Nitriles carbanions

Carboxyl and nitrile groups are usually introduced in synthesis with commercial carboxylic acid derivatives, nitriles, or cyanide anion. Carbanions can be carboxylated with carbon dioxide (H.F. Ebel, 1970) or dialkyl carbonate (J. Schmidlin, 1957). 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

Nucleophilic attack by carbanion occurs in the reaction of 2-nitrobenzamides 154 treated with sodium ethoxide (72JCS(P1)835). The reaction mixtures usually contain small amounts of nitrile 155 and carboxamide 156, the product of decarboxylation 158 being usually the principal product (Scheme 24). The corresponding bromo derivatives under the used conditions did not react. 

The reaction is similar to the reduction of a nitrile to an amine, except that only one nucleophilic addition occurs rather than two, and the attacking nucleophile is a carbanion (R ) rather than a hydride ion. For example ... 

Addition and substitution reactions of nitrile-stabilized carbanions S. Arseniyadis, K. S. Kyler and D. S. Watt, Organic Reactions 31,1 (1984). Note. Includes ArC (OTMS)CN, and HetAr (OTMS)CN. 

Enaminosulphoxides 459 have been obtained in the reaction of the carbanion of methyl methylthiomethyl sulphoxide 324 with nitriles. This procedure has been applied for converting nitriles into a-aminoacids 460527 and a-ketoacids 461528 (equation 275). 

Treatment of the carbanion derived from 94 with nitriles was shown to give enaminesulfoxides 136, which can be converted to a-ketoesters or a-ketoacylamides185, besides the ester of JV-acetylamino acid 137. Using this reaction, the methyl ester of dl-JV-acetyl-5-hydroxytryprophane 138 was synthesized186. 

Treatment of a-lithionitriles with vinylic sulfones resulted in the formation of cyclized products, i.e., 3-oxothian-l, 1-dioxides 346 or cyclopropane derivatives 348. When a-lithiated aliphatic nitriles were used, carbanions 343, formed by the nucleophilic addition,... 

The catalytic conditions (aqueous concentrated sodium hydroxide and tetraalkylammonium catalyst) are very useful in generating dihalo-carbenes from the corresponding haloforms. Dichlorocarbene thus generated reacts with alkenes to give high yields of dichlorocyclopropane derivatives,16 even in cases where other methods have failed,17 and with some hydrocarbons to yield dicholromethyl derivatives.18 Similar conditions are suited for the formation and reactions of dibromocar-benc,19 bromofluoro- and chlorofluorocarbene,20 and chlorothiophenoxy carbene,21 as well as the Michael addition of trichloromethyl carbanion to unsaturated nitriles, esters, and sulfones.22... 

Esters, acid chlorides, nitriles 56) react with carbanionic sites — provided their nucleophilicity is high enough — to yield terminal ketone functions. If excess reagent is used, further attack of the ketone by carbanionic sites can be prevented. 

The addition of a carbanion to a double bond conjugated with a carbonyl, nitrile, or sulfonyl group can give the usual simple addition product or it can give an intermediate carbanion which continues the reaction as a chain polymerization. 

Since alkyllithium compounds and their carbanions have an isoelectronic structure with alkoxides, their reaction behavior with carbenes is expected to be similar to that of alkoxides, showing enhanced reactivity in both C-H insertion and hydride abstraction.35 In this reaction, the hydride abstraction cannot be followed by recombination and, therefore, can be differentiated from the insertion. Indeed, the reaction of alkyllithium compounds 70 or nitrile anions (see Section IV.B) with ethyl(phenylthio)carbenoid, which is generated by the reaction of 1-chloropropyl sulfide 69 with BuLi, takes place at the -position of 70 more or less in a similar manner giving both insertion product 71 and hydride abstraction products 72 and 73, respectively. This again supports a general rule C-H bonds at the vicinal position of a negatively charged atom are activated toward carbene insertion reactions (Scheme 22). 

An explanatory mechanism for the formation of vinyl sulfides is shown in Scheme 24. In route a, (phenylthio)carbene 77 generated from chlorosulfide 75 reacts with the nitrile anion to form (phenylthio)carbanion 79, which then undergoes elimination of cyanide ion to produce vinyl sulfide 76. In route b, 75 reacts first with the nitrile anion 74 to produce P-(phenylthio)nitrile 78 followed by base-catalyzed P-elimination. However, route b is unlikely because 79 cannot be generated from 68 due to a larger pKa value of its ot proton than that of the nitrile. In fact, the reaction of chlorosulfide 75a with lithionitrile 80 gave a different product 81 in 63% yield. 

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... 

Carbamate herbicides, 13 320 Carbamates, 13 108 amine, 16 359 Carbamic acid nitrile, 3 158 Carbamide derivatives, as cellulose solvents, 11 272 Carbamodiimide, 8 158 Carbamoylated gelatin, 12 444 Carbamoyl-methylphosphoryl family, extractants of, 10 789 Carbamyl chlorides, 12 180 Carbanion coordination, 13 656—657 Carbanions, 21 101... 

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