Aldehydes cyanide addition

The presence of an aldehyde function m their open chain forms makes aldoses reactive toward nucleophilic addition of hydrogen cyanide Addition yields a mixture of diastereo meric cyanohydrins... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

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. 

Scheme 6.20. Zr-catalyzed cyanide addition to an aldehyde is facilitated by the presence of 4 A molecular sieves.

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

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 potential substrates for the Strecker reaction fall into two categories ald-imines (derived from aldehydes, for which cyanide addition results in formation of a tertiary stereocenter) and ketoimines (derived from ketones, for which addition results in a quaternary stereocenter). As in the case of carbonyl cyanation, significant differences are observed between the substrate subclasses. To date, while a few catalyst systems have been found to display broad substrate scope with respect to aldimine substrates, successful Strecker reactions of ketoimines have been reported in only two cases. As is the case for all asymmetric catalytic methodologies, the breadth of the substrate scope constitutes a crucial criterion for the application of the Strecker reaction to a previously unexplored substrate. 

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... 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

These are O-, S- and iVnucleophiles. Halide ions are not able to react as nucleophiles with carbonyl compounds, but a pseudohahdethat is, the cyanide ion, is. The addition of the cyanide ion to aldehydes and ketones displays considerable analogies with the addition reactions of ()-, S- and N nucleophiles and this is why Section 9.1 addresses these cyanide additions. 

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-... 

Synthesis from Glyoxal.—Glyoxal, being a di-aldehyde, (p. 261), forms a di-addition product with hydrogen cyanide, HCN, and this di-cyanide addition product hydrolyzes and yields tartaric acid. The reaction may be expressed as follows,... 

Reactions.—The general properties and reactions of the aromatic aldehydes and ketones are like those of their aliphatic relatives. The aldehydes are easily oxidized to acids and reduce ammoniacal silver nitrate solution. Both aldehydes and ketones are easily reduced to alcohols. The aldehydes form addition products with sodium bisulphite and with hydrogen cyanide. With ammonia, however, they do not form addition products but react with the elimination of wafer and the formation of a condensation product which is a derivative of two molecules of ammonia. 

In the presence of 168 a (9mol%) and a phosphine oxide (Bu),P(O) and Ph2P(O)Me for aromatic and ahphatic aldehydes, respectively, 36 mol%), slow addition of TMSCN achieves excellent enantioselectivity with a wide range of aldehydes (86-100%, 83-98% ee). The Al complex has been proposed to work as a bifunctional catalyst for dual activation of the two reactants - the Lewis acidic Al center enhances the electrophilicity of aldehydes and the Lewis basic phosphine oxide induces cyanide addition by nucleophihc activation (Scheme 10.240). This catalytic asymmetric cyanosilylation has been used for the total synthesis of epothilones [652]. 

A more recent synthesis by our group utilized Mukaiyama s trimethylsilyl cyanide addition to aldehydes as the key step to introduce the carboxy functionality [33,36], This approach also required the preparation of (Z)-5-pentadecenal as the key intermediate, Fig. (12). In this case, commercially available decyl aldehyde was coupled with 4-carboxybutyltriphenylphosphonium bromide under Wittig conditions, resulting in a 10 1 mixture of the known (Z)- and ( )-5-pentadecenoic acids. The acids were then reduced to the desired (Z)-5-pentadecenal via (Z)-5-pentadecen-l-ol, a known pheromone. Addition of trimethylsilyl cyanide to (Z)-5-pentadecenal, under triethylamine catalysis, yielded... 

Bisulfite addition to an aldehyde or ketone is similar to cyanide addition, although the nucleophile in this case is sulfur. Sodium bisulfite adds to many aldehydes and ketones to give an addition product, often a nicely isolable solid (Rg. 16.36). 

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