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Synlett 2002(12): 2065-2067
DOI: 10.1055/s-2002-35594
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N-Acetyl-1,3-dimethyltetrahydroisoquinolines by Intramolecular Amidomercuration: Stereochemical Aspects

C. B. de Koning*, Joseph P. Michael, Willem A. L. van Otterlo
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa
Fax: +27(11)7176749; e-Mail: dekoning@aurum.chem.wits.ac.za;
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Publication History

Received 27 September 2002
Publication Date:
20 November 2002 (online)

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Abstract

Mercury(II)-mediated ring closure of N-[1-(2-allyl-3-benzyloxy-4,6-dimethoxyphenyl)ethyl]acetamide 4 afforded N-acetyl-5-benzyloxy-6,8-dimethoxy-1,3-trans-dimethyl-1,2,3,4-te­trahydroisoquinoline 3. The product was shown to exist as a mixture of rotamers by NMR spectroscopy, since signals coalesced at higher temperatures. 2-[2-[1-(Acetylamino)ethyl]-6-(benzyloxy)-3,5-di­methoxyphenyl]-1-methylethyl methanesulfonate 8 was also cyclized with sodium hydride to afford rotameric products with the same isoquinoline skeleton, but as a mixture of 1,3-cis- and trans-dimethyl isomers.

