Influence of Geminal Disubstitution on Samarium Diiodide Induced Reductive Cyclizations of γ-Aryl Ketones

Abstract

Geminal disubstitution at the alkyl chain of γ-aryl ketones significantly influences the efficacy of samarium diiodide ­induced cyclizations providing significantly higher yields. β,β-Di­substituted aryl ketones 11a-e and γ,γ-disubstituted aryl ketone 14 could be converted into the corresponding hexahydronaphthalene derivatives in good yields. On the other hand, α,α-disubstituted ketone 9 only gave the secondary alcohol 10 along with recovered starting material. Aryl ketones containing substituents with hetero­atoms could also be cyclized in high yields and substrates such as 11d with sterically demanding cyclic substituents efficiently afforded spiro compounds.

samarium diiodide - cyclization - geminal disubstitution - γ-aryl ketone - hexahydronaphthalene

References and Notes

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10 Compound 9 was synthesized in a two-step procedure: 1. ethyl isobutyrate, phenethyl iodide, LDA, HMPA, THF, -78 ˚C; 2. TMSCH₂Li, pentane, 0 ˚C then MeOH, 55% (2 steps). For the second step, see: Demuth M. Helv. Chim. Acta  1978,  61:  3136 

11

Conjugate addition of a benzyl cuprate to mesityl oxide furnished compound 11a in low yield: BnMgCl, CuCN, BF₃˙OEt₂, mesityl oxide, Et₂O, -78 ˚C, 15%.

12 Mahmud SA. Ansell MF. J. Chem. Soc., Perkin Trans. 1  1973,  2789 

13

The samarium ketyl is very likely in equilibrium with ketone 9 which was re-isolated. Reduction of the ketyl and subsequent protonation furnishes 10.

14

General Procedure for Samarium Diiodide Induced Cyclizations of Aryl Ketones HMPA (18 equiv) was added to a previously prepared stock solution of SmI₂ in THF (0.1 M, 3 equiv) under argon, and the solution was stirred for 20 min. During this time the solution turned from dark blue to dark violet. In a separate flask, the substrate (1 equiv) and t-BuOH (2 equiv) were dissolved in THF (10 mL) under argon. Argon was bubbled through the solution for 20 min. The substrate solution was then transferred with a syringe to the samarium diiodide solution. The mixture was stirred at r.t. until the color changed from violet to grey. Saturated aq NaHCO₃ solution was added, the organic layer was separated, and the aqueous layer was extracted with Et₂O (3×). The combined organic layers were washed with H₂O and brine, dried with MgSO₄, and the solvent was removed under reduced pressure to give the crude product, which still contained small amounts of HMPA. Flash chromatography on Al₂O₃ (activity grade 3) yielded the cyclization products.

