Imines Hantzsch esters

Simon L, Goodman JM (2008) Theoretical study of the mechanism of Hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acids. J Am Chem Soc 130 8741-8747... 

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. 

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

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... 

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. 

MISCELLANEOUS REACTIONS OF DIHYDROPYRIDINES Additional tests for net hydride transfers initiated by single-electron transfer include the use of substrates in which such pathways would necessarily involve readily ring-opened cyclopropylmethyl or readily cyclized 5-hexenyl radicals. Products from these radical reactions are not formed in NAD+/ NADH dependent enzymic reductions or oxidations (Maclnnes et al., 1982, 1983 Laurie et al., 1986 Chung and Park, 1982). Such tests have also been applied in non-enzymic reductions. Thus cyclopropane rings in cyclopropyl 2-pyridyl ketones, or imines of formylcyclopropane (van Niel and Pandit, 1983, 1985 Meijer et al., 1984) survive Mg+2 catalysed reduction by BNAH or Hantzsch esters but are opened by treatment with tributylin hydride. 

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. 

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). 

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. 

Hydrogen transfer. Using Hantzsch ester as hydrogen source imines undergo asymmetric reduction that is catalyzed by BINOL phosphates. The 3,3 -bis(9-anthracenyl)-binaphthyl phosphate ent-lA mediates the saturation of C=N bond and semihydrogenation of a conjugated triple bond. ... 

Hydrogenation and reduction of C=N bond. Chiral Bronsted acids possessing a bulky backbone such as VAPOL derivative 9 attract and hold imine molecules in the concave space, and this reasoning has led to successful development of a protocol for the s3mthesis of a-amino acid derivatives from imino precursors by transfer hydrogenation (from Hantzsch ester). ... 

Imines are reduced to the corresponding amines in high yields by the Hantzsch ester (HEH). 

An interesting application of heteroaromatic (V-imines involves dehydrogenation of piperidine, anabasine, and Hantzsch ester.266-269... 

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]. 

The asymmetric reduction of imines and iminium species can be achieved using organocatalysts. The transfer hydrogenation of imines is catalysed by acids and this has led to the development of biomimetic asymmetric reductions using enan-tioselective Bronsted acids in combination with Hantzsch esters as a hydride... 

Steevens JB, Pandit UK (1983) Metal ion catalyzed reduction of imines by 3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (Hantzsch ester). Tetrahedron 39 1395-1400... 

A bio-inspired catalyst comprising a combined organic hydride donor with metal centre has been reported for TH of imines. A previously used catalyst relied on a Hantzsch ester, but the newer derivative benefits from easier preparation and greater accessibility. Yields are high for the Rh complex containing all the components, and more than for the Ir complex or the complex containing the phenanthroline ligand alone (Fig. 38) [122, 123]. 

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]. 

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brpnsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see [45-58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brpnsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester lb giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see [59-61]). 

This method allows the reduction of the imine functionality even if included within an aromatic ring. In a recent example [111], a quinoline is formed by a Friedlander reaction, and subsequently reduced by hydride transfer from a Hantzsch ester to a chiral tetrahydroquinoline (Scheme 26.23). 

Imines (34) have been C-alkylated to give amines (35), in an unusual alkyl transfer arising from C-C cleavage. Hantzsch ester analogues such as (36) can act as hydride-transfer agents, but they have now been used to transfer alkyl groups, using Brpnsted or Lewis acid catalysts. Benzyl-substituted dihydropyridines (i.e., 36, with R = Bn) are particularly efficient. Evidence for a concerted transfer process is discussed. 

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... 

The first report of the combinahon of chiral phosphoric acid and Hantzsch ester 39 as the hydrogen source dealt with the asymmetric reduchon of an imine deriva-hve. Rueping s group and List s group independently found that the combination of 1 and 39 was very effechve in the enantioselechve transfer hydrogenahon of kehmines (Scheme 11.10) [20, 21]. 

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