Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source

Abstract

Asymmetric 1,2‐additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al–F–salen complex. This allowed for unprecedented turnover numbers of up to 104. DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.

Recent Advances on O-Ethoxycarbonyl and O-Acyl Protected Cyanohydrins

“…With aliphatic aldehydes (entries 22 and 23) the enantioselectivity of the reaction is moderate. [30]. When KCN is used as the only cyanide source with ethyl pyrocarbonate, rather similar results are obtained (Table 14).…”

“…The incorporation of an aprotic onium moiety (ammonium ion) to the complex in addition to the Al-F Lewis acidic center converts X in a bifunctional cooperative catalyst. With these characteristics of the catalyst, the cyanation reaction is facilitated by a nucleophilic attack of a loosely bounded cyanide anion with the ammonium center to the carbonyl of the aldehyde activated by the Al center [ 30 ].…”

“…Table 13. Enantioselective cyanation of aldehydes catalyzed by alumminium complex a [30]. facilitated by a nucleophilic attack of a loosely bounded cyanide anion with the ammonium center to the carbonyl of the aldehyde activated by the Al center [30].…”

“…Table 13. Enantioselective cyanation of aldehydes catalyzed by alumminium complex a [30]. Table 13 summarizes the results with various aldehydes.…”

Al(Salen) Metal Complexes in Stereoselective Catalysis

“…However, these showed quite modest results in the case of Al(salen) complexes [41]. Peters reported a recent improvement for the preparation of a cooperative catalyst (Scheme 4) [42,43].…”