Hindered nitriles

A related method for the synthesis of aldehydes from nitriles has also been studied.8 This method, which has been found to be extremely effective for the reduction of hindered nitriles to aldehydes, uses moist, preformed Raney nickel catalyst in formic acid. Compounds synthesized by this method are illustrated in Table II. 

An unusual rearrangement provides the key to the preparation of a highly substituted pyrrolidone, doxapram (26-7), that is used as a respiratory stimulant. The synthesis starts with the displacement of chlorine on pyrrolidine (26-1) by the carbanion from diphenylacetonitrile (26-2) to give (26-3) as the product. The quite hindered nitrile is then hydrolyzed to the corresponding carboxylic acid (26-4) by basic hydrolysis. The reaction of acid with thionyl chloride presumably proceeds initially to form the corresponding acid chloride. The close proximity of that group to basic... 

Jiang, X., Minnaard, A.J., Feringa, B.L. and de Vries, J.G. (2004) Platinum-catalyzed selective hydration of hindered nitriles and nitriles with acid- or base-sensitive groups. J. Org. Chem., 69, 2327-2331. 

Direct dehydrogenation of oximes is also possible, particularly for sterically hindered nitrile oxides. The most successful oxidizing agents are alkaline hypobromite and NBS in the presence of base, the latter being valuable when basic groups are present. Lead tetraacetate and alkaline hypochlorite have also been employed, but the yields are lower. The formation of furoxans from the reaction of alkoximes with nitrogen oxides is believed to proceed via the corresponding nitrolic acids. 

Some authors believe that EF material is released at the external surface of zeolites. The use of hindered nitriles, however, demonstrated that the EF material produced by thermal treatment in H-MOR is in the interior of the side pockets [150]. Similarly in a sample of H-MFl, EF material was found to be located in the interior of the channels [150]. 

The external versus internal surface has also been investigated in the case of Co-H-zeolites active in the selective catalytic reduction of NO by methane [20]. The highly hindered nitrile, ortho-toluonitrile (oTN) has been used, co-adsorbed with CO and NO. The pre-adsorption of oTN poisons the external cationic sites of Co-H-ZSM5. Successive adsorption of CO shows that some of the Co ions are on the inner surface and some on the outer surface. The coadsorption of oTN and NO shows that trivalent Co ions are actually located in the internal cavity surface of Co-H-ZSM-5 while divalent Co ions distribute almost equally in the internal and external surface. 

Similarly, Co ions at the external surface of Co-H-FER and Co-H-MOR have been detected. Similar experiments with hindered nitriles show the location of alkali ions at the external surface ofalkali-MOR zeolites [160]. CO mainly adsorbs at the external surface of the small pore zeolite 3A (K-LTA) while it enters the cavities of zeolite 4A (Na-LTA) [161]. 

Raney copper is prepared from the commercially available copper aluminum alloy. It does not have much to offer the synthetic chemist as only a few reactions are reported to be affected by this catalyst. Raney copper, as well as Raney cobalt, generally produces fewer side reactions than Raney nickel even though they usually require higher reaction temperatures for the same reaction. Raney copper is, however, quite usefiil for the selective hydrogenation of substituted dinitro benzenes (Eqn. 8.6) with its activity apparently increasing with continued reuse. Raney copper can also be used for the catalytic hydrolysis of hindered nitriles to the amides (Eqn. 12.13). "2... 

Nitriles [1, 725-726, after citation of ref. 23]. The original method of Backeberg and Staskun23 for conversion of a nitrile to an aldehyde does not proceed well with hindered nitriles in this case, use of moist Raney nickel in formic acid is recommended.233 The formic acid serves as a source of hydrogen, and the nickel catalyzes both decomposition of the acid and reduction of the nitrile. 

