Michael acceptors unsaturated nitriles

Another less common class of nucleophile that does conjugate addition is nitriles. We used unsaturated nitriles a moment ago as Michael acceptors, and nitriles are usually electrophiles rather than nucleophiles. We did see in Chapter 17 that nitriles will act as nucleophiles in the S>jl reaction (the Ritter reaction). The next reaction is related to the Ritter reaction. 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Rovis and co-workers have also shown that pre-catalyst 129 is competent with a wide range of Michael acceptors including oc,P-unsaturated aldehydes, amides, nitriles, esters, thioesters, vinylphosphonates and vinylphosphine oxides (Scheme 12.25) [58,60],... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Co(III)] complexes. For example, the coupling of 3-halocholestanes (333) and Michael acceptors affords epimeric mixtures of the 3-homologated steroids (334). The electrochemical nucleophilic acylation of a, 3-unsaturated aldehydes, a,3-unsaturated ketones and a,(3-unsaturated nitriles with acyl anhydrides affords adducts (335) in moderate yields.226a-b Similarly, the reduction of N-methyloxazolinium salts (336) affords die A, O-acetal intermediates (337) which are readily hydrolyzed (Scheme 102).226c... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Conjugate addition to acyclic Michael acceptors. Sakurai and Hosomi (9, 445-446) reported one example of the fluoride ion-catalyzed reaction of allyltrimethylsilane with an acyclic enone. In that case (reaction with C6H5CH=CHCOCH,). 1.2- and 1,4-adducts are obtained in the ratio 2 1.1,4-Addition is enhanced by use of DMF and HMPT as solvent and by increase in the size of the group adjacent to the carbonyl group. 1,4-Addition is the main or predominant reaction with a,3-unsaturated esters or nitriles. In this case, it is superior to or competitive with allylation with lithium diallylcuprate. Yields in 1,4-additions to a,p-enones can compare favorably with those obtained with reactions catalyzed by TiC. ... 

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. 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

A wide variety of Michael acceptors have been reacted with sulfoxonium methylides, e.g. a,p-unsaturated ketones, nitriles, sulfones, sulfonamides and nitro compounds, to give good yields of the corresponding cyclopropane derivatives.1,2a Steric hindrance may decrease the rate of reaction but need not prevent reaction for example, the very hindered compound 4,6,6-trimethyl-3-hepten-2one (61) reacts with dimethylsulfoxonium methylide (33) to give the cyclopropane (62) (Scheme 24). 

Oxo-2-cyclohexenyl-2-carbonitrile is an exceptional Michael acceptor that reacts conjugately with Grignard reagents without catalysis.3 In most cases the intermediate enolates are silylated to afford substituted p-siloxy unsaturated nitriles, several of which are excellent precursors to cis- and trans-decalins (Scheme 3).8 For example, unmasking the latent ketone enolate of siloxy unsaturated nitriles provides... 

The reaction of Michael acceptors with dimethyloxosulfonium methanide has been extensively explored.3 4,111 112 115 In addition to carbene (or carbenoid) additions (Section 1.2.1.) and the Simmons-Smith method,114 (see also Section 1.2.1.1,) this is the most widely utilized method for the introduction of a cyclopropane ring, in good to excellent yield, to a,/J-unsaturated ketones,120- 126 esters118 120,122,128 - 130,132 amides,118,119 133 nitriles,1l8-119,126 isonit-... 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Both pyrrole and indole anions are sufficiently nucleophilic to react with Michael acceptors such as unsaturated esters, ketones and nitriles. When the reaction is done under alkaline conditions the alkylation usually occurs at nitrogen. Pyrrole and indole are also reactive Michael acceptors under... 

A reminder from Chapter 22 a Michael acceptor is a compound capable of undergoing conjugate addition—an a,[5 unsaturated carbonyl compound or nitrile for example. Many Michael acceptors are toxic and carcinogenic compounds, and must be handled with care. 

Michael acceptors a,p-unsaturated nitriles, esters, and ketones. 

More than forty years ago, Stetter reported for the first time a different reactivity of the Breslow intermediate that involved a nucleophilic attack to an electron-deficient alkene, a Michael acceptor, giving access to 1,4-dicarbonyl compounds.This reaction can happen under conditions where the benzoin condensation is reversible and allows the use of a,p-unsaturated esters, ketones, nitriles, sulfones or phosphonates. " Regarding the mechanism, studies have yet to be conducted, and the current proposal is based on the one disclosed by Breslow for the benzoin reaction (Scheme 2.20). ... 

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

The asymmetric conjugate addition of activated methylenes is one of the most studied organocatalytic reactions. A wide variety of Michael acceptors such as enals, enones, a,P-unsaturated nitriles, nitroolefins, a,(i-unsaturated imides, and vinyl sulfones have been successfully employed as elechophiles with high degree of stereocontrol. 

Acrylic acid derivatives as well as a,p-unsaturated nitriles, imides, phosphonates, and sulfones have been also studied as Michael acceptors for activated methylenes. Dixon et al. have demonstrated the efficacy of bifunctional cupreidine 125 (Fig. 2.12)... 

The use of unsaturated nitriles as Michael acceptors represents a facet of the synthetic utility of cyano-compounds that nicely complements the reactivity discussed above. Michael addition of 2-lithio-1,3-dithianes to a,B-unsaturated nitrile derivatives appears to be of use in the preparation of protected cyanoketones, although the method may be limited by the fact that reactions of substrates unable to stabilise the negative charge of the adduct before workup were difficult to achieve satisfactorily. 

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