Acrylonitrile, 2- addition reactions with enolates

Brown proposed a mechanism where the enolate radical resulting from the radical addition reacts with the trialkylborane to give a boron enolate and a new alkyl radical that can propagate the chain (Scheme 24) [61]. The formation of the intermediate boron enolate was confirmed by H NMR spectroscopy [66,67]. The role of water present in the system is to hydrolyze the boron enolate and to prevent its degradation by undesired free-radical processes. This hydrolysis step is essential when alkynones [68] and acrylonitrile [58] are used as radical traps since the resulting allenes or keteneimines respectively, react readily with radical species. Maillard and Walton have shown by nB NMR, ll NMR und IR spectroscopy, that tri-ethylborane does complex methyl vinyl ketone, acrolein and 3-methylbut-3-en-2-one. They proposed that the reaction of triethylborane with these traps involves complexation of the trap by the Lewis acidic borane prior to conjugate addition [69]. 

We end this chapter with a simple commercial synthesis of a drug molecule described as a dopaminergic antagonist. It uses four reactions that you have met conjugate addition of an enolate to acrylonitrile reduction of CN to a primary amine alkylation and reduction of the amide. There is another reaction involved—cyclization to an amide—but this occurs spontaneously. These reactions may be simple but they are important. 

Michael Addition. Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and f-butyl acrylate react with excellent diastereoselection (eq 21 ). - Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(0-j-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass p-substituted, a,p-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substimted unsamrated esters do not act as competent Michael acceptors at all under these conditions. 

Arynes react readily with simple alkenes to give either benzocyclobutenes or substituted benzenes (Scheme 7.31). The formation of benzocyclobutenes by [2+2] cycloaddition reaction of the aryne to the alkene proceeds best for strained and electron-rich carbon-carbon (C=C) double bonds. For example, dicyclopentadiene reacts to give the ex o-isomer of the corresponding four-membered ring in good yield. The addition to cyanoethene (acrylonitrile) and the reaction with the electron-rich ethoxyethene (ethyl vinyl ether) gives the cyano- and ethoxy-benzocyclobutenes in 20% and 40% yields, respectively. The latter reaction almost certainly involves nucleophilic addition of the enol ether to the electrophilic aryne followed by coUapse... 

Whereas dibutylboron enolates may be used as specific enolates in aldol condensations, their reactions with alkyl halides are relatively poor. However, the addition of one equivalent of lithium 2-dimethylaminoethoxide results in site-specific mono-a-alkylation in excellent yield. Organotin enamines add to electrophilic alkenes such as acrylonitrile. The use of an optically active... 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

This reaction appears to be generally applicable to dienophiles. Acrylonitrile or fumaronitrile react with triethyl phosphite in ethanol to provide the corresponding j -cyanophosphonate esters (44% and 55%, respectively). Ethyl propiolate, triethyl phosphite, and ethanol furnish diethyl 2-carbethoxy-l-ethoxyethylphosphonate, which most probably arises by addition of ethanol to an intermediate species rather than to reactant or product. Reaction of crotonaldehyde with triethyl phosphite in phenol provides the diphenyl acetal of jS-(diethoxyphosphinyl) butyraldehyde (36) (82%). Substitution of ethanol for phenol in this reaction results in a somewhat lower yield (59%) of the corresponding diethyl acetal as well as a 19% yield of the ethyl enol ether of this same aldehyde. 

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