Nucleophiles reaction with nitriles

S-Nucleophiles are very reactive in 1,3-addition reactions with nitrile oxides. A series of a-glucosinolates 27 (R = CR1=NOH R1 =Ph, CH2PI1, CH2CH2PI1, ( )-CH=CHPh, 3-indolylmethyl) was prepared by addition reactions of thiol 27 (R = H) with nitrile oxides (123). The indolyl-substituted glucosinolate was then converted to a-glucobrassicin 28. 

Cyclodditions to Carbon-Heteroatom Triple Bonds. Transient electrophilic carbenes are known to react with nitriles to give transient46 or even stable nitrile ylides 30.47 No reaction of transient nucleophilic carbenes with nitriles has been reported. 

It was concluded from these results that ketones are incapable of intermolecular reactions with nitriles. Starting from a general concept on the stability and reactivity of carbenium ions75,76 it can be explained that the carbenium ion intermediates 105 formed from ketones under acid catalysis are more stable than those (106) formed from aldehydes and, therefore, the former are less reactive in the reactions with the weak nucleophilic nitriles. 

The molecular formula of 7-10 indicates that trichloroacetonitrile has reacted with the starting material. By using Hint 1.2, three rings and/or ir bonds are calculated. Because the starting alcohol has two rr bonds and the nitrile has two n bonds, a nucleophilic reaction with the nitrile is likely. Potassium hydride should remove the most acidic proton from the starting alcohol, the proton on the oxygen. 

The CpCo(CO)2 (10 mol %) catalyzed reaction of diyne 125 and cyanomesylate 126 under microwave heating (120 °C) delivered dehydrotylophorine (127) directly in 78% yield. Notably, during the course of this reaction cascade, the nonnucleophilic N-center of a nitrile is converted into a nucleophilic pyridine moiety that subsequently undergoes an intramolecular nucleophilic reaction with the tethered sulfonate leaving group. This facile tandem reaction has also been used in a synthetic approach to the spiroindolinone framework of the marine alkaloids citranin A and B [38]. 

The carbon-nitrogen triple bond of nitriles is much less reactive toward nucleophilic addition than is the carbon-oxygen double bond of aldehydes and ketones Strongly basic nucleophiles such as Gngnard reagents however do react with nitriles in a reaction that IS of synthetic value... 

Enamine salts react with many nucleophilic reagents. The reaction with the cyanide ion is noteworthy. l-Methyl-2-ethyl-2-cyanopyrrolidine (170) is formed on treatment of alkali cyanide with l-methyl-2-ethyl-.d -pyrrolin-ium perchlorate (242). The reduction of the tertiary nitrile (170) with... 

It is often advantageous to proceed to a desired product through two nucleophilic displacements rather than directly when one can exploit a difference in the reactivity of two leaving groups. An example is the conversion of 4-chloro-2,6-dimethoxypyrimidine (109) (not satisfactorily reactive with sulfanilamide anion) by means of trimethylamine into the more reactive trimethylammonio derivative 110. Conversion of chloro-quinohnes and -pyrimi-dines into nitriles is best accomplished by conversion (with sulfite) into the sulfonic acids before reaction with cyanide. 

A similar reaction is probably involved in the reaction of 4-nitrophthalodi-nitrile (27) with dimedone (28), which provided under milder condition compound 29 and at a higher temperature tricyclic compound 30 (87ZOR2629). Similarly as in the vicarious nucleophilic reactions, intermediate 29 is formed by nucleophilic displacement of the ort/io-hydrogen atom in 27 (Scheme 3). 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

Arenes, on complexation with Cr, Fe, Mn, and so forth, acquire strongly electrophilic character such complexes in reactions with nucleophiles behave as electrophilic nitroarenes.71 Synthesis of aromatic nitriles via the temporary complexation of nitroarenes to the cationic cyclopentadienyliron moiety, cyanide addition, and oxidative demetalation with DDQ has been reported (Eq. 9.43).72... 

