Diels-Alder/benzoin reaction

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

Scheme 2.32 Tandem Diels-Alder-benzoin reaction catalysed by chiral diphenyl-prolinol trimethylsilyl ether and an Af-heterocyclic carbene.

Fused indanes and tetrahydrocarbazoles can be obtained as the result of a Diels-Alder/benzoin reaction organocascade using a catalytic mixture of proline and NHC carbene (Scheme 7.29) [47]. 

Scheme 729 Organocatalyzed Diels-Alder/benzoin reaction cascade.

Liu, Y., Nappi, M., Escudero-Ad i, E. C., Melchiorre, P. (2012). Multicatalytic asymmetric synthesis of complex tetrahydrocarbazoles via a Diels-Alder/Benzoin reaction sequence. Organic Letters, 14, 1310-1313. 

A review of organocatalytic asymmetric 2-1-2- and 4 -1- 2-cycloaddition reactions of ketenes has been published. The domino 1,4-dipolar addition and the Diels-Alder reaction of in situ generated Huisgen 1,4-dipoles (4), from dimethyl acetylenedicarboxy-late (DMAD) and 4-dimethylaminopyridine to 3-phenylacyhdeneoxindole (5), formed complex dispirooxindole-fused heterocyclic compounds (6) (Scheme 2). A multicat-alytic one-pot Diels-Alder/benzoin reaction sequence has been developed for the synthesis of complex tetrahydrocarbazoles possessing four stereogenic centres. ... 

A one-pot Diels-Alder/benzoin reaction sequence to tran -fused tetracyclic indoles has been reported." ... 

General Procedure for One-Pot Diels-Alder/Benzoin Condensation A vial equipped with a Teflon-coated stir bar and a plastic screw cap was charged with (f )-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (0.02 mmol, 6.5 mg, 20 mol%). Then, 2,4,6-trimethylbenzoic acid (TMBA, 0.02 mmol, 3.2 mg, 20mol%) and toluene (0.2 mL) were added in one portion, and the resulting solution was stirred at ambient temperature for 10 min to allow the catalyst salt formation. The reaction was started by the sequential addition of the aldehyde (0.12 mmol, 1.2 equiv) and dibenzoylethylene (0.1 mmol). The vial was sealed and kept in a water bath (ther-mostated at 40 °C). After 48 h, the vial was removed from the water bath and cooled to room temperature. Then, 0.3 mL of toluene, sodium acetate (0.2 mmol, 16.4 mg. 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Numerous organic reactions have been studied in aqueous solutions. It was observed that water is able to induce dramatic rate accelerations in Diels-Alder cycloadditions [66], benzoin condensation [67], Claisen rearrangements [68], Mu-kaiyama aldol reactions [57], Michael reactions [69], Baylis-Hillman reactions [70], and 1,3-dipolar cycloadditions [71], All these reactions are characterized by negative volume changes and negative volumes of activation. It is expected that ground state destabilization in aqueous media associated with transition state stabilization is one of the determining kinetic factors. 

Melchione s team reported the asymmetric catalysis of Diels-Alder reactions of IQDs (Scheme 11, equation 1) [69, 70], In addition to other nitro-substituted arylethenes, methyleneindolinones were employed as dienophiles. A limited selection of the compounds synthesized is shown in Scheme 11 (30-32). The third compound (32) is the result of a final cross-benzoin condensation. Chen and colleagues effected an asymmetric Diels-Alder reaction of IQDs (33) generated under mild acidic conditions from 2-methyl-3-indolemethanols and a,p-unsaturated aldehydes (equation 2) [71], Three representative indoles that were prepared in this fashion are 34 to 36. The IQD 33 is presumed to be in equilibrium with the 3-vinylindolenium species. A wide range of substituted trani-cinnamalde-hydes was successfully employed. Although other acids (HOAc, TFA, PhCO H, silica gel) effected the reaction, Montmorillonite KIO clay was superior in terms of yield, enantioselectivity, and diastereoselectivity. 

This reaction provides quantities of benzoin for use in the multistep synthesis of hexaphenylbenzene (see Experiment [A4ab])- Benzoin is synthesized in this first step of the a series of the Sequential Experiments. In this sequence of reactions, benzoin is converted by oxidation (Experiment [A2a]) to benzil and then to tetraphenylcyclopentadienone (Experiment [A3a]).The latter compound undergoes a Diels-Alder addition with diphenylacetylene (Experiment [A3b]) to give hexaphenylbenzene (Experiment [A4ab]). 

We also detected a hydrophobic effect in the benzoin condensation [14]. In this case, in contrast to the Diels-Alder reaction, it is not formally required that the two hydrophobic phenyl groups come together in the transition state, but our studies indicated that they do. Again there was a large increase in rate when water was the solvent, but in an ionic reaction of this sort such solvent effects could well be related only to the effect on the ions of the polar character of the medium. However, we saw that the reaction rate was increased with LiCl, but decreased when LiC104 was added. In this system LiC104 is a salting... 

The hydrophobic interaction between hydrocarbons and water is a powerful ordering force in mixtures of lipophiles and hydrophiles [53, 54]. Domains of lipophiles provide a solubilizing phase for all like substances added to lipophile-water mixtures. These same forces have been successfully used to order water-insoluble organic molecules for enhancement of Diels-Alder reactions, the benzoin condensation and others which require molecular ordering in the transition state [55]. 

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