An overview of the cycloaddition chemistry of fulvenes and emerging applications

The unusual electronic properties and unique reactivity of fulvenes have interested researchers for over a century. The propensity to form dipolar structures at relatively low temperatures and to participate as various components in cycloaddition reactions, often highly selectively, makes them ideal for the synthesis of complex polycyclic carbon scaffolds. As a result, fulvene cycloaddition chemistry has been employed extensively for the synthesis of natural products. More recently, fulvene cycloaddition chemistry has also found application to other areas including materials chemistry and dynamic combinatorial chemistry. This highlight article discusses the unusual properties of fulvenes and their varied cycloaddition chemistry, focussing on applications in organic and natural synthesis, dynamic combinatorial chemistry and materials chemistry, including dynamers, hydrogels and charge transfer complexes. Tables providing comprehensive directories of fulvene cycloaddition chemistry are provided, including fulvene intramolecular and intermolecular cycloadditions complete with reactant partners and their resulting cyclic adducts, which provide a useful reference source for synthetic chemists working with fulvenes and complex polycyclic scaffolds.


Introduction
Fulvenes are an interesting organic class of cross-conjugated, cyclic molecules first discovered by Thiele in 1900, with the preparation of pentafulvenes by condensation of aldehydes and ketones with cyclopentadiene [1][2][3][4][5][6][7][8]. Most commonly encountered are pentafulvenes, although tria- [4,[9][10][11][12], hepta- [9,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] and nonafulvenes have also been studied ( Figure 1). Historically, fulvenes were of great interest as a result of their unique reactivity resulting from their exocyclic double bond [9,[29][30][31][32], and more recently, as intermediates in the synthesis of more complex polycyclic scaffolds via cycloaddition reactions. While this highlight article will focus primarily on the cycloaddition chemistry of fulvenes and its applications, a brief introduction to the properties and reactivity of fulvenes, important to understanding their participation in cycloaddition reactions, is initially provided. For a more general background on the chemistry of pentafulvenes, in particular their fundamental properties, synthetic transformations, organometallic chemistry and metal-catalysed reactions, an excellent review was recently published by Radhakrishnan and co-workers [33]. This highlight article is intended to give the reader an overview of the varied and exceptional cycloaddition chemistry of fulvenes, and applications that can arise from this. The replacement of skeletal carbon atoms with heteroatoms affords heterofulvenes. Some common heterofulvenes include oxa-, aza-, sila-, phospha-and thiafulvene derivatives ( Figure 2). The introduction of heteroatoms results in differing reactivities, which can be further influenced by substituents, making them useful building blocks for the synthesis of polycyclic compounds [32,[35][36][37][38][39]. This is another rich and interesting area of chemistry, although further discussion of heterofulvenes is outside the scope of the current overview and the reader is directed to a very good review by Kawase and Kurata [32].
In addition, substituents that are distant, but conjugated to the fulvene group, influence the aromaticity of the molecule [69,71], ultimately allowing modification of the molecule's reactivity for a given reaction. This was demonstrated in a study by Gugelchuck et al. [71], where the reaction rate of various p-substituted 6-phenylpentafulvenes with maleimides was investigated. Substituents of an electron-donating nature (e.g., H, halogens) generally increased the reaction rate through stabilisation of the Diels-Alder transition state, whilst those which were electron-withdrawing (e.g., NO 2 , CN, NMeAc) decreased the reaction rate. Interestingly, strong EDG (e.g., OMe, NMe 2 ) exhibited a slower reaction rate than predicted, but this is likely due to the increased stabilisation of the reactant, rather than the transition state [71].
An interesting physical characteristic of pentafulvene derivatives is their bright colour, which results from their cross conjugation, and varies with substitution, particularly at the exocyclic C6 position [1,2,6,42,71]. Considering molecular orbital theory, pentafulvenes have a high-energy highest occupied molecular orbital (HOMO) and low-energy lowest unoccupied molecular orbital (LUMO) [1,2,6,42] (HOMO-LUMO) energy gap that is small enough to allow the absorption of long wavelength UV radiation, thus the molecule appears yellow or red [2]. The size of this energy gap can be altered by EWG (−M effect) and EDG (+M effect) substituents (Figure 3), through decreasing or increasing the LUMO energy, respectively [1][2][3]6,7,42,62,67,71]. In some cases, this can result in a bathochromic shift [2,42]. Consideration of frontier molecular orbital theory allows the electronic nature and general reactivity patterns of fulvenes to be interpreted.

