**6. One-pot Wittig- and HWE olefination/addition reaction**

Electrophiles can be added to the alkene function obtained, in a one-pot reaction with the Wittig olefination. A typical example is the stereoselective bromination of the Wittig product with oxalyl bromide (**71**), where triphenylphosphine oxide (**70**) as side product of the olefination step acts as a catalyst in the bromination (**Scheme 17**) [140]. Hamza and Blum have developed a sol–gel entrapped tertiary phosphine by co-polycondensation of tetramethoxysilane, 2-diphenyl(phosphino)ethyltri(ethoxy)silane and *N*-2-(aminoethyl)-3-aminopropyltri(methoxy) silane. This could be reacted in a Wittig type olefination with benzyl chlorides (e.g., **76**) and benzaldehydes, prepared *in situ* from benzyl alcohols (e.g., **75**). The strategy allows for the combination of the process with a bromination step in one pot by addition of sol–gel-bound pyridinium hydrobromide perbromide after completion of the Wittig reaction (**Scheme 18**) [71].

Alternatively, the process can be combined with a hydrogenation step by the addition of hydrogen in the presence of an added heterogenized Wilkinson catalyst (**Scheme 19**) [141]. A further Wittig olefination—hydrogenation sequence was developed by Zhou et al. who obtained α-CF<sup>3</sup> -γ-ketoesters **82** by adding trichlorosilane to the reaction mixture where triphenylphosphine oxide (again as side product of the Wittig olefination) acts as a Lewis base and activates the silane as hydrogenating agent (**Scheme 20**) [142]. The routine was expanded to other aldehydes including alkanals as educts [143]. This reaction was also carried out with

**Scheme 17.** Wittig olefination—Ph<sup>3</sup> PO-catalyzed addition of bromine.

Lu and Toy showed that the Wittig-olefination—trichloromethylsilane conjugate addition sequence can be coupled with the initial preparation of the phosphorane in one pot [145]. The conjugate addition to furnish the silyl enol ether can be combined with a reductive Aldol reaction, where for the Wittig reaction and for the reductive Aldol reaction two separate aldehydes can be used (**Scheme 22**) [145]. The reactions above can be run with a triarylphosphine-

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As many Wittig olefinations can be performed in aqueous medium, it is possible to combine the reaction with an enzymatic step. One such sequence is the enzymatic reduction of the olefinic moiety by a recombinant enoate reductase from *Gluconobacter oxydans*, carried out with an enzyme-coupled *in situ* cofactor regeneration with a glucose dehydrogenase as enzyme

Interestingly, a Wittig reaction can also be run in combination with an enzymatic reduction, where the *in situ* prepared enone **93** is transformed to the alkenol **94** (**Scheme 24**) [148].

bound triarylphosphine oxide also exerts a catalyzing effect on the addition of Cl<sup>3</sup>

**Scheme 21.** Furan synthesis by one-pot Wittig olefination—hydrogenation—Paal-Knorr reaction.


), where the polymer

SiH while

tertiary amine bifunctional polymeric reagent (Rasta-Resin-PPh<sup>3</sup>

**Scheme 20.** Wittig reaction—triphenylphosphine oxide catalyzed hydrogenation.

component and d-glucose as co-substrate (**Scheme 23**) [147].

making it possible to recycle the polymer [146].

**Scheme 18.** Wittig olefination—addition of bromine.

**Scheme 19.** Wittig olefination—hydrogenation.

glyoxal derivatives **84** as starting materials, where after conjugate addition of trichlorosilane a few drops of methanol were added to the solution resulting in conversion of the trichlorosilylenol ether (**86**) to the keto compound **87** while at the same time generating HCl, which then promoted a Paal-Knorr reaction of **87** to the furan **88** (**Scheme 21**) [144].

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**Scheme 20.** Wittig reaction—triphenylphosphine oxide catalyzed hydrogenation.

**Scheme 17.** Wittig olefination—Ph<sup>3</sup>

14 Alkenes

**Scheme 18.** Wittig olefination—addition of bromine.

**Scheme 19.** Wittig olefination—hydrogenation.

PO-catalyzed addition of bromine.

glyoxal derivatives **84** as starting materials, where after conjugate addition of trichlorosilane a few drops of methanol were added to the solution resulting in conversion of the trichlorosilylenol ether (**86**) to the keto compound **87** while at the same time generating HCl, which then

promoted a Paal-Knorr reaction of **87** to the furan **88** (**Scheme 21**) [144].

