**1. 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

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

a π2 s/π2 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 reaction strategies. These include the preparation of phosphoranes and their reaction *in situ*, one-pot oxidation of alcohols to aldehydes and Wittig-olefination, *in situ*-recycling of phosphine oxides and catalytic Wittig reactions, one-pot Wittig-olefination metal catalyzed C─C bond forming reactions such as Suzuki-Miyaura, Sonogashira- and Heck reactions, Wittig and Horner-Emmons reactions in combination with polar cyclizations, Wittig-reactions carried out in combination with electrocyclic reactions, one-pot Wittig and Horner Emmons-addition reactions; cascade reactions featuring (triphenylphosphoranylidene)-ethenone and similar

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

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

5

**2. Wittig and Horner-Wadsworth-Emmons (HWE) olefination reactions** 

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

**with phosphoranes and phosphonates prepared** *in situ*

**Scheme 2.** General reaction mechanism of the HWE reaction.

phosphoranes.

**Scheme 1.** Schematic presentation of the reaction mechanism of the Wittig olefination.

Tandem-, Domino- and One-Pot Reactions Involving Wittig- and Horner-Wadsworth-Emmons... http://dx.doi.org/10.5772/intechopen.70364 5

**Scheme 2.** General reaction mechanism of the HWE reaction.

a π2 s/π2

4 Alkenes

synthesis of the pharmaceutical [5].

with further transformations [17].

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

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

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

**Scheme 1.** Schematic presentation of the reaction mechanism of the Wittig olefination.

reaction strategies. These include the preparation of phosphoranes and their reaction *in situ*, one-pot oxidation of alcohols to aldehydes and Wittig-olefination, *in situ*-recycling of phosphine oxides and catalytic Wittig reactions, one-pot Wittig-olefination metal catalyzed C─C bond forming reactions such as Suzuki-Miyaura, Sonogashira- and Heck reactions, Wittig and Horner-Emmons reactions in combination with polar cyclizations, Wittig-reactions carried out in combination with electrocyclic reactions, one-pot Wittig and Horner Emmons-addition reactions; cascade reactions featuring (triphenylphosphoranylidene)-ethenone and similar phosphoranes.