Fulvene cycloadditions
The multiple cycloaddition pathways observed for fulvenes provides access to a diverse and unique range of fused ring and polycyclic scaffolds. In the subsequent sections, the cycloaddition chemistry of fulvenes will be discussed in terms of their dimerization, and intra-and intermolecular reactions. Whereas the high reactivity and poor stability of triafulvenes have limited studies into their cycloaddition chemistry [1,2,4,[10][11][12], the relative stability of pentafulvenes has allowed extensive research into their participation as 2π, 4π and 6π components. Additionally, pentafulvenes participating as 8π, 10π and 12π components via an extended conjugated chain at the exocyclic C6 position have also been reported. For higher-order heptaand nonafulvenes, the extended conjugated system also allows them to act as 8π components, as well as 2-6π components.
In some cases, cycloaddition reactions involving fulvenes may be difficult to characterise due to the high reactivity of the fulvene group, and the ability to act as multiple cycloaddition components, leading to multiple mechanistic pathways. For example, the cycloaddition of tropone and fulvenes was initially Scheme 5: Reactions of (a) 6,6-dimethylpentafulvene participating as 2π and 4π components in cycloadditions with p-benzoquinone to afford [2 + 3] (7) and [4 + 2] (8) cycloadducts, and (b) 6-(dimethylamino)pentafulvene participating as a 6π component in a [6 + 3] cycloaddition with p-benzoquinone to afford cycloadduct 9 [32].
There have been numerous reports of pentafulvenes undergoing dimerization via Diels-Alder cycloadditions (DACs) (Scheme 8) at room temperature [6,66,108,109,114,115,117,119]. In some cases, the resulting dimers can undergo subsequent cycloadditions to form trimers via [6 + 4] cycloadditions [109,110] or polymeric products [6,71,109,118], which are often not desired due to the difficulties associated with purification. Additionally, a formal [6 + 4] dimerization was reported by Mömming et al. utilising frustrated Lewis pair chemistry (Scheme 9), however, the mechanism of this process requires further clarification [116]. Scheme 9: Dimerization of pentafulvenes via frustrated Lewis pair chemistry as reported by Mömming et al. [116].
The rate of dimerization is partly dependent on the fulvene reactivity, which is strongly influenced by its substituents (as discussed previously). For instance, stabilised tria-and heptafulvenes with EWG and penta-and nonafulvenes with EDGs dimerize more slowly [42,64,65,67,71]. The rate of dimerization is also affected by the hydrophilicity and solubility of the fulvene, with groups that lower the hydrophobic character appearing to decrease the rate. For example, the anti-aromatic resonance structure of pentafulvene (1a') (Scheme 1), which is highly reactive, is prone to dimerization and polymerisation [59,111]. If the reaction is conducted under aqueous conditions, the probability of dimerization has been reported to increase further due to hydrophobic packing of the fulvene molecules [120,121].

Intramolecular cycloadditions
Whilst not as widely reported as intermolecular cycloaddition reactions, there are some interesting reports regarding the intramolecular cycloaddition of fulvenes, summarised in Table 1.
For the intramolecular cycloadditions of pentafulvenes, the fulvene has been reported to react as both diene and dienophile depending on the reacting partner in the structure [91,119,127]. For example, pentafulvenes tethered to various dienes have been employed as precursors to various polycyclic ring systems, including kigelinol, neoamphilectane and kempane skeletons, which can be formed in a stereospecific manner depending upon the tether length of the extended pentafulvene chain, and the role of the fulvene in the reaction (diene or dienophile) [127].
In these examples, kigelinol and neoamphilectane are of great interest in biomimetic and natural product chemistry, as they exhibit antitrypanosomal [128,129] and antimalarial [130] activity, respectively. Soldier nasute termites use secretion of tetracyclic kempane skeletons as a defence mechanism [131], so their complete synthesis would invite further characterisation of the termite species. In a comprehensive study by Hong et al., precursor skeletons to kigelinol and kempane (Scheme 10) polycyclic ring systems were synthesised using DACs with extended-chain pentafulvenes, in 5 and 9 steps, respectively [127]. Progress has also been made towards synthesis of a neoamphilectane skeleton, but requires further optimisation to obtain the desired products.
A versatile organocatalytic, enantioselective intramolecular cycloaddition reaction was reported by Hayashi et al. for the synthesis of various tricyclopentanoids from pentafulvenes with δ-formyl groups tethered to the exocyclic C6 position via structurally distinct spacers [85]. The intramolecular [6 + 2] cycloaddition was found to occur between the fulvene and an enamine generated through the reaction of the formyl group with the organocatalyst, diphenylprolinol silyl ether. Variation of the spacer structure provided access to a range of triquinane derivatives (Scheme 11), an important precursor in biomimetic and natural products [85].
Scheme 10: Simplified reaction scheme for the formation of kempane from an extended-chain pentafulvene [127].
There are very few papers reporting the aforementioned reaction occurring in aqueous conditions [175] most likely as a result of the poor solubility of fulvene derivatives in water [175].
Although the stereochemistry of DACs can usually be predicted by the 'endo rule' [92,176,229,232], there are some exceptions, particularly when sterically-demanding fulvenes, such as norbornyl-fused fulvenes [229] or adamantilydenefulvene [174] are involved. In the literature, many cycloaddition reactions have been conducted with dimethylfulvene [52,97,106,118,133,134] or diphenylfulvene [20,103,114,133,163,180]. In each instance, the endo stereochemistry of the cycloadduct is dominant [91,176,180], indicating that the fulvene substituents in the exocyclic C6 position are too distal to impact the stereoselectivity [76,229].
Whilst many of the documented reactions focus on chemical synthesis and characterisation rather than applications, several synthetically interesting scaffolds have been synthesised, including products which exhibit biological activity, complex ligands in coordination chemistry, and several natural product skeletons ( Table 3).

