Enolization in the Reformatsky Reaction

Newman, Melvin S.

doi:10.1021/ja01261a033

Cited by 19 publications

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“…The latter product is shown to be l,5,8-trioxobenz[/]indolizidine (13), a material which is of synthetic interest because of its structural relationship to the phenanthroindolizidine and Amaryllidaceae alkaloids. The precursor to ketone 4,1 -diazo-4-phthalimido-2-butanone (7), was found to give 13 directly in preparatively acceptable yield via a novel rearrangement of its derived ketocarbene (17).…”

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A novel intramolecular homologation of a phthalimide group. 1,5,8-Trioxobenz[f]indolizidine

Krauser¹,

Watterson²

1978

J. Org. Chem.

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7) For convenience these compounds will be referred to as K a r y l -K methylbenzamides containing "aza', "aza oxide", and "methyiazonium" substituents, respectively. (8) M. Liveris and T'he Reformatsky reaction between ethyl bromoacetate and l-acetoxy-4-phthalimido~2-butanone (4) produces in rnodest yield ~-acetoxy-~-(2-phthalimidoethyl)butyrolactone (10). a product of normal addition to the ketone carbonyl, and in low yield a second compound, which arises from transformation of the phthalimide group. The latter product is shown to be 1,5,8-trioxobenz~]indolizidine (13), a material which is of synthetic interest because of its *jtructural relationship to the phenanthroindolizidine and Amaryllidaceae alkaloids. The precursor to ketone 4, l-diazo-4-phthalimido-2-butanone (7), was found to give 13 directly in preparatively acceptable yield via a novel rearrangement of its derived ketocarbene (17).We are presently investigating a synthetic approach to the ring system of cocculolidine ( 1),2 a member of the D-ring lactone subgroup of the Erythrina group of alkaloids. This approach requires the as yet unknown aminobutenolide 2, and our immediate synthetic goal was the amine-protected lactone 3.T was and n 1 2 , R = H 3, R = o-phthaloyl e key step in an initial sequence designed to produce 3 he Reformatsky reaction between ethyl bromoacetate -acetoxy-4-phthalimido-2-butanone (4). This ketone was 4, Z = CH,OA.c 7 , Z == CHN, 5 , Z = OH 8, Z = CH,OCHO 6 , Z = C1 9, Z = CH,Cl readily prepared in four steps from /3-alanine (3-aminopropionic acid) via intermediates 5 , 6 , and 7, respectively.The major product of the Reformatsky reaction was the acetoxylactone 10, which was formed in modest yield (20%) and presumalily arose from normal addition to the ketone followed by transesterification and cyclization. This reaction also produced a second, highly colored, product "A" in lower 10, Y = OAc 11, Y = OCHO 12, Y =

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confidence: 99%

A novel intramolecular homologation of a phthalimide group. 1,5,8-Trioxobenz[f]indolizidine

Krauser¹,

Watterson²

1978

J. Org. Chem.

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“…(6)], but the use of the analogous isovalerate led to a low yield and complex diastereomer mixtures. [10] The results with 1 b and 1 c were somewhat unexpected, as diastereoselectivities in Reformatsky reactions with simple ketones are generally modest. [11] The use of other alkyl esters or other silyl groups in the silyl glyoxylate reagent generally led to lower yields and/or diastereoselectivities.…”

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“…[10] The highly substituted g-butyrolactones were purified conveniently in most cases through selective crystallization from pentane after column chromatography to afford the products as single diastereomers. [12] The high diastereoselectivity observed in the formation of isobenzofuranone 10 q (terminating electrophile: methyl 2-acetylbenzoate), which must result from lactonization via a different transition state, suggests that selective lactonization by one of a mixture of equilibrating stereoisomeric aldolates is probably not responsible for the remarkable diastereoselectivity.…”

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Diastereoselective Synthesis of Pentasubstituted γ‐Butyrolactones from Silyl Glyoxylates and Ketones through a Double Reformatsky Reaction

