Metathesis of heteroatom-substituted olefins and alkynes: Current scope and limitations

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Abstract

The use of vinyl- or alkynyl derivatives of the type Cdouble bondC–X or Ctriple bondC–X (where X is an heteroatom) as substrates for metathesis increases further this reaction’s versatility. Selected examples illustrating recent progress in this area of research are presented. Current scope and future potential developments are discussed.

Graphical abstract

The use of vinyl- or alkynyl derivatives of the type Cdouble bondC–X or Ctriple bondC–X (where X is an heteroatom) as substrates for metathesis increases further this reaction’s versatility. Selected examples illustrating recent progress in this area of research are presented. Current scope and future potential developments are discussed.

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Introduction

Over the last 10 years or so, thanks to the development of well-defined catalysts (Fig. 1), diene and enyne metathesis in their various versions: ring-closing metathesis (RCM), ring-opening metathesis (ROM) and cross-metathesis (CM) have emerged as major tools for the synthesis of complex molecules [1]. The product of the widely used diene metathesis is an olefin that can be further modified but only to a limited extent and generally with low regioselectivity (unless the olefinic carbons are clearly different for steric or electronic reasons) [2]. Therefore, in most literature examples, the newly formed double bond is either present in the final product or undergoes only simple chemical transformations in which regioselectivity is not a problem (e.g. hydrogenation, dihydroxylation or epoxidation). The product of enyne metathesis is a conjugated diene that offers more possibilities for further conversions. For example, the enyne metathesis/Diels–Alder reaction sequence has been used in several instances in total synthesis [3]. Enyne RCM/cyclopropanation has also been described [4].

On the other hand, olefinic double bonds bearing heteroatom substituents (e.g. vinyl silanes, vinyl halides, enol ethers, etc.) offer vast functionalization possibilities and, of course, regioselectivity is not a problem anymore (Scheme 1). However, whether these versatile synthetic intermediates can be generally prepared by metathesis of dienes or enynes remains unclear. In particular, a key question that has not yet been fully answered, is whether Fisher carbene species (formed during the first cycle of electron-rich olefin metatheses) are reactive enough for the catalytic cycle to proceed [5].

The present review aims at summarizing our knowledge of metathesis when applied to heteroatom-substituted olefins or acetylenes, with emphasis on the perspectives of the metathesis products as synthetic intermediates. Accordingly, we will restrict ourselves to substrates leading to “productive” metathesis (i.e. when the heteroatom is incorporated in the product). For example the RCM of 1-substituted olefins in which the substituent is lost in the process is of limited synthetic interest and will not be discussed. The review is not intended to be exhaustive and only limited examples (usually the most recent ones) will be provided for illustrating our purpose.

Section snippets

Ene-ene

Pioneering methodological and mechanistic studies by Pietraszuk, Marciniec and Fischer have shown that cross-metathesis between vinylsilanes substituted by alkoxy-, siloxy- or electron-withdrawing groups and cyclic or acyclic alkenes can be efficiently catalyzed by Grubbs generation 1 and 2 complexes (hereafter called [Ru]-1 and [Ru]-2, respectively) [6]. Cross-metathesis of vinyl(trialkoxy)silanes with terminal olefins (including vinyl sulfides (see Scheme 73)) allows the construction of

Ene-ene RCM

α-Amino acrylamides 70ac can be efficiently transformed into α-amino α,β-unsaturated lactams 71ac using ring-closing metathesis reactions (Scheme 23) [25]. A limitation to this method was observed for the RCM of substrate 70d leading to the eight-membered heterocycle 71d. The amide needs to be N-protected (various benzyl-like protecting groups) since no reaction occurred with the unprotected nitrogen atom under a variety of conditions. This approach was used to construct sublibraries of

Vinyl and alkynyl ethers

In 1994 Grubbs reported the first metathesis involving enol ethers, catalyzed by well-defined metal alkylidene catalysts. Treatment of acyclic olefinic enol ethers (generated from the corresponding olefinic esters by stoechiometric use of the Tebbe reagent or related reagents), with 5–12 mol% [Mo] afforded the corresponding cyclic enol ethers in good yields. In contrast ruthenium alkylidene [Ru]-1 catalyzed the slow dimerization of the starting material without formation of the cyclic enol

RCM

Hanson and Stoianova were the first to report a preparation of P-heterocycles by RCM of acyclic vinylphosphonates or phosphonamides (Scheme 48) [54].

In general the reaction worked well using [Ru]-1 as the catalyst although in some cases (e.g. for R = Ph) the reaction was sluggish. Shortly afterwards, the same team developed an RCM-mediated desymmetrization of nonracemic pseudo-C2-symmetric phosphonamides that led to P-heterocycles containing a stereogenic phosphorus atom (Scheme 49) [55].

van Boom

RCM

In their pioneering work, Renaud and Ouellet demonstrated that RCM is a practical and reliable procedure for the synthesis of trisubstituted cyclic vinylboronates (Scheme 60) [68].

The reaction appeared to work well at room temperature, although it sometimes required a long time (up to 10 days for X = O, n = 1), affording very good yields of cyclic vinylboronates 196 using Grubbs catalyst [Ru]-1 ([Mo] was not efficient). Although further conversion of the resulting boronates was not examined, this

Vinyl chalcogenides

Despite the potential of vinyl sulfides and selenides as synthetic intermediates, we are aware of only two reports dealing with their preparation by metathesis. ROM/CM experiments involving norbornene and phenylvinyl sulfide, selenide or telluride were carried out (Scheme 73). First, Fischer-type carbenes 256ad, prepared by reaction of [Ru]-1 with the corresponding vinyl chalcogenides were used. As shown in Scheme 73 the best results were obtained using the selenium-containing carbene 256c as

Vinyl halides and pseudohalides

Vinyl halides and pseudohalides (e.g. enol phosphates or sulfonates) are well known versatile intermediates for the creation of new C–C bonds via transition metals-catalyzed coupling reactions. Their preparation, however, except in simple cases is not straightforward. Metathesis, if applicable, would be the ideal method to prepare complex vinylic halides or pseudohalides starting from simpler, more readily available members of this family of compounds. At this point, several questions are

Discussion/conclusion

Within a short period of only a few years, organic chemists’ understanding of olefin and alkyne metathesis has progressed to a level that allows the use of this powerful reaction for the preparation of many, structurally diverse complex molecules. In most cases, the substitution pattern of metathesis substrates encompasses hydrogen or substituents linked by a C–C bond (e.g, alkyl or aryl residues, carbonyl groups, etc.). As a result, during the metathesis process, alkenes, dienes or alkynes

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