Samarium Diiodide-Induced Diastereoselective Synthesis of Hexahydro-quinoline Derivatives

Abstract

Samarium diiodide-induced cyclization of aniline derivatives 5, 9, 12, 14, and 16 afforded hexahydroquinolines such as 6, 10, 13, 15, and 17 in moderate to good yields and excellent diastereoselectivities. Phenol was found to be a surprisingly effective proton source in some of these samarium-ketyl cyclizations. The influence of different substituents at nitrogen as well as at the aromatic ring of the aniline moiety was studied. Whereas para-donor-substituted aniline derivatives 19 and 21 provided the expected products 20 and 22, the corresponding para-cyano derivatives 23 and 26 took an alternative pathway. Ipso-substitution involving spiro intermediates 29 resulted in formation of rearranged products 24 and 28.

samarium diiodide - electron transfer - ketyl - radicals - hexahydroquinolines

References

For related phenyl-carbonyl coupling reactions, see:

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1d

ref.(14).

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6

Typical procedure, cyclization of 16 to 17: Samarium (0.329 g, 2.19 mmoL) and 1,2-diiodoethane (0.571 g, 2.02 mmol) were suspended in freshly distilled THF (30 mL) under an argon atmosphere and stirred for 2 h at room temperature. To the resulting dark blue solution HMPA (1.45 g, 8.1 mmol) was added. Ketone 16 (200 mg, 0.81 mmol) and tert-butanol (0.15 mL, 1.62 mmol), dissolved in THF (20 mL), were then added in one portion to the deep violet solution. After 16 h the reaction was quenched with saturated aqueous solution of sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with diethyl ether (3 ¥ 25 mL). The combined ether extracts were washed with brine (25 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting crude product was purified by flash chromatography on silica gel using hexane-ethyl acetate (5:1 to 1:3) to give 17 (0.128 g, 63%) as a colourless solid. Data for (2R*,4S*,4aS*)-1-acetyl-2-(iso-propyl)-4-hydroxy-4-methyl-1,2,3,4,4a,7-hexahydroquinoline (17): colourless crystals; mp 164 °C; ¹H NMR (C₆D₆, 270 MHz): δ = 0.82, 0.91 (2d, J = 6.6 Hz, 3 H each, CH₃), 1.18 (s, 3 H, 4-CH₃), 1.74 (m_c, 2 H, 3-H, 2-CH), 2.05 (s, 3 H, COCH₃), 2.05 (m_c, 1 H, 3-H), 2.25 (s, 1 H, br, OH), 2.67 (m_c, 1 H, 4a-H), 2.28 (m_c, 2 H, 7-H), 4.33 (dd, J = 6.6, 11.8 Hz, 1 H, 2-H), 5.58 (s, 1 H, br, 8-H), 5.81 (m_c, 2 H, 5-H, 6-H); ¹³C NMR (CDCl₃, 68 MHz): δ = 19.8, 20.3 (2q, CH₃), 21.8 (q, COCH₃), 24.4 (q, 4-CH₃), 27.1 (t, C-7), 28.7 (d, 2-CH), 40.4 (t, C-3), 48.9 (d, C-4a), 55.7 (d, C-2), 73.0 (s, C-4), 123.3 (d, C-8), 123.9 (d, C-6), 124.4 (d, C-5), 134.6 (s, C-8a), 169.2 (s, CO); IR (KBr): ν = 3390 (OH), 3030 (=CH), 2975-2820 (CH), 1610 (CO) cm^-1; Calcd. for C₁₅H₂₃NO₂ (249.4): C 72.23, H 9.30, N 5.62; Found: C 72.49, H 9.10, N 5.50.

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8

Since samarium(II/III) species are Lewis acids one might assume a simple electrophilic substitution reaction for the formation of 2 and 4. This possibility was excluded by performing a test reaction with preformed samarium(III) iodide under the same reaction conditions but no cyclization product was observed (in the presence of HMPA as strong donor ligand the Lewis acidity of the samarium salts is effectively reduced).

9

The relative configuration was determined by NOESY-NMR spectroscopy. For 17 a crystal structure was obtained to prove the relative configuration.

10a List B. J. Am. Chem. Soc.  2000,  122:  9336 

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10c List B. Pojarliev P. Biller WT. Martin HJ. J. Am. Chem. Soc.  2002,  124:  827 ; Basically, this Mannich reaction leads to optically active compounds with considerable enantioselectivity, but since our interest was focused on the chemo- and diastereoselectivity of the cyclization reaction the enantiomeric excess of these starting materials and the resulting products was so far not determined.

11

Brüdgam, I.; Hartl, H. Institut für Chemie, FU Berlin, 2002 unpublished results.

12

When phenol was applied in related SmI₂-induced cyclizations yields were at least equivalent to those with tert-butanol as proton source, however, so far no rule is recognizable for which substrates phenol improves the outcome. Other proton sources were also examined (including 2,6-di-tert-butylphenol or 2,2,2-trifluoroethanol) but no effect similar to that of phenol was discovered.

13

The related ortho- and meta-substituted aromatic compounds generally cyclize with considerably lower efficiency. For cyano-substituted derivatives the yields are particularly low.

14 For a recent report on related samarium diiodide induced spirocyclizations to electron-deficient aromatic compounds, see: Ohno H. Maeda S. Okumura M. Wakayama R. Tanaka T. Chem. Commun.  2002,  316