Nitrile anions

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

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). 

B. Preparation of Vinyl Sulfides by the Reaction of (Phenylthio)carbenes with Nitrile Anions... 

Treatment of a mixture of nitrile anion 74 and 1-chloroalkyl phenyl sulfides... 

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. 

The MoOPH reagent also hydroxylates branched or unbranched ester, amide, and nitrile anions. 7 For unknown reasons, MoOPH hydroxylations often do not give complete conversion of enolates into products, and recovery of 5-15% of the starting carbonyl substrate is to be expected. 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

Silyl ketene imines have been acylated asymmetrically by anhydrides evidence for a silyl-free nitrile anion intermediate is discussed.86 An aza-Baylis-Hillman reaction of N-sul fonated imines is described below. 

Nitriles are weakly acidic because the nitrile anion can be stabilized by resonance involving the it bond of the nitrile group. 

THF at - 20°. All other anions should be prepared separately, and 2 should be added to 1 at - 20°. By these procedures mono- and disubstituted olefins, vinyl sulfides, vinyl ethers, and allylsilanes are available in 35-80% yield, usually as cis-trans mixtures. Trisubstituted olefins are best prepared by similar routes from a -branched nitrile anions. 

Three examples of nitrile-stabilized enolates have been described by Boche et al. Two of these structures incorporate the anion of phenylacetonitrile. Hie TMEDA-solvated dimer (178) crystallizes out of benzene solution however, the mixed nitrile anion LDA-(TMEDA)2 complex (179) is obtained when excess LDA is present. This latter complex has often been mistaken as a geminal d anion since it frequently gives products that appear to arise from a dianion. The crystal structure of the anion l-cyano-2,2-dimethylcyclopropyllithium (180) consists of an infinite polymer (181) that is solvated by THF. Interestingly, there are C— Li contacts in this structure and the carbanionic carbon remains tetrahedral. 

Finally, the crystal structure of a lithiated amino nitrile (196) has been described in Boche s recent review article as a dimer (197) similar to the other nitrile anions (179), (180) and (182). However, there... 

From a historical perspective, the a-(dialkylamino)nitrile anions were the first acyl anion equivalents to undergo systematic investigation. More recent studies indicate that anions of a-(dialkylamino)nitriles derived from aliphatic, aromatic or heteroaromatic aldehydes intercept an array of electrophiles including alkyl halides, alkyl sulfonates, epoxides, aldehydes, ketones, acyl chlorides, chloroformates, unsaturated ketones, unsaturated esters and unsaturated nitriles. Aminonitriles are readily prepared and their anions are formed with a variety of bases such as sodium methoxide, KOH in alcohol, NaH, LDA, PhLi, sodium amide, 70% NaOH and potassium amide. Regeneration of the carbonyl group can be achieved... 

Deprotonation of alkylnitriles with LDA or lithium hexamethyldisilazide (LHMDS" ) and treatment of the resultant ambident a-nitrile anions with 1° and 2°-alkyl halides affords C-alkylated products in good yield. However, the a-anions of highly substituted nitriles may undergo N-alkylation to give amides on aqueous workup. 

A useful alternative to the carbonylation route to ketones and trialkylmethanols from alkylboranes is the cyanidation reaction. The nitrile anion [(-) C=N ] is isoelectronic with CO and also reacts with R3B. However, the cyanoborate salts are thermally stable and therefore require an electrophile such as benzoyl chloride or trifluoroacetic anhydride (TFAA) to induce 1,2-migration. 

BU3S11CH2I (600), MesSnCHd and Bu"I (10 000). Fluoride-induced elimination takes place at 0 °C in less than 5 minutes (Scheme 47). Nitrile anions adkylate even faster than sulfones with BusSnCHiI, but the subsequent elimination requires MeLi. Both reactions proceed in good yield (Scheme 48). Silica gel is also effective in causing elimination of 3-trialkylstannyl sulfones to alkenes. ... 

The reaction employed was the substitution of the bromine of 1-bromohexane by nitrile anion. The alkyl bromide composed one phase and a concentrated aqueous solution of either KCN or NaCN made up the other phase. The crown ethers functioned as soluble PTC s while polymer 2 suspended at the interface served as an insoluble catalyst. A reaction temperature of 85° was employed to give reasonable conversion times. The reactions were followed with NMR by monitoring the integrated intensities of the hydrogens adjacent to the halide and nitrile groups. The two triplets associated with these peaks are well separated at 3.236 and 2.156 allowing direct comparison of their relative ratios in the reaction mixtures. While this method has limited accuracy, it does allow rapid initial evaluations. Figure 3 shows the relative rates of conversion of 1-bromohexane to the nitrile with KCN. 

Aryl-2,6-bis(dialkylamino)-l,3,5-oxadiazinium perchlorates (62) undergo attack by malono-nitrile anion at C-6 to give ultimately 2-ami no-6-aryl-5-cyano-4-ureidopyrimidines (64) by rearrangement of intermediates (63) (Scheme 5) <85T537i>. 

Intramolecular displacement of benzylic chlorides by nitrile anions was previously demonstrated as an efficient method making substituted pyrrolidines " however, the question of enanti-oselectivity was not addressed. Recent works on the synthesis of substituted cyclopentane showed that intramolecular enolate displacement of benzylic phosphate proceeded in clean inversion. Thus, it was envisioned that an appropriately substituted cyano phosphonate could be used to construct the pyrrolidine ring (Scheme 5.23). This intermediate could potentially be produced by the addition of a fert-butylamine to acrylonitrile. The desired amine could be produced via reaction... 

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