‘Phospha-variations’ on the themes of Staudinger and Wittig: phosphorus analogs of Wittig reagents

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Abstract

The Wittig and Aza-Wittig reactions have undergone tremendous development over the past 50 years in light of their potential in organic synthesis to construct carbon–carbon and carbon–nitrogen double bonds. In contrast, the development of the analogous phospha-Wittig reaction has only seen progress over the last 12 years. A phospha-Wittig process is one that uses phosphaylides to convert carbonyl compounds to new materials possessing phosphorus–carbon double bonds (phosphaalkenes). The phospha-Wittig reaction has evolved from initial work involving metal-assisted phospha-Wittig reactions to phospha-Wittig reactions, of terminal phosphinidene complexes to, more recently, free phosphanylidene-σ4-phosphoranes as phospha-Wittig reagents. The major developments in the phospha-Wittig reaction are highlighted and divided into these three methodologies. The complementary nature and the differences between the three approaches is also discussed. Finally, wherein applicable, comparisons between the Wittig reaction and the phospha-Wittig reaction are presented.

Introduction

The Wittig reaction, the process by which phosphorus ylides convert aldehydes and ketones to alkenes, is perhaps one of the most seminal contributions to the field of organic chemistry (Eq (1.1)).

The incipient development and potential applications of the Wittig reaction was brought to widespread attention by Georg Wittig and his students in the early 1950s [1], [2]. Since then, the reaction has been of unparalleled significance in formation of carbon–carbon double bonds, and has influenced virtually every sphere of modern organic chemistry. The Wittig reaction has seen use in applications ranging from the synthesis of simple alkenes to the construction of complex biologically active molecules for the pharmaceutical industry. The enormous number of applications of the Wittig reaction eventually led to the conferral of the Nobel Prize in chemistry to Georg Wittig in 1979 [3], [4].

Wittig reagents or alkylidenephosphoranes (I) belong to a broad class of compounds termed as ylides. A ylide is defined as ‘a substance in which a carbanion is attached directly to a heteroatom carrying a substantial degree of positive charge and in which the positive charge is created by the sigma bonding of substituents to the heteroatom’ [5].

Different resonance structures are commonly drawn (Chart 1, left). A charge-separated canonical description is probably more befitting such compounds, rather than the double bond notation which is commonly employed for ease of representation.

Although the chemistry of ylides received a tremendous boost after Wittig's initial report in 1953, the first compounds of this nature were actually synthesized during the turn of the 20th century. In 1894, Michaelis and co-workers [6] had unknowingly prepared the first example of a phosphonium ylide, although it was not until almost 70 years later in 1961, that its structure was correctly described as (C6H5)3PC(H)CO2C2H5 [7]. In 1919, Staudinger and Meyers prepared PhNPPh3, the first example of an Aza-Wittig reagent, the nitrogen analog of a Wittig reagent [8]. Aza-Wittig reagents or iminophosphoranes (II) can also be portrayed in a similar fashion (Chart 1, right). Strikingly, the above report by Staudinger also describes the synthesis of Ph2CPPh3 and its Wittig-type reactivity with substrates such as phenylisocyanate. Similar to Wittig reagents, Aza-Wittig reagents react with organic carbonyls to effect the Aza-Wittig reaction (Eq. (1.2)).

Although Staudinger described the first phosphorus ylide as formulated in Chart 1, it was not till Wittig's work more than 30 years later that the reaction became accepted practise. As a consequence, Wittig's lecture describing his initial work was suitably titled ‘Variations on a theme of Staudinger’ [9]. A further detailed historical sketch of carbon (and nitrogen) based phosphonium ylides is much beyond this review, but the interested reader is referred to Johnson's excellent treatise on the subject [5].

The last 30 years has seen intense efforts to unveil relationships between phosphorus and carbon chemistry, and emphasize the realistic nature of the diagonal analogy between the two elements [10]. Amongst these efforts has also been the goal to extend the Wittig and Aza-Wittig reactions to include ‘phospha-Wittig’ for the synthesis of phosphaalkenes (Eq. (1.3)).

The main obstacle to achieving this goal has been the synthesis of phosphanylidene-σ4-phosphoranes [11], the phosphorus analogs of Wittig reagents (III, Chart 2), that can serve as efficient phospha-Wittig reagents in reactions with aldehydes and ketones. Such phosphanylidene-σ4-phosphoranes are often unstable and their chemistry rather undeveloped.

Examples now exist of the phospha-Wittig reaction whereby stability issues of these unusual analogues of Wittig reagents have been overcome by assistance of transition metals and complexation. More recently, the authors have serendipitously encountered stable examples of phosphanylidene-σ4-phosphoranes which participate in reactions with aldehydes to achieve phospha-Wittig reactions and produce stable phosphaalkenes.

In this review, the authors aim to highlight efforts leading to the development of phospha-Wittig reactions, which in a historical sense, represent ‘phospha-variations’ on the themes of Staudinger and Wittig. Additionally, taking into account the widespread recognition of the carbon–phosphorus diagonal relationship, it seemed timely, and perhaps enlightening, to parallel the chemistry of phospha-Wittig reagents to the more popular Wittig reagents.

Section snippets

The first breakthrough: metal-assisted phospha-Wittig reactions

The first examples of phospha-Wittig reactions were pioneered by Mathey and Marinetti in 1988 [12]. Deprotonation of transition-metal phosphorylphosphine complexes (1a) led to phosphorylphosphide complexes (2a) that react with aldehydes and ketones to afford phosphaalkene complexes (Eq. (2.1)).

.

The reaction as delineated in Eq. (2.1) is, strictly speaking, the phosphorus analog of an extension of the Wittig reaction, the Wadworth–Emmons synthesis, whereby phosphonate carbanions react with

Phospha-Wittig reactions of terminal phosphinidene complexes

Critical to the success of Mathey's pioneering work in developing the phospha-Wittig reaction was the previous discovery by the same group that transient electrophilic terminal phosphinidene complexes could be generated by thermolysis (Eq. (3.1)) [27].

.

In particular, species 3 can be visualized as the adducts of the highly reactive electrophilic terminal phosphinidene complex and tributylphosphine (see Eq. (2.4)).

The wide-ranging applications of transition-metal carbene [LnM=CRR′] complexes [37]

Free phosphanylidene-σ4-phosphoranes as phospha-Wittig reagents

During efforts to explore the reactivity of [Cp2ZrPDmp(PMe3)] (Dmp=2,6-dimesitylphenyl) (8), a close analog of Stephan's terminal phosphinidene complex 7, reactions with dichloroarylphosphines proved to be particularly enigmatic [54]. From literature precedence [55], [56], as well as the ability of [Cp2ZrPMes*(PMe3)] to effect the phospha-Wittig reaction, it was anticipated that 8 would react with the aryldichlorophosphine DmpPCl2 to produce the diphosphene DmpPPDmp (Scheme 5) and [Cp2ZrCl2]

Conclusions

The past 12 or so years have seen substantial progress in the development of the phospha-Wittig reaction. As detailed above, each of the three general approaches complement one another and each has its own special merits. Clearly the systems utilizing the [(CO)nM] complexes to tame the behavior of the phospha-Wittig reagent and stabilize the resulting phosphaalkene make this approach the most general for materials without regard to sterically demanding groups. Phospha-Wittig reactions based on

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