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Synlett 2004(15): 2732-2735  
DOI: 10.1055/s-2004-835657
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Alexandra Hölemann, Hans-Ulrich Reissig*
Institut für Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
Further Information

Publication History

Received 8 September 2004
Publication Date:
10 November 2004 (online)

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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.

Key words

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

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 (δA = 4.31, δB = 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.

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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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.