Imines hydrocyanation

Zuend, S. J. Jacobsen, E. N. Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation Transition State Stabilization via Multiple Non-Covalent Interactions. ]. Am. Chem. Soc. 2009,131,15358-15374. 

Table 30.4 Imine hydrocyanation using Jacobsen s second-generation thiourea catalyst.

Scheme 30.11 Imine-hydrocyanation using urea-catalyst 44 derived from D-glucosamine.

Table 30.13 Imine hydrocyanation promoted by a sugar-derived catalyst.

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). 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

The asymmetric reactions discussed in this chapter may be divided into three different types of reaction, as (1) hydrometallation of olefins followed by the C—C bond formation, (2) two C C bond formations on a formally divalent carbon atom, and (3) nucleophilic addition of cyanide or isocyanide anion to a carbonyl or its analogs (Scheme 4.1). For reaction type 1, here described are hydrocarbonyla-tion represented by hydroformylation and hydrocyanation. As for type 2, Pauson-Khand reaction and olefin/CO copolymerization are mentioned. Several nucleophilic additions to aldehydes and imines (or iminiums) are described as type 3. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Recently, Kunz et al. reported a new organocatalyst for the asymmetric Strecker reaction [132]. The paracyclophane-derived imine catalyst (280) promotes the hydrocyanation of various imines, both aromatic and aliphatic (Scheme 79). 

Fig. 11 Kunz s hypothesized pre-transition state for the asymmetric hydrocyanation of imines promoted by a novel paracyclophane imine catalyst...

While all of the aryl imine substrates examined for this Strecker methodology existed predominantly or exclusively as the E-isomers, this did not appear to be a requirement for high enantioselectivity as demonstrated in the asymmetric 42-cat-alyzed (2 mol% loading) hydrocyanation of the cyclic Z-imine 3,4-dihydroisoquino-line, which was converted to the corresponding adduct (88% yield, 91% cc) with the same sense of stereoinduction with respect to the benzylic stereogenic center as the examined acyclic E-imines (Schemes 6.41 and 6.42) [196]. 

Hydrocyanic acid - [CYANIDES] (Vol 7) -atmospheric synthesis [IMINES, CYCLIC] (Vol 14)... 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

Interestingly, completely different types of organocatalyst have been found to have catalytic hydrocyanation properties. Among these molecules are chiral diketo-piperazine [4, 5], a bicydic guanidine [6], and imine-containing urea and thiourea derivatives [7-13]. All these molecules contain an imino bond which seems to be beneficial for catalyzing the hydrocyanation process. Chiral N-oxides also promote the cyanosilylation of aldimines, although stoichiometric amounts of the oxides are required [14]. 

A very efficient method for hydrocyanation of aldimines and ketimines has been developed by the Jacobsen group. Chiral urea or thiourea derivatives containing an imine bond of type 9 and 10 were used as organocatalysts [7-13]. The core... 

In addition, acyclic aliphatic N-allyl imines and cycloalkylimines were acceptable starting materials for the asymmetric hydrocyanation and enantioselectivity of up to 95% ee was obtained by use of 10a as catalyst [10]. Representative examples of the range of substrates are summarized in Scheme 5.6. It should be added that as an alternative to the N-allyl imines the analogous N-benzyl imines can be efficiently used as starting material [10]. An optimized procedure for preparation of the catalyst 10a has recently been reported by the Jacobsen group [11]. 

Jacobsen et al. have also demonstrated the usefulness of this method for asymmetric hydrocyanation of cyclic imines [10]. An example is the efficient synthesis of (R)-14 in 88% yield and with 91% ee (Scheme 5.7). Thus, in addition to the hydrocyanation of acyclic imines which are mainly fc-isomcrs, Z-i mines can also be used efficiently. 

Several organocatalysts have been recycled efficiently (selected examples are shown in Scheme 14.2). For example, the Jacobsen group has reported results from an impressive study of the recycling of the immobilized urea derivative 6, a highly efficient organocatalyst for asymmetric hydrocyanation of imines (Scheme 14.2) [11]. It was discovered that the catalyst can be recycled and re-used very efficiently - over ten reaction cycles the product was obtained with similar yield and enantioselectivity (96-98% yield, 92-93% ee). 

The asymmetric catalytic Strecker reaction is an elegant means of synthesis of optically active a-amino acids. The Jacobsen group developed optimized organocata-lysts [21, 44-48], optically active urea or thiourea derivatives, which were found to be the most efficient type of catalyst yet for asymmetric hydrocyanation of imines (see also Section 5.1 on the hydrocyanation of imines). Because of its high efficiency, Jacobsen hydrocyanation technology has already been used commercially at Rodia ChiRex [49]. The concept of the reaction is shown in Scheme 14.7. In the presence of a catalytic amount (2 mol%) of the readily available organocatalyst... 

Hydrocyanation of imines [5.1] Mannich reaction [5.2] Hydrophosphonylation of imines [5.5]... 

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