Applications of fulvene cycloadditions
Organic and natural product synthesis A variety of organic molecules and natural products have been synthesised using fulvenes in cycloadditions (Table 3). Penta- fulvenes appear to be the only fulvenes used in this approach, likely due to their relative stability compared to other members of the fulvene family, diverse cycloaddition chemistry, and easy access [42,45,64,67]. The synthesis of the listed organic molecules (Table 3) is generally successful, with high yields in almost all cases. However, some of these synthetic pathways are multistep [124], hence require optimisation for viability and large-scale production.
Similarly, pentafulvenes have been used as key reactants for the synthesis of natural products and their skeletons ( Table 3). The complexity of these molecules requires extensive multistep pathways (ranging from 5-12 steps [127,187]), decreasing overall yields, and thus requiring further optimisation for commercial production. Narayan et al. developed a programmable enantioselective one-pot synthesis of molecules with eight stereocentres greatly improving the efficiency of natural product synthesis [83].
Each of these natural products are biologically active, hence their total synthesis will allow further characterisation of their reactivity and mechanisms of action.
All components must be completely soluble, including the products. Failure to achieve this would cause irreversible precipitation of a product, and an inevitable shift in dynamic equilibrium.
Several types of reversible reactions have been successfully employed in the formation of DCL, including transesterification, peptide bond exchange, disulphide exchange, olefin metathesis and boronic ester formation [189,233]. Boul et al. recently investigated the application of fulvene DAC in DCC [189]. While the reaction is reversible, the retro-DAC generally only occurs at higher temperatures, which is not ideal. However, the combination of fulvenes and di-or tricyanoethylenecarboxylates was found to be reversible (and dynamic) under mild conditions at 25-50 °C (Scheme 18) [189]. At lower temperatures (−10 to 0 °C) the reaction was considerably slower, but overall suggests that certain fulvene DACs can be applied in DCC.

Materials chemistry
Despite their reactive nature, fulvenes have been successfully used in the formation of several materials, including dynamic polymers (dynamers) [190], hydrogels [191], and precursors to charge-transfer complexes [181,234,235]. Dynamers, referred to as dynamers, are a class of adaptive polymers formed through reversible covalent bonds or noncovalent interactions, allowing continuous modification through bond formation and/ or breaking. This dynamic nature facilitates reorganisation through the exchange of building blocks, or incorporation of new substituents, even after the initial polymer has been formed [192]. The fulvene DAC is a good candidate for dynamer formation, as it is reversible at elevated temperatures [7,192]. A recent study by Reutenauer et al. developed dynamers using DAC of fulvenes (diene) and dicyanofumarate or tricyanoethylenecarboxylate (dienophile) (Scheme 19) [190]. The polymerisation (including the dynamic reversibility) was conducted at room temperature and the resulting polymers were processed as thin films. As a result of the dynamic nature of the Diels-Alder adducts, the films were shown to possess self-healing capabilities [190].
The formed hydrogels exhibited self-healing at physiological temperatures, as well as low levels of cytotoxicity against mouse fibroblast 3T3 cells [191]. With these characteristics in mind, the outlook for these hydrogels having therapeutic applications is promising, with further optimisation [236].
Pentafulvenes have also been used to prepare monomers for ring-opening metathesis polymerisation (ROMP) to generate facially amphiphilic polymers [182,235,237,238]. Ilker et al. employed the DAC between alkyl pentafulvenes and maleic anhydride to initially prepare norbornene anhydride monomers that could be further functionalised to afford norbornene imide monomers (Scheme 21) [105,237]. ROMP of the monomers, followed by deprotection yielded facially amphiphilic polynorbornenes that displayed lipid membrane disruption and antimicrobial activities [237,238].
The facially amphiphilic polynorbornenes with pendent ammonium groups were found to disrupt negatively charged phospholipid unilamellar vesicles at low concentrations (5 µg/mL), and in a dose and molecular weight dependent fashion, indicating their potential antimicrobial properties. Further studies revealed that co-polymerisation of norbornene imide monomers with different alkyl groups provided optimal antimicrobial properties and low haemolytic activities [237].

Conclusion
This review provides an account of the properties and application of fulvene cycloaddition reactions. The interest in fulvenes due to their unique electronic properties and ability to undergo Scheme 21: Ring-opening metathesis polymerisation of norbornene derivatives derived from fulvenes and maleimides to furnish facially amphiphilic polymers. multiple highly selective cycloaddition reactions have fuelled advances in organic and natural product synthesis, dynamic combinatorial chemistry and materials science, including dynamers, hydrogels and charge transfer complexes. The recent advances show that potential applications for fulvene cycloaddition reactions are varied and wide in scope. We believe this review will lead to increased interest in these fields, and others yet to be investigated.