Enals cyclopropanation

Enantioselective organocatalytic cyclopropanations have been performed using directed electrostatic activation conditions.164 Using a new class of iminium catalysts, cyclopropanation has been conducted with enals but not electron deficient alkenes, such as unsaturated nitrile, nitro, or alkylidene malonate systems. 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

A primary alcohol and amines can be used as an aldehyde precursor, because it can be oxidized by transfer hydrogenation. For example, the reaction of benzyl alcohol with excess olefin afforded the corresponding ketone in good yield in the presence of Rh complex and 2-amino-4-picoline [18]. Similarly, primary amines, which were transformed into imines by dehydrogenation, were also employed as a substrate instead of aldehydes [19]. Although various terminal olefins, alkynes [20], and even dienes [21] have been commonly used as a reaction partner in hydroiminoacylation reactions, internal olefins were ineffective. Recently, methyl sulfide-substituted aldehydes were successfully applied to the intermolecu-lar hydroacylation reaction [22], Also in the intramolecular hydroacylation, extension of substrates such as cyclopropane-substituted 4-enal [23], 4-alkynal [24], and 4,6-dienal [25] has been developed (Table 1). 

General Procedure of Cyclopropanation of Enals with Sulfonium Ylides [46] (p. 104)... 

The chiral version of the Simmons-Smith reaction requires the presence of proper ligands for the organozinc reagent. Representatives are 99, 100, 101 " for cyclopropanation of allylic alcohols. Enals undergo diastereoselective cyclopropanation (de >99%) via acetals with (+)-phenyl exo,ex o-2,3-dihydroxybomane-10-sulfonate. ... 

Cyclopropane formation is also observed in transition-metal-mediated conversions of pent-4-enals. This reaction proceeds via oxidative addition of the metal to the aldehyde C —H group, decarbonylation and cyclization of the resulting homoallylmetal complex. 

Substituted (2/J,3/J)-ethyl azmdine-2-carboxylates are synthesized from imines and ethyl diazoacetate. The catalyst system is composed from (PhOlsB and (Sl-VAPOL." Asymmetric cyclopropanation of electron-deficient aUcenes can be carried out with a Co(II) porphyrinate in which chiral substituents are set in two disjunct mero-positions. The presence of 129 or 130 renders the Corey-Chaykovsky method for cyclopiopana-tion of conjugated aldehydes asymmetric. Thus it is easy to access (15,2/J)-2-formylcyclo-propyl ketones from enals and acymethylsulfonium ylides. ... 

An alternate approach, pioneered by Kunz and MacMillan, proceeds by reaction of sulfur ylides with a,(3-unsaturated iminium ions, formed by reaction of a,p-enals with enantiomerically pure amines. In this approach the sulfur ylide (9.87) reacts with a range of (3-aryl- and P-alkyl-substituted enals, including (9.88), in the presence of the dihydroindole (9.89) to give the cyclopropane with ees ranging from 89 to 96%. More recently, it has been shown that replacement of the carboxylate functional group in (9.89) with an isosteric tetrazolic acid gives an improved catalyst that effects cyclopropanation with 99% ees in all cases studied. 

It is important to note that all these cyclopropanation reactions require the incorporation of a stoichiometric amount of a base additive for the reaction to proceed to completion or in order to reach full conversion in a reasonable time, which is thought to operate as scavenger of the HBr generated as the reaction proceeds. However, the presence of this basic additive has been found to promote a competitive retro-Michael process on the cyclopropane products obtained in the reaction of bromomalonates with enals, leading to... 

Vicario reported that cyclopropanation also works well in water.Using typical Cl catalyst, the reaction worked well with p-aryl substituted enals, however, it failed with alkyl enals. Therefore, they used a 4-hydro3gr>roliii derived catalyst with a long aliphatic chain C2b (Figure 8.3). Later, this laboratory introduced a dialkylamino group in the 4 position of the... 

Indoline-2-carboxylic acid /9S767-06-7/M 163.2, m 177"(dec), [a] +11.0" (c 0.3, MeOH)- Purify it as for the S-enantiomer below. The R-(+)-hydrochloride has [172152-19-1]. It is a proline based oiganocatalyst which promotes the enantioseleetive formation of cyclopropanes by reaction between 2-(dimethyl-X -sulfanylidene)-l-phenyl-ethanone (for stable sulfonium ylides see Ratts Yao J Org Chem 31 1185 1966) and but-2-enals in high yields and very high stereoselectivity involving Direct Electrostatic Activation (DEA) [Kunz Mac Millan JA/w Chem Soc 127 3240 2005.]... 

Whereas the preceding processes involving ring openings of cyclopropanes provide useful [3+2] entries to cyclopentanes, the use of simpler substrates in [3+2] cycloadditions is made possible by the development of reductive cycloaddition pathways. Such reactions were initially developed in the context of stoichiometric processes, where metallacycles were prepared by oxidative cyclizations of enones and alkynes, followed by either protonation or alkylation of the nickel 0-enolate functionality. Catalytic protocols involving various intramolecular combinations of 7t-systems include formal [3+2] reductive cycloadditions of bis-enones to form bicyclooctanols (Scheme 3-33), of enones with unsaturated acyl oxazolidinones to form triquinane derivatives, and of enals with alkynes to form bicyclooctenols. ... 

SCHEME 2.15. MacMillan s proline-catalyzed cyclopropanation of enals. 

Organocatalytic Asymmetric Synthesis of Cyclopropanes [12]. The first report of synthesis of cyclopropanes was published by MacMillan and co-workers in 2005. Their methodology deals with the reaction between enals (15) and benzoylmethyl sulfonium ylides (16) to afford the final cyclopropanes (17) in good yields and enantioselectivities (Scheme 10.8,(a)) [13]. 

In 2007 two independent contributions made by Cordova and co-workers [14] and by W. Wang and co-workers [15] reported a simple and highly stereoselective cyclopropanation via the reaction of enals (15) and 2-bromomalonates (18). Catalyst VII allowed, based on a Michael addition and subsequent intramolecular a-alkylation (i.e., a Bingel-Hirsch reaction) of the enamine intermediate, the production of the cyclopropane motif 17 (Scheme 10.9, B). 

Scheme 12.23 Tandem asymmetric epoxidation, aziridination, or cyclopropanation/ esterification of enals.

Scheme 37.13 Synthesis of functionalized cyclopropanes through [2-1-1] cycloaddition of sulfur ylides and enals (Pent= pentyl).

In contrast to the use of the specific type of sulfur ylides and related compounds, the employment of readily available alkyl halides for a catalytic Michael-alkylation reaction with enals to produce the corresponding formal [2-1-1] cycloadducts is an extremely challenging task. As an example, Wang [82a] and Cordova [82b, 83a] independently reported the enantioselective organocatalytic reaction of bromoma-lonates 78 and enals, which led to the corresponding cyclopropanes 79. In both cases, chiral diarylprolinol trimethylsilyl ethers 8 and 80 were involved as catalysts, giving access to the corresponding 2-formylcyclopropane derivatives 79 in... 

Scheme 37.14 Synthesis of functionalized cyclopropanes through the [2+1] cycloaddition of enals and arsonium ylides.

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