15

Cyclization of 11a According to the general procedure, the SmI₂ solution in THF (15.8 mL, 1.58 mmol), HMPA (1.66 mL, 9.47 mmol), 11a (0.100 g, 0.53 mmol), and t-BuOH (0.078 g, 1.05 mmol) afforded after purification by flash chromatography (hexane-EtOAc, 9:1) compounds 12a and 13a as a 83:17 mixture in 75% yield (76 mg). Spectroscopic Data for (1 S *,8a S *)-1,3,3-Trimethyl-1,2,3,4,8,8a-hexahydronaphthalen-1-ol (12a) ^¹H NMR (700 MHz, CDCl₃): δ = 0.93, 0.96. 1.26* (3 s, 3 H each, CH₃), 1.28* (br s, 1 H, OH), 1.50 (d, J = 13.4 Hz, 1 H, 2-H), 1.62 (dd, J = 2.2, 13.4 Hz, 1 H, 2-H), 1.88 (dd, J = 2.2, 12.6 Hz, 1 H, 4-H), 2.03 (d, J = 12.6 Hz, 1 H, 4-H), 2.23 (dd, J = 3.5, 13.0 Hz, 1 H, 8a-H), 2.49 (tdd, J = 3.1, 13.0, 19.5 Hz, 1 H, 8-H), 2.57 (m, 1 H, 8-H), 5.54 (tddd, J = 0.9, 3.1, 8.6, 9.5 Hz, 1 H, 7-H), 5.58-5.60 (m, 1 H, 5-H), 5.67 (dddd, J = 1.3, 3.1, 5.4, 9.5 Hz, 1 H, 6-H) ppm; * overlapping signals. ^¹³C NMR (176 MHz, CDCl₃): δ = 22.4 (t, C-8), 23.2, 26.6 (2 q, CH₃), 32.8 (s, C-3) 33.9 (q, CH₃), 46.9 (d, C-8a), 48.7 (t, C-4), 55.9 (t, C-2), 74.9 (s, C-1), 118.9, 122.2, 123.5 (3 d, C-5, C-6, C-7), 136.5 (s, C-4a) ppm.
Spectroscopic Data for (1 S *,8a S *)-1,3,3-Trimethyl-1,2,3,4,6,8a-hexahydronaphthalen-1-ol (13a)
^¹H NMR (700 MHz, CDCl₃): δ = 0.90, 0.98, 1.12 (3 s, 3 H each, CH₃), 1.52 (br s, 1 H, OH), 1.59 (d, J = 13.2 Hz, 1 H, 2-H), 1.68 (dd, J = 2.2, 13.2 Hz, 1 H, 2-H), 1.87, 1.92 (AB part of an ABX system, J _AB = 13.0 Hz, J _BX = 2.2 Hz, 1 H each, 4-H), 2.62 (m_c, 1 H, 8a-H), 2.67-2.71 (m, 2 H, 6-H), 5.47 (X part, m_c, 1 H, 5-H), 5.85 (m_c, 2 H, 7-H, 8-H) ppm. ^¹³C NMR (176 MHz, CDCl₃): δ = 24.9, 26.2 (2 q, CH₃), 27.0 (t, C-6), 32.2 (s, C-3), 33.9 (q, CH₃), 48.7 (t, C-4), 49.0 (d, C-8a), 55.3 (t, C-2), 74.5 (s, C-1), 120.1 (d, C-5), 124.3, 125.6 (2 d, C-7, C-8), 141.6 (s, C-4a) ppm. Data from mixture: IR (film): ν = 3365 (OH), 2950-2830 (CH), 1630 (C=C) cm^-¹. HRMS (EI, 80 eV, 60 ˚C): m/z calcd for C₁₃H₂₀O [M]⁺: 192.1514; found: 192.1513. Anal. Calcd for C₁₃H₂₀O (192.1): C, 81.20; H, 10.48; found: C, 80.93; H, 10.31.
Cyclization of 14 According to the general procedure, the SmI₂ solution in THF (15.8 mL, 1.58 mmol), HMPA (1.66 mL, 9.47 mmol), 14 (0.100 g, 0.53 mmol), and t-BuOH (0.078 g, 1.05 mmol) afforded after purification by flash chromatography (hexane-EtOAc, 9:1) compounds 15, 16, and 17 as a 74:19:7 mixture in 70% yield (71 mg). Separation by HPLC yielded pure samples.
Analytical Data for (1 S *,8a S *)-1,4,4-Trimethyl-1,2,3,4,8,8a-hexahydronaphthalen-1-ol (15) Colorless solid; mp 50-52 ˚C. ^¹H NMR (700 MHz, CDCl₃): δ = 1.09, 1.14, 1.17 (3 s, 3 H each, CH₃), 1.35 (dt, J = 4.5, 13.6 Hz, 1 H, 3-H), 1.46* (br s, 1 H, OH), 1.47* (ddd, J = 2.9, 4.4, 13.6 Hz, 1 H, 3-H), 1.60 (ddd, J = 2.9, 4.4, 13.6 Hz, 1 H, 2-H), 1.77 (dt, J = 4.5, 13.6 Hz, 1 H, 2-H), 2.47 (tdd, J = 3.1, 13.8, 20.0 Hz, 1 H, 8-H), 2.61-2.67 (m, 2 H, 8-H, 8a-H), 5.52 (dddd, J = 0.8, 3.3, 5.0, 9.0 Hz, 1 H, 7-H), 5.64 (br d, J = 5.7 Hz, 1 H, 5-H), 5.69 (dddd, J = 1.4, 3.0, 5.7, 9.0 Hz, 1 H, 6-H) ppm; * overlapping signals. ^¹³C NMR (176 MHz, CDCl₃): δ = 20.4 (q, CH₃), 22.7 (t, C-8), 26.2, 28.5 (2 q, CH₃), 35.9 (s, C-4), 38.5, 38.8 (2 t, C-3, C-2), 42.4 (d, C-8a), 75.6 (s, C-1), 115.2 (d, C-5), 122.2 (d, C-6), 123.1 (d, C-7), 145.0 (s, C-4a) ppm. IR (film): ν = 3375 (OH), 2970-2865 (=CH, CH), 1665 (C=C) cm^-¹.
Analytical Data for (1 S *,8a S *)-1,4,4-Trimethyl-1,2,3,4,6,8a-hexahydronaphthalen-1-ol (16)
^¹H NMR (700 MHz, CDCl₃): δ = 1.03, 1.08. 1.09 (3 s, 3 H each, CH₃), 1.32 (dt, J = 4.2, 13.8 Hz, 1 H, 3-H), 1.43 (ddd, J = 2.9, 4.4, 13.8 Hz, 1 H, 3-H), 1.55 (br s, 1 H, OH), 1.63 (ddd, J = 2.9, 4.2, 12.9 Hz, 1 H, 2-H), 1.86 (ddd, J = 2.9, 4.2, 12.9 Hz, 1 H, 2-H), 2.66-2.70 (m, 2 H, 6-H), 2.97-3.01 (m, 1 H, 8a-H), 5.47-5.51 (m, 1 H, 5-H), 5.81-5.85 (m, 1 H, 7-H), 5.87 (tdd, J = 1.8, 3.3, 10.2 Hz, 1 H, 8-H) ppm. ^¹³C NMR (176 MHz, CDCl₃): δ = 21.5, 25.7 (2 q, CH₃), 27.1 (t, C-6), 28.7 (q, CH₃), 34.4 (s, C-4), 37.8, 38.0 (2 t, C-2, C-3), 44.7 (d, C-8a), 71.0 (s, C-1), 116.2 (d, C-5), 124.5, 125.4 (2 d,
C-8, C-7), 142.2 (s, C-4a) ppm. IR (film): ν = 3410 (OH), 2960-2810 (=CH, CH), 1650 (C=C) cm^-¹. HRMS (ESI-TOF-MS): m/z calcd for C₁₃H₂₀ONa [M + Na]⁺: 215.1406; found: 215.1405.