Primary amine formation is equally well promoted in alkaline medium, e.g., aqueous ethanolic NaOH solution, that selectively poisons the catalyst for hydrogenolysis reactions. However, saturated NH3/alcohol solutions best afford almost quantitative yields of primary amines from catalytic reduction of nitriles. Ammonia adds to imine 1 to give a 1,1-diamine, which is hydrogenolyzed to the primary amine. In the presence of NHj, finely divided Ni can be used, platinized finely divided Ni for the hydrogenation of hindered nitriles, and rhodium-on-alumina for sensitive compounds. Mild reduction of 3-indoleacetonitrile to tryptamine [equation (c)] is effected at RT over 5% rhodium-on-alumina in 10% ethanolic NH3 with little side reaction , and branched chain amino sugars are conveniently prepared using this selective hydrogenation [equation (d)] . 

Nitriles give good yields of 4-aminopyridine derivatives with y-dianions, as shown in reaction 15. Very hindered nitriles, such as t-BuCN, do not undergo this reaction. ... 

The tetrazole functional group is of particular interest in medicinal chemistry, because of its potential role as a bioisostere of the carboxyl group. In this context, Schulz et al. have demonstrated the synthetic utility of the cyano group of arylni-trile boronates as a source of tetrazole derivatives under microwave conditions. The reaction is conducted with azidotrimethylsilane and dibutyltin oxide as catalyst to provide aryltetrazole boronates in yields ranging from 60 to 93% [56]. In the same manner, microwaves may assist successful conversion of sterically hindered nitriles into tetrazoles [57]. 

Those hindered pyridines could be successfully prepared using microwave irradiation as an energy source. Reaction conditions (Scheme 56c) gave the best results with the optimal molar ratio being nitrile/Bu2SnO/Me3SiN3 = 1 3 4. All experiments were carried out at 140 °C for 8 h. This shows that microwave irradiation may assist the conversion of sterically-hindered nitriles into tetrazoles that are difficult to achieve by other means. 

For the TBAF-promoted reaction, it was noted that the reaction does not require a full equivalent of fluoride source the carrier was not identified but could likely be the tetrazole anion. Again, this method was general for both alkyl and aryl nitriles 36 and worked well with sterically hindered nitriles like /-butyl nitrile to provide 5-substituted-l//-tetrazoles 7. 

Further modification was derived by adding a Lewis acid to the azide. Sedelmeir and Aureggi showed this reaction to be very general and provided good yields of the 5-substituted-tetrazole. The conditions were also conducive to retaining the stereochemistry a to the nitrile. Note that thiocyanates, hydroxyl groups, sterically hindered nitriles, electron-rich... 

As can be observed by the yields reported, the benzyl carbamate, hydroxyl group, and thiophene were well tolerated. The Boc group must react under these conditions, but the conditions also worked well with sterically hindered nitriles. These conditions were reported to provide retention of stereochemistry on substrates containing an asymmetric center a to the nitrile. 

Isoxazoles from nitrile oxides and acetylene derivatives—Diene syntheses s, 18, 758 isoxazoles from stable sterically hindered nitrile oxides s. G. Grund-mann and J. M. Dean, J. Org. Ghem. 30, 2809 (1965) reactions with cyanogen di-N-oxide s. G. Grundmann et al., A. 687, 191 (1965)... 

As it concerns Lewis acidity, adsorption of hindered nitriles reveals the presence of such sites at the external surface of H-FER, H-MFI and H-MOR, after outgassing at 673-773 K. Recently, van Bokhoven et aL showed that in these conditions tri-coordinated Al species can be detected by in-situ XANES at the Al-K-edge on H-MOR and H-BEA [105]. These species were proposed to be at framework positions, though it is not possible to determine whether of the internal or external surface. 

Sodium nitrite/sulfuric acid Carboxylic acids from hindered nitriles... 

In hydrolysis with alkaline hydrogen peroxide (67) the nitrile is mixed with 3% hydrogen peroxide and alcohol or acetone (the amount necessary for complete dissolution should be used) and the mixture is alkalized with 6 N NaOH (test with litmus) and heated at 60 °C for 4 hr. The solution should be alkaline throughout the experiment. After hydrolysis the mixture is neutralized with dilute sulfuric acid and the solvent is distilled off. The amide is isolated either by filtration under suction or by extraction with chloroform. The method is not universal and fails with sterically hindered nitriles (68, 69) ... 

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