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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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Publikationsverlauf

Received 18 January 2010
Publikationsdatum:
25. März 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

  • 1 Rubiralta M. Giralt E. Diez A. Piperidines. Structure, Preparation, Reactivity and Synthetic Application of Piperidines and its Derivatives   Elsevier; Amsterdam: 1991. 
    Google Scholar
  • For selected examples, see:
  • 2a Vuckovic S. Prostran M. Ivanovic M. Dosen-Micovic Lj. Todorovic Z. Nesic Z. Stojanovic R. Divac N. Mikovic Z. Curr. Med. Chem.  2009,  16:  2468 
    Google Scholar
  • 2b Kaellstroem S. Leino R. Bioorg. Med. Chem.  2008,  16:  601 
    Google Scholar
  • 2c Carroll FI. Chaudhari S. Thomas JB. Mascarella SW. Gigstad KM. Deschamps J. Navarro HA. J. Med. Chem.  2005,  48:  8182 
    Google Scholar
  • 2d Leung D. Abbenante G. Fairlie DP. J. Med. Chem.  2000,  43:  305 
    Google Scholar
  • 2e Vacher B. Bonnaud B. Funes P. Jubault N. Koek W. Assie MB. Cosi C. Kleven M. J. Med. Chem.  1999,  42:  1648 
    Google Scholar
  • 2f Webber RK. Metz S. Moore WM. Connor JR. Currie MG. Fok KF. Hagen TJ. Hansen DW. Jerome GM. Manning PT. Pitzele BS. Toth MV. Trivedi M. Zupec ME. Tjoeng FS. J. Med. Chem.  1998,  41:  96 
    Google Scholar
  • 2g Babine RE. Bender SL. Chem. Rev.  1997,  97:  1359 
    Google Scholar
  • For recent reviews on synthesis of functionalized piperidines, see:
  • 3a De Risi C. Fanton G. Pollini GP. Trapella C. Valente F. Zanirato V. Tetrahedron: Asymmetry  2008,  19:  131 
    Google Scholar
  • 3b Koulocheri SD. Pitsinos EN. Haroutounian SA. Curr. Org. Chem.  2008,  12:  1454 
    Google Scholar
  • 3c Remuson R. Gelas-Mialhe Y. Mini-Rev. Org. Chem.  2008,  5:  193 
    Google Scholar
  • 3d Escolano C. Amat M. Bosch J. Chem. Eur. J.  2006,  12:  8198 
    Google Scholar
  • 3e Pearson MSM. Mathé-Allainmat M. Fargeas V. Lebreton J. Eur. J. Org. Chem.  2005,  2159 
    Google Scholar
  • 3f Cossy J. Chem. Rec.  2005,  5:  70 
    Google Scholar
  • 3g Buffat MGP. Tetrahedron  2004,  60:  1701 
    Google Scholar
  • 3h Weintraub PM. Sabol JS. Kane JM. Borcherding DR. Tetrahedron  2003,  59:  2953 
    Google Scholar
  • 3i Bates R. Sa-Ei K. Tetrahedron  2002,  58:  5957 
    Google Scholar
  • 3j Laschat S. Dickner T. Synthesis  2000,  1781 
    Google Scholar
  • 4 Jagodziński TS. Chem. Rev.  2003,  103:  197 
    CrossrefGoogle Scholar
  • 5 See, for example: Bélanger G. Larouche-Gauthier R. Ménard F. Nantel M. Barabé F. Org. Lett.  2005,  7:  4431 
    CrossrefGoogle Scholar
  • 6 Sośnicki JG. Synlett  2003,  1673 
    Artikel in Thieme ConnectGoogle Scholar
  • 7a Sośnicki JG. Tetrahedron Lett.  2006,  47:  6809 
    Google Scholar
  • 7b Sośnicki JG. Synlett  2009,  2508 
    Google Scholar
  • 8 Sośnicki JG. Tetrahedron  2007,  63:  11862 
    CrossrefGoogle Scholar
  • 9 Sośnicki JG. Struk Ł. Synlett  2009,  1812 
    Artikel in Thieme ConnectGoogle Scholar
  • 10 The Alkaloids   Vol. 27:  Szántay C. Blaskó G. Honty K. Dornyei G. Brossi A. Academic Press; New York: 1986.  p.131 
    Google Scholar
  • 11 Atta-ur-Rahman . Akhtar MN. Choudhary MI. Tsuda Y. Sener B. Khalid A. Parvez M. Chem. Pharm. Bull.  2002,  50:  1013 
    CrossrefGoogle Scholar
  • 12 Andersen D. Storz T. Liu P. Wang X. Li L. Fan P. Chen X. Allgeier A. Burgos A. Tedrow J. Baum J. Chen Y. Crockett R. Huang L. Syed R. Larsen RD. Martinelli M. J. Org. Chem.  2007,  72:  9648 
    CrossrefGoogle Scholar
  • 13a Amat M. Brunaccini E. Checa B. Pérez M. Llor N. Bosch J. Org. Lett.  2009,  11:  4370 
    Google Scholar
  • 13b Wache N. Christoffers J. Synlett  2009,  3016 
    Google Scholar
  • 13c Allin SM. Duffy LJ. Towler JMR. Bulman PC. Elsegood MRJ. Saha B. Tetrahedron  2009,  63:  10230 
    Google Scholar
  • 13d Korapala CS. Qin J. Friestad GK. Org. Lett.  2007,  9:  4243 
    Google Scholar
  • 13e Lei Y. Wrobleski AD. Golden JE. Powell DR. Aube J.
