Imines organocatalysts

Takemoto and co-workers communicated that bifunctional organocatalyst 166 would promote aza-Henry reactions of phosphinoyl imines with nitroalkanes (Scheme 52) [104]. The catalytic additions provided high selectivities and yields... 

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). 

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

Chiral phosphoric acids powerful organocatalysts for asymmetric addition reactions to imines (S. J. Connon, 2006) [5a]. 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Keywords Cyanation, a-Cyanohydrin, a-Aminonitrile, Cyanide, HCN, TMSCN, Lewis acid, Metal-free, Organocatalyst, C=0 bond, C=N bond, Strecker, Reissert, Aldehydes, Ketones, Imines, Aldimines, Ketoimines... 

Formamides derived from L-pipecolinic acid act as Lewis base organocatalysts for reduction of A-arylimines with trichlorosilane, giving yields and ees in the high 90s for a wide range of imine substrates.54... 

Chiral BINOL (60) is a bifunctional organocatalyst in addition to the phenolic Brpnsted acid groups, it has a Lewis base unit attached via a spacer moiety.167 This particular combination holds the groups in a conformational lock, where they can doubly activate a substrate while giving a high level of stereocontrol. For this example of an aza-Morita-Baylis-Hillman reaction of an enone and an imine, yields up to 100% and ees up to 96% have been achieved. 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

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... 

A 3D-structure of the substrate-catalyst complex, which was supported by molecular modeling, revealed that the large group of the imine is directed away from the catalyst. This complex of the catalyst with the Z imine, and a solution structure of the organocatalyst, are shown in Figure 5.1 [12]. This explains the broad substrate tolerance which is independent of steric or electronic properties. A further important hypothesis is that addition of HCN occurs over the diaminocyclohexane framework in 10a this led to the prediction that a more bulky amino acid/amide portion should give a further improved catalyst. This conclusion led to (model-driven) optimization which resulted in the improved and highly enantioselective Strecker catalyst 10b (for preparative results with this catalyst see Scheme 5.8 and related text) [12]. 

In addition, chiral Schiff base catalysts, which were developed previously for the Strecker reaction, were also found to be suitable catalysts for the Mannich reaction starting from imines and enolates [36, 37]. Very recently, further efficient organocatalysts for the Mannich reaction, such as chiral pyrrolidinyltetrazole and chiral binaphthyl phosphoric acids, have been reported [38]. 

Interestingly, however, another comparative study [24] revealed the capacity of other amines related to L-proline (S)-27 to function as organocatalysts in the Mannich reaction under modified reaction conditions [24]. As shown for a model reaction using preformed imines derived from o-anisidine, the thiazolidine carboxylic... 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

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... 

Another class of bifunctional organocatalysts for the enantioselective aza-Morita-Baylis-Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid-base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (<95% ee) 52... 

---