Nitriles preparation tables

This procedure, which involves the addition of an anion derived from a nitrile to an unactivated acetylenic bond under rather mild conditions, is a convenient general method for the synthesis of a-vinyl-nitriles (see Table I). The reaction proceeds smoothly in either dimethyl sulfoxide or hexamethylphosphoric triamide (see p. 103 for warning) as solvent with a tetraalkylam monium salt as catalyst. The products thus prepared are obtained in yields higher2 than those obtained under conventional conditions, which generally require higher temperatures and elevated pressures.3-4... 

Several [CoL(NH3)5]3+ and m-[CoL(X)(en)2]2+ complexes have been prepared (Table 26) and some crystal structures are available (Table 25). Pentaammine complexes are easily made from [Co(DMSO)(NH3)5](C104)3, and there is no need to use a better leaving group.340,341 The physical properties ( H NMR, visible-UV, 13C NMR, pATa) for both systems (L = imH) have been comprehensively documented.341,342 The acidity of the N3 proton in (65) is enhanced by coordination and the imidazolate anion is readily accessible (pXa 10.0 vs. 14.1 for imH). Several deprotonated bimetallic bridged species have been prepared and structure (66) has been put forward as a model for heterobiometallic protein centres.343 The tetrazole complexes (68) exist predominantly in the anionic form (pA 1-2)351 and preparation normally gives the N(2)-bonded form. However Ellis and Purcell352 have prepared the N(l) isomer by reacting a coordinated nitrile with N3 ion at pH 5 (equation 52). Properties of both isomers are available.351... 

I 75 Nitrilase- and Nitrile Hydratase-catalyzed Enantiosekctive Preparation Table 15.5 Synthesis of enantioenriched y-amino acids... 

Miyatake and Yashikawa have prepared several 2,4-disubstituted thiazoies in fairly low yield (16 to 40%) by the action of a-mercaptoketones (226) on nitriles (227) (Scheme 118 and Table IT38). The reaction was carried out in benzene solution at 0 C by passing a current of dry hydrogen chloride through the mixture. After 3 hr the mixture was filtered and washed with benzene. When the resins had been removed and the remaining solution alkalinized, the product was extracted. 

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

Finally, Vogtle and his coworkers have prepared a number of cascade molecules which are structurally related to the aforementioned systems. These are repeating ring units of increasingly large cavity size and are prepared by repetitive synthetic procedures. Typically, an amine is cyanoethylated, the nitrile reduced to an amine which may then be further cyanoethylated and reduced or cyclized with a diacid halide. The rather elaborate scheme is illustrated in ref. 61 and examples of the structural type are shown in Table 8.4. 

Section 20.18 Nitriles are prepared by nucleophilic substitution (Sn2) of alkyl halides with cyanide ion, by converting aldehydes or ketones to cyanohydrins (Table 20.6), or by dehydration of fflnides. 

TABLE 9. Preparation of cyclopropanes 111 from a,/ -unsaturated sulfones 109 and a-metallated nitriles 11071... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

The compounds benzonitrile, p-methylbenzonitrile, /)-methoxybenzonitrile, p-trifluoromethyl-benzonitrile, /)-methoxycarbonylbenzonitrile, and triethoxysilane are commercial products and are degassed and stored under argon before use. Trimethylsilane was prepared according to a literature report [38]. The nitrile (9.8 mmol) and the hydrosilane (49 mmol) are added to the rhodium catalyst (0.1 mmol) contained in a Carius tube. When using trimethylsilane, the operation is performed at —20°C. The tube is closed and the mixture stirred at 100 °C for 15h. The liquid is separated by filtration and the excess of hydrosilane removed under vacuum to leave the N, Wdisilylamine derivative. If necessary, a bulb to bulb distillation is performed to obtain a completely colorless liquid. The yields obtained in the different runs are reported in Table 6. The product have been characterized by elemental analysis, NMR spectroscopy, and GC-MS analysis. 

