Primary-tertiary diamines

Among unsolvated organolithium compounds only the alkyllithiums are soluble in noncoordinating solvents such as alkanes and arenes. Their states of aggregation depend on the structure close to lithium. Thus primary, tertiary and secondary alkyllithiums, all unsolvated, assemble into respectively hexamers, tetramers and equilibrium mixtures of hexamers and tetramers. Most organolithium compounds dissolve in and coordinate with donor compounds such as ethers and tertiary amines. The actual structures depend critically on the nature of the donor. Thus, diethyl ether solvates tend to be mainly cubic tetramers (with some dimers) while THF favors mixtures of monomers and dimers. Tertiary vicinal diamines such as TMEDA and 1,2-di-Af-piperidinoethane, DPE, favor bidentated coordinated dimers. Finally, in the presence of triamines such as pentamethyl-triethylenediamine PMDTA and l,4,7-trimethyl-l,4,7-triazacyclononane TMTAN, many organolithium compounds form tridentately complexed monomers. 

The aldol reaction of cyclic ketones and acetone with aromatic aldehydes were carried out in combination with triflic acid in water at 25°C [250]. Other chiral primary-tertiary diamine catalyst such as compound 167 (20 mol%) was used in combination with solid polyoxometalate acid support (6.67% mol) in the aldol reaction between dihydroxyacetone (149a) and aromatic aldehydes in NMP as solvent at 25°C to afford mainly iyn-aldol products in good yields (59-97%) and high diastereo- and enantioselectivities (78-99% de, 84-99% ee). The combination of catalyst 167 with triflic acid was used in the reaction of acyclic ketones and a-hydroxyketones 8 with aromatic aldehydes also with good results [251]. Simple chiral diamine 168 (10 mol%) in the presence of Iriflic acid (20 mol%) was applied as catalyst in the reaction between acetone and cyclohexanone with aromatic aldehydes in water at 25°C, giving aldol adducts 4 in low yields (15-58%) and moderate diastereo- and enantioselectivities (50-98% de, 45-93% ee) [252]. 

SCHEME 3.14. Primary-tertiary diamine-catalyzed aldol reaction leading to either the syn-or fl ri-aldol [76],... 

The use of an (5)-threonine/a,a-(5)-diphenylvalinol-derived ionic liquid 81 gave comparable results to the 0-iBu-L-tyrosine-catalyzed reaction, but the recovery of the catalyst was simpler [100]. The simple primary-tertiary diamine 38 proved syn-selective, though it works only for aromatic aldehydes [76]. For the synthesis of iy -aldols derived from active benzaldehydes, other catalysts bearing primary amine functionalities also gave satisfactory results [90b, 60, 100, 101]. 

Lu and Jiang designed primary-tertiary diamine catalyst derived from L-serine for the reaction of glyoxylates with acetone (1) [153]. Their catalyst provides a useful level of selectivity, though the reactions are rather slow. Ca-symmetric bisprolina-mide 12 assures the efficient formation of hydroxy esters with high stereoselectivity for a broad range of aryl a-ketoesters and cyclohexyl-substituted derivatives [154]. P,7-Unsaturated a-ketoesters furnish the desired compounds in excellent yields and ee when a cinchona-based catalytic system was used [155]. 

Following the same iminium ion activation mode but with cinchona primary-tertiary diamine bifunctional catalyst 9, Chen and co-workers [108] described the asymmetric intramolecular aza-Michael addition of enone carbamates (Scheme 11.29). The reactions proceed in high yield and with good to excellent stereocontrol (up to 99% ee). 

An efEcient chemoenzymatic method to prepare optically active primary-tertiary trans-cycloalkane-1,2-diamines. Tetrahedron, 65 (38), 8028-8034. 

Quite recently, chiral diamines have been recognized as effective catalysts in asymmetric catalysis [16]. Utilizing primary amino acid structural scaffolds, several novel diamine catalysts have been developed, which can be classified as primarysecondary diamines (12-14) and primary-tertiary diamines (15-18). Notably, such diamines are often used in combination with Bronsted acid additives for effective activation of substrates. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

Scheme 3.8 Aldol reactions catalyzed by primary-tertiary diamines.