Fluorinated 1,2,5-oxadiazoles 255 (Equation 52) undergo photolytic loss of a nitrile fragment and reaction with a nucleophile to give the fluorinated 1,2,4-oxadiazoles 256 <2000TL7977, 2001T5865, 2004JFC165>. 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

Interesting examples of the addition of N-nucleophiles to nitrile oxides are syntheses of chelated Z-amidoxime, N-[2-(dimethylaminomethyl)phenyl]mesitylene-carboamidoxime (118), and pyranosyl amidoximes (119) from the respective nitrile oxides and amines. Aromatic aldoximes undergo unusual reactions with chloramine-T (4 equiv, in refluxing MeOH). N-(p-toly 1 )-N-(p-tosy 1 )benzamides are formed via addition of 2 equiv of chloramine-T to the intermediate nitrile oxide followed by elimination of sulfur dioxide (120). 

Addition of C-nucleophiles to nitrile oxides is of special interest. There are examples of reactions with both carbanions and neutral carbon nucleophiles. To the former group belong reactions of nitrile oxides with organometallic... 

Arylethynyl(phenyl)iodonium salts, RC=CI+Ph 4-MeC6H4S03-, react as 1,3-dipolarophiles with nitrile oxides R CNO to afford phenyl(substituted isox-azolyl)iodonium salts 210, which give iodoisoxazoles on reaction with nucleophiles. The crystal structure of 210 (R = Ph, R1 = mesityl) has been determined (369). 

The formation of the latter compounds can be attributed to the result of the direct attack of the nucleophile R on the a- or p-carbon atoms of SENAs after elimination of the corresponding protons. However, it is most likely that the reaction proceeds through nitrile oxides or conjugated nitrosoalkenes (see Scheme 3.93). This interpretation is evidenced by generation of silyl esters of hydroxamic acids R CONHOSi as by-products. The reactions with more saturated solutions give the latter compounds as the major products. 

By contrast, softer nucleophiles, such as thiols (111), evidently do react with SENAs at the a-C atom (307) (see Scheme 3.94). This interpretation is confirmed by a substantial difference in the configuration of thiohydroxamate 112a isolated in the reaction with silyl nitronate (a) and analogous product 112b (b) prepared from authentic nitrile oxide. 

Nucleophilic additions of titanium nucleophiles to nitriles or isonitriles are relatively rare. Eisch et al. recently reported the formation of three-membered ring titanacycles of type 84 and their reactions with benzonitrile and carbon dioxide, respectively (Scheme 34).119,120... 

Decarboxylation of 1,3-dimethylorotic acid in the presence of benzyl bromide yields 6-benzyl-1,3-dimethyluracil and presumably involves a C(6) centered nucleophilic intermediate which could nonetheless have either a carbene or ylide structure. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to explore the gas-phase reactions of methyl nitrate with anions from active methylene compounds anions of aliphatic ketones and nitriles react by the 5n2 mechanism and Fco reactions yielding N02 ions are also observed nitronate ions are formed on reaction with the carbanions derived from toluenes and methylpyridines. 

The basic hydrolysis (reaction with water) of a nitrile (R-CN) followed by acidification yields a carboxylic acid. In general, an reaction (nucleophilic substitution) of an alkyl halide is used to generate the nitrile before hydrolysis. Figure 12-12 illustrates the formation of a carboxylic acid beginning with an alkyl halide. 

Nitrile oxides are widely used as dipoles in cycloaddition reactions for the synthesis of various heterocyclic rings. In order to promote reactions between nitrile oxides and less reactive carbon nucleophiles, Auricchio and coworkers studied the reactivity of nitrile oxides towards Lewis acids. They observed that, in the presence of gaseous BF3, nitrile oxides gave complexes in which the electrophilicity of the carbon atom was so enhanced that it could react with aromatic systems, stereoselectively yielding aryl oximes 65 and 66 (Scheme 35). ... 

---