Nitriles, electron-deficient

In contrast to other furoxans, the cycloreversion of 3,4-dinitrofuroxan to nitro-formonitrile oxide was observed even at room temperature. The nitrile oxide could be trapped in situ with electron-deficient nitriles (Scheme 149) (95MC231). Attempts to obtain cyclo adducts with styrene, phenylacetylene, rran.s-stilbene, and cyclohexene failed. 

Based on this work, Itoh and co-workers developed ruthenium(n)-catalyzed [2 + 2 + 2]-cyclotrimerizations of 1,6-diynes 174 and electron-deficient nitriles (Equation (34)),368>368a These partially intramolecular cycloadditions proceed through ruthenacycle intermediates as well. The importance of using electronically activated nitriles is underlined by the fact that acetonitrile and benzonitrile gave only very low yields. 

Electron-deficient nitriles, such as for instance trichloroacetonitrile and trifluoroacetonitrile (A=B A = N B = CCC13, CCF3), are known to undergo direct and reversible, base-catalyzed addition of alcohols providing O-alkyl trichloroacetimidates (1,50). This imidate synthesis has the advantage that the free imidates can be isolated as stable adducts, which are less sensitive to hydrolysis than their corresponding salts. 

The 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles yields 3,5-disubstituted 1,2,4-thiadiazoles of unequivocal structure. This method has received considerable attention in recent years. Electron deficient nitriles such as tosyl cyanide afford high yields of 5-tosyl derivatives (341) (Equation (53) see also Scheme 61) <93JHC357). 

Reaction between trichloroacetonitrile and Ph2CN2 at low temperatures yields 67 other electron-deficient nitriles give different products. It is possible that the reaction proceeds via an unstable 3//-1,2,4-triazole intermediate, which loses N2 to form a nitrile ylide before adding a second mole of nitrile as in Scheme 13. 

A special case involves the thermal decomposition of 3,4-dinitrofuroxan (104). The cycloreversion is already observed at room temperature and the nitroformo-nitrile oxide could be trapped with electron-deficient nitriles. The cycloadditions with styrene, phenylacetylene, frani-stilbene, and cyclohexene, however, led to complex mixtures of products that could not be separated (104). In the related case of a furoxan with an a-hydrogen adjacent to the sulfonyl group, the reaction was proposed to proceed according to course (b) (Scheme 6.7). 

The reaction of 69 with electron-deficient nitriles furnished 4//-1,3-ben zothiazines358 and a wide array of cumulenes were allowed to react with this intermediate359. On the other hand, the reaction with styrenes afforded a variety of benzothiapyrans487. 

Strategies to pyridines include a ruthenium-mediated [2+2+2] cycloaddition to produce annulated products <20010L2117>. Reaction of 1,6-heptadiynes with electron-deficient nitriles yields the pyridine (Equation 175), whereas the same strategy using isocyanates leads to the 2-pyridone (Equation 176). 

Bicyclic pyridines were regioselectively formed by reaction with electron-deficient nitriles [97] or dicyanides [98] (Eq. 75). 

There is only sparse literature on [4 + 2] cycloadditions of nitriles with 1,3-dienes. In general, simple alkyl and aryl nitriles will only react at high temperatures and under these conditions the product dihy-drc yridines usually disproportionate.However, certain types of electron-deficient nitriles appear to be reactive dienophiles under milder conditions. For example, aiylsulfonyl cyanides cycloadd to 1,3-dienes to afiord adducts as shown in Scheme 1This methodology has not been widely explored and little is known about the regiochemistry of the process. 

The original imidate procedure was further developed by Schmidt [283] with the introduction of trichloroacetimidates. The electron-deficient nitrile, trichloroacetonitrile, readily adds to the free hydroxyl of lactols under basic conditions. In the presence of a weak base, such as potassium carbonate, the (3-imidate 122 can be isolated as the kinetic product, whereas the use of strong bases, such as sodium hydride or DBU, results in the formation of the thermodynamically more stable a-trichloroacetimidates 123 [284,285] (Scheme 4.20). 

Ene reactions of electron-deficient nitriles and trisubstituted alkenes in the presence of boron trichloride offer related routes to 3,7-unsaturated ketones. ... 

