Aldol condensation reaction tandem

Scheme 6.77 Hydroformylation-(aldol condensation)-hydrogenation tandem reaction and...

The use of phosphoric acid ml-lGd for the catalysis of a tandem double F-C reaction gave rise to fluorene derivatives (up to 96% ee) by the reaction between indoles and 2-formylbiphenyl derivatives [74]. Vinyl indole derivatives combined with a,P-unsaturated aldehydes gave rise to functionalized tetrahydrocarbazoles with two or more stereocenters via an intermolecular triple cascade process by means of secondary amine 7a catalysis [75]. Catalyst 7a also promoted a quadruple F-C/Michael/Michael/aldol condensation reaction between indoles, acrolein, and aromatic nitroolefins (Scheme 35.19) [76]. This work provides a straightforward... 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Fig. 12.13. An acid-catalyzed Michael addition. Unlike base-catalyzed Michael additions, which are also known (Section 13.6.1), a Michael addition occurring under acidic conditions cannot be followed by the formation of a six-mem-bered ring through aldol addition, aldol condensation or— starting from other reactants than the ones shown here— acylation. Under basic conditions, however, the corresponding tandem reactions are quite common (see Section 13.6.2).

Fig. 13.71. Tandem reaction I, consisting of a Michael addition and an aldol condensation Robinson annulation reaction for the synthesis of six-membered rings that are condensed to an existing ring.

Fig. 13.72. Tandem reaction II, consisting of Michael addition and aldol condensation.

Besides the very low stereosdectivities, a major problem encountered with this substrate is the low chemical yield (due to subsequent reaction between the resulting zinc enolate and the starting material) and the hi volatility of the product. Using TADDOL-phosphoramidite 27 in a tandem lj4-addition-aldol condensation to cydopentenone we were only able to obtain an ee of 37%, but the enantiosele-ctLvity was raised to 62% in the presence of wet powdered molecular sieves (4 A) [52]. This beneficial effect of water and molecular sieves in some catalytic 1,4-additions has been observed in other cases recently [52, 59]. Important to note is that the yidds in the tandem version are dramatically increased, presumably due to in situ trapping of the reactive enolate (vide infra). Pfaltz et al. reported a 72% ee in the addition of Et Zn to 44 when using BINOL-oxazoline phosphite ligand 22 [47]. 

Dommo-type reactions involve careful design of a multistep reaction in a one-pot sequence in which the first step creates the functionality to trigger the second reaction and so on, making this approach economical and environmentally friendly. A classical example of a tandem reaction is the Robinson annulation (a Michael reaction followed by aldol condensation and dehydration). 

An alternative tandem Michael addition/aldol condensation for the synthesis of 3,5-diaryl-substituted phenols 121 employs, instead of 1-(2-oxopropyl)pyridinium chloride (112), l-(benzotriazol-l-yl)propan-2-one (119) in the presence of excess of NaOH in refluxing ethanol (equation 106) ". Under these conditions, several types of 3,5-diaryl-substituted phenols 121 have been obtained in 52-94% yield. The reaction proceeds by Michael addition of the enolate of 119 to the a,/3-unsaturated ketone 118 to afford intermediate 120, which then undergoes an intramolecular aldol condensation with elimination of benzotriazole. 

Tandem conjugate addition ofenolates and aldol reactions Tandem conjugate addition of chiral amines and aldol reactions Part III - Intermediate is an Unstable Imine or Enamine Intermediate Would Be Formed by Amide Condensation... 

Synthesis of fused cyclohexenones by reaction of cyclanones with vinyl ketones (base or acid catalyzed), a tandem Michael addition-aldol condensation (see 1st edition). 

Various benzylic alcohols, as well as cinnamyl alcohol and cyclohexanol, were dehydrogenated using large amounts of GiO under sonication [71] or GeO [72]. Despite the high GeO loadings (200 wt%), the material acted as an aerobic oxidation catalyst, since hardly any reaction occurred under nitrogen and the material could be recycled many times. Interestingly, GiO acted as a multifunctional tandem alcohol oxidation-alkyne hydration-aldol condensation catalyst for chal-cone formation directly from phenylacetylenes and benzyl alcohols [73]. 

A tandem reaction using Ti +-mont and HT that comprises deprotection and aldol condensation from malononitrile and benzaldehyde dimethyl acetal as starting materials is outlined in Table 2. The product is obtained only when both Ti + mont and HT are present and it is synthesized by Ti +-mont-catalyzed deacetalization of benzaldehyde dimethyl acetal, followed by the aldol reaction of malononitrile with benzaldehyde. When either Ti +-mont or HT was replaced by a homogeneous reagent such as p-toluenesulfonic acid or piperidine, neither the deacetalization nor the aldol reactions occurred to any great extent. 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

The reaction started with the tandem oxa-Michael-Michael reaction of 83 and 84 to give 87 in 76% yield and greater than 99% ee. The following Michael-aldol condensation with 4,4-dimethoxy-but-2-enal 85 works nicely in 69% yield and also excellent enantioselectivity. The obtained hexahydro-6//-benzo[c]chromene 88 is a highly functionalized intermediate in the total synthesis of (+)-conicol 89. The two-step reaction could be achieved in one pot from 83 and 84, without isolation of the intermediate 87, with a 55% overall isolated yield of 88. 

The propionaldehyde that forms can be subjected to an aldol reaction with formaldehyde to produce methacrolein, as claimed by BASF [20]. Hydroformylation and aldol condensation can also be performed as a tandem reaction in an aqueous two-phase system [21]. Both approaches to methacrolein are interesting alternatives to the partial oxidation of isobutene on heterogeneous catalysts [22]. 

Special hydroformylation protocols allow the one-step production of alcohols (hydroformylation-hydrogenation tandem reaction, see also Section 5.2), which are also of crucial importance as aroma compounds. Acetals, which have similar odors like their aldehydic precursors, maybe produced in the hydroformylation in alcohols as solvent under acidic conditions (hydroformylation-acetalization tandem reaction, see also Section 5.3) [15]. The acetal formed protects the aldehyde toward oxidations, reactions with amines, or aldol condensations. Especially in demanding fragrances, these modifications that may affect the scent impression are not desired. 

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