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

The Wittig olefination utilizing phosphoranes and the related Horner-WadsworthEmmons (HWE) reaction using phosphonates transform aldehydes and ketones into substituted alkenes. Because of the versatility of the reactions and the compatibility of many functional groups towards the transformations, both Wittig olefination and HWE reactions are a mainstay in the arsenal of organic synthesis. Here, an overview is given on Wittigand Horner-Wadsworth-Emmons (HWE) reactions run in combination with other transformations in one-pot procedures. The focus lies on one-pot oxidation Wittig/HWE protocols, Wittig/HWE olefinations run in concert with metal catalyzed cross-coupling reactions, Domino Wittig/HWE—cycloaddition and Wittig-Michael transformations.


Introduction
The Wittig olefination utilizing phosphoranes and the related Horner-Wadsworth-Emmons (HWE) reaction using phosphonates transform aldehydes and ketones into substituted alkenes. Because of the versatility of the reactions and the compatibility of many functional groups in the transformations, both Wittig olefination and HWE reactions are a mainstay in the arsenal of organic synthesis. The mechanism of the Wittig olefination has been the subject of intense debate [1]. While initially it was supposed that all Wittig olefination reactions lead via 1,2-addition to betaine structures 4 as zwitterionic intermediates that would form oxaphosphetane 3 with a final release of alkene and phosphine oxide by ring opening (syn-cycloreversion process), it has been seen more recently that especially under salt-free, aprotic conditions, many ylides undergo a π 2 s/π 2 a [2+2]-cycloaddition with the carbonyl component leading to the oxaphosphetane 3 directly [2], which in certain cases can be in equilibrium with betaine structures 4 (Scheme 1). In HWE reactions, the deprotonated phosphonate 6a undergoes a nucleophilic addition to the carbonyl compound (e.g., 7), which usually is the rate limiting step [3]. The elimination to the final products proceeds through oxaphosphetane 9 (Scheme 2). The Wittig olefination has been used industrially in the synthesis of terpenoids [4]. Recently, a one-pot synthesis of the vasodilator and anti-platelet agent Beraprost sodium, a prostacyclin analog, was communicated with the HWE reaction as the key transformation with the idea of using the approach in an industrial synthesis of the pharmaceutical [5].
For years after the discovery of the Wittig olefination [6,7], most Wittig transformations were carried out under inert atmosphere using dry solvents such as THF [8], DME [9], diethyl ether [10] and benzene [11]. Later it was realized that stabilized and semi-stabilized Wittig reagents can be reacted in non-de-aerated solvents, where the solvents need not be dried specifically. Most of these conjugated Wittig reagents are thermally stable and tolerate water, air and mild oxidants, while maintaining reactivity towards aldehydes and often also towards ketones. This allows for a plethora of reaction conditions for many Wittig olefination reactions such as obviating solvents altogether [12,13] or running the reactions in aqueous solutions [14,15] or in mixed solvents [16]. Also, it permits one-pot transformations of Wittig olefinations in combination with other reactions, also because the stabilized and to some extent the semi-stabilized phosphoranes are inert to mild oxidizing and reducing agents. However, also with non-stabilized phosphoranes, where reactions have to be performed under the exclusion of air and moisture, Wittig reactions can be performed in conjunction with further transformations [17].
This chapter is to give an insight into the types of transformations that can be combined with Wittig-and Horner-Wadsworth-Emmons olefinations in Domino-, tandem and one-pot  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][23][24][25][26] or an alkene [27] was shown to give α,β-unsaturated esters [17,[22][23][24][25][26][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 4 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 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 K 2 CO 3 as base [31][32][33][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][39][40][41][42].
Other preparation methods of aldehydes in conjunction with Wittig olefinations or HWE reactions have been reported. Thus, an oxidative cleavage of a glycol can be carried out in combination with a subsequent Wittig-olefination [102][103][104][105] (Scheme 7). Also a one-pot carboxylic acid to aldehyde reduction and Wittig reaction is known [106]. Finally, a Domino hydroformylation/Wittig olefination procedure has been developed, starting from allylamines (Scheme 8). The aldehyde is not isolated [107]. Domino/hydroformylation/Wittig olefination protocols have been introduced with other olefinic starting materials, also [108][109][110].
Hilt and Hengst have published a cobalt(I)-catalyzed Diels Alder reaction of alkynyltriphenylphosphonium and 1,3-dienes with a consecutive Wittig reaction of the cycloadduct with Scheme 9. One-pot Heck cross-coupling/Wittig reaction.
Alkenes various aldehydes in one pot that lead after a further dehydrogenative step to substituted stilbenes and styrenes (Scheme 11) [133].
The transformation sequence Diels-Alder/Wittig can be part of a more complex reaction chain. Thus, Ramachary and Barbas III [135] have forwarded a Domino Wittig/Knoevenagel/ Scheme 10. Oxidation-Wittig-olefination-Diels-Alder reaction sequence.  Oxidation of benzyl alcohols to benzaldehydes can be incorporated into a Wittig-Diels Alder sequence [69]. Also, hetero-Diels-Alder reactions can be run in tandem with a Wittig olefination as shown by Ramachary et al. in their synthesis of tetrahydropyrans 64 (Scheme 15) [136]. Here, diamine 63 is used as a catalyst. The reaction, however, gives the product only in low enantiomeric excess (Scheme 15).
Huisgen type [3+2]-cycloaddition reactions can be run also in a simple tandem process rather than incorporated in a more complex reaction chain (see above). A typical example is shown in Scheme 16, where azidoethyl-tetrahydro-hydroxyfuran 66 is treated with phosphorane 21 to give triazoline 68 alongside diazoamine 69 [137]. Further such approaches are known [138,139]. 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 3 -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