Polyoxometalates (POMs) are transition metal oxygen clusters with well-defined atomic coordination structures. POMs are used as functional nano-colloidal materials and also as supports for catalysts via ion-pair interactions due to their acidic properties. Combinations of chiral diamines and POM 225 effectively catalyze enamine-based aldol reactions. Less than 1 mol% of chiral amine loading is suf-ficientto catalyze the reaction (Table 28.10, entries 1 and 2) [114]. Highly diastereo-and enantioselective cross-aldol reactions of aldehydes are accomplished using chiral diamine-POM 226 under emulsion conditions (entries 3 and 4) [115]. Sul-fonated polystyrene or fluoropolymer Nafion NR50 are also good supports for the immobilization of primary-tertiary diamines. The catalyst 227 can be recovered by filtration and reused for at least four cycles with no loss of stereoselectivity (entries 5 and 6) [116]. 

Luo S, Xu H, Li J, Zhang L, Cheng JP. A simple primary-tertiary diamine-Brpnsted acid catalyst for asymmetric direct aldol reactions of linear aliphatic ketones. J. Am. Chem. Soc. 2007 129 3074 3075. 

DFT calculations, focusing on the C-C bond forming steps, have been used to rationalize the high regio- and stereo-selectivities found for direct aldol reactions of aliphatic ketones (propanone, butanone, and cyclohexanone) with a chiral primary-tertiary diamine catalyst (trans-N,N-dimethy diaminocyclohexane). ... 

Inspired by the primary aminocatalytic motif in nature, our group is interested in developing simple and efficient chiral primary amine catalysts. With Hine s pioneering contribution as a starting point, we developed simple primary-tertiary diamine catalysts derived from chiral tran -cyclohexanediamine such as 24 for asymmetric aldol reaction with excellent efficiency and enantioselectivity. 

The simple primary-tertiary diamine salts can be successfully applied in the aldol reactions of a-hydroxyketones with good activity and excellent stereoselectivity. Notably, the catalyst enabled the reaction of dihydroxyacetone (DHA), a versatile C3-building block in the chemical and enzymatic synthesis of carbonhydrates. By employing either free or protected DHA, syn- or anh-diols could be selectively formed with excellent enantioselectivity (Scheme 5.7). Since enantiomers of diamine 26 and 29 are readily available, this class of chiral primary amine catalysts thus functionally mimics four types of DHA aldolases in nature [17b]. Later, simple chiral primary-tertiary diamine 27 derived from amino acid was also found to be a viable catalyst for the iyn-selective aldol reactions of hydroxyacetone and free DHA (Scheme 5.7) [18]. 

The obtained syn diastereoselectivity with acyclic ketone donors could be explained by Z-enamine transition state (Scheme 5.8), whereas the reactions of cyclic ketones such as protected DHA, which are capable only of forming fi-enamine due to ring size constraints, give preferentially fl h-aldol adducts (Scheme 5.8). These models can be applied to other primary-tertiary diamine catalyzed aldol reactions. 

Subsequently, the catalytic potentials of chiral primary-tertiary diamines have been further explored in the direct aldol reactions of pyruvic donors. Primary-tertiary diamine-TfOH conjugate can effectively catalyze the coupling of pyruvic... 

Very recently, a similar primary-tertiary diamine 33-DNBS conjugate was identified to catalyze the first direct aldol reactions of acetoacetal. The reactions afforded vinylogous-type aldol adducts with good yields and excellent enantiose-lectivity (Scheme 5.10). In cases of substituted acetoacetals, good 5yn-diastereose-lectivity was obtained again [20]. 

Aldol reaction is well known to be an intrinsically reversible process. Microscopically, asymmetric retro aldol reaction would address those challenging substrates which are normally sluggish under the typical asymmetric aldol conditions. Unfortunately, though principally conceivable, such asymmetric retro aldol processes remain basically underdeveloped in asymmetric synthesis. In their further explorations on chiral primary amine catalysis, Luo group found that simple chiral primary-tertiary diamine such as 24,26,27,29, 33 catalyze unprecedentedly stereoselective retro aldol reactions (Scheme 5.13). 

In a covalent immobilization strategy, magnetic nanoparticle (MNP), was selected as the support due to its easy separation via magnetic force, large surface area, easy preparation and low cost. The desired chiral primary-tertiary diamine is... 

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