3-substituted dendralene

Sy 1 -phenylethyltrifluorosilane 439 1-phenylethylzinc chloride 27, 29 1 -phenyl-3-methyl-1,2-butadiene 475 (1Z,3E)-1-phenyl-1,3-octadiene, synthesis 84-5 phenylpalladium iodide complex 137 l-phenylpent-4-en-l-yne 196-7 (Z)-phenyl-substituted dendralene 117 ( -(-)-1 -phenyl-1 -trifluoroacetoxy-2-propyne 475 l-phenyl-4-triinethylsilyl but-2-ene 351... 

The first syntheses of dendralenes by C2-C3 bond formation (Scheme 1.25) were reported by Tsuge and coworkers in 1985 and 1986, and proceed via substitution at either a bromide 160 or an epoxide 163, followed by elimination (Scheme 1.26) [116, 117]. Similar addition/elimination sequences to carbonyl groups or epoxides [120], and substitution reactions [121], followed. Such methods have been superseded by cross-coupling techniques that take place between a 2-functionalized 1,3-butadiene and an alkene (each can be either electrophilic or nucleophilic) or a 4-functionalized 1,2-butadiene and alkene, and occur with allylic transposition (Scheme 1.25). No doubt due to the ready availability of alkenyl halides and allenes, and the variety of increasingly mild and selective reaction variants, cross-coupling has provided access to a large number of diversely substituted dendralenes over the past 20 years, some of which have even been part of natural product syntheses [14,122,123]. 

Another C-H activation method that has potential in the synthesis of dendralenes was reported by Gulras and coworkers in 2015 (Scheme 1.35) [159]. A stable dendralene intermediate 217 was prepared from substituted phenol 215 and allene 216, as an intermediate in the Rh(III)-catalyzed synthesis of 2f/-chromenes. In principle, this method could be adapted to target substituted dendralenes. 

CarbopaUadation by an arylpalladium iodide across the triple bond of a 1,6-enyne with a methylenecyclopropane terminus under Heck conditions led to a phenyl-substituted cross-conjugated triene (a so-called dendralene) along with terminally phenylated enyne (Scheme 5). ... 

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. 

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 1.7 Representative examples of substituted [3]dendralene syntheses involving enyne metathesis or an equivalent transformation [28, 31-33].

Uncatalyzed metathesis can also be performed on substrates that contain two reactive alkyne sites, for the rapid synthesis of highly substituted [4]dendralenes. Diederich and coworkers recently reported double [2+2] cycloaddition/retro-4n-electrocychzation cascades to yield a number of fully substituted [4]dendralenes 68 featuring push-pull chromophores (Scheme 1.10) [46, 48]. Using a similar double alkyne substrate 67, Diederich has also used different alkenes to incorporate varied functional groups into the product dendralene, a strategy recently also adopted by Morita and coworkers [47], who in 2012 reported stepwise or one-pot reactions to incorporate both TCNE (55) and TTF (60) into the structure of [4]dendralenes 69, via double uncatalyzed metathesis. 

Scheme 1.14 The Pd-catalyzed cascade synthesis of substituted [3]dendralenes by Muller and coworkers [67].

In a very nice titanium-mediated annulation cascade, Cheng and Micalizio [80] synthesized functionalized, bicychc [3] dendralenes 133 in situ as intermediates that were trapped via a subsequent DA reaction (Scheme 1.18). The report includes one example of a DA dimerization product, seven examples of intermolecular metallocycle-mediated annulation followed by intermolecular [4-1-2] cycloaddition reaction to afford (135), and one example of an isolated, acyclic substituted [3]dendralene 137. 

The most obvious method to install the C1-C2 alkene of a dendralene is an olefination reaction (Scheme 1.19), but it has seen very little use, because of the propensity of 2-carbonyl-1,3-butadiene derivatives to undergo rapid Diels-Alder dimerization [81]. In fact, the only successful uses of 2-carbonyl-1,3-butadienes in such processes feature substrates stabilized by 1,1-disubstitution and a 4Z substituent. Such an example is the iterative formylation/olefination sequence reported by Yoshida and coworkers (Scheme 1.20) [82]. A selective, single electrophilic formylation followed by a Wittig reaction gave hexa-substituted... 

In 2012, Misaki and coworkers [86] prepared three examples of compounds containing two hexa-substituted [3]dendralene subunits 148 using a double HWE... 

Recently, Sherburn and coworkers [87] attempted to use Wittig olefination to synthesize 1-substituted [3]dendralenes, only to determine that [3]dendralenes featuring a l -conjugating substituent underwent rapid DA dimerization and could not be isolated. The Wittig reaction furnished only an isolated example of a IZ-phenyl substituted [3]dendralene in low yield (20%), along with a mixture of three Diels-Alder dimerization products. This led to the development of a cross-metathesis approach involving tricarbonyl-iron complexed dendralenes, which is discussed in Section 1.4. 

