Nitriles deprotonation

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

Among the most successful classes of asymmetric acyl anion equivalents are the dioxane-containing a-amino nitriles 99 introduced by Enders and coworkers. These are deprotonated by EDA, and the resulting anions act as efficient equivalents of RCO for addition to a, (3-unsaturated esters [90AG(E)179],... 

This method has been made more general by use of modern reagents low temperatures and the strong hindered base i-Pr NLi allow the deprotonation of many nitriles and their capture by a variety of epoxides. Acid hydrolysis gives lactones,... 

Nitriles can also be converted to anions and alkylated. Acetonitrile (p DMso = 31.3) can be deprotonated, provided a strong nonnucleophilic base such as LDA is used. 

Another useful approach to aldehydes is by partial reduction of nitriles to imines. The reduction stops at the imine stage because of the low electrophilicity of the deprotonated imine intermediate. The imines are then hydrolyzed to the aldehyde. Diisobutylaluminum hydride seems to be the best reagent for this purpose.88,89... 

Van Muijlwijk-Koezen and co-workers utilized the reaction sequence beginning with the deprotonation of aminonitrile 139, which when trapped with various nitriles produced aminoquinazolines 140 upon acid-promoted cyclization, in their preparation of numerous aminoquinazoline as antagonists for the human adenosine A3 receptor <00JMC2227>. 

Rather than the expected [3 + 2] cycloaddition, a novel ene-like cycloisomerization occurs on deprotonation of allyltrimethylsilyl-oxime compounds, when the j3-sp2 carbon atom of the allyltrimethylsilyl moiety is tethered to the oxime unit. The resulting nitrile oxide group serves as an enophile, and the final cyclized product still has two functional groups suitable for further manipulations. Thus, ene-like cycloisomerization of allyltrimethylsilyl-oxime 375 with NaOCl in CH2CI2 gives 82% of cyclized product 376 (423). See also Reference 424. 

Here both deprotonation of the a-carbon atom followed by generation of nitrile oxides and deprotonation of the j3-carbon atom can occur, giving rise to stabilized... 

The probable pathway resulting in the stereoselective formation of silylated ene nitrile (586) from enoxime (584) is presented on the right of Scheme 3.282. At higher temperature, the latter eliminates trimethylsilanol to give ene-nitrile (586) under the action of silyl Lewis acid (TfOSiMe3). Evidently, the reaction of compound (585) with TfOSiMe3 at room temperature involves initial silylation of the nitrogen atom to form the cationic intermediate B, which is deprotonated with triethylamine, followed by the thermodynamically favorable l,3-N,C-shift... 

C2 is electrophilic, and C4 is. .. electrophilic To make a bond between them, C2 must be turned into a nucleophile (umpolung). This must be the purpose of the -CN. Aldehydes are not acidic at the carbonyl C, so the CN cannot simply deprotonate C2. Instead, it must add to C2. Now C2 is a to a nitrile, it is much more acidic, and it can be deprotonated by excess CN to give an enolate, which can add to C4. Finally, deprotonation of 01 and elimination of CN gives the observed product. 

Whether the dianion of azohenzene is able to deprotonate MeCN (pK 31.3) has been discussed [62, 64, 68]. However, on a preparative scale generation of CH2CN takes place at the potential of the second reduction of azohenzene, and reactions initiated by cyanomethylation of benzamide [108], carbonyl compounds (or their Schiff bases) or Q , 8-unsaturated nitriles either present in situ [69, 109] or added subsequently [110-112] have been studied. A mixture of products is normally obtained. 

Addition of GGh" to a,/ -unsubstituted esters or nitriles, (43), can be carried out using less than stoichiometric amounts of (33) , since the anion formed by addition is sufficiently basic to deprotonate CHCI3 [128]. Yields in the range 70 to 80% are obtained when R = H, Me. The acidic... 

Further information concerning the stereochemical properties of the rearrangement were evaluated by submitting rigid cyclohexane derivatives 254/255 to the reaction conditions. In 1975, House described the allylation of a cyclohexyl cyanide 248 [53]. The initial deprotonation with LDA led to a ketene imine anion 249, which was then treated with allyl bromide. Two potential paths rationalized the outcome an AT-allylation generated the intermediate ketene imines 250/251, which underwent aza-Claisen rearrangement to deliver the nitriles 252/253 alternatively, the direct C-allylation of249 produced the nitriles. 

As with their trans isomers, treatment of the nitrile complexes cw-[ReCl(NCR)(dppe)2] (R = aryl) with [Et20H][BF4] or TMSCF3SO3 in CH2CI2 leads to the formation of the methylenamide compounds cA-[ReCl NC(E)R (dppe)2] (E = H, TMS) and tra x-[ReCl(NCHR)-(dppe)2]. The products undergo deprotonation by bases such as [NBu4]OH to form the trans isomers of the corresponding nitrile complexes [ReCl(NCR)(dppe)2]. Reactions of cis-[ReCl(NCR)(dppe)2] complexes with [Et30][PFg] result in oxidation and isomerization to afford the rhenium(II) complexes tra 5-[ReCl(NCR)(dppe)2][PF6]. ... 

As indicated in Section ni.B, deprotonation of a carbamate affords a dipole-stabilized a-amino-organolithium that can be transmetalated with copper salts to form cuprates, thereby expanding the versatility of the organolithium. Suitable electrophiles include enones, alkenyl, alkynyl, allenyl and dienyl carboxylic acid derivatives, nitriles and sulfoxides. Dieter and coworkers have shown that the same process can be accomplished via transmetalation of a stannane (Scheme 36). The procedure is particularly... 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

The nitrile 153 similarly can be formed below - 105°C by a kinetically controlled deprotonation with LDA, but on warming above -100°C it readily rearranges to the thermodynamically more stable vinyllithium derivative 154 [77AG(E)853]. In contrast the morpholino derivative 155 is... 

The 1,2,4-diazaarsoles are colorless oils or crystals. The unsubstituted compound is deprotonated by butyllithium and subsequently alkylated or acylated at N-1 <86TL2957>. The 1-acyl derivatives (9) (R = Me, Ph) readily undergo a regiospecific cycloaddition of nitrones, nitrile oxides and diazoacetic esters (Scheme 1). The cycloaddition of diphenyl nitrile imine is more general in respect to the 1-substituent (R = H, Me, Ph, COMe). The cycloreversion of the adduct (10) at higher temperatures provides an in situ access to the 1,3-diphenyl diazaarsole (11) which immediately enters another cycloaddition (Scheme 2) <86TL2957>. 

The synthesis of anastrozole (Scheme 3.3) began with an 8 2 displacement of commercially available 3,5-fc (bromomethyl)toluene (19) using potassium nitrile and a phase-transfer catalyst, tetrabutylammonium bromide (Edwards and Large, 1990). The resulting fcw-nitrile 20 in DMF was then deprotonated with sodium hydride in the presence of excess methyl iodide to give the fc -dimethylated product 21. Subsequently, a Wohl-Ziegler reaction on 21 was carried out using A-bromosuccinamide (NBS), and a catalytic amount of benzoyl peroxide (BPO) as the radical initiator. Finally, an Sn2 displacement of benzyl bromide 22 with sodium triazole in DMF afforded anastrozole (2) as a white solid. 

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