Key words

amidomercuration - cyclization - isoquinoline - Mitsunobu - rotamers

    References

  • 1a The Chemistry and Biology of Isoquinoline Alkaloids   Philipson JD. Roberts MF. Zenk MH. Springer-Verlag; Berlin: 1985. 
    CrossrefGoogle Scholar
  • 1b For a recent example see: Iwasa K. Moriyasu M. Tachibana Y. Kim H.-S. Wataya Y. Wiegrebe W. Bastow KF. Cosentino LM. Kozuka M. Lee K.-H. Bioorg. Med. Chem.  2001,  9:  2871 
    CrossrefGoogle Scholar
  • 2 Bringmann G. Pokorny F. In The Alkaloids. Chemistry and Pharmacology   Vol. 46:  Cordell GA. Academic Press; San Diego: 1995.  Chap. 4. p.127-271  
    Google Scholar
  • Some recent representative syntheses and references therein:
  • 3a Bringmann G. Götz R. Keller PA. Walter R. Boyd MR. Lang F. Garcia A. Walsh JJ. Tellitu I. Bhaskar KV. Kelly TR. J. Org. Chem.  1998,  63:  1090 
    CrossrefGoogle Scholar
  • 3b Hobbs PD. Upender V. Dawson MI. Synlett  1997,  965 
    CrossrefGoogle Scholar
  • 3c Hoye TR. Chen M. Mi L. Priest OP. J. Org. Chem.  1999,  64:  7184 
    CrossrefGoogle Scholar
  • 3d Lipshutz BH. Keith JM. Angew Chem. Int. Ed.  1999,  38:  3530 
    CrossrefGoogle Scholar
  • 3e Rizzacasa MA. Sargent MV. J. Chem. Soc., Perkin Trans. 1  1991,  2773 
    CrossrefGoogle Scholar
  • Some recent examples from groups working in the area:
  • 4a Bringmann G. Wenzel M. Kelly TR. Boyd MR. Gulakowski RJ. Kaminsky R. Tetrahedron  1999,  55:  1731 
    CrossrefGoogle Scholar
  • 4b Bringmann G. Holenz J. Weirich R. Rübenacker M. Funke C. Boyd MR. Gulakowski RJ. François G. Tetrahedron  1998,  54:  497 
    CrossrefGoogle Scholar
  • 4c Bringmann G. Saeb W. Kraus J. Brun R. François G. Tetrahedron  2000,  56:  3523 
    CrossrefGoogle Scholar
  • 4d Bringmann G. Tasler S. Tetrahedron  2001,  57:  331 
    CrossrefGoogle Scholar
  • 4e Rao AVR. Gurjar MK. Ramana DV. Chheda AK. Heterocycles  1996,  43:  1 
    CrossrefGoogle Scholar
  • 4f Zhang H. Zembower DE. Chen Z. Bioorg. Med. Chem. Lett.  1997,  7:  2687 
    CrossrefGoogle Scholar
  • 4g Upender V. Pollart DJ. Liu J. Hobbs PD. Olsen C. Chao W.-R. Bowden B. Crase JL. Thomas DW. Pandey A. Lawson JA. Dawson MI. J. Hetero-cycl. Chem.  1996,  33:  1371 
    CrossrefGoogle Scholar
  • 4h de Koning CB. Michael JP. van Otterlo WAL. Tetrahedron Lett.  1999,  40:  3037 
    CrossrefGoogle Scholar
  • 4i de Koning CB. Michael JP. van Otterlo WAL. J. Chem. Soc., Perkin Trans. 1  2000,  799 
    CrossrefGoogle Scholar
  • 5a Bringmann G. Weirich R. Reuscher H. Jansen JR. Kinzinger L. Ortmann T. Liebigs Ann. Chem.  1993,  877 
    CrossrefGoogle Scholar
  • 5b Hoye TR. Chen M. Tetrahedron Lett.  1996,  37:  3099 
    CrossrefGoogle Scholar
  • 5c Watanabe T. Uemura M. Chem. Commun.  1998,  871 
    CrossrefGoogle Scholar
  • 6 Bringmann G. Götz R. Harmsen S. Holenz J. Walter R. Liebigs Ann. Chem.  1996,  2045 
    Google Scholar
  • 7 Toda J. Matsumoto S. Saitoh T. Sano T. Chem. Pharm. Bull.  2000,  48:  91 
    Google Scholar
  • 9a Kametani T. In The Total Synthesis of Natural Products   Vol. 3:  ApSimon J. John Wiley and Sons, Inc.; New York: 1977.  p.1-272  
    CrossrefGoogle Scholar
  • 9b Rozwadowska MD. Heterocycles  1994,  39:  903 
    CrossrefGoogle Scholar
  • 10a Mitsunobu O. Wada M. Sano T. J. Am. Chem. Soc.  1972,  94:  679 
    Google Scholar
  • 10b A review: Mitsunobu O. Synthesis  1981,  1 
    Google Scholar
  • 10c See also: Hughes DL. Org. React.  1992,  42:  335 
    Google Scholar
  • 11 Wolfe S. Hasan SK. Can. J. Chem.  1970,  48:  3572 
    Google Scholar
  • 13 Kometani T. Takeuchi Y. Yoshii E. J. Chem. Soc., Perkin Trans. 1  1981,  1197 
    CrossrefGoogle Scholar
  • 14a Larock RC. In Solvomercuration/Demercuration Reactions in Organic Synthesis   Springer-Verlag; Berlin: 1986.  Chap. VI. p.443-521  
    Google Scholar
  • 14b Larock RC. In Comprehensive Organometallic Chemistry II   Vol. 11:  McKillop A. Elsevier Science Ltd.; Amsterdam: 1995.  Chap. 9. p.389-459  
    Google Scholar
  • 14c Wilson SR. Sawicki RA. J. Org. Chem.  1979,  44:  330 
    Google Scholar
  • 14d Barluenga J. Jimènez C. Nájera C. Yus M. J. Chem. Soc., Chem. Commun.  1981,  670 
    Google Scholar
  • 14e Takahata H. Bandoh H. Momose T. Heterocyles  1995,  41:  1797 
    Google Scholar
  • 15 For a related example using PhSeCl see: Clive DCL. Farina V. Singh A. Wong CK. Kiel WA. Menchen SM. J. Org. Chem.  1980,  45:  2120 
    Google Scholar
  • 18 Example of rotational isomers in tetrahydroisoquinolines due to N-acetyl and N-formyl substituents: Bringmann G. Holenz J. Wiesen B. Nugroho BW. Proksch P. J. Nat. Prod.  1997,  60:  342 
    CrossrefGoogle Scholar
  • 21 Hoffmann RW. Chem. Rev.  1989,  89:  1841 
    CrossrefGoogle Scholar
8

This work is taken from the PhD thesis of W. A. L. van Otterlo, University of the Witwatersrand, 1999.