Highly functionalized tetraaryl-4,5-dihydro-l,2,4-triazoles 118a-y have been prepared on a soluble polymer support (PEG4000) from the cycloaddition of diarylimines with a nitrile imine, prepared in situ from the arylhydra-zone 119. The triazole products are highly fluorescent and several have reasonable fluorescence quantum yields (Scheme 8 and Table 19) <2005S3535>. 

Table 8 Preparation of 1,3,4-thiadiazoles from thiohydrazide and nitrile derivatives...

The scope of this reaction (Scheme 16) has been extended to other 5-substituted tetrazoles, readily prepared by the reaction of nitriles with aluminium azide <2002J(P1)1543>. Using triphenylphosphine under mild conditions, the resulting dithiazolimines 169 are rapidly converted into cyanothiadiazoles 170 in high yield (Equation 61 and Table 10). 

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

Table 4.18. Preparation of 1,3-oxazoles from acceptor-substituted carbene complexes and nitriles.

Trapping of the intermediate acyl nitrile ylide with dimethyl acetylenedicar-boxylate leads to pyrroles in low yields (< 18%) [1250]. Representative examples of the preparation of oxazoles with carbene complexes are listed in Table 4.18. 

This reaction can be applied to different reagent combinations. The reagents most often used are carboxamides and formaldehyde or nitriles and formaldehyde (67FRP1478076 71ITP886285, 71S92 93T3907). The cycloalkane[e]oxazines 173 prepared by this method are listed in Table II. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Reaction of carbon dioxide with Af-[l-chloro-2,2,2-trifluoro-l-(trifluoromethyl)-ethyl]-A, A -dialkylformamidines has been described as a procedure to prepare 4-(diaLkylamino)-5(2f/)-oxazolones 51 (Scheme 7.13 Table 7.9, Fig. 7.10). Mechanistically, this reaction probably does not proceed via a nitrile ylide given the observed regioselectivities and the dependence of the reaction rate on the solvent. 

Table 5 shows the list of the oxadiazoles sjmthesized by method N. Table 5- Oxadiazoles prepared from nitriles and hydroxamyl chlorides (method N)...

The conversion of benzaldehyde by the encapsulated HNLs afforded mandelo-nitrile in 96-98% yield and 97-99% for all three enzymes. Free and entrapped HfoHNL catalyzed the conversion of hexanal with 94% , whereas ee-values of only 85 and 87% could be achieved with MeHNL and PaHNL preparations, respectively, limited by the intrinsic enantioselectivity of the enzymes (Table 9.4). Furthermore, the CLEAs from HfoHNL and PaHNL suffered from activity loss under the reaction conditions in contrast to MeHNL CLEA, indicating that the cross-linked aggregates from MeHNL are particularly robust and necessitate only traces of water to keep the catalytic activity [87]. 

This procedure is general for the preparation of secondary nitriles (Table I), and can be used in the presence of other functional groups by the appropriate choice of oxidation and decomposition reagents.14... 

DSM jointly with Du Pont de Nemours308 have patented platinum catalysts generated from the water soluble sulfonated ligand 30 (Table 2 m=0, n=0, m=l, n=2 m=l, n=l, Ar=nBu-S03Li) and used in the aqueous phase hydroformylation of internally unsaturated carboxylic acids, esters or nitriles to their corresponding formyl derivatives which are useful intermediates for the preparation of di-carboxylic acids (e.g. adipic acid). For example, TOFs up to 105 h-1 were achieved in the hydroformylation of 3-pentenoic acid catalysed by Pt/30 (m=0, n=0) at 100°C and 80 bar CO/H2 to give aldehydes with a selectivity of 83% (n/i=3.4), valeric acid (4.6%) and adipic acid (8.1%).308 The products were separated from the aqueous catalyst solution by extraction with ether. Five recycles of the aqueous catalyst solution showed that the Pt/30 (m=0, n=0) catalyst retains its activity. 

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