Acrylonitrile conjugate addition

Indoles can also be alkylated by conjugate addition under alkaline conditions. Under acidic conditions, alkylation normally occurs at C3 (see Section 11.1). Table 9.1 includes examples of alkylation by ethyl acrylate, acrylonitrile, acrylamide and 4-vinylpyridine. 

Acrylonitrile (H2C=CHC=N) readily undergoes conjugate addition when treated with... 

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 ... 

Attachment of a basic amino group to the side chain leads to a compound with antiparkinsonian activity. Alkylation of the carbanion from phenylacetonitrile with 2-chlorotriethylamine affords the product, 36. Conjugate addition of the anion from this to acrylonitrile gives the glutarodinitrile (37). Partial hydrolysis of this in a mixture of sulfuric and acetic acid leads to phenglutarimide (38). ... 

BF3 —Cu— R Conjugate addition, including acrylate esters and acrylonitrile S substitutionof allylic halides k... 

Lengthening the side chain produces the antidepressant maprotiline (73), which has a topological relationship to the clinically useful tricyclic antidepressants. The requisite acid is constructed by conjugate addition of the carbanion of anthrone (64) to acrylonitrile, followed by hydrolysis to give 70. Reduction of the carbonyl group with zinc and ammonia gives anthracene 71 by dehydration of the intermediate... 

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]. 

Lithium butyldimethylzincate, 221 Lithium sec-butyldimethylzincate, 221 Organolithium reagents, 94 Organotitanium reagents, 213 Palladium(II) chloride, 234 Titanium(III) chloride-Diisobutylalu-minum hydride, 303 Tributyltin chloride, 315 Tributyl(trimethylsilyl)tin, 212 3-Trimethylsilyl-l, 2-butadiene, 305 Zinc-copper couple, 348 Intramolecular conjugate additions Alkylaluminum halides, 5 Potassium t-butoxide, 252 Tetrabutylammonium fluoride, 11 Titanium(IV) chloride, 304 Zirconium(IV) propoxide, 352 Miscellaneous reactions 2-(Phenylseleno)acrylonitrile, 244 9-(Phenylseleno)-9-borabicyclo[3.3.1]-nonane, 245 Quina alkaloids, 264 Tributyltin hydride, 316 Conjugate reduction (see Reduction reactions)... 

Few examples exist for the conjugate addition of ester enolates to a,(3-unsaturated esters typically the incipient enolate undergoes decomposition and secondary reactions. The first examples, described by Schlessinger,144 are the addition of /-butyl lithioacetate and /-butyl a-lithio-a-(methylthio)propionate to butenolide (176 Scheme 69). Similarly, Normant reported that cyclopropanes are obtained from a-ha-loesters (177) and ethyl acrylate or acrylonitrile.145... 

The polarisation produced by co-ordination to the metal may be transmitted through a conjugated system. Michael addition reactions of nucleophiles to TV-bonded acrylonitrile are known, and provide a convenient method for the preparation of derivatives. A wide range of nucleophiles may be used in these conjugate additions. For example, the anion of nitromethane (generated in situ) reacts with the ruthenium(m) complex [Ru(NH3)5N=CCH=CH2)]3+, 4.6, to yield a complex of 4-nitrobutyronitrile (Fig. 4-18). 

The following outlines a synthesis of (3-alanine in which conjugate addition to acrylonitrile plays a key role. 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Supposing there is no oxygen-based functionality at all, as in the diamine 23 It is not necessary to have a carbonyl group for conjugate addition, in fact a nitrile is much better. So we do FGI on the primary amine and disconnect the secondary amine Et2NH from acrylonitrile 25. The synthesis is to mix those two and reduce 24 catalytically or with LiAlH4-... 

Other groups beside nitro can be reduced in the same step. So the diamine 19, needed for polyamine manufacture, could come from the unsaturated nitro compound 20 that would in turn come from an aldol reaction between the anion of nitromethane 1 and the aldehyde 21. This has a 1,5-diX relationship and acrylonitrile 23 is excellent at conjugate addition (chapter 21) so we can use isobutyraldehyde 24 as a starting material. 

Propose a mechanism for the conjugate addition of a nucleophile (Nuc ) to acrylonitrile (H2C = CHCN) and to nitroethylene. Use resonance forms to show how the cyano and nitro groups activate the double bond toward conjugate addition. 

The first step is conjugate addition, exactly as we saw with acrylonitrile at the beginning of this chapter. The second step shows the return of the negative charge and the expulsion of the best leaving group. Thiols are acidic compounds, and MeS ... 

The regioselectivity of enolata formation is governed by the usual factors so that methyl benzyl ketone forms the more stable enolate with sodium metal. This undergoes smooth and rapid conjugate addition to acrylonitrile, which is unsubstituted at the (3 position and so very reactive. 

The simplest amino acid, glycine, would be an ideal starting material for the synthesis of more complicated amino acids but it does not easily form enols or enoiates. The methyl ester of the ben-zaldehyde imine has two electro n-withdra wing groups to help stabilization of the enolate and conjugate addition of acrylonitrile is now possible. The base used was solid potassium carbonate with a quaternary ammonium chloride as phase transfer catalyst. Simple hydrolysis of the alkylated product leads to the extended amino acid. 

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. 

In this example a f-butyl radical does conjugate addition on to acrylonitrile. 

A large number of aza crowns are made by these routes. Stepwise addition of CH2CH2NHTs groups occurs readily by reaction of the appropriate tolu-enesulfonamide with 2-bromoacetamide followed by borane reduction and A-tosylation. If a trimethylene spacer is desired, then reaction of the tosyla-mide with acrylonitrile followed by reduction and tosylation gives good yields of the desired product (Scheme 1.2). An example of such a sequence is provided by the synthesis of the symmetrical [24]-N6 cycle, 4 (Scheme 1.3).9 In this particular case, introduction of the desired C3 spacer was undertaken on the. electrophilic component by conjugate addition of the tosylamide with methyl acrylate followed by reduction with LiAlH4 and mesylation. 

Enantioselective Copjugate Additions. The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,p-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine. Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2) ... 

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