A,3-Unsaturated nitriles

The allyl cyanoacetate 731 can be converted into an a, /3-unsaturated nitrile by the decarboxylation-elimination reaction[460], but allyl malonates cannot be converted into unsaturated esters, the protonation and allylation products being formed instead. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,/3-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and /3-keto and a-alkynic nitriles with hydroxylamine (62HC(l7)l, pp. 3,7). 

Among the most successful classes of asymmetric acyl anion equivalents are the dioxane-containing a-amino nitriles 99 introduced by Enders and coworkers. These are deprotonated by EDA, and the resulting anions act as efficient equivalents of RCO for addition to a, (3-unsaturated esters [90AG(E)179],... 

Interaction of carbonyl compounds with a, (3-unsaturated nitriles as a convenient route to carbo- and heterocycles 98UK442. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

In a, 3-unsaturated ketones, nitriles, and esters (e.g., 125), the y hydrogen assumes the acidity normally held by the position a to the carbonyl group, especially when R is not hydrogen and so cannot compete. This principle, called vinylology, operates because the resonance effect is transmitted through the double bond. However, because of the resonance, alkylation at the a position (with allylic rearrangement) competes with alkylation at the y position and usually predominates. 

Although hydrogenation of A-benzylideneaniline in the presence of 11 afforded the corresponding product (eq. 1 in Scheme 11), the a,(3-unsaturated ketone was converted into a mixture of unsaturated and saturated alcohols in the 42 56 ratio (eq. 2 in Scheme 11). Several substrates (nitrile derivatives, epoxides, esters, internal alkynes, and terminal alkenes), which are shown in Fig. 4, are not hydrogenated in this catalytic system. 

Isoxazolines are good precursors of a,(3-unsaturated ketones.63,94 This transformation is useful for synthesis of polyenes. For example, nitrile oxide cycloaddition chemistry is used to prepare 4-oxo-2-alkenylphosphonates, which are useful to synthesize a long polyethylenic unit via Woodworth-Emmons olefination (Eq. 8.66).101... 

Naphthoquinone, ketone-alcohol reduction, diastereoselectivity, 76-77 Nitrile reduction, a,/3-unsaturated nitriles, 96... 

The C0/H20 systems have been used to catalyze hydrogenation of olefins in Reppe hydroformylation 437), and a Rh6(CO)16-catalyzed system has been used to reduce the olefinic bond in a,/3-unsaturated carbonyls and nitriles 337, 338, Section IV,A). 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Dioxolanes 39 derived from a, 3-unsaturated aldehydes react with nitrile oxides R2CNO to give the corresponding isoxazolines 40 with the 1,3-dioxolan-2-yl substituent in position 4 as main products, and their 5-isomers as minor products with good regioselectivity and synthetically useful yields. The corresponding... 

Lowe H, Hessel V, Hubbard S, Lob P (2006) Addition of secondary amines to a, 3-unsaturated carbonyl compounds and nitriles by using microstructured reactors. Org Proc Res Dev 10 1144-1152... 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Table 21 Ring closures to [1,2,4]triazolo[1,5-a]pyrimidines by reaction of 3-aminotriazoles with a,/3-unsaturated ketones, esters, or nitriles...

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