Nitriles Michael addition with

So-called lower order cyanocuprates RCu(CN)Li do not generally react with acceptor-substituted enynes. An exception is the cuprate t-BuCu(CN)Li which undergoes anti-Michael additions with 2-cn-4-ynoates and nitriles (equation 61)151. The mechanistic aspects of this very unusual reaction are unknown radical intermediates and electron transfer steps have not been found. 

Related dendrimers possessing primary amines were synthesized135 from hexaacrylo-nitrile, a by-product in acrylonitrile polymerization, which was converted to the corresponding hexaester. Aminolysis with ethylenediamine and Michael addition with ethyl acrylate follow Tomalia s process the sequence was repeated to generate the higher generations. 

An enzymatic acrylonitrile hydration was first patented in 1981 8nitrile hydratases of different origin have been shown to be able to convert acrylonitrile into acrylamide. However, a major problem associated with biocatalysis for production of acrylonitrile is the short half-life of the enzyme due to substrate and product inhibition. Acrylonitrile is a strong alkylating agent which reacts by Michael addition with the sulfhydryl groups of proteins f 8, 69L... 

The sodium dianions obtained from acids, treated by NaNH2 in liquid ammonia are easily alkylated (refs. 28-30). These dianions have also been used for Michael addition with benzalacetophenone or ethyl cinnamate. A similar Michael addition (ref. 31) is also observed with the enolate of ethyl phenylacetate (Fig. 4). Nitriles can also be deprotonated with NaNH2 in liquid ammonia. The resulting anion was able to give aldol reaction followed by dehydration (ref. 32) or an alkylation reaction (ref. 33). 

Carbanions 26 are derived from azlactones by the action of bases. They undergo a Michael addition with alkenes possessing electron-withdrawing substituents such as acrylonitrile. On hydrolysis, the adducts 27 yield keto nitriles 28 [80] ... 

Substituted a,(3-unsaturated mono(sulfone) with other activating groups such as nitrile or ester were also applicable in the Michael addition with aldehydes. As reported by the group headed by Palomo [26], a-ethoxycarbonyl vinyl sulfones could react with aldehydes in the presence of 7 or 25 to give, after reduction and cyclization, the corresponding lactone adducts in nearly optical pure form with reasonable diastereoselectivity. Similar results were also obtained for a-cyano vinyl sulfones (Scheme 5.14). 

Nitrile anions are generated by treatment of an alkyl nitrile with a suitable base. These carbanionic reagent can undergo Michael addition with an appropriate conjugated ester to give aryl cyano-esters. Subsequent reduction of the cyano group... 

As a direct route for the constructing carbon-carbon bonds, catalytic asymmetric Michael additions with various carbon-based nucleophiles including malonic esters, cyanide, electron-deficient nitrile derivatives, a-nitroesters, nitroalkanes, Horner-Wadsworth-Emmons reagent, indoles, and silyl enol ethers have attracted considerable attention. 

Recently, the Michael addition of the optically active Q ,y-disubstituted tetronic acids 146c,e with a variety of Q ,/3-unsaturated aldehydes, ketones, esters, and nitriles was studied (Scheme 53) (99H1321). 

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 ... 

Fusion of an all cyclic ring onto the piperidine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56 onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid ( ) followed by Curtius rearrangement leads to isocyanate Acid... 

The catalytic conditions (aqueous concentrated sodium hydroxide and tetraalkylammonium catalyst) are very useful in generating dihalo-carbenes from the corresponding haloforms. Dichlorocarbene thus generated reacts with alkenes to give high yields of dichlorocyclopropane derivatives,16 even in cases where other methods have failed,17 and with some hydrocarbons to yield dicholromethyl derivatives.18 Similar conditions are suited for the formation and reactions of dibromocar-benc,19 bromofluoro- and chlorofluorocarbene,20 and chlorothiophenoxy carbene,21 as well as the Michael addition of trichloromethyl carbanion to unsaturated nitriles, esters, and sulfones.22... 

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

A new three-component approach to the highly substituted 2,5-dihydro-l,2,4-oxadiazoles 359 has been reported from the reaction of nitriles 354 under mild conditions with iV-alkylhydroxylamines 355 in the presence of electron-deficient alkynes 356 (Scheme 60) <20050L1391>. This synthesis is proposed to proceed via the initial formation of the alkyl or arylamidoximes 357, which then undergo a sequential double Michael addition to the electron deficient alkyne. The intermediate alkyl or arylamidoximes 357 can be isolated and then reacted with the alkyne to produce the product. The initial Michael adduct 358 is stable in cases where R2 is H. 

Lower order cyanocuprates RCu(CN)Li displayed again a different behavior although they usually do not react with acceptor-substituted enynes, the cyanocuprate tBuCu(CN)Li nevertheless underwent anti-Michael additions to 2-en-4-ynoates (e.g. 70) and nitriles affording allenes of type 73 (Scheme 2.26) [51]. Unfortunately, an adequate interpretation of the abnormal behavior of this particular cuprate is still lacking. 

PPI dendrimers are synthesized via the reaction sequence as shown in Fig. 2. This repetitive reaction sequence involves a Michael addition of two equivalents of acrylonitrile to a primary amine, followed by hydrogenation of the nitrile groups to primary amines. Commercially available PPI dendrimers are usually terminated with amine groups. 

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. ... 

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