C-H activation is an important and rapidly developing area of dendralene synthesis. In very recent years, several C2-C3 bond forming approaches to dendralenes involving C-H activation have been reported. In 2013, Glorius and coworkers developed a Rh(III)-catalyzed, Heck-type alkenyl C-H activation and coupling reaction with allenyl carbinol carbonates 205 and acrylamides 206 (Scheme 1.33) [157]. This new reaction performs well for the synthesis of highly substituted [3]dendralenes. 

A similar transformation was subsequently reported in 2014 by Fu and coworkers, who used allene and carbamate precursors to generate [3] dendralenes via rhodium(III) catalysis (Scheme 1.34) [158]. A variety of different carbamates 213 successfully rmderwent Rh(III)-catalyzed C-H activation and coupling to generate cychc and acyclic substituted [3] dendralenes 214. While the general route works quite well between the tri-substituted allene and acyclic carbamates, the reaction is not high yielding if the enol ester is cychc or the allene is mono- or tetra-substituted. 

A final recent contribution to C-H activation-based methods is the work by Oro and coworkers, who reported the Rh(I)-catalyzed hydrovinylation of alkynes 218 with Al-vinylpyrazoles 220 to form pyrazole-containing [3]dendralenes 221 (Scheme 1.36) [160, 161]. Some of these dendralenes could also be subjected to thermal Alder-ene reactions to alter the substitution pattern on the dendralene products. 

Fallis and coworkers [191, 192] have synthesized substituted [3] dendralenes using a similar approach, by reacting indium metal with bromodiene 238, and using the resulting indium pentadienyl species in addition/elimination sequences with a number of functionalized aldehydes or ketones 239 (Scheme 1.40 (b)). This strategy builds on work by the Miginiacs in 1964 [193], and has also seen subsequent use [12, 194-196]. 

Instances where a dendralenic alkene participates as a nucleophile in an addition or substitution, and the alkene is regenerated by elimination, appear surprisingly rare. One such example is the preparation of the Vilsmeier salt 271 of cyclic [3]dendralene 270 (Scheme 1.46) [208]. Formylation of very electron-rich dendraienes has also been reported, such as part of the iterative formyla-tion/olefination sequence to build higher dendraienes reported by Yoshida et al. (Scheme 1.20) [82]. 

Halodendralenes are valuable substrates for dendralene to dendralene transformations that preserve or extend the dendralene framework. They are intermediates in the synthesis of [7]- and [8]dendralene (Scheme 1.26) [23], as are their nucleophilic relatives, pinacolatoboryldendralenes, in the synthesis of substituted [4]-, [5]-, and [6] dendraienes [25, 27]. (Pseudo)halodendralenes have also been used in Stille [209] and Sonagashira cross-couplings [178, 210]. Dendralene dimers can be obtained via homocoupling of halodendralenes [211]. Dendralene frameworks can also be extended by uncatalyzed metathesis reactions on alkyne-containing dendraienes, and olefination reactions on carbonyl-containing ones [1, 211-214], each of which has been discussed. 

Elimination reactions to reveal masked dendralenes featured prominently in early attempts to synthesize cross-conjugated compounds [1]. Cheletropic extrusion of sulfur dioxide was used to convert lower dendralenes to [5], [6], and [8] dendralene [10], and to make substituted chiral [4] dendralenes [12]. 

Electrocyclization reactions are powerful synthetic tools to prepare compounds of great molecular diversity. These reactions allow for the formation of many substituted cyclic and polycychc compounds important in medicine, materials science, cosmetics, and so on. The well-established mechanisms and predictable outcomes of electrocyclization reactions permit the elaboration of logical blueprints for the synthesis of important molecules. Among these, the Nazarov cyclization is a salient member of the family. Reported first in 1941 by Ivan Nikolaevich Nazarov [1], this reaction has been studied extensively and many variations and applications have been developed over the years. In this chapter, we will present selected examples highlighting the versatility and synthetic power of this transformation [2]. In its simplest form, the Nazarov employs a divinyl ketone as the starting material, a cross-conjugated compound which can be regarded as a 3 -oxa-[3]dendralene. 

The unique titanocene- or hafnocene-substituted [4]radialenes 86 [78] and 87 [79] were formed in low yields from diphenylbutadiyne and Cp2H(Ti -MegSiC CSiMej) or Cp2Hf(n-Bu)2, respectively (Scheme 4.18). Other 1,3-diynes did not react analogously. Efforts to liberate the free radialene from these organometallics by acidolysis were only partly successful treatment of 86 with hydrogen chloride led to the [3]dendralene 88 in high yield, while 87 furnished the tetraphenyl[4] radialene 89 only as an unstable, impure product. 

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