacek G. Sośnicki*, Łukasz Struk
West Pomeranian University of Technology, Institute of Chemistry and Environmental Protection, Al. Piastów 42, 71065 Szczecin, Poland
Fax: +48(91)4494639; e-Mail: sosnicki@zut.edu.pl;
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Received 18 January 2010
Publication Date:
25 March 2010 (online)

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Abstract

A convenient synthesis of trans-4a,5,8,8a-tetrahydro-2H-isoquinolin-1-ones from 4-allyl-3,4-dihydro-1H-pyridine-2-thiones via stereoselective alkylation at C-3 (trans with respect to 4-allyl substituent), subsequent N-alkylation (optionally for NH derivatives) followed by ring-closing metathesis (RCM) of corresponding trans-3,4-diallyl-3,4-dihydro-1H-pyridine-2-ones is described. The high synthetic potential of the obtained bicyclic pi­peridinones, exemplified by the synthesis of threecyclic [1,3]oxazino[3,2-b]isoquinolin-6-one via N-acyliminum cation, is presented.

Key words

4a,5,8,8a-tetrahydro-2H-isoquinolin-1-ones - stereo­selective trans-alkylation - δ-(thio)lactams - N-acyliminum cation - RCM

    References and Notes

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  • 18 Typical Procedure for the Synthesis of N-Substituted δ-Lactams 5f-h from NH δ-Thiolactams 3a-c To a stirred mixture of 3a-c (1.77 mmol) and DBU (27.3 mg, 0.18 mmol) in MeCN (5 mL) a portion of ethyl acrylate (0.25 mL, 2.3 mmol) was added. The mixture was stirred for 1-1.5 h (TLC control) at r.t. After addition of aq sat. NH4Cl (5 mL), the solution was extracted with EtOAc (2 × 80 mL), and the combined organic layers were dried over MgSO4. Filtration, concentration in vacuo, and purification by column chromatography (silica gel, n-hexane-EtOAc = 8:2 to 7:3) afforded 3k-m as oils.To a solution of δ-thiolactam 3 (1.42 mmol) in acetone (20.5 mL) and H2O (2 mL), NaHCO3 (0.54g, 6.4 mmol) was added at 0-2 ˚C. To a stirred and still cooled suspension Oxone® (215 mg, 0.7 mmol) was added. After 15 min of stirring the next 5 portions of Oxone® (107 mg, 0.35 mmol were added at 15 min intervals. After addition of the last portion of Oxone® the solution was stirred for additional 30 min at 0-2 ˚C, cold H2O (20 mL) was added, and the solution was stirred for additional 30 min at 0 ˚C and warmed to r.t. (30 min) The solution was extracted with EtOAc (3 × 50 mL). The organic phase separated was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel. Selected Spectroscopic Data 3-[(3 RS ,4 SR )-4-Allyl-3-(2-methylallyl)-2-oxo-3,4-dihydro-2 H -pyridin-1-yl]-propionic Acid Ethyl Ester (5g) Colorless oil. IR (film): ν = 3076, 2980, 2940, 1736, 1664, 1448, 1390 (br), 1184 (br), 1020, 894, 720 cm-¹. MS (EI, 70eV): m/z = 291 (14) [M+], 290 (13), 250 (85), 246 (24), 235 (14), 204 (35), 162 (37), 155 (15), 150 (100), 134 (16), 122 (15), 109 (11), 96 (24), 73 (12), 55 (71). ¹H NMR (400.1 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.2 Hz, CH2CH 3), 1.72 (3 H, br s, CH3), 1.97-2.14 (2 H, m, 4-CH2), 2.15-2.30 (3 H, m, 3-CH2, CH-4), 2.52-2.62 (3 H, m, CH-3, COCH2), 3.66 (1 H, dt, J = 13.8, 6.6 Hz, NCHH), 3.77 (1 H, dt, J = 13.8, 6.7 Hz, NCHH), 4.14 (2 H, quart, J = 7.2 Hz, OCH2), 4.66 (1 H, br s, =CHH), 4.98-5.08 (3 H, m, =CH2, =CH-5), 4.80 (1 H, br s, =CHH), 5.62-5.74 (1 H, m, =CH), 6.07 (1 H, d, J = 7.7 Hz, =CH-6). ¹³C NMR (100.6 MHz, CDCl3): δ = 14.19 (CH2 CH3), 21.72 (CH3), 33.41 (COCH2), 34.96 (CH-4), 38.44 (4-CH2), 38.77 (3-CH2), 42.97 (NCH2), 43.92 (CH-3), 60.69 (OCH2), 107.59 (=CH-5), 113.30, 117.39 (2 × =CH2), 128.88 (=CH-6), 135.00 (=CH), 142.38 (=CCH3), 171.28, 171.75 (2 × C=O). Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.99; H, 8.61; N, 4.89.
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  • 21 Typical Synthesis of (4a RS ,8a SR )-4a,5,8,8a-tetrahydro-2 H -isoquinolin-1-ones (6a-i,j,l) To a solution of 3,4-diallyl substituted δ-lactam 5 (0.65 mmol) in dry, degassed toluene (7 mL) ruthenium catalyst 7 was added (Table 2), and the reaction mixture was vigorously stirred under slowly passing stream of argon at 70 ˚C. After the reaction was complete (Table 2), toluene was evaporated at reduced pressure, and the residue was left standing for 48 h followed by purification on column chromatography. Selected Spectroscopic Data 3-[(4a SR ,8a RS )-7-Methyl-1-oxo-4a,5,8,8a-tetrahydro-1 H -isoquinolin-2-yl]-propionic Acid Ethyl Ester (6g) Colorless oil. IR (film): ν = 2964, 2912, 2840, 1734, 1666, 1446, 1392, 1296, 1266, 1184, 1054, 790 cm-¹. MS (EI, 70eV): m/z (%) = 263 (100) [M+], 234 (32), 218 (27), 195 (38), 176 (26), 162 (33), 148 (19), 146 (23), 132 (14), 123 (22), 105 (14), 95 (35), 91 (25), 80 (19), 67 (14), 55 (26), 41 (10), 29 (23). ¹H NMR (400.1 MHz, CDCl3): δ = 1.25 (3 H, t, J = 7.1 Hz, CH2CH 3), 1.70 (3 H, br s, 7-CH3), 1.90-2.01 (1 H, m, CHH), 2.08-2.46 (5 H, m, CHH, CH2, CH-8a, CH-4a), 2.54-2.68 (2 H, m, COCH2), 3.67 (1 H, dt, J = 13.8, 6.7 Hz, NCHH), 3.81 (1 H, dt, J = 13.8, 6.8 Hz, NCHH), 4.14 (2 H, quart, J = 7.1 Hz, OCH2), 4.97 (1 H, br d, J = ca. 7.7 Hz, =CH-4), 5.36 (1 H, br s, =CH-6), 6.09 (1 H, dd, J = 7.7, 2.7 Hz, =CH-3). ¹³C NMR (100.6 MHz, CDCl3): δ = 14.2 (CH3), 23.4 (7-CH3), 31.0 (CH2-5), 31.6 (CH2-8), 32.6 (CH-4a), 33.5 (COCH2), 41.7 (CH-8a), 42.9 (NCH2), 60.7 (OCH2), 111.2 (=CH-4), 119.4 (=CH-6), 129.1 (=CH-3), 133.8 (=C-7), 171.5, 171.8 (2 × C=O). HRMS (EI): m/z calcd for C15H21NO3: 263.1521; found: 263.1521.
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24

MM2 calculations were performed using the HyperChem program (7.52 release).