Hydride Hantzsch ester

Complex hydrides have been used rather frequently for the conjugate reduction of activated dienes92-95. Just and coworkers92 found that the reduction of a,ft-unsaturated ketene 5,5-acetals with lithium triethylborohydride provided mixtures of 1,4- and 1,6-reduction products which were transformed into enals by treatment with mercuric salts (equation 27). Likewise, tetrahydro-3//-naphthalen-2-ones can be reduced with L-Selectride to the 1,6-reduction products93 -95 this reaction has been utilized in the stereoselective synthesis of several terpenes, e.g. of (/ )-(—)-ligularenolide (equation 28)95. Other methods for the conjugate reduction of acceptor-substituted dienes involve the use of methylcopper/diisobutylaluminum hydride96 and of the Hantzsch ester... 

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... 

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... 

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. 

In 2001, we reasoned that this catalysis strategy might be applicable to the conjugate reduction of a, 3-unsaturated carbonyl compounds if a suitable hydride donor could be identified (Scheme 18). Hantzsch ester 11 seemed to be particularly promising since its reaction with preformed a, 3-unsaturated iminium ions had already been established (Makino et al. 1977 Baba et al. 1980). 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

A brief discussion of some aspects of alcohol dehydrogenase will be used to illustrate the potential for catalysis. This system is chosen for illustration because it has been studied so extensively. Lessons drawn can be applied in a broader context. The 1,4-dihydropyridine (2a) is the reductant and this affords a nico-tinium ion (1) on transfer of hydride, as illustrated in equation (1). This process is mimicked in many abiotic systems by derivatives of (2 R = alkyl or benzyl), by Hantzsch esters (7), which are synthetically readily accessible, and 1,4-dihydro derivatives (8) of pyridine-3,5-dicarboxylic acid. A typical abiotic reaction is the reduction of the activated carbonyl group of an alkyl phenylglyoxylate (9), activated by a stoichiometric amount of the powerful electrophile Mg(CI04)2, by, for example, (2b equation 8). After acrimonious debate the consensus seems to be that such reactions involve a one-step mechanism (i.e. equation 5), unless the reaction partner strongly demands a radical intermediate, as in the reduction of iron(II) to iron(III). 

The hydride-donating potential of 1,4-dihydropyridines has already been discussed in a mechanistic context in Section 1.3.2.3. Commonly available 1,4-dihydropyridines are the Hantzsch esters (7 X = OR), obtained from condensation of a -keto ester with ammonia and an aldehyde. By far the simplest syntheses of Hantzsch esters involve condensation of ammonia (substituted amines react in general poorly) and an aldehyde if a hydride equivalent at the 4-position is desired. The Hantzsch synthesis has been used in many guises, also to produce nonsymmetrical systems. The interest in these compounds as calcium antagonists has doubtless stimulated the extensive synthetic effort. ... 

In this transfer hydrogenation, aromatization of the dihydropyridine (Hantzsch ester) to form a pyridine derivative is essential for it to act as the hydride source. 

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... 

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... 

According to the proposed mechanism (Scheme 6.20), the first step of this cascade reaction is protonation of the substituted pyridine by CPA to generate the pyridinium salt 51. Then, the reduction of 51 by 1,4-hydride transfer from the Hantzsch ester gives the enamine intermediate 52, which isomeri-zes to iminium 53 in the presence of CPA. The subsequent AFC reaction will afford the desired product and release the chiral phosphoric acid. 

Transfer hydrogenation with Hantzsch esters and related organic hydride... 

Nature makes use of NADH (reduced nicotinamide adenine dinucleotide) as a cofactor for enantioselective biochemical hydrogenations, which are typical hydride-transfer reactions. Dihydropyridines and benzimidazolines derivatives are active hydride donors due to the presence of the nitrogen atom and the ability of the molecule to undergo aromatisation. Organocatalytic enantioselective reductions carried out using hydride donors has been studied, and effective reductions have been achieved with imidazoli-dinone organocatalysts, both with a,p unsaturated aldehydes and ketones. Generally, a stoichiometric quantity of reductant (Hantzsch ester 4) is required for these transformations (Scheme 18.5). 

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). 

Substituted 3-aminoindolizines could be obtained via one-pot multistep reactions, from 2-pyridine carboxyaldehide and various nitriles, after 3 h reaction in toluene at 105°C, by adding 1.1 eq of Hantzsch ester as a hydride transfer agent and catalytic amounts of piperidinium acetate [20]. 

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... 

In 2009, Gong s group reported the dynamic kinetic transfer hydrogenation reaction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[ )][l,4]diazepines, using chiral phosphoric acids as organocatalysts and Hantzsch ester as the hydride source. ° A 3,3 -H8-BINOL-derived phosphoric acid was identified as the optimal chiral catalyst for this process, affording the corresponding 1,3-diamine derivatives with moderate diastereoselectivities of up to 78% de, and enan-tioselectivities of up to 94% ee, as shown in Scheme 2.107. 

Fukuzumi S, Kondo Y, Tanaka T (1983c) Evidence for a single electron transfer activation in the hydride transfer from an NADH model compound to tetracyanoethylene. Chem Lett 751-754 Fushimi M, Baba N, Oda J, Inouye Y (1980) Asymmetric reduction of a-keto-esters and trifluoroacetophenone with N-anionized Hantzsch ester. Bull Inst Chem Res Kyoto Univ 58 357-365 Gase RA, Boxhoorn G, Pandit UK (1976) Metal-complex mediated catalysis of reduction of 2-benzoylpyridine by an NADH-model. 

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