**2. Wittig and Horner-Wadsworth-Emmons (HWE) olefination reactions with phosphoranes and phosphonates prepared** *in situ*

Primarily, phosphoranes as Wittig reagents are prepared by the reaction of a triarylphosphine, usually triphenylphosphine, or, more seldom, a trialkylphosphine, and an alkyl halide with subsequent dehydrohalogenation of the triaryl(alkyl)alkylphosphonium halide produced. Non-stabilized Wittig reagents are not stable enough to be stored over longer periods of time; therefore, it is the norm that the Wittig-ylide is formed *in situ* from the oftentimes stable phosphonium salt, usually with a strong base, and then reacted directly with the carbonyl compound. In the case of stabilized phosphoranes, they are often stable enough to store, and the dehydrohalogenation necessitates only a weak base such as sodium carbonate or even sodium bicarbonate [18]. Nevertheless, this likewise allows the preparation of the phosphorane and the subsequent Wittig olefination in one pot [19], where even protic solvents can be used, such as water. Similarly, semi-stabilized phosphoranes can be obtained *in situ* from their respective phosphonium salts, also even in aqueous medium, where LiCl promotes the Wittig olefination and suppresses the decomposition of the phosphoranes [14, 15]. Furthermore, all the catalytic Wittig reactions (see below) rely on the fact that the phosphorane is produced *in situ.*

developed further with one-pot transformations that were managed with catalytic amounts (2 mol%) of poly(ethylene glycol) and (PEG)-supported tellurides in the presence of K2

Tandem-, Domino- and One-Pot Reactions Involving Wittig- and Horner-Wadsworth-Emmons...

as base [31–34]. Also, micellar reaction systems such as micellar solutions of sodium dodecyl sulfate (SDS) in water have been used, in which Wittig olefinations were carried out between aldehydes and phosphoranes, synthesized *in situ* [35, 36]. A. Galante has per Wittig reactions

Traditionally, stabilized halophosphoranes have been prepared by the halogenation of the nonhalogenated parent phosphoranes and a subsequent dehydrohalogenation of the halogenated phosphonium salt obtained. Karama et al. have combined this *in situ* halogenation: dehydrohalogenation step with the Wittig reaction itself. Additionally, an *in situ* alcohol oxidation to provide the aldehyde starting material was integrated into many of these reaction

in the fluorous phase with *in situ* pre-formed perfluorinated ylides [37].

**3.** *In situ* **alcohol oxidation—Wittig/HWE reactions; other** *in situ*

The tolerance of stabilized phosphoranes towards mild oxidants allows for the oxidation of an alcohol to an aldehyde and its Wittig reaction in one-pot (**Schemes 5** and **6**). As oxi-

perruthenate (TPAP)/*N*-methylmorpholine *N*-oxide (NMO) [49–54] and TPAP/*N*,*N*,*N′*,*N′*-

Dess-Martin periodinane [59–61], DMSO-oxalyl chloride (Swern conditions) [62–64], DMSO-

chlorochromate (PCC) or PCC/celite [66–69] as well as pyridinium dichromate (PDC) [70] such as PDC encapsulated in sol gel [71] have been used. In addition, metal catalyzed aerobic oxidation reactions of aldehydes with concomitant olefination reactions are known, where [(eta-

oxyhydroxide [73] or on silica gel [74], and nickel nanoparticles [75, 76] (**Scheme 6**) have been used as catalyst in the case of a concomitant Wittig reaction and gold/palladium bimetallic nanoparticles in the case of a concomitant Horner-Wadsworth-Emmons (HWE) reaction [77],

Taylor et al. give a good overview of the tandem oxidation-Wittig processes developed until 2005, focusing especially on the tandem oxidation process (TOP) developed by his group [43–46],

Cu(I)-phenanthroline as a catalyst in an oxidation: HWE: sequential procedure [78].

[43–46], barium permanganate [47, 48], tetra-*n*-propylammonium

(**27**) [72], nanoparticulate ruthenium supported on highly porous aluminum

) [55], *o*-iodoxybenzoic acid (IBX) [56–58],


**aldehyde preparations run with subsequent Wittig/HWE** 

**Scheme 4.** One-pot oxidation, halogenation, and Wittig reaction to 2-haloacrylates.


sequences (**Scheme 4**) [38–42].