Bis(trifluoromethyl)-l,3-diazabuta-1,3-diene 18 reacts with cyanamide, acetonitrile, and benzonitrile to give [4 + 2] cycloadducts, l,4-dihydro-l,3,5-triazines 22 (84CZ205). With electron-deficient nitriles (trifluoroacetonitrile, trichloroacetoni-trile, and 4-chlorophenylaza-nitrile) the six-membered heterocycle undergoes a skeletal rearrangement forming 23 (Scheme 22). 

Cp Ru(cod)Cl affords pyridone 3 in excellent yield <01OL2117>. The authors have also shown that the same strategy can be applied with 1,6-heptadiynes and electron-deficient nitriles (i+4 5) <01CC1102>. Other metal-mediated processes include the formation of pyridines through the palladium-catalyzed cyclization of olefinic ketone O-pentafluorobenzoyloximes <01CL526>. 

Cu2(OTf)2 PhH complex was used to catalyze tetrazole formation from alkyl azides and electron deficient nitriles. In this instance, the sterics seem to modulate the amount of 1,5- and 2,5-disubstituted tetrazoles. Increased Cu loading provided more 2,5-disubstituted tetrazole. Bosch et al. reported either stirring at room temperature or using microwave irradiation to promote the reaction. Mild conditions and modest to excellent yields of the 1,5-disubstituted tetrazole 41 were reported using 10 mol% catalyst. However, when more than 50 mol% of Cu2(OTf)2 PhH complex was used, the 2,5-disubstituted tetrazole predominated. The rationale for the difference in selectivity was suggested to be due to Cu forming a complex, with both the nitrile and the azide and altering the mode of addition. 

A systematic study on the use of [CpCo(CO)(dmfu)] (dmfu = dimethyl fumarate) [12] as a precatalyst for the cocyclization of alkynes and nitriles was published in 2011 [13]. By this catalyst, the incorporation of electron-deficient nitriles into the pyridine core was realized. 3- or 4-Aminopyridines can be produced regioselectively by modifying the substitution pattern at the yne-ynamide. Based on DFT computations, the author suggested that 3-aminopyridines are formed by formal [4 + 2] cycloaddition between the nitrile and the intermediate cobaltacyclopenta-diene, whereas 4-aminopyridines arise from an insertion pathway. This catalytic system was applied in the synthesis of bicyclic 3- or 4-aminopyridines from yne-ynamides and nitriles (Scheme 3.1) [14]. 

In addition to cobalt catalysts, ruthenium catalysts were applied in [2 + 2 + 2] cycloaddition reactions as well. In 2001, Itoh and coworkers reported a ruthenium-catalyzed cyclization of 1,6-diynes with dicyanides to produce the desired bicyclic pyridines in good yields [28]. By applying Cp Ru(cod)Cl (Cp = pentamethylcyclopentadienyl) as the catalyst, good yields of the products can be achieved (Scheme 3.12). Meanwhile, they explored the catalyst system in cyclization of 1,6-diynes with electron deficient nitriles as well. The desired bicyclic pyridines can be isolated in moderate to high yields [29]. Later on, in 2005, Yamamoto and coworkers performed systematic studies on this... 

In 2003, Saa and coworkers performed a comprehensive study on cationic [Cp Ru(CH3CN)3]PF6 complex-catalyzed [2 -I- 2 -I- 2] cycloaddition of 1,6-diynes to a,CT-dinitriles or electron-deficient nitriles (Scheme 3.13) [33]. The reaction with asymmetric electron-deficient alkynes could give the corresponding 2,3,6-trisubstituted pyridines in good yield. Based on their studies, they propose that the reactions with dinitriles seem likely to proceed via ruthenacyclopentadiene intermediates and the reactions with electron-poor nitriles via azaruthenacyclopentadienes. 

In 2011, Nissen and Detert [9] reported a partially intramolecular [2+2+2] aromatization for the synthesis of lavendamycin (Scheme 9.4). Lavendamydn is an antitumor antibiotic produced by Straptomyces lavendulae. Both Rh and Ru catalyses were used for this [2+2+2] cycloaddition of a 1,6-diyne and an electron-deficient nitrile. What was interesting was the observation that the symmetrical adduct was always preferred with Rh catalysis, and when Ru catalysis was employed, only the desired unsymmetrical p-carboline product was obtained. The pentacyclic core of lavendamycin was then converted to lavendamydn methyl ester via a sequence of functional group manipulations. 

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. 

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