Reactions catalyzed cyanide addition

Maruoka and co-workers recently reported an example of a Zr-catalyzed cyanide addition to an aldehyde [64]. As is also illustrated in Scheme 6.20, the reaction does not proceed at all if 4 A molecular sieves are omitted from the reaction mixture. It has been proposed that the catalytic addition proceeds through a Meerwein—Ponndorf—Verley-type process (cf. the transition structure drawn) and that the crucial role of molecular sieves is related to facilitating the exchange of the product cyanohydrin oxygen with that of a reagent acetone cyanohydrin. The example shown is the only catalytic example reported to date the other reported transformations require stoichiometric amounts of the chiral ligand and Zr alkoxide. 

In addition to Evans CuflD-catalyzed and Carreira s Ti-catalyzed asymmetric aldol reactions, there is omit Shibasaki s La-catalyzed protocol1141 A recent total synthesis of one of the more celebrated targets of the nineties, epothilone A, utilizes both an enan-tioseledive Al-catalyzed cyanide addition to an aldehyde (75 —> 77) and a La-catalyzed enantioseled-... 

The BINOL phosphate catalyzed cyanide addition was also examined as a three-component-Strecker reaction of an acetophenone derivative with an aniUne component only poor stereoselectivities (20-40% ee) were obtained in reasonable yields (73-81%) [49]. 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

Zr-Catalyzed Enantioselective Cyanide Additions to Imines (Strecker Reactions)... 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

It is of some historical interest that Kiliani s cyanohydrin synthesis (24) enabled Emil Fischer (25) to carry out the first asymmetric synthesis. Lapworth (26) used this base-catalyzed nucleophilic 1,2-addition reaction in one of the first studies of a reaction mechanism. Bredig (27,28) appears to have been the first to use quinine (29) in this reaction as the chiral basic catalyst. More recently, others (20) have used basic polymers to catalyze the addition of cyanide to aldehydes. The structure of quinine has been known since 1908 (30). Yet it is of critical importance that Prelog s seminal work on the mechanism of this asymmetric transformation (eq. [4]) could not have begun (16) until the configuration of quinine was established in 1944 (31,32). 

Aminomalononitrile (6), an HCN trimer, no doubt forms as an intermediate in the base-catalyzed formation of DAMN from HCN (Section II,C,1). However, its rate of formation is slower than its reaction with an additional 1 mol hydrogen cyanide. Aminomalononitrile has been synthesized from malononitrile and shown to give DAMN upon treatment with cyanide (730SC33 730SC344). 

Nucleophiles attack DISN at the imine carbon with subsequent loss of either ammonia or hydrogen cyanide (72JOC4136). Neutral or basic conditions favor the loss of cyanide ion. A small amount of a strong acid catalyzes the addition, after which cyanide is lost. However strong acids not only catalyze the reaction, but when they are present in larger amounts, they can... 

The nickel-catalyzed transformation of aromatic halides into the corresponding nitriles by reaction with cyanide ions is reported. Both tris(triarylphosphine)nickel(0) complexes and tY2ins-chloro( aryl )bis( triarylphosphine )nickel(II) complexes catalyze the reaction. The influence of solvents, organophos-phines, and substituents on the aromatic nucleus on catalytic cyanation is studied. A mechanism of the catalytic process is suggested based on the study of stoichiometric cyanation of ti3ins-chloro(aryl)bis(triphenylphosphine)nickel-(II) complexes with NaCN and the oxidative addition reaction of Ni[P(C6H5)3]s with substituted aryl halides. 

Addition of hydrogen sulfide and thiols is qualitatively similar to reaction with alcohols in that there are two stages, formation of hemithioacetal (or hemithio-ketal) followed by acid-catalyzed elimination of the hydroxy group and substitution of a second —SR (Equations 8.47 and 8.48). The transformation has been studied less extensively than hydration and acetal formation, and relatively little information on mechanism is available. The initial addition appears to be specific base-catalyzed, an observation that implies that RS is the species that adds. The situation is thus similar to cyanide addition. General acid catalysis has, however, been found at pH 1 to 2 for addition of weakly acidic alkyl thiols, and the reaction rate as a function of pH has a minimum and rises both on the... 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

The selected examples by Cole et al. [120] and Shimizu et al. [121] reported the parallel synthesis of a small library of solid supported dipeptide Schiff bases as ligands for the Ti-catalyzed enantioselective addition of trimethylsilyl cyanide to meso epoxides, and the determination of their catalytic activity on different substrates. The catalyzed addition reaction and the general structure of the dipeptide ligands are shown in Figure 7.15. 

The benzoin condensation catalyzed by N-heterocyclic carbenes has been investigated intensively. First investigations date back to 1832 when Wohler and Liebig discovered the cyanide-catalyzed coupling of benzaldehyde to benzoin (Wohler and Liebig 1832). In 1903 Lapworth postulated a mechanism for this reaction in which an intermediate car-banion is formed by hydrogen cyanide addition to benzaldehyde fol-... 

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries [2-9]. Consequently their enantioselective synthesis has attracted considerable attention (Scheme 5.1). Their preparation by the addition of HCN to an aldehyde or a ketone is 100% atom efficient. It is, however, an equilibrium reaction. The racemic addition of HCN is base-catalyzed, thus the enantioselective, enzymatic cyanide addition should be performed under mildly acidic conditions to suppress the undesired background reaction. While the formation of cyanohydrins from aldehydes proceeds readily, the equilibrium for ketones lies on the side of the starting materials. The latter reaction can therefore only be performed successfully by either bio- or chemo-cat-... 

Scheme 12 Lipase-catalyzed amidation resolution of CDS-4A, CDS-4B conjugated with cyanide addition reaction...

The reaction of S,S,S-(136) with tris-dimethylaminophosphine/PCl3 in CH3CN at 0°C gave the chiral azaphosphatrane (137) in overall 56% yield. Unfortunately (137) did not induce asymmetry in mandelonitrile formed from the catalyzed reaction of Me3SiCN with PhCHO. It was also inefficient in catalyzing the addition of alkyl cyanide to benzaldehyde, and was not sufficiently basic to effect rearrangement of cyclohexene oxide to 2-cyclohexenol. Further experiments with analogues of (137) are promised for future publications. 

If a vinylic double bond is connected to the bicyclic skeleton of norbomene, a competition experiment shows that under the conditions employed hydrogen cyanide addition proceeds only at the endocyclic strained double bond. It is also noted that isomerization of the exocyclic olefinic bond may take place in the course of the reaction [22, 23, 37]. These experiments already reveal the most important features of homogeneously catalyzed hydrocyanation - the influence of the steric structure of the substrate and the fact that the catalyst also promotes isomerizations (cf. Section 2.5.5.1). 

---