Download PDF
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;
Further Information

Publication History

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

    Permissions and Reprints All articles of this category

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

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.