Cyanohydrin formation reactions

Undoubtedly, the cyanohydrin formation reactions catalysed by the Me- and HbHnls remain the preferred method for (S)-cyanohydrin formation. 

Formaldehyde reacts quickly and quantitatively with HCN. Most other aldehydes have equilibrium constants that favor cyanohydrin formation. Reactions of HCN with ketones have equilibrium constants that may favor either the ketones or the cyanohydrins, depending on the structure. Ketones that are hindered by large alkyl groups react slowly with HCN and give poor yields of cyanohydrins. 

The ElcB mechanism is rare in practice when the elimination reaction would result in a carbon/carbon double bond. When a carbon/oxygen double bond is to be formed then it is far more common. For example, the ElcB mechanism is found in the reverse of the cyanohydrin formation reaction. You will recall that the forward reaction involves the addition of a cyanide anion to a carbonyl group. Write down the pathway for the reverse reaction, i.e. the elimination reaction. 

The AdN2 reaction on a carbonyl is often carried out in two separate and sequential reaction conditions if the nucleophile is a strong base (and would react with proton sources). The addition of the nucleophile occurs in basic aprotic media, followed by addition of a weak acid in the workup for the proton transfer step. The reversibility of the Ad>f2 can usually be predicted by the ApA a rule, but in protic solvents if the nucleophilic attack forms a stronger base, a following irreversible proton transfer step may make the overall reaction favorable. This very favorable p.t. step is the driving force for the cyanohydrin formation reaction below. 

In the benzaldehyde test-bed reaction, the unusual catalysts (6.66) and (6.67) have provided 84% ee (R) and 90% ee (S) respectively in the cyanohydrin formation reaction, and were shown to work well over a range of electron-rich arylaldehydes. Both of these catalytic systems use fairly low catalyst loadings. 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

Production of cyanohydrins is accompHshed through the base-cataly2ed combination of hydrogen cyanide and the carbonyl compound in a solvent, usually the cyanohydrin itself (17). The reaction is carried out at high dilution of the feeds, at 10—15°C, and pH 6.5—7.5. The product is continuously removed from the reaction 2one, cooled to push the equilibrium toward cyanohydrin formation, and then stabili2ed with mineral acid. Purification is usually effected by distillation. 

Like the formation of a-cyanohydrins, this reaction is catalyzed by bases or cyanide ion, but unlike the a-cyanohydrin case this reaction is not reversible, and under certain conditions it can proceed with violence. Ethylene cyanohydrin can also be prepared by the reaction of ethylene chlorohydrin and alkaH cyanides (39). 

Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C=N. Studies carried out in the early 1900s by Arthur Eapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN. Alternatively, a small amount of KCN can be added to HCN to catalyze the reaction. Addition of CN- takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN-. 

Claisen rearrangement, 660 conjugate carbonyl addition reaction, 725-726 Curtius rearrangement, 935 cyanohydrin formation, 707 dichlorocarbene formation, 227 Dieckmann cyclization reaction, 892-893... 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Griengl reported the first example of hydroxynitrile lyase-catalyzed cyanohydrin formation in a mixed solvent system of [bmim][BF4] and buffer (pH 3.7) (1 1) (Fig. 19). In the reaction, a mixed solvent system was essential, but excellent results were obtained. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

Those carbonyl compounds for which the equilibrium with HCN does not lie over in favour of cyanohydrin formation may often be converted satisfactorily into a derivative of the cyanohydrin through reaction with Me3SiCN ... 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

When the reaction is carried out in MeOH neither step (2), the formation of the carbanion (127), nor step (3), addition of this carbanion to the carbonyl carbon of the acceptor molecule (128), is completely rate-limiting in itself. These steps are followed by rapid proton transfer, (129)— (130), and, finally, by rapid loss of eCN—a good leaving group—i.e. reversal of cyanohydrin formation (cf. p. 212) on the product... 

Still another reaction of these aldehydic structures (formed by periodate oxidation), cyanohydrin formation, has been investigated.223... 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

The endo-spiro-OZT could be prepared through a reaction sequence similar to that applied for the exo-epimer, with spiro-aziridine intermediates replacing the key spiro-epoxides (Scheme 18). Cyanohydrin formation from ketones was tried under kinetic or thermodynamic conditions, and only reaction with the d-gluco derived keto sugar offered efficient stereoselectivity, while no selectivity was observed for reaction with the keto sugar obtained from protected D-fructose. The (R) -cyanohydrin was prepared in excellent yield under kinetic conditions (KCN, NaHC03, 0 °C, 10 min) a modified thermodynamic procedure was applied to produce the (S)-epimer in 85% yield (Scheme 18). 

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