**8. 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 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].

A different mechanism to C-glucosides operates when 5,6-dideoxy-5,6-anhydro-6-nitro-d-glucofuranose **122** is reacted with an excess of phosphorane **21**. Here, **21** acts as a base and **122** experiences an anion driven ring opening to **123**, which undergoes an oxy-Michael addition to **124** with concomitant Wittig reaction, resulting in C-vinyl glycoside **125** (**Scheme 32**) [156].

A highly stereoselective tandem Wittig-reaction-Michael addition has been developed by Liu et al. [157] when reacting 3-carboxy2-oxopropylidene)triphenylphosphorane **126** with

**Scheme 30.** Synthesis of ω-amino-*β*-d-furanoribosylacetic acid derivative **115** utilizing a Wittig olefination-ring closure reaction en route.

**Scheme 31.** Synthesis of C-glucosides with a HWE—ring closure reaction.

aluminum catalyst **109** was used as Lewis acid to activate the keto function in the cyanosilylation. Products were obtained with high enantioselectivity [68–93%ee]. TMSCN and chiral catalyst **109**

As Wittig reactions can be carried out in aqueous medium, enzymatic reactions can be integrated into the process (*vide supra*). In this regard, M. Krauβer et al. showed that 4-phenylbut-3-en-2-ones (**93**), obtained by Wittig olefination, are reduced to the corresponding 4-phenylbut-3-en-2-ols (**94**) in >99 ee(%) using (*S*)-alcohol dehydrogenase [(*S*)-ADH] from

*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

were added after completion of the Wittig reaction, albeit in one pot (**Scheme 29**) [143].

*Rhodococcus* sp. or (*R*)-ADH from *Lactobacillus kefir* [148].

**Scheme 27.** One-pot Wittig reaction—ester hydrolysis.

18 Alkenes

**Scheme 28.** One-pot Wittig reaction—acetal hydrolysis.

**8. One-pot Wittig- and HWE olefination/cyclization**

**Scheme 29.** Wittig reaction—cyanosilylation.

**Scheme 32.** Tandem oxy-Michael addition—Wittig reaction.

enaldehydes (e.g., **15**), using a chiral pyrrolidine-based catalyst such as **128** (**Scheme 33**). Most likely, the asymmetric Michael addition proceeds by the reaction of **15** with the iminium compound **129** (**Scheme 33**), formed from **15** with catalyst **128**.

Beltrán-Rodil et al. have elaborated a retro-aldol initiated Wittig-olefination-Michael addition sequence leading to an exchange of the hydroxyl function in **130** for a carbalkoxymethyl group in **134**. The retro-aldol reaction is effected by the commercially available trimethylamine *N*-oxide (TMAO, **131**) [158] (**Scheme 34**).

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 condi-

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**Scheme 35.** One-pot phosphorane synthesis—Wittig-reaction—6π-electrocyclization—oxidative dehydrogenation.

A number of tandem Wittig/HWE reaction—Claisen/Cope rearrangements have been reported [160–173]. A typical example is shown in **Scheme 37**, where neat (4-fluorophenoxyacetyl)cyanomethylene)triphenylphosphorane **139** is subjected to microwave irradiation at 450 W in a sealed tube to undergo an intramolecular Wittig reaction—Claisen rearrangement

Mali et al. achieved the synthesis of seselin and angelicin derivatives (e.g., **148** and **150**) by a tandem Wittig-olefination—Claisen rearrangement from propargyl and chloroalkyl ethers of 2,4-dihydroxybenzaldehyde and 2,4-dihydroxyacetophenone (e.g., **146** and **149**)

Nevertheless, sometimes, these reactions are not easy to control. Thus, a cascade of Wittig reaction and double Claisen and Cope rearrangements starting from 2,4-prenyloxybenzaldehyde

tions to produce phenanthrene (**138**) (**Scheme 36**) [71].

**Scheme 36.** Wittig olefination—photocyclization—oxidative dehydrogenation.

**Scheme 34.** Retro-aldol-Wittig-olefination-Michael addition cascade.

to furnish benzofuran **134** (**Scheme 37**) [173].

(**Scheme 38**) [164].

