Phase transfer nitriles

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

These reactions proceed more rapidly in polar aprotic solvents. In DMSO, for example, primary alkyl chlorides are converted to nitriles in 1 h or less at temperatures of 120°-140°C.36 Phase transfer catalysis by hexadecyltributylphosphonium bromide permits conversion of 1-chlorooctane to octyl cyanide in 95% yield in 2 h at 105° C.37... 

A typical phase transfer catalytic reaction of the liquid/liquid type is the cyanation of an alkyl halide in an organic phase using sodium or potassium cyanide in an aqueous phase. When these phases are stirred and heated together very little reaction occurs. However, addition of a small amount of crown ether (or cryptand) results in the reaction occurring to yield the required nitrile. The crown serves to transport the cyanide ion, as its ion pair with the complexed potassium cation, into the organic phase allowing the reaction to proceed. 

Probably the most important group of phase transfer reactions, and certainly the commonest, are those in which an anion is transferred from the aqueous phase into the organic solvent, where nucleophilic substitution occurs. These would once have been performed in a dipolar aprotic solvent such as DMF. A good example is the reaction between an alkyl halide (such as 1-chlorooctane), and aqueous sodium cyanide, shown in Scheme 5.5. Without PTC, the biphasic mixture can be stirred and heated together for 2 weeks and the only observable reaction will be hydrolysis of the cyanide group. Addition of a catalytic amount of a quaternary onium salt, or a crown ether, however, will lead to the quantitative conversion to the nitrile within 2 h. 

The simplest C-C bond formation reaction is the nucleophilic displacement of a halide ion from a haloalkane by the cyanide ion. This was one of the first reactions for which the kinetics under phase-transfer catalysed conditions was investigated and patented [l-3] and is widely used [e.g. 4-12], The reaction has been the subject of a large number of patents and it is frequently used as a standard reaction for the assessment of the effectiveness of the catalyst. Although the majority of reactions are conducted under liquiddiquid two-phase conditions, it has also been conducted under solidrliquid two-phase conditions [13] but, as with many other reactions carried out under such conditions, a trace of water is necessary for optimum success. Triphase catalysis [14] and use of the preformed quaternary ammonium cyanide [e.g. 15] have also been applied to the conversion of haloalkanes into the corresponding nitriles. Polymer-bound chloroalkanes react with sodium cyanide and cyanoalkanes under phase-transfer catalytic conditions [16],... 

Simple aliphatic nitriles, aldehydes, ketones and esters are not readily alkylated under liquiddiquid phase-transfer conditions. Direct alkylation of aldehydes under even mildly basic phase-transfer conditions has to compete with aldol and Cannizzaro reactions and yields are low and variable [e.g. 6], a,a-Disubstituted aldehydes are C-alkylated, e.g. formylcyclohexane has been alkylated (>70%) with a range of reagents using benzyltrimethylammonium isopropoxide as the basic catalyst [7], whereas a-unsubstituted alkanals tend to undergo aldol condensation under basic liquid liquid two-phase conditions [8]. 

The Hoffman rearrangement of amides by quaternary ammonium hypochlorites is not particularly efficient under phase-transfer catalytic conditions and only low yields of nitrile, aldehydes, or ketones, which result from oxidation of the amines, are... 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

During these reactions, nitriles are also formed as by-products and it is probable that they result from dehydration of the oxime by the carbon disulphide under the phase-transfer catalytic conditions [9] (see Chapter 9). Under modified conditions, it is possible to carry out a one-pot high-yielding conversion of the nitro compounds into the nitriles [10]. 

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. 

By reacting quinoline first with benzoyl chloride and then with aqueous potassium cyanide, the corresponding Reissert compound is obtained. The reaction is normally carried out in one operation using a two-phase system plus a phase transfer catalyst. The N-benzoy group can then be removed by heating with sodium hydroxide solution, and the reaction is continued to hydrolyse the nitrile function to the acid ... 

Much the same activity is displayed in a compound in which the nitriles are attached to aliphatic (and highly stericaUy hindered ) carbon. The displacement of benzUlic bromine from the mesytilene derivative (118-1) by treatment with potassium cyanide under phase transfer conditions affords the dinitrile (118-2). Exhaustive... 

Owing to a sufficient reactivity of the secondary halogen atoms towards nucleophiles, the telomers 421 (n = 1) have also been transformed286 into tetroses. Reaction of 430 with sodium cyanide, induced by a phase-transfer catalyst, afforded trans-438 and ci.s-439 nitriles in... 

The phase-transfer catalyst, Bu N Cl, reacts with CN to form a quaternary cyanide salt that is slightly soluble in the organic phase because of the bulky, nonpolar, butyl groups. Reaction with CN" to form the nitrile is rapid because it is not solvated or ion-paired in the organic phase it is a free, strong nucleophile. The... 

Oxidative decyanation (6, 430). This reaction can be conducted under phase-transfer conditions with 50% NaOH in DMSO with catalytic amounts of benzyl-triethylammonium chloride (TEBA). The method fails with purely aliphatic nitriles. The highest yields (85-90%) are obtained with aromatic secondary nitriles. 

Amides from nitriles. One classical reagent for this reaction is H202-Na0H in a suitable solvent.3 This reaction can be carried out advantageously under phase-transfer catalyzed conditions.4 Tetra-n-butylammonium hydrogen sulfate is satisfactory the effectiveness varies with the structure of the nitrile. An excess of 30% H202 is used the solvent system is CH2C12 20% NaOH. Yields are 85-95%. 

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