Alkyne To nitrile

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)... 

The catalytic transformation of alkynes has been a hot research topic in the community for its wide application in synthesis of useful molecules, such as ketones, carboxylic acids, and polycyclic hydrocarbons [144—146]. Recendy, C=C triple bonds have been developed as the new carbon source in nitrile synthesis. In addition, transformation of alkynes to nitriles via C-H bond functionalization is also included in this section. 

Transformation of Alkynes to Nitriles via C=C Triple Bond Cleavage... 

The direct formation of nitriles via C=C bond cleavage was untouched until Jiao and co-workers developed a concise silver-catalyzed transformation of terminal alkynes to nitriles [147]. Ag2C03 was the indispensable catalyst to the reaction. Other transition-metals did not work well in this reaction. TMSN3 and DMSO were the best choice of nitrogen source and solvent respectively. 

Scheme 4.42 The silver catalyzed direct transformation of alkynes to nitriles...

Scheme 4.47 Transformation of alkynes to nitriles using tert-buiyl nitrite as nitrogen source...

Okamoto N, Ishikura M, Yanada R (2013) Cleavage of catbon=caibon triple bond direct transformation of alkynes to nitriles. Org Lett 15(ll) 2571-2573... 

Cycloaddition reactions also have important applications for acyclic chalcogen-nitrogen species. Extensive studies have been carried out on the cycloaddition chemistry of [NSa]" which, unlike [NOa]", undergoes quantitative, cycloaddition reactions with unsaturated molecules such as alkenes, alkynes and nitriles (Section 5.3.2). ° The frontier orbital interactions involved in the cycloaddition of [NSa]" and alkynes are illustrated in Fig. 4.13. The HOMO ( Tn) and LUMO ( r ) of the sulfur-nitrogen species are of the correct symmetry to interact with the LUMO (tt ) and HOMO (tt) of a typical alkyne, respectively. Although both... 

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 chemoselectivity of Schwartz s reagent (1) toward alkynes, alkenes, nitriles, and carbonyl groups, and thus its general functional group compatibility, can be modulated. However, it is important to keep in mind that the presence of functional groups may have regiochemical consequences on the hydrozirconation reaction. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

The photoelimination of carbon dioxide from esters and lactones is a process that has been the subject of detailed investigations. Discussion here is limited to nitrogen containing systems. 3,4-Diphenylsydnone (464), on irradiation in benzene, is converted via the nitrile imine 465 into 2,4,5-triphenyl-1,2,3-triazole (466)388 initial bond formation between N-2 and C-4 followed by loss of carbon dioxide to give the diazirine 467 is proposed to account for the formation of the nitrile imine. Nitrile imines generated in this way have been trapped with alkenes and alkynes to give pyrazoles389... 

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]. 

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. 

The penam nitrile oxide 36 underwent 1,3-DC reactions with various alkenes and alkynes to give cycloadducts of general formula 37. The corresponding acids (37 R=H) exhibited potent P-lactamase inhibitory activity <00OL3087>. 

Novel transition metal-mediated strategies were also well represented this past year. Takahashi and co-workers reported a s nickel-catalyzed reaction between azaziconacyclopentadienes (9) and alkynes to form pyridines (10) of varying substitution patterns <00JA4994>. This methodology, a formal cyclotrimerization, is also noteworthy since two different alkynes can be used. In similar fashion, Eaton reported an aqueous, cobalt(II) catalyzed cyclotrimerization between two identical acetylenes and one nitrile to afford substituted pyridines . 

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. 

Larock et al. reported the palladium-catalyzed reactions of alkynes and nitriles with 2-iodophenyl group (Equations (116)-(118)).473,473a 473c Ketones and naphthylamines are obtained presumably through the formation of vinylpalladium species followed by their addition to nitriles to afford palladium imine intermediates. 

The potential synthetic utility of titanium-based olefin metathesis and related reactions is evident from the extensive documentation outlined above. Titanium carbene complexes react with organic molecules possessing a carbon—carbon or carbon—oxygen double bond to produce, as metathesis products, a variety of acyclic and cyclic unsaturated compounds. Furthermore, the four-membered titanacydes formed by the reactions of the carbene complexes with alkynes or nitriles serve as useful reagents for the preparation of functionalized compounds. Since various types of titanium carbene complexes and their equivalents are now readily available, these reactions constitute convenient tools available to synthetic chemists. 

In the presence of Co(I)-catalysts alkynes and nitriles can be co-trimerized in organic solvents to yield substituted pyridines under rather harsh conditions. The reaction is biased by formation of large quantities of benzene derivatives and with acetylene gas as much as 30 % of all products may arise from homotrimerization. It has been found recently, that with cobalt(I) catalysts heterotrimerization of various nitriles and C2H2 could be achieved under ambient conditions using aqueous/organic biphasic systems and irradiating the reaction mixture with visible light (Scheme 7.12) [39,40]. 

Hydration of olefins, alkynes and nitriles calls explicitely for the use of aqueous solvents. Indeed, one of the earliest investigations originates from 1969, when hydration of fluoroalkenes were studied with Ru(II)-chloride catalysts (Scheme 9.6). The reaction has no synthetic value but the studies helped to clarify the mechanism of the interaction of olefins with Ru(II)... 

The cobalt-catalyzed pyridine synthesis is the only known one-step process for the selective preparation of the industrially significant 2-substituted-pyridine derivatives. Moreover, the method is applicable to a broad variety of substituted alkynes and nitriles, thereby giving access to a whole range of pyridine derivatives having 1,2,3 or 5 substituents in the ring. Selected examples follow and are compared to the prior state of the art. 

The cobalt catalyzed cocyclization of alkynes with heterofunctional substrates is not limited to nitriles. cpCo-core complexes are capable of co-oligomerizing alkynes with a number of C,C, C,N or C,0 double bonds in a Diels-Alder-type reaction. Chen, in our laboratories, has observed that these cycloadditions are best performed with the help of stabilizers such as ketones or acetic esters that are weakly coordinated to the cobalt and prevent the alkynes from being cyclotrimerized at the metal center... 

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