*Electrocyclizations*, *incl. photocyclizations*, *and pericyclic reactions*: Electrocyclization can be run in concert with Wittig reactions. One such example is shown in **Scheme 35**, where allylic bromide **135**, the product of a Morita-Baylis-Hillman transformation, is converted with triphenylphosphine to the corresponding phosphonium salt, which is reacted with benzaldehyde (**11**) to give triene **136**. **136**, heated under aeration, undergoes a 6π-electrocyclization—base catalyzed aerobic oxidation to *o*-terphenyl derivative **137** (**Scheme 35**) [159].

**Scheme 33.** Asymmetric Michael-addition-Wittig-olefination.

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**Scheme 34.** Retro-aldol-Wittig-olefination-Michael addition cascade.

enaldehydes (e.g., **15**), using a chiral pyrrolidine-based catalyst such as **128** (**Scheme 33**). Most likely, the asymmetric Michael addition proceeds by the reaction of **15** with the imin-

Beltrán-Rodil et al. have elaborated a retro-aldol initiated Wittig-olefination-Michael addition sequence leading to an exchange of the hydroxyl function in **130** for a carbalkoxymethyl group in **134**. The retro-aldol reaction is effected by the commercially available trimethyl-

*Electrocyclizations*, *incl. photocyclizations*, *and pericyclic reactions*: Electrocyclization can be run in concert with Wittig reactions. One such example is shown in **Scheme 35**, where allylic bromide **135**, the product of a Morita-Baylis-Hillman transformation, is converted with triphenylphosphine to the corresponding phosphonium salt, which is reacted with benzaldehyde (**11**) to give triene **136**. **136**, heated under aeration, undergoes a 6π-electrocyclization—base catalyzed aerobic oxidation to *o*-terphenyl derivative **137**

ium compound **129** (**Scheme 33**), formed from **15** with catalyst **128**.

amine *N*-oxide (TMAO, **131**) [158] (**Scheme 34**).

**Scheme 33.** Asymmetric Michael-addition-Wittig-olefination.

**Scheme 32.** Tandem oxy-Michael addition—Wittig reaction.

(**Scheme 35**) [159].

20 Alkenes

**Scheme 35.** One-pot phosphorane synthesis—Wittig-reaction—6π-electrocyclization—oxidative dehydrogenation.

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].

A number of tandem Wittig/HWE reaction—Claisen/Cope rearrangements have been reported [160–173]. A typical example is shown in **Scheme 37**, where neat (4-fluorophenoxyacetyl)cyanomethylene)triphenylphosphorane **139** is subjected to microwave irradiation at 450 W in a sealed tube to undergo an intramolecular Wittig reaction—Claisen rearrangement to furnish benzofuran **134** (**Scheme 37**) [173].

Mali et al. achieved the synthesis of seselin and angelicin derivatives (e.g., **148** and **150**) by a tandem Wittig-olefination—Claisen rearrangement from propargyl and chloroalkyl ethers of 2,4-dihydroxybenzaldehyde and 2,4-dihydroxyacetophenone (e.g., **146** and **149**) (**Scheme 38**) [164].

Nevertheless, sometimes, these reactions are not easy to control. Thus, a cascade of Wittig reaction and double Claisen and Cope rearrangements starting from 2,4-prenyloxybenzaldehyde

**Scheme 36.** Wittig olefination—photocyclization—oxidative dehydrogenation.

**Scheme 37.** Intramolecular Wittig reaction—Claisen rearrangement.

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

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Finally, the possibility of a tandem Wittig-olefination—aza-Wittig rearrangement should be mentioned—this combination was carried out on 2-benzoylaziridine **161** to give stereoiso-

(**Scheme 40**) [175].

meric dehydropiperidines **163**/**164** (**Scheme 41**) [176].

**Scheme 40.** Wittig-ene cascade as a key step towards the synthesis of kainic acid (**160**).

**Scheme 39.** Wittig reaction—double Claisen and cope rearrangements.

**Scheme 38.** One-pot syntheses of seselin and angelicin derivatives.

**151** leads to a plethora of products through the range of reactions that are possible with the intermediate **153**, itself produced through the Wittig reaction and a first Claisen rearrangement. The final products found include gravelliferone (**154**, 10%), balsamiferone (**155**, 5%), and 6,8-diprenylumbelliferone (**156**, 15%) (**Scheme 39**) [169].

