Reductive Cyclization of Ketones Tethered to Activated Olefins Mediated by Magnesium in Methanol

Abstract

The reductive cyclizations of various ketones tethered to activated olefins such as a,/3-unsaturated esters, nitriles, sulfoxides, and sulfides were mediated by magnesium in dry methanol in the presence of mercuric chloride. When treated with magnesium in dry methanol at -23 6C all of the ketones except nitrile 9 (42%) and 5-oxa-8-keto-2-enoate 5 (13%) gave excellent yields (79-98%) of monoand bicyclic alcohol products resulting from carbon-carbon bond formation between the /3-carbon of the activated olefin and the carbonyl carbon. The reaction was accelerated by the catalytic amount of mercuric chloride, although the stereoselectivity was not affected by the catalyst. For all the substrates except 8-keto-2-enoate 3 and 5-aza-8-keto-2-enoate 6, the configuration of the major product was trans between the hydroxy and (methoxycarbonyl)methyl groups. The product isomer ratios were independent of the substrate geometry (25 or Z). In contrast to the ketones, aldehydes tethered to a,/3-unsaturated esters gave products of simple reduction of the double bond and/or saturated alcohols instead of the cyclized products. When the reaction temperature was lowered, the yields of cyclized product were significantly affected by the production of appreciable amounts of saturated product, but the stereoselectivity was not improved. Under the same reaction conditions a,/3-unsaturated sulfoxide 16 gave deoxygenated sulfide 18 (85%) as the major product along with a small amount (9%) of cyclized product 19t. In contrast, sulfone 17 underwent desulfonylation instead of cyclization to give olefin 20 (54%). With excess magnesium (15 equiv), however, a,/Sunsaturated sulfoxide 16 gave cyclized sulfide 19t (95 %) via deoxygenated sulfide 18. Both 16Z and 1625 afforded product 19t as a single isomer. It is suggested that the reductive cyclization of the a,/3-unsaturated esters and nitriles proceed by means of nucleophilic attack of a /3-carbon radical anion, formed by initial electron transfer from magnesium metal to the activated olefin, on the carbonyl group. The cyclization of the a,/3-unsaturated sulfide proceeds by nucleophilic attack of the ketyl on the olefinic double bond.

Autoxidation of Conjugated Linoleic Acid Methyl Ester in the Presence of α‐Tocopherol: The Hydroperoxide Pathway

“…Purification by silica gel column chromatography (DCM) afforded methyl 8-oxooctanoate (1.24 g, 7.20 mmol, 42%) as a colourless oil, R f (EtOAc/DCM=1/10, v/v)=0.59. The 1 H and 13 C NMR data agreed with published data (Lee et al 1994). …”

The Julia Reaction

“…Since then, the combination SmI 2 /HMPA or SmI 2 and various additives [105] has continued to prove its usefulness [106][107][108]. In addition, other reductive methods are regularly reported, such as the use of Mg/HgCl 2 [109,110], NaTeH [111], and sulfoxide/alkyllithium [52,53] combinations.…”

Some Synthetic Uses of Double‐Bonded Functional Groups

“…This reaction has proved to be synthetically very useful for the preparation of poly-oxygenated compounds (equation 139) 523 . This reductive coupling process may also be promoted in dry methanol, using Mg metal and a trace amount of mercuric chloride 524 …”