    J. Am. Chem. Soc.  2005,  127:  4552 
    Google Scholar
  • 13f MaGee DI. Lee ML. Tetrahedron Lett.  2001,  42:  7177 
    Google Scholar
  • 13g Liras S. Allen MP. Blake JF. Org. Lett.  2001,  3:  3483 
    Google Scholar
  • 13h Overman LE. Kamatani A. Org. Lett.  2001,  3:  1229 
    Google Scholar
  • 13i Dennison PR. Gibson A. Gray AI. Patrick GL. J. Chem. Soc., Perkin Trans. 1  1997,  721 
    Google Scholar
  • 13j Patrick GL. J. Chem. Soc., Perkin Trans. 1  1995,  1273 
    Google Scholar
  • 13k Aubé J. Ghosh S. Tanol M. J. Am. Chem. Soc.  1994,  116:  9009 
    Google Scholar
  • 13l Wilson SR. Di Grandi MJ. J. Org. Chem.  1991,  56:  4766 
    Google Scholar
  • 14a Song D. Rostami A. West FG. J. Am. Chem. Soc.  2007,  129:  12019 
    Google Scholar
  • 14b Hua DH. Bharathi SN. Panangadan JAK. Tsujimoto A. J. Org. Chem.  1991,  56:  6998 
    Google Scholar
  • 14c Back TG. Brunner K. J. Org. Chem.  1989,  54:  1904 
    Google Scholar
  • 15 Takahata H. Suzuki T. Yamazaki T. Heterocycles  1986,  24:  1247 
    CrossrefGoogle Scholar
  • 16a Takahata H. Suzuki T. Maruyama M. Moriyama K. Mozumi M. Takamatsu T. Yamazaki T. Tetrahedron  1988,  44:  4777 
    Google Scholar
  • 16b Takahata H. Suzuki T. Yamazaki T. Heterocycles  1985,  23:  2213 
    Google Scholar
  • 17 Typical Procedure for the Synthesis of (3 RS ,4 SR )-3,4-Diallyl-substituted 3,4-Dihydropyridine-2-thiones 3a-j To a cooled (-2 ˚C to 0 ˚C) and stirred solution of 2 (3.2 mmol) in dry THF (40 mL) a portion of 3.36 mmol (in the case of NR thiolactams 2c-f) or 6.56 mmol (in the case of NH derivatives 2a,b) of n-BuLi (2.5 M solution in hexane) was added via syringe under argon, and the solution was stirred for 30 min. Subsequently, 3.42 mmol of allyl bromide or its corresponding derivative was added via syringe. The resulting solution was stirred for 20-30 min at 0 ˚C. After addition of aq sat. NH4Cl (15 mL), the water layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over MgSO4. Filtration, concentration in vacuo, and purification by flash column chromatography (silica gel, n-hexane-EtOAc = 7:3 or 8:2) yielded 3a-j as a yellow solids or oils. Selected Spectroscopic Data (3 RS ,4 SR )-4-Allyl-3-(2-methylallyl)-3,4-dihydro-1 H -pyridine-2-thione (3b) Yellow oil. IR (film): ν = 3204 (br), 3140 (br), 3076, 2976, 2920, 1642, 1528, 1492, 1374, 1330, 1140, 1028, 992, 918, 894, 746, 728 cm-¹. MS (EI, 70eV): m/z (%) = 207 (<1) [M+], 166 (100), 112 (26), 111 (16), 67 (11), 55 (13). ¹H NMR (400.1 MHz, CDCl3): δ = 1.74 (3 H, s, CH3), 1.96-2.06 (1 H, m, 4-CHH), 2.10-2.30 (3 H, m, 4-CHH, 3-CHH, CH-4), 2.35 (1 H, dd, J = 13.4, 4.4 Hz, 3-CHH), 3.10 (1 H, dd, J = 11.4, 4.3 Hz, CH-3), 4.69 (1 H, br s, =CHH), 4.84 (1 H, br s, =CHH), 5.03-5.10 (2 H, m, =CH2), 5.35-5.41 (1 H, m, =CH-5), 5.62-5.74 (1 H, m, =CH), 6.07 (1 H, dd, J = 7.6, 4.4 Hz, =CH-6), 9.31 (1 H, br s, NH). ¹³C NMR (100.6 MHz, CDCl3): δ = 21.6 (CH3), 32.6 (CH-4), 38.0 (4-CH2), 40.7 (3-CH2), 50.0 (CH-3), 112.2 (=CH-5), 113.9, 117.8 (2 × =CH2), 122.9 (=CH-6), 134.5 (=CH), 142.0 (=CCH3), 203.9 (C=S). Anal. Calcd for C12H17NS: C, 69.51; H, 8.26; N, 6.76; S, 15.47. Found: C, 69.44; H, 8.31; N, 6.77; 15.55.
  • 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.
  • 19 Nowaczyk S. Alayrac C. Reboul V. Metzner P. Averbuch-Pouchot M.-T. J. Org. Chem.  2001,  66:  7841 
    CrossrefGoogle Scholar
  • 20 Barluenga J. Jardon J. Gotor V. Synthesis  1988,  146 
    Artikel in Thieme ConnectGoogle Scholar
  • 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.
  • 22a Yazici A. Pyne SG. Synthesis  2009,  339 
    Google Scholar
  • 22b Huang P.-Q. Synlett  2006,  1133 
    Google Scholar
  • 22c Petrini M. Chem. Rev.  2005,  105:  3949 
    Google Scholar
  • 22d Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
    Google Scholar
  • 23 Haasnoot CAG. DeLeeuw FAAM. Altona A. Tetrahedron  1980,  36:  2783 
    CrossrefGoogle Scholar
24

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