Less common is the tandem Wittig and ene reaction. Tilve et al. have published such a combination of Wittig and ene reaction in their total synthesis of (±)-kainic acid (**160**), an amino Tandem-, Domino- and One-Pot Reactions Involving Wittig- and Horner-Wadsworth-Emmons... http://dx.doi.org/10.5772/intechopen.70364 23

**Scheme 39.** Wittig reaction—double Claisen and cope rearrangements.

**151** leads to a plethora of products through the range of reactions that are possible with the intermediate **153**, itself produced through the Wittig reaction and a first Claisen rearrangement. The final products found include gravelliferone (**154**, 10%), balsamiferone (**155**, 5%), and

Less common is the tandem Wittig and ene reaction. Tilve et al. have published such a combination of Wittig and ene reaction in their total synthesis of (±)-kainic acid (**160**), an amino

6,8-diprenylumbelliferone (**156**, 15%) (**Scheme 39**) [169].

**Scheme 38.** One-pot syntheses of seselin and angelicin derivatives.

**Scheme 37.** Intramolecular Wittig reaction—Claisen rearrangement.

22 Alkenes

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].

Finally, the possibility of a tandem Wittig-olefination—aza-Wittig rearrangement should be mentioned—this combination was carried out on 2-benzoylaziridine **161** to give stereoisomeric dehydropiperidines **163**/**164** (**Scheme 41**) [176].

**Scheme 40.** Wittig-ene cascade as a key step towards the synthesis of kainic acid (**160**).

[178]. A metathesis reaction completes the sequence to **171**. In this case, the metathesis reaction

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Nevertheless, one-pot Wittig—metathesis reactions are well known from the literature [179–181]. A typical example is shown in **Scheme 44**, where catalyst **174** serves both as a catalyst for the metathesis as well as for the Wittig olefination, when the *in situ* produced aldehyde **175** is treated

Due to the fact that phosphoranes and phosphonates are stable under more diverse conditions than was initially realized, it has become possible to perform reaction cascades and one-pot reactions with Wittig- and HWE reactions as an integral part of the reaction sequence. Frequently, Wittig olefination reactions are carried out with *in situ* prepared phosphonium salts and phosphoranes [17, 22–27]. One-pot oxidation—Wittig olefination reactions are also quite common [40, 43–110], especially when the carbonyl component is labile [89, 97]. Often, the oxidant of choice is

 [40, 43–46, 79–97], although a number of reactions are known where transformations were carried with air oxygen using metals and metal oxides as catalysts [72–78]. As many Wittig- and HWE reactions tolerate metal catalysts, this allows the running of Wittig/HWE reactions in combination with metal catalyzed cross coupling reactions and olefinations such as Heck [114–123], Suzuki [111–113], Sonogashira [119–121], and metathesis reactions [179–181]. The alkenes gained in the olefination reactions can be submitted to cycloaddition reactions, including Diels Alder reactions [69]. Furthermore, the alkenes lend themselves to 1,2-addition reactions [71, 140] in one-pot procedures. In cases where enones or enaldehydes are produced in the olefination reaction, a 1,4-addition becomes a possibility; this includes the Michael addition [149–151]. Also, the combination of ring opening of cyclic hemiacetals or acetals, olefination reaction and a 1,4-addition leading to ring closure is quite common [154–156]. The outcome of one-pot sequences of olefination reaction—electrocyclic rearrangement can be predicted less easily. Nevertheless, one-pot Wittig olefination—Claisen- [173], Wittig olefination—Cope- [169], and Wittig olefination—aza Wittig [176] rearrangement reactions have been published. Lastly, Wittig olefination and HWE reactions have been combined with functional group transformations, including the

hydrolysis of an ester function [152] and the reduction of a carbonyl group [148].

with triphenylphosphine and ethyl diazoacetate (**176**) in one pot (**Scheme 44**).

is not run in one pot with the previous transformations.

**10. Conclusion**

**Scheme 44.** One-pot Wittig—Metathesis reaction.

MnO2

**Scheme 41.** Tandem Wittig-olefination—aza-Wittig-rearrangement.
