Tandem reactions addition-trapping

Scheme 8.3. Tandem Reactions Involving Trapping of Enolates Generated by Conjugate Addition...

Tandem reactions involving trapping of enolates generated by conjugate addition of organocopper reagents... 

Carbonyl ylides continue to be targets of opportunity because of their suitability for trapping by dipolar addition. High enantiocontrol has been achieved in the process described by Eq. 16 [109], but such high enantioselectivity is not general [110] and is dependent on those factors suggested by Scheme 11. Using achiral dirhodium(II) catalysts, Padwa and coworkers have developed a broad selection of tandem reactions of which that in Eq. 17 is illustrative [111] these... 

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

Sibi and Chen [42] reported a related tandem intermolecular nucleophilic free-radical addition-trapping reaction of enoate 168 establishing chirality at both a and /(-centers with control over both absolute and relative stereochemistry (Scheme 9.30) using a Lewis acid catalyst and the bisoxazoline ligand 169. They observed... 

Scheme 9.30. Enantioselective tandem intermolecular free-radical addition-trapping reaction of enoates.

The reaction has been further extended into a tandem conjugate addition/ enolate trapping sequence, whereby the in situ generated zinc enolate was trapped with benzaldehyde. This resulted in an approximately 3 7 mixture of trans-erythro trans-threo aldol adducts, isolated in 88% yield. Subsequent oxidation of these products gave a single isomer of the corresponding diketone with 95% ee. 

The 5-alkyl cyclohexenone that we have chosen as our example gives the best results. The mechanism suggests that the enolate intermediate is protonated on the top face (axial addition again) though we cannot tell this. But, if we carry out a tandem reaction with the enolate trapped by a different electrophile, the product is again that of axial attack. 

Metal-Catalyzed Tandem Conjugate Addition/Electrophilic Trapping Reactions... 

The addition of organolithiums to allylic alcohols followed by trapping of the intermediates by electrophiles is a good example of the usefulness of this type of carbolithiation. The sequence leads, generally, to the formation of diastereomeric alcohols, but the use of chiral ligands confers enantioselectivity to the tandem reaction. 

Watanabe et al. examined a similar addition/trapping tandem involving vinylic sulfones [178]. Acceptable ee s were obtained when bidentate chelation was made possible, as was the case when benzimidazolyl moities were attached to the sulfur atom (the ligand was again a box derivative). Yet only one stereogenic center was created during the reaction. 

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]. 

Scheme 7.10 Indium-mediated tandem radical addition-cyclisation-trapping reactions in aqueous media.

Both these silyl enol ethers 50 and 52 could of course be hydrolysed to the saturated aldehydes, but that would be to sacrifice the useful reactivity of these intermediates in aldol and other reactions explored in chapters 2-6. A more productive development is to react the silyl enol ether with an electrophile and hence develop a synthesis from three components in two consecutive reactions.23 This approach has formed the basis of many modern syntheses as it develops the target molecule so quickly and is discussed in chapter 37 under tandem reactions . It is not necessary to trap the enolate with Me3SiCl when lithium cuprates are used with ketones as the lithium enolate is the product of 1,4-addition. You may choose the lithium enolate or the silyl enol ether, whichever is more appropriate for the next step. 

The same group reported indium-mediated tandem radical addition-cyclization-trap reactions in aqueous media [52c], The use of water-soluble radical initiator 2,2 -azobis[2-(2-imidazolin-2-yl)propane], water-soluble chain carrier 1-ethyl-piperidinium hypophosphite (EPHP) and surfactant cetylammonium bromide (CTAB) allowed the C-C bond-forming radical reactions of highly hydrophobic substrates in water [53], Similarly, the use of CTAB and EPHP in presence of 4,4 -azobis(4-cyanovaleric acid) promoted the indium-mediated radical addition to P-substituted conjugated alkenes in water [54]. 

The conjugate addition of a nucleophile to a, 3-unsaturated carbonyl compounds results in formation of the corresponding enolate subsequent to the initial addition step. This reactive intermediate can be trapped by a variety of electrophiles, and thus opens up opportunities for tandem reaction sequences [108]. 

Feringa and co-workers reported a new enantioselective Cu(I)/Tol-BINAP-cata-lyzed tandem conjugate addition-enolate trapping reaction of Grignard reagents with 4-chloro-a,p-unsaturated esters, thioesters, and ketones to yield tran -l-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee (Scheme 38)... 

Scheme 38 Asymmetric tandem conjugate addition-intramolecular enolate trapping reaction...

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