Analytical Data for 1,4,4-Trimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (17) Colorless solid; mp 68-70 ˚C. ^¹H NMR (700 MHz, CDCl₃): δ = 1.30, 1.31, 1.55 (3 s, 3 H each, CH₃), 1.68 (br s, 1 H, OH), 1.71-1.83, 1.96-1.99 (2 m, 4 H, 2-H, 3-H), 7.18-7.24 (m, 2 H, Ar), 7.29-7.31 (m, 1 H, Ar), 7.58-7.59 (m, 1 H, Ar) ppm. ^¹³C NMR (176 MHz, CDCl₃): δ = 30.8, 31.5, 31.7 (3 q, CH₃), 34.06 (s, C-4), 35.9, 36.1 (2 t, CH₂), 71.0 (s, C-1), 126.0, 126.1, 126.4, 127.4 (4 d, Ar), 142.0, 144.7 (2 s, Ar) ppm. IR (film): ν = 3385 (OH), 2960-2860 (=CH, CH), 1660 (C=C) cm^-¹. HRMS (ESI-TOF-MS): m/z calcd for C₁₃H₁₈ONa [M + Na]⁺: 213.1250; found: 213.1250.

16

At the moment it is more likely that the isolation of isomeric mixtures is the result of an unselective kinetically controlled protonation. Since equilibration experiments with the products isolated are so far not fully conclusive, further investigation of this problem is required.