**Scheme 21.** Furan synthesis by one-pot Wittig olefination—hydrogenation—Paal-Knorr reaction.

Lu and Toy showed that the Wittig-olefination—trichloromethylsilane conjugate addition sequence can be coupled with the initial preparation of the phosphorane in one pot [145]. The conjugate addition to furnish the silyl enol ether can be combined with a reductive Aldol reaction, where for the Wittig reaction and for the reductive Aldol reaction two separate aldehydes can be used (**Scheme 22**) [145]. The reactions above can be run with a triarylphosphinetertiary amine bifunctional polymeric reagent (Rasta-Resin-PPh<sup>3</sup> -NBn<sup>i</sup> Pr2 ), where the polymer bound triarylphosphine oxide also exerts a catalyzing effect on the addition of Cl<sup>3</sup> SiH while making it possible to recycle the polymer [146].

As many Wittig olefinations can be performed in aqueous medium, it is possible to combine the reaction with an enzymatic step. One such sequence is the enzymatic reduction of the olefinic moiety by a recombinant enoate reductase from *Gluconobacter oxydans*, carried out with an enzyme-coupled *in situ* cofactor regeneration with a glucose dehydrogenase as enzyme component and d-glucose as co-substrate (**Scheme 23**) [147].

Interestingly, a Wittig reaction can also be run in combination with an enzymatic reduction, where the *in situ* prepared enone **93** is transformed to the alkenol **94** (**Scheme 24**) [148].

**7. One-pot Wittig-olefination/functional group interconversion**

**Scheme 26.** Synthetic route to utilizing a one-pot Michael addition—HWE reaction.

Wittig-cyanosilylation was developed by Zhou et al., where again Ph<sup>3</sup>

(**Scheme 28**) [153].

**Scheme 25.** One-pot Michael addition—HWE reaction.

Wittig reactions can be performed with alkoxycarbonylmethylidenetriphenylphosphorane (**21**) in aq. NaOH, where the cinnamates formed are hydrolysed *in situ* to cinnamic acids **106** (**Scheme 27**) [152]. After completion of the reaction, triphenylphosphine oxide can be filtered off from the strongly basic, aqueous solution, and the cinnamic acids are isolated by simple filtration after acidification of the filtrate. Pinacol-acetal tripropylphosphonium salt **107** has been reacted in aq, 1 M NaOH with different benzaldehydes **37**; the cinnamaldehyde *O*,*O*pinacol acetal can be hydrolyzed directly to the cinnamaldehydes **108** with 25w% aq. H<sup>3</sup>

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This procedure provides a nice alternative to the reaction of benzaldehydes with triphenylphosphoranylideneacetaldehyde, which often produces dienals and trienals as side-products. A tandem

Wittig olefination acts as Lewis base to catalyze TMSCN in the cyanosilylation step. Chiral salen

PO<sup>4</sup>

PO as side product of the

**Scheme 22.** Wittig olefination—reductive Aldol reaction.

**Scheme 23.** Wittig-olefination—enzymatic ene-hydrogenation.

**Scheme 24.** Wittig-olefination—enzymatic keto-reduction.

The possibility of a combination of a Wittig/HWE olefination and a Michael addition has been studied by a number of research groups. Thus, Piva and Comesse have added phosphonoesters to copper enolates derived from the 1,4 addition of cuprates **97** to enones **96** with the idea that the enolate would deprotonate the phosphonoester **98** producing the reactive ketone and phosphonate, which undergo HWE reaction. Products **99** of the tandem Michael-HWE reaction are produced in acceptable yield (**Scheme 25**) [149, 150]. This strategy was used with *p*-methylcinnamaldehyde (**100**) as carbonyl component in the total synthesis of (±)-*ar*-turmerone (**105**), a bisabolane-type natural product found in *Zingiber* and *Curcuma* species (**Scheme 26**) [151].

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**Scheme 25.** One-pot Michael addition—HWE reaction.

**Scheme 22.** Wittig olefination—reductive Aldol reaction.

16 Alkenes

**Scheme 23.** Wittig-olefination—enzymatic ene-hydrogenation.

**Scheme 24.** Wittig-olefination—enzymatic keto-reduction.

*Curcuma* species (**Scheme 26**) [151].

The possibility of a combination of a Wittig/HWE olefination and a Michael addition has been studied by a number of research groups. Thus, Piva and Comesse have added phosphonoesters to copper enolates derived from the 1,4 addition of cuprates **97** to enones **96** with the idea that the enolate would deprotonate the phosphonoester **98** producing the reactive ketone and phosphonate, which undergo HWE reaction. Products **99** of the tandem Michael-HWE reaction are produced in acceptable yield (**Scheme 25**) [149, 150]. This strategy was used with *p*-methylcinnamaldehyde (**100**) as carbonyl component in the total synthesis of (±)-*ar*-turmerone (**105**), a bisabolane-type natural product found in *Zingiber* and

**Scheme 26.** Synthetic route to utilizing a one-pot Michael addition—HWE reaction.
