Samarium Diiodide in the Synthesis of Medium-Sized Rings - Carbocycles and Heterocycles by Intramolecular Addition of Samarium Ketyls to Alkynes

Abstract

A series of alkynyl-substituted ketones and aldehydes was subjected to samarium diiodide in the presence of HMPA to study the scope and limitations of their ketyl-alkyne coupling. Seven- and eight-membered heterocycles such as 4, 6, 8, 25, 27, 29, 33, and 35 could be isolated in moderate to good yields. Other ­cyclization products were isolated in low yields only. The efficacy of the reductive cyclization strongly depends on the substitution pattern and the presence of heteroatoms and/or benzene rings in the spacer between the alkyne and carbonyl group. First subsequent transformations of azocine 29 leading to enone 38 or epoxide 39 demonstrate the synthetic potential of this method.

alkynes - 8-endo-dig-cyclizations - ketyl radicals - medium-sized rings - samarium diiodide

References

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13

Typical Procedure: Cyclization of 5 to 6. Samarium powder (0.361 g, 2.40 mmol) and 1,2-diiodoethane (0.620 g, 2.20 mmol) were suspended in freshly distilled anhyd THF (25 mL) under an argon atmosphere and stirred for 2 h at r.t. To the resulting dark blue solution HMPA (3.3 g, 18 mmol) was added. Alkynyl ketone 5 (0.230 g, 0.80 mmol) and
t-BuOH (0.150 g, 2.00 mmol) were dissolved in anhyd THF (15 mL) and then added to the deep violet solution. After 16 h at r.t., the mixture was quenched with sat. aq solution of NaHCO₃ (15 mL) and H₂O (10 mL), the organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 15 mL). The combined organic extracts were washed with H₂O (15 mL) and brine (2 × 20 mL), dried with anhyd MgSO₄, filtered and evaporated. The resulting crude oil was purified by column chromatography on silica gel using n-hexane-EtOAc (5:1) as eluent. Compound 6 (0.181 g, 78%) was obtained as a colorless oil. Data for tert-butyl 5-hydroxy-5-methyl-5,6-dihydro-1-benzazocin-1(2H)-carboxylate (6): ¹H NMR (500 MHz, CDCl₃, 334 K): δ = 7.22-7.12 (m, 4 H, Ar), 5.49 (dd, J = 1.0, 12.4 Hz, 1 H, 4-H), 5.27 (td, J = 6.9, 12.4 Hz, 1 H, 3-H), AB part of the ABX system (δ_A = 4.31, δ_B = 4.22, J _AB = 15.3 Hz, J _AX = J _BX = 6.9 Hz, each 1 H, 2-H), 3.17 (d, J = 13.8 Hz, 1 H, 6-H), 2.84 (d, J = 13.8 Hz, 1 H, 6-H), 1.94 (br s, 1 H, OH), 1.44 (s, 3 H, 5-CH₃), 1.39 [s, 9 H, C(CH₃)₃]. ¹³C NMR (126 MHz, CDCl₃, 334 K): δ = 154.6 (s, CO), 141.8 (d, C-4), 140.3, 135.9 (2 s, Ar), 130.1, 129.0, 127.2, 126.8 (4 d, Ar), 121.4 (d, C-3), 80.3, 28.3 [s, q, C(CH₃)₃], 74.5 (s, C-5), 47.4 (t, C-2), 45.4 (t, C-6), 29.5 (q, 5-CH₃). IR (film): ν = 3450 (O-H), 3065-2930 (=C-H, C-H), 1695 (C=O), 1605-1495 (C=C) cm^-1. Anal. Calcd for C₁₇H₂₃NO₃ (289.4): C, 70.56; H, 8.01; N, 4.84. Found: C, 70.32; H, 8.04; N, 4.39.

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15

Attempts to replace HMPA by less toxic co-solvents have so far not been successful in general. In individual examples, related additives (e.g. N-methylpyrrolidinone or other phosphoramide derivatives) were efficient but unfortunately, no rule has yet been recognized in which cases these additives are applicable. Berndt, M.; Gross, S.; Hölemann, A.; Reissig, H.-U. unpublished results.

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17b

The diastereoselectivity in favor of the trans-isomer may be explained by assuming that the sterically demanding samarium-alkoxy group and the alkyl group are in equatorial positions in the transition state of cyclization.

18

The formation of allene 14 could not be mechanistically elucidated so far, but it can probably be explained by assuming a samarium(II) or samarium(III)-induced isomerization of the alkyne to an allene moiety.

19

The configuration of the double bond was unambiguously determined by NOESY spectroscopy.

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