Hantzsch ester reductive aminations with

Scheme 11.11 Enantioselective reductive amination with Hantzsch ester 39.

List was the first to explore this possibility, examining the Hantzsch ester mediated reduction of a,P-unsaturated aldehydes [209], Using 20 mol% of the binaphthyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of P-aryl a,P-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch ester 154 with excellent levels of absolute stereocontrol (96-98% ee) (Scheme 63). The method was also applied to the aliphatic substrates ( )-citral and famesal to give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in line with many of the chiral secondary amine catalysed transformations described above the reactions follow a simple and practical procedure without the need for exclusion of moisture and air. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

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... 

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... 

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). 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

Transfer hydrogenation reactions of ketimines were successfully catalyzed by phosphoric acid with the use of a Hantzsch ester as a hydrogen source. Rueping et al. and List and co-workers independently reported the reaction by means of 21 d and 21e [77]. MacMillan and co-workers reported reductive amination (Equation 10.37) [78-80]. 

Reduction. Carboxamides are reduced to amines with Hantzsch ester, upon conversion (in situ) into A,(9-ketene triflates with Tf20. ... 

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... 

Within the context of chiral secondary amine-catalyzed conjugate reduction, the polyethylene glycol grafted polystyrene resin-supported peptide 18 was developed as an effective catalyst for the 1,6-selective transfer hydrogenation of 3-methyl-2,4-dienals with Hantzsch ester, followed by enantioselective 1,4-reduction (Scheme 14) [26]. The combination of the five terminal residues of the catalyst. 

Using catalytic amounts of the morphoUne salt of a chiral phosphoric acid such as compound 241 and Hantzsch ester 242 as the hydride source. List et al. were able to achieve highly selective reductions of a broad variety of a,p-unsaturated carbonyl compounds like famesal (243) as demonstrated in the enantioselective synthesis of the bee pheromone (/ )-244 (210) (Scheme 56). Notably, this method was found to be superior when compared to the use of chiral amine-based catalysts with respect to enantioselectivity in several examples employing stericaUy unhindered aliphatic aldehydes (209). 

Hantzsch ester (2, R = Et) and an organocatalyst -benzyl isothiouronium chloride, prepared from thiourea, catalysed the reductive amination of aromatic, aliphatic, heterocyclic, and cyclic aldehydes to amines in high yields. Aliphatic aldehydes reacted with difficulty and required a higher temperature. Nitro, nitrile, and carbonyl moieties were not reduced. ... 

Reductive amination of a-branched ketones and p-anisidine using Hantzsch ester as a hydride source and chiral Bronsted acid, TRIP, as a catalyst gave chiral p-branched amine (Scheme 5.17) [58]. This catalyst system was extended to three-component Kabachnik-Eields reaction, which uses phosphite as nucleophile instead of hydride, to give p-branched a-amino phosphonate [59]. Reductive ami-nation of p-keto ester or p-keto nitrile with trichlorosilane as a hydride source... 

The direct reductive amination of aromatic aldehydes has been achieved with excellent yields using a gold(I) catalyst along with a Hantzsch ester as the hydrogen source under mild reaction conditions [154]. In another example, B(C6F5)3- is shown to act as a catalyst for the transfer of hydrogen from a Hantzsch ester to an imine [155]. 

A short synthesis of (-f)-monomorine (1562) by Maruoka and coworkers used the chiral phase-transfer catalyst (R)-1672 to mediate an enantioselective conjugate addition between enone 1673 and the imine-protected glycine ester 1674 (Scheme 213). In a remarkable one-pot reaction, the intermediate adduct 1675 was then treated with Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate) in mildly acidic medium, which brought about deprotection of the acetal and imine as well as a double reductive amination in which the dihydropyridine acted as the hydrogen transfer agent. The resulting indolizidine ester (—)-1676 was... 

At almost the same time, MacMillan and coworkers found that the reductive amination starting from aldehyde, amine, and Hantzsch ester 39 also proceeded smoothly by means of 1 in the presence of 5 A MS to afford benzylic amines 43 with 83-97% ee (Scheme 11.11) [22]. They proved that dialkyl ketones as well as alkyl aryl ketones were suitable substrates even methyl ethyl ketone was reduc-tively aminated with 83% ee. They also reported the asymmetric reduction of pyruvic-acid-derived cyclic imino ester 44. In this reaction, the structure of 44 exhibited a remarkable correlation to MM3 calculations in terms of both hydrogen bond orientation and specific architectural elements that dictate iminium enan-tiofacial discrimination. 

The high performance of 64 compared to Hantzsch ester 39 was demonstrated by Akiyama and coworkers in the asymmetric transfer hydrogenation of trifluor-omethylacetophenone derivatives (Scheme 11.17a) [31]. Benzothiazoline 64c afforded 68 in 89% yield with 96% ee. In contrast, a significant reduction of reactivity and enantioselectivity was observed when 39 was used (4% yield, 45% ee). Enders and coworkers also reported the superiority of benzothiazoline over Hantzsch ester in a symmetric synthesis of tetrahydroisoquinolines via the reductive amination/aza-Michael addition sequence (Scheme 11.17b) [32]. Benzothiazoline 64d had a beneficial effect on both chemical yield and selectivity (98% yield,... 

Subsequently, the same group disclosed that in the presence of 10mol% of 5b, diketones 39, primary amine 40, and Hantzsch ester 37b could also undergo a cascade aldol-reduction reaction to provide cyclohexylamine derivatives 41 with up to 96% ee (Scheme 2.11) [18]. 

As mentioned. List et al. used TRIP derivative 31 in combination with a Hantzsch ester to perform the first asymmetric, oiganocatalytic reductive amination. Acetophenone was stirred for 9 hours at room temperature with anisi-dine in the presence of 4 A molecular sieves to first form the imine. Subsequently, 5 mol% 31 and 1.4 equivalents... 

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