Enals catalysis

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

It has been thought that the use of 3-methylbut-2-enal derivatives in the synthesis of chromenes was restricted to the reaction with electron rich phenols. Not so The reaction is efficiently catalysed by pyridine and 3-methylpyridine and is most successful with the more acidic phenols, indicating the need for a careful balance between acid and base catalysis (95JOC3397). 

Chiral asymmetric epoxidations have been intensively investigated due to the fundamental importance of epoxides in organic chemistry [69, 70], Nevertheless, catalytic asymmetric Lewis acid epoxidation of a,/i-unsaturated aldehydes remains a challenge to chemists. Recently, Jorgensen and co-workers developed the first asymmetric approach to epoxides of enals, in which chiral pyrrolidine 11 was used as catalyst and H2O2 as oxidant, thus following the concept of iminium catalysis (Scheme 3.9) [71-73]. Importantly, reaction conditions are tolerant to a variety of functionalities and this chemical transformation proceeds in different solvents, with no loss of enantioselectivity. (For experimental details see Chapter 14.13.1). 

Rhodium catalysis is very well developed with respect to its two-electron catalysis [464]. Applications involving radicals are rather rare. Similar to the cobalt-catalyzed processes, the reductive cleavage of endoperoxides 424 proceeds with rhodium(I) catalysts. Hagenbuch and Vogel reported the formation of bicyclic hydroxymethyl enals 425 catalyzed by 3.8 mol% [Rh(CO)2Cl]2 (Fig. 100) [465, 466]. 

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

The cychzation of pent-4-enals and related compounds to cyclopentanones is catalyzed by [RhCl(PPh3)3] in a reaction that involves oxidative addition of the -CHO group to the rhodium(I) catalyst. This reaction has much in common with the decarbonylation that most aldehydes undergo in the presence of this catalyst (see Decarbonylation Catalysis). 

The readily prepared and air-stable complex trans 4, catalyzes Diels-Alder reactions between 1,3-dienes and a,]3-unsaturated methyl ketones or enals. Nitro-methane is the best solvent, and rate accelerations are up to a factor of 10 compared to the uncatalyzed reaction and up to 10 compared to catalysis by trifluoroacetic acid (Scheme 10.20) [34]. 

Corey s method20 relies on metal exchange with the bromocyclopropane 69 prepared by carbene addition. The extra stabilisation of cyclopropyl anions (chapter 8) makes both this lithium derivative and the ylid 63 more easily handled. Addition to aldehydes or ketones gives mixtures of adducts 70 [it turns out that none of the stereochemistry of 69 or 70 matters] which fragment under Lewis acid catalysis to give the thioacetal 71. Careful hydrolysis releases the 3,4-enal -72, the product of a homoaldol reaction with an aldehyde homoenolate and RCHO and a difficult compound to make as the double bond moves into conjugation very easily. 

Asymmetric Diels-Alder reaction and its applications based on catalysis by bis(oxa-zoline)copper(II) complexes have been published in full details. This method has been further extended to the synthesis of 2,3-dihydropyran-6-ylphosphonates, 4-aminodihy-dropyrans, and piperidones. Note that both epimeric amines are accessible by merely changing the diene substrate, that is, ( )- versus (Z)-configuration. Diazolidi-none 75 serves as a chiral catalyst that also activates enals (actual dienophiles being the iminium ions)." ... 

The use of ot,p-unsaturated aldehydes as Michael acceptors always represents a challenging situation because of the tendency of enals to undergo 1,2- rather than the desired 1,4- addition reaction. Moreover, working under phase-transfer catalysis conditions incorporates an additional element of difficulty, because of the propensity of enolizable enals to undergo self-condensation side reactions. For this reason, there are only a few examples reporting enantioselective Michael reactions with ot,p-unsaturated aldehydes as Michael acceptors under PTC conditions, both coming from the Maruoka research team and also both making use of chiral tV-spiro quaternary ammonium salts as catalysts. 

The Studer group presented a new cascade for the highly enantioselec-tive synthesis of substituted indane derivatives. Three stereocenters are formed in the NHC-catalyzed cascade reaction of enals with various p-dike-tones to give the corresponding indane derivatives with excellent stereoselectivity (up to 74% yield, 99% ee). It is predicted that the reaction occurs via a catalytic cycle using oxidative NHC catalysis. Reaction of the enal with NHC in the presence of an oxidant generates an o,p-unsaturated acylazolium ion. Conjugate addition of the likely deprotonated 1,3-dicarbonyl compound... 

The Chi group disclosed the first oxidative y-addition of enals to trifluo-romethyl ketones and enantioselective control via Lewis acid/NHC cooperative catalysis to give unsaturated 5-lactones. Enantioselective control involving the relatively remote enal y-carbon was achieved via Lewis acid and NHC cooperative catalysis (up to 81% yield and 94% ee). A reaction pathway... 

The Chi group recently achieved the first NHC-eatalyzed diastereo- and enantioselective [3 + 4] cycloaddition of azomethine imines and enals via 1,4-dipolarophile intermediates generated by oxidative catalytic remote y-car-bon aetivation of enals. Dinitrogen fused seven-membered heterocyclic products were produced with high enantiomerie purity (up to 81% yield and 99% ee). Racemic azomethine imines ean be used as 1,3-dipolar substrates to afford dinitrogen-fused seven-membered heterocyclic compounds with high enantiomeric purity (s-factor up to 339). The key vinyl enolate intermediate is generated by oxidative y-carbon activation of enal via NHC catalysis as the reactive 1,4-dipolarophile (Scheme 7.116). 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

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