Enals hydrogenation

Marriner GA, Gamer SA, Jang H-Y, Krische MJ (2004) Metallo-aldehyde enolates via enal hydrogenation catalytic cross aldolization with glyoxal partners as applied to the synthesis of 3,5-disubstituted pyridazines. J Org Chem 69 1380-1382... 

The coupling of enals and glyoxals was realized by hydrogen-mediated reaction with the cationic Rh complex and PI13P [35]. The intermediate aldehyde enolates derived via Rh-catalyzed hydrogenation were trapped with glyoxals to form (l-hydroxy-y-kclo-aldchydes, which were treated sequentially with hydrazine to give pyridazines in a one-pot transformation to provide, for example, a 62% yield of 72 (Scheme 21). 

Scheme 21 Hydrogen-mediated reaction of enals and glyoxals and sequential pyridazine synthesis...

Perhaps the most elusive variant of the aldol reaction involves the addition of metallo-aldehyde enolates to ketones. A single stoichiometric variant of this transformation is known [29]. As aldolization is driven by chelation, intramolecular addition to afford a robust transition metal aldolate should bias the enolate-aldolate equilibria toward the latter [30, 31]. Indeed, upon exposure to basic hydrogenation conditions, keto-enal substrates provide the corresponding cycloal-dol products, though competitive 1,4-reduction is observed (Scheme 22.7) [24 d]. 

Selective oxidation of allylic alcohols.1 This zircononcene complex when used in catalytic amount can effect an Oppenauer-type oxidation of alcohols, including allylic ones, in the presence of a hydrogen acceptor, usually benzaldehyde or cyclohexanone. This system oxidizes primary alcohols selectively in the presence of secondary ones. Thus primary allylic alcohols are oxidized to the enals with retention of the configuration of the double bond in 75-95% yield. The method is not useful for oxidation of propargylic alcohols. 

Conjugate hydrogenation. The combination of zinc and NiCl2 (9 1) effects conjugate reduction of a,(3-enones in an aqueous alcohol in which both the enone and product are completely soluble. Ultrasound increases the rate and the yields. Presumably the salt is reduced to a low-valent form that is absorbed on the zinc. No reduction takes place with a 1 1 Zn-NiCl2 couple. The method is not applicable to a,(3-unsaturated enals. Isolated double bonds are also reduced by this method, but this hydrogenation can be inhibited by addition of ammonia or triethylamine. 

Organocatalytic transfer hydrogenation of enals has been discussed as a route for synthesis of some lepidopteran pheromones. 

Triethylammonium hydrogen fluorides (Et,N - nHF complexes, n = 4 6) allow the fluorocyclization of unsaturated aldehydes such as 2,6-dimethylhcpt-5-enal (7) to livc-mem-bered cyclic fluoro alcohols, such as 8 and 9 (yields 55-81 %).39s... 

It is noticeable that neither the most commonly used less acidic triethylamine tris(hydrogen fluoride) nor the more acidic Olah s reagent (70% HF/pyridine) lead to the generation of a cyclic fluoro alcohol from 2,6-dimethylhept-5-enal (7).395... 

P-Bromo acetals and ketals. These useful derivatives are generally prepared by addition of an a./J-unsaturated carbonyl compound to a solution of HBr in the diol. The same products can be obtained by addition of HBr to the a,/J-enal or enone followed by acetalization. The method is improved if only a stoichiometric amount of HBr is used. Dicinnamalacetone (equation I)2 is used to determine the end point. Hydrogen bromide is added to the initially yellow solution until a red color persists. 

All the steps of this reaction are reversible but the position of the equilibrium is significantly in favour of the aldol, which generally may be obtained when the reaction is carried out at room temperature or below, followed by extraction and careful distillation under reduced pressure. When the required product is the unsaturated aldehyde the reaction is carried out at a higher temperature, and dehydration of the aldol occurs readily (e.g. 2-ethylhex-2-enal, Expt 5.212). In the case of aldehydes with only one a-hydrogen atom, aldol formation occurs but the resulting / -hydroxyaldehyde cannot undergo the dehydration step. 

A primary alcohol and amines can be used as an aldehyde precursor, because it can be oxidized by transfer hydrogenation. For example, the reaction of benzyl alcohol with excess olefin afforded the corresponding ketone in good yield in the presence of Rh complex and 2-amino-4-picoline [18]. Similarly, primary amines, which were transformed into imines by dehydrogenation, were also employed as a substrate instead of aldehydes [19]. Although various terminal olefins, alkynes [20], and even dienes [21] have been commonly used as a reaction partner in hydroiminoacylation reactions, internal olefins were ineffective. Recently, methyl sulfide-substituted aldehydes were successfully applied to the intermolecu-lar hydroacylation reaction [22], Also in the intramolecular hydroacylation, extension of substrates such as cyclopropane-substituted 4-enal [23], 4-alkynal [24], and 4,6-dienal [25] has been developed (Table 1). 

General Procedure for Transfer Hydrogenation of Enals Using Symmetric Hantzsch Ester [97] (pp. 110 and 394)... 

Two short syntheses of P-lapachone from readily available naphthols and 3-methylbut-2-enal via a mild phenyl-boronic acid mediated cyclization to 2//-chromenes have been reported. Catalytic hydrogenation of 2H-chromenes with H /Pd-C in ethyl acetate afforded the corresponding naturally occurring chromanes (72) and (73). Oxidation of the adequate chromane with an excess of cerium ammonium nitrate (CAN) furnished P-lapachone in 62% yield [153]. 

Epoxidation of enones, enals, a,unsaturated esters.1 Epoxidation of these substrates is generally effected with alkaline hydrogen peroxide, but can also be effected with this new reagent with high stereoselectivity. 

Methylglyoxalacetal (21) is obtained from acetone (39) by oxidation with methyl nitrite in the presence of methanol and an acid catalyst. Ethynylation and partial hydrogenation yield 2-hydroxy-2-methyl-but-3-enal-dimethylacetal (27), which, after acetylation, yields the P-formylcrotyl acetate (8 b)34 via a copper-catalyzed allyl rearrangement with subsequent hydrolysis. 

Benzaldehyde yielded no dibenzyl ditellurium. In the reation with 3-phenylprop-2-enal the double bond was hydrogenated and bis[3-phenylpropyl ditellurium was isolated in 48% yield. Ketones reacted only sluggishly under these conditions. Cyclohexanone gave dicyclohexyl ditellurium in a yield of only 11%. 

The next example is particularly impressive. The enol partner is a symmetrical ketone that is very hindered—there is only one a hydrogen on either side. The electrophilic partner is a conjugated enal that is not enolizable but that might accept the nucleophile in a conjugate manner. In spite of these potential problems, the reaction goes in excellent yield. 

Scheme 25. Asymmetric counteranion-directed catalysis transfer hydrogenation of enals...

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