12

Spectroscopic Data for 4. 1H NMR (400 MHz; CDCl3): δ = 7.47-7.26 (5 H, m, 5 × PhH), 6.79 (1 H, br d, J = 9.3 Hz, NH), 6.49 (1 H, s, 5-H), 6.01-5.93 (1 H, m, 2′-H), 5.46-5.42 (1 H, m, CHCH3), 5.02-4.85 (2 H, m, 3′-H), 4.91 (1 H, d,
J = 10.8 Hz, OCH2), 4.86 (1 H, d, J = 10.8, OCH2), 3.90 (3 H, s, OCH3), 3.87 (3 H, s, OCH3), 3.64-3.63 (2 H, m, 1′-H), 1.92 (3 H, s, COCH3), 1.40 (3 H, d, J = 6.9 Hz, CHCH 3). 13C NMR (100.63 MHz; CDCl3): δ = 168.4 (C=O), 154.4, 152.1, 140.2 (3 × ArC-O), 137.9 (ArC-C), 136.9 (2′-C), 132.5 (ArC-C), 128.2, 127.8, 127.6 (3 × PhC), 122.2 (ArC-C), 115.4 (3¢-C), 96.2 (5-C), 74.9 (OCH2), 55.9, 55.6 (2 × OCH3), 43.7 (CHCH3), 30.7 (1′-C), 23.6 (COCH3), 20.9 (CHCH3). IR (thin film): νmax = 3331 br (N-H st), 2876 m (C-H st, O-CH2), 2837 m (C-H st, O-CH3), 1637 vs (C=O st), 1597 (ArC=C st) cm-1; MS (EI): m/z = M+ 369.1933 (C22H27NO4 requires 369.1940), 369 (M+, 14%) 326(1), 278(77), 219(86) 204(16), 193(84), 189(16), 91(40), 43(16).

16

Hg(OAc)2 (0.27 g, 0.85 mmol, 1.5 mol equiv) was added to amide 4 (0.19 g, 0.51 mmol) dissolved in THF (10 cm3). The yellow mixture was then stirred, in the dark, under argon for 21 h at 25 ºC. A further portion of Hg(OAc)2 (0.18 g, 0.51 mmol, 1 mol equiv) was added and the mixture was stirred for a further 18 h. A mixture of NaBH4 (0.049 g, 1.3 mmol, 2.5 mol equiv) in aq NaOH (5 cm3, 2.5 M) was then added whilst stirring. After stirring for a further 1 h a sat. aq Na2CO3 solution (5 cm3) was added and the mixture was stirred for 20 min. The reaction was allowed to stand for 30 min and the THF was removed under reduced pressure. Sat. brine solution (10 cm3) and Et2O (10 cm3) were added and the mixture was extracted with diethyl ether (3 × 10 cm3). The organic extracts were combined, filtered through alu-mina to remove traces of Hg, dried (MgSO4) and evaporated in vacuo. Preparative layer chromatography on silica gel (EtOAc-hexane-aq NH4OH, 66:33:1) afforded the 1,3-trans-dimethyl cyclized product 3 (0.11 g, 56%) as a light yellow oil.

