Catalysts Hantzsch ester

Combination of the Hantzsch ester mediated transfer hydrogenation together with chlorine (116) or fluorine (117) electrophiles allows for the formal addition of HCl or HF aaoss a double bond in a catalytic asymmetric manner (Scheme 48) [178], Within this paper the reactions were further refined by the use of two cycle-specific secondary amines which effectively operated independently within the same reaction mixture. Impressively, this allowed access to either diastereoisomer of the product depending upon the absolute configuration of the catalyst used in the second step of the sequence. 

The MacMillan laboratory has produced an interesting study on the reductive amination of a broad scope of aromatic and aliphatic methyl ketones catalyzed by ent-lk, utilizing Hantzsch ester as a hydride source (Scheme 5.26) [48]. Apphcation of corresponding ethyl ketones gave very low conversions. Computational studies indicated that while catalyst association with methyl ketones exposes the C=N Si face to hydride addition, substrates with larger alkyl groups are forced to adopt conformations where both enantiofaces of the iminium ir... 

Scheme 6.24 Amines obtained from the transfer hydrogenation of aldimines in the presence of catalyst 9 and Hantzsch ester 19.

Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 °C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. 

An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

This area has undergone very recent development, with List et al. first reporting the possibility of using ammonium salts as catalysts for the reduction of otf-unsaturated aldehyde in 2004 [12]. These authors used a Hantzsch ester 1 (commercially available) as the hydride source, and preliminary screening showed that several ammonium salts were able to catalyze the reduction in an efficient manner. Some typical examples are indicated in Scheme 11.4, where salt 2 serves as the catalyst. 

The reversible formation of a N,N-dibenzyl iminium intermediate, which is reduced by hydride capture from the Hantzsch ester 1 was proposed. Subsequent hydrolysis regenerates catalyst 2 and releases the saturated aldehyde. The transition state A has been suggested for the hydride transfer. An example of the asymmetric version of this reaction was also realized, by using a chiral imidazolidi-none catalyst (the McMillan imidazolidinium salt 3 [13]) (see Scheme 11.4). 

In 2005, the groups of List and McMillan simultaneously described excellent results in the asymmetric reduction of a,/ -unsaturated aldehydes with a prochiral center in the ft position [14, 15]. (For experimental details see Chapters 14.22.1 and 14.22.2). In both cases the catalyst used was a chiral imidazolidinone (6 or 8), and some representative examples are listed in Tables 11.1 and 11.2. The reactions were run at 10-20 mol% of catalyst, at moderate temperature (13 °C or 4 °C) over several hours. The hydride source (Hantzsch ester) was utilized in stoichiometric quantities, and the chemical yields and enantiomeric excesses proved to be... 

In 2005, both Rueping et al. and List et al. reported the first transfer hydrogenation with Hantzsch ester 1 of several N-protected ketimines catalyzed by chiral Bronsted acids derived from l,l -binaphthol [17, 18]. The reaction typically requires 1 to 20 mol% of catalyst, is performed in benzene at 60 °C, and enantio-selectivities of up to 90% are obtained. The chiral Bronsted acid protonates the lcetimine at nitrogen, giving an ion-pair which is reduced by Hantzsch ester 1. (For experimental details see Chapter 14.21.2). A preferred transition state has... 

The organocatalytic enantioselective reduction of C=C, C=0, and C=N double bonds is a relatively young area for which many new and exciting developments can be expected in the near future. Hantzsch esters are useful organic hydrides, and a recent review has summarized the results obtained to date in organocataly-sis [27]. The case of silicon hydrides is convenient for imine or ketone reductions, as a chiral base can act as an organic catalyst. The asymmetric reductions of ketones catalyzed by oxazaborolidines and pioneered by Itsuno [28] and Corey [29] could not be included in this chapter. 

A solution of / ,/ -disubstituted enal (1 mmol) in CHC13 (0.2 M) was cooled to the desired temperature. Catalyst-TCA (20 mol%) and Hantzsch ester (1.2 equiv)... 

To a stirred solution of a,/ -unsaturated aldehyde (0.5 mmol) in dioxane (7 mL) at 13 °C was added catalyst (20.4 mg, 0.05 mmol, 10 mol%) and, after a further 5 min, crystalline dihydropyridine (Hantzsch ester, 129.2 mg, 0.51 mmol). After a reaction time of 48 h the mixture was poured into distilled water (20 mL) and extracted with DCM (2 x 125 mL). The combined organic layers were dried (MgSCh), filtered, and concentrated. The product was isolated by FC (Si02, ethyl acetate/hexane) to give the saturated aldehyde. Enantiomeric excess was measured by chiral stationary phase GC-analysis. 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

In 2005, Rueping et al. reported that chiral phosphoric acids function as an efficient catalyst for the enantioselective reduction of ketimines (Scheme 3.40a 1) [87]. A variety of aryl methyl ketimines were reduced to the corresponding amines in optically active forms using Hantzsch ester as the hydrogenation transfer reagent (HEH) [88]. Subsequently, List and coworkers improved the catalytic efficiency and enantioselectivity by thorough optimization of the substituents (G) that were introduced to the phosphoric acid catalyst (Scheme 3.40a 2) [89]. Almost simulta neously, MacMillan and coworkers successfully developed the enantioselective... 

Hantzsch ester (2.2 equiv) to give p.y unsaturated a amino esters. Although the chemical yields were moderate, high enantio and trans selectivities were achieved using the same chiral phosphoric acid catalyst Ig. 

More recent efforts to effect metal-free hydrogenations have fallen in the realm of organo-catalysts. For example, the hydrogenation of enones, imines, unsaturated a,P-aldehydes, and quinolines have been achieved without a metal, however, in these cases the stoichiometric source of H2 was a Hantzsch ester (Scheme 11.3) [10-14], Such a protocol can be applied to asymmetric reductions, as substituted enones can be reduced with reasonable enantiomer excesses between 73 and 91%. A variety of organocatalyst systems have been reviewed [15, 16]. 

Chiral phosphoric acids like TRYP (60a) or analogues, in association with primary amines, have already been employed as catalysts in the conjugate reduction of a,p-unsaturated aldehydes using Hantzsch esters as hydride-transfer reagents (see Scheme 3.27 in Chapter 3). However, as pointed out... 

The transfer hydrogenation of 3-substituted quinolines was also studied, with the particularity that the stereogenic center was generated in this case during the conjugate addition step (Scheme 4.60). ° The reaction needed for a more sterically demanding catalyst such as partially hydrogenated derivative 60f and, in addition, the nature of the Hantzsch ester required further optimization in order to achieve the best enantioselectivities, which still remained in values around 80% ee. In this case, the scope of the reaction was limited to the use of quinolines with aromatic or heteroaromatic substituents at the 3-position. 

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