Ketones hydrocyanation

The addition of cyanide to an aldehyde or ketone (hydrocyanation) is an old reaction, but it has been the subject of renewed interest since Reetz s discovery that a chiral Lewis acid could be used to catalyze the asymmetric addition of trimethyl-silylcyanide to isobutyraldehyde ([91] reviews [59,92]). The general process, illustrated in Scheme 4.7, usually employs trimethylsilylcyanide because hydrogen cyanide itself catalyzes the addition as well (nonselectively). Most of the catalysts are chiral titanium complexes some of the more selective examples are shown in Table 4.6. A clear mechanistic picture of the titanium catalyzed additions nis not yet emerged. ... 

Amin omethyl-3,5,5-trimethyl cyclohexyl amine (21), commonly called isophoronediamine (IPD) (51), is made by hydrocyanation of (17) (52), (53) followed by transformation of the ketone (19) to an imine (20) by dehydrative condensation of ammonia (54), then concomitant hydrogenation of the imine and nitrile functions at 15—16 MPa (- 2200 psi) system pressure and 120 °C using methanol diluent in addition to YL NH. Integrated imine formation and nitrile reduction by reductive amination of the ketone leads to alcohol by-product. There are two geometric isomers of IPD the major product is ds-(22) [71954-30-5] and the minor, tram-(25) [71954-29-5] (55). 

Acrylics are chemically resistant at room temperature to dilute acids, except hydrofluoric and hydrocyanic, all alkalis and mineral oils. They are attacked by chlorinated solvents, aromatic hydrocarbons, ketones, alcohols, ethers and esters [60]. 

A" -3-Ketones do not undergo the exchange reaction with acetone cyanohydrin, although the formation of a 3-cyaiiohydrin has been reported by reaction with hydrocyanic acid. ... 

Mandelic Acid.—The reaction furnishes a simple and general method for obtaining hydroxy-acids from aldehydes or ketones by the aid of the cyanhydrin. The formation of the cyanhydrin may be effected in the manner described or by the action of hydrochloric acid on a mixture of the aldehyde or ketone with potassium cyanide, or, as in the case of the sugais, by the use of liquid hydrocyanic acid and a little amme-nia. 

A general property of aldehydes and ketones is that when heated with hydrocyanic acid, additive compounds, termed nitriles or cyanohydrins, are produced, according to the general equations—... 

I.3.7.I.3. (/ )-Oxynitrilase-Catalyzed Addition of Hydrocyanic Acid to Ketones... 

Very few optically active cyanohydrins, derived from ketones, are described in the literature. High diastcrcosclectivity is observed for the substrate-controlled addition of hydrocyanic acid to 17-oxosteroids27 and for the addition of trimethyl(2-propenyl)silane to optically active acyl cyanides28. The enantioselective hydrolysis of racemic ketone cyanohydrin esters with yeast cells of Pichia miso occurs with only moderate chemical yields20. 

A general method for preparing (/ )-cyanohydrins, derived from ketones, is the (/ )-oxyni-trilase-catalyzed addition of hydrocyanic acid to ketones in an organic solvent30. The (R)-cyanohydrins are obtained with good chemical yields and in high optical purity (Table 3)30. 

A solution of (R)-oxynilrilase (F.C 4.1.2.10, 100 pi., 1000 unils/ml.) is dropped onto 1.5 g of Avicel cellulose (soaked in 0.02 M sodium acetate buffer. pH 4.5). 20 mL of diisopropyl ether are added, followed by 5 mmol of ketone and 200 pL of hydrocyanic acid, and the mixture is stirred (Table 3). The catalyst is filtered off. washed with diisopropyl ether, and the combined filtrates are concentrated. 

By simply hydrolyzing the easily accessible 2-hydroxy-2-methylalkanenitriles with concentrated acid, 2-hydroxy-2-methylalkanoic acids are obtained without measurable racemization (Table 3). The reaction sequence from the starting ketone to the carboxylic acid can be carried out in one pot without isolation of the cyanohydrin. The enantiomeric excesses of the (/ )-cyanohydrins and the (ft)-2-hydroxyalkanoic acids are determined from the ( + )-(/T)-Mosher ester derivatives and as methyl alkanoates by capillary GC, respectively. The most efficient catalysis by (R)-oxynitrilase is observed for the reaction of hydrocyanic acid with 2-alkanoncs. 3-Alkanoncs are also substrates for (ft)-oxynitrilase, to give the corresponding (/ )-cyanohydrins32. 

If the solution becomes too alkaline, the nitrile formed will add to a second molecule of unsaturated ketone so readily that the product will consist almost entirely of a high-melting (284-286°) substance. For this reason it is essential to measure the acetic acid accurately if too much is used, addition of hydrocyanic acid will not take place. 

Methylethyl ketone Methylpropyl ketone Methylbutyl ketone Acids Acetic acid Hydrocyanic acid... 

Figure 15 Postulated mechanism for the hydrocyanation of an o-epoxy ketone by Et2AICN.

Remarks on Sections 6 and 7.-—The method here described for the synthesis of cyanohydrins—treatment of the bisulphite compound of the aldehyde with potassium cyanide—cannot be used in all cases. Concentrated solutions of hydrocyanic acid or anhydrous hydrogen cyanide are often used. The general method for the synthesis of a-amino-acids, the nitriles of which are formed by the union of ammonium cyanide with aldehydes or ketones (Strecker), is to be contrasted with that for the synthesis of a-hydroxy acids. For additional amino-acid syntheses see Chap. VII. 2, p. 276. 