**sequences in one pot**

dants, activated MnO2

*p*-cymene)RuCl2

] 2

SO<sup>3</sup>

tetramethylenediamine dioxide (TMEDAO2

CO<sup>3</sup>

7

http://dx.doi.org/10.5772/intechopen.70364

Perhaps more interesting is the one-pot reaction of an alkyl halide, a phosphine and a carbonyl compound (**Scheme 3**). This can be achieved by consecutive addition of the components, when one or more of the components are sensitive, or by mixing of all components simultaneously. A consecutive addition of components in one pot was pursued by McNulty and Das who reacted air-sensitive triethylphosphine with benzyl bromides to the respective benzyltriethylphosphonium bromides, which were transformed to the phosphoranes with aq. NaOH, before being reacted with benzaldehydes to give (*E*)-stilbenes in an aqueous Wittig olefination [20]. Here, the triethylphosphine oxide by-product is water soluble. This reaction procedure has been diversified further by a one-pot preparation of benzyltriethylphosphonium bromides from the air-stable triethylphosphine hydrobromide and benzyl alcohols and subsequent Wittig olefination with aromatic aldehydes in aqueous medium [21]. Simultaneous mixing of alkyl halide such as α-haloesters (e.g., **13**), α-halonitriles, α-halocarbonyl compounds and α-alkyl-α-halocarbonyl compounds, triphenylphosphine (**12**), and carbonyl compound (e.g., **11**, **15**, **18**) in the presence either of a base [17, 22–26] or an alkene [27] was shown to give α,β-unsaturated esters [17, 22–27] (e.g., **14**, **17**, **19**), α,β-unsaturated nitriles [23, 26] and enones [27], respectively (**Scheme 3**). Epoxides are stable under these reaction conditions as can be seen in the transformation of **18** to **19** (**Scheme 1**). A one-pot, fluoride catalyzed Wittigolefination has also been devised, where ethyl bromoacetate is reacted with carbaldehydes in the presence of tri-*n*-butylphosphine and tetrabutylammonium fluoride (Bu<sup>4</sup> NF) to give (*E*) configured α,β-unsaturated esters in good yield [28]. The synthesis of α,β-unsaturated esters has also been achieved from their alkyl halide and aldehyde constituents using tributylarsine [29] or a substituted triarylarsine instead of triphenylphosphine [30]. The use of tributylarsine in the presence triphenyl phosphite [29] led to the creation of a catalytic system which was

**Scheme 3.** *In situ* preparation of phosphoranes and subsequent Wittig olefination.

developed further with one-pot transformations that were managed with catalytic amounts (2 mol%) of poly(ethylene glycol) and (PEG)-supported tellurides in the presence of K2 CO<sup>3</sup> as base [31–34]. Also, micellar reaction systems such as micellar solutions of sodium dodecyl sulfate (SDS) in water have been used, in which Wittig olefinations were carried out between aldehydes and phosphoranes, synthesized *in situ* [35, 36]. A. Galante has per Wittig reactions in the fluorous phase with *in situ* pre-formed perfluorinated ylides [37].

Traditionally, stabilized halophosphoranes have been prepared by the halogenation of the nonhalogenated parent phosphoranes and a subsequent dehydrohalogenation of the halogenated phosphonium salt obtained. Karama et al. have combined this *in situ* halogenation: dehydrohalogenation step with the Wittig reaction itself. Additionally, an *in situ* alcohol oxidation to provide the aldehyde starting material was integrated into many of these reaction sequences (**Scheme 4**) [38–42].

**Scheme 4.** One-pot oxidation, halogenation, and Wittig reaction to 2-haloacrylates.

as water. Similarly, semi-stabilized phosphoranes can be obtained *in situ* from their respective phosphonium salts, also even in aqueous medium, where LiCl promotes the Wittig olefination and suppresses the decomposition of the phosphoranes [14, 15]. Furthermore, all the catalytic Wittig reactions (see below) rely on the fact that the phosphorane is produced *in situ.* Perhaps more interesting is the one-pot reaction of an alkyl halide, a phosphine and a carbonyl compound (**Scheme 3**). This can be achieved by consecutive addition of the components, when one or more of the components are sensitive, or by mixing of all components simultaneously. A consecutive addition of components in one pot was pursued by McNulty and Das who reacted air-sensitive triethylphosphine with benzyl bromides to the respective benzyltriethylphosphonium bromides, which were transformed to the phosphoranes with aq. NaOH, before being reacted with benzaldehydes to give (*E*)-stilbenes in an aqueous Wittig olefination [20]. Here, the triethylphosphine oxide by-product is water soluble. This reaction procedure has been diversified further by a one-pot preparation of benzyltriethylphosphonium bromides from the air-stable triethylphosphine hydrobromide and benzyl alcohols and subsequent Wittig olefination with aromatic aldehydes in aqueous medium [21]. Simultaneous mixing of alkyl halide such as α-haloesters (e.g., **13**), α-halonitriles, α-halocarbonyl compounds and α-alkyl-α-halocarbonyl compounds, triphenylphosphine (**12**), and carbonyl compound (e.g., **11**, **15**, **18**) in the presence either of a base [17, 22–26] or an alkene [27] was shown to give α,β-unsaturated esters [17, 22–27] (e.g., **14**, **17**, **19**), α,β-unsaturated nitriles [23, 26] and enones [27], respectively (**Scheme 3**). Epoxides are stable under these reaction conditions as can be seen in the transformation of **18** to **19** (**Scheme 1**). A one-pot, fluoride catalyzed Wittigolefination has also been devised, where ethyl bromoacetate is reacted with carbaldehydes in

6 Alkenes

the presence of tri-*n*-butylphosphine and tetrabutylammonium fluoride (Bu<sup>4</sup>

**Scheme 3.** *In situ* preparation of phosphoranes and subsequent Wittig olefination.

configured α,β-unsaturated esters in good yield [28]. The synthesis of α,β-unsaturated esters has also been achieved from their alkyl halide and aldehyde constituents using tributylarsine [29] or a substituted triarylarsine instead of triphenylphosphine [30]. The use of tributylarsine in the presence triphenyl phosphite [29] led to the creation of a catalytic system which was

NF) to give (*E*)-
