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

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<A NAME="RD19002ST-2">2</A> Bringmann G. Pokorny F. In The Alkaloids. Chemistry and Pharmacology   Vol. 46:  Cordell GA. Academic Press; San Diego: 1995.  Chap. 4. p.127-271  

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<A NAME="RD19002ST-8">8</A>

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

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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).

<A NAME="RD19002ST-13">13</A> Kometani T. Takeuchi Y. Yoshii E. J. Chem. Soc., Perkin Trans. 1  1981,  1197 

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<A NAME="RD19002ST-14D">14d</A> Barluenga J. Jimènez C. Nájera C. Yus M. J. Chem. Soc., Chem. Commun.  1981,  670 

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<A NAME="RD19002ST-15">15</A> 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 

<A NAME="RD19002ST-16">16</A>

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.

<A NAME="RD19002ST-17">17</A>

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.

<A NAME="RD19002ST-18">18</A> 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 

<A NAME="RD19002ST-19">19</A>

de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L., unpublished results.

<A NAME="RD19002ST-20">20</A>

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.

<A NAME="RD19002ST-21">21</A> Hoffmann RW. Chem. Rev.  1989,  89:  1841 

<A NAME="RD19002ST-22">22</A>

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.