Reactivity. Flammable polymerizes violently in the presence of trace amounts of metals or acids can react violently with acid anhydrides, alcohols, ketones, phenols, ammonia, hydrocyanic acid, hydrogen sulfide, halogens, phosphorus, isocyanates, strong alkalis and amines (American Conference of Governmental Industrial Hygienists, 1991)... 

The use of the cone, hydrocyanic acid necessary in the above reactions can be avoided, and the amino-nitrile synthesised in one stage by using ammonium cyanide or an equimolecular mixture of ammonium chloride and potassium cyanide this also brings ketones within the scope of the reaction (0. S., XI., 4). The condensation is carried out in aqueous or aqueous alcoholic solutions. An extension of this reaction permits the use of primary aromatic amines and potassium cyanide in place of ammonium chloride and potassium cyanide (D.R.P., 157710 157709 158090, 158346 J. C. S 1931, 653 Am. Soc., 53, 2809.)... 

The Sorghum (S)-oxynitrilase exclusively catalyzes the addition of hydrocyanic acid to aromatic aldehydes with high enantioselectivity, but not to aliphatic aldehydes or ketones [519, 526], In contrast, the Hevea (S)-oxynitrilase was also found to convert aliphatic and a,/ -unsaturated substrates with medium to high selectivity [509, 527]. The stereocomplementary almond (R)-oxynitrilase likewise has a very broad substrate tolerance and accepts both aromatic, aliphatic, and a,/ -unsaturated aldehydes [520, 521, 523, 528, 529] as well as methyl ketones [530] with high enantiomeric excess (Table 9). It is interesting to note that this enzyme will also tolerate sterically hindered substrates such as pivalaldehyde and suitable derivatives 164 which are effective precursors for (R)-pantolactone 165 [531],... 

In 1999, Belokon reported the use of catalyst 3b for the hydrocyanation of several acetophenone derivatives in up to 70% ee (Fig. 1) [38]. More recently, three research groups have provided even more impressive solutions for the cy-anation of a wide variety of ketones. Discussion of these methods follows. 

Stereoelectronic effects should also play an important role in the nucleophilic 1,4-additions of anions to conjugated systems. These effects should therefore influence the Michael reaction as well as the hydrocyanation of a,6-unsaturated ketones. Studies on these reactions provided evidence that the kinetically controlled addition of a nucleophile to a cyclohexenone derivative is indeed subject to stereoelectronic effects. 

Interestingly, the hydrocyanation of 4-t-butylcyclohexenone gave, as the kinetic product, not the cis (124) but the trans cyanoketone 123. We have seen that there is good evidence that stereoelectronic effects play an important role in the hydrocyanation of conjugated ketones. Consequently, this result can be explained by the above steric argument on the basis of which the formation of the cis isomer 124 is disfavored. 

It was mentioned at the beginning of this chapter that alkaloids were among the first catalysts to be used for asymmetric hydrocyanation of aldehydes. More recent work by Tian and Deng has shown that the pseudo-enantiomeric alkaloid derivatives 5/6 and 7/8 catalyze the asymmetric addition of ethyl cyanoformate to aliphatic ketones (Scheme 6.6) [50]. It is believed that the catalytic cycle is initiated by the alkaloid tertiary amine reacting with ethyl cyanoformate to form a chiral cyanide/acylammonium ion pair, followed by addition of cyanide to the ketone and acylation of the resulting cyanoalkoxide. Potentially, the latter reaction step occurs with dynamic kinetic resolution of the cyano alkoxide intermediate... 

The hydrocyanation of alkenes [1] has great potential in catalytic carbon-carbon bond-formation because the nitriles obtained can be converted into a variety of products [2]. Although the cyanation of aryl halides [3] and carbon-hetero double bonds (aldehydes, ketones, and imines) [4] is well studied, the hydrocyanation of alkenes has mainly focused on the DuPont adiponitrile process [5]. Adiponitrile is produced from butadiene in a three-step process via hydrocyanation, isomerization, and a second hydrocyanation step, as displayed in Figure 1. This process was developed in the 1970s with a monodentate phosphite-based zerovalent nickel catalyst [6],... 

The hydrocyanation reactions of electrophilic aldehydes, ketones and their corresponding imines gives direct access to synthetic derivatives of several important structures, including a-hydroxy carboxylic acids, / -amino alcohols and a-tertiary and a-quaternary-a-amino acids. The asymmetric hydrocyanation reaction provides access to chiral synthons, which have proven useful for the construction of many structurally complex and biologically active compounds. Catalysis of these reactions is especially attractive with respect to avoiding the cost and relative chemical inefficiency associated with the use of chiral auxiliaries. 

At a loading as low as 1 mol%, 10b promoted the hydrocyanation of A-allyl or -benzyl imines derived from aromatic and aliphatic aldehydes and of some ketones in very high yield and almost complete stereoselectivity (see Scheme 2). It is interesting to note that the soluble and the resin-bound catalysts performed equally well. Recovery and recycling of the supported catalyst was shown to occur without any erosion of chemical or stereochemical efficiency over ten reaction cycles. 

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