Greszler

Johnson

2009

Angewandte Chemie

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The prevalence of g-butyrolactone substructures in natural products continues to stimulate interest in the development of concise and selective methods for their preparation. The assembly of g-butyrolactones that contain multiple stereocenters typically requires the synthesis of complex precursors through specialized routes. [1] Modular assembly strategies that circumvent this limitation would be welcome additions to the synthetic toolbox. Herein, we report diastereoselective reactions of Reformatsky reagents, silyl glyoxylates, and ketones that provide densely functionalized pentasubstituted g-butyrolactones containing three contiguous stereocenters. The reactions collectively constitute a rare example of the diastereoselective generation of vicinal stereogenic tertiary alcohols through aldolization. [2] Silyl glyoxylates are conjunctive reagents that participate in coupling reactions initiated by hydrides and nonstabilized carbon nucleophiles. [2c, 3] We examined the use of enolates and their equivalents in an effort to expand the range of nucleophilic promoters in transformations based on silyl glyoxylates. The projected transformation, outlined in Scheme 1, involves aldol addition to the silyl glyoxylate 2 to expose, after a [1,2]-Brook rearrangement, [4,5] a new enolate 3 capable of a second aldol reaction with an aldehyde or ketone electrophile. Lactonization would then provide g-butyrolactone 5.Initial experiments with magnesium and lithium enolates provided complex product mixtures; the desired lactones or their acyclic precursors were formed in low yield. We speculated that moderation of the enolate reactivity might be necessary and screened Reformatsky reagents under standard conditions. [6][7][8] The use of zinc enolates in combination with the appropriate reaction temperature facilitated the development of a workable experimental protocol (Scheme 2). The hydroxysilane 8 was isolated as the predominant product when the reaction was conducted at À20 8C. This result reflects an inability of the initial zinc aldolate to undergo Brook rearrangement at this temperature [Scheme 2, Eq. (1)]. [9] We took advantage of this finding by forming the initial adduct between the Reformatsky reagent and the silyl glyoxylate at À20 8C prior to the introduction of the ketone electrophile. Once the initial reaction between the silyl glyoxylate and the zinc enolate was complete, the addition of the ketone, followed by warming to À10 8C for 30 min, gave the desired product 7 in 33 % yield; however, 8 was still the major product [Scheme 2, Eq. (2)]. Optimal conditions involved this stepwise addition of the reagents, with an initial reaction temperature of À30 8C; the reaction mixture was then warmed to room temperature and stirred at this temperature for 1 h to afford the desired product in 73 % yield along Scheme 1. Three-component lactone synthesis. Bn = benzyl, TBS = tertbutyldimethylsilyl.Scheme 2. Optimization of the double Reformatsky reaction. General conditions for all reactions: enolate (1.5 equiv), ketone (2.0 e...

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“…[9] Ac omplementary,a nd more popular approach to generate activated zinc metal is to remove zinc oxide from the metal surface by chemical reaction or entrainment, typically achieved using chemical additives such as TMSCl, 1,2-dibromoethane,b romine,o ri odine. [10,11] All of the methods described for preparing activated zinc require an inert atmosphere,a nd those derived from zinc metal are highly dependent on the physical form of zinc used, with multiple different forms of zinc commercially available (Scheme 2, and photograph in the Supporting Information). We have identified mechanical activation, by ball-milling,a s ag eneral technique that could simplify and enable organometallic chemistry by obviating the need for strictly dry solvents and specific base metal forms whilst providing greater reproducibility in the generation of these important materials.…”

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Mechanochemical Activation of Zinc and Application to Negishi Cross‐Coupling

et al. 2018

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A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross‐coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3)–C(sp2) and C(sp2)–C(sp2) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods.

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Enolization in the Reformatsky Reaction

Cited by 19 publications

References 0 publications

A novel intramolecular homologation of a phthalimide group. 1,5,8-Trioxobenz[f]indolizidine

A novel intramolecular homologation of a phthalimide group. 1,5,8-Trioxobenz[f]indolizidine

Diastereoselective Synthesis of Pentasubstituted γ‐Butyrolactones from Silyl Glyoxylates and Ketones through a Double Reformatsky Reaction

Mechanochemical Activation of Zinc and Application to Negishi Cross‐Coupling

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