Nitrile To alkene

Asymmetric cycloaddition of functionalized alkenes to nitrile oxides and nitrones 98YGK11. 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

The 1,3-dipolar cycloaddition of alkenes to nitrile oxides is a fundamental reactions because the resulting isoxazolines are very useful building blocks ... 

The traditional transformations towards aryl nitriles usually require harsh conditions. One of the groundbreaking researches in the direct transformation of alkenes to nitriles was reported by Denton et al. in 1950 (Scheme 4.12) [98]. In this alumna supported molybdic oxide catalyzed ammoxidation, alkyl and alkenyl aromatic hydrocarbons were converted to aromatic nitriles at high temperatures (524-552 °C). 

Transformation of Alkenes to Nitriles via C=C Double Bond Cleavage... 

Scheme 4 32 Eaily work in the transformation of alkenes to nitriles...

On the whole, the cycloaddition of alkynes to nitrile N-oxides is one of the most important routes to isoxazoles, but in spite of its potentially wide application, its synthetic utility is less than that of the corresponding reaction with alkenes for the following reasons. (1)... 

Rahman and Clapp decomposed dinitromethane derivatives in DMF in the presence of alkenes to obtain 2-isoxazolines. Without any alkene present, an acid and KNO2 were obtained. They proposed a mechanism which proceeded via a three-membered ring or a nitrocarbene which rearranged to a nitrile oxide (76JOC122, 75MI41612). 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

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... 

Treatment with alkaline H2O2 oxidizes trialkylboranes to esters of boric acid. This reaction does not affect double or triple bonds, aldehydes, ketones, halides, or nitriles. The R group does not rearrange, and this reaction is a step in the hydro-boration method of converting alkenes to alcohols (15-16). The mechanism has been formulated as involving a rearrangement from boron to oxygenr ... 

Alkenes of the form RCH=CHR and RR C=CH2 add to nitriles in the presence of mercuric nitrate to give, after treatment with NaBHj, the same amides that would be obtained by the Ritter reaction. This method has the advantage of avoiding strong acids. 

A process that is effective for epoxidation and avoids acidic conditions involves reaction of an alkene, a nitrile, and hydrogen peroxide.82 The nitrile and hydrogen peroxide react, forming a peroxyimidic acid, which epoxidizes the alkene, by a mechanism similar to that for peroxyacids. An important contribution to the reactivity of the peroxyimidic acid comes from the formation of the stable amide carbonyl group. 

The synthesis of nitrogen containing heterocyclic systems by photocylo-addition processes is virtually limited to examples involving [ 2 + 2] cycloaddition of imines, nitriles, and azo compounds. Successful additions are few in number and the requirements for success uncertain. The reactions do not proceed with the facility with which carbonyl containing compounds undergo photocycloaddition to alkenes to give oxetans, and various explanations have been advanced to account for this observed lack of reactivity.226... 

One obvious synthetic route to isoxazoles and dihydroisoxazoles is by [3+2] cycloadditions of nitrile oxides with alkynes and alkenes, respectively. In the example elaborated by Giacomelli and coworkers shown in Scheme 6.206, nitroalkanes were converted in situ to nitrile oxides with 1.25 equivalents of the reagent 4-(4,6-di-methoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 10 mol% of N,N-dimethylaminopyridine (DMAP) as catalyst [373], In the presence of an alkene or alkyne dipolarophile (5.0 equivalents), the generated nitrile oxide 1,3-dipoles undergo cycloaddition with the double or triple bond, respectively, thereby furnishing 4,5-dihydroisoxazoles or isoxazoles. For these reactions, open-vessel microwave conditions were chosen and full conversion with very high isolated yields of products was achieved within 3 min at 80 °C. The reactions could also be carried out utilizing a resin-bound alkyne [373]. For a related example, see [477]. 

Nitrile oxides generated under neutral conditions by thermal fragmentation of nitrolic acids 32, were trapped in situ with alkenes to afford isoxazolines 33 in 53-97% yields <00TL1191>. Nitrile oxides were also produced by treating O-silylated hydroxamic acids 34 with triflic anhydride and TEA . ... 

The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane, provides 9,ll-ethano-13,15-isoxazolinoprostanoids, PGH analogs, with alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (461). Chemical transformations of 9,11-ethano-13,15-isoxazolinoprostanoids furnish prostanoids with bifunctional fragments of P-hydroxyketone and a-aminoalcohol in the oo-chain. The reaction of P-hydroxy ketones with methanesulfonyl chloride gives rise to prostanoids with an enone component in the oo-chain. 9,ll-Ethano-16-thiaprostanoids have been prepared, for the first time, by nucleophilic addition of thiols to the polarized double bond in the oo-chain. The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane provides 9,ll-ethano-13,15-isoxazolinoprostanoids with an alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (462). 

Recently, addition of organorhodium species to nitriles has been reported.420 4203 4201 Intermolecular reaction of benzonitrile with phenylborate (accompanied with r//w-aryiation) (Equation (65)), arylative cyclization of acetylenic nitriles (Equation (66)), and cyclization of 2-cyanophenylboronic acid with alkynes or strained alkenes (Equation (67)) are proposed to proceed via this process. 

Unsaturated esters and silanes are not the only functionalised alkenes to have been employed as cross-metathesis substrates unsaturated alkyl chlorides [9], silylethers [10] and nitriles have all participated in metathesis reactions utilising... 

For a cis alkene to be formed the reaction would have to proceed through a czs-a,p-disubstituted metallacyclobutane intermediate (cis isomer of 10). Although it was unclear why there was a preference for forming a cis metallacycle, which leads to the thermodynamically less stable product, it was probably related to the small size or the electron-withdrawing properties of the nitrile group. 

Scheme 12. Proposed mechanism leading to the allylic imide observed as a side product in the allylic oxidation of alkenes in nitrile solvents. [Adapted from (120).]...

Kobayashi et al. developed the polymeric scandium(lll)-catalyst (42) (PA-Sc-TAD) which promotes the three-component couphng reactions of aldehydes and aromatic amines with either alkenes to generate quinohnes or silylated nucleophiles to form y9-amino ketones, esters and nitriles. This methodology turned out to be highly efficient with regard to automated high throughput synthesis (Scheme 4.27) [119]. 

The 1,3-dipolar cycloadditions of benzonitrile oxides with tertiary cinnamides yield the 5-phenyl and 4-phenyl regioisomers in a reversal of the expected regioselectiv-ities shown with methyl cinnamate. Calculations have shown that steric factors are responsible for this reversal of regioselectivity." The 1,3-dipolar cycloadditions of benzonitrile oxide with electron-rich and electron-poor dipolarophiles are accelerated by sodium dodecyl sulfate micelles. Phenyl nitrile ylides react with electron-deficient alkenes to produce five-membered -heterocycles where measured rate constants are between 4 x 10 and 7 x 10 lmoP ... 

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

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