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

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.

amidomercuration - cyclization - isoquinoline - Mitsunobu - rotamers

References

1a The Chemistry and Biology of Isoquinoline Alkaloids   Philipson JD. Roberts MF. Zenk MH. Springer-Verlag; Berlin: 1985. 

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 

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  

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 

3b Hobbs PD. Upender V. Dawson MI. Synlett  1997,  965 

3c Hoye TR. Chen M. Mi L. Priest OP. J. Org. Chem.  1999,  64:  7184 

3d Lipshutz BH. Keith JM. Angew Chem. Int. Ed.  1999,  38:  3530 

3e Rizzacasa MA. Sargent MV. J. Chem. Soc., Perkin Trans. 1  1991,  2773 

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 

4b Bringmann G. Holenz J. Weirich R. Rübenacker M. Funke C. Boyd MR. Gulakowski RJ. François G. Tetrahedron  1998,  54:  497 

4c Bringmann G. Saeb W. Kraus J. Brun R. François G. Tetrahedron  2000,  56:  3523 

4d Bringmann G. Tasler S. Tetrahedron  2001,  57:  331 

4e Rao AVR. Gurjar MK. Ramana DV. Chheda AK. Heterocycles  1996,  43:  1 

4f Zhang H. Zembower DE. Chen Z. Bioorg. Med. Chem. Lett.  1997,  7:  2687 

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 

4h de Koning CB. Michael JP. van Otterlo WAL. Tetrahedron Lett.  1999,  40:  3037 

4i de Koning CB. Michael JP. van Otterlo WAL. J. Chem. Soc., Perkin Trans. 1  2000,  799 

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5c Watanabe T. Uemura M. Chem. Commun.  1998,  871 

6 Bringmann G. Götz R. Harmsen S. Holenz J. Walter R. Liebigs Ann. Chem.  1996,  2045 

7 Toda J. Matsumoto S. Saitoh T. Sano T. Chem. Pharm. Bull.  2000,  48:  91 

8

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

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9b Rozwadowska MD. Heterocycles  1994,  39:  903 

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10b A review: Mitsunobu O. Synthesis  1981,  1 

10c See also: Hughes DL. Org. React.  1992,  42:  335 

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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): ν_max = 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).

13 Kometani T. Takeuchi Y. Yoshii E. J. Chem. Soc., Perkin Trans. 1  1981,  1197 

14a Larock RC. In Solvomercuration/Demercuration Reactions in Organic Synthesis   Springer-Verlag; Berlin: 1986.  Chap. VI. p.443-521  

14b Larock RC. In Comprehensive Organometallic Chemistry II   Vol. 11:  McKillop A. Elsevier Science Ltd.; Amsterdam: 1995.  Chap. 9. p.389-459  

14c Wilson SR. Sawicki RA. J. Org. Chem.  1979,  44:  330 

14d Barluenga J. Jimènez C. Nájera C. Yus M. J. Chem. Soc., Chem. Commun.  1981,  670 

14e Takahata H. Bandoh H. Momose T. Heterocyles  1995,  41:  1797 

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 

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): ν_max = 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.

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 

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.

21 Hoffmann RW. Chem. Rev.  1989,  89:  1841 

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.