Alkenes
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 3 -NBn i Pr 2 ), where the polymer bound triarylphosphine oxide also exerts a catalyzing effect on the addition of Cl 3 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]. 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].

One-pot Wittig-olefination/functional group interconversion
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,Opinacol acetal can be hydrolyzed directly to the cinnamaldehydes 108 with 25w% aq. H 3 PO 4 (Scheme 28) [153].
This procedure provides a nice alternative to the reaction of benzaldehydes with triphenylphosphoranylideneacetaldehyde, which often produces dienals and trienals as side-products.

One-pot Wittig-and HWE olefination/cyclization
Michael type cyclization-cyclic hemiacetals can be used efficiently as substrates in Wittig olefination reactions with stabilized Wittig reagents. After the Wittig reaction, the tethered alcohol Scheme 27. One-pot Wittig reaction-ester hydrolysis.

Scheme 29. Wittig reaction-cyanosilylation.
Alkenes function induces a cyclization through a Michael reaction. This reaction sequence has been used especially in the construction of functionalized C-glycosides such as in the stereospecific synthesis of ω-amino-β-d-furanoribosylacetic acid derivative 115 (Scheme 30) [154].
In their synthesis to C-glycoside amphiphiles, Ranoux et al. followed a similar strategy, reacting non-protected sugars with HWE reagents in aqueous or solventless conditions, leading to C-glucosides 117 and 121 (Scheme 31) [155].

Alkenes 20
Similarly, Hamza and Blum [71], who developed a Wittig olefination with a sol-gel entrapped tertiary phosphine derived phosphorane (vide supra, Schemes 18 and 19) showed that the Wittig reaction can be run in concert with a photochemical cyclization under aerobic conditions to produce phenanthrene (138) (Scheme 36) [71].

Alkenes 22
acid found in different species of red algae [174]. Here, the product was formed in 65% yield as a mixture of diastereoisomers 1598a/159b in a ratio of 1:5. Previously, the authors had synthesized (±)-kainic acid (160) utilizing a Wittig-Michael reaction as the key step (Scheme 40) [175].