17

The product 3 showed two distinct sets of signals in its 1H NMR spectrum, indicating rotamers about the amide C-N bond. Spectroscopic Data for 3. 1H NMR (400 MHz; CDCl3): δ = 7.43-7.32 (10 H, m, 10 × PhH), 6.44 (1 H, s,
7-H), 6.43 (1 H, s, 7-H), 5.50 (1 H, q, J = 6.4 Hz, 1-H), 5.16 (1 H, q, J = 6.6 Hz, 1-H), 4.95-4.86 (4 H, m, 2 × OCH2), 4.68-4.62 (1 H, m, 3-H), 4.23-4.15 (1 H, m, 3-H), 3.91 (6 H, s, 2 × OCH3), 3.86 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 2.99 (2 H, dd, J = 15.2 and 2.4 Hz, 4-H pseudo-equatorial), 2.64-2.54 (2 H, m, 2 × 4-H pseudo-axial), 2.24 (3 H, s, COCH3), 2.17 (3 H, s, COCH3), 1.28 (6 H, d, J = 6.6 Hz, 2 × 1-CH3), 0.84 (3 H, d, J = 6.2 Hz, 3-CH3), 0.83 (3 H, d, J = 6.1 Hz,
3-CH3); 13C NMR (50.32 MHz; CDCl3): δ = 170.0, 169.7 (2 × NCOCH3), 151.9, 151.5, 151.4, 150.7, 138.9, 139.0 (6 × ArC-O), 137.6, 137.5, 129.0 (3 × ArC-C), 128.5, 128.5, 128.3, 128.0 (4 × PhC), 119.5, 118.6 (2 × ArC-C), 95.2, 94.9 (2 × 7-C), 75.2 (OCH2), 55.9, 55.6, 55.6 (3 × OCH3), 49.1, 46.7 (2 × 1-C), 46.3, 44.4 (2 × 3-C), 28.6, 27.8 (2 × 4-C), 23.3, 22.3, 22.3, 21.3, 20.9, 19.2 (6 × CH3). IR (thin film): νmax = 2820 m (C-H st, OCH3), 1635 vs (C=O st), 1583 m (ArC = C st) cm-1; MS (EI): m/z = M+ 369.1931 (C22H27NO4 requires 369.1940), 369 (M+, 20%) 354(83), 278(95), 263(9), 219(78), 193(100), 91(34), 43(16).
Heating compound 3 in an NMR tube in toluene-d 8 up to 90 °C resulted in coalescence of the two sets of signals. Characteristic chemical shifts in the 1H NMR spectrum: δ = 2.99 ppm (doublet of doublets, J = 15.2 and 2.4 Hz) and δ = 2.64-2.54 ppm (multiplet) for the pseudo-equatorial and pseudo-axial protons at C-4 respectively. Four sets of signals corresponding to the two protons at C-1 and C-3 were also clearly visible as quartets at δ = 5.50 (J = 6.4 Hz) and 5.16
(J = 6.6 Hz) ppm and as multiplets at δ = 4.68-4.62 and 4.23-4.15 ppm respectively. The 13C NMR spectrum also showed two characteristic sets of resonances: at δ = 49.1 and 46.7 (C-1) ppm, δ = 46.3 and 44.4 (C-3) ppm and δ = 28.6 and 27.8 (C-4) ppm.

19

de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L., unpublished results.

20

For isomer 3, the C-1 methyl substituent showed an NOE with the H-4 pseudo-axial proton, indicating that the C-1 methyl substituent must be pseudo-axial. For the cis-isomer 9 the same NOE was seen, as well as an NOE between the 1-methyl and 3-methyl substituents, thereby fixing the cis-arrangement. Therefore in isomer 3 the C-1 methyl and C-3 methyl groups must be trans.

22

NaH (60% in oil, 0.03 g, 0.86 mmol, 10 mol equiv) was added to mesylate 8 (0.040 g, 0.086 mmol), dissolved in anhyd THF (10 cm3), under an argon atmosphere. The reaction mixture was stirred for 18 h, after which the mixture was cooled to 0 ºC. Water (10 cm3) was added dropwise and the mixture was extracted with diethyl ether (2 × 10 cm3). The organic solvent was washed with brine (10 cm3), dried and concentrated in vacuo. Preparative layer chromato-graphy on silica gel (EtOAc-hexane-aq NH4OH, 66:33:1) afforded an equimolar mixture of the 1,3-trans-dimethyl product 3, its 1,3-cis-dimethyl isomer 9 (0.027 g, 85%) as rotamers about the N-Ac bond.