Chapter 1
Synthesis of Dendralenes

Nicholas J. Green, Mehmet F. Saglam and Michael S. Sherburn

1.1 Introduction

The synthesis and study of conjugated polyenes has been at the heart of the chemical sciences ever since an appreciation of their structure began to develop. Of the five classes of conjugated alkenes that arise from the different possible modes of connectivity (Figure 1.1), some have received significantly more attention than others. The linear and cyclic classes featuring vicinal connections between alkene units - the linear polyenes 1 and annulenes 2 - are common structural motifs in naturally occurring compounds and contrived structures of industrial, commercial, and academic importance, and have hence been extensively synthesized and studied. Oligoalkenes with geminal connections between alkenes - cyclic radialenes 4 and acyclic dendralenes 5 - are yet to receive such attention, nor are "hybrid" structures featuring both geminal and vicinal connections, the fulvenes 3. There is, however, undoubtedly a growing interest in the subject of this chapter: the synthesis of dendralenes.

Figure 1.1 Fundamental conjugated hydrocarbons.

Dendralenes have been the subject of two comprehensive reviews [1, 2]. The first covers research in the area until 1984; and the second covers the period between 1984 and 2011. While it would be impossible to summarize the evolution of dendralene synthesis without some repetition of the key strategies found in each of these reviews, we seek to present the subject differently herein, by summarizing the best methods from both reviews, and placing emphasis on the significant work that has appeared between 2011 and the present. We also present the synthetic strategies in a new way, based on which carbon-carbon bonds of the dendralene are formed in the approach. Newly formed bonds are highlighted in bold, and should not be confused with wedged bonds, used to indicate stereochemistry. A broad measure of the synthetic power of a strategy is the number of bonds formed in the process, and we have therefore first highlighted strategies that form more than one bond per step [3]. This has allowed us insight into the strengths, weaknesses, and gaps present amongst current approaches. Our review covers examples in the literature up until April 2015, and we exclusively deal with the synthesis of the parent and substituted dendralenes, directing readers to other reviews or chapters of this book dealing with their closely related, cross-conjugated relatives (fulvenes [4], radialenes [5, 6], quinomethanes [7], etc.). We have not included related compounds that may be generated by substituting a carbon atom in the dendralene backbone with a similar unsaturated moiety, such as an alkyne or aromatic ring. We have also limited our survey to exclude cross-conjugated polymers, which have been reviewed elsewhere [8].

1.2 Multibond Forming Processes

1.2.1 Double Alkenylation Reactions

The double alkenylation approach (Scheme 1.1) has only been exploited relatively recently, most probably because of the rise to prominence of cross-coupling methodologies in recent times. The first double cross-couplings between 1,1-dihaloalkenes and metalloalkenes were isolated examples appearing in 1998 [9] and 2000 [10]. In 2002, Oh and Lim [11] reported a series of double Suzuki-Miyaura reactions between a 1,1-dibromoalkene 6 and alkenyl boronic acids 7 (Scheme 1.2). In 2007 and 2008, the Sherburn research group reported syntheses of substituted [3]dendralenes [12] and the state-of-the-art synthesis of [5]dendralene [13] respectively, transforming a 1,1-dihaloalkene via double Negishi or Kumada cross-couplings to incorporate one alkenyl substituent (9 or 12) twice, and also, in the former case, the related stepwise, stereoselective Stille couplings to form unsymmetrically substituted, chiral [3]dendralenes 16 (Scheme 1.2). An application of this stepwise approach en route to the natural product triptolide [14] highlighted that when using two different metalloalkene cross-coupling partners, complete control of the stereochemistry of the resulting alkene is sometimes unattainable. Thus, most successful applications of this method incorporate two identical alkenes, so no issues of stereochemistry arise. A recent example is the synthesis by Ichikawa and coworkers [15] of a single tetra-fluoro[3]dendralene via double Negishi cross-coupling of 2,2-difluorovinylzinc bromide to a dibromoolefin.

Scheme 1.1 Double alkenylation approaches to [3]- and [4]dendralene, via sp2-sp2 cross-coupling.

Scheme 1.2 Examples of double cross-coupling approaches to dendralenes by Oh and Lim [11] and Sherburn and coworkers [12, 13].

Recently, a new benchmark in alkenyl cross-coupling syntheses was set by the Sherburn group, using an extension of this double cross-coupling strategy. Tetravinylethylene (TVE) and substituted analogs 19, previously only accessible by longer, lower yielding, sequences [16-18], were generated via a fourfold Stille cross-coupling of alkenyl stannanes 18 and tetrachloroethylene (17), a cheap and readily available starting material produced annually on a kiloton scale (Scheme 1.3) [19-21]. TVEs possess an interesting carbon framework composed of two [3]dendralene subunits sharing the same central, tetrasubstituted alkene. The bold, one-step approach was used to generate six different symmetrically substituted TVEs, is unique in its use of a tetrachloroalkene, and cannot be surpassed in terms of step economy [22].

Scheme 1.3 Synthesis of TVEs via fourfold sp2-sp2 cross-coupling reactions [19, 20].

Higher dendralenes are accessible by double cross-coupling by including branched alkenes into the electrophile unit. For example, in their state-of-the-art synthesis of the parent dendralenes [23], Sherburn and coworkers prepared [6]dendralene (21) by the reaction between 2,3-dichloro-1,3-butadiene (20), and the Grignard reagent (9) prepared from chloroprene, another readily available unsaturated halide produced annually on a megaton scale (Scheme 1.4) [24]. The scope of this reaction in the synthesis of substituted higher dendralenes remains unexplored.

Scheme 1.4 Synthesis of [6]dendralene via a double sp2-sp2 cross-coupling reaction [23].

The same double cross-couplings are feasible by swapping the reactivity of components, that is, using a double nucleophilic ethylene or 1,3-butadiene and two alkenyl electrophiles. So far, apart from an isolated example by the Sherburn group using 2,3-bis(trimethylstannyl)-1,3-butadiene [10], the Shimizu group is presently the only one to explore this avenue of dendralene synthesis, and have published a series of papers detailing the use of 1,1-bis(pinacolatoboryl)ethylene (22) and 2,3-bis(pinacolatoboryl)-1,3-butadiene (23) as nucleophilic components in Suzuki-Miyaura cross-coupling reactions (Scheme 1.5) [25-27]. A double cross-coupling reaction leads to symmetrically substituted [4]-, [5]-, and [6]dendralenes (32, 25, 36), and a two-step process leads to unsymmetrically substituted [3]-, [4]-, and [5]dendralenes (30, 35, 27, 37). While the yields for many of these reactions remain quite low, the potential scope is broad. The two strategies are complementary, and many interesting substituted dendralene frameworks are within rapid, step-economic reach from some very readily available starting materials.

Scheme 1.5 Syntheses of dendralenes utilizing a double nucleophilic cross-coupling building block, from the Shimizu group [25-27].

1.2.2 Double Alkenation Reactions

Various approaches that synthesize butadienes by the installation of methylene groups on two adjacent carbon atoms can be classified as the same overall transformation as the enyne metathesis reaction (Scheme 1.6). Unsurprisingly, metal-catalyzed enyne metathesis has proved versatile in this regard, as have [2+2] cycloaddition/4p electrocyclic ring-opening sequences (referred to herein as uncatalyzed enyne metathesis reactions), but other complementary examples of multibond forming processes that effect the same bond formations have also been developed.

In 2003, Bruneau and coworkers reported the first use of enyne metathesis to synthesize masked dendralenes 39 (Scheme 1.7 (a)) [28]. This work paved the way for a series of related syntheses of dendralenes with a variety of substitution patterns [29, 30], including a remarkable synthesis of a [4]dendralene via a double intramolecular enyne metathesis/double elimination sequence by Park and Lee [29]; however, because the products are masked dendralenes, the carbon-carbon bond disconnections for this strategy are different from the direct metathesis approach, in which the newly formed butadiene unit stays intact (Scheme 1.6). It was Bruneau again who first developed this route, using metathesis between ethylene (42) and propargylic carbonates 41 to synthesize 1,3-butadiene 43, revealing the third alkene via subsequent elimination (Scheme 1.7 (b)) [31]. The same group has now published metathesis reactions that directly furnish intact [3]dendralenes